FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Hyman, S Volkow, N Nutt, D AF Hyman, Steve Volkow, Nora Nutt, David TI Pharmacological cognitive enhancement in healthy people: Potential and concerns SO NEUROPHARMACOLOGY LA English DT Editorial Material C1 [Volkow, Nora] NIDA, NIH, Bethesda, MD USA. [Nutt, David] Univ London Imperial Coll Sci Technol & Med, Neuropsychopharmacol Unit, Div Brain Sci, London SW7 2AZ, England. OI nutt, david/0000-0002-1286-1401 FU Intramural NIH HHS [Z99 DA999999]; Medical Research Council [G1002226] NR 0 TC 0 Z9 0 U1 0 U2 23 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 JAN PY 2013 VL 64 SI SI BP 8 EP 12 DI 10.1016/j.neuropharm.2012.07.040 PG 5 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 039MN UT WOS:000311250300003 PM 23145451 ER PT J AU Silverman, JL Oliver, CF Karras, MN Gastrell, PT Crawley, JN AF Silverman, J. L. Oliver, C. F. Karras, M. N. Gastrell, P. T. Crawley, J. N. TI AMPAKINE enhancement of social interaction in the BTBR mouse model of autism SO NEUROPHARMACOLOGY LA English DT Article DE Social behavior; Repetitive behavior; BTBR; Mouse model; Autism; Pharmacological rescue ID T PLUS TF/J; HIGH-FUNCTIONING AUTISM; SHORT-TERM-MEMORY; SPECTRUM DISORDERS; RECEPTOR MODULATORS; NEUROTROPHIC FACTOR; SYNAPTIC PLASTICITY; COGNITIVE ENHANCERS; ALZHEIMERS-DISEASE; APPROACH BEHAVIORS AB Autism is a neurodevelopmental disorder in which the first diagnostic symptom is unusual reciprocal social interactions. Approximately half of the children diagnosed with an autism spectrum disorder also have intellectual impairments. General cognitive abilities may be fundamental to many aspects of social cognition. Cognitive enhancers could conceivably be of significant benefit to children and adults with autism. AMPAKINE compounds are a novel class of pharmacological agents that act as positive modulators of AMPA receptors to enhance excitatory glutamatergic neurotransmission. This class of compounds was reported to improve learning and memory in several rodent and non-human primate tasks, and to normalize respiratory abnormalities in a mouse model of Rett syndrome. Here we evaluate the actions of AMPA compounds in adult male and female BTBR mice, a well characterized mouse model of autism. Acute treatment with CX1837 and CX1739 reversed the deficit in sociability in BTBR mice on the most sensitive parameter, time spent sniffing a novel mouse as compared to time spent sniffing a novel object. The less sensitive parameter, time in the chamber containing the novel mouse versus time in the chamber Containing the novel object, was not rescued by CX1837 or CX1739 treatment. Preliminary data with CX546, in which beta-cyclodextrin was the vehicle, revealed behavioral effects of the acute intraperitoneal and oral administration of vehicle alone. To circumvent the artifacts introduced by the vehicle administration, we employed a novel treatment regimen using pellets of peanut butter for drug delivery. Absence of vehicle treatment effects when CX1837 and CX1739 were given in the peanut butter pellets, to multiple cohorts of BTBR and B6 control mice, confirmed that the pharmacologically-induced improvements in sociability in BTBR were not confounded by the administration procedures. The highest dose of CX1837 improved the cognitive deficit in novel object recognition in BTBR. No drug effects were detected on the high levels of repetitive self-grooming in BTBR. In open field tests. CX1837 and CX1739 did not induce hyperactivity or sedation in either strain. It is interesting to speculate that the ability of CX1837 and CX1739 to restore aspects of sociability in BTBR mice could utilize synaptic mechanisms regulating social cognition, suggesting a potential pharmacological target for interventions to treat symptoms of autism. This article is part of a Special Issue entitled 'Cognitive Enhancers'. Published by Elsevier Ltd. C1 [Silverman, J. L.; Oliver, C. F.; Karras, M. N.; Gastrell, P. T.; Crawley, J. N.] NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. RP Silverman, JL (reprint author), Univ Calif Davis, Sch Med, MIND Inst, Sacramento, CA 95817 USA. EM jill.silverman@ucdmc.ucdavis.edu FU National Institute of Mental Health Intramural Research Program FX We are sincerely grateful to Drs. Mark Varney and Stephen Johnson for their generous donation of CX1837 and CX1739 for our experiments, and for their essential advice on doses, time points, and vehicles throughout the design and implementation of these studies. We appreciate the conceptual and methodological advice kindly contributed by Drs. Gary Lynch, Christine Gall and Julie Lauterborn, University of California Irvine. We thank Cathy Gonzalez, Pfizer Global Research, Groton, CT for guidance in the methods for peanut butter pellet formulation and administration. Our gratitude is extended to Dr. Jennifer Brielmaier, Dr. Mu Yang, Ms. Julia Senerth, and Ms. Danielle Abrams, in our Laboratory of Behavioral Neuroscience, who contributed valuable assistance in developing the protocol for novel object recognition. Supported by the National Institute of Mental Health Intramural Research Program. NR 114 TC 43 Z9 44 U1 3 U2 21 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 JAN PY 2013 VL 64 SI SI BP 268 EP 282 DI 10.1016/j.neuropharm.2012.07.013 PG 15 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 039MN UT WOS:000311250300031 PM 22801296 ER PT J AU Ricciardi, E Handjaras, G Bernardi, G Pietrini, P Furey, ML AF Ricciardi, Emiliano Handjaras, Giacomo Bernardi, Giulio Pietrini, Pietro Furey, Maura L. TI Cholinergic enhancement reduces functional connectivity and BOLD variability in visual extrastriate cortex during selective attention SO NEUROPHARMACOLOGY LA English DT Article DE Cholinergic system; Neural efficiency; Physostigmine; Attention; Functional magnetic resonance imaging ID CEREBRAL-BLOOD-FLOW; WORKING-MEMORY; TIME-SERIES; COGNITIVE NEUROSCIENCE; CORTICAL AREAS; MODULATION; TASK; FMRI; PERFORMANCE; EFFICIENCY AB Enhancing cholinergic function improves performance on various cognitive tasks and alters neural responses in task specific brain regions. We have hypothesized that the changes in neural activity observed during increased cholinergic function reflect an increase in neural efficiency that leads to improved task performance. The current study tested this hypothesis by assessing neural efficiency based on cholinergically-mediated effects on regional brain connectivity and BOLD signal variability. Nine subjects participated in a double-blind, placebo-controlled crossover fMRI study. Following an infusion of physostigmine (1 mg/h) or placebo, echo-planar imaging (EPI) was conducted as participants performed a selective attention task. During the task, two images comprised of superimposed pictures of faces and houses were presented. Subjects were instructed periodically to shift their attention from one stimulus component to the other and to perform a matching task using hand held response buttons. A control condition included phase-scrambled images of superimposed faces and houses that were presented in the same temporal and spatial manner as the attention task; participants were instructed to perform a matching task. Cholinergic enhancement improved performance during the selective attention task, with no change during the control task. Functional connectivity analyses showed that the strength of connectivity between ventral visual processing areas and task-related occipital, parietal and prefrontal regions reduced significantly during cholinergic enhancement, exclusively during the selective attention task. Physostigmine administration also reduced BOLD signal temporal variability relative to placebo throughout temporal and occipital visual processing areas, again during the selective attention task only. Together with the observed behavioral improvement, the decreases in connectivity strength throughout task-relevant regions and BOLD variability within stimulus processing regions support the hypothesis that cholinergic augmentation results in enhanced neural efficiency. This article is part of a Special Issue entitled 'Cognitive Enhancers'. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Ricciardi, Emiliano; Handjaras, Giacomo; Bernardi, Giulio; Pietrini, Pietro] Univ Pisa, AOUP Santa Chiara, Lab Clin Biochem & Mol Biol, I-56126 Pisa, Italy. [Pietrini, Pietro] Univ Pisa, AOUP Santa Chiara, Clin Psychol Branch, I-56126 Pisa, Italy. [Furey, Maura L.] NIMH, Expt Therapeut & Pathophysiol Branch, NIH, Bethesda, MD 20892 USA. RP Ricciardi, E (reprint author), Univ Pisa, AOUP Santa Chiara Ed, Lab Clin Biochem & Mol Biol, 43 Via Roma 67, I-56126 Pisa, Italy. EM emiliano.ricciardi@bioclinica.unipi.it; giacomo.handjaras@gmail.com; giulio.bernardi@for.unipi.it; pietro.pietrini@med.unipi.it; mfurey@mail.nih.gov RI Furey, Maura/H-5273-2013; Ricciardi, Emiliano/E-6929-2011; Bernardi, Giulio/B-1452-2012; OI Ricciardi, Emiliano/0000-0002-7178-9534; Bernardi, Giulio/0000-0003-4045-7075; Handjaras, Giacomo/0000-0001-5677-8434 FU NIMH-IRP FX We would like to thank James Haxby for collaborative input and Joanna Szczepanik for technical support. This work was supported by the NIMH-IRP. NR 57 TC 16 Z9 16 U1 3 U2 11 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 JAN PY 2013 VL 64 SI SI BP 305 EP 313 DI 10.1016/j.neuropharm.2012.07.003 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 039MN UT WOS:000311250300034 PM 22906685 ER PT J AU Uchiumi, O Kasahara, Y Fukui, A Hall, FS Uhl, GR Sora, I AF Uchiumi, Osamu Kasahara, Yoshiyuki Fukui, Asami Hall, F. Scott Uhl, George R. Sora, Ichiro TI Serotonergic involvement in the amelioration of behavioral abnormalities in dopamine transporter knockout mice by nicotine SO NEUROPHARMACOLOGY LA English DT Article DE alpha(7) nACh receptor; alpha(4)beta(2) nACh receptor; 5-HT1A receptor; Schizophrenia; Locomotor activity; Prepulse inhibition ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; PREPULSE INHIBITION DEFICITS; RAT PREFRONTAL CORTEX; RECEPTOR ACTIVATION; ACOUSTIC STARTLE; COCAINE REWARD; FRONTAL-CORTEX; OUT MICE; IN-VIVO; NOREPINEPHRINE TRANSPORTER AB Dopamine transporter knockout (DAT KO) mice exhibit elevated extracellular dopamine levels in brain regions that include the striatum and the nucleus accumbens, but not the prefrontal cortex. DAT KO mice model some aspects of psychiatric disorders, including schizophrenia. Smoking is more common in patients with schizophrenia, suggesting that nicotine might ameliorate aspects of the behavioral abnormalities and/or treatment side effects seen in these individuals. We report nicotine-induced normalization of effects on locomotion and prepulse inhibition of acoustic startle (PPI) in DAT KO mice that require intact serotonin 5-HT1A systems. First, we observed that the marked hyperactivity displayed by DAT KO mice was reduced by administration of nicotine. This nicotine effect was blocked by pretreatment with the non-specific nicotinic acetylcholine (nACh) receptor antagonist mecamylamine, or the 5-HT1A antagonist WAY100635. Secondly, we examined the effects of nicotine on PPI in DAT KO mice. Treatment with nicotine significantly ameliorated the PPI deficits observed in DAT KO mice. The ameliorating action of nicotine on PPI deficits in DAT KO mice was blocked by mecamylamine, the alpha(7) nACh receptor antagonist methyllycaconitine or WAY100635, while the alpha(4)beta(2) nACh receptor antagonist dihydro-beta-erythroidinehydrobromide (DF beta E) produced only a non-significant trend toward attenuation of nicotine effects. Finally, we observed that administration of the 5-HT1A receptor agonist 8-OH-DPAT also ameliorated the deficit in PPI observed in DAT KO mice. This amelioration was antagonized by pretreatment with WAY100635. These data support the idea that nicotine might ameliorate some of the cognitive dysfunctions found in schizophrenia in a 5-HT1A-dependent fashion. This article is part of a Special Issue entitled 'Cognitive Enhancers'. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Uchiumi, Osamu; Kasahara, Yoshiyuki; Fukui, Asami; Sora, Ichiro] Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, Aoba Ku, Sendai, Miyagi 9808574, Japan. [Hall, F. Scott; Uhl, George R.] NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD USA. RP Sora, I (reprint author), Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, Aoba Ku, 1-1 Seiryo Machi, Sendai, Miyagi 9808574, Japan. EM sora@med.tohoku.ac.jp RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Smoking Research Foundation, Japan; MECSST; MHLW, Japan; Global COE, MEXT, Japan; National Institute on Drug Abuse, USA FX This work was supported by Grant from the Smoking Research Foundation, Japan, Grants-in-Aid from MECSST and Health Sciences Research Grants from MHLW, Japan, and the Global COE Program, MEXT, Japan. This work was also supported in part by funding from the Intramural Research Program of the National Institute on Drug Abuse, USA (FSH, GRU). NR 70 TC 8 Z9 8 U1 2 U2 9 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 JAN PY 2013 VL 64 SI SI BP 348 EP 356 DI 10.1016/j.neuropharm.2012.07.016 PG 9 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 039MN UT WOS:000311250300039 PM 22809709 ER PT J AU Whittle, N Schmuckermair, C Cinar, OG Hauschild, M Ferraguti, F Holmes, A Singewald, N AF Whittle, Nigel Schmuckermair, Claudia Cinar, Ozge Gunduz Hauschild, Markus Ferraguti, Francesco Holmes, Andrew Singewald, Nicolas TI Deep brain stimulation, histone deacetylase inhibitors and glutamatergic drugs rescue resistance to fear extinction in a genetic mouse model SO NEUROPHARMACOLOGY LA English DT Article DE Fear extinction; Metabotropic glutamate receptor; Epigenetics; HDAC inhibitor; Ventral striatum deep brain stimulation; NMDA receptor ID POSTTRAUMATIC-STRESS-DISORDER; OBSESSIVE-COMPULSIVE DISORDER; COGNITIVE-BEHAVIORAL THERAPY; NUCLEUS-ACCUMBENS REGION; PLACEBO-CONTROLLED TRIAL; CENTRAL-NERVOUS-SYSTEM; CONDITIONED FEAR; PANIC DISORDER; D-CYCLOSERINE; VALPROIC ACID AB Anxiety disorders are characterized by persistent, excessive fear. Therapeutic interventions that reverse deficits in fear extinction represent a tractable approach to treating these disorders. We previously reported that 129S1/SvImJ (S1) mice show no extinction learning following normal fear conditioning. We now demonstrate that weak fear conditioning does permit fear reduction during massed extinction training in Si mice, but reveals specific deficiency in extinction memory consolidation/retrieval. Rescue of this impaired extinction consolidation/retrieval was achieved with D-cycloserine (N-methly-D-aspartate partial agonist) or MS-275 (histone deacetylase (HDAC) inhibitor), applied after extinction training. We next examined the ability of different drugs and non-pharmacological manipulations to rescue the extreme fear extinction deficit in S1 following normal fear conditioning with the ultimate aim to produce low fear levels in extinction retrieval tests. Results showed that deep brain stimulation COBS) by applying high frequency stimulation to the nucleus accumbens (ventral striatum) during extinction training, indeed significantly reduced fear during extinction retrieval compared to sham stimulation controls. Rescue of both impaired extinction acquisition and deficient extinction consolidation/retrieval was achieved with prior extinction training administration of valproic acid (a GABAergic enhancer and HDAC inhibitor) or AMN082 [metabotropic glutamate receptor 7 (mGlu7) agonist], while MS-275 or PEPA (AMPA receptor potentiator) failed to affect extinction acquisition in S1 mice. Collectively, these data identify potential beneficial effects of DBS and various drug treatments, including those with HDAC inhibiting or mGlu7 agonism properties, as adjuncts to overcome treatment resistance in exposure-based therapies. This article is part of a Special Issue entitled 'Cognitive Enhancers'. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Whittle, Nigel; Schmuckermair, Claudia; Hauschild, Markus; Singewald, Nicolas] Univ Innsbruck, Dept Pharmacol & Toxicol, Inst Pharm, A-6020 Innsbruck, Austria. [Whittle, Nigel; Schmuckermair, Claudia; Hauschild, Markus; Singewald, Nicolas] Univ Innsbruck, CMBI, A-6020 Innsbruck, Austria. [Cinar, Ozge Gunduz; Holmes, Andrew] NIAAA, Lab Behav & Genom Neurosci, NIH, Bethesda, MD 20852 USA. [Cinar, Ozge Gunduz; Holmes, Andrew] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Ferraguti, Francesco] Innsbruck Med Univ, Dept Pharmacol, A-6020 Innsbruck, Austria. RP Whittle, N (reprint author), Univ Innsbruck, Dept Pharmacol & Toxicol, Inst Pharm, Innrain 80,82-3, A-6020 Innsbruck, Austria. EM nigel.whittle@uibk.ac.at RI Gunduz Cinar, Ozge/B-2970-2009; Gunduz Cinar, Ozge/E-5756-2010; OI Gunduz Cinar, Ozge/0000-0002-3826-8905; , Markus/0000-0003-3539-7661; Ferraguti, Francesco/0000-0002-3843-5857 FU Austrian Science Funds FWF SFB [F4410, P22969-B11]; NIAAA Intramural Research Program; Department of Defense in the Center for Neuroscience and Regenerative Medicine FX The authors would like to acknowledge that funding for this study was provided by the Austrian Science Funds FWF SFB F4410 (NS) and P22969-B11 (FF), and the NIAAA Intramural Research Program and Department of Defense in the Center for Neuroscience and Regenerative Medicine (AH). Neither the Austrian Science Fund nor NIH had a role in the study design; in the collection, analysis and interpretation of data; in the writing of the manuscript; or in the decision to submit the paper for publication. NR 109 TC 26 Z9 26 U1 3 U2 19 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 JAN PY 2013 VL 64 SI SI BP 414 EP 423 DI 10.1016/j.neuropharm.2012.06.001 PG 10 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 039MN UT WOS:000311250300047 PM 22722028 ER PT J AU Meany, H Dombi, E Reynolds, J Whatley, M Kurwa, A Tsokos, M Salzer, W Gillespie, A Baldwin, A Derdak, J Widemann, B AF Meany, Holly Dombi, Eva Reynolds, James Whatley, Millie Kurwa, Ambereen Tsokos, Maria Salzer, Wanda Gillespie, Andrea Baldwin, Andrea Derdak, Joanne Widemann, Brigitte TI 18-Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) Evaluation of Nodular Lesions in Patients With Neurofibromatosis Type 1 and Plexiform Neurofibromas (PN) or Malignant Peripheral Nerve Sheath Tumors (MPNST) SO PEDIATRIC BLOOD & CANCER LA English DT Article DE 18-fluorodeoxyglucose-positron emission tomography (FDG-PET); malignant peripheral nerve sheath tumors (MPNST); neurofibromatosis; plexiform neurofibromas (PN) ID MRI AB Background. Individuals with Neurofibromatosis type 1 (NF1) are at risk for developing malignant peripheral nerve sheath tumors (MPNST), which frequently arise in preexisting plexiform neurofibromas (PN). Magnetic resonance imaging (MRI) with volumetric analysis and 18-fluorodeoxyglucose-positron emission tomography (FDG-PET) were utilized to monitor symptomatic nodular lesions. Procedure. Patients with NF1 and PN on a NCI natural history trial were monitored for total body tumor volume (TTV) using volumetric MRI. FDG-PET was performed in individuals with a nodular well-demarcated lesion >= 3 cm if they were growing, painful, or there was a prior history of MPNST (target lesions). Asymptomatic nodular lesions were evaluated as non-target lesions. Results. Fifteen patients (8m, 7f) median age of 18.3 years (range, 10-45 years) had a single target and non-target (n = 46) nodular lesions identified on MRI. Target lesions arose within (n = 8) or outside (n = 3) a PN, and all but 1 had increased FDG uptake. FDG uptake was increased in non-target lesions but to a lesser degree. FDG uptake in the surrounding PN was low, similar to background activity. Pathologic evaluation performed in 11 patients demonstrated neurofibroma (n = 6), atypical neurofibroma (n = 2) and malignancy (n = 3). Conclusions. Nodular target lesions identified on MRI in individuals with NF1 and PN demonstrate increased FDG uptake similar to MPNST, but may be benign on biopsy. Nodular target lesions may be at greater risk for malignant transformation, but their biologic and clinical behavior has not been well studied. Careful longitudinal evaluation will be required to better understand the malignant potential of these lesions. Pediatr Blood Cancer 2013; 60: 59-64. (C) 2012 Wiley Periodicals, Inc. C1 [Meany, Holly] Childrens Natl Med Ctr, Dept Hematol Oncol, Washington, DC 20010 USA. [Meany, Holly; Dombi, Eva; Kurwa, Ambereen; Salzer, Wanda; Gillespie, Andrea; Baldwin, Andrea; Derdak, Joanne; Widemann, Brigitte] NCI, Pharmacol & Expt Therapeut Sect, Pediat Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Reynolds, James; Whatley, Millie] NCI, Dept Nucl Med, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Tsokos, Maria] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Meany, H (reprint author), Childrens Natl Med Ctr, Dept Hematol Oncol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM hmeany@cnmc.org NR 26 TC 11 Z9 11 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1545-5009 EI 1545-5017 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JAN PY 2013 VL 60 IS 1 BP 59 EP 64 DI 10.1002/pbc.24212 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 038IG UT WOS:000311167800012 PM 22645095 ER PT J AU Nesterova, G Gahl, WA AF Nesterova, Galina Gahl, William A. TI Cystinosis: the evolution of a treatable disease SO PEDIATRIC NEPHROLOGY LA English DT Review DE Cystinosis; Nephropathic; Fanconi; Complications; Cysteamine ID INFANTILE NEPHROPATHIC CYSTINOSIS; RENAL FANCONI SYNDROME; TERM-FOLLOW-UP; CYSTEAMINE THERAPY; HUMAN-FIBROBLASTS; ORAL CYSTEAMINE; NATURAL-HISTORY; CORONARY-ARTERY; CHILDREN; TRANSPLANTATION AB Cystinosis is a rare autosomal recessive disorder involving lysosomal storage of the amino acid cystine due to a defect in the membrane transport protein, cystinosin. Since the introduction of kidney transplants and the availability of cystine-depleting medical therapy, this previously fatal disease was transformed into a treatable disorder. Renal allografts and medical therapy targeting the basic metabolic defect have altered the natural hisotry of cystinosis so drastically that patients have a life expectancy extending past 50 years. Consequently, early diagnosis and appropriate therapy are critically important. In this article, we offer a review of the manifestations of cystinosis, including the proximal tubular dysfunction of renal Fanconi syndrome, and discuss the prevention and treatment of the disorder's systemic complications. We focus on the nephropathic forms of cystinosis, aiming to assist nephrologists and other physicians to develop early recognition and appropriate management of cystinosis patients. C1 [Nesterova, Galina; Gahl, William A.] NHGRI, Med Biochem Genet Sect, NIH, Bethesda, MD 20892 USA. RP Nesterova, G (reprint author), NHGRI, Med Biochem Genet Sect, NIH, Bethesda, MD 20892 USA. EM nesterovag@mail.nih.gov NR 72 TC 33 Z9 35 U1 1 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD JAN PY 2013 VL 28 IS 1 BP 51 EP 59 DI 10.1007/s00467-012-2242-5 PG 9 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 042WE UT WOS:000311501500006 PM 22903658 ER PT J AU Bal, E Yerys, BE Sokoloff, JL Celano, MJ Kenworthy, L Giedd, JN Wallace, GL AF Bal, Elgiz Yerys, Benjamin E. Sokoloff, Jennifer L. Celano, Mark J. Kenworthy, Lauren Giedd, Jay N. Wallace, Gregory L. TI Do social attribution skills improve with age in children with high functioning autism spectrum disorders? SO RESEARCH IN AUTISM SPECTRUM DISORDERS LA English DT Article DE Autism spectrum disorders; High functioning autism; Theory of mind; Social attribution ID ASPERGER-SYNDROME; ANIMATED SHAPES; MENTAL STATES; MIND; INDIVIDUALS; ABILITY; TASK AB Age-related changes in social attribution skills were assessed using the "Triangles Playing Tricks" task in 7-17 year old high functioning children with ASDs (n = 41) and in typically developing (TD) children (n = 58) matched on age. IQ and sex ratio. Children with ASDs gave responses that received lower intentionality and appropriateness ratings than did TD children in both the goal-directed and theory of mind (TOM) conditions. Results remained unchanged when the effects of verbal output (i.e., number of clause produced) and verbal IQ were included as covariates in the analyses. Whereas age was highly associated with ToM performance in the TD children, this relationship was not as strong among children with ASDs. These results indicate not only a diminished tendency among high functioning children with ASDs to attribute social meaning and intentionality to ambiguous visual displays of interactive forms but also an aberrant developmental trajectory. That is, children with ASDs may fall further behind their typically developing peers in social attribution abilities as they get older. Published by Elsevier Ltd. C1 [Celano, Mark J.; Giedd, Jay N.; Wallace, Gregory L.] NIMH, Bethesda, MD 20892 USA. [Bal, Elgiz; Yerys, Benjamin E.; Sokoloff, Jennifer L.; Kenworthy, Lauren] Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Wallace, GL (reprint author), NIMH, 10 Ctr Dr Bldg 10,Room 4C104, Bethesda, MD 20892 USA. EM gregwallace@mail.nih.gov RI Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Wallace, Gregory/0000-0003-0329-5054 FU Intramural NIH HHS [Z99 MH999999]; NICHD NIH HHS [P30 HD040677]; NIMH NIH HHS [U54 MH066417] NR 25 TC 7 Z9 8 U1 0 U2 35 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1750-9467 J9 RES AUTISM SPECT DIS JI Res. Autism Spectr. Disord. PD JAN-MAR PY 2013 VL 7 IS 1 BP 9 EP 16 DI 10.1016/j.rasd.2012.07.004 PG 8 WC Education, Special; Psychology, Developmental; Psychiatry; Rehabilitation SC Education & Educational Research; Psychology; Psychiatry; Rehabilitation GA 044WN UT WOS:000311656000002 PM 23130085 ER PT J AU Chio, A Mora, G Restagno, G Brunetti, M Ossola, I Barberis, M Ferrucci, L Canosa, A Manera, U Moglia, C Fuda, G Traynor, BJ Calvo, A AF Chio, Adriano Mora, Gabriele Restagno, Gabriella Brunetti, Maura Ossola, Irene Barberis, Marco Ferrucci, Luigi Canosa, Antonio Manera, Umberto Moglia, Cristina Fuda, Giuseppe Traynor, Bryan J. Calvo, Andrea TI UNC13A influences survival in Italian amyotrophic lateral sclerosis patients: a population-based study SO NEUROBIOLOGY OF AGING LA English DT Article DE Amyotrophic lateral sclerosis; UNC13A; Prognosis; Risk factor ID CLINICAL CHARACTERISTICS; NEURITE OUTGROWTH; REPEAT EXPANSION; ALS PATIENTS; EPIDEMIOLOGY; C9ORF72; ASSOCIATION; MUNC13-1; COHORT AB The common variant rs12608932, located within an intron of UNC13A gene on chromosome 19p13.3, has been suggested to influence susceptibility to amyotrophic lateral sclerosis (ALS), as well as survival, in patients of north European descent. To examine this possibility further, we evaluated the association of rs12608932 with susceptibility and survival in a population-based cohort of 500 Italian ALS patients and 1457 Italian control samples. Although rs12608932 was not associated with ALS susceptibility in our series (p = 0.124), it was significantly associated with survival under the recessive model (median survival for AA/AC genotypes = 3.5 years [interquartile range, 2.2-6.4]; CC = 2.5 years [interquartile range, 1.6-4.2]; p = 0.017). Furthermore, rs12608932 genotype remained an independent prognostic factor in Cox multivariable analysis adjusting for other factors known to influence survival (p = 0.023). Overall, minor allele carrier status of rs12608932 was strongly associated with an approximate 1-year reduction of survival in ALS patients, making it a significant determinant of phenotype variation. The identification of UNC13A as a modifier of prognosis among sporadic ALS patients potentially provides a new therapeutic target aimed at slowing disease progression. (C) 2013 Elsevier Inc. All rights reserved. C1 [Chio, Adriano; Canosa, Antonio; Manera, Umberto; Moglia, Cristina; Fuda, Giuseppe; Calvo, Andrea] Univ Turin, ALS Ctr, Dept Neurosci, Turin, Italy. [Chio, Adriano] Azienda Osped Univ San Giovanni Battista, Dept Neurosci, ALS Ctr, Turin, Italy. [Mora, Gabriele] IRCCS, Ist Sci, Fdn Salvatore Maugeri, Dept Neurol Rehabil, Milan, Italy. [Restagno, Gabriella; Brunetti, Maura; Ossola, Irene; Barberis, Marco] Azienda Osped Osped Regina Margherita, Mol Genet Lab, Turin, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. [Traynor, Bryan J.] NIA, Neuromuscular Dis Res Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Chio, A (reprint author), Univ Turin, ALS Ctr, Dept Neurosci, Turin, Italy. EM achio@usa.net RI Traynor, Bryan/G-5690-2010; Calvo, Andrea/K-4141-2016; Moglia, Cristina/K-4142-2016; OI Calvo, Andrea/0000-0002-5122-7243; Moglia, Cristina/0000-0001-7377-7222; Chio, Adriano/0000-0001-9579-5341 FU Federazione Italiana Giuoco Calcio; Fondazione Vialli e Mauro per la Sclerosi Laterale Amiotrofica onlus; Ministero della Salute; Regione Piemonte, Progetti Finalizzati; European Community [259867, 278611]; NIH, National Institute on Aging [Z01-AG000949-02] FX This work was funded in part by Federazione Italiana Giuoco Calcio, Fondazione Vialli e Mauro per la Sclerosi Laterale Amiotrofica onlus, Ministero della Salute (Ricerca Sanitaria Finalizzata, 2007), and Regione Piemonte, Progetti Finalizzati (A. Chio). The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013) (grant agreements no. 259867 and 278611; A. Chio). This work was supported in part by the Intramural Research Programs of the NIH, National Institute on Aging (Z01-AG000949-02) (BJT). We thank the patients and their families for having participated in this study. NR 24 TC 10 Z9 10 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JAN PY 2013 VL 34 IS 1 AR 357.e1 DI 10.1016/j.neurobiolaging.2012.07.016 PG 5 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 036LF UT WOS:000311026700033 PM 22921269 ER PT J AU Kim, G Chung, JY Jun, SY Eom, DW Bae, YK Jang, KT Kim, J Yu, E Hong, SM AF Kim, Gwangil Chung, Joon-Yong Jun, Sun-Young Eom, Dae Woon Bae, Young Kyung Jang, Kee-Taek Kim, Jihun Yu, Eunsil Hong, Seung-Mo TI Loss of S100A14 Expression Is Associated with the Progression of Adenocarcinomas of the Small Intestine SO PATHOBIOLOGY LA English DT Article DE Adenocarcinoma; p21; p53; S100A14; Small intestine ID SMALL-BOWEL ADENOCARCINOMA; SQUAMOUS-CELL CARCINOMA; COLORECTAL-CANCER; PROTEINS; FAMILY; PATHOGENESIS; TUMORS; ROLES AB Objectives: Small intestinal adenocarcinoma (SIAC) is an exceedingly rare human malignant tumor, and its association with the S100A14 gene is not known yet. We aimed to investigate the clinicopathological correlations between S100A14 expression and SIAC. Methods: Immunohistochemical analyses of S100A14, p21 and p53 were performed using tissue microarray analysis of 175 surgically resected SIACs. Results: Of 175 SIACs, loss of S100A14 expression was observed in 128 cases (73.1%). Loss of S100A14 expression was associated with lymph node metastasis (p = 0.009) and advanced disease stage (p = 0.013), and was more frequently observed in distal than duodenal tumors (p = 0.043). The majority of SIACs lost p21 expression (93.7%), and significant loss of p21 expression was observed in cancers with high pT stages (pT 3 and pT 4; p = 0.011), lymph node metastasis (p = 0.029) and advanced cancer stage defined by the American Joint Committee on Cancer (p = 0.005). Overexpression of p53 was found in 23.4% of cases. Positive expression of p53 was associated with distally located SIACs (jejunum or ileum; p = 0.006). There was no association between the expression of S100A14 and p21 or p53. Conclusion: Loss of S100A14 in SIAC is common and is associated with higher metastatic potential and advanced clinical stage. Copyright (C) 2012 S. Karger AG, Basel C1 [Kim, Jihun; Yu, Eunsil; Hong, Seung-Mo] Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, Seoul 138736, South Korea. [Kim, Gwangil] CHA Univ, Bundang CHA Med Ctr, Dept Pathol, Songnam, South Korea. [Chung, Joon-Yong] NCI, Appl Mol Lab, NIH, Bethesda, MD 20892 USA. [Chung, Joon-Yong] NCI, Tissue Array Res Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Jun, Sun-Young] Catholic Univ Korea, Coll Med, Incheon St Mary Hosp, Dept Pathol, Inchon, South Korea. [Eom, Dae Woon] Univ Ulsan, Coll Med, Gangneung Asan Hosp, Dept Pathol, Kangnung, South Korea. [Bae, Young Kyung] Yeungnam Univ, Coll Med, Dept Pathol, Taegu, South Korea. [Jang, Kee-Taek] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Pathol, Seoul, South Korea. RP Hong, SM (reprint author), Univ Ulsan, Coll Med, Asan Med Ctr, Dept Pathol, 388-1 Pungnap Dong, Seoul 138736, South Korea. EM smhong28@gmail.com OI Hong, Seung-Mo/0000-0002-8888-6007; Eom, Dae-Woon/0000-0001-9718-996X; Chung, Joon-Yong/0000-0001-5041-5982 FU Basic Science Research Program through the National Research Foundation of Korea; Ministry of Education, Science and Technology [2010-0004807] FX This research was supported by the Basic Science Research Program through the National Research Foundation of Korea and funded by the Ministry of Education, Science and Technology (2010-0004807). We would like to thank the members of the Korean Small Intestinal Cancer Study Group: Dr. Hee-Kyung Chang, Kosin University College of Medicine, Pusan; Dr. Eun Sun Jung, Catholic University of Korea College of Medicine, Seoul; Drs. Ghil Suk Yoon and Han-Ik Bae, Kyungpook National University, Dague; Dr. Joon Mee Kim, Inha University College of Medicine, Incheon; Dr. Young-Ha Oh, Hanyang University College of Medicine, Seoul; Dr. Soo Jin Jung, Inje University College of Medicine, Busan; Dr. Mi Jin Gu, Fatima Hospital, Daegu; Dr. Jung Yeon Kim, Inje University Sanggye Paik Hospital, Seoul; Dr. Kyu Yun Jang, Chonbuk National University Medical School, Jeonju; Dr. Kye Won Kwon, Bundang Jesaeng General Hospital, Seongnam; Dr. Gyeong Hoon Kang, Seoul National University College of Medicine, Seoul; Dr. Jae Bok Park, Catholic University of Daegu, Daegu; Dr. Soon Won Hong, Yonsei University College of Medicine, Seoul, and Dr. Ji Shin Lee, Chonnam National University Medical School, Gwangju, South Korea. NR 25 TC 9 Z9 11 U1 0 U2 6 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1015-2008 J9 PATHOBIOLOGY JI Pathobiology PY 2013 VL 80 IS 2 BP 95 EP 101 DI 10.1159/000342394 PG 7 WC Cell Biology; Pathology SC Cell Biology; Pathology GA 030MZ UT WOS:000310576100005 PM 23038644 ER PT J AU Dadashzadeh, ER Hobson, M Bryant, LH Dean, DD Frank, JA AF Dadashzadeh, Esmaeel R. Hobson, Matthew Bryant, L. Henry, Jr. Dean, Dana D. Frank, Joseph A. TI Rapid spectrophotometric technique for quantifying iron in cells labeled with superparamagnetic iron oxide nanoparticles: potential translation to the clinic SO CONTRAST MEDIA & MOLECULAR IMAGING LA English DT Article DE relaxometry; iron content; cell labeling; stem cells; superparamagnetic iron oxide nanoparticles; ferumoxides; ferumoxytol; ICP-MS; spectrophotometry; Prussian Blue; MRI ID STEM-CELLS; PROTAMINE SULFATE; CELLULAR MRI; CONTRAST AGENTS; RESONANCE; FERUMOXYTOL; TRACKING; QUANTIFICATION; FERUMOXIDES; OPTIMIZATION AB Labeling cells with superparamagnetic iron oxide (SPIO) nanoparticles provides the ability to track cells by magnetic resonance imaging. Quantifying intracellular iron concentration in SPIO labeled cells would allow for the comparison of agents and techniques used to magnetically label cells. Here we describe a rapid spectrophotometric technique (ST) to quantify iron content of SPIO-labeled cells, circumventing the previous requirement of an overnight acid digestion. Following lysis with 10% sodium dodecyl sulfate (SDS) of magnetically labeled cells, quantification of SPIO doped or labeled cells was performed using commonly available spectrophotometric instrument(s) by comparing absorptions at 370 and 750 nm with correction for turbidity of cellular products to determine the iron content of each sample. Standard curves demonstrated high linear correlation (R-2 = 0.998) between absorbance spectra of iron oxide nanoparticles and concentration in known SPIO-doped cells. Comparisons of the ST with inductively coupled plasmamass spectroscopy (ICP-MS) or nuclear magnetic resonance relaxometric (R-2) determinations of intracellular iron contents in SPIO containing samples resulted in significant linear correlation between the techniques (R-2 vs ST, R-2 > 0.992, p < 0.0001; ST vs ICP-MS, R-2 > 0.995, p < 0.0001) with the limit of detection of ST for iron = 0.66 mu g ml(-1) for 10(6) cells ml(-1). We have developed a rapid straightforward protocol that does not require overnight acid digestion for quantifying iron oxide content in magnetically labeled cells using readily available analytic instrumentation that should greatly expedite advances in comparing SPIO agents and protocols for labeling cells. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. C1 [Dadashzadeh, Esmaeel R.; Hobson, Matthew; Dean, Dana D.; Frank, Joseph A.] NIH, Frank Lab, Ctr Clin, Bethesda, MD 20892 USA. [Frank, Joseph A.] NIH, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. [Frank, Joseph A.] NIH, Intramural Res Program, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. RP Frank, JA (reprint author), NIH, Frank Lab, Ctr Clin, Bldg 10,Room B1N256,10 Ctr Dr,MSC 1074, Bethesda, MD 20892 USA. EM jafrank@helix.nih.gov FU Intramural Research Program at the Clinical Center at the National Institutes of Health FX This work was supported by the Intramural Research Program at the Clinical Center at the National Institutes of Health. The authors would like to thank the Center for Bone Marrow Stromal Cell Transplantation at our institution for providing the BMSC used in these studies. Neural Stem Cells were provided as part of a material transfer agreement by Dr Karen Aboody at the City of Hope. NR 35 TC 9 Z9 9 U1 2 U2 19 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1555-4309 J9 CONTRAST MEDIA MOL I JI Contrast Media Mol. Imaging PD JAN-FEB PY 2013 VL 8 IS 1 BP 50 EP 56 DI 10.1002/cmmi.1493 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 029GK UT WOS:000310482600007 PM 23109392 ER PT J AU Kosaka, N Mitsunaga, M Choyke, PL Kobayashi, H AF Kosaka, Nobuyuki Mitsunaga, Makoto Choyke, Peter L. Kobayashi, Hisataka TI In vivo real-time lymphatic draining using quantum-dot optical imaging in mice SO CONTRAST MEDIA & MOLECULAR IMAGING LA English DT Article DE lymphatic imaging; optical imaging; quantum dot ID CANCER-CELLS; FLUORESCENT PROTEINS; TUMOR; NODES; LYMPHANGIOGENESIS; NANOPARTICLES; TRAFFICKING; METASTASIS; MULTICOLOR; DELIVERY AB The lymphatic system is essential for fluid regulation and for the maintenance of host immunity. However, in vivo lymph flow is difficult to track in real time, because of the lack of an appropriate imaging method. In this study, we combined macro-zoom fluorescence microscopy with quantum-dot (Qdot) optical lymphatic imaging to develop an in vivo real-time optical lymphatic imaging method that allows the tracking of lymph through lymphatic channels and into lymph nodes. After interstitial injection of Qdots in a mouse, rapid visualization of the cervical lymphatics and cervical lymph nodes was achieved. Real-time monitoring of the injected Qdots revealed that the cortex of the node enhanced first followed by a net-like pattern in the central portion of the node. Histology revealed that the rim and net-like enhancing regions corresponded to the subcapsular sinuses and medullary sinuses respectively. Additionally, multiplexed two-color real-time lymphatic tracking was performed with two different Qdots. With this real-time imaging system, we successfully tracked microscopic lymphatic flow in vivo. This method could have a potential impact for lymphatic research in visualizing normal or abnormal functional lymphatic flows. Published 2012. This article is a U.S. Government work and is in the public domain in the USA. C1 [Kosaka, Nobuyuki; Mitsunaga, Makoto; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room B3B69,MSC1088, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 31 TC 12 Z9 12 U1 3 U2 24 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1555-4309 J9 CONTRAST MEDIA MOL I JI Contrast Media Mol. Imaging PD JAN-FEB PY 2013 VL 8 IS 1 BP 96 EP 100 DI 10.1002/cmmi.1487 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 029GK UT WOS:000310482600013 PM 23109398 ER PT J AU Okayama, H Saito, M Oue, N Weiss, JM Stauffer, J Takenoshita, S Wiltrout, RH Hussain, SP Harris, CC AF Okayama, Hirokazu Saito, Motonobu Oue, Naohide Weiss, Jonathan M. Stauffer, Jimmy Takenoshita, Seiichi Wiltrout, Robert H. Hussain, S. Perwez Harris, Curtis C. TI NOS2 enhances KRAS-induced lung carcinogenesis, inflammation and microRNA-21 expression SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE lung cancer; KRAS; NOS2; miR-21; inflammation ID NITRIC-OXIDE SYNTHASE; ENDOTHELIAL GROWTH-FACTOR; HUMAN BREAST-CANCER; ONCOGENIC K-RAS; TUMOR-GROWTH; MAMMALIAN TARGET; UP-REGULATION; MICE LACKING; T-CELLS; TUMORIGENESIS AB Mutant KRAS in lung cancers induces molecular pathways that regulate cellular proliferation, survival and inflammation, which enhance tumorigenesis. Inducible nitric oxide synthase (NOS2) upregulation and sustained nitric oxide generation are induced during the inflammatory response and correlate positively with lung tumorigenesis. To explore the mechanistic contribution of NOS2 to KRAS-induced lung tumorigenesis and inflammation, we used a genetic strategy of crossing NOS2 knockout (NOS2KO) C57BL6 inbred mice with a KRAS(G12D)-driven mouse lung cancer model. KRAS(G12D);NOS2KO mice exhibited delayed lung tumorigenesis and a longer overall survival time compared to that of KRAS(G12D);NOS2WT (wild-type) controls. Correspondingly, tumors in KRAS(G12D);NOS2KO mice had reduced tumor cell proliferation in adenomas and carcinomas. NOS2 deficiency also led to markedly suppressed inflammatory response by attenuation of macrophage recruitment into alveoli and within tumor foci. In contrast, FOXP3+ regulatory T cells were increased in tumors from KRAS(G12D);NOS2KO mice. We further analyzed the expression of microRNA-21 (miR-21), an oncogenic noncoding RNA involved in oncogenic Ras signaling, by quantitative reverse-transcription polymerase chain reaction and in situ hybridization. Lung carcinomas dissected from KRAS(G12D);NOS2KO mice showed a significantly reduced miR-21 expression along with decreased tumor cell proliferation, suggesting that NOS2 deficiency could attenuate RAS signaling pathways that transactivate miR-21 expression. Therefore, deletion of NOS2 decreases lung tumor growth as well as inflammatory responses initiated by oncogenic KRAS, suggesting that both KRAS and NOS2 cooperate in driving lung tumorigenesis and inflammation. Inhibition of NOS2 may have a therapeutic value in lung cancers with oncogenic KRAS mutations. C1 [Okayama, Hirokazu; Saito, Motonobu; Oue, Naohide; Hussain, S. Perwez; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Okayama, Hirokazu; Saito, Motonobu; Takenoshita, Seiichi] Fukushima Med Univ, Sch Med, Dept Organ Regulatory Surg, Fukushima, Japan. [Weiss, Jonathan M.; Stauffer, Jimmy; Wiltrout, Robert H.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 3068, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov FU Intramural Research Program of the National Cancer Institute, National Institutes of Health FX Grant sponsor: Intramural Research Program of the National Cancer Institute, National Institutes of Health NR 50 TC 24 Z9 25 U1 2 U2 15 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0020-7136 EI 1097-0215 J9 INT J CANCER JI Int. J. Cancer PD JAN 1 PY 2013 VL 132 IS 1 BP 9 EP 18 DI 10.1002/ijc.27644 PG 10 WC Oncology SC Oncology GA 029HZ UT WOS:000310486800002 PM 22618808 ER PT J AU Halec, G Schmitt, M Dondog, B Sharkhuu, E Wentzensen, N Gheit, T Tommasino, M Kommoss, F Bosch, FX Franceschi, S Clifford, G Gissmann, L Pawlita, M AF Halec, Gordana Schmitt, Markus Dondog, Bolormaa Sharkhuu, Enkhtuya Wentzensen, Nicolas Gheit, Tarik Tommasino, Massimo Kommoss, Friedrich Bosch, Franz X. Franceschi, Silvia Clifford, Gary Gissmann, Lutz Pawlita, Michael TI Biological activity of probable/possible high-risk human papillomavirus types in cervical cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE human papillomavirus; cervical cancer; E6*I; mRNA; p16(INK4a) ID E7 MESSENGER-RNA; TRANSCRIPTION PATTERNS; P53 DEGRADATION; EARLY GENES; E6; ASSAY; CARCINOMA; PROTEINS; PCR; ONCOPROTEIN AB Judging the carcinogenicity of human papillomavirus (HPV) types rarely found in cervical cancer (CxCa) is hindered by lack of studies of their biological activity in cancer tissues. To asses transcriptional activity of HPV types, we have developed ultra-short amplimer, splice-site specific, E6*I mRNA RT-PCR assays for 12 high-risk (HR)-HPV (IARC Group 1) and eight probable/possible high-risk (pHR)-HPV types (IARC Group 2A/B carcinogens). Previously unreported E6*I splice sites of the six pHR-HPV types 26, 53, 67, 70, 73 and 82 were identified by cloning and sequencing. We analyzed 97 formalin-fixed paraffin-embedded (FFPE) Mongolian CxCa biopsies for presence of HPV DNA by two sensitive genotyping assays, for E6*I transcripts of all HR-/pHR-HPV types identified and for expression of HPV surrogate markers p16(INK4a), pRb and p53. E6*I of at least one HR-/pHR-HPV was expressed in 94 (98%) of cancer tissues including seven with pHR-HPV types 26, 66, 70 or 82 as single transcribed types. Fifty-eight of E6*I mRNA transcribing cases were analyzable by immunohistochemistry and displayed p16(INK4a) overexpression in 57 (98%), pRb downregulation in 56 (97%) and p53 downregulation in 36 (62%) tissues. The newly developed E6*I mRNA RT-PCR assays appeared to be highly sensitive method to analyze HPV transcription in FFPE materials. Our finding of viral oncogene transcription of pHR-HPV types 26, 66, 70 and 82 in cervical tumors, in the absence of any other transcriptionally active HR-type and with p16(INK4a) overexpression and pRb downregulation, may support a reassessment of the carcinogenicity classification of these pHR-HPV types. C1 [Pawlita, Michael] German Canc Res Ctr, Dept Genome Modificat & Carcinogenesis, Res Program Infect & Canc, D-69120 Heidelberg, Germany. [Halec, Gordana; Bosch, Franz X.] Univ Heidelberg, Mol Biol Lab, Heidelberg, Germany. [Dondog, Bolormaa; Gheit, Tarik; Tommasino, Massimo; Franceschi, Silvia; Clifford, Gary] IARC, Lyon, France. [Sharkhuu, Enkhtuya] NCCM, Ulaanbaatar, Mongol Peo Rep. [Wentzensen, Nicolas] NCI, NIH, Rockville, MD USA. [Kommoss, Friedrich] Referral Ctr Gynecopathol, Inst Pathol, Mannheim, Germany. [Gissmann, Lutz] King Saud Univ, Dept Bot & Microbiol, Riyadh, Saudi Arabia. RP Pawlita, M (reprint author), German Canc Res Ctr, Dept Genome Modificat & Carcinogenesis, Res Program Infect & Canc, Neuenheimer Feld 242, D-69120 Heidelberg, Germany. EM m.pawlita@dkfz.de RI Pawlita, Labor/C-9720-2011; Schmitt, Markus/B-6410-2008; Gissmann, Lutz/H-4688-2011; Waterboer, Tim/G-1252-2010; OI Schmitt, Markus/0000-0002-7827-6694; Pawlita, Michael/0000-0002-4720-8306 FU Qiagen; Roche FX Grant sponsor: Research funding from Qiagen and Roche in the field of HPV diagnostics NR 40 TC 33 Z9 33 U1 1 U2 9 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 JAN 1 PY 2013 VL 132 IS 1 BP 63 EP 71 DI 10.1002/ijc.27605 PG 9 WC Oncology SC Oncology GA 029HZ UT WOS:000310486800007 PM 22514107 ER PT J AU Wentzensen, N Walker, J Schiffman, M Yang, HP Zuna, RE Dunn, ST Allen, RA Zhang, R Sherman, M Gold, MA Wang, SS AF Wentzensen, Nicolas Walker, Joan Schiffman, Mark Yang, Hannah P. Zuna, Rosemary E. Dunn, S. Terence Allen, R. Andy Zhang, Roy Sherman, Mark Gold, Michael A. Wang, Sophia S. TI Heterogeneity of high-grade cervical intraepithelial neoplasia related to HPV16: Implications for natural history and management SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE HPV16; CIN3; biopsy; colposcopy; screening ID HUMAN-PAPILLOMAVIRUS TYPES; EARLY END-POINTS; CANCER; WOMEN; RISK; DETERMINANTS; PROGRESSION AB Factors associated with progression from cervical intraepithelial neoplasia (CIN) grades 2 and 3 to invasive cancer are not well understood; most CIN2 and CIN3 do not progress to cancer. Among carcinogenic human papillomavirus (HPV) types, infections with HPV16 have the highest risk of progressing to cancer. We evaluated the heterogeneity of risk factors, lesion size, colposcopic impression and colposcopic biopsy results in relation to HPV16 status among 627 women with CIN2 or CIN3 in women referred to colposcopy at the University of Oklahoma. Loop excision specimens were evaluated in 12 radial segments to estimate lesion size. The mean age at CIN3 was 27.7 years for HPV16-positive women (n = 225) and 33.6 years for HPV16-negative women (n = 104). The average lesion size did not differ by HPV16 status (p = 0.83). Among HPV16-positive women with CIN3, lesions were significantly larger in women 30 years and older (p = 0.03). Colposcopic impression was worse in women with HPV16 infections (p = 0.009), but the detection of CIN3 at the preceding biopsy was not improved in HPV16-positive women. CIN3 is detected at the same lesion size, but at much younger age in women with HPV16 infections, suggesting faster growth. CIN2 lesion size in women without HPV16 peaks below 30 years and then decreases, suggesting frequent regression, whereas HPV16-related CIN2 is more likely to persist. Lesion size seems to be an important determinant of colposcopy and biopsy performance. Genotyping for HPV16 in cervical cancer screening can improve risk stratification but may pose challenges to finding small lesions in colposcopy. C1 [Wentzensen, Nicolas; Schiffman, Mark; Yang, Hannah P.; Sherman, Mark; Wang, Sophia S.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Walker, Joan; Zuna, Rosemary E.; Dunn, S. Terence; Allen, R. Andy; Zhang, Roy] Univ Oklahoma, Hlth Sci Ctr, Dept Pathol, Oklahoma City, OK USA. [Walker, Joan; Zuna, Rosemary E.; Dunn, S. Terence; Allen, R. Andy; Zhang, Roy] Univ Oklahoma, Hlth Sci Ctr, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA. [Gold, Michael A.] Vanderbilt Univ, Dept Obstet & Gynecol, Nashville, TN USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Div Canc Etiol, Duarte, CA 91010 USA. [Wang, Sophia S.] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA 91010 USA. RP Wentzensen, N (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 5024, Rockville, MD 20852 USA. EM wentzenn@mail.nih.gov FU Intramural Research Program of the National Cancer Institute FX Grant sponsor: Intramural Research Program of the National Cancer Institute NR 17 TC 14 Z9 15 U1 0 U2 5 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 JAN 1 PY 2013 VL 132 IS 1 BP 148 EP 154 DI 10.1002/ijc.27577 PG 7 WC Oncology SC Oncology GA 029HZ UT WOS:000310486800016 PM 22488167 ER PT J AU Baris, D Karagas, MR Koutros, S Colt, JS Johnson, A Schwenn, M Fischer, AH Figueroa, JD Berndt, SI Han, S Freeman, LEB Lubin, JH Cherala, S Cantor, KP Jacobs, K Chanock, S Chatterjee, N Rothman, N Silverman, DT AF Baris, Dalsu Karagas, Margaret R. Koutros, Stella Colt, Joanne S. Johnson, Alison Schwenn, Molly Fischer, Alexander H. Figueroa, Jonine D. Berndt, Sonja I. Han, Summer Freeman, Laura E. Beane Lubin, Jay H. Cherala, Sai Cantor, Kenneth P. Jacobs, Kevin Chanock, Stephen Chatterjee, Nilanjan Rothman, Nathaniel Silverman, Debra T. TI Nonsteroidal anti-inflammatory drugs and other analgesic use and bladder cancer in northern New England SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE bladder cancer; nonsteroidal anti-inflammatory drugs; gene-drug interaction; CYP3A ID TRANSITIONAL-CELL CARCINOMA; GENE-ENVIRONMENT INDEPENDENCE; P75(NTR) TUMOR-SUPPRESSOR; ACUTE URINARY RETENTION; CYCLOOXYGENASE-2 COX-2; ADULT-POPULATION; ASPIRIN USE; KAPPA-B; RISK; PREVENTION AB A few epidemiologic studies have found that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with reduced risk of bladder cancer. However, the effects of specific NSAID use and individual variability in risk have not been well studied. We examined the association between NSAIDs use and bladder cancer risk, and its modification by 39 candidate genes related to NSAID metabolism. A population-based case-control study was conducted in northern New England, enrolling 1,171 newly diagnosed cases and 1,418 controls. Regular use of nonaspirin, nonselective NSAIDs was associated with reduced bladder cancer risk, with a statistically significant inverse trend in risk with duration of use (ORs of 1.0, 0.8, 0.6 and 0.6 for <5, 5-9, 10-19 and 20+ years, respectively; p(trend) = 0.015). This association was driven mainly by ibuprofen; significant inverse trends in risk with increasing duration and dose of ibuprofen were observed (p(trend) = 0.009 and 0.054, respectively). The reduced risk from ibuprofen use was limited to individuals carrying the T allele of a single nucleotide polymorphism (rs4646450) compared to those who did not use ibuprofen and did not carry the T allele in the CYP3A locus, providing new evidence that this association might be modified by polymorphisms in genes that metabolize ibuprofen. Significant positive trends in risk with increasing duration and cumulative dose of selective cyclooxygenase (COX-2) inhibitors were observed. Our results are consistent with those from previous studies linking use of NSAIDs, particularly ibuprofen, with reduced risk. We observed a previously unrecognized risk associated with use of COX-2 inhibitors, which merits further evaluation. C1 [Baris, Dalsu; Koutros, Stella; Colt, Joanne S.; Fischer, Alexander H.; Figueroa, Jonine D.; Berndt, Sonja I.; Han, Summer; Freeman, Laura E. Beane; Lubin, Jay H.; Cantor, Kenneth P.; Jacobs, Kevin; Chanock, Stephen; Chatterjee, Nilanjan; Rothman, Nathaniel; Silverman, Debra T.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20852 USA. [Karagas, Margaret R.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Community & Family Med,Sect Biostat, Hanover, NH 03756 USA. [Schwenn, Molly] Maine Dept Hlth & Human Serv, Augusta, ME USA. [Johnson, Alison] Vermont Canc Registry, Burlington, VT USA. [Cherala, Sai] New Hampshire Dept Hlth & Human Serv, Concord, NH 03301 USA. RP Baris, D (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS Room 8008, Bethesda, MD 20852 USA. EM barisd@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Cherala, Sai/0000-0002-3485-574X FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics [N02-CP-01037] FX Grant sponsor: Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics; Grant number: N02-CP-01037 NR 50 TC 6 Z9 7 U1 3 U2 12 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 JAN 1 PY 2013 VL 132 IS 1 BP 162 EP 173 DI 10.1002/ijc.27590 PG 12 WC Oncology SC Oncology GA 029HZ UT WOS:000310486800018 PM 22505343 ER PT J AU Liu, KJ He, JH Su, XD Sim, HM Xie, JD Chen, XG Wang, F Liang, YJ Singh, S Sodani, K Talele, TT Ambudkar, SV Chen, ZS Wu, HY Fu, LW AF Liu, Ke-Jun He, Jie-Hua Su, Xiao-Dong Sim, Hong-May Xie, Jing-Dun Chen, Xing-Gui Wang, Fang Liang, Yong-Ju Singh, Satyakam Sodani, Kamlesh Talele, Tanaji T. Ambudkar, Suresh V. Chen, Zhe-Sheng Wu, Hai-Ying Fu, Li-Wu TI Saracatinib (AZD0530) is a potent modulator of ABCB1-mediated multidrug resistance in vitro and in vivo SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE saracatinib; Src/Abl kinase inhibitor; multidrug resistance; ATP-binding cassette transporters subfamily B member 1(ABCB1) ID SUBFAMILY-B MEMBER-1; BREAST-CANCER CELLS; SRC FAMILY KINASES; P-GLYCOPROTEIN; DRUG-RESISTANCE; PHASE-II; BINDING; INHIBITION; PI3K/AKT; PROTEIN AB Saracatinib, a highly selective, dual Src/Abl kinase inhibitor, is currently in a Phase II clinical trial for the treatment of ovarian cancer. In our study, we investigated the effect of saracatinib on the reversal of multidrug resistance (MDR) induced by ATP-binding cassette (ABC) transporters in vitro and in vivo. Our results showed that saracatinib significantly enhanced the cytotoxicity of ABCB1 substrate drugs in ABCB1 overexpressing HeLa/v200, MCF-7/adr and HEK293/ABCB1 cells, an effect that was stronger than that of gefitinib, whereas it had no effect on the cytotoxicity of the substrates in ABCC1 overexpressing HL-60/adr cells and its parental sensitive cells. Additionally, saracatinib significantly increased the doxorubicin (Dox) and Rho 123 accumulation in HeLa/v200 and MCF-7/adr cells, whereas it had no effect on HeLa and MCF-7 cells. Furthermore, saracatinib stimulated the ATPase activity and inhibited photolabeling of ABCB1 with [I-125]-iodoarylazidoprazosin in a concentration-dependent manner. In addition, the homology modeling predicted the binding conformation of saracatinib within the large hydrophobic drug-binding cavity of human ABCB1. However, neither the expression level of ABCB1 nor the phosphorylation level of Akt was altered at the reversal concentrations of saracatinib. Importantly, saracatinib significantly enhanced the effect of paclitaxel against ABCB1-overexpressing HeLa/v200 cancer cell xenografts in nude mice. In conclusion, saracatinib reverses ABCB1-mediated MDR in vitro and in vivo by directly inhibiting ABCB1 transport function, without altering ABCB1 expression or AKT phosphorylation. These findings may be helpful to attenuate the effect of MDR by combining saracatinib with other chemotherapeutic drugs in the clinic. C1 [Liu, Ke-Jun; He, Jie-Hua; Su, Xiao-Dong; Xie, Jing-Dun; Chen, Xing-Gui; Wang, Fang; Liang, Yong-Ju; Wu, Hai-Ying; Fu, Li-Wu] Sun Yat Sen Univ, State Key Lab Oncol So China, Ctr Canc, Guangzhou 510060, Guangdong, Peoples R China. [Sim, Hong-May; Ambudkar, Suresh V.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Singh, Satyakam; Sodani, Kamlesh; Talele, Tanaji T.; Chen, Zhe-Sheng] St Johns Univ, Coll Pharm & Allied Hlth Profess, Dept Pharmaceut Sci, Jamaica, NY 11439 USA. RP Wu, HY (reprint author), Sun Yat Sen Univ, State Key Lab Oncol So China, Ctr Canc, 651 Dongfeng Rd E, Guangzhou 510060, Guangdong, Peoples R China. EM drwuhy@163.net; fulw@mail.sysu.edu.cn OI Singh, Satyakam/0000-0001-9115-3296 FU National Natural Sciences Foundation of China (NSFC) [81072669, 81061160]; 863 Project Foundation [2006AA02A404]; NIH R15 [1R15CA143701]; Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH FX Grant sponsor: National Natural Sciences Foundation of China (NSFC); Grant numbers: 81072669, 81061160; Grant sponsor: 863 Project Foundation; Grant number: 2006AA02A404; Grant sponsor: NIH R15; Grant number: 1R15CA143701; Grant sponsor: Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH NR 48 TC 20 Z9 23 U1 4 U2 31 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 JAN 1 PY 2013 VL 132 IS 1 BP 224 EP 235 DI 10.1002/ijc.27649 PG 12 WC Oncology SC Oncology GA 029HZ UT WOS:000310486800025 PM 22623106 ER PT J AU Meltzer, JA Braun, AR AF Meltzer, Jed A. Braun, Allen R. TI P600-like positivity and left anterior negativity responses are elicited by semantic reversibility in nonanomalous sentences SO JOURNAL OF NEUROLINGUISTICS LA English DT Article DE Syntax; EEG; Language; ERP; N400; LAN; Working memory; Reanalysis ID EVENT-RELATED POTENTIALS; BRAIN POTENTIALS; WORKING-MEMORY; LANGUAGE COMPREHENSION; RELATIVE CLAUSES; SYNTAX; ANIMACY; WORDS; MAGNETOENCEPHALOGRAPHY; INFORMATION AB ERPs are commonly elicited by semantic and syntactic violations in sentences, leading to proposals that they reflect neural activity underlying ordinary language comprehension. We examined ERPs in an auditory sentence-picture-matching task, using nonanomalous sentences that were either semantically reversible, (boy pushes girl) or irreversible, (boy eats apple). Timelocked to the end of the critical clause, which occurred in the middle of a longer sentence, we observed an enhanced central-posterior positivity in response to the reversible sentences. The topography of this response is consistent with the P600 potential reported in studies of syntactic anomalies and other manipulations related to sentence structure. Following the end of the sentence, during a memory delay period prior to picture onset, reversible sentences also evoked a protracted anterior negativity, predominantly on the left. This negativity was stronger for sentences containing relative clauses compared to simple active sentences, but did not differ between object-embedded and the less complex subject-embedded clauses. The observation of a P600 occurring selectively in reversible sentences supports the interpretation of that potential as reflecting the syntactic processing of thematic relationships, as irreversible sentences contained alternative cues for thematic roles. The left anterior negativity likely reflects later processes of rehearsal and reanalysis of sentence content in working memory. Published by Elsevier Ltd. C1 [Meltzer, Jed A.] Baycrest Ctr Geriatr Care, Rotman Res Inst, Toronto, ON, Canada. [Braun, Allen R.] NIDCD, Language Sect, NIH, Bethesda, MD USA. RP Meltzer, JA (reprint author), Baycrest Ctr Geriatr Care, Rotman Res Inst, 3560 Bathurst St, Toronto, ON, Canada. EM jed.meltzer@aya.yale.edu OI Meltzer, Jed/0000-0002-4301-1901 FU intramural program of the National Institute on Deafness and Other Communication Disorders FX We thank Joseph McArdle, Susannah Hoffman, Elizabeth Rawson, and Judy Mitchell-Francis for assistance with EEG recording. This work was supported by the intramural program of the National Institute on Deafness and Other Communication Disorders. NR 53 TC 4 Z9 4 U1 3 U2 28 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0911-6044 J9 J NEUROLINGUIST JI J. Neurolinguist. PD JAN PY 2013 VL 26 IS 1 BP 129 EP 148 DI 10.1016/j.jneuroling.2012.06.001 PG 20 WC Linguistics; Neurosciences; Psychology, Experimental SC Linguistics; Neurosciences & Neurology; Psychology GA 028HM UT WOS:000310413400008 ER PT J AU Guthrie, LC Lessl, K Ochi, O Ward, MM AF Guthrie, Lori C. Lessl, Kristen Ochi, Onyinyechukwu Ward, Michael M. TI Time Perspective and Smoking, Obesity, and Exercise in a Community Sample SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article DE time perspective; smoking; exercise; obesity; socioeconomic status ID FUTURE CONSEQUENCES; SUBSTANCE USE; INDIVIDUAL-DIFFERENCES; PHYSICAL-ACTIVITY; YOUNG-ADULTS; BODY-MASS; HEALTH; BEHAVIOR; ADOLESCENTS; ORIENTATION AB Objective: To examine associations between time perspective and smoking, body mass index, and exercise. Methods: In this community-based survey, adults reported smoking and exercise habits and weight and height and completed the Zimbardo Time Perspective Inventory. Results: Subjects (N=265) who were more future oriented reported more frequent exercise, but were more likely to smoke. Fatalistic and hedonistic present orientations were not associated with smoking, obesity, or exercise. Conclusions: Time perspective is not consistently associated with common health behaviors in adults. C1 [Guthrie, Lori C.; Lessl, Kristen; Ochi, Onyinyechukwu; Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS [ZIA AR041153-09] NR 39 TC 11 Z9 11 U1 2 U2 24 PU PNG PUBLICATIONS PI OAK RIDGE PA 2205-K OAK RIDGE RD, #115, OAK RIDGE, NC 27310 USA SN 1945-7359 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PY 2013 VL 37 IS 2 BP 171 EP 180 DI 10.5993/AJHB.37.2.4 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 014GC UT WOS:000309362200004 PM 23026098 ER PT J AU Bertke, AS Apakupakul, K Ma, A Imai, Y Gussow, AM Wang, KN Cohen, JI Bloom, DC Margolis, TP AF Bertke, Andrea S. Apakupakul, Kathleen Ma, AyeAye Imai, Yumi Gussow, Anne M. Wang, Kening Cohen, Jeffrey I. Bloom, David C. Margolis, Todd P. TI LAT Region Factors Mediating Differential Neuronal Tropism of HSV-1 and HSV-2 Do Not Act in Trans SO PLOS ONE LA English DT Article ID HERPES-SIMPLEX-VIRUS; LATENCY-ASSOCIATED TRANSCRIPT; PRIMARY SENSORY NEURONS; IMMUNOHISTOCHEMICAL ANALYSIS; PRODUCTIVE INFECTION; VIRAL REPLICATION; GENE-EXPRESSION; TYPE-1; REACTIVATION; INTRON AB After HSV infection, some trigeminal ganglion neurons support productive cycle gene expression, while in other neurons the virus establishes a latent infection. We previously demonstrated that HSV-1 and HSV-2 preferentially establish latent infection in A5+ and KH10+ sensory neurons, respectively, and that exchanging the latency-associated transcript (LAT) between HSV-1 and HSV-2 also exchanges the neuronal preference. Since many viral genes besides the LAT are functionally interchangeable between HSV-1 and HSV-2, we co-infected HSV-1 and HSV-2, both in vivo and in vitro, to determine if transacting viral factors regulate whether HSV infection follows a productive or latent pattern of gene expression in sensory neurons. The pattern of HSV-1 and HSV-2 latent infection in trigeminal neurons was no different following co-infection than with either virus alone, consistent with the hypothesis that a trans-acting viral factor is not responsible for the different patterns of latent infection of HSV-1 and HSV-2 in A5+ and KH10+ neurons. Since exchanging the LAT regions between the viruses also exchanges neuronal preferences, we infected transgenic mice that constitutively express 2.8 kb of the LAT region with the heterologous viral serotype. Endogenous expression of LAT did not alter the pattern of latent infection after inoculation with the heterologous serotype virus, demonstrating that the LAT region does not act in trans to direct preferential establishment of latency of HSV-1 and HSV-2. Using HSV1-RFP and HSV2-GFP in adult trigeminal ganglion neurons in vitro, we determined that HSV-1 and HSV-2 do not exert trans-acting effects during acute infection to regulate neuron specificity. Although some neurons were productively infected with both HSV-1 and HSV-2, no A5+ or KH10+ neurons were productively infected with both viruses. Thus, trans-acting viral factors do not regulate preferential permissiveness of A5+ and KH10+ neurons for productive HSV infection and preferential establishment of latent infection. C1 [Bertke, Andrea S.; Apakupakul, Kathleen; Ma, AyeAye; Imai, Yumi; Margolis, Todd P.] Univ Calif San Francisco, Francis I Proctor Fdn, San Francisco, CA 94143 USA. [Bertke, Andrea S.; Apakupakul, Kathleen; Ma, AyeAye; Imai, Yumi; Margolis, Todd P.] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA USA. [Gussow, Anne M.; Bloom, David C.] Univ Florida, Coll Med, Dept Mol Genet & Microbiol, Gainesville, FL USA. [Wang, Kening; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, Bethesda, MD 20892 USA. RP Margolis, TP (reprint author), Univ Calif San Francisco, Francis I Proctor Fdn, San Francisco, CA 94143 USA. EM todd.margolis@ucsf.edu FU That Man May See (San Francisco, CA); National Institute of Allergy and Infectious Diseases; National Institutes of Health (NIH) [AI048633]; NICHD FX This research was supported in part by That Man May See (San Francisco, CA), and the intramural research program of the National Institute of Allergy and Infectious Diseases and National Institutes of Health (NIH) grant AI048633. Monoclonal antibodies FE-A5 developed by B. Fenderson and KH10 developed by T. M. Jessell and J. Dodd were obtained from the Developmental Studies Hybridoma Bank developed under the auspices of the NICHD and maintained by The University of Iowa, Department of Biological Sciences, Iowa, IA 52242. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 21 TC 5 Z9 6 U1 1 U2 9 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 DEC 31 PY 2012 VL 7 IS 12 AR e53281 DI 10.1371/journal.pone.0053281 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 075GO UT WOS:000313872600080 PM 23300908 ER PT J AU Berquist, BR Wilson, DM AF Berquist, Brian R. Wilson, David M., III TI Pathways for repairing and tolerating the spectrum of oxidative DNA lesions SO CANCER LETTERS LA English DT Review DE Oxidative DNA damage; Excision repair; Interstrand crosslink; Hereditary disorder ID BASE-EXCISION-REPAIR; CROSS-LINK REPAIR; FANCONI-ANEMIA PATHWAY; STRUCTURE-SPECIFIC NUCLEASES; THYMINE GLYCOL LESIONS; HAMSTER OVARY CELLS; GROUP-B PROTEIN; COCKAYNE-SYNDROME; TRANSLESION SYNTHESIS; POLYMERASE-ETA AB Reactive oxygen species (ROS) arise from both endogenous and exogenous sources. These reactive molecules possess the ability to damage both the DNA nucleobases and the sugar phosphate backbone, leading to a wide spectrum of lesions, including non-bulky (8-oxoguanine and formamidopyrimidine) and bulky (cyclopurine and etheno adducts) base modifications, abasic sites, non-conventional single-strand breaks, protein-DNA adducts, and intra/interstrand DNA crosslinks. Unrepaired oxidative DNA damage can result in bypass mutagenesis during genome copying or gene expression, or blockage of the essential cellular processes of DNA replication or transcription. Such outcomes underlie numerous pathologies, including, but not limited to, carcinogenesis and neurodegeneration, as well as the aging process. Cells have adapted and evolved defense systems against the deleterious effects of ROS, and specifically devote a number of cellular DNA repair and tolerance pathways to combat oxidative DNA damage. Defects in these protective pathways trigger hereditary human diseases that exhibit increased cancer incidence, developmental defects, neurological abnormalities, and/or premature aging. We review herein classic and atypical oxidative DNA lesions, outcomes of encountering these damages during DNA replication and transcription, and the consequences of losing the ability to repair the different forms of oxidative DNA damage. We particularly focus on the hereditary human diseases Xeroderma Pigmentosum, Cockayne Syndrome and Fanconi Anemia, which may involve defects in the efficient repair of oxidative modifications to chromosomal DNA. Published by Elsevier Ireland Ltd. C1 [Wilson, David M., III] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Berquist, Brian R.] Texas A&M Hlth Sci Ctr, Dept Mol & Cellular Med, Coll Med, College Stn, TX 77843 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM wilsonda@mail.nih.gov FU Intramural Research Program of the NIH, National Institute on Aging FX This research was supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 166 TC 54 Z9 54 U1 1 U2 51 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD DEC 31 PY 2012 VL 327 IS 1-2 SI SI BP 61 EP 72 DI 10.1016/j.canlet.2012.02.001 PG 12 WC Oncology SC Oncology GA 033SM UT WOS:000310821400007 PM 22353689 ER PT J AU Ivashkevich, A Redon, CE Nakamura, AJ Martin, RF Martin, OA AF Ivashkevich, Alesia Redon, Christophe E. Nakamura, Asako J. Martin, Roger F. Martin, Olga A. TI Use of the gamma-H2AX assay to monitor DNA damage and repair in cancer research SO CANCER LETTERS LA English DT Review DE gamma-H2AX; Double-strand breaks (DSBs); Translational research; Chemotherapy; Radiation therapy; Radiosensitivity; Biodosimetry; Imaging ID DOUBLE-STRAND BREAKS; HISTONE H2AX PHOSPHORYLATION; MEASURE CHROMOSOMAL RADIOSENSITIVITY; PERIPHERAL-BLOOD LYMPHOCYTES; AUTOMATED BIODOSIMETRY TOOL; CORONARY CT ANGIOGRAPHY; IN-VIVO FORMATION; RADIATION SENSITIVITY; BIOLOGICAL DOSIMETRY; IONIZING-RADIATION AB Formation of gamma-H2AX in response to DNA double stranded breaks (DSBs) provides the basis for a sensitive assay of DNA damage in human biopsies. The review focuses on the application of gamma-H2AX-based methods to translational studies to monitor the clinical response to DNA targeted therapies such as some forms of chemotherapy, external beam radiotherapy, radionuclide therapy or combinations thereof. The escalating attention on radiation biodosimetry has also highlighted the potential of the assay including renewed efforts to assess the radiosensitivity of prospective radiotherapy patients. Finally the gamma-H2AX response has been suggested as a basis for an in vivo imaging modality. (c) 2011 Elsevier Ireland Ltd. All rights reserved. C1 [Ivashkevich, Alesia; Martin, Roger F.; Martin, Olga A.] Peter MacCallum Canc Ctr, Lab Mol Radiat Biol, Melbourne, Vic, Australia. [Redon, Christophe E.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Nakamura, Asako J.] Osaka Med Coll, Dept Anat & Cell Biol, Osaka, Japan. [Martin, Olga A.] Peter MacCallum Canc Ctr, Dept Radiat Oncol, Melbourne, Vic, Australia. RP Martin, OA (reprint author), Peter MacCallum Canc Ctr, Dept Radiat Oncol, 12 St Andrews Pl, Melbourne, Vic 3002, Australia. EM olga.martin@petermac.org FU Intramural Research Program of the National Cancer Institute, National Institutes of Health; NIAID Radiation/Nuclear Countermeasures Program FX This study was partly funded by the Intramural Research Program of the National Cancer Institute, National Institutes of Health and by the NIAID Radiation/Nuclear Countermeasures Program. NR 141 TC 96 Z9 99 U1 4 U2 45 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD DEC 31 PY 2012 VL 327 IS 1-2 SI SI BP 123 EP 133 DI 10.1016/j.canlet.2011.12.025 PG 11 WC Oncology SC Oncology GA 033SM UT WOS:000310821400013 PM 22198208 ER PT J AU Posch, M Proschan, MA AF Posch, Martin Proschan, Michael A. TI Unplanned adaptations before breaking the blind SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT 32nd Annual Conference of the International-Society-for-Clinical-Biostatistics CY AUG 21-25, 2011 CL Ontario, CANADA DE adaptive methods; permutation tests; type I error rate control; multiple comparisons; blinded interim analysis ID SAMPLE-SIZE; TRIAL; TESTS; HYPOTHESES; VARIANCE AB Occasionally, things go so wrong in a clinical trial that a change must be made. For example, the originally planned primary outcome may be measured completely unreliably. Is there any recourse? One may still be able to salvage the trial using a permutation test if a change is made before breaking the treatment blind. The solution is not a panacea; we discuss the limitations and legitimate grounds for criticism. Still, when it is needed, the procedure is preferable to rigid adherence to a design that makes no sense. Published 2012. This article is a US Government work and is in the public domain in the USA. C1 [Posch, Martin] European Med Agcy, London E14 4HB, England. [Proschan, Michael A.] NIAID, Bethesda, MD 20892 USA. RP Posch, M (reprint author), European Med Agcy, 17 Westferry Circus, London E14 4HB, England. EM Martin.Posch@ema.europa.eu RI Posch, Martin/C-7907-2009 OI Posch, Martin/0000-0001-8499-8573 FU Austrian Science Fund (FWF) [P23167] FX This work was supported by the Austrian Science Fund (FWF): P23167. NR 19 TC 4 Z9 4 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD DEC 30 PY 2012 VL 31 IS 30 SI SI BP 4146 EP 4153 DI 10.1002/sim.5361 PG 8 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 055XJ UT WOS:000312451000002 PM 22736397 ER PT J AU Ryan, PB Madigan, D Stang, PE Overhage, JM Racoosin, JA Hartzema, AG AF Ryan, Patrick B. Madigan, David Stang, Paul E. Overhage, J. Marc Racoosin, Judith A. Hartzema, Abraham G. TI Empirical assessment of methods for risk identification in healthcare data: results from the experiments of the Observational Medical Outcomes Partnership SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT 32nd Annual Conference of the International-Society-for-Clinical-Biostatistics CY AUG 21-25, 2011 CL Ontario, CANADA DE product surveillance; postmarketing; pharmacoepidemiology; epidemiologic methods; causality; electronic health records; adverse drug reactions ID CLINICAL-TRIALS; CASE-CROSSOVER; SURVEILLANCE; SCIENCE; DESIGNS AB Background: Expanded availability of observational healthcare data (both administrative claims and electronic health records) has prompted the development of statistical methods for identifying adverse events associated with medical products, but the operating characteristics of these methods when applied to the real-world data are unknown. Methods: We studied the performance of eight analytic methods for estimating of the strength of association-relative risk (RR) and associated standard error of 53 drugadverse event outcome pairs, both positive and negative controls. The methods were applied to a network of ten observational healthcare databases, comprising over 130 million lives. Performance measures included sensitivity, specificity, and positive predictive value of methods at RR thresholds achieving statistical significance of p < 0.05 or p < 0.001 and with absolute threshold RR > 1.5, as well as threshold-free measures such as area under receiver operating characteristic curve (AUC). Results: Although no specific method demonstrated superior performance, the aggregate results provide a benchmark and baseline expectation for risk identification method performance. At traditional levels of statistical significance (RR > 1, p < 0.05), all methods have a false positive rate >18%, with positive predictive value <38%. The best predictive model, high-dimensional propensity score, achieved an AUC = 0.77. At 50% sensitivity, false positive rate ranged from 16% to 30%. At 10% false positive rate, sensitivity of the methods ranged from 9% to 33%. Conclusions: Systematic processes for risk identification can provide useful information to supplement an overall safety assessment, but assessment of methods performance suggests a substantial chance of identifying false positive associations. Copyright (c) 2012 John Wiley & Sons, Ltd. C1 [Ryan, Patrick B.; Stang, Paul E.] Johnson & Johnson Pharmaceut Res & Dev LLC, Titusville, NJ USA. [Ryan, Patrick B.; Madigan, David; Stang, Paul E.; Overhage, J. Marc; Racoosin, Judith A.; Hartzema, Abraham G.] Fdn Natl Inst Hlth, Bethesda, MD USA. [Ryan, Patrick B.] Univ N Carolina, UNC Eshelman Sch Pharm, Chapel Hill, NC USA. [Madigan, David] Columbia Univ, Dept Stat, New York, NY USA. [Overhage, J. Marc] Indiana Univ Sch Med, Indianapolis, IN USA. [Overhage, J. Marc] Regenstrief Inst Hlth Care, Indianapolis, IN 46202 USA. [Racoosin, Judith A.] US FDA, Ctr Drug Evaluat & Res, Silver Spring, MD USA. [Hartzema, Abraham G.] Univ Florida, Coll Pharm, Gainesville, FL USA. RP Ryan, PB (reprint author), Johnson & Johnson Consumer Prod Inc, 1125 Trenton Harbourton Rd,POB 200,MS K304, Titusville, NJ 08560 USA. EM ryan@omop.org FU Foundation for the National Institutes of Health through Abbott; Foundation for the National Institutes of Health through Amgen; Foundation for the National Institutes of Health through AstraZeneca; Foundation for the National Institutes of Health through Bayer Healthcare Pharmaceuticals, Inc.; Foundation for the National Institutes of Health through Pharmaceutical Research Manufacturers of America; Foundation for the National Institutes of Health through Roche; Foundation for the National Institutes of Health through Sanofi; Foundation for the National Institutes of Health through Schering-Plough Corporation; Foundation for the National Institutes of Health through Takeda FX The OMOP is funded by the Foundation for the National Institutes of Health through generous contributions from the following: Abbott, Amgen Inc., AstraZeneca, Bayer Healthcare Pharmaceuticals, Inc., Bristol-Myers Squibb, Eli Lilly & Company, GlaxoSmithKline, Johnson & Johnson, Lundbeck, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc, Pharmaceutical Research Manufacturers of America, Roche, Sanofi, Schering-Plough Corporation, and Takeda. Drs Ryan and Stang are employees of Johnson & Johnson, and Dr. Ryan is a past employee of GlaxoSmithKline. The authors thank and acknowledge the research contributions of the OMOP Distributed Partners, Department of Veterans Affairs Center for Medication Safety/Outcomes Research, Pharmacy Benefits Management Services, Humana Inc., Indiana University-Regenstrief Institute, Massachusetts General Hospital supporting the work of Partners HealthCare System, and SDI Health, who were supported by a grant from the Foundation for the National Institutes of Health. The authors appreciate the thoughtful feedback from the OMOP Executive and Advisory Boards, notably Elizabeth Andrews, Andrew Bate, Jesse Berlin, Jeffrey Brown, Diane MacKinnon, and Judy Staffa. No compensation was given for the reviews. NR 22 TC 77 Z9 77 U1 3 U2 22 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD DEC 30 PY 2012 VL 31 IS 30 SI SI BP 4401 EP 4415 DI 10.1002/sim.5620 PG 15 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 055XJ UT WOS:000312451000021 PM 23015364 ER PT J AU Liu, ST Han, J Nacif, MS Jones, J Kawel, N Kellman, P Sibley, CT Bluemke, DA AF Liu, Songtao Han, Jing Nacif, Marcelo S. Jones, Jacquin Kawel, Nadine Kellman, Peter Sibley, Christopher T. Bluemke, David A. TI Diffuse myocardial fibrosis evaluation using cardiac magnetic resonance T1 mapping: sample size considerations for clinical trials SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article ID EXTRACELLULAR VOLUME FRACTION; AMERICAN-HEART-ASSOCIATION; INVERSION-RECOVERY MOLLI; GD-DTPA; INTRAINDIVIDUAL ASSESSMENT; ENDOMYOCARDIAL BIOPSY; INTERSTITIAL FIBROSIS; CONTRAST ENHANCEMENT; CARDIOMYOPATHY; DISEASE AB Background: Cardiac magnetic resonance (CMR) T1 mapping has been used to characterize myocardial diffuse fibrosis. The aim of this study is to determine the reproducibility and sample size of CMR fibrosis measurements that would be applicable in clinical trials. Methods: A modified Look-Locker with inversion recovery (MOLLI) sequence was used to determine myocardial T1 values pre-, and 12 and 25min post-administration of a gadolinium-based contrast agent at 3 Tesla. For 24 healthy subjects (8 men; 29 +/- 6 years), two separate scans were obtained a) with a bolus of 0.15mmol/kg of gadopentate dimeglumine and b) 0.1mmol/kg of gadobenate dimeglumine, respectively, with averaged of 51 +/- 34 days between two scans. Separately, 25 heart failure subjects (12 men; 63 +/- 14 years), were evaluated after a bolus of 0.15mmol/kg of gadopentate dimeglumine. Myocardial partition coefficient (lambda) was calculated according to (Delta R1myocardium/Delta R1blood), and ECV was derived from lambda by adjusting (1-hematocrit). Results: Mean ECV and lambda were both significantly higher in HF subjects than healthy (ECV: 0.287 +/- 0.034 vs. 0.267 +/- 0.028, p = 0.002; lambda:0.481 +/- 0.052 vs. 442 +/- 0.037, p < 0.001, respectively). The inter-study ECV and. variation were about 2.8 times greater than the intra-study ECV and lambda variation in healthy subjects (ECV: 0.017 vs. 0.006, lambda:0.025 vs. 0.009, respectively). The estimated sample size to detect ECV change of 0.038 or lambda change of 0.063 (corresponding to similar to 3% increase of histological myocardial fibrosis) with a power of 80% and an alpha error of 0.05 for heart failure subjects using a two group design was 27 in each group, respectively. Conclusion: ECV and. quantification have a low variability across scans, and could be a viable tool for evaluating clinical trial outcome. C1 [Liu, Songtao; Nacif, Marcelo S.; Jones, Jacquin; Kawel, Nadine; Sibley, Christopher T.; Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Liu, Songtao; Nacif, Marcelo S.; Sibley, Christopher T.; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Mol Biomed Imaging Lab, Bethesda, MD USA. [Han, Jing] US FDA, Rockville, MD 20857 USA. [Kellman, Peter] NHLBI, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), NIH, Ctr Clin, Bethesda, MD 20892 USA. EM bluemked@cc.nih.gov RI Sibley, Christopher/C-9900-2013; OI Bluemke, David/0000-0002-8323-8086 FU National Institutes of Health (NIH) FX Funded by the National Institutes of Health (NIH) intramural program. NR 47 TC 32 Z9 32 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD DEC 28 PY 2012 VL 14 AR 90 DI 10.1186/1532-429X-14-90 PG 8 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 096BH UT WOS:000315378200003 PM 23272704 ER PT J AU Chen, M Ma, YL Duan, S Xing, H Yao, ST Su, YZ Luo, HB Yang, L Chen, HC Fu, LR Qu, AJ Ou, CY Jia, MH Lu, L AF Chen, Min Ma, Yanling Duan, Song Xing, Hui Yao, Shitang Su, Yingzhen Luo, Hongbing Yang, Li Chen, Huichao Fu, Liru Qu, Aijuan Ou, Chin-Yih Jia, Manhong Lu, Lin TI Genetic diversity and drug resistance among newly diagnosed and antiretroviral treatment-naive HIV-infected individuals in western Yunnan: a hot area of viral recombination in China SO BMC INFECTIOUS DISEASES LA English DT Article DE HIV-1; Genetic diversity; Drug resistance; Injecting drug use; Dehong; China ID SOUTH-EAST ASIA; CIRCULATING RECOMBINANT; TYPE-1 GENOME; PROVINCE; PREVALENCE; MYANMAR; STRAINS; DEHONG; FORMS; B' AB Background: The emergence of an HIV-1 epidemic in China was first recognized in Dehong, western Yunnan. Due to its geographic location, Dehong contributed greatly in bridging HIV-1 epidemics in Southeast Asia and China through drug trafficking and injection drug use; and also extensively to the HIV genetic diversity in Yunnan and China. We attempt to monitor HIV-1 in this area by studying the HIV-1 genetic distribution and transmitted drug resistance (TDR) in various at-risk populations. Methods: Blood samples from a total of 320 newly HIV-1 diagnosed individuals, who were antiretroviral therapy (ART)-naive, were collected from January 2009 to December 2010 in 2 counties in Dehong. HIV-1 subtypes and pol gene drug resistance (DR) mutations were genotyped. Results: Among 299 pol sequences successfully genotyped (93.4%), subtype C accounted for 43.1% (n=129), unique recombinant forms (URFs) for 18.4% (n=55), CRF01_AE for 17.7% (n=54), B for 10.7% (n=32), CRF08_BC for 8.4% (n=25) and CRF07_BC for 1.7% (n=5). Subtype distribution in patients infected by different transmission routes varied. In contract to the previous finding of CRF01_AE predominance in 2002-2006, subtype C predominated in both injecting drug users (IDUs) and heterosexually transmitted populations in this study. Furthermore, we found a high level of BC, CRF01_AE/C and CRF01_AE/B/C recombinants suggesting the presence of active viral recombination in the area. TDR associated mutations were identified in 4.3% (n=13) individuals. A total of 1.3% of DR were related to protease inhibitors (PIs), including I85IV, M46I and L90M; 0.3% to nucleoside reverse transcriptase inhibitors (NRTIs), including M184I; and 2.7% to non-nucleoside reverse transcriptase inhibitors (NNRTIs), including K103N/S, Y181C, K101E and G190A. Conclusion: Our work revealed diverse HIV-1 subtype distributions and intersubtype recombinations. We also identified a low but significant TDR mutation rate among ART-naive patients. These findings enhance our understanding of HIV-1 evolution and are valuable for the development and implementation of a comprehensive public health approach to HIV-1 DR prevention and treatment in the region. C1 [Chen, Min; Ma, Yanling; Su, Yingzhen; Luo, Hongbing; Yang, Li; Chen, Huichao; Fu, Liru; Jia, Manhong; Lu, Lin] Yunnan Ctr Dis Control & Prevent, Yunnan Ctr AIDS STD Control & Prevent, Kunming 650022, Yunnan, Peoples R China. [Duan, Song; Yao, Shitang] Dehong Ctr Dis Control & Prevent, Dept HIV AIDS Control & Prevent, Dehong 678400, Yunnan, Peoples R China. [Xing, Hui] Chinese Ctr Dis Control & Prevent, Natl Ctr AIDS STD Control & Prevent, Beijing 102206, Peoples R China. [Qu, Aijuan] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ou, Chin-Yih] US Ctr Dis Control & Prevent, Global AIDS Program China, Beijing 100600, Peoples R China. RP Jia, MH (reprint author), Yunnan Ctr Dis Control & Prevent, Yunnan Ctr AIDS STD Control & Prevent, Kunming 650022, Yunnan, Peoples R China. EM jmanhong@yahoo.com.cn; lulin@yncdc.cn FU Major Project of China's "Eleventh Five-Years Plan" for Science and Technologies Development [2009ZX10004-902, 2008ZX10001-004]; China Postdoctoral Science Foundation [200902022] FX We acknowledge the NIH Fellows Editorial Board, Serena Fuller and Marc Bulterys for editorial and manuscript preparation assistance. This work was supported by the Major Project of China's "Eleventh Five-Years Plan" for Science and Technologies Development (2009ZX10004-902 and 2008ZX10001-004) and the special grade of the financial support from China Postdoctoral Science Foundation (200902022). NR 30 TC 17 Z9 20 U1 0 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD DEC 28 PY 2012 VL 12 AR 382 DI 10.1186/1471-2334-12-382 PG 8 WC Infectious Diseases SC Infectious Diseases GA 078KV UT WOS:000314098600001 PM 23270497 ER PT J AU Pfister, TD Hollingshead, M Kinders, RJ Zhang, YP Evrard, YA Ji, JP Khin, SA Borgel, S Stotler, H Carter, J Divelbiss, R Kummar, S Pommier, Y Parchment, RE Tomaszewski, JE Doroshow, JH AF Pfister, Thomas D. Hollingshead, Melinda Kinders, Robert J. Zhang, Yiping Evrard, Yvonne A. Ji, Jiuping Khin, Sonny A. Borgel, Suzanne Stotler, Howard Carter, John Divelbiss, Raymond Kummar, Shivaani Pommier, Yves Parchment, Ralph E. Tomaszewski, Joseph E. Doroshow, James H. TI Development and Validation of an Immunoassay for Quantification of Topoisomerase I in Solid Tumor Tissues SO PLOS ONE LA English DT Article ID DNA COVALENT COMPLEXES; PARP INHIBITOR ABT-888; ADP-RIBOSE POLYMERASE; CELL-LINES; CAMPTOTHECIN ACTIVITY; CLEAVAGE COMPLEXES; COLORECTAL-CANCER; ANTICANCER DRUG; PHASE-I; TOPOTECAN AB Background: Topoisomerase I (Top1) is a proven target for cancer therapeutics. Recent data from the Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (FOCUS) trial demonstrated that nuclear staining of Top1 correlates with chemotherapeutic efficacy. Such a correlation may help identify patients likely to respond to Top1 inhibitors and illuminate their mechanism of action. Cellular response to Top1 inhibitors is complex, but Top1 target engagement is a necessary first step in this process. This paper reports the development and validation of a quantitative immunoassay for Top1 in tumors. Methodology/Principal Findings: We have developed and validated a two-site enzyme chemiluminescent immunoassay for quantifying Top1 levels in tumor biopsies. Analytical validation of the assay established the inter-day coefficient of variation at 9.3%+/- 3.4% and a 96.5%+/- 7.3% assay accuracy. Preclinical fit-for-purpose modeling of topotecan time- and dose-effects was performed using topotecan-responsive and -nonresponsive xenografts in athymic nude mice. Higher baseline levels of Top1 were observed in topotecan-responsive than -nonresponsive tumors. Top1 levels reached a maximal decrease 4 to 7 hours following treatment of engrafted mice with topotecan and the indenoisoquinoline NSC 724998. Conclusions/Significance: Our analysis of Top1 levels in control and treated tumors supports the previously proposed mechanism of action for Top1 inhibitor efficacy, wherein higher baseline Top1 levels lead to formation of more covalent-complex-dependent double-strand break damage and, ultimately, cell death. In contrast, xenografts with lower baseline Top1 levels accumulate fewer double-stand breaks, and may be more resistant to Top1 inhibitors. Our results support further investigation into the use of Top1 levels in tumors as a potential predictive biomarker. The Top1 immunoassay described in this paper has been incorporated into a Phase I clinical trial at the National Cancer Institute to assess pharmacodynamic response in tumor biopsies and determine whether baseline Top1 levels are predictive of response to indenoisoquinoline Top1 inhibitors. C1 [Pfister, Thomas D.; Kinders, Robert J.; Khin, Sonny A.; Parchment, Ralph E.] Frederick Natl Lab Canc Res, SAIC Frederick Inc, Appl Dev Res Support Directorate, Lab Human Toxicol & Pharmacol, Frederick, MD USA. [Hollingshead, Melinda] Frederick Natl Lab Canc Res, Biol Testing Branch, Dev Therapeut Program, Frederick, MD USA. [Zhang, Yiping; Ji, Jiuping] Frederick Natl Lab Canc Res, SAIC Frederick Inc, Natl Clin Target Validat Lab, Frederick, MD USA. [Kummar, Shivaani; Tomaszewski, Joseph E.; Doroshow, James H.] NCI, Div Canc Treatment & Diag, Ctr Canc Res, Bethesda, MD 20892 USA. [Pommier, Yves; Doroshow, James H.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Pfister, TD (reprint author), Frederick Natl Lab Canc Res, SAIC Frederick Inc, Appl Dev Res Support Directorate, Lab Human Toxicol & Pharmacol, Frederick, MD USA. EM pfistert@mail.nih.gov FU National Cancer Institute, National Institutes of Health (NIH) [HHSN261200800001E]; Intramural Research Program of the NIH; National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part by federal funds from the National Cancer Institute, National Institutes of Health (NIH), 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. No additional external funding received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 10 Z9 10 U1 0 U2 16 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 DEC 28 PY 2012 VL 7 IS 12 AR e50494 DI 10.1371/journal.pone.0050494 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 064DQ UT WOS:000313051500005 PM 23284638 ER PT J AU Bergeron, SA Hannan, MC Codore, H Fero, K Li, GH Moak, Z Yokogawa, T Burgess, HA AF Bergeron, Sadie A. Hannan, Markus C. Codore, Hiba Fero, Kandice Li, Grace H. Moak, Zachary Yokogawa, Tohei Burgess, Harold A. TI Brain selective transgene expression in zebrafish using an NRSE derived motif SO FRONTIERS IN NEURAL CIRCUITS LA English DT Article DE transgenesis; enhancer trap; ablation; NRSE; rest; zebrafish ID TOL2 TRANSPOSABLE ELEMENT; SODIUM-CHANNEL GENE; IN-VIVO; TARGET GENES; SILENCER ELEMENT; LARVAL ZEBRAFISH; NEURAL CIRCUITRY; ENHANCER TRAP; CELL ABLATION; NEURONS AB Transgenic technologies enable the manipulation and observation of circuits controlling behavior by permitting expression of genetically encoded reporter genes in neurons. Frequently though, neuronal expression is accompanied by transgene expression in non-neuronal tissues, which may preclude key experimental manipulations, including assessment of the contribution of neurons to behavior by ablation. To better restrict transgene expression to the nervous system in zebrafish larvae, we have used DNA sequences derived from the neuron-restrictive silencing element (NRSE). We find that one such sequence, REx2, when used in conjunction with several basal promoters, robustly suppresses transgene expression in non-neuronal tissues. Both in transient transgenic experiments and in stable enhancer trap lines, suppression is achieved without compromising expression within the nervous system. Furthermore, in REx2 enhancer trap lines non-neuronal expression can be de-repressed by knocking down expression of the NRSE binding protein RE1-silencing transcription factor (Rest). In one line, we show that the resulting pattern of reporter gene expression coincides with that of the adjacent endogenous gene, hapln3. We demonstrate that three common basal promoters are susceptible to the effects of the REx2 element, suggesting that this method may be useful for confining expression from many other promoters to the nervous system. This technique enables neural specific targeting of reporter genes and thus will facilitate the use of transgenic methods to manipulate circuit function in freely behaving larvae. C1 [Bergeron, Sadie A.; Hannan, Markus C.; Codore, Hiba; Fero, Kandice; Li, Grace H.; Moak, Zachary; Yokogawa, Tohei; Burgess, Harold A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, Unit Behav Neurogenet, Bethesda, MD USA. RP Burgess, HA (reprint author), NICHHD, Program Genom Differentiat, Bldg 6B,Room 308,6 Ctr Dr, Bethesda, MD 20892 USA. EM burgessha@mail.nih.gov RI Burgess, Harold/B-8474-2015; OI Burgess, Harold/0000-0003-1966-7801; Bergeron, Sadie/0000-0002-1238-8730 FU Intramural Research Program of the National Institute of Child Health and Human Development FX The authors thank Ben White for a critical reading of the manuscript and members of the Weinstein lab for advice on vasculature. This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development. NR 68 TC 10 Z9 10 U1 0 U2 11 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1662-5110 J9 FRONT NEURAL CIRCUIT JI Front. Neural Circuits PD DEC 28 PY 2012 VL 6 AR 110 DI 10.3389/fncir.2012.00110 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 062IL UT WOS:000312912600001 PM 23293587 ER PT J AU Kargl, J Balenga, N Parzmair, GP Brown, AJ Heinemann, A Waldhoer, M AF Kargl, Julia Balenga, Nariman Parzmair, Gerald P. Brown, Andrew J. Heinemann, Akos Waldhoer, Maria TI The Cannabinoid Receptor CB1 Modulates the Signaling Properties of the Lysophosphatidylinositol Receptor GPR55 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; DELTA-OPIOID RECEPTORS; L-ALPHA-LYSOPHOSPHATIDYLINOSITOL; CANCER-CELL PROLIFERATION; INTERNATIONAL UNION; IN-VIVO; HETERODIMERIZATION; IDENTIFICATION; ACTIVATION; MU AB The G protein-coupled receptor (GPCR) 55 (GPR55) and the cannabinoid receptor 1 (CB1R) are co-expressed in many tissues, predominantly in the central nervous system. Seven transmembrane spanning (7TM) receptors/GPCRs can form homo-and heteromers and initiate distinct signaling pathways. Recently, several synthetic CB1 receptor inverse agonists/antagonists, such as SR141716A, AM251, and AM281, were reported to activate GPR55. Of these, SR141716A was marketed as a promising anti-obesity drug, but was withdrawn from the market because of severe side effects. Here, we tested whether GPR55 and CB1 receptors are capable of (i) forming heteromers and (ii) whether such heteromers could exhibit novel signaling patterns. We show that GPR55 and CB1 receptors alter each others signaling properties in human embryonic kidney (HEK293) cells. We demonstrate that the co-expression of FLAG-CB1 receptors in cells stably expressing HA-GPR55 specifically inhibits GPR55-mediated transcription factor activation, such as nuclear factor of activated T-cells and serum response element, as well as extracellular signal-regulated kinases (ERK1/2) activation. GPR55 and CB1 receptors can form heteromers, but the internalization of both receptors is not affected. In addition, we observe that the presence of GPR55 enhances CB1R-mediated ERK1/2 and nuclear factor of activated T-cell activation. Our data provide the first evidence that GPR55 can form heteromers with another 7TM/GPCR and that this interaction with the CB1 receptor has functional consequences in vitro. The GPR55-CB1R heteromer may play an important physiological and/or pathophysiological role in tissues endogenously co-expressing both receptors. C1 [Kargl, Julia; Balenga, Nariman; Parzmair, Gerald P.; Heinemann, Akos; Waldhoer, Maria] Med Univ Graz, Inst Expt & Clin Pharmacol, A-8010 Graz, Austria. [Brown, Andrew J.] GlaxoSmithKline, Med Res Ctr, Dept Screening & Compound Profiling, Stevenage SG1 2NY, Herts, England. [Balenga, Nariman] NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Kargl, J (reprint author), Med Univ Graz, Inst Expt & Clin Pharmacol, A-8010 Graz, Austria. EM julia.kargl@medunigraz.at; mriw@novonordisk.com RI Aghaei Balenga, Nariman/A-5895-2011; OI Aghaei Balenga, Nariman/0000-0002-2741-9595; Parzmair, Gerald/0000-0002-7915-6758; Heinemann, Akos/0000-0002-8554-2372 FU Austrian Science Fund [P18723, P22521]; Jubilaumsfonds of the Austrian National Bank Grant [12552]; Lanyar Stiftung; Medical University of Graz; Austrian Government; START-Funding Program (MUG); BA/CA visiting scientist program FX This work was supported by Austrian Science Fund Grants P18723 (to M. W.) and P22521 (to A. H.), Jubilaumsfonds of the Austrian National Bank Grant 12552 (to M. W.), grants form the Lanyar Stiftung (to M. W.), and the Ph.D. program Molecular Medicine from the Medical University of Graz, a research fellowship from the Austrian Government, the START-Funding Program (MUG), and the BA/CA visiting scientist program (to J. K.). NR 66 TC 24 Z9 26 U1 1 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 28 PY 2012 VL 287 IS 53 BP 44234 EP 44248 DI 10.1074/jbc.M112.364109 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 062RI UT WOS:000312938600022 PM 23161546 ER PT J AU Andrew, AJ Berndsen, CE Kao, S Strebel, K AF Andrew, Amy J. Berndsen, Christopher E. Kao, Sandra Strebel, Klaus TI The Size and Conservation of a Coiled-coil Structure in the Ectodomain of Human BST-2/Tetherin Is Dispensable for Inhibition of HIV-1 Virion Release SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CLATHRIN-MEDIATED ENDOCYTOSIS; ANTI-TETHERIN ACTIVITIES; CELL-SURFACE; OLIGOMERIZATION STATE; MOLECULAR-CLONING; PARTICLE RELEASE; DOWN-MODULATION; VIRUS RELEASE; LIPID RAFTS; VPU PROTEIN AB BST-2/CD317/tetherin is a host factor that inhibits HIV-1 release and is counteracted by HIV-1 Vpu. Structural studies indicate that the BST-2 ectodomain assumes a coiled-coil conformation. Here we studied the role of the BST-2 ectodomain for tethering function. First, we addressed the importance of the length and structure of the ectodomain by adding or substituting heterologous coiled-coil or non-coiled-coil sequences. We found that extending or replacing the BST-2 ectodomain using non-coiled-coil sequences resulted in loss of BST-2 function. Doubling the size of the BST-2 ectodomain by insertion of a heterologous coiled-coil motif or substituting the BST-2 coiled-coil domain with a heterologous coiled-coil motif maintained tethering function. Reductions in the size of the BST-2 coiled-coil domain were tolerated as well. In fact, deletion of the C-terminal half of the BST-2 ectodomain, including a series of seven consecutive heptad motifs did not abolish tethering function. However, slight changes in the positioning of deletions affecting the relative placing of charged or hydrophobic residues on the helix severely impacted the functional properties of BST-2. Overall, we conclude that the size of the BST-2 ectodomain is highly flexible and can be reduced or extended as long as the positioning of residues important for the stability of the dimer interface is maintained. C1 [Andrew, Amy J.; Kao, Sandra; Strebel, Klaus] NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Berndsen, Christopher E.] James Madison Univ, Dept Chem & Biochem, Harrisonburg, VA 22807 USA. RP Strebel, K (reprint author), NIAID, Viral Biochem Sect, Mol Microbiol Lab, NIH, Bldg 4,Rm 310,4 Ctr Dr MSC 0460, Bethesda, MD 20892 USA. EM kstrebel@nih.gov OI Berndsen, Christopher/0000-0002-4285-4341 FU Intramural Research Program of the NIAID, National Institutes of Health FX This work was supported by the Intramural Research Program of the NIAID, National Institutes of Health. NR 58 TC 7 Z9 7 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 DEC 28 PY 2012 VL 287 IS 53 BP 44278 EP 44288 DI 10.1074/jbc.M112.418822 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 062RI UT WOS:000312938600026 PM 23152502 ER PT J AU Andre, P Wang, QY Wang, N Gao, B Schilit, A Halford, MM Stacker, SA Zhang, XM Yang, YZ AF Andre, Philipp Wang, Qianyi Wang, Na Gao, Bo Schilit, Arielle Halford, Michael M. Stacker, Steven A. Zhang, Xuemin Yang, Yingzi TI The Wnt Coreceptor Ryk Regulates Wnt/Planar Cell Polarity by Modulating the Degradation of the Core Planar Cell Polarity Component Vangl2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR TYROSINE KINASE; NEURAL-TUBE DEFECTS; CONVERGENT EXTENSION MOVEMENTS; RECESSIVE ROBINOW-SYNDROME; BRACHYDACTYLY TYPE-B; ZEBRAFISH GASTRULATION; AXON GUIDANCE; HAIR-CELLS; PATHWAY; ROR2 AB The Wnt signaling pathways control many critical developmental and adult physiological processes. In vertebrates, one fundamentally important function of Wnts is to provide directional information by regulating the evolutionarily conserved planar cell polarity (PCP) pathway during embryonic morphogenesis. However, despite the critical roles of Wnts and PCP in vertebrate development and disease, little is known about the molecular mechanisms underlying Wnt regulation of PCP. Here, we have found that the receptor-like tyrosine kinase (Ryk), a Wnt5a-binding protein required in axon guidance, regulates PCP signaling. We show that Ryk interacts with Vangl2 genetically and biochemically, and such interaction is potentiated by Wnt5a. Loss of Ryk in a Vangl2(+/-) background results in classic PCP defects, including open neural tube, misalignment of sensory hair cells in the inner ear, and shortened long bones in the limbs. Complete loss of both Ryk and Vangl2 results in more severe phenotypes that resemble the Wnt5a(-/-) mutant in many aspects such as shortened anterior-posterior body axis, limb, and frontonasal process. Our data identify the Wnt5a-binding protein Ryk as a general regulator of the mammalian Wnt/PCP signaling pathway. We show that Ryk transduces Wnt5a signaling by forming a complex with Vangl2 and that Ryk regulates PCP by at least in part promoting Vangl2 stability. As human mutations in WNT5A and VANGL2 are found to cause Robinow syndrome and neural tube defects, respectively, our results further suggest that human mutations in RYK may also be involved in these diseases. C1 [Andre, Philipp; Gao, Bo; Schilit, Arielle; Yang, Yingzi] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA. [Wang, Qianyi; Wang, Na; Zhang, Xuemin] China Natl Ctr Biomed Anal, Inst Basic Med Sci, State Key Lab Prote, Beijing 100850, Peoples R China. [Halford, Michael M.; Stacker, Steven A.] Peter MacCallum Canc Ctr, Tumour Angiogenesis Program, Melbourne, Vic 3002, Australia. [Stacker, Steven A.] Univ Melbourne, Sir Peter MacCallum Dept Oncol, Parkville, Vic 3010, Australia. RP Yang, YZ (reprint author), NHGRI, Genet Dis Res Branch, 49 Convent Dr,MSC 4472, Bethesda, MD 20892 USA. EM yingzi@mail.nih.gov FU intramural research program of National Human Genome Research Institute; National Health and Medical Research Council of Australia FX This work was supported by the intramural research program of National Human Genome Research Institute and by the National Health and Medical Research Council of Australia. NR 45 TC 35 Z9 36 U1 0 U2 23 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 DEC 28 PY 2012 VL 287 IS 53 BP 44518 EP 44525 DI 10.1074/jbc.M112.414441 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 062RI UT WOS:000312938600048 PM 23144463 ER PT J AU Khan, SH Awasthi, S Guo, CH Goswami, D Ling, J Griffin, PR Simons, SS Kumar, R AF Khan, Shagufta H. Awasthi, Smita Guo, Chunhua Goswami, Devrishi Ling, Jun Griffin, Patrick R. Simons, S. Stoney, Jr. Kumar, Raj TI Binding of the N-terminal Region of Coactivator TIF2 to theIntrinsically Disordered AF1 Domain of the Glucocorticoid Receptor Is Accompanied by Conformational Reorganizations SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEAR HORMONE-RECEPTORS; CALF THYMUS DNA; TRANSCRIPTIONAL ACTIVITY; COREPRESSOR BINDING; CHROMATIN ACCESSIBILITY; TRANSACTIVATION DOMAIN; PROGESTERONE-RECEPTOR; ANTAGONIST COMPLEXES; INDUCTION PROPERTIES; SECONDARY STRUCTURE AB Control of gene transcription by glucocorticoid receptors (GRs) is important for many physiological processes. Like other steroid hormone receptors, the regulation of target genes by GR is mediated by two transactivation domains: activation function 1 (AF1) in the N-terminal domain and AF2 in the C-terminal ligand-binding domain (LBD). Full receptor activity requires both AF1 and -2 plus assorted coregulatory proteins. Crystal structures of the ligand-bound LBD have provided insight regarding how AF2 interacts with specific coactivators. However, despite its being the major activation domain of GRs, knowledge of AF1 structure/function has languished. This is mainly because of the highly disorganized structure of the GR N-terminal domain. This lack of AF1 structure is shared by all members of the steroid/nuclear receptor superfamily for which it has been examined and AF1 is thought to allow productive interactions with assorted cofactors via protein-induced changes in secondary/tertiary structures. To date, there are no reports of a classical coactivator altering the secondary/tertiary structure of the GR AF1 domain. Earlier, we reported an N-terminal fragment of the p160 coactivator TIF2, called TIF2.0, that binds the GR N-terminal domain and alters GR transcriptional activity. We therefore proposed that TIF2.0 binding to AF1 changes both its conformation and transcriptional activity. We now report that TIF2.0 interacts with the GR AF1 domain to increase the amount of alpha-helical structure in the complex. Furthermore, TIF2 coactivator activity is observed in the absence of the GR LBD in a manner that requires the AF1 domain. This contrasts with previous models where TIF2 receptor interaction domains binding to GR LBD somehow alter AF1 conformation. Our results establish for the first time that coactivators can modify the structure of the AF1 domain directly via the binding of a second region of the coactivator and suggest a molecular explanation for how coactivators increase the transcriptional activity of GR-agonist complexes. C1 [Khan, Shagufta H.; Ling, Jun; Kumar, Raj] Commonwealth Med Coll, Dept Basic Sci, Scranton, PA 18509 USA. [Simons, S. Stoney, Jr.] NIDDK, Steroid Hormones Sect, LERB, NIH,CEB, Bethesda, MD 20892 USA. [Goswami, Devrishi; Griffin, Patrick R.] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL 33458 USA. RP Simons, SS (reprint author), NIDDK, Steroid Hormones Sect, LERB, NIH,CEB, Bldg 10,Rm 8N-307B, Bethesda, MD 20892 USA. EM stoneys@helix.nih.gov; rkumar@tcmedc.org RI Guo, Chunhua/N-2586-2014 FU National Institutes of Health Intramural Research Program of the NIDDK FX This work was supported in part by the National Institutes of Health Intramural Research Program of the NIDDK (to S. S. S., Jr.). NR 71 TC 15 Z9 15 U1 0 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 28 PY 2012 VL 287 IS 53 BP 44546 EP 44560 DI 10.1074/jbc.M112.411330 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 062RI UT WOS:000312938600051 PM 23132854 ER PT J AU Bachu, M Yalla, S Asokan, M Verma, A Neogi, U Sharma, S Murali, RV Mukthey, AB Bhatt, R Chatterjee, S Rajan, RE Cheedarla, N Yadavalli, VS Mahadevan, A Shankar, SK Rajagopalan, N Shet, A Saravanan, S Balakrishnan, P Solomon, S Vajpayee, M Satish, KS Kundu, TK Jeang, KT Ranga, U AF Bachu, Mahesh Yalla, Swarupa Asokan, Mangaiarkarasi Verma, Anjali Neogi, Ujjwal Sharma, Shilpee Murali, Rajesh V. Mukthey, Anil Babu Bhatt, Raghavendra Chatterjee, Snehajyoti Rajan, Roshan Elizabeth Cheedarla, Narayana Yadavalli, Venkat S. Mahadevan, Anita Shankar, Susarla K. Rajagopalan, Nirmala Shet, Anita Saravanan, Shanmugam Balakrishnan, Pachamuthu Solomon, Suniti Vajpayee, Madhu Satish, Kadappa Shivappa Kundu, Tapas K. Jeang, Kuan-Teh Ranga, Udaykumar TI Multiple NF-kappa B Sites in HIV-1 Subtype C Long Terminal Repeat Confer Superior Magnitude of Transcription and Thereby the Enhanced Viral Predominance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; CLADE-SPECIFIC DIFFERENCES; SP1 BINDING-ELEMENTS; GENE-EXPRESSION; TAT PROTEIN; WIDE-RANGE; T-CELLS; INFECTION; REPLICATION; IDENTIFICATION AB Wedemonstrate that at least three different promoter variant strains of HIV-1 subtype C have been gradually expanding and replacing the standard subtype C viruses in India, and possibly in South Africa and other global regions, over the past decade. The new viral strains contain an additional NF-kappa B, NF-kappa B-like, or RBEIII site in the viral promoter. Although the acquisition of an additional RBEIII site is a property shared by all the HIV-1 subtypes, acquiring an additional NF-kappa B site remains an exclusive property of subtype C. The acquired kappa B site is genetically distinct, binds the p50-p65 heterodimer, and strengthens the viral promoter at the levels of transcription initiation and elongation. The 4-kappa B viruses dominate the 3-kappa B "isogenic" viral strains in pairwise competition assays in T-cell lines, primary cells, and the ecotropic human immunodeficiency virus mouse model. The dominance of the 4-kappa B viral strains is also evident in the natural context when the subjects are coinfected with kappa B-variant viral strains. The mean plasma viral loads, but not CD4 counts, are significantly different in 4-kappa B infection suggesting that these newly emerging strains are probably more infectious. It is possible that higher plasma viral loads underlie selective transmission of the 4-kappa B viral strains. Several publications previously reported duplication or deletion of diverse transcription factor-binding sites in the viral promoter. Unlike previous reports, our study provides experimental evidence that the new viral strains gained a potential selective advantage as a consequence of the acquired transcription factor-binding sites and importantly that these strains have been expanding at the population level. C1 [Neogi, Ujjwal; Shet, Anita] St Johns Natl Acad Hlth Sci, Bengaluru 560034, India. [Bhatt, Raghavendra; Rajagopalan, Nirmala] Freedom Fdn, Bengaluru 560043, India. [Chatterjee, Snehajyoti; Kundu, Tapas K.] Jawaharlal Nehru Ctr Adv Sci Res, Mol Biol & Genet Unit, Transcript & Dis Lab, Bengaluru 560064, India. [Bachu, Mahesh; Yalla, Swarupa; Asokan, Mangaiarkarasi; Verma, Anjali; Sharma, Shilpee; Murali, Rajesh V.; Mukthey, Anil Babu; Rajan, Roshan Elizabeth; Cheedarla, Narayana; Ranga, Udaykumar] Jawaharlal Nehru Ctr Adv Sci Res, Mol Biol & Genet Unit, HIV AIDS Lab, Bengaluru 560064, India. [Yadavalli, Venkat S.; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Mahadevan, Anita; Shankar, Susarla K.] Natl Inst Mental Hlth & Neurosci, Dept Neuropathol, Bengaluru 560029, India. [Saravanan, Shanmugam; Balakrishnan, Pachamuthu; Solomon, Suniti] YRG Ctr AIDS Res & Educ, Madras 600113, Tamil Nadu, India. [Vajpayee, Madhu] All India Inst Med Sci, Dept Microbiol, HIV & Immunol Div, New Delhi 110029, India. [Satish, Kadappa Shivappa] Seva Free Clin, Bengaluru 560010, India. [Satish, Kadappa Shivappa] Chest & Matern Ctr, Bengaluru 560010, India. RP Ranga, U (reprint author), Jawaharlal Nehru Ctr Adv Sci Res, Mol Biol & Genet Unit, HIV AIDS Lab, Jakkur PO, Bangalore 560064, Karnataka, India. EM udaykumar@jncasr.ac.in RI Neogi, Ujjwal/E-4274-2012; OI Neogi, Ujjwal/0000-0002-0844-3338; Shet, Anita/0000-0002-7204-8164; sharma, shilpee/0000-0003-4645-9442 FU Freedom Foundation were generated at the Foundation's Center for HIV/AIDS Medicine and Research at Bengaluru, India; Department of BioTechnology, Government of India [BT/01CEIB/10/III/01]; intramural funds from Jawaharlal Nehru Centre for Advanced Scientific Research FX Several reagents were obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, NIAID, National Institutes of Health. We thank Drs. Vinayaka Prasad and Brian Wigdahl for critical reading of the manuscript. The clinical samples provide by the Freedom Foundation were generated at the Foundation's Center for HIV/AIDS Medicine and Research at Bengaluru, India, funded through a unique partnership with the Institute for Molecular Medicine and Infectious Disease at the Drexel University College of Medicine in Philadelphia, PA, under the direction of Dr. Brian Wigdahl.; This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported by the Department of BioTechnology, Government of India (Chromatin and Disease) Program Support Grant BT/01CEIB/10/III/01 and intramural funds from Jawaharlal Nehru Centre for Advanced Scientific Research (to T. K. K. and U. R.). NR 73 TC 21 Z9 21 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 DEC 28 PY 2012 VL 287 IS 53 BP 44714 EP 44735 DI 10.1074/jbc.M112.397158 PG 22 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 062RI UT WOS:000312938600067 PM 23132857 ER PT J AU Driscoll, JJ De Chowdhury, R AF Driscoll, James J. De Chowdhury, Roopa TI Molecular crosstalk between the proteasome, aggresomes and autophagy: Translational potential and clinical implications SO CANCER LETTERS LA English DT Review DE Ubiquitin; Proteasome; Bortezomib; Aggresome; Autophagy ID HISTONE DEACETYLASE INHIBITORS; QUALITY-CONTROL AUTOPHAGY; DOUBLE-EDGED-SWORD; SELECTIVE AUTOPHAGY; MULTIPLE-MYELOMA; CANCER-THERAPY; HEPATOCELLULAR-CARCINOMA; UBIQUITINATED TARGETS; PROTEIN-DEGRADATION; TUMOR XENOGRAFTS AB Targeting the ubiquitin+proteasome protein degradation pathway with the therapeutic agent bortezomib has significantly improved the survival of cancer patients but drug resistance inevitably develops. Aggresomes and the autophagy pathway serve as compensatory protein-clearance mechanisms that eradicate potentially toxic proteins to promote resistance to proteasome inhibitors and, hence, tumor survival. Preclinical evidence has emerged to demonstrate active crosstalk between these protein degradation pathways and has revealed novel therapeutic targets and strategies. Translational research and clinical trials are now focused on these pathways to prevent the emergence of drug resistance, enhance apoptosis and further improve the survival of cancer patients. Published by Elsevier Ireland Ltd. C1 [Driscoll, James J.] Univ Cincinnati, Coll Med, Div Hematol & Oncol, Cincinnati, OH 45267 USA. [Driscoll, James J.] Univ Cincinnati, Vontz Ctr Mol Studies, Cincinnati, OH 45267 USA. [De Chowdhury, Roopa] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Driscoll, JJ (reprint author), Univ Cincinnati, Coll Med, Div Hematol & Oncol, Cincinnati, OH 45267 USA. EM driscojs@uc.edu NR 92 TC 18 Z9 19 U1 1 U2 30 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD DEC 28 PY 2012 VL 325 IS 2 BP 147 EP 154 DI 10.1016/j.canlet.2012.06.016 PG 8 WC Oncology SC Oncology GA 007QZ UT WOS:000308904500005 PM 22781397 ER PT J AU Gudmundsdottir, ET Barkardottir, RB Arason, A Gunnarsson, H Amundadottir, LT Agnarsson, BA Johannsson, OT Reynisdottir, I AF Gudmundsdottir, Eydis Th Barkardottir, Rosa B. Arason, Adalgeir Gunnarsson, Haukur Amundadottir, Laufey Th Agnarsson, Bjarni A. Johannsson, Oskar Th Reynisdottir, Inga TI The risk allele of SNP rs3803662 and the mRNA level of its closest genes TOX3 and LOC643714 predict adverse outcome for breast cancer patients SO BMC CANCER LA English DT Article DE TOX3; LOC643714; rs380662; Risk allele; Breast cancer; Clinical; Pathological; Survival; Oestrogen receptor ID COMPARATIVE GENOMIC HYBRIDIZATION; BRCA2 MUTATION CARRIERS; AFRICAN-AMERICAN WOMEN; SUSCEPTIBILITY LOCI; DEPENDENT TRANSCRIPTION; WIDE ASSOCIATION; VARIANTS; SUBTYPES; PREDISPOSITION; POLYMORPHISMS AB Background: The minor allele of SNP rs3803662 has been shown to correlate with increased breast cancer risk and with lower expression of TOX3. The SNP is closely located to TOX3 residing within an uncharacterised gene LOC643714. The aim of the study was to examine the association of the risk allele with expression of TOX3 and LOC643714, and of mRNA levels and genotype with clinical and pathological characteristics. Methods: The SNP was genotyped in DNA isolated from blood and normal tissue from 160 breast cancer patients and mRNA levels were measured by microarrays and quantitative real-time (qRT)-PCR in breast tumours. Association with clinical and pathological characteristics was analysed by parametric tests. Results: An association of the risk allele of rs3803662 with lower TOX3 expression was confirmed in oestrogen receptor (ER) positive tumours. It was more often observed in lobular tumours (p = 0.04), and carriers of the risk allele who had been diagnosed with luminal A tumours had shorter overall survival (OS) than carriers of the non-risk allele (p = 0.01). Positive correlation between the mRNA levels of TOX3 and LOC643714 was observed (r = 0.44 and p < 0.001). Association analysis with tumour pathology showed that low TOX3 and LOC643714 expression correlated with high Ki67 levels (p = 0.026 and p = 0.002) and the basal subtype (p < 0.001 and p < 0.001), whereas high expression correlated with ER (p = 0.004 and p < 0.001) and progesterone receptor (PgR) (p = 0.005 and p < 0.001) expression. Furthermore, high TOX3 and LOC643714 correlated with positive lymph nodes (p < 0.001 and p = 0.01). Patients with ER positive tumours and high levels of TOX3 mRNA had shorter overall-and distant metastasis free-survival (p = 0.017 and p = 0.021), an effect mostly attributable to patients with luminal B tumours. Conclusions: The results suggest that the effect of the risk allele of rs3803662 is strongest in luminal A tumours and that the expression levels of TOX3 and/or LOC643714 affect the progression of breast cancer. The effect may vary depending on the subtype and developmental stage of the tumour. C1 [Gudmundsdottir, Eydis Th; Barkardottir, Rosa B.; Arason, Adalgeir; Gunnarsson, Haukur; Agnarsson, Bjarni A.; Reynisdottir, Inga] Landspitali Univ Hosp, Dept Pathol, IS-101 Reykjavik, Iceland. [Barkardottir, Rosa B.; Arason, Adalgeir; Agnarsson, Bjarni A.; Johannsson, Oskar Th] Univ Iceland, BMC, Fac Med, IS-101 Reykjavik, Iceland. [Amundadottir, Laufey Th] NCI, US Dept HHS, Lab Translat Genom, Div Canc Epidemiol & Genet,NIH, Bethesda, MD 20892 USA. [Johannsson, Oskar Th] Landspitali Univ Hosp, Dept Oncol, IS-101 Reykjavik, Iceland. RP Reynisdottir, I (reprint author), Landspitali Univ Hosp, Dept Pathol, IS-101 Reykjavik, Iceland. EM ingar@landspitali.is RI Amundadottir, Laufey/L-7656-2016; OI Amundadottir, Laufey/0000-0003-1859-8971; Arason, Adalgeir/0000-0003-0480-886X FU Landspitali-University Hospital Research Fund; "Gongum saman", a supporting group for breast cancer research in Iceland FX This work was funded by the Landspitali-University Hospital Research Fund and "Gongum saman", a supporting group for breast cancer research in Iceland. NR 42 TC 12 Z9 14 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD DEC 27 PY 2012 VL 12 AR 621 DI 10.1186/1471-2407-12-621 PG 10 WC Oncology SC Oncology GA 079XP UT WOS:000314205800001 PM 23270421 ER PT J AU Reynolds, SJ Sendagire, H Newell, K Castelnuovo, B Nankya, I Kamya, M Quinn, TC Manabe, YC Kambugu, A AF Reynolds, Steven J. Sendagire, Hakim Newell, Kevin Castelnuovo, Barbara Nankya, Immaculate Kamya, Moses Quinn, Thomas C. Manabe, Yukari C. Kambugu, Andrew TI Virologic versus immunologic monitoring and the rate of accumulated genotypic resistance to first-line antiretroviral drugs in Uganda SO BMC INFECTIOUS DISEASES LA English DT Article DE HIV-1; Antiretroviral therapy; Drug resistance ID RESOURCE-LIMITED SETTINGS; NON-INFERIORITY TRIAL; TREATMENT FAILURE; SOUTH-AFRICA; THERAPY; CRITERIA; ZIDOVUDINE; MUTATIONS; MORTALITY; ADULTS AB Background: Viral load monitoring (VLM) to identify individuals failing antiretroviral therapy (ART) is not widely available in resource-limited settings. We compared the genotypic resistance patterns between clients with VLM versus immunological monitoring (IM). Methods: Between 2004-2008, 559 ART naive clients were enrolled in a prospective cohort, initiated on ART, and monitored with viral load (VL) and CD4+ cell counts every 6 months (VLM group). From February 2008 through June 2009, 998 clients on ART for 36-40 months (corresponding to the follow-up time of the VLM group) at the same clinic and monitored with CD4+ cell counts every 6 months were recruited into a cross sectional study (IM group). Samples from VLM clients at 12, 24 and 36 months and IM clients at 36-40 months with VL > 2000 copies/ml underwent genotypic drug resistance testing. Results: Baseline characteristics were similar. Virologic failure (VL > 400 copies/ml) at 12, 24 and 36 months in the VLM group were 12%, 6% and 8% respectively, and in the IM group 10% at 36-40 months. Samples from 39 VLM and 70 IM clients were genotyped. 23/39 (59%) clients in the VLM group (at 12, 24 or 36 months) compared to 63/70 (90%) in the IM group, (P < 0.0001) had at least 1 non-nucleoside reverse transcriptase mutation. 19/39 (49%) of VLM clients had an M184V mutation compared to 61/70 (87%) in the IM group (P < 0.0001). Only 2/39 (5%) of VLM clients developed thymidine analogue mutations compared to 34/70 (49%) of IM clients (P < 0.0001). Conclusions: Routine VL monitoring reduced the rate of accumulated genotypic resistance to commonly used ART in Uganda. C1 [Reynolds, Steven J.; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Reynolds, Steven J.; Quinn, Thomas C.; Manabe, Yukari C.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Sendagire, Hakim] Uganda Minist Hlth, Kampala, Uganda. [Sendagire, Hakim] Makerere Univ, Coll Hlth Sci, Dept Microbiol, Kampala, Uganda. [Newell, Kevin] SAIC Frederick Inc, Clin Res Directorate, Clin Monitoring Res Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Castelnuovo, Barbara; Kamya, Moses; Manabe, Yukari C.; Kambugu, Andrew] Makerere Univ, Coll Hlth Sci, Infect Dis Inst, Kampala, Uganda. [Nankya, Immaculate] Joint Clin Res Ctr, Kampala, Uganda. [Reynolds, Steven J.] NIAID NIH ICER Program, Kampala, Uganda. RP Reynolds, SJ (reprint author), NIAID, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sjreynolds@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This research was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. 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. 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. NR 24 TC 11 Z9 11 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2334 J9 BMC INFECT DIS JI BMC Infect. Dis. PD DEC 27 PY 2012 VL 12 AR 381 DI 10.1186/1471-2334-12-381 PG 8 WC Infectious Diseases SC Infectious Diseases GA 080HV UT WOS:000314233200001 PM 23270482 ER PT J AU Kahn, J Tofilon, PJ Camphausen, K AF Kahn, Jenna Tofilon, Philip J. Camphausen, Kevin TI Preclinical models in radiation oncology SO RADIATION ONCOLOGY LA English DT Review DE Preclinical models; Radiation oncology; Radiosensitizer; Orthotopic xenograft model ID MOUSE MODEL; IONIZING-RADIATION; HUMAN GLIOBLASTOMA; GENE-EXPRESSION; BRAIN-TUMORS; IN-VITRO; CANCER; GLIOMA; EFFICACY; GROWTH AB As the incidence of cancer continues to rise, the use of radiotherapy has emerged as a leading treatment modality. Preclinical models in radiation oncology are essential tools for cancer research and therapeutics. Various model systems have been used to test radiation therapy, including in vitro cell culture assays as well as in vivo ectopic and orthotopic xenograft models. This review aims to describe such models, their advantages and disadvantages, particularly as they have been employed in the discovery of molecular targets for tumor radiosensitization. Ultimately, any model system must be judged by its utility in developing more effective cancer therapies, which is in turn dependent on its ability to simulate the biology of tumors as they exist in situ. Although every model has its limitations, each has played a significant role in preclinical testing. Continued advances in preclinical models will allow for the identification and application of targets for radiation in the clinic. C1 [Kahn, Jenna; Tofilon, Philip J.; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Kahn, Jenna] Brown Univ, Warren Alpert Sch Med, Providence, RI 02912 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,CRC Rm B2-3561, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov NR 23 TC 15 Z9 15 U1 1 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-717X J9 RADIAT ONCOL JI Radiat. Oncol. PD DEC 27 PY 2012 VL 7 AR 223 DI 10.1186/1748-717X-7-223 PG 5 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 076TZ UT WOS:000313982300002 PM 23270380 ER PT J AU Cinelli, MA Reddy, PVN Lv, PC Liang, JH Chen, L Agama, K Pommier, Y van Breemen, RB Cushman, M AF Cinelli, Mans A. Reddy, P. V. Narasimha Lv, Peng-Cheng Liang, Jian-Hua Chen, Lian Agama, Keli Pommier, Yves van Breemen, Richard B. Cushman, Mark TI Identification, Synthesis, and Biological Evaluation of Metabolites of the Experimental Cancer Treatment Drugs Indotecan (LMP400) and Indimitecan (LMP776) and Investigation of Isomerically Hydroxylated Indenoisoquinoline Analogues as Topoisomerase I Poisons SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PLANT ANTITUMOR AGENTS; DNA CLEAVAGE; CAMPTOTHECIN ANALOGS; GENETIC ALGORITHM; ANTICANCER DRUGS; O-DEMETHYLATION; INHIBITORS; DERIVATIVES; COMPLEXES; RING AB Hydroxylated analogues of the anticancer topoisomerase I (Top1) inhibitors indotecan (LMP400) and indimitecan (LMP776) have been prepared because (1) a variety of potent Top1 poisons are known that contain strategically placed hydroxyl groups, which provides a clear rationale for incorporating them in the present case, and (2) the hydroxylated compounds could conceivably serve as synthetic standards for the identification of metabolites. Indeed, incubating LMP400 and LMP776 with human liver microsomes resulted in two major metabolites of each drug, which had HPLC retention times and mass fragmentation patterns identical to those of the synthetic standards. The hydroxylated indotecan and indimitecan metabolites and analogues were tested as Top1 poisons and for antiproliferative activity in a variety of human cancer cell cultures and in general were found to be very potent. Differences in activity resulting from the placement of the hydroxyl group are explained by molecular modeling analyses. C1 [Cinelli, Mans A.; Reddy, P. V. Narasimha; Lv, Peng-Cheng; Liang, Jian-Hua; Cushman, Mark] Purdue Univ, Sch Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Cinelli, Mans A.; Reddy, P. V. Narasimha; Lv, Peng-Cheng; Liang, Jian-Hua; Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. [Chen, Lian; van Breemen, Richard B.] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. [Agama, Keli; Pommier, Yves] NCI, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. EM cushman@purdue.edu RI Puram, Venkat Narasimha R/A-6339-2013; Lv, Peng-Cheng/B-9765-2011; Liang, Jian-Hua/A-1186-2013; Chen, Lian/C-5948-2017 OI Puram, Venkat Narasimha R/0000-0001-5090-8330; FU National Institutes of Health (NIH) [UO1 CA89566]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This work was facilitated by the National Institutes of Health (NIH) through support with Research Grant UO1 CA89566. M.A.C. thanks Dr. Karl Wood for consultation and valuable discussions. Joe Fornefeld of Midwest Microlab and Dr. Martin Conda-Sheridan (Purdue University, IN) provided additional assistance. This project has also 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. NR 68 TC 20 Z9 21 U1 3 U2 26 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 DEC 27 PY 2012 VL 55 IS 24 BP 10844 EP 10862 DI 10.1021/jm300519w PG 19 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 059CD UT WOS:000312681100003 PM 23215354 ER PT J AU Bodelon, C Pfeiffer, RM Bollati, V Debbache, J Calista, D Ghiorzo, P Fargnoli, MC Bianchi-Scarra, G Peris, K Hoxha, M Hutchinson, A Burdette, L Burke, L Fang, SY Tucker, MA Goldstein, AM Lee, JE Wei, QY Savage, SA Yang, XHR Amos, C Landi, MT AF Bodelon, Clara Pfeiffer, Ruth M. Bollati, Valentina Debbache, Julien Calista, Donato Ghiorzo, Paola Fargnoli, Maria Concetta Bianchi-Scarra, Giovanna Peris, Ketty Hoxha, Mirjam Hutchinson, Amy Burdette, Laurie Burke, Laura Fang, Shenying Tucker, Margaret A. Goldstein, Alisa M. Lee, Jeffrey E. Wei, Qingyi Savage, Sharon A. Yang, Xiaohong R. Amos, Christopher Landi, Maria Teresa TI On the Interplay of Telomeres, Nevi and the Risk of Melanoma SO PLOS ONE LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; GENOME-WIDE ASSOCIATION; MEDITERRANEAN POPULATION; FAMILIAL MELANOMA; DYSPLASTIC NEVUS; DNA-REPAIR; SUSCEPTIBILITY; MC1R; VARIANTS; DISEASE AB The relationship between telomeres, nevi and melanoma is complex. Shorter telomeres have been found to be associated with many cancers and with number of nevi, a known risk factor for melanoma. However, shorter telomeres have also been found to decrease melanoma risk. We performed a systematic analysis of telomere-related genes and tagSNPs within these genes, in relation to the risk of melanoma, dysplastic nevi, and nevus count combining data from four studies conducted in Italy. In addition, we examined whether telomere length measured in peripheral blood leukocytes is related to the risk of melanoma, dysplastic nevi, number of nevi, or telomere-related SNPs. A total of 796 cases and 770 controls were genotyped for 517 SNPs in 39 telomere-related genes genotyped with a custom-made array. Replication of the top SNPs was conducted in two American populations consisting of 488 subjects from 53 melanoma-prone families and 1,086 cases and 1,024 controls from a case-control study. We estimated odds ratios for associations with SNPs and combined SNP P-values to compute gene region-specific, functional group-specific, and overall P-value using an adaptive rank-truncated product algorithm. In the Mediterranean population, we found suggestive evidence that RECQL4, a gene involved in genome stability, RTEL1, a gene regulating telomere elongation, and TERF2, a gene implicated in the protection of telomeres, were associated with melanoma, the presence of dysplastic nevi and number of nevi, respectively. However, these associations were not found in the American samples, suggesting variable melanoma susceptibility for these genes across populations or chance findings in our discovery sample. Larger studies across different populations are necessary to clarify these associations. C1 [Bodelon, Clara; Pfeiffer, Ruth M.; Debbache, Julien; Hutchinson, Amy; Burdette, Laurie; Burke, Laura; Tucker, Margaret A.; Goldstein, Alisa M.; Savage, Sharon A.; Yang, Xiaohong R.; Landi, Maria Teresa] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bollati, Valentina; Hoxha, Mirjam] Univ Milan, Dept Environm & Occupat Hlth, Ctr Mol & Genet Epidemiol, Milan, Italy. [Bollati, Valentina; Hoxha, Mirjam] IRCCS Osped Maggiore Policlin, Fdn Ca Granda, Milan, Italy. [Debbache, Julien] Univ Zurich, Div Cell & Dev Biol, Zurich, Switzerland. [Calista, Donato] Osped Gen Provinciale M Bufalini, Dept Dermatol, Cesena, Italy. [Ghiorzo, Paola; Bianchi-Scarra, Giovanna] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Ghiorzo, Paola; Bianchi-Scarra, Giovanna] IRCCS AOU San Martino IST, Lab Genet Rare Hereditary Canc, Genoa, Italy. [Fargnoli, Maria Concetta; Peris, Ketty] Univ Aquila, Dept Dermatol, I-67100 Laquila, Italy. [Fang, Shenying; Lee, Jeffrey E.] Univ Texas MD Anderson Canc Ctr, Dept Surg Oncol, Houston, TX 77030 USA. [Wei, Qingyi] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. [Amos, Christopher] Dartmouth Coll, Ctr Genom Med, Dept Community & Family Med, Lebanon, NH USA. RP Landi, MT (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI Bianchi Scarra, Giovanna/G-8933-2014; Tucker, Margaret/B-4297-2015; Savage, Sharon/B-9747-2015; OI Bianchi Scarra, Giovanna/0000-0002-6127-1192; Savage, Sharon/0000-0001-6006-0740; Peris, Ketty/0000-0002-5237-0463; Fargnoli, Maria Concetta/0000-0002-7249-2556; Bollati, Valentina/0000-0002-0370-9598 FU United States National Institutes of Health (NIH), National Cancer Institute, Division of Cancer Epidemiology and Genetics; NIH [CA 5558 - 01A2, 2P50CA093459]; Marit Peterson Fund for Melanoma Research; Associazione Italiana per la Ricerca sul Cancro FX This study was supported by the Intramural Research Program of United States National Institutes of Health (NIH), National Cancer Institute, Division of Cancer Epidemiology and Genetics and by the RO1 Grant (CA 5558 - 01A2) from the NIH to M. T. Landi. The MD Anderson Cancer Center study was supported by the NIH grant 2P50CA093459 (SF, JEL, QW, CA), and the Marit Peterson Fund for Melanoma Research (SF, JEL). Telomere length quantification was supported by the Associazione Italiana Ricerca sul Cancro (AIRC) (MFAG 10361) To V. Bollati. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 10 Z9 10 U1 0 U2 13 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 DEC 27 PY 2012 VL 7 IS 12 AR e52466 DI 10.1371/journal.pone.0052466 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 061EA UT WOS:000312829100052 PM 23300679 ER PT J AU Vaucher, YE Peralta-Carcelen, M Finer, NN Carlo, WA Gantz, MG Walsh, MC Laptook, AR Yoder, BA Faix, RG Das, A Schibler, K Rich, W Newman, NS Vohr, BR Yolton, K Heyne, RJ Wilson-Costello, DE Evans, PW Goldstein, RF Acarregui, MJ Adams-Chapman, I Pappas, A Hintz, SR Poindexter, B Dusick, AM McGowan, EC Ehrenkranz, RA Bodnar, A Bauer, CR Fuller, J O'Shea, TM Myers, GJ Higgins, RD AF Vaucher, Yvonne E. Peralta-Carcelen, Myriam Finer, Neil N. Carlo, Waldemar A. Gantz, Marie G. Walsh, Michele C. Laptook, Abbot R. Yoder, Bradley A. Faix, Roger G. Das, Abhik Schibler, Kurt Rich, Wade Newman, Nancy S. Vohr, Betty R. Yolton, Kimberly Heyne, Roy J. Wilson-Costello, Deanne E. Evans, Patricia W. Goldstein, Ricki F. Acarregui, Michael J. Adams-Chapman, Ira Pappas, Athina Hintz, Susan R. Poindexter, Brenda Dusick, Anna M. McGowan, Elisabeth C. Ehrenkranz, Richard A. Bodnar, Anna Bauer, Charles R. Fuller, Janell O'Shea, T. Michael Myers, Gary J. Higgins, Rosemary D. CA Eunice Kennedy Shriver NICHD Neona TI Neurodevelopmental Outcomes in the Early CPAP and Pulse Oximetry Trial SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID BIRTH-WEIGHT INFANTS; EXTREMELY PRETERM INFANTS; FREQUENCY OSCILLATORY VENTILATION; CEREBRAL-PALSY; OXYGEN-SATURATION; CONVENTIONAL VENTILATION; NEONATAL MORBIDITIES; AGE; RETINOPATHY; METAANALYSIS AB BACKGROUND Previous results from our trial of early treatment with continuous positive airway pressure (CPAP) versus early surfactant treatment in infants showed no significant difference in the outcome of death or bronchopulmonary dysplasia. A lower (vs. higher) target range of oxygen saturation was associated with a lower rate of severe retinopathy but higher mortality. We now report longer-term results from our prespecified hypotheses. METHODS Using a 2-by-2 factorial design, we randomly assigned infants born between 24 weeks 0 days and 27 weeks 6 days of gestation to early CPAP with a limited ventilation strategy or early surfactant administration and to lower or higher target ranges of oxygen saturation (85 to 89% or 91 to 95%). The primary composite outcome for the longer-term analysis was death before assessment at 18 to 22 months or neurodevelopmental impairment at 18 to 22 months of corrected age. RESULTS The primary outcome was determined for 1234 of 1316 enrolled infants (93.8%); 990 of the 1058 surviving infants (93.6%) were evaluated at 18 to 22 months of corrected age. Death or neurodevelopmental impairment occurred in 27.9% of the infants in the CPAP group (173 of 621 infants), versus 29.9% of those in the surfactant group (183 of 613) (relative risk, 0.93; 95% confidence interval [CI], 0.78 to 1.10; P = 0.38), and in 30.2% of the infants in the lower-oxygen-saturation group (185 of 612), versus 27.5% of those in the higher-oxygen-saturation group (171 of 622) (relative risk, 1.12; 95% CI, 0.94 to 1.32; P = 0.21). Mortality was increased with the lower-oxygen-saturation target (22.1%, vs. 18.2% with the higher-oxygen-saturation target; relative risk, 1.25; 95% CI, 1.00 to 1.55; P = 0.046). CONCLUSIONS We found no significant differences in the composite outcome of death or neurodevelopmental impairment among extremely premature infants randomly assigned to early CPAP or early surfactant administration and to a lower or higher target range of oxygen saturation. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute; SUPPORT ClinicalTrials.gov number, NCT00233324.) C1 [Finer, Neil N.] Univ Calif San Diego, Div Neonatol, Dept Pediat, San Diego, CA 92013 USA. [Hintz, Susan R.] Stanford Univ, Sch Med, Dept Pediat, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. [Hintz, Susan R.] Lucile Packard Childrens Hosp, Palo Alto, CA USA. [Peralta-Carcelen, Myriam; Carlo, Waldemar A.] Univ Alabama Birmingham, Dept Pediat, Birmingham, AL USA. [Gantz, Marie G.] RTI Int, Stat & Epidemiol Unit, Res Triangle Pk, NC USA. [Goldstein, Ricki F.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [O'Shea, T. Michael] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Walsh, Michele C.; Newman, Nancy S.; Wilson-Costello, Deanne E.] Case Western Reserve Univ, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. [Schibler, Kurt; Yolton, Kimberly] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH USA. [Schibler, Kurt; Yolton, Kimberly] Univ Cincinnati, Cincinnati, OH 45221 USA. [Laptook, Abbot R.; Vohr, Betty R.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. [Yoder, Bradley A.; Faix, Roger G.; Bodnar, Anna] Univ Utah, Sch Med, Dept Pediat, Div Neonatol, Salt Lake City, UT USA. [Das, Abhik] RTI Int, Stat & Epidemiol Unit, Rockville, MD USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Heyne, Roy J.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. [Evans, Patricia W.] Univ Texas Houston, Med Sch Houston, Houston, TX USA. [Acarregui, Michael J.] Univ Iowa, Dept Pediat, Iowa City, IA 52242 USA. [Adams-Chapman, Ira] Emory Univ, Sch Med, Dept Pediat, Atlanta, GA USA. [Adams-Chapman, Ira] Childrens Healthcare Atlanta, Atlanta, GA USA. [Pappas, Athina] Wayne State Univ, Dept Pediat, Detroit, MI 48202 USA. [Poindexter, Brenda; Dusick, Anna M.] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN USA. [McGowan, Elisabeth C.] Floating Hosp Children, Tufts Med Ctr, Div Newborn Med, Dept Pediat, Boston, MA USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Bauer, Charles R.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Fuller, Janell] Univ New Mexico, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Myers, Gary J.] Univ Rochester, Med Ctr, Dept Pediat, Rochester, NY 14642 USA. RP Finer, NN (reprint author), Univ Calif San Diego, Div Neonatol, Dept Pediat, 200 W Arbor Dr, San Diego, CA 92013 USA. EM nfiner@ucsd.edu FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Heart, Lung, and Blood Institute FX Supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute. NR 37 TC 70 Z9 73 U1 0 U2 15 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 DEC 27 PY 2012 VL 367 IS 26 BP 2495 EP 2504 DI 10.1056/NEJMoa1208506 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 059OG UT WOS:000312714200007 PM 23268664 ER PT J AU Jiao, S Hsu, L Berndt, S Bezieau, S Brenner, H Buchanan, D Caan, BJ Campbell, PT Carlson, CS Casey, G Chan, AT Chang-Claude, J Chanock, S Conti, DV Curtis, KR Duggan, D Gallinger, S Gruber, SB Harrison, TA Hayes, RB Henderson, BE Hoffmeister, M Hopper, JL Hudson, TJ Hutter, CM Jackson, RD Jenkins, MA Kantor, ED Kolonel, LN Kury, S Le Marchand, L Lemire, M Newcomb, PA Potter, JD Qu, CH Rosse, SA Schoen, RE Schumacher, FR Seminara, D Slattery, ML Ulrich, CM Zanke, BW Peters, U AF Jiao, Shuo Hsu, Li Berndt, Sonja Bezieau, Stephane Brenner, Hermann Buchanan, Daniel Caan, Bette J. Campbell, Peter T. Carlson, Christopher S. Casey, Graham Chan, Andrew T. Chang-Claude, Jenny Chanock, Stephen Conti, David V. Curtis, Keith R. Duggan, David Gallinger, Steven Gruber, Stephen B. Harrison, Tabitha A. Hayes, Richard B. Henderson, Brian E. Hoffmeister, Michael Hopper, John L. Hudson, Thomas J. Hutter, Carolyn M. Jackson, Rebecca D. Jenkins, Mark A. Kantor, Elizabeth D. Kolonel, Laurence N. Kuery, Sebastien Le Marchand, Loic Lemire, Mathieu Newcomb, Polly A. Potter, John D. Qu, Conghui Rosse, Stephanie A. Schoen, Robert E. Schumacher, Fred R. Seminara, Daniela Slattery, Martha L. Ulrich, Cornelia M. Zanke, Brent W. Peters, Ulrike TI Genome-Wide Search for Gene-Gene Interactions in Colorectal Cancer SO PLOS ONE LA English DT Article ID SUSCEPTIBILITY LOCI; ASSOCIATION SCAN; ENVIRONMENT INTERACTIONS; RANDOM FORESTS; HUMAN-DISEASES; VARIANTS; RISK; METAANALYSIS; EPISTASIS; SEROTONIN AB Genome-wide association studies (GWAS) have successfully identified a number of single-nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG) is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI). With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p < 10(-4)). For the known locus rs10795668 (10p14), we found an interacting SNP rs367615 (5q21) with replication p = 0.01 and combined p = 4.19x10(-8). Among the top marginal SNPs after LD pruning (n = 163), we identified an interaction between rs1571218 (20p12.3) and rs10879357 (12q21.1) (nominal combined p = 2.51x10(-6); Bonferroni adjusted p = 0.03). Our study represents the first comprehensive search for GxG in CRC, and our results may provide new insight into the genetic etiology of CRC. C1 [Jiao, Shuo; Hsu, Li; Carlson, Christopher S.; Curtis, Keith R.; Harrison, Tabitha A.; Hutter, Carolyn M.; Kantor, Elizabeth D.; Newcomb, Polly A.; Potter, John D.; Qu, Conghui; Rosse, Stephanie A.; Ulrich, Cornelia M.; Peters, Ulrike] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Berndt, Sonja; Chanock, Stephen] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Bezieau, Stephane; Kuery, Sebastien] CHU Nantes, Serv Genet Med, F-44035 Nantes 01, France. [Bezieau, Stephane; Hoffmeister, Michael] German Canc Res Ctr, Div Clin Epidemiol & Aging Res, Heidelberg, Germany. [Buchanan, Daniel] Queensland Inst Med Res, Canc & Populat Studies Grp, Brisbane, Qld 4006, Australia. [Caan, Bette J.] Kaiser Permanente Med Care Program, Div Res, Oakland, CA 94611 USA. [Campbell, Peter T.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Carlson, Christopher S.; Newcomb, Polly A.; Potter, John D.; Ulrich, Cornelia M.; Peters, Ulrike] Univ Washington, Sch Publ Hlth, Seattle, WA 98195 USA. [Casey, Graham; Conti, David V.; Gruber, Stephen B.; Henderson, Brian E.; Schumacher, Fred R.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Chan, Andrew T.] Massachusetts Gen Hosp, Div Gastroenterol, Boston, MA 02114 USA. [Chan, Andrew T.] Harvard Univ, Sch Med, Boston, MA USA. [Chan, Andrew T.] Brigham & Womens Hosp, Channing Div Network Med, Boston, MA 02115 USA. [Chang-Claude, Jenny] German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ USA. [Gallinger, Steven] Toronto Gen Hosp, Univ Hlth Network, Dept Surg, Toronto, ON, Canada. [Hayes, Richard B.] NYU, Sch Med, Div Epidemiol, New York, NY USA. [Hopper, John L.; Jenkins, Mark A.] Univ Melbourne, Melbourne Sch Populat Hlth, Melbourne, Vic, Australia. [Hudson, Thomas J.; Lemire, Mathieu] Ontario Inst Canc Res, Toronto, ON, Canada. [Hudson, Thomas J.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. [Hudson, Thomas J.] Univ Toronto, Dept Mol Genet, Toronto, ON, Canada. [Jackson, Rebecca D.] Ohio State Univ, Div Endocrinol Diabet & Metab, Columbus, OH 43210 USA. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Program Epidemiol, Honolulu, HI 96822 USA. [Potter, John D.] Massey Univ, Ctr Publ Hlth Res, Wellington, New Zealand. [Schoen, Robert E.] Univ Pittsburgh, Med Ctr, Dept Med & Epidemiol, Pittsburgh, PA USA. [Seminara, Daniela] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Slattery, Martha L.] Univ Utah, Hlth Sci Ctr, Dept Internal Med, Salt Lake City, UT USA. [Ulrich, Cornelia M.] Natl Ctr Tumor Dis, Div Prevent Oncol, Heidelberg, Germany. [Zanke, Brent W.] Ottawa Hosp, Res Inst, Clin Epidemiol Program, Ottawa, ON, Canada. RP Jiao, S (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA. EM sjiao@fhcrc.org RI Gallinger, Steven/E-4575-2013; Hoffmeister, Michael/B-5745-2012; KURY, Sebastien/G-5971-2015; Bezieau, stephane/G-5621-2015; Jenkins, Mark/P-7803-2015; Brenner, Hermann/B-4627-2017; OI Hoffmeister, Michael/0000-0002-8307-3197; KURY, Sebastien/0000-0001-5497-0465; Bezieau, stephane/0000-0003-0095-1319; Buchanan, Daniel/0000-0003-2225-6675; Jenkins, Mark/0000-0002-8964-6160; Brenner, Hermann/0000-0002-6129-1572; Kantor, Elizabeth/0000-0002-9124-5323; Potter, John/0000-0001-5439-1500 FU Hospital Clinical Research Program (PHRC); Regional Council of Pays de la Loire; Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC); Association Anne de Bretagne Genetique; Ligue Regionale Contre le Cancer (LRCC); National Cancer Institute, National Institutes of Health [U01 CA074783, U01 CA122839]; Ontario Research Fund [GL2]; Canadian Institutes of Health Research; Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute; Ontario Institute for Cancer Research; National Cancer Institute [R01 CA60987]; National Cancer Institute, National Institutes of Health under RFA [CA-95-011]; Australasian Colorectal Cancer Family Registry [U01 CA097735]; Seattle Colorectal Cancer Family Registry [U01 CA074794]; Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783]; German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]; German Federal Ministry of Education and Research [01KH0404, 01ER0814]; National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services [R01 CA48998, U01 CA137088, R01 CA059045]; National Institutes of Health [P01 CA 055075, R01 137178, P50 CA 127003, P01 CA 087969, CA42182, R01 CA076366]; Intramural Research Program of the Division of Cancer Epidemiology and Genetics; Division of Cancer Prevention, National Cancer Institute, NIH, DHHS; Intramural Research Program of the National Cancer Institute; National Institutes of Health, Genes, Environment and Health Initiative [NIH GEI] [Z01 CP 010200]; National Cancer Institute; Gene Environment Association Studies, GENEVA Coordinating Center [U01 HG004446]; NIH GEI [U01 HG 004438]; National Institutes of Health from the National Cancer Institute and Office of Dietary Supplements [K05 CA154337]; National Heart, Lung, and Blood Institute, National Institutes of Health, U. S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221, 268200764316C]; [R37 CA54281]; [P01 CA033619]; [R01 CA63464] FX ASTERISK was funded by a Hospital Clinical Research Program (PHRC) and supported by the Regional Council of Pays de la Loire, the Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC), the Association Anne de Bretagne Genetique and the Ligue Regionale Contre le Cancer (LRCC). ARCTIC is partly supported by the National Cancer Institute, National Institutes of Health through funding allocated to the Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783); see CCFR section below. ARCTIC is also supported by a GL2 grant from the Ontario Research Fund, the Canadian Institutes of Health Research, and the Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute. TJH and BWZ are recipients of Senior Investigator Awards from the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Economic Development and Innovation. COLO2&3 is supported by the National Cancer Institute (R01 CA60987). CCFR is supported by the National Cancer Institute, National Institutes of Health under RFA # CA-95-011 and through cooperative agreements with members of the Colon Cancer Family Registry and P.I.s. This genome wide scan was supported by the National Cancer Institute, National Institutes of Health by U01 CA122839. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the CFR. The following Colon CFR centers contributed data to this manuscript and were supported by the following sources: Australasian Colorectal Cancer Family Registry (U01 CA097735), Seattle Colorectal Cancer Family Registry (U01 CA074794) and Ontario Registry for Studies of Familial Colorectal Cancer (U01 CA074783). DACHS was supported by grants from the German Research Council (Deutsche Forschungsgemeinschaft, BR 1704/6-1, BR 1704/6-3, BR 1704/6-4 and CH 117/1-1), and the German Federal Ministry of Education and Research (01KH0404 and 01ER0814). DALS was supported by the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (R01 CA48998 to MLS). GECCO is supported by National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (U01 CA137088). Funding for the genome-wide scan of DALS, PLCO, and WHI was provided by the National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (R01 CA059045). HPFS, NHS, PHS: The National Institutes of Health supported HPFS (P01 CA 055075, R01 137178, P50 CA 127003), NHS (R01 137178, P50 CA 127003, P01 CA 087969), and PHS (CA42182). MEC is supported by R37 CA54281, P01 CA033619, and R01 CA63464. PLCO was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics and supported by contracts from the Division of Cancer Prevention, National Cancer Institute, NIH, DHHS. Control samples were genotyped as part of the Cancer Genetic Markers of Susceptibility (CGEMS) prostate cancer scan, supported by the Intramural Research Program of the National Cancer Institute. The datasets used in this analysis were accessed with appropriate approval through the dbGaP online resource (http://www.cgems.cancer.gov/data_acess.html) through dbGaP accession number 000207v.1p1.c1.; (National Cancer Institute (2009) Cancer Genetic Markers of Susceptibility (CGEMS) data website, http://cgems.cancer.gov/data_access.html; Yeager et al. 2007). Control samples were also genotyped as part of the GWAS of Lung Cancer and Smoking (Landi et al. 2009). Funding for this work was provided through the National Institutes of Health, Genes, Environment and Health Initiative [NIH GEI] (Z01 CP 010200). The human subjects participating in the GWAS are derived from the Prostate, Lung, Colon and Ovarian Screening Trial and the study is supported by intramural resources of the National Cancer Institute. Assistance with genotype cleaning, as well as with general study coordination, was provided by the Gene Environment Association Studies, GENEVA Coordinating Center (U01 HG004446). Assistance with data cleaning was provided by the National Center for Biotechnology Information. Funding support for genotyping, which was performed at the Johns Hopkins University Center for Inherited Disease Research, was provided by the NIH GEI (U01 HG 004438). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000093. PMH was supported by the National Institutes of Health (R01 CA076366 to PAN). VITAL was supported, in part, by the National Institutes of Health (K05 CA154337) from the National Cancer Institute and Office of Dietary Supplements. WHI: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221, and 268200764316C. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 21 Z9 22 U1 0 U2 17 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 DEC 26 PY 2012 VL 7 IS 12 AR e52535 DI 10.1371/journal.pone.0052535 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 071TV UT WOS:000313618800103 PM 23300701 ER PT J AU Roescher, N Vosters, JL Lai, ZA Uede, T Tak, PP Chiorini, JA AF Roescher, Nienke Vosters, Jelle L. Lai, Zhenan Uede, Toshimitsu Tak, Paul P. Chiorini, John A. TI Local Administration of Soluble CD40:Fc to the Salivary Glands of Non-Obese Diabetic Mice Does Not Ameliorate Autoimmune Inflammation SO PLOS ONE LA English DT Article ID NF-KAPPA-B; GENE-EXPRESSION; SIGNALING PATHWAYS; SJOGRENS-SYNDROME; EPITHELIAL-CELLS; ACTIVATION; THERAPY; VECTORS; CD40IG; BETA AB Objective: CD40-CD154 (CD40 ligand) interaction in the co-stimulatory pathway is involved in many (auto) immune processes and both molecules are upregulated in salivary glands of Sjogren's syndrome (SS) patients. Interference within the CD40 pathway has ameliorated (auto) inflammation in a number of disease models. To test the potential role of the CD40 pathway in loss of gland function and inflammation in SS, an inhibitor of CD40-CD154 interaction was overexpressed in the salivary glands (SGs) of a spontaneous murine model of SS; the Non-Obese Diabetic (NOD) mouse. Materials and Methods: At different disease stages an adeno associated viral vector encoding CD40 coupled to a human Fc domain (CD40: Fc) was injected locally into the SGs of NOD mice. Delivery was confirmed by PCR. The overall effect on local inflammation was determined by assessment of the focus score (FS), quantification of infiltrating cell types, immunoglobulin levels, and microarray analysis. The effect on SG function was determined by measuring stimulated salivary flow. Results: CD40: Fc was stably expressed in the SG of NOD mice, and the protein was secreted into the blood stream. Microarray analysis revealed that expression of CD40: Fc affected the expression of many genes involved in regulation of the immune response. However, FS, infiltrating cell types, immunoglobulin levels, and salivary gland output were similar for treated and control mice. Discussion: Although endogenous CD40 is expressed in SG inflammatory foci in the SG of NOD mice, the expression of soluble CD40: Fc did not lead to reduced overall inflammation and/or improved salivary gland function. These data indicate possible redundancy of the CD40 pathway in the SG and suggests that targeting CD40 alone may not be sufficient to alter the disease phenotype. C1 [Roescher, Nienke; Vosters, Jelle L.; Lai, Zhenan; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Roescher, Nienke; Vosters, Jelle L.; Tak, Paul P.] Univ Amsterdam, Acad Med Ctr, Div Clin Immunol & Rheumatol, NL-1105 AZ Amsterdam, Netherlands. [Tak, Paul P.] GlaxoSmithKline, London, England. [Uede, Toshimitsu] Hokkaido Univ, Inst Med Genet, Div Mol Immunol, Sapporo, Hokkaido, Japan. RP Chiorini, JA (reprint author), Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. EM jchiorini@dir.nidcr.nih.gov FU United States National Institutes of Health FX The study was funded by a United States National Institutes of Health intramural grant to JAC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 7 Z9 7 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 DEC 26 PY 2012 VL 7 IS 12 AR e51375 DI 10.1371/journal.pone.0051375 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 071TV UT WOS:000313618800016 PM 23300544 ER PT J AU Wang, XY Jensen-Taubman, SM Keefe, KM Yang, DL Linnoila, RI AF Wang, Xiao-Yang Jensen-Taubman, Sandra M. Keefe, Kathleen M. Yang, Danlei Linnoila, R. Ilona TI Achaete-Scute Complex Homolog-1 Promotes DNA Repair in the Lung Carcinogenesis through Matrix Metalloproteinase-7 and O(6)-Methylguanine-DNA Methyltransferase SO PLOS ONE LA English DT Article ID O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; NEUROENDOCRINE TUMORS; TRANSGENIC MICE; HISTONE H2AX; CANCER; CELL; GENE; DIFFERENTIATION; TUMORIGENESIS; 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE AB Lung cancer is the leading cause of cancer-related deaths in the world. Achaete-scute complex homolog-1 (Ascl1) is a member of the basic helix-loop-helix (bHLH) transcription factor family that has multiple functions in the normal and neoplastic lung such as the regulation of neuroendocrine differentiation, prevention of apoptosis and promotion of tumor-initiating cells. We now show that Ascl1 directly regulates matrix metalloproteinase-7 (MMP-7) and O(6)-methylguanine-DNA methyltransferase (MGMT). Loss- and gain-of-function experiments in human bronchial epithelial and lung carcinoma cell lines revealed that Ascl1, MMP-7 and MGMT are able to protect cells from the tobacco-specific nitrosamine NNK-induced DNA damage and the alkylating agent cisplatin-induced apoptosis. We also examined the role of Ascl1 in NNK-induced lung tumorigenesis in vivo. Using transgenic mice which constitutively expressed human Ascl1 in airway lining cells, we found that there was a delay in lung tumorigenesis. We conclude that Ascl1 potentially enhances DNA repair through activation of MMP-7 and MGMT which may impact lung carcinogenesis and chemoresistance. The study has uncovered a novel and unexpected function of Ascl1 which will contribute to better understanding of lung carcinogenesis and the broad implications of transcription factors in tobacco-related carcinogenesis. C1 [Wang, Xiao-Yang; Jensen-Taubman, Sandra M.; Keefe, Kathleen M.; Yang, Danlei; Linnoila, R. Ilona] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wang, XY (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM xiaoyangwang@gmail.com; linnoila@mail.nih.gov FU Intramural Research Program of the National Cancer Institute at National Institutes of Health FX This study was supported by the Intramural Research Program of the National Cancer Institute at 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 38 TC 2 Z9 3 U1 1 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 DEC 26 PY 2012 VL 7 IS 12 AR e52832 DI 10.1371/journal.pone.0052832 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 071TV UT WOS:000313618800156 PM 23300791 ER PT J AU Varmus, H AF Varmus, Harold TI Arlen Specter: A retrospective SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material C1 NCI, Off Director, Bethesda, MD 20892 USA. RP Varmus, H (reprint author), NCI, Off Director, Bethesda, MD 20892 USA. EM harold.varmus@nih.gov NR 0 TC 0 Z9 0 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 DEC 26 PY 2012 VL 109 IS 52 BP 21178 EP 21179 DI 10.1073/pnas.1219606110 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 071WR UT WOS:000313627700016 ER PT J AU Plummer, NW Spicher, K Malphurs, J Akiyama, H Abramowitz, J Nurnberg, B Birnbaumer, L AF Plummer, Nicholas W. Spicher, Karsten Malphurs, Jason Akiyama, Haruhiko Abramowitz, Joel Nuernberg, Bernd Birnbaumer, Lutz TI Development of the mammalian axial skeleton requires signaling through the G alpha(i) subfamily of heterotrimeric G proteins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mouse; thoracic; sternum; lateral plate mesoderm ID LATERAL SOMITIC FRONTIER; TARGETED INACTIVATION; COUPLED RECEPTORS; ADENYLYL-CYCLASE; TRANSGENIC MOUSE; MICE; GENE; EXPRESSION; FAMILY; GROWTH AB 129/SvEv mice with a loss-of-function mutation in the heterotrimeric G protein alpha-subunit gene Gnai3 have fusions of ribs and lumbar vertebrae, indicating a requirement for Gai (the "inhibitory" class of alpha-subunits) in somite derivatives. Mice with mutations of Gnai1 or Gnai2 have neither defect, but loss of both Gnai3 and one of the other two genes increases the number and severity of rib fusions without affecting the lumbar fusions. No myotome defects are observed in Gnai3/Gnai1 double-mutant embryos, and crosses with a conditional allele of Gnai2 indicate that G alpha(i) is specifically required in cartilage precursors. Penetrance and expressivity of the rib fusion phenotype is altered in mice with a mixed C57BL/6 x 129/SvEv genetic background. These phenotypes reveal a previously unknown role for G protein-coupled signaling pathways in development of the axial skeleton. C1 [Plummer, Nicholas W.; Malphurs, Jason; Abramowitz, Joel; Birnbaumer, Lutz] NIEHS, Lab Neurobiol, NIH, Dept Hlth & Human Serv, Durham, NC 27709 USA. [Spicher, Karsten] Fed Inst Drugs & Med Devices BfArM, D-53175 Bonn, Germany. [Akiyama, Haruhiko] Kyoto Univ, Dept Orthopaed, Kyoto 6068507, Japan. [Nuernberg, Bernd] Univ Tubingen, Dept Pharmacol & Expt Therapy, Inst Expt & Clin Pharmacol & Toxicol, D-72074 Tubingen, Germany. [Nuernberg, Bernd] Interfac Ctr Pharmacogen & Drug Res, D-72074 Tubingen, Germany. RP Plummer, NW (reprint author), NIEHS, Lab Neurobiol, NIH, Dept Hlth & Human Serv, Durham, NC 27709 USA. EM plummer@niehs.nih.gov; birnbau1@niehs.nih.gov RI Abramowitz, Joel/A-2620-2015; OI Plummer, Nicholas/0000-0003-2971-814X FU Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [Z01-ES-101643] FX The authors thank Tom Sliwa for animal husbandry, Mitzie Walker for assistance with genotyping, and Jennifer Moran for SNP analysis. The template for the Sox9 in situ probe was generously provided by Masahiro Iwamoto (Thomas Jefferson University), and the Tg(Myog-cre) 1Eno mice were generously provided by Eric Olson (University of Texas Southwestern Medical Center). This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Project Z01-ES-101643). NR 50 TC 12 Z9 13 U1 0 U2 17 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 DEC 26 PY 2012 VL 109 IS 52 BP 21366 EP 21371 DI 10.1073/pnas.1219810110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 071WR UT WOS:000313627700052 PM 23236180 ER PT J AU Hadj-Bouziane, F Liu, N Bell, AH Gothard, KM Luh, WM Tootell, RBH Murray, EA Ungerleider, LG AF Hadj-Bouziane, Fadila Liu, Ning Bell, Andrew H. Gothard, Katalin M. Luh, Wen-Ming Tootell, Roger B. H. Murray, Elisabeth A. Ungerleider, Leslie G. TI Amygdala lesions disrupt modulation of functional MRI activity evoked by facial expression in the monkey inferior temporal cortex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neuroimaging; nonhuman primate; social stimuli; temporal lobe ID PREFRONTAL CORTEX; RHESUS-MONKEYS; NEUROTOXIC LESIONS; MACAQUE MONKEY; HIPPOCAMPAL-FORMATION; IMPAIRED RECOGNITION; ORBITOFRONTAL CORTEX; SELECTIVE RESPONSES; EMOTIONAL RESPONSES; NONHUMAN-PRIMATES AB We previously showed that facial expressions modulate functional MRI activity in the face-processing regions of the macaque monkey's amygdala and inferior temporal (IT) cortex. Specifically, we showed that faces expressing emotion yield greater activation than neutral faces; we term this difference the "valence effect." We hypothesized that amygdala lesions would disrupt the valence effect by eliminating the modulatory feedback from the amygdala to the IT cortex. We compared the valence effects within the IT cortex in monkeys with excitotoxic amygdala lesions (n = 3) with those in intact control animals (n = 3) using contrast agent-based functional MRI at 3 T. Images of four distinct monkey facial expressions-neutral, aggressive (open mouth threat), fearful (fear grin), and appeasing (lip smack)-were presented to the subjects in a blocked design. Our results showed that in monkeys with amygdala lesions the valence effects were strongly disrupted within the IT cortex, whereas face responsivity (neutral faces > scrambled faces) and face selectivity (neutral faces > non-face objects) were unaffected. Furthermore, sparing of the anterior amygdala led to intact valence effects in the anterior IT cortex (which included the anterior face-selective regions), whereas sparing of the posterior amygdala led to intact valence effects in the posterior IT cortex (which included the posterior face-selective regions). Overall, our data demonstrate that the feedback projections from the amygdala to the IT cortex mediate the valence effect found there. Moreover, these modulatory effects are consistent with an anterior-to-posterior gradient of projections, as suggested by classical tracer studies. C1 [Hadj-Bouziane, Fadila; Liu, Ning; Bell, Andrew H.; Tootell, Roger B. H.; Ungerleider, Leslie G.] NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. [Murray, Elisabeth A.] NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Luh, Wen-Ming] NIMH, Funct MRI Facil, NIH, Bethesda, MD 20892 USA. [Gothard, Katalin M.] Univ Arizona, Coll Med, Dept Physiol, Tucson, AZ 85724 USA. [Tootell, Roger B. H.] Massachusetts Gen Hosp, Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. RP Hadj-Bouziane, F (reprint author), CNRS, INSERM, U1028, Lyon Neurosci Res Ctr,ImpAct Team,UMR 5292, F-69500 Bron, France. EM fadila.hadj-bouziane@inserm.fr; ungerlel@mail.nih.gov OI Bell, Andrew/0000-0001-8420-4622; Murray, Elisabeth/0000-0003-1450-1642 FU National Institute of Mental Health Intramural Research Program FX We thank Shruti Japee, Ziad Saad, and Gang Chen for help with data analysis; Lucas Glover, Fern Baldwin, and James Ellis for assistance with animal training and scanning; Gary Griffiths for providing the contrast agent, MION; George Dold, David Ide, and Tom Talbot for technical assistance; and Kadharbatcha Saleem for preparing images of Nissl-stained histological sections. This study was supported by the National Institute of Mental Health Intramural Research Program (F.H.-B., N.L., A.H.B., E.A.M., and L.G.U.). NR 68 TC 32 Z9 32 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 DEC 26 PY 2012 VL 109 IS 52 BP E3640 EP E3648 DI 10.1073/pnas.1218406109 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 071WR UT WOS:000313627700008 PM 23184972 ER PT J AU Weng, MT Lee, JH Wei, SC Li, QN Shahamatdar, S Hsu, D Schetter, AJ Swatkoski, S Mannan, P Garfield, S Gucek, M Kim, MKH Annunziata, CM Creighton, CJ Emanuele, MJ Harris, CC Sheu, JC Giaccone, G Luo, J AF Weng, Meng-Tzu Lee, Jih-Hsiang Wei, Shu-Chen Li, Qiuning Shahamatdar, Sina Hsu, Dennis Schetter, Aaron J. Swatkoski, Stephen Mannan, Poonam Garfield, Susan Gucek, Marjan Kim, Marianne K. H. Annunziata, Christina M. Creighton, Chad J. Emanuele, Michael J. Harris, Curtis C. Sheu, Jin-Chuan Giaccone, Giuseppe Luo, Ji TI Evolutionarily conserved protein ERH controls CENP-E mRNA splicing and is required for the survival of KRAS mutant cancer cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE synthetic lethality; spliceosome ID RAS ONCOGENE; CHROMOSOME CONGRESSION; KINETOCHORE LOCALIZATION; GENOMIC INSTABILITY; RUDIMENTARY HOMOLOG; SPINDLE CHECKPOINT; MOLECULAR PARTNER; HUMAN ENHANCER; BUDDING YEAST; FISSION YEAST AB Cancers with Ras mutations represent a major therapeutic problem. Recent RNAi screens have uncovered multiple nononcogene addiction pathways that are necessary for the survival of Ras mutant cells. Here, we identify the evolutionarily conserved gene enhancer of rudimentary homolog (ERH), in which depletion causes greater toxicity in cancer cells with mutations in the small GTPase KRAS compared with KRAS WT cells. ERH interacts with the spliceosome protein SNRPD3 and is required for the mRNA splicing of the mitotic motor protein CENP-E. Loss of ERH leads to loss of CENP-E and consequently, chromosome congression defects. Gene expression profiling indicates that ERH is required for the expression of multiple cell cycle genes, and the gene expression signature resulting from ERH down-regulation inversely correlates with KRAS signatures. Clinically, tumor ERH expression is inversely associated with survival of colorectal cancer patients whose tumors harbor KRAS mutations. Together, these findings identify a role of ERH in mRNA splicing and mitosis, and they provide evidence that KRAS mutant cancer cells are dependent on ERH for their survival. C1 [Weng, Meng-Tzu; Lee, Jih-Hsiang; Li, Qiuning; Shahamatdar, Sina; Hsu, Dennis; Kim, Marianne K. H.; Annunziata, Christina M.; Giaccone, Giuseppe; Luo, Ji] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Weng, Meng-Tzu] Natl Taiwan Univ, Grad Inst Clin Med, Taipei 100, Taiwan. [Weng, Meng-Tzu] Far Eastern Mem Hosp, Taipei 220, Taiwan. [Wei, Shu-Chen; Sheu, Jin-Chuan] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei 100, Taiwan. [Wei, Shu-Chen; Sheu, Jin-Chuan] Coll Med, Taipei 100, Taiwan. [Schetter, Aaron J.; Harris, Curtis C.] NCI, Lab Human Carcinogenesis, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Swatkoski, Stephen] NHLBI, Prote Core Facil, NIH, Bethesda, MD 20892 USA. [Mannan, Poonam; Garfield, Susan] NCI, Confocal Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. [Creighton, Chad J.] Baylor Coll Med, Dept Med, Houston, TX 77030 USA. [Creighton, Chad J.] Baylor Coll Med, Dan L Duncan Canc Ctr, Div Biostat, Houston, TX 77030 USA. [Emanuele, Michael J.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Emanuele, Michael J.] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Luo, J (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ji.luo@nih.gov RI Annunziata, Christina/L-3219-2016; Giaccone, Giuseppe/E-8297-2017; OI Annunziata, Christina/0000-0003-2033-6532; Giaccone, Giuseppe/0000-0002-5023-7562; SHEU, JIN-CHUAN/0000-0002-2503-7139 FU Liver Disease Prevention and Treatment Research Foundation (Taiwan) Fellowship; US National Cancer Institute Center for Canter Research (NCI-CCR) Intramural Research Program [ZIA BC 011259] FX We thank Drs. Stephen Elledge, Tom Misteli, Mary Dasso, and Lewis Cantley for critical reading and comments on this manuscript. We thank Dr. Stephen Taylor for antibodies and Drs. Bert Vogelstein, Thomas Ried, and Mary Dasso for cell lines. This work is supported by a Liver Disease Prevention and Treatment Research Foundation (Taiwan) Fellowship (to M.-T.W.) and US National Cancer Institute Center for Canter Research (NCI-CCR) Intramural Research Program ZIA BC 011259 (to J.L.). NR 57 TC 16 Z9 16 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 DEC 26 PY 2012 VL 109 IS 52 BP E3659 EP E3667 DI 10.1073/pnas.1207673110 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 071WR UT WOS:000313627700010 PM 23236152 ER PT J AU Levy, D AF Levy, Daniel TI Combating the Epidemic of Heart Disease SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 [Levy, Daniel] NHLBI, NIH, Bethesda, MD 20892 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte,Ste 2, Framingham, MA 01702 USA. EM levyd@nhlbi.nih.gov NR 13 TC 5 Z9 5 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 26 PY 2012 VL 308 IS 24 BP 2624 EP 2625 DI 10.1001/jama.2012.164971 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 062JR UT WOS:000312916600029 PM 23268522 ER PT J AU Lee, SJ Gldstein, JA AF Lee, Su-Jun Gldstein, Joyce A. TI Comparison of CYP3A4 and CYP3A5: The Effects of Cytochrome b5 and NADPH-cytochrome P450 Reductase on Testosterone Hydroxylation Activities SO DRUG METABOLISM AND PHARMACOKINETICS LA English DT Article DE CYP3A4; CYP3A5; cytochrome b5; NADPH-cytochrome P450 oxidoreductase; testosterone; reconstitution ID ESCHERICHIA-COLI; IN-VITRO; B(5); METABOLISM; NIFEDIPINE; EXPRESSION; HEME; CATALYSIS; MIDAZOLAM AB CYP3A4 and CYP3A5 require cytochrome b5 (b5) and NADPH-cytochrome P450 oxidoreductase (CPR) for optimum metabolism, but little is known about the specific requirements for b5 and CPR to produce optimal activities for these enzymes. The metabolism of testosterone (TT) by CYP3A4 and CYP3A5 was analyzed by various combinations of b5 and CPR using a fixed amount of recombinant P450 which had been purified from an Escherichia coli expression system. CYP3A4 and CYP3A5 required 4- and 8-fold more of CPR than of the P450s, respectively, for optimal activity. The requirement of b5 for optimal activity showed the same pattern for both CYP3A4 and CYP3A5, exhibiting a gradual stimulation of the activity reaching a maximum at 16 fold more b5 than P450. Although CYP3A4 exhibited higher activities than CYP3A5 in all combinations, both enzymes exhibited the same dependency profile for b5 and CPR. Therefore, the stronger activity of CYP3A4 compared to CYP3A5 appears to be intrinsic to the CYP3A4 protein itself and not to different requirements for b5 and CPR. Since the relative amounts of b5 and CPR are important in the maintenance of CYP3A4 and CYP3A5 activities, different levels of these proteins in vitro and in vivo may cause altered metabolism of their substrates or misinterpretation of enzyme properties. C1 [Lee, Su-Jun] Inje Univ, Dept Pharmacol, Coll Med, Pusan 614735, South Korea. [Lee, Su-Jun] Inje Univ, Pharmacogenom Res Ctr, Coll Med, Pusan 614735, South Korea. [Gldstein, Joyce A.] NIEHS, Human Metab Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Lee, SJ (reprint author), Inje Univ, Dept Pharmacol, Coll Med, 633-165 Gaegum Dong, Pusan 614735, South Korea. EM 2sujun@inje.ac.kr FU Intramural Research Program of NIH, National Institute of Environmental Health Sciences under NIH intramural project [Z01ES02124]; National Research Foundation of Korea (NRF); Korea government (MEST) [R13-2007-023-00000-0] FX This study was supported by the Intramural Research Program of NIH, National Institute of Environmental Health Sciences under NIH intramural project number Z01ES02124 and by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. R13-2007-023-00000-0). NR 25 TC 7 Z9 11 U1 1 U2 12 PU JAPANESE SOC STUDY XENOBIOTICS PI TOKYO PA INT MED INF CENTER SHINANOMACHI RENGAKAN, 35 SHINANO-MACHI SHINJUKU-KU, TOKYO, 160-0016, JAPAN SN 1347-4367 J9 DRUG METAB PHARMACOK JI Drug Metab. Pharmacokinet. PD DEC 25 PY 2012 VL 27 IS 6 BP 663 EP 667 DI 10.2133/dmpk.DMPK-12-SH-030 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 058EL UT WOS:000312616800013 PM 22785258 ER PT J AU Forman, DE Fleg, JL Kitzman, DW Brawner, CA Swank, AM McKelvie, RS Clare, RM Ellis, SJ Dunlap, ME Bittner, V AF Forman, Daniel E. Fleg, Jerome L. Kitzman, Dalane W. Brawner, Clinton A. Swank, Ann M. McKelvie, Robert S. Clare, Robert M. Ellis, Stephen J. Dunlap, Mark E. Bittner, Vera TI 6-Min Walk Test Provides Prognostic Utility Comparable to Cardiopulmonary Exercise Testing in Ambulatory Outpatients With Systolic Heart Failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiopulmonary exercise testing; heart failure; prognosis; walking test ID PEAK OXYGEN-UPTAKE; AEROBIC CAPACITY; TEST-PERFORMANCE; CONTROLLED-TRIAL; MORTALITY; MORBIDITY; SURVIVAL; ASSOCIATION; DYSFUNCTION; STATEMENT AB Objectives The goal of this study was to compare the prognostic efficacy of the 6-min walk (6MW) and cardiopulmonary exercise (CPX) tests in stable outpatients with chronic heart failure (HF). Background CPX and 6MW tests are commonly applied as prognostic gauges for systolic HF patients, but few direct comparisons have been conducted. Methods Stable New York Heart Association (NYHA) functional class II and III systolic HF patients (ejection fraction <= 35%) from the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) trial were studied. 6MW distance (6MWD) and CPX indices (peak oxygen consumption [VO2] and ventilatory equivalents for exhaled carbon dioxide [VE/VCO2] slope) were compared as predictors of all-cause mortality/hospitalization and all-cause mortality over 2.5 years of mean follow-up. Results A total of 2,054 HF-ACTION participants underwent both CPX and 6MW tests at baseline (median age 59 years; 71% male; 64% NYHA functional class II and 36% NYHA functional class III/IV). In unadjusted models and in models that included key clinical and demographic covariates, C-indices of 6MWD were 0.58 and 0.65 (unadjusted) and 0.62 and 0.72 (adjusted) in predicting all-cause mortality/hospitalization and all-cause mortality, respectively. C-indices for peak VO2 were 0.61 and 0.68 (unadjusted) and 0.63 and 0.73 (adjusted). C-indices for VE/VCO2 slope were 0.56 and 0.65 (unadjusted) and 0.61 and 0.71 (adjusted); combining peak VO2 and VE/VCO2 slope did not improve the C-indices. Overlapping 95% confidence intervals and modest integrated discrimination improvement values confirmed similar prognostic discrimination by 6MWD and CPX indices within adjusted models. Conclusions In systolic HF outpatients, 6MWD and CPX indices demonstrated similar utility as univariate predictors for all-cause hospitalization/mortality and all-cause mortality. However, 6MWD or CPX indices added only modest prognostic discrimination to models that included important demographic and clinical covariates. (J Am Coll Cardiol 2012;60:2653-61) (C) 2012 by the American College of Cardiology Foundation C1 [Forman, Daniel E.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Forman, Daniel E.] Vet Adm Boston Healthcare Syst, New England Geriatr Res Educ & Clin Care, Boston, MA USA. [Fleg, Jerome L.] NHLBI, Bethesda, MD 20892 USA. [Kitzman, Dalane W.] Wake Forest Univ Hlth Sci, Cardiol Sect, Dept Internal Med, Winston Salem, NC USA. [Kitzman, Dalane W.] Wake Forest Univ Hlth Sci, Sect Geriatr, Dept Internal Med, Winston Salem, NC USA. [Brawner, Clinton A.] Henry Ford Hosp, Div Cardiovasc Med, Detroit, MI 48202 USA. [Swank, Ann M.] Univ Louisville, Dept Hlth & Sport Sci, Louisville, KY 40292 USA. [McKelvie, Robert S.] Hamilton Hlth Sci, Hamilton, ON, Canada. [Clare, Robert M.; Ellis, Stephen J.] Duke Clin Res Inst, Durham, NC USA. [Dunlap, Mark E.] Case Western Reserve Univ, Heart & Vasc Ctr, Cleveland, OH 44106 USA. [Bittner, Vera] Univ Alabama Birmingham, Dept Med, Div Cardiovasc Dis, Birmingham, AL 35294 USA. RP Forman, DE (reprint author), Brigham & Womens Hosp, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA. EM deforman@partners.org OI Bittner, Vera/0000-0001-9456-850X; Brawner, Clinton A./0000-0002-1705-6620 FU NHLBI NIH HHS [U01 HL068973] NR 38 TC 47 Z9 48 U1 2 U2 16 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 DEC 25 PY 2012 VL 60 IS 25 BP 2653 EP 2661 DI 10.1016/j.jacc.2012.08.1010 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 056YG UT WOS:000312527000010 PM 23177293 ER PT J AU McGill, LA Ismail, TF Nielles-Vallespin, S Ferreira, P Scott, AD Roughton, M Kilner, PJ Ho, SY McCarthy, KP Gatehouse, PD de Silva, R Speier, P Feiweier, T Mekkaoui, C Sosnovik, DE Prasad, SK Firmin, DN Pennell, DJ AF McGill, Laura-Ann Ismail, Tevfik F. Nielles-Vallespin, Sonia Ferreira, Pedro Scott, Andrew D. Roughton, Michael Kilner, Philip J. Ho, S. Yen McCarthy, Karen P. Gatehouse, Peter D. de Silva, Ranil Speier, Peter Feiweier, Thorsten Mekkaoui, Choukkri Sosnovik, David E. Prasad, Sanjay K. Firmin, David N. Pennell, Dudley J. TI Reproducibility of in-vivo diffusion tensor cardiovascular magnetic resonance in hypertrophic cardiomyopathy SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Hypertrophic cardiomyopathy; Diffusion tensor imaging; Diffusion weighted imaging; Cardiovascular magnetic resonance; Disarray ID MUSCLE CELL DISORGANIZATION; LEFT-VENTRICULAR MYOCARDIUM; ENGINEERING MECHANICS; DIASTOLIC FUNCTION; SUCCESSIVE STATES; HEART-ASSOCIATION; FIBER DISARRAY; TASK-FORCE; DIAGNOSIS; WALL AB Background: Myocardial disarray is an important histological feature of hypertrophic cardiomyopathy (HCM) which has been studied post-mortem, but its in-vivo prevalence and extent is unknown. Cardiac Diffusion Tensor Imaging (cDTI) provides information on mean intravoxel myocyte orientation and potentially myocardial disarray. Recent technical advances have improved in-vivo cDTI, and the aim of this study was to assess the interstudy reproducibility of quantitative in-vivo cDTI in patients with HCM. Methods and results: A stimulated-echo single-shot-EPI sequence with zonal excitation and parallel imaging was implemented. Ten patients with HCM were each scanned on 2 different days. For each scan 3 short axis mid-ventricular slices were acquired with cDTI at end systole. Fractional anisotropy (FA), mean diffusivity (MD), and helix angle (HA) maps were created using a cDTI post-processing platform developed in-house. The mean +/- SD global FA was 0.613 +/- 0.044, MD was 0.750 +/- 0.154 x 10(-3) mm(2)/s and HA was epicardium -34.3 +/- 7.6 degrees, mesocardium 3.5 +/- 6.9 degrees and endocardium 38.9 +/- 8.1 degrees. Comparison of initial and repeat studies showed global interstudy reproducibility for FA (SD = +/- 0.045, Coefficient of Variation (CoV) = 7.2%), MD (SD = +/- 0.135 x 10(-3) mm(2)/s, CoV = 18.6%) and HA (epicardium SD = +/- 4.8 degrees; mesocardium SD = +/- 3.4 degrees; endocardium SD = +/- 2.9 degrees). Reproducibility of FA was superior to MD (p = 0.003). Global MD was significantly higher in the septum than the reference lateral wall (0.784 +/- 0.188 vs 0.750 +/- 0.154 x10(-3) mm(2)/s, p < 0.001). Septal HA was significantly lower than the reference lateral wall in all 3 transmural layers (from -8.3 degrees to -10.4 degrees, all p < 0.001). Conclusions: To the best of our knowledge, this is the first study to assess the interstudy reproducibility of DTI in the human HCM heart in-vivo and the largest cDTI study in HCM to date. Our results show good reproducibility of FA, MD and HA which indicates that current technology yields robust in-vivo measurements that have potential clinical value. The interpretation of regional differences in the septum requires further investigation. C1 [McGill, Laura-Ann; Ismail, Tevfik F.; Nielles-Vallespin, Sonia; Ferreira, Pedro; Scott, Andrew D.; Roughton, Michael; Kilner, Philip J.; Ho, S. Yen; McCarthy, Karen P.; Gatehouse, Peter D.; de Silva, Ranil; Prasad, Sanjay K.; Firmin, David N.; Pennell, Dudley J.] Royal Brompton Hosp, Cardiovasc Magnet Resonance Unit, London SW3 6NP, England. [McGill, Laura-Ann; Nielles-Vallespin, Sonia; Ferreira, Pedro; Scott, Andrew D.; Kilner, Philip J.; Ho, S. Yen; McCarthy, Karen P.; de Silva, Ranil; Prasad, Sanjay K.; Firmin, David N.; Pennell, Dudley J.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. [Nielles-Vallespin, Sonia] NHLBI, NIH, DHHS, Bethesda, MD 20892 USA. [Speier, Peter; Feiweier, Thorsten] Siemens AG Med Solut, MR R&D, Erlangen, Germany. [Mekkaoui, Choukkri; Sosnovik, David E.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Martinos Ctr Biomed Imaging, Boston, MA USA. RP Firmin, DN (reprint author), Royal Brompton Hosp, Cardiovasc Magnet Resonance Unit, Sydney St, London SW3 6NP, England. EM d.firmin@imperial.ac.uk OI Gatehouse, Peter/0000-0002-0260-4719 FU National Institute of Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital London; Imperial College, London; British Heart Foundation FX This work was supported by the National Institute of Health Research Cardiovascular Biomedical Research Unit at the Royal Brompton Hospital and Imperial College, London. Dr Ismail is funded by the British Heart Foundation. NR 40 TC 33 Z9 33 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD DEC 24 PY 2012 VL 14 AR 86 DI 10.1186/1532-429X-14-86 PG 15 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 096BB UT WOS:000315377600001 PM 23259835 ER PT J AU Kotani, K Sakane, N Ueda, M Mashiba, S Hayase, Y Tsuzaki, K Yamada, T Remaley, AT AF Kotani, Kazuhiko Sakane, Naoki Ueda, Masashi Mashiba, Shinichi Hayase, Yasuyuki Tsuzaki, Kokoro Yamada, Toshiyuki Remaley, Alan T. TI Oxidized high-density lipoprotein is associated with increased plasma glucose in non-diabetic dyslipidemic subjects SO CLINICA CHIMICA ACTA LA English DT Article DE Atherosclerosis; Hyperlipidemia; Oxidative stress; Small dense LDL; LDL particle size ID APOLIPOPROTEIN-A-I; NON ENZYMATIC GLYCATION; CORONARY-HEART-DISEASE; CARDIOVASCULAR-DISEASE; HEMODIALYSIS-PATIENTS; OXIDATIVE STRESS; RISK-FACTORS; LDL; ATHEROSCLEROSIS; HDL AB Background: Oxidized high-density lipoprotein (oxHDL) has reduced capacity for cholesterol efflux and some of other anti-atherogenic properties of HDL, but the role of oxHDL in the pathogenesis of cardiometabolic disease has not been fully demonstrated. This study investigated the association of oxHDL with plasma glucose (PC) and the other atherosclerotic risk variables in non-diabetic dyslipidemic subjects. Methods: Conventional atherosclerotic markers and LDL particle size (LDL-PS), as determined by gel electrophoresis, were measured in 155 non-diabetic subjects (mean age of 57 years) with dyslipidemia Serum oxHDL levels were quantified using an antibody against oxidized human apoA-I in a sandwich ELISA format. Results: Multiple regression analysis adjusted for possible confounders revealed that HDL-cholesterol was independently, significantly and positively correlated with LDL-PS and oxHDL By multiple regression analysis, oxHDL was independently, significantly and positively correlated with fasting PG (beta = 0.19, P = 0.01). Subjects in the highest PG tertile group had approximately 30% higher oxHDL levels than the lowest PG tertile group. Conclusions: These results suggest that high PG levels may contribute to the HDL oxidation, irrespective of HDL-cholesterol levels, even in non-diabetic subjects with dyslipidemia, and that the measurement of oxHDL may be a useful marker of dysfunctional HDL. (C) 2012 Elsevier B.V. All rights reserved. C1 [Kotani, Kazuhiko] Natl Hosp Org, Kyoto Med Ctr, Clin Res Inst, Dept Prevent Med,Div Prevent Med,Fushimi Ku, Kyoto 6128555, Japan. [Kotani, Kazuhiko; Yamada, Toshiyuki] Jichi Med Univ, Dept Clin Lab Med, Shimotsuke, Tochigi 3290498, Japan. [Kotani, Kazuhiko; Remaley, Alan T.] NHLBI, Lipoprot Metab Sect, NIH, Bethesda, MD 20892 USA. [Ueda, Masashi; Mashiba, Shinichi; Hayase, Yasuyuki] Ikagaku Co Ltd, Kyoto 6048852, Japan. RP Kotani, K (reprint author), Natl Hosp Org, Kyoto Med Ctr, Clin Res Inst, Dept Prevent Med,Div Prevent Med,Fushimi Ku, 1-1 Fukakusa Mukaihata, Kyoto 6128555, Japan. EM kazukotani@jichi.ac.jp FU National Heart, Lung, and Blood Institute from the NIH FX This study was partly supported by research funds from the intramural National Heart, Lung, and Blood Institute from the NIH. NR 47 TC 3 Z9 3 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD DEC 24 PY 2012 VL 414 BP 125 EP 129 DI 10.1016/j.cca.2012.08.021 PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 059DU UT WOS:000312685400026 PM 22981508 ER PT J AU Brown, VL Rohani, P AF Brown, V. L. Rohani, Pejman TI The consequences of climate change at an avian influenza 'hotspot' SO BIOLOGY LETTERS LA English DT Article DE avian influenza virus; Delaware Bay; climate change; transmission model ID DELAWARE BAY; MIGRATION; BIRDS; VIRUSES AB Avian influenza viruses (AIVs) pose significant danger to human health. A key step in managing this threat is understanding the maintenance of AIVs in wild birds, their natural reservoir. Ruddy turnstones (Arenaria interpres) are an atypical bird species in this regard, annually experiencing high AIV prevalence in only one location-Delaware Bay, USA, during their spring migration. While there, they congregate on beaches, attracted by the super-abundance of horseshoe crab eggs. A relationship between ruddy turnstone and horseshoe crab (Limulus polyphemus) population sizes has been established, with a declining horseshoe crab population linked to a corresponding drop in ruddy turnstone population sizes. The effect of this interaction on AIV prevalence in ruddy turnstones has also been addressed. Here, we employ a transmission model to investigate how the interaction between these two species is likely to be altered by climate change. We explore the consequences of this modified interaction on both ruddy turnstone population size and AIV prevalence and show that, if climate change leads to a large enough mismatch in species phenology, AIV prevalence in ruddy turnstones will increase even as their population size decreases. C1 [Brown, V. L.; Rohani, Pejman] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Brown, V. L.; Rohani, Pejman] Univ Michigan, Ctr Study Complex Syst, Ann Arbor, MI 48109 USA. [Rohani, Pejman] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Brown, VL (reprint author), Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. EM vlbrown@umich.edu FU James S. McDonnell Foundation; National Science Foundation [DEB-0917853]; RAPIDD program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX This work was supported by the James S. McDonnell Foundation and the National Science Foundation (DEB-0917853). P.R. was also supported by the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. NR 14 TC 8 Z9 8 U1 4 U2 66 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1744-9561 J9 BIOL LETTERS JI Biol. Lett. PD DEC 23 PY 2012 VL 8 IS 6 BP 1036 EP 1039 DI 10.1098/rsbl.2012.0635 PG 4 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 036KP UT WOS:000311025100038 PM 22933039 ER PT J AU Dagdug, L Berezhkovskii, AM Bezrukov, SM AF Dagdug, Leonardo Berezhkovskii, Alexander M. Bezrukov, Sergey M. TI Particle lifetime in cylindrical cavity with absorbing spot on the wall: Going beyond the narrow escape problem SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE diffusion AB The mean lifetime of a particle diffusing in a cylindrical cavity with a circular absorbing spot on the cavity wall is studied analytically as a function of the spot radius, its location on the wall, the particle initial position, and the cavity shape determined by its length and radius. When the spot radius tends to zero our formulas for the mean lifetime reduce to the result given by the solution of the narrow escape problem, according to which the mean lifetime is proportional to the ratio of the cavity volume to the spot radius and is independent of the cavity shape, the spot location on the cavity wall, and the particle starting point, assuming that this point is not too close to the spot. When the spot radius is not small enough, the asymptotic narrow escape formula for the mean lifetime fails, and one should use more general formulas derived in the present study. To check the accuracy and to establish the range of applicability of the formulas, we compare our theoretical predictions with the results of Brownian dynamics simulations. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4772183] C1 [Dagdug, Leonardo] Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. [Dagdug, Leonardo; Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Dagdug, L (reprint author), Univ Autonoma Metropolitana Iztapalapa, Dept Fis, Mexico City 09340, DF, Mexico. FU Intramural Research Program of the National Institutes of Health (NIH), Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We are grateful to Vladimir Zitserman for numerous discussions of different aspects of the problem and to Super Computer Division of Universidad Autonoma Metropolitana-Iztapalapa for the use of their computational facilities. This study was supported by the Intramural Research Program of the National Institutes of Health (NIH), Center for Information Technology and Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 13 TC 2 Z9 2 U1 0 U2 5 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 DEC 21 PY 2012 VL 137 IS 23 AR 234108 DI 10.1063/1.4772183 PG 6 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 060LT UT WOS:000312780300010 PM 23267472 ER PT J AU Sodt, AJ Pastor, RW AF Sodt, Alexander J. Pastor, Richard W. TI The tension of a curved surface from simulation SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE deformation; Laplace equations; molecular dynamics method; organic compounds; surface tension; water ID LIQUID-VAPOR INTERFACE; PARTICLE MESH EWALD; MOLECULAR-DYNAMICS; COMPUTER-SIMULATION; MEMBRANE CURVATURE; LIPID-BILAYERS; LIQUID/LIQUID INTERFACES; BENDING ELASTICITY; HEXAGONAL PHASES; LOCAL PRESSURE AB This paper demonstrates a method for calculating the tension of a system with a curved interface from a molecular dynamics simulation. To do so, the pressure of a subset of the system is determined by applying a local (virtual) mechanical deformation, fitting the response to that of a bulk fluid, and then using the Young-Laplace equation to infer the tension of the interface. The accuracy of the method is tested by calculating the local pressure of a series of water simulations at various external pressures. The tension of a simulated curved octane-water interface is computed with the method and compares well with the planar tension (approximate to 46.7 dyn/cm). Finally, an ambiguity is resolved between the Harasima and Irving-Kirkwood methods of calculating the local pressure as a means for computing the tension. [http://dx.doi.org/10.1063/1.4769880] C1 [Sodt, Alexander J.; Pastor, Richard W.] NHLBI, NIH, Bethesda, MD 20892 USA. RP Sodt, AJ (reprint author), NHLBI, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM pastorr@nhlbi.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute FX This work was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Heart, Lung, and Blood Institute. NAMD was developed by the Theoretical and Computational Biophysics Group in the Beckman Institute for Advanced Science and Technology at the University of Illinois at Urbana-Champaign. NR 52 TC 9 Z9 9 U1 3 U2 58 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 DEC 21 PY 2012 VL 137 IS 23 AR 234101 DI 10.1063/1.4769880 PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 060LT UT WOS:000312780300003 PM 23267465 ER PT J AU Schnitzler, CE Pang, K Powers, ML Reitzel, AM Ryan, JF Simmons, D Tada, T Park, M Gupta, J Brooks, SY Blakesley, RW Yokoyama, S Haddock, SHD Martindale, MQ Baxevanis, AD AF Schnitzler, Christine E. Pang, Kevin Powers, Meghan L. Reitzel, Adam M. Ryan, Joseph F. Simmons, David Tada, Takashi Park, Morgan Gupta, Jyoti Brooks, Shelise Y. Blakesley, Robert W. Yokoyama, Shozo Haddock, Steven H. D. Martindale, Mark Q. Baxevanis, Andreas D. TI Genomic organization, evolution, and expression of photoprotein and opsin genes in Mnemiopsis leidyi: a new view of ctenophore photocytes SO BMC BIOLOGY LA English DT Article DE Bioluminescence; ctenophore; Mnemiopsis leidyi; opsin; photocyte; photoprotein; photoreception; phototransduction ID CALCIUM-ACTIVATED PHOTOPROTEINS; BLUE FLUORESCENT PROTEIN; SENSITIVE PHOTOPROTEIN; MAXIMUM-LIKELIHOOD; SEQUENCE-ANALYSIS; SEA-ANEMONE; CA2+-REGULATED PHOTOPROTEINS; PHYLOGENETIC ANALYSIS; PORICHTHYS-NOTATUS; MIXED MODELS AB Background: Calcium-activated photoproteins are luciferase variants found in photocyte cells of bioluminescent jellyfish (Phylum Cnidaria) and comb jellies (Phylum Ctenophora). The complete genomic sequence from the ctenophore Mnemiopsis leidyi, a representative of the earliest branch of animals that emit light, provided an opportunity to examine the genome of an organism that uses this class of luciferase for bioluminescence and to look for genes involved in light reception. To determine when photoprotein genes first arose, we examined the genomic sequence from other early-branching taxa. We combined our genomic survey with gene trees, developmental expression patterns, and functional protein assays of photoproteins and opsins to provide a comprehensive view of light production and light reception in Mnemiopsis. Results: The Mnemiopsis genome has 10 full-length photoprotein genes situated within two genomic clusters with high sequence conservation that are maintained due to strong purifying selection and concerted evolution. Photoprotein-like genes were also identified in the genomes of the non-luminescent sponge Amphimedon queenslandica and the non-luminescent cnidarian Nematostella vectensis, and phylogenomic analysis demonstrated that photoprotein genes arose at the base of all animals. Photoprotein gene expression in Mnemiopsis embryos begins during gastrulation in migrating precursors to photocytes and persists throughout development in the canals where photocytes reside. We identified three putative opsin genes in the Mnemiopsis genome and show that they do not group with well-known bilaterian opsin subfamilies. Interestingly, photoprotein transcripts are co-expressed with two of the putative opsins in developing photocytes. Opsin expression is also seen in the apical sensory organ. We present evidence that one opsin functions as a photopigment in vitro, absorbing light at wavelengths that overlap with peak photoprotein light emission, raising the hypothesis that light production and light reception may be functionally connected in ctenophore photocytes. We also present genomic evidence of a complete ciliary phototransduction cascade in Mnemiopsis. Conclusions: This study elucidates the genomic organization, evolutionary history, and developmental expression of photoprotein and opsin genes in the ctenophore Mnemiopsis leidyi, introduces a novel dual role for ctenophore photocytes in both bioluminescence and phototransduction, and raises the possibility that light production and light reception are linked in this early-branching non-bilaterian animal. C1 [Schnitzler, Christine E.; Blakesley, Robert W.; Baxevanis, Andreas D.] NHGRI, Genome Technol Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Pang, Kevin; Ryan, Joseph F.] Sars Int Ctr Marine Mol Biol, N-5008 Bergen, Norway. [Powers, Meghan L.; Haddock, Steven H. D.] Monterey Bay Aquarium Res Inst, Moss Landing, CA 95039 USA. [Reitzel, Adam M.] Univ N Carolina, Dept Biol, Charlotte, NC 28223 USA. [Simmons, David; Martindale, Mark Q.] Univ Hawaii Manoa, Pacific Biosci Res Ctr, Kewalo Marine Lab, Honolulu, HI 96813 USA. [Tada, Takashi; Yokoyama, Shozo] Emory Univ, Dept Biol, Atlanta, GA 30322 USA. [Park, Morgan; Gupta, Jyoti; Brooks, Shelise Y.; Blakesley, Robert W.] NHGRI, NIH Intramural Sequencing Ctr, NIH, Rockville, MD 20852 USA. RP Baxevanis, AD (reprint author), NHGRI, Genome Technol Branch, Div Intramural Res, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM andy@nhgri.nih.gov RI Schnitzler, Christine/G-8733-2013 FU National Human Genome Research Institute, National Institutes of Health (NIH); Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH [F32HD062178]; National Institute of General Medical Sciences, NIH [GM087198]; National Eye Institute, NIH [EY016400] FX This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (NIH). In addition, AMR was supported by Award Number F32HD062178 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH; MP and SHDH were supported by Award Number GM087198, National Institute of General Medical Sciences, NIH; and SY was supported by Award Number EY016400, National Eye Institute, NIH. NR 107 TC 43 Z9 43 U1 4 U2 82 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD DEC 21 PY 2012 VL 10 AR 107 DI 10.1186/1741-7007-10-107 PG 26 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 086ND UT WOS:000314690700001 PM 23259493 ER PT J AU Flores, R Shi, JX Fuhrman, B Xu, X Veenstra, TD Gail, MH Gajer, P Ravel, J Goedert, JJ AF Flores, Roberto Shi, Jianxin Fuhrman, Barbara Xu, Xia Veenstra, Timothy D. Gail, Mitchell H. Gajer, Pawel Ravel, Jacques Goedert, James J. TI Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article DE Microbiome; Feces; Enterohepatic circulation; beta-glucuronidase; beta-glucosidase; Postmenopausal estrogens; Fecal estrogens; Estrogen metabolites ID HORMONE-BINDING GLOBULIN; CHROMATOGRAPHY-MASS SPECTROMETRY; BREAST-CANCER RISK; POSTMENOPAUSAL WOMEN; ENTEROHEPATIC RECIRCULATION; ENDOGENOUS ESTROGENS; STEROID-HORMONES; SEX-HORMONES; OLDER MEN; SERUM AB Background: High systemic estrogen levels contribute to breast cancer risk for postmenopausal women, whereas low levels contribute to osteoporosis risk. Except for obesity, determinants of non-ovarian systemic estrogen levels are undefined. We sought to identify members and functions of the intestinal microbial community associated with estrogen levels via enterohepatic recirculation. Methods: Fifty-one epidemiologists at the National Institutes of Health, including 25 men, 7 postmenopausal women, and 19 premenopausal women, provided urine and aliquots of feces, using methods proven to yield accurate and reproducible results. Estradiol, estrone, 13 estrogen metabolites (EM), and their sum (total estrogens) were quantified in urine and feces by liquid chromatography/tandem mass spectrometry. In feces, beta-glucuronidase and beta-glucosidase activities were determined by realtime kinetics, and microbiome diversity and taxonomy were estimated by pyrosequencing 16S rRNA amplicons. Pearson correlations were computed for each log(e) estrogen level, loge enzymatic activity level, and microbiome alpha diversity estimate. For the 55 taxa with mean relative abundance of at least 0.1%, ordinal levels were created [zero, low (below median of detected sequences), high] and compared to loge estrogens, beta-glucuronidase and beta-glucosidase enzymatic activity levels by linear regression. Significance was based on two-sided tests with alpha=0.05. Results: In men and postmenopausal women, levels of total urinary estrogens (as well as most individual EM) were very strongly and directly associated with all measures of fecal microbiome richness and alpha diversity (R >= 0.50, P <= 0.003). These non-ovarian systemic estrogens also were strongly and significantly associated with fecal Clostridia taxa, including non-Clostridiales and three genera in the Ruminococcaceae family (R=0.57-0.70, P=0.03-0.002). Estrone, but not other EM, in urine correlated significantly with functional activity of fecal beta-glucuronidase (R=0.36, P=0.04). In contrast, fecal beta-glucuronidase correlated inversely with fecal total estrogens, both conjugated and deconjugated (R <=-0.47, P <= 0.01). Premenopausal female estrogen levels, which were collected across menstrual cycles and thus highly variable, were completely unrelated to fecal microbiome and enzyme parameters (P >= 0.6). Conclusions: Intestinal microbial richness and functions, including but not limited to beta-glucuronidase, influence levels of non-ovarian estrogens via enterohepatic circulation. Thus, the gut microbial community likely affects the risk for estrogen-related conditions in older adults. Understanding how Clostridia taxa relate to systemic estrogens may identify targets for interventions. C1 [Flores, Roberto; Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Flores, Roberto] NCI, Canc Prevent Fellowship Program, Rockville, MD 20852 USA. [Shi, Jianxin; Gail, Mitchell H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Fuhrman, Barbara] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Xu, Xia; Veenstra, Timothy D.] SAIC Frederick, Lab Prote & Analyt Technol, Adv Technol Program, Frederick, MD 21702 USA. [Gajer, Pawel; Ravel, Jacques] Univ Maryland, Sch Med, Inst Genome Sci, Baltimore, MD 21201 USA. RP Goedert, JJ (reprint author), NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7068, Rockville, MD 20852 USA. EM goedertj@mail.nih.gov OI Fuhrman, Barbara/0000-0002-1777-9888; Ravel, Jacques/0000-0002-0851-2233 NR 38 TC 22 Z9 23 U1 3 U2 54 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD DEC 21 PY 2012 VL 10 AR 253 DI 10.1186/1479-5876-10-253 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 077SL UT WOS:000314048000001 PM 23259758 ER PT J AU Borges, R Johnson, WE O'Brien, SJ Vasconcelos, V Antunes, A AF Borges, Rui Johnson, Warren E. O'Brien, Stephen J. Vasconcelos, Vitor Antunes, Agostinho TI The Role of Gene Duplication and Unconstrained Selective Pressures in the Melanopsin Gene Family Evolution and Vertebrate Circadian Rhythm Regulation SO PLOS ONE LA English DT Article ID RETINAL GANGLION-CELLS; DETECTING POSITIVE SELECTION; FUNCTIONAL DIVERGENCE; CIONA-INTESTINALIS; MAXIMUM-LIKELIHOOD; PHOTOPIGMENT MELANOPSIN; PHOTORECEPTIVE SYSTEMS; MOLECULAR ADAPTATION; PHYLOGENETIC TREES; CRYSTAL-STRUCTURE AB Melanopsin is a photosensitive cell protein involved in regulating circadian rhythms and other non-visual responses to light. The melanopsin gene family is represented by two paralogs, OPN4x and OPN4m, which originated through gene duplication early in the emergence of vertebrates. Here we studied the melanopsin gene family using an integrated gene/protein evolutionary approach, which revealed that the rhabdomeric urbilaterian ancestor had the same amino acid patterns (DRY motif and the Y and E conterions) as extant vertebrate species, suggesting that the mechanism for light detection and regulation is similar to rhabdomeric rhodopsins. Both OPN4m and OPN4x paralogs are found in vertebrate genomic paralogons, suggesting that they diverged following this duplication event about 600 million years ago, when the complex eye emerged in the vertebrate ancestor. Melanopsins generally evolved under negative selection (omega = 0.171) with some minor episodes of positive selection (proportion of sites = 25%) and functional divergence (theta(I) = 0.349 and theta(II) = 0.126). The OPN4m and OPN4x melanopsin paralogs show evidence of spectral divergence at sites likely involved in melanopsin light absorbance (200F, 273S and 276A). Also, following the teleost lineage-specific whole genome duplication (3R) that prompted the teleost fish radiation, type I divergence (theta(I) = 0.181) and positive selection (affecting 11% of sites) contributed to amino acid variability that we related with the photo-activation stability of melanopsin. The melanopsin intracellular regions had unexpectedly high variability in their coupling specificity of G-proteins and we propose that Gq/11 and Gi/o are the two G-proteins most-likely to mediate the melanopsin phototransduction pathway. The selection signatures were mainly observed on retinal-related sites and the third and second intracellular loops, demonstrating the physiological plasticity of the melanopsin protein group. Our results provide new insights on the phototransduction process and additional tools for disentangling and understanding the links between melanopsin gene evolution and the specializations observed in vertebrates, especially in teleost fish. C1 [Borges, Rui; Vasconcelos, Vitor; Antunes, Agostinho] Univ Porto, CIMAR CIIMAR, Ctr Interdisciplinar Invest Marinha & Ambiental, P-4100 Oporto, Portugal. [Borges, Rui; Vasconcelos, Vitor; Antunes, Agostinho] Univ Porto, Dept Biol, Fac Ciencias, P-4100 Oporto, Portugal. [Johnson, Warren E.; O'Brien, Stephen J.; Antunes, Agostinho] NCI, Lab Genom Divers, Frederick, MD 21701 USA. [O'Brien, Stephen J.] St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Bioinformat, St Petersburg, Russia. RP Antunes, A (reprint author), Univ Porto, CIMAR CIIMAR, Ctr Interdisciplinar Invest Marinha & Ambiental, Rua Bragas, P-4100 Oporto, Portugal. EM aantunes@ciimar.up.pt RI Vasconcelos, Vitor/A-8933-2008; Scientific output, CIIMAR/E-5122-2012; Johnson, Warren/D-4149-2016; Borges, Rui/H-5873-2016; OI Vasconcelos, Vitor/0000-0003-3585-2417; Scientific output, CIIMAR/0000-0001-6270-2153; Johnson, Warren/0000-0002-5954-186X; Borges, Rui/0000-0003-3931-9476; O'Brien, Stephen J./0000-0001-7353-8301; Antunes, Agostinho/0000-0002-1328-1732 FU Portuguese Foundation for Science and Technology (FCT) [SFRH/BD/79850/2011, PTDC/AAC-AMB/104983/2008 (FCOMP-01-0124-FEDER-008610), PTDC/AAC-AMB/121301/2010 (FCOMP-01-0124-FEDER-019490)]; Intramural Research Program of the National Institutes of Health, National Cancer Institute FX The authors acknowledge the Portuguese Foundation for Science and Technology (FCT) for financial support to RB (SFRH/BD/79850/2011) and the projects PTDC/AAC-AMB/104983/2008 (FCOMP-01-0124-FEDER-008610) and PTDC/AAC-AMB/121301/2010 (FCOMP-01-0124-FEDER-019490) to AA. This research received support by the Intramural Research Program of the National Institutes of Health, National Cancer Institute to WEJ and SJO. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 82 TC 8 Z9 8 U1 1 U2 23 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 DEC 21 PY 2012 VL 7 IS 12 AR e52413 DI 10.1371/journal.pone.0052413 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 065OW UT WOS:000313158800064 PM 23285031 ER PT J AU Legros, M Xu, CG Okamoto, K Scott, TW Morrison, AC Lloyd, AL Gould, F AF Legros, Mathieu Xu, Chonggang Okamoto, Kenichi Scott, Thomas W. Morrison, Amy C. Lloyd, Alun L. Gould, Fred TI Assessing the Feasibility of Controlling Aedes aegypti with Transgenic Methods: A Model-Based Evaluation SO PLOS ONE LA English DT Article ID MARK-RELEASE-RECAPTURE; BORNE DISEASE-CONTROL; DENGUE CONTROL; COMMUNITY PARTICIPATION; MESOCYCLOPS COPEPODA; CULICIDAE PRODUCTION; DIPTERA-CULICIDAE; VECTOR MOSQUITOS; SOUTHERN MEXICO; GENETIC-CONTROL AB Suppression of dengue and malaria through releases of genetically engineered mosquitoes might soon become feasible. Aedes aegypti mosquitoes carrying a conditionally lethal transgene have recently been used to suppress local vector populations in small-scale field releases. Prior to releases of transgenic insects on a wider scale, however, most regulatory authorities will require additional evidence that suppression will be effective in natural heterogeneous habitats. We use a spatially explicit stochastic model of an Ae. aegypti population in Iquitos, Peru, along with an uncertainty analysis of its predictions, to quantitatively assess the outcome of varied operational approaches for releases of transgenic strains with conditional death of females. We show that population elimination might be an unrealistic objective in heterogeneous populations. We demonstrate that substantial suppression can nonetheless be achieved if releases are deployed in a uniform spatial pattern using strains combining multiple lethal elements, illustrating the importance of detailed spatial models for guiding genetic mosquito control strategies. C1 [Legros, Mathieu; Xu, Chonggang; Okamoto, Kenichi; Gould, Fred] N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. [Legros, Mathieu; Scott, Thomas W.; Morrison, Amy C.] Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. [Xu, Chonggang] Los Alamos Natl Lab, Div Earth & Environm Sci, Los Alamos, NM 87545 USA. [Scott, Thomas W.; Lloyd, Alun L.; Gould, Fred] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Lloyd, Alun L.] N Carolina State Univ, Grad Program, Dept Math & Biomath, Raleigh, NC 27695 USA. RP Legros, M (reprint author), N Carolina State Univ, Dept Entomol, Raleigh, NC 27695 USA. EM legros.mathieu@gmail.com RI Legros, Mathieu/E-6767-2011; Lloyd, Alun/H-4944-2012; OI Legros, Mathieu/0000-0003-3807-8594; Xu, Chonggang/0000-0002-0937-5744 FU National Institutes of Health [R01-AI54954-0IA2]; Regents of the University of California from the Foundation for the National Institutes of Health Grand Challenges in Global Health initiative FX This work was funded by National Institutes of Health grant R01-AI54954-0IA2, and through the Regents of the University of California from the Foundation for the National Institutes of Health Grand Challenges in Global Health initiative. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 13 Z9 13 U1 2 U2 37 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 DEC 21 PY 2012 VL 7 IS 12 AR e52235 DI 10.1371/journal.pone.0052235 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 065OW UT WOS:000313158800039 PM 23284949 ER PT J AU Xiao, S Nayak, B Samuel, A Paldurai, A Kanabagattebasavarajappa, M Prajitno, TY Bharoto, EE Collins, PL Samal, SK AF Xiao, Sa Nayak, Baibaswata Samuel, Arthur Paldurai, Anandan Kanabagattebasavarajappa, Mallikarjuna Prajitno, Teguh Y. Bharoto, Eny E. Collins, Peter L. Samal, Siba K. TI Generation by Reverse Genetics of an Effective, Stable, Live-Attenuated Newcastle Disease Virus Vaccine Based on a Currently Circulating, Highly Virulent Indonesian Strain SO PLOS ONE LA English DT Article ID PROTEIN CLEAVAGE SITE; SHEDDING FOLLOWING VACCINATION; FUSION PROTEIN; CHICKENS; IMMUNIZATION; CHALLENGE; DIVERSITY; CANDIDATE; SEQUENCES; WATERFOWL AB Newcastle disease virus (NDV) can cause severe disease in chickens. Although NDV vaccines exist, there are frequent reports of outbreaks in vaccinated chickens. During 2009-2010, despite intense vaccination, NDV caused major outbreaks among commercial poultry farms in Indonesia. These outbreaks raised concern regarding the protective immunity of current vaccines against circulating virulent strains in Indonesia. In this study, we investigated whether a recombinant attenuated Indonesian NDV strain could provide better protection against prevalent Indonesian viruses. A reverse genetics system for the highly virulent NDV strain Banjarmasin/010/10 (Ban/010) isolated in Indonesia in 2010 was constructed. The Ban/010 virus is classified in genotype VII of class II NDV, which is genetically distinct from the commercial vaccine strains B1 and LaSota, which belong to genotype II, and shares only 89 and 87% amino acid identity for the protective antigens F and HN, respectively. A mutant virus, named Ban/AF, was developed in which the virulent F protein cleavage site motif "RRQKR down arrow F" was modified to an avirulent motif "(G) under bar RQ (G) under barR down arrow(L) under bar" by three amino acid substitutions (underlined). The Ban/AF vaccine virus did not produce syncytia or plaques in cell culture, even in the presence of added protease. Pathogenicity tests showed that Ban/AF was completely avirulent. Ban/AF replicated efficiently during 10 consecutive passages in chickens and remained genetically stable. Serological analysis showed that Ban/AF induced higher neutralization and hemagglutination inhibition antibody titers against the prevalent viruses than the commercial vaccines B1 or LaSota. Both Ban/AF and commercial vaccines provided protection against clinical disease and mortality after challenge with virulent NDV strain Ban/010 (genotype VII) or GB Texas (genotype II). However, Ban/AF significantly reduced challenge virus shedding from the vaccinated birds compared to B1 vaccine. These results suggest that Ban/AF can provide better protection than commercial vaccines and is a promising vaccine candidate against NDV strains circulating in Indonesia. C1 [Xiao, Sa; Nayak, Baibaswata; Samuel, Arthur; Paldurai, Anandan; Kanabagattebasavarajappa, Mallikarjuna; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Prajitno, Teguh Y.] Japfa Comfeed Indonesia, Jakarta, Indonesia. [Bharoto, Eny E.] Vaksindo Satwa Nusantara, Jakarta, Indonesia. [Collins, Peter L.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu RI Nayak, Baibaswata/L-6156-2016 FU National Institute of Allergy and Infectious Diseases (NIAID) [N01A060009]; NIAID, National Institutes of Health (NIH) Intramural Research Program FX This research was supported by National Institute of Allergy and Infectious Diseases (NIAID) contract no. N01A060009 (85% support) and NIAID, National Institutes of Health (NIH) Intramural Research Program (15% support). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 17 Z9 18 U1 1 U2 14 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 DEC 21 PY 2012 VL 7 IS 12 AR e52751 DI 10.1371/journal.pone.0052751 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 065OW UT WOS:000313158800094 PM 23285174 ER PT J AU Ragusa, MJ Stanley, RE Hurley, JH AF Ragusa, Michael J. Stanley, Robin E. Hurley, James H. TI Architecture of the Atg17 Complex as a Scaffold for Autophagosome Biogenesis SO CELL LA English DT Article ID SMALL-ANGLE SCATTERING; SACCHAROMYCES-CEREVISIAE; MONITORING AUTOPHAGY; MEMBRANE CURVATURE; PROTEIN-KINASE; EARLY STEPS; YEAST; FIP200; MACROMOLECULES; TUMORIGENESIS AB Macroautophagy is a bulk clearance mechanism in which the double-membraned phagophore grows and engulfs cytosolic material. In yeast, the phagophore nucleates from a cluster of 20-30 nm diameter Atg9-containing vesicles located at a multiprotein assembly known as the preautophagosomal structure (PAS). The crystal structure of a 2:2:2 complex of the earliest acting PAS proteins, Atg17, Atg29, and Atg31, was solved at 3.05 angstrom resolution. Atg17 is crescent shaped with a 10 nm radius of curvature. Dimerization of the Atg17-Atg31-Atg29 complex is critical for both PAS formation and autophagy, and each dimer contains two separate and complete crescents. Upon induction of autophagy, Atg17-Atg31-Atg29 assembles with Atg1 and Atg13, which in turn initiates the formation of the phagophore. The C-terminal EAT domain of Atg1 was shown to sense membrane curvature, dimerize, and tether lipid vesicles. These data suggest a structural mechanism for the organization of Atg9 vesicles into the early phagophore. C1 [Ragusa, Michael J.; Stanley, Robin E.; Hurley, James H.] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM james.hurley@nih.gov FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; U.S. DOE [DE-AC02-06CH11357]; NIH, NIDDK; Damon Runyon Cancer Research Fellowship; Ruth Kirschtein NRSA fellowship [GM099319] FX We thank D. Klionsky and W. Prinz for strains, constructs, and technical advice; X. Zuo for assistance with SAXS; X.-F. Ren and R. Ghirlando for light scattering assistance; B. Canagarajah for assistance with Figure 7; and T.R. Serio for a vector. Crystallographic data were collected at the Southeast Regional Collaborative Access Team 22-ID and 22-BM beamlines at the Advanced Photon Source, Argonne National Laboratory. SAXS data were collected at NCI beamline 12ID-B. Use of the Advanced Photon Source was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract number W-31-109-Eng-38 and was supported by the U.S. DOE under contract number DE-AC02-06CH11357. This research was supported by the Intramural Program of the NIH, NIDDK (J.H.H.), a Damon Runyon Cancer Research Fellowship (R.E.S.), and a Ruth Kirschtein NRSA fellowship GM099319 (M.J.R.). NR 50 TC 89 Z9 92 U1 3 U2 27 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 21 PY 2012 VL 151 IS 7 BP 1501 EP 1512 DI 10.1016/j.cell.2012.11.028 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 062AA UT WOS:000312890300015 PM 23219485 ER PT J AU Plotnikov, SV Pasapera, AM Sabass, B Waterman, CM AF Plotnikov, Sergey V. Pasapera, Ana M. Sabass, Benedikt Waterman, Clare M. TI Force Fluctuations within Focal Adhesions Mediate ECM-Rigidity Sensing to Guide Directed Cell Migration SO CELL LA English DT Article ID PAXILLIN PHOSPHORYLATION; VINCULIN RECRUITMENT; MATRIX; KINASE; GROWTH; LAMELLIPODIA; CHEMOTAXIS; PHENOTYPE; DYNAMICS; ARP2/3 AB Cell migration toward areas of higher extracellular matrix (ECM) rigidity via a process called "durotaxis" is thought to contribute to development, immune response, and cancer metastasis. To understand how cells sample ECM rigidity to guide durotaxis, we characterized cell-generated forces on the nanoscale within single mature integrin-based focal adhesions (FAs). We found that individual FAs act autonomously, exhibiting either stable or dynamically fluctuating ("tugging") traction. We show that a FAK/phosphopaxillin/vinculin pathway is essential for high FA traction and to enable tugging FA traction over a broad range of ECM rigidities. We show that tugging FA traction is dispensable for FA maturation, chemotaxis, and haptotaxis but is critical to direct cell migration toward rigid ECM. We conclude that individual FAs dynamically sample rigidity by applying fluctuating pulling forces to the ECM to act as sensors to guide durotaxis, and that FAK/phosphopaxillin/vinculin signaling defines the rigidity range over which this dynamic sensing process operates. C1 [Plotnikov, Sergey V.; Pasapera, Ana M.; Waterman, Clare M.] NHLBI, Cell Biol & Physiol Ctr, NIH, Bethesda, MD 20892 USA. [Sabass, Benedikt] Univ Stuttgart, Inst Theoret Phys, D-70550 Stuttgart, Germany. RP Waterman, CM (reprint author), NHLBI, Cell Biol & Physiol Ctr, NIH, Bldg 10, Bethesda, MD 20892 USA. EM watermancm@nhlbi.nih.gov OI Waterman, Clare/0000-0001-6142-6775; Sabass, Benedikt/0000-0002-7769-8043 FU Division of Intramural Research, National Heart Lung and Blood Institute FX We thank Mary Beckerle for mouse embryonic fibroblasts, Michael Davidson for mApple paxillin, William Shin for support of the Waterman Lab microscopes, Sharon Campbell and Robert Fischer for helpful suggestions, and the NHLBI flow cytometry core facility. This research was supported by the Division of Intramural Research, National Heart Lung and Blood Institute. NR 40 TC 189 Z9 191 U1 5 U2 137 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 21 PY 2012 VL 151 IS 7 BP 1513 EP 1527 DI 10.1016/j.cell.2012.11.034 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 062AA UT WOS:000312890300016 PM 23260139 ER PT J AU Polo, JM Anderssen, E Walsh, RM Schwarz, BA Nefzger, CM Lim, SM Borkent, M Apostolou, E Alaei, S Cloutier, J Bar-Nur, O Cheloufi, S Stadtfeld, M Figueroa, ME Robinton, D Natesan, S Melnick, A Zhu, JF Ramaswamy, S Hochedlinger, K AF Polo, Jose M. Anderssen, Endre Walsh, Ryan M. Schwarz, Benjamin A. Nefzger, Christian M. Lim, Sue Mei Borkent, Marti Apostolou, Effie Alaei, Sara Cloutier, Jennifer Bar-Nur, Ori Cheloufi, Sihem Stadtfeld, Matthias Figueroa, Maria Eugenia Robinton, Daisy Natesan, Sridaran Melnick, Ari Zhu, Jinfang Ramaswamy, Sridhar Hochedlinger, Konrad TI A Molecular Roadmap of Reprogramming Somatic Cells into iPS Cells SO CELL LA English DT Article ID PLURIPOTENT STEM-CELLS; MOUSE; EXPRESSION; FIBROBLASTS; INDUCTION; DISCOVERY AB Factor-induced reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) is inefficient, complicating mechanistic studies. Here, we examined defined intermediate cell populations poised to becoming iPSCs by genome-wide analyses. We show that induced pluripotency elicits two transcriptional waves, which are driven by c-Myc/Klf4 (first wave) and Oct4/Sox2/Klf4 (second wave). Cells that become refractory to reprogramming activate the first but fail to initiate the second transcriptional wave and can be rescued by elevated expression of all four factors. The establishment of bivalent domains occurs gradually after the first wave, whereas changes in DNA methylation take place after the second wave when cells acquire stable pluripotency. This integrative analysis allowed us to identify genes that act as roadblocks during reprogramming and surface markers that further enrich for cells prone to forming iPSCs. Collectively, our data offer new mechanistic insights into the nature and sequence of molecular events inherent to cellular reprogramming. C1 [Polo, Jose M.; Anderssen, Endre; Walsh, Ryan M.; Schwarz, Benjamin A.; Borkent, Marti; Apostolou, Effie; Cloutier, Jennifer; Bar-Nur, Ori; Cheloufi, Sihem; Stadtfeld, Matthias; Robinton, Daisy; Ramaswamy, Sridhar; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Canc, Boston, MA 02114 USA. [Polo, Jose M.; Anderssen, Endre; Walsh, Ryan M.; Schwarz, Benjamin A.; Borkent, Marti; Apostolou, Effie; Cloutier, Jennifer; Bar-Nur, Ori; Cheloufi, Sihem; Stadtfeld, Matthias; Robinton, Daisy; Ramaswamy, Sridhar; Hochedlinger, Konrad] Massachusetts Gen Hosp, Ctr Regenerat Med, Boston, MA 02114 USA. [Polo, Jose M.; Anderssen, Endre; Walsh, Ryan M.; Schwarz, Benjamin A.; Borkent, Marti; Apostolou, Effie; Cloutier, Jennifer; Bar-Nur, Ori; Cheloufi, Sihem; Stadtfeld, Matthias; Robinton, Daisy; Ramaswamy, Sridhar; Hochedlinger, Konrad] Harvard Stem Cell Inst, Cambridge, MA 02138 USA. [Polo, Jose M.; Nefzger, Christian M.; Lim, Sue Mei; Alaei, Sara] Monash Univ, Monash Immunol & Stem Cell Labs, Clayton, Vic 3800, Australia. [Polo, Jose M.] Monash Univ, Australian Regenerat Med Inst, Clayton, Vic 3800, Australia. [Anderssen, Endre; Ramaswamy, Sridhar] Broad Inst MIT & Harvard, Cambridge Ctr 7, Cambridge, MA 02142 USA. [Borkent, Marti] Erasmus MC, Dept Reprod & Dev, NL-3015 GE Rotterdam, Netherlands. [Figueroa, Maria Eugenia; Melnick, Ari] Weill Cornell Med Coll, Dept Med, Div Hematol Oncol, New York, NY 10065 USA. [Natesan, Sridaran] Sanofi Aventis, Cambridge, MA 02139 USA. [Zhu, Jinfang] NIAID, NIH, Bethesda, MD 20892 USA. [Hochedlinger, Konrad] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Hochedlinger, Konrad] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA. [Hochedlinger, Konrad] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. RP Ramaswamy, S (reprint author), Massachusetts Gen Hosp, Ctr Canc, 185 Cambridge St, Boston, MA 02114 USA. EM sridhar@mgh.harvard.edu; khochedlinger@helix.mgh.harvard.edu RI Zhu, Jinfang/B-7574-2012; OI Polo, Jose M/0000-0002-2531-778X; Stadtfeld, Matthias/0000-0002-5852-9906; Alaei, Sara/0000-0003-4897-6339 FU ECOR postdoctoral fellowship; Monash Larkins Program; NHMRC CDF; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, USA; NIH [DP2OD003266, R01HD058013]; HHMI FX We thank members of the Hochedlinger and Ramaswamy labs for helpful suggestions and critical reading of the manuscript. We thank Laura Prickett and Kat Folz-Donahue at the MGH/HSCI flow cytometry core and Flowcore Monash for expert cell sorting; Paul Lacaze, Danielle Evans, and Michelle Garred at Millenium Science for support with the Fluidigm experiments; and Lucy Dagostino from Lifetech Australia for help in miRNA assays. We are grateful to Ben Wittner for help with formatting and uploading genome-wide data. Support to J.M.P. was from an ECOR postdoctoral fellowship, Monash Larkins Program, and a NHMRC CDF. J.Z. was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, USA. K.H. was supported by the NIH (DP2OD003266 and R01HD058013). S.R. was supported by an HHMI Physican-Scientist Early Career Award. NR 26 TC 312 Z9 320 U1 16 U2 133 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 21 PY 2012 VL 151 IS 7 BP 1617 EP 1632 DI 10.1016/j.cell.2012.11.039 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 062AA UT WOS:000312890300024 PM 23260147 ER PT J AU Joo, HS Otto, M AF Joo, Hwang-Soo Otto, Michael TI Molecular Basis of In Vivo Biofilm Formation by Bacterial Pathogens SO CHEMISTRY & BIOLOGY LA English DT Review ID POLYSACCHARIDE INTERCELLULAR ADHESIN; FOREIGN-BODY INFECTION; ACETYLGLUCOSAMINE SURFACE POLYSACCHARIDE; PSEUDOMONAS-AERUGINOSA INFECTION; ACCUMULATION-ASSOCIATED PROTEIN; STAPHYLOCOCCUS-AUREUS BIOFILMS; CATHETER-ASSOCIATED INFECTION; FIBRONECTIN-BINDING PROTEINS; QUORUM-SENSING CONTROL; D-AMINO ACIDS AB Bacterial biofilms are involved in a multitude of serious chronic infections. In recent years, modeling of biofilm infection in vitro has led to the identification of microbial determinants that govern biofilm development. However, we lack information as to whether the biofilm formation mechanisms identified in vitro have relevance for biofilm-associated infection. Here, we discuss the molecular basis of biofilm formation. Staphylococci and Pseudomonas aeruginosa are used to illustrate key points because their biofilm development process has been well studied. We focus on in vivo findings, such as obtained in animal infection models, and critically evaluate the in vivo relevance of in vitro findings. Although conflicting results about the role of quorum sensing in biofilm formation have been obtained, we argue that integration of in vitro and in vivo studies allows a differentiated view of this mechanism as it relates to biofilm infection. C1 [Joo, Hwang-Soo; Otto, Michael] NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. RP Otto, M (reprint author), NIAID, Pathogen Mol Genet Sect, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI JOO, HWANG-SOO/0000-0003-4668-3225; Otto, Michael/0000-0002-2222-4115 FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, U.S. National Institutes of Health. NR 117 TC 57 Z9 59 U1 2 U2 83 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD DEC 21 PY 2012 VL 19 IS 12 BP 1503 EP 1513 DI 10.1016/j.chembiol.2012.10.022 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 064PG UT WOS:000313087300004 PM 23261595 ER PT J AU Fowler, AK Hewetson, A Agrawal, RG Dagda, M Dagda, R Moaddel, R Balbo, S Sanghvi, M Chen, YK Hogue, RJ Bergeson, SE Henderson, GI Kruman, II AF Fowler, Anna-Kate Hewetson, Aveline Agrawal, Rajiv G. Dagda, Marisela Dagda, Raul Moaddel, Ruin Balbo, Silvia Sanghvi, Mitesh Chen, Yukun Hogue, Ryan J. Bergeson, Susan E. Henderson, George I. Kruman, Inna I. TI Alcohol-induced One-carbon Metabolism Impairment Promotes Dysfunction of DNA Base Excision Repair in Adult Brain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID METHYLENETETRAHYDROFOLATE REDUCTASE; GENOMIC INSTABILITY; CELL-DEATH; DAMAGE; APOPTOSIS; FOLATE; MECHANISMS; CANCER; ACETALDEHYDE; DEFICIENCY AB The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr(+/-) mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C -> T, common in human population, may exaggerate the adverse effects of ethanol on the brain. C1 [Fowler, Anna-Kate; Hewetson, Aveline; Agrawal, Rajiv G.; Dagda, Marisela; Chen, Yukun; Hogue, Ryan J.; Bergeson, Susan E.; Henderson, George I.; Kruman, Inna I.] Texas Tech Univ, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Lubbock, TX 79430 USA. [Dagda, Raul] Texas Tech Univ, Hlth Sci Ctr, Dept Pathol, Lubbock, TX 79430 USA. [Moaddel, Ruin; Sanghvi, Mitesh] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Balbo, Silvia] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. RP Kruman, II (reprint author), Texas Tech Univ, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Lubbock, TX 79430 USA. EM inna.kruman@ttuhsc.edu RI Sanghvi, Mitesh/C-6740-2013 FU Foundation for Alcohol Research; South Plains Alcohol and Addiction Research Center; National Institute of Health Intramural Research Program FX This work was supported by the Foundation for Alcohol Research (to I. I. K.), the South Plains Alcohol and Addiction Research Center and in part, by National Institute of Health Intramural Research Program (to R.M.). NR 55 TC 10 Z9 10 U1 0 U2 15 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 DEC 21 PY 2012 VL 287 IS 52 BP 43533 EP 43542 DI 10.1074/jbc.M112.401497 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 062SA UT WOS:000312940800034 PM 23118224 ER PT J AU Madenspacher, JH Azzam, KM Gong, WH Gowdy, KM Vitek, MP Laskowitz, DT Remaley, AT Wang, JM Fessler, MB AF Madenspacher, Jennifer H. Azzam, Kathleen M. Gong, Wanghua Gowdy, Kymberly M. Vitek, Michael P. Laskowitz, Daniel T. Remaley, Alan T. Wang, Ji Ming Fessler, Michael B. TI Apolipoproteins and Apolipoprotein Mimetic Peptides Modulate Phagocyte Trafficking through Chemotactic Activity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; A-I; BIOLOGICAL-PROPERTIES; DENSITY-LIPOPROTEIN; IMMUNE-RESPONSES; HUMAN MONOCYTES; MURINE MODEL; LUNG INJURY; APOA-I; INFLAMMATION AB The plasma lipoprotein-associated apolipoproteins (apo) A-I and apoE have well described anti-inflammatory actions in the cardiovascular system, and mimetic peptides that retain these properties have been designed as therapeutics. The anti-inflammatory mechanisms of apolipoprotein mimetics, however, are incompletely defined. Whether circulating apolipoproteins and their mimetics regulate innate immune responses at mucosal surfaces, sites where transvascular emigration of leukocytes is required during inflammation, remains unclear. Herein, we report that Apoai(-/-) and Apoe(-/-) mice display enhanced recruitment of neutrophils to the airspace in response to both inhaled lipopolysaccharide and direct airway inoculation with CXCL1. Conversely, treatment with apoA-I (L-4F) or apoE (COG1410) mimetic peptides reduces airway neutrophilia. We identify suppression of CXCR2-directed chemotaxis as a mechanism underlying the apolipoprotein effect. Pursuing the possibility that L-4F might suppress chemotaxis through heterologous desensitization, we confirmed that L-4F itself induces chemotaxis of human PMNs and monocytes. L-4F, however, fails to induce a calcium flux. Further exploring structure-function relationships, we studied the alternate apoA-I mimetic L-37pA, a bihelical analog of L-4F with two Leu-Phe substitutions. We find that L-37pA induces calcium and chemotaxis through formyl peptide receptor (FPR) 2/ALX, whereas its D-stereoisomer (i.e. D-37pA) blocks L-37pA signaling and induces chemotaxis but not calcium flux through an unidentified receptor. Taken together, apolipoprotein mimetic peptides are novel chemotactic agents that possess complex structure-activity relationships to multiple receptors, displaying anti-inflammatory efficacy against innate immune responses in the airway. C1 [Madenspacher, Jennifer H.; Azzam, Kathleen M.; Gowdy, Kymberly M.; Fessler, Michael B.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. [Wang, Ji Ming] NCI, Mol Immunoregulat Lab, Canc & Inflammat Program, NIH, Frederick, MD 21702 USA. [Vitek, Michael P.; Laskowitz, Daniel T.] Duke Univ, Med Ctr, Dept Med Neurol, Durham, NC 27710 USA. [Vitek, Michael P.] Cognosci Inc, Res Triangle Pk, NC 27709 USA. [Remaley, Alan T.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Gong, Wanghua] SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. RP Fessler, MB (reprint author), 111 TW Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, NC 27709 USA. EM fesslerm@niehs.nih.gov FU National Institutes of Health Intramural Research Program NIEHS [Z01 ES102005]; NCI, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NCI, National Institutes of Health FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program NIEHS Grant Z01 ES102005.; Supported in part by funds from the NCI, National Institutes of Health, under Contract HHSN261200800001E and the Intramural Research Program of the NCI, National Institutes of Health. NR 50 TC 13 Z9 14 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 DEC 21 PY 2012 VL 287 IS 52 BP 43730 EP 43740 DI 10.1074/jbc.M112.377192 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 062SA UT WOS:000312940800052 PM 23118226 ER PT J AU Ravichandran, S Collins, JR Singh, N Wainer, IW AF Ravichandran, Sarangan Collins, Jack R. Singh, Nagendra Wainer, Irving W. TI A molecular model of the enantioselective liquid chromatographic separation of (R,S)-ifosfamide and its N-dechloroethylated metabolites on a teicoplanin aglycon chiral stationary phase SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article DE Teicoplanin chiral stationary phase; Macrocyclic antibiotics; Chiral recognition; Oxazaphosphorine; Computational docking; Chiral chromatography ID STEREOSELECTIVE RECOGNITION MECHANISMS; CAMBRIDGE STRUCTURAL DATABASE; CRYSTAL-STRUCTURES; IFOSFAMIDE; PERFORMANCE; ENANTIOSEPARATIONS; VANCOMYCIN; SOFTWARE AB The enantioselective separations of the chiral oxazaphosphorines (R,S)-ifosfamide (IF), (R,S)-2-N-dechloroethyl-IF (2-DCE-IF) and (R,S)-3-N-dechloroethyl-IF (3-DCE-IF) were achieved on teicoplanin-based chiral stationary phase using isopropanol:methanol (60:40, v/v) as the mobile phase. Computational models of the teicoplanin and teicoplanin aglycon (TAG) chiral selectors were constructed and used in docking experiments to examine the chiral recognition mechanism associated with the observed resolutions. Initial data showed no significant differences between the simulated selector-selectand complexes using teicoplanin and TAG, and the full study was conducted using TAG. The data from the study indicate that hydrophobic interactions arise between the chlorine atom present in the cholorethyl moieties of the oxazaphosphorine molecules and hydrophobic pockets within the TAG basket and that these interactions anchored and positioned the selectands within the selector-selectand complexes. The complexes were stabilized through the formation of a network of hydrogen bond and cation-pi interactions, in which the latter involved the phosphorous atom of the phosphoramide moiety and aromatic components of the TAG aglycon basket. The chirality of the oxazaphosphorine molecule determined the number and strength of the stabilizing interactions which resulted in significant differences in the relative mean binding energies between the complexes formed by the (R) and (S) enantiomers of the selectands. These differences were consistent with the observed chromatographic enantioselectivity and suggest a multi-step chrial recognition mechanism involving the tethering of the selectand to the selector followed by conformational adjustments and stabilization of the selectand-selector complex. Published by Elsevier B.V. C1 [Wainer, Irving W.] NIA, Clin Invest Lab, Biomed Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. [Ravichandran, Sarangan; Collins, Jack R.] SAIC Frederick Inc, FNLCR, Informat Syst Program, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Wainer, IW (reprint author), NIA, Clin Invest Lab, Biomed Res Ctr, Intramural Res Program,NIH, 8B133,251 Bayview Blvd, Baltimore, MD 21224 USA. EM wainerir@grc.nia.nih.gov RI Singh, Nagendra/K-8966-2015 FU NIA Intramural Research Program (IWW); National Cancer Institute/National Institutes of Health [HHSN261200800001E] FX This work was supported in part by funds from the NIA Intramural Research Program (IWW), and from the National Cancer Institute/National Institutes of Health contract no. HHSN261200800001E. SR would like to thank Dr. Brian Luke for many valuable discussions. The authors would like to thank the referees for their comments. NR 25 TC 4 Z9 4 U1 2 U2 25 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 DEC 21 PY 2012 VL 1269 SI SI BP 218 EP 225 DI 10.1016/j.chroma.2012.08.019 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 056GB UT WOS:000312475300017 PM 22917979 ER PT J AU Zane, L Yasunaga, J Mitagami, Y Yedavalli, V Tang, SW Chen, CY Ratner, L Lu, XB Jeang, KT AF Zane, Linda Yasunaga, Junichiro Mitagami, Yu Yedavalli, Venkat Tang, Sai-Wen Chen, Chia-Yen Ratner, Lee Lu, Xiongbin Jeang, Kuan-Teh TI Wip1 and p53 contribute to HTLV-1 Tax-induced tumorigenesis SO RETROVIROLOGY LA English DT Article ID T-CELL LEUKEMIA; VIRUS TYPE-1 TAX; NF-KAPPA-B; DNA-DAMAGE RESPONSE; LYMPHOTROPIC VIRUS; I TAX; TUMOR-SUPPRESSOR; PROTEIN PHOSPHATASE; GENE-EXPRESSION; BREAST-CANCER AB Background: Human T-cell Leukemia Virus type 1 (HTLV-1) infects 20 million individuals world-wide and causes Adult T-cell Leukemia/Lymphoma (ATLL), a highly aggressive T-cell cancer. ATLL is refractory to treatment with conventional chemotherapy and fewer than 10% of afflicted individuals survive more than 5 years after diagnosis. HTLV-1 encodes a viral oncoprotein, Tax, that functions in transforming virus-infected T-cells into leukemic cells. All ATLL cases are believed to have reduced p53 activity although only a minority of ATLLs have genetic mutations in their p53 gene. It has been suggested that p53 function is inactivated by the Tax protein. Results: Using genetically altered mice, we report here that Tax expression does not achieve a functional equivalence of p53 inactivation as that seen with genetic mutation of p53 (i.e. a p53(-/-) genotype). Thus, we find statistically significant differences in tumorigenesis between Tax(+)p53(+/+) versus Tax(+)p53(-/-) mice. We also find a role contributed by the cellular Wip1 phosphatase protein in tumor formation in Tax transgenic mice. Notably, Tax(+)Wip1(-/-) mice show statistically significant reduced prevalence of tumorigenesis compared to Tax(+)Wip1(+/+) counterparts. Conclusions: Our findings provide new insights into contributions by p53 and Wip1 in the in vivo oncogenesis of Tax-induced tumors in mice. C1 [Zane, Linda; Yedavalli, Venkat; Tang, Sai-Wen; Chen, Chia-Yen; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Yasunaga, Junichiro; Mitagami, Yu] Kyoto Univ, Inst Virus Res, Lab Virus Control, Kyoto 606, Japan. [Ratner, Lee] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Lu, Xiongbin] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. RP Jeang, KT (reprint author), NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM KJEANG@nih.gov OI Yasunaga, Jun-ichirou/0000-0002-7939-2080 FU NIAID; NIH [R01CA136549] FX This work was supported by intramural NIAID funding. XL was supported by NIH grant R01CA136549. We thank members of the Jeang laboratory for critical readings of the manuscript; Qingpin Liu for her help with mouse tissues and Melissa Foster and Ryan Hamilton for caring of the mice. NR 119 TC 11 Z9 12 U1 2 U2 8 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD DEC 21 PY 2012 VL 9 AR 114 DI 10.1186/1742-4690-9-114 PG 12 WC Virology SC Virology GA 065VG UT WOS:000313177100001 PM 23256545 ER PT J AU Vale, RD DeRisi, J Phillips, R Mullins, RD Waterman, C Mitchison, TJ AF Vale, Ronald D. DeRisi, Joseph Phillips, Rob Mullins, R. Dyche Waterman, Clare Mitchison, Timothy J. TI Interdisciplinary Graduate Training in Teaching Labs SO SCIENCE LA English DT Editorial Material ID SCIENCE-EDUCATION; BIOLOGY EDUCATION C1 [Vale, Ronald D.; Mullins, R. Dyche; Waterman, Clare; Mitchison, Timothy J.] Marine Biol Lab, Woods Hole, MA 02543 USA. [Vale, Ronald D.; DeRisi, Joseph; Mullins, R. Dyche] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Vale, Ronald D.; DeRisi, Joseph] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. [Phillips, Rob] CALTECH, Pasadena, CA 91106 USA. [Waterman, Clare] NHLBI, Bethesda, MD 20824 USA. [Mitchison, Timothy J.] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Vale, RD (reprint author), Marine Biol Lab, Woods Hole, MA 02543 USA. EM vale@cmp.ucsf.edu OI Waterman, Clare/0000-0001-6142-6775 FU NIH [GM085967, T32 EB009383]; Howard Hughes Medical Institute; Burroughs Wellcome Fund; National Institute of Biomedical Imaging and Bioengineering; Caltech Rosen Center for Bioengineering FX The MBL Physiology Course is supported by grants from the NIH (GM085967), the Howard Hughes Medical Institute, and the Burroughs Wellcome Fund. The UCSF iPQB courses are supported by a National Institute of Biomedical Imaging and Bioengineering, NIH, Interfaces grant (T32 EB009383), and the CalTech boot camp receives funding from the Caltech Rosen Center for Bioengineering. NR 10 TC 9 Z9 9 U1 2 U2 33 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD DEC 21 PY 2012 VL 338 IS 6114 BP 1542 EP 1543 DI 10.1126/science.1216570 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 057AE UT WOS:000312533100032 PM 23258877 ER PT J AU Shi, YB Matsuura, K Fujimoto, K Wen, L Fu, LZ AF Shi, Yun-Bo Matsuura, Kazuo Fujimoto, Kenta Wen, Luan Fu, Liezhen TI Thyroid hormone receptor actions on transcription in amphibia: The roles of histone modification and chromatin disruption SO CELL AND BIOSCIENCE LA English DT Review DE Transcriptional coactivator; Corepressor; Thyroid hormone receptor; Stem cell; Apoptosis; Metamorphosis; Xenopus laevis and tropicalis; Histone methylation; Histone acetylation; Nucleosome removal ID ARGININE METHYLTRANSFERASE 1; TARGETED GENE DISRUPTION; FROG XENOPUS-TROPICALIS; INTESTINAL STEM-CELLS; ACTION IN-VIVO; NUCLEAR-RECEPTOR; POSTEMBRYONIC DEVELOPMENT; COREPRESSOR COMPLEX; CO-REPRESSOR; PROTEIN METHYLTRANSFERASE AB Thyroid hormone (T3) plays diverse roles in adult organ function and during vertebrate development. The most important stage of mammalian development affected by T3 is the perinatal period when plasma T3 level peaks. Amphibian metamorphosis resembles this mammalian postembryonic period and is absolutely dependent on T3. The ability to easily manipulate this process makes it an ideal model to study the molecular mechanisms governing T3 action during vertebrate development. T3 functions mostly by regulating gene expression through T3 receptors (TRs). Studies in vitro, in cell cultures and reconstituted frog oocyte transcription system have revealed that TRs can both activate and repress gene transcription in a T3-dependent manner and involve chromatin disruption and histone modifications. These changes are accompanied by the recruitment of diverse cofactor complexes. More recently, genetic studies in mouse and frog have provided strong evidence for a role of cofactor complexes in T3 signaling in vivo. Molecular studies on amphibian metamorphosis have also revealed that developmental gene regulation by T3 involves histone modifications and the disruption of chromatin structure at the target genes as evidenced by the loss of core histones, arguing that chromatin remodeling is an important mechanism for gene activation by liganded TR during vertebrate development. C1 [Shi, Yun-Bo; Matsuura, Kazuo; Wen, Luan; Fu, Liezhen] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, PCRM, NIH, Bethesda, MD 20892 USA. [Fujimoto, Kenta] Saitama Med Univ, Res Ctr Genom Med, Div Gene Struct & Funct, Hidaka, Saitama 3501241, Japan. RP Shi, YB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, PCRM, NIH, Bethesda, MD 20892 USA. EM Shi@helix.nih.gov FU NICHD, NIH FX This research was supported in part by the Intramural Research Program of NICHD, NIH. NR 127 TC 14 Z9 15 U1 2 U2 26 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD DEC 20 PY 2012 VL 2 AR 42 DI 10.1186/2045-3701-2-42 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 089TG UT WOS:000314932300001 PM 23256597 ER PT J AU Maxwell, EK Ryan, JF Schnitzler, CE Browne, WE Baxevanis, AD AF Maxwell, Evan K. Ryan, Joseph F. Schnitzler, Christine E. Browne, William E. Baxevanis, Andreas D. TI MicroRNAs and essential components of the microRNA processing machinery are not encoded in the genome of the ctenophore Mnemiopsis leidyi SO BMC GENOMICS LA English DT Article DE Mnemiopsis leidyi; Ctenophore; Metazoa; microRNA; miRNA; Drosha; Pasha; Microprocessor complex; Ribonuclease III; RNase III ID ALGA CHLAMYDOMONAS-REINHARDTII; TRICHOMONAS-VAGINALIS; SMALL RNAS; GENE-EXPRESSION; EVOLUTION; BIOGENESIS; ANIMALS; IDENTIFICATION; PROTEIN; MIRNAS AB Background: MicroRNAs play a vital role in the regulation of gene expression and have been identified in every animal with a sequenced genome examined thus far, except for the placozoan Trichoplax. The genomic repertoires of metazoan microRNAs have become increasingly endorsed as phylogenetic characters and drivers of biological complexity. Results: In this study, we report the first investigation of microRNAs in a species from the phylum Ctenophora. We use short RNA sequencing and the assembled genome of the lobate ctenophore Mnemiopsis leidyi to show that this species appears to lack any recognizable microRNAs, as well as the nuclear proteins Drosha and Pasha, which are critical to canonical microRNA biogenesis. This finding represents the first reported case of a metazoan lacking a Drosha protein. Conclusions: Recent phylogenomic analyses suggest that Mnemiopsis may be the earliest branching metazoan lineage. If this is true, then the origins of canonical microRNA biogenesis and microRNA-mediated gene regulation may postdate the last common metazoan ancestor. Alternatively, canonical microRNA functionality may have been lost independently in the lineages leading to both Mnemiopsis and the placozoan Trichoplax, suggesting that microRNA functionality was not critical until much later in metazoan evolution. C1 [Maxwell, Evan K.; Ryan, Joseph F.; Schnitzler, Christine E.; Baxevanis, Andreas D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Maxwell, Evan K.] Boston Univ, Bioinformat Program, Boston, MA 02215 USA. [Ryan, Joseph F.] Univ Bergen, Sars Int Ctr Marine Mol Biol, N-5008 Bergen, Norway. [Browne, William E.] Univ Miami, Dept Biol, Coral Gables, FL 33146 USA. RP Baxevanis, AD (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM andy@nhgri.nih.gov RI Schnitzler, Christine/G-8733-2013; Browne, William/D-4267-2013 OI Browne, William/0000-0001-8200-6489 FU NIH Graduate Research Fellowship; Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health; University of Miami, College of Arts and Sciences; Provost Research Award FX The authors would like to thank the NIH Intramural Sequencing Center, particularly A. Young, for performing the small RNA sequencing and describing the protocol, K. Pang for providing samples, M. Martindale for reviewing the manuscript, D. Gildea for assistance with short RNA sequencing analysis, J. Fekecs and D. Leja for assistance in the creation and editing of figures, M. Srivastava for input regarding selection of protein sequences, N. Trivedi for input on figure design, and A. Nguyen for assistance with miRNA predictions. This work was supported by an NIH Graduate Research Fellowship (E.K.M.), by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health (E.K.M., J.F.R., C.E.S., A.D.B.), and by the University of Miami, College of Arts and Sciences and Provost Research Award (W.E.B.). NR 54 TC 19 Z9 19 U1 0 U2 25 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD DEC 20 PY 2012 VL 13 AR 714 DI 10.1186/1471-2164-13-714 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 085HE UT WOS:000314605100001 PM 23256903 ER PT J AU Zheng, YH Jeang, KT Tokunaga, K AF Zheng, Yong-Hui Jeang, Kuan-Teh Tokunaga, Kenzo TI Host restriction factors in retroviral infection: promises in virus-host interaction SO RETROVIROLOGY LA English DT Review ID HUMAN-IMMUNODEFICIENCY-VIRUS; SINGLE AMINO-ACID; MURINE LEUKEMIA-VIRUS; E3 UBIQUITIN LIGASE; HIV-1 REVERSE TRANSCRIPTION; RNA-EDITING ENZYME; CD4(+) T-CELLS; CYTIDINE DEAMINASE APOBEC3H; SMALL NONCODING RNAS; SILENCING SUPPRESSOR ACTIVITY AB Retroviruses have an intricate life cycle. There is much to be learned from studying retrovirus-host interactions. Among retroviruses, the primate lentiviruses have one of the more complex genome structures with three categories of viral genes: structural, regulatory, and accessory genes. Over time, we have gained increasing understanding of the lentivirus life cycle from studying host factors that support virus replication. Similarly, studies on host restriction factors that inhibit viral replication have also made significant contributions to our knowledge. Here, we review recent progress on the rapidly growing field of restriction factors, focusing on the antiretroviral activities of APOBEC3G, TRIM5, tetherin, SAMHD1, MOV10, and cellular microRNAs (miRNAs), and the counter-activities of Vif, Vpu, Vpr, Vpx, and Nef. C1 [Zheng, Yong-Hui] Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. [Jeang, Kuan-Teh] NIH, Bethesda, MD 20892 USA. [Tokunaga, Kenzo] Natl Inst Infect Dis, Dept Pathol, Tokyo, Japan. RP Zheng, YH (reprint author), Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. EM zhengyo@msu.edu FU Ministry of Education, Science, Technology, Sports and Culture of Japan [22590428]; Ministry of Health, Labor, and Welfare of Japan [H24-005, -008]; NIAID, NIH; Office of the Director, NIH; Bill and Melinda Gates Foundation; NIH [AI063944, AI080225] FX Due to space limitation, the authors apologize to those in the field whose work is not cited in this article. The opinions expressed in this review represent the authors' personal views and do not necessary reflect the views of their employers, particularly the National Institutes of Health (NIH), USA. Research performed in KT's laboratory is supported by grants from the Ministry of Education, Science, Technology, Sports and Culture of Japan (22590428), and from the Ministry of Health, Labor, and Welfare of Japan (Research on HIV/AIDS project no. H24-005, and -008). Research performed in KTJ's laboratory is supported by intramural funds from the NIAID, NIH; the IATAP program from the Office of the Director, NIH; and by the Bill and Melinda Gates Foundation. Research performed in YHZ's laboratory is supported by NIH grants AI063944 and AI080225. NR 423 TC 35 Z9 36 U1 1 U2 29 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD DEC 20 PY 2012 VL 9 AR 112 DI 10.1186/1742-4690-9-112 PG 28 WC Virology SC Virology GA 076NC UT WOS:000313962200001 PM 23254112 ER PT J AU Malide, D Metais, JY Dunbar, CE AF Malide, Daniela Metais, Jean-Yves Dunbar, Cynthia E. TI Dynamic clonal analysis of murine hematopoietic stem and progenitor cells marked by 5 fluorescent proteins using confocal and multiphoton microscopy SO BLOOD LA English DT Article ID BONE-MARROW CELLS; IN-VIVO; MUSCLE REGENERATION; 2-PHOTON MICROSCOPY; RETROVIRAL VECTORS; MAMMALIAN-CELLS; GENE-THERAPY; TRACKING; MOUSE; NICHE AB We demonstrate a methodology for tracing the clonal history of hematopoietic stem and progenitor cells (HSPCs) behavior in live tissues in 4 dimensions (4D). This integrates genetic combinatorial marking using lentiviral vectors encoding various fluorescent proteins (FPs) with advanced imaging methods. Five FPs: Cerulean, EGFP, Venus, tdTomato, and mCherry were concurrently used to create a diverse palette of color-marked cells. A key advantage of imaging using a confocal/2-photon hybrid microscopy approach is the simultaneous assessment of uniquely 5FP-marked cells in conjunction with structural components of the tissues at high resolution. Volumetric analyses revealed that spectrally coded HSPC-derived cells can be detected noninvasively in various intact tissues, including the bone marrow, for extensive periods of time after transplantation. Live studies combining video-rate multiphoton and confocal imaging in 4D demonstrate the possibility of dynamic cellular and clonal tracking in a quantitative manner. This methodology has applications in the understanding of clonal architecture in normal and perturbed hematopoiesis. (Blood. 2012; 120(26): e105-e116) C1 [Metais, Jean-Yves; Dunbar, Cynthia E.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Malide, Daniela] NHLBI, Light Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. RP Dunbar, CE (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10 CRC,Rm 4E-5132,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dmalide@nih.gov; dunbarc@nhlbi.nih.gov FU National Heart, Lung, Blood Institute of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Heart, Lung, Blood Institute of the National Institutes of Health. NR 51 TC 17 Z9 17 U1 1 U2 21 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 DEC 20 PY 2012 VL 120 IS 26 BP E105 EP E116 DI 10.1182/blood-2012-06-440636 PG 12 WC Hematology SC Hematology GA 065CB UT WOS:000313123900001 PM 22995900 ER PT J AU Yee, D Haddad, T Albain, K Barker, A Benz, C Boughey, J Buxton, M Chien, AJ DeMichele, A Dilts, D Elias, A Haluska, P Hogarth, M Hu, A Hytlon, N Kaplan, HG Kelloff, GG Khan, Q Lang, JL Leyland-Jones, B Liu, M Nanda, R Northfelt, D Olopade, OI Park, J Parker, B Parkinson, D Pearson-White, S Perlmutter, J Pusztai, L Symmans, F Rugo, H Tripathy, D Wallace, A Wholley, D van't Veer, L Berry, DA Esserman, L AF Yee, Douglas Haddad, Tufia Albain, Kathy Barker, Anna Benz, Christopher Boughey, Judy Buxton, Meredith Chien, Amy Jo DeMichele, Angela Dilts, David Elias, Anthony Haluska, Paul Hogarth, Michael Hu, Alan Hytlon, Nola Kaplan, Henry G. Kelloff, Gary G. Khan, Qamar Lang, Julie Leyland-Jones, Brian Liu, Minetta Nanda, Rita Northfelt, Donald Olopade, Olufunmilayo I. Park, John Parker, Barbara Parkinson, David Pearson-White, Sonia Perlmutter, Jane Pusztai, Lajos Symmans, Fraser Rugo, Hope Tripathy, Debu Wallace, Anne Wholley, David van't Veer, Laura Berry, Donald A. Esserman, Laura TI Adaptive Trials in the Neoadjuvant Setting: A Model to Safely Tailor Care While Accelerating Drug Development SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID BREAST-CANCER; CHEMOTHERAPY; SURVIVAL C1 [Yee, Douglas] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. [Haddad, Tufia; Boughey, Judy; Haluska, Paul] Mayo Clin, Ctr Canc, Rochester, MN USA. [Albain, Kathy] Loyola Univ, Cardinal Bernardin Canc Ctr, Maywood, IL 60153 USA. [Barker, Anna] Arizona State Univ, Tempe, AZ USA. [Barker, Anna] Quantum Leap Healthcare Collaborat, Tempe, AZ USA. [Benz, Christopher] Buck Inst Age Res, Novato, CA USA. [Chien, Amy Jo] Univ Calif San Francisco, Carol Franc Buck Breast Care Ctr, San Fransciso, CA USA. [DeMichele, Angela] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Dilts, David] Oregon Hlth & Sci Univ, Quantum Leap Healthcare Collaborat, Portland, OR 97201 USA. [Elias, Anthony] Univ Colorado, Boulder, CO 80309 USA. [Hogarth, Michael] Univ Calif Davis, Davis, CA 95616 USA. [Hu, Alan] Quantum Leap Healthcare Collaborat, San Francisco, CA USA. [Hytlon, Nola] Univ Calif San Francisco, Magnet Resonance Sci Ctr, San Francisco, CA 94143 USA. [Kaplan, Henry G.] Swedish Canc Inst, Seattle, WA USA. [Kelloff, Gary G.] NCI, Bethesda, MD 20892 USA. [Khan, Qamar] Univ Kansas, Med Ctr, Ctr Canc, Kansas City, KS 66103 USA. [Lang, Julie] Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. [Leyland-Jones, Brian] Sanford Hlth, Fargo, ND USA. [Liu, Minetta] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Nanda, Rita] Univ Chicago, Ctr Adv Med, Chicago, IL 60637 USA. [Northfelt, Donald] Mayo Clin Arizona, Scottsdale, AZ USA. [Olopade, Olufunmilayo I.] Univ Chicago, Ctr Clin Canc Genet, Chicago, IL 60637 USA. [Park, John] Univ Calif San Francisco, Bay Area Breast Canc SPORE, San Francisco, CA 94143 USA. [Parker, Barbara] Univ Calif San Diego, Moores Canc Ctr, San Diego, CA 92103 USA. [Parkinson, David] Nodality, San Francisco, CA USA. [Pearson-White, Sonia] Fdn Natl Inst Hlth, Bethesda, MD USA. [Perlmutter, Jane] Gemini Grp, Ann Arbor, MI USA. [Pusztai, Lajos; Symmans, Fraser; Berry, Donald A.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Tripathy, Debu] Univ So Calif, Norris Comprehens Canc Ctr, Los Angeles, CA USA. [Wholley, David] NIH, Biomarkers Consortium Fdn, Bethesda, MD 20892 USA. [Esserman, Laura] Univ Calif San Francisco, Carol Franc Buck Breast Care Ctr, San Francisco, CA 94143 USA. RP Yee, D (reprint author), Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA. RI Pearson-White, Sonia/S-2570-2016 NR 8 TC 8 Z9 8 U1 0 U2 5 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 DEC 20 PY 2012 VL 30 IS 36 BP 4584 EP 4586 DI 10.1200/JCO.2012.44.1022 PG 4 WC Oncology SC Oncology GA 060YT UT WOS:000312815000029 PM 23169510 ER PT J AU Buxbaum, JD Daly, MJ Devlin, B Lehner, T Roeder, K State, MW AF Buxbaum, Joseph D. Daly, Mark J. Devlin, Bernie Lehner, Thomas Roeder, Kathryn State, Matthew W. CA Autism Sequencing Consortium TI The Autism Sequencing Consortium: Large-Scale, High-Throughput Sequencing in Autism Spectrum Disorders SO NEURON LA English DT Editorial Material ID DE-NOVO MUTATIONS; COPY NUMBER VARIATION AB Research during the past decade has seen significant progress in the understanding of the genetic architecture of autism spectrum disorders (ASDs), with gene discovery accelerating as the characterization of genomic variation has become increasingly comprehensive. At the same time, this research has highlighted ongoing challenges. Here we address the enormous impact of high-throughput sequencing (HTS) on ASD gene discovery, outline a consensus view for leveraging this technology, and describe a large multisite collaboration developed to accomplish these goals. Similar approaches could prove effective for severe neurodevelopmental disorders more broadly. C1 [Buxbaum, Joseph D.] Mt Sinai Sch Med, Seaver Autism Ctr, Dept Psychiat, New York, NY 10029 USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Seaver Autism Ctr, Dept Neurosci, New York, NY 10029 USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Seaver Autism Ctr, Dept Genet & Genom Sci, New York, NY 10029 USA. [Buxbaum, Joseph D.] Mt Sinai Sch Med, Friedman Brain Inst, New York, NY 10029 USA. [Daly, Mark J.] Harvard Univ, Sch Med, Broad Inst, Boston, MA 02114 USA. [Daly, Mark J.] Harvard Univ, Sch Med, Translat Genet Unit, Boston, MA 02114 USA. [Devlin, Bernie] Univ Pittsburgh, Sch Med, Dept Psychiat, Pittsburgh, PA 15213 USA. [Lehner, Thomas] NIMH, NIH, Bethesda, MD 20892 USA. [Roeder, Kathryn] Carnegie Mellon Univ, Dept Stat, Pittsburgh, PA 15213 USA. [Roeder, Kathryn] Carnegie Mellon Univ, Lane Ctr Computat Biol, Pittsburgh, PA 15213 USA. [State, Matthew W.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA. [State, Matthew W.] Yale Univ, Program Neurogenet, Ctr Child Study, New Haven, CT 06520 USA. RP Buxbaum, JD (reprint author), Mt Sinai Sch Med, Seaver Autism Ctr, Dept Psychiat, New York, NY 10029 USA. EM joseph.buxbaum@mssm.edu; matthew.state@yale.edu RI Scherer, Stephen /B-3785-2013; Yuen, Ryan/J-4876-2012; OI Scherer, Stephen /0000-0002-8326-1999; Yuen, Ryan/0000-0001-7273-4968; Chahrour, Maria/0000-0002-3174-1480; Buxbaum, Joseph/0000-0001-8898-8313; Barrett, Jeffrey/0000-0002-1152-370X; Shendure, Jay/0000-0002-1516-1865 FU National Institute of Mental Health (NIMH); National Human Genome Research Institute (NHGRI) FX The authors thank the National Institute of Mental Health (NIMH), the National Human Genome Research Institute (NHGRI), and the Seaver Foundation for supporting the ASC meetings and calls and for facilitating and encouraging broad participation. The authors also thank Jessica Brownfeld for help with organization and manuscript preparation. NR 14 TC 57 Z9 58 U1 4 U2 23 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD DEC 20 PY 2012 VL 76 IS 6 BP 1052 EP 1056 DI 10.1016/j.neuron.2012.12.008 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 065NI UT WOS:000313154800004 PM 23259942 ER PT J AU Jinde, S Zsiros, V Jiang, ZH Nakao, K Pickel, J Kohno, K Belforte, JE Nakazawa, K AF Jinde, Seiichiro Zsiros, Veronika Jiang, Zhihong Nakao, Kazuhito Pickel, James Kohno, Kenji Belforte, Juan E. Nakazawa, Kazu TI Hilar Mossy Cell Degeneration Causes Transient Dentate Granule Cell Hyperexcitability and Impaired Pattern Separation SO NEURON LA English DT Article ID TEMPORAL-LOBE EPILEPSY; INDUCED STATUS EPILEPTICUS; FASCIA-DENTATA; INHIBITORY INTERNEURONS; COMMISSURAL CONNECTIONS; FEEDFORWARD INHIBITION; HIPPOCAMPAL-FORMATION; PILOCARPINE MODEL; RAT HIPPOCAMPUS; MOLECULAR LAYER AB Although excitatory mossy cells of the hippocampal hilar region are known to project both to dentate granule cells and to interneurons, it is as yet unclear whether mossy cell activity's net effect on granule cells is excitatory or inhibitory. To explore their influence on dentate excitability and hippocampal function, we generated a conditional transgenic mouse line, using the Cre/loxP system, in which diphtheria toxin receptor was selectively expressed in mossy cells. One week after injecting toxin into this line, mossy cells throughout the longitudinal axis were degenerated extensively, theta wave power of dentate local field potentials increased during exploration, and deficits occurred in contextual discrimination. By contrast, we detected no epileptiform activity, spontaneous behavioral seizures, or mossy-fiber sprouting 5-6 weeks after mossy cell degeneration. These results indicate that the net effect of mossy cell excitation is to inhibit granule cell activity and enable dentate pattern separation. C1 [Jinde, Seiichiro; Zsiros, Veronika; Jiang, Zhihong; Nakao, Kazuhito; Belforte, Juan E.; Nakazawa, Kazu] NIMH, Unit Genet Cognit & Behav, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Pickel, James] NIMH, Transgen Core Facil, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Jinde, Seiichiro] Univ Tokyo, Grad Sch Med, Dept Neuropsychiat, Tokyo 1138655, Japan. [Kohno, Kenji] Nara Inst Sci & Technol, Grad Sch Biol Sci, Lab Mol & Cell Genet, Nara 6300192, Japan. RP Nakazawa, K (reprint author), NIMH, Unit Genet Cognit & Behav, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM nakazawk@mail.nih.gov RI Nakazawa, Kazutoshi/J-6195-2015 OI Nakazawa, Kazutoshi/0000-0001-5699-9093 FU NIMH; Ministry of Education, Culture, Sports, Science and Technology, Japan [22591274]; Japan Society for the Promotion of Science (JSPS) FX We thank R.S. Sloviter for discussions and helpful comments on the manuscript. We also thank R.D. Palmiter for a gift of anti-ZnT3, S. Itohara for anti-Netrin G2, N.M. Vargas-Pinto, E.R. Sklar, and S. Zhang for technical assistance, and S. Kolata and E. Sherman for critical reading of the manuscript. This research was supported by the Intramural Research Programs of the NIMH. This research was partially supported by a Grant-in-Aid for Scientific Research of Ministry of Education, Culture, Sports, Science and Technology, Japan (Grant #: 22591274). S.J. was supported by a Japan Society for the Promotion of Science (JSPS) fellowship. NR 70 TC 44 Z9 44 U1 1 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD DEC 20 PY 2012 VL 76 IS 6 BP 1189 EP 1200 DI 10.1016/j.neuron.2012.10.036 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 065NI UT WOS:000313154800015 PM 23259953 ER PT J AU Dave, H Anver, MR Butcher, DO Brown, P Khan, J Wayne, AS Baskar, S Rader, C AF Dave, Hema Anver, Miriam R. Butcher, Donna O. Brown, Patrick Khan, Javed Wayne, Alan S. Baskar, Sivasubramanian Rader, Christoph TI Restricted Cell Surface Expression of Receptor Tyrosine Kinase ROR1 in Pediatric B-Lineage Acute Lymphoblastic Leukemia Suggests Targetability with Therapeutic Monoclonal Antibodies SO PLOS ONE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; MOUSE DEVELOPMENT; RNAI SCREEN; BLINATUMOMAB; PHENOTYPE; CHILDREN; SURVIVAL; DISEASE; TARGET; CLL AB Background: Despite high cure rates for pediatric B-lineage acute lymphoblastic leukemia (B-ALL), short-term and long-term toxicities and chemoresistance are shortcomings of standard chemotherapy. Immunotherapy and chemoimmunotherapy based on monoclonal antibodies (mAbs) that target cell surface antigens with restricted expression in pediatric B-ALL may offer the potential to reduce toxicities and prevent or overcome chemoresistance. The receptor tyrosine kinase ROR1 has emerged as a candidate for mAb targeting in select B-cell malignancies. Methodology and Principal Findings: Using flow cytometry, Western blotting, immunohistochemistry, and confocal immunofluorescence microscopy, we analyzed the cell surface expression of ROR1 across major pediatric ALL subtypes represented by 14 cell lines and 56 primary blasts at diagnosis or relapse as well as in normal adult and pediatric tissues. Cell surface ROR1 expression was found in 45% of pediatric ALL patients, all of which were B-ALL, and was not limited to any particular genotype. All cell lines and primary blasts with E2A-PBX1 translocation and a portion of patients with other high risk genotypes, such as MLL rearrangement, expressed cell surface ROR1. Importantly, cell surface ROR1 expression was found in many of the pediatric B-ALL patients with multiply relapsed and refractory disease and normal karyotype or low risk cytogenetics, such as hyperdiploidy. Notably, cell surface ROR1 was virtually absent in normal adult and pediatric tissues. Conclusions and Significance: Collectively, this study suggests that ROR1 merits preclinical and clinical investigations as a novel target for mAb-based therapies in pediatric B-ALL. We propose cell surface expression of ROR1 detected by flow cytometry as primary inclusion criterion for pediatric B-ALL patients in future clinical trials of ROR1-targeted therapies. C1 [Dave, Hema; Wayne, Alan S.; Baskar, Sivasubramanian; Rader, Christoph] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Dave, Hema; Khan, Javed; Wayne, Alan S.] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Anver, Miriam R.; Butcher, Donna O.] NCI, Pathol Histotechnol Lab, Sci Applicat Int Corp Frederick, Frederick Natl Lab Canc Res,NIH, Frederick, MD 21701 USA. [Brown, Patrick] Johns Hopkins Univ Hosp, Dept Oncol & Pediat, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA. [Rader, Christoph] Scripps Res Inst, Dept Canc Biol, Jupiter, FL USA. [Rader, Christoph] Scripps Res Inst, Dept Mol Therapeut, Jupiter, FL USA. RP Rader, C (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM crader@scripps.edu FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH); NCI; NIH [HHSN261200800001E] FX This research was funded by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), and in part with federal funds from the NCI and NIH under Contract No. HHSN261200800001E. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 14 Z9 15 U1 0 U2 19 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 DEC 20 PY 2012 VL 7 IS 12 AR e52655 DI 10.1371/journal.pone.0052655 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 060RA UT WOS:000312794500220 PM 23285131 ER PT J AU Harris, B Klein, R Jerosch-Herold, M Hoffman, EA Ahmed, FS Jacobs, DR Klein, BEK Wong, TY Lima, JAC Cotch, MF Barr, G AF Harris, Bianca Klein, Ronald Jerosch-Herold, Michael Hoffman, Eric A. Ahmed, Firas S. Jacobs, David R., Jr. Klein, Barbara E. K. Wong, Tien Y. Lima, Joao A. C. Cotch, Mary Frances Barr, Graham TI The Association of Systemic Microvascular Changes with Lung Function and Lung Density: A Cross-Sectional Study SO PLOS ONE LA English DT Article ID OBSTRUCTIVE PULMONARY-DISEASE; RETINAL VASCULAR CALIBER; AIR-FLOW OBSTRUCTION; ATHEROSCLEROSIS MESA LUNG; CIGARETTE-SMOKE; CARDIOVASCULAR MORTALITY; MYOCARDIAL-PERFUSION; ALBUMIN EXCRETION; MEDIATED DILATION; REFERENCE VALUES AB Smoking causes endothelial dysfunction and systemic microvascular disease with resultant end-organ damage in the kidneys, eyes and heart. Little is known about microvascular changes in smoking-related lung disease. We tested if microvascular changes in the retina, kidneys and heart were associated with obstructive spirometry and low lung density on computed tomography. The Multi-Ethnic Study of Atherosclerosis recruited participants age 45-84 years without clinical cardiovascular disease. Measures of microvascular function included retinal arteriolar and venular caliber, urine albumin-to-creatinine ratio and, in a subset, myocardial blood flow on magnetic resonance imaging. Spirometry was measured following ATS/ERS guidelines. Low attenuation areas (LAA) were measured on lung fields of cardiac computed tomograms. Regression models adjusted for pulmonary and cardiac risk factors, medications and body size. Among 3,397 participants, retinal venular caliber was inversely associated with forced expiratory volume in one second (FEV1) (P<0.001) and FEV1/forced vital capacity (FVC) ratio (P = 0.04). Albumin-to-creatinine ratio was inversely associated with FEV1 (P = 0.002) but not FEV1/FVC. Myocardial blood flow (n = 126) was associated with lower FEV1 (P = 0.02), lower FEV1/FVC (P = 0.001) and greater percentage LAA (P = 0.04). Associations were of greater magnitude among smokers. Low lung function was associated with microvascular changes in the retina, kidneys and heart, and low lung density was associated with impaired myocardial microvascular perfusion. These cross-sectional results suggest that microvascular damage with end-organ dysfunction in all circulations may pertain to the lung, that lung dysfunction may contribute to systemic microvascular disease, or that there may be a shared predisposition. C1 [Harris, Bianca; Ahmed, Firas S.; Barr, Graham] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY 10027 USA. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI USA. [Jerosch-Herold, Michael] Univ Minnesota, Sch Med, Dept Radiol, Minneapolis, MN 55455 USA. [Jerosch-Herold, Michael] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Radiol, Boston, MA USA. [Hoffman, Eric A.] Univ Iowa, Dept Radiol, Iowa City, IA 52242 USA. [Ahmed, Firas S.] Columbia Univ, Coll Phys & Surg, Dept Radiol, New York, NY USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Jacobs, David R., Jr.] Univ Oslo, Dept Nutr, Oslo, Norway. [Wong, Tien Y.] Univ Melbourne, Ctr Eye Res Australia, Melbourne, Vic, Australia. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Barr, Graham] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. RP Barr, G (reprint author), Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY 10027 USA. EM rgb9@columbia.edu OI Cotch, Mary Frances/0000-0002-2046-4350; Klein, Ronald/0000-0002-4428-6237 FU National Institutes of Health [R01-HL077612, R01-HL093081, R01-HL075476]; Vida Diagnostics; [N01-HC95159-HC95169]; [UL1-TR000040] FX This study was funded by National Institutes of Health R01-HL077612, R01-HL093081, and R01-HL075476. MESA is supported by N01-HC95159-HC95169 and UL1-TR000040. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.; Funding was provided by federal sources, an interest in Vida Diagnostics (EA Hoffman) and a gift of a fish oil supplement, Omax3, provided by Cenestra Health for a federally funded randomized clinical trial (RG Barr). These conflicts-of-interest do not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. NR 62 TC 8 Z9 8 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 DEC 20 PY 2012 VL 7 IS 12 AR e50224 DI 10.1371/journal.pone.0050224 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 060RA UT WOS:000312794500012 PM 23284634 ER PT J AU Brister, JR Le Mercier, P Hu, JC AF Brister, J. Rodney Le Mercier, Phillippe Hu, James C. TI Microbial virus genome annotation-Mustering the troops to fight the sequence onslaught SO VIROLOGY LA English DT Review DE Viral genomics; Genome annotation; Biological sequence databases ID GENE ONTOLOGY; DATABASE; STANDARDS; RESOURCE AB The revolution in virus genome sequencing promises to effectively map the extant biological universe and reveal fundamental relationships between viral biology, genome structure, and evolution. Indeed, microbial virus genomes include large numbers of conserved coding sequences of unknown function as well as unique gene combinations, implying that that these viruses will be a significant source of novel protein biochemistry and genome architecture. Yet, making sense of the approaching phalanx of A's, G's, Ts, and C's stretching across the genome sequencing horizon will require innovation and an unprecedented coordination of annotation efforts among stakeholders. Published by Elsevier Inc. C1 [Brister, J. Rodney] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Le Mercier, Phillippe] CMU, Swiss Inst Bioinformat, Swiss Prot Grp, CH-1211 Geneva 4, Switzerland. [Hu, James C.] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. RP Brister, JR (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM jamesbr@ncbi.nlm.nih.gov; philippe.lemercier@isb-sib.ch; jimhu@tamu.edu FU Intramural Research Program of the NIH, National Library of Medicine; SIB Swiss Institute of Bioinformatics; NIGMS [U24GM088849]; NIH [R01 GM089636] FX This research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. Work by PLM was supported by the SIB Swiss Institute of Bioinformatics. Work by JH was supported by the NIGMS No. U24GM088849 and the NIH No. R01 GM089636. NR 25 TC 7 Z9 7 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 0042-6822 J9 VIROLOGY JI Virology PD DEC 20 PY 2012 VL 434 IS 2 SI SI BP 175 EP 180 DI 10.1016/j.virol.2012.09.027 PG 6 WC Virology SC Virology GA 056RP UT WOS:000312509300006 PM 23084289 ER PT J AU Farkouh, ME Domanski, M Sleeper, LA Siami, FS Dangas, G Mack, M Yang, M Cohen, DJ Rosenberg, Y Solomon, SD Desai, AS Gersh, BJ Magnuson, EA Lansky, A Boineau, R Weinberger, J Ramanathan, K Sousa, JE Rankin, J Bhargava, B Buse, J Hueb, W Smith, CR Muratov, V Bansilal, S King, S Bertrand, M Fuster, V AF Farkouh, Michael E. Domanski, Michael Sleeper, Lynn A. Siami, Flora S. Dangas, George Mack, Michael Yang, May Cohen, David J. Rosenberg, Yves Solomon, Scott D. Desai, Akshay S. Gersh, Bernard J. Magnuson, Elizabeth A. Lansky, Alexandra Boineau, Robin Weinberger, Jesse Ramanathan, Krishnan Sousa, J. Eduardo Rankin, Jamie Bhargava, Balram Buse, John Hueb, Whady Smith, Craig R. Muratov, Victoria Bansilal, Sameer King, Spencer, III Bertrand, Michel Fuster, Valentin CA FREEDOM Trial Investigators TI Strategies for Multivessel Revascularization in Patients with Diabetes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID PERCUTANEOUS CORONARY INTERVENTION; HEART-ASSOCIATION; RANDOMIZED-TRIAL; BYPASS-SURGERY; DISEASE; ANGIOPLASTY; STROKE; BARI; MELLITUS; OUTCOMES AB BACKGROUND In some randomized trials comparing revascularization strategies for patients with diabetes, coronary-artery bypass grafting (CABG) has had a better outcome than percutaneous coronary intervention (PCI). We sought to discover whether aggressive medical therapy and the use of drug-eluting stents could alter the revascularization approach for patients with diabetes and multivessel coronary artery disease. METHODS In this randomized trial, we assigned patients with diabetes and multivessel coronary artery disease to undergo either PCI with drug-eluting stents or CABG. The patients were followed for a minimum of 2 years (median among survivors, 3.8 years). All patients were prescribed currently recommended medical therapies for the control of low-density lipoprotein cholesterol, systolic blood pressure, and glycated hemoglobin. The primary outcome measure was a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke. RESULTS From 2005 through 2010, we enrolled 1900 patients at 140 international centers. The patients' mean age was 63.1 +/- 9.1 years, 29% were women, and 83% had three-vessel disease. The primary outcome occurred more frequently in the PCI group (P=0.005), with 5-year rates of 26.6% in the PCI group and 18.7% in the CABG group. The benefit of CABG was driven by differences in rates of both myocardial infarction (P<0.001) and death from any cause (P=0.049). Stroke was more frequent in the CABG group, with 5-year rates of 2.4% in the PCI group and 5.2% in the CABG group (P=0.03). CONCLUSIONS For patients with diabetes and advanced coronary artery disease, CABG was superior to PCI in that it significantly reduced rates of death and myocardial infarction, with a higher rate of stroke. (Funded by the National Heart, Lung, and Blood Institute and others; FREEDOM ClinicalTrials.gov number, NCT00086450.) C1 [Fuster, Valentin] Mt Sinai Sch Med, Michael A Wiener Cardiovasc Inst, New York, NY 10029 USA. [Dangas, George] Cardiovasc Res Fdn, New York, NY USA. [Smith, Craig R.] New York Presbyterian Med Ctr, New York, NY USA. [Farkouh, Michael E.] Univ Toronto, Peter Munk Cardiac Ctr, Toronto, ON, Canada. [Farkouh, Michael E.] Univ Toronto, Li Ka Shing Knowledge Inst, Toronto, ON, Canada. [Ramanathan, Krishnan] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Sleeper, Lynn A.; Siami, Flora S.; Yang, May; Muratov, Victoria] New England Res Inst, Watertown, MA 02172 USA. [Solomon, Scott D.; Desai, Akshay S.] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Mack, Michael] Baylor Univ, Med Ctr, Dallas, TX USA. [Cohen, David J.; Magnuson, Elizabeth A.] Univ Missouri Kansas City, St Lukes Midamer Heart Inst, Kansas City, MO USA. [Rosenberg, Yves; Boineau, Robin] NHLBI, Bethesda, MD 20892 USA. [Gersh, Bernard J.] Mayo Clin, Rochester, MN USA. [Lansky, Alexandra] Yale Univ, New Haven, CT USA. [Sousa, J. Eduardo] Univ Sao Paulo, Sch Med, Dante Pazzanese Hosp, Sao Paulo, Brazil. [Hueb, Whady] Univ Sao Paulo, Sch Med, Heart Inst InCor, Sao Paulo, Brazil. [Rankin, Jamie] Royal Perth Hosp, Perth, WA, Australia. [Bhargava, Balram] All India Inst Med Sci, New Delhi, India. [Buse, John] Univ N Carolina, Chapel Hill, NC USA. [King, Spencer, III] St Josephs Hosp, Atlanta, GA USA. [Bertrand, Michel] Univ Lille, Lille, France. [Fuster, Valentin] Ctr Nacl Invest Cardiovasc, Madrid, Spain. RP Fuster, V (reprint author), Mt Sinai Sch Med, Michael A Wiener Cardiovasc Inst, 1 Gustave L Levy Pl,Box 1030, New York, NY 10029 USA. EM valentin.fuster@mssm.edu RI Hueb, Whady/A-7919-2013; Lemos, Pedro/G-5758-2013; Caramori, Paulo/I-1370-2012; Deplanque, Dominique/E-4901-2015; Solomon, Scott/I-5789-2013; Wijesekera, Vishva/G-3259-2014; Hankey, Graeme /H-4968-2014; Frey, Norbert/A-9695-2010; Ponikowski, Piotr/O-6454-2015; Fuster, Valentin/H-4319-2015 OI Ung, Kjell-Arne/0000-0002-2346-8031; Kruithof-de Julio, Marianna/0000-0002-6085-7706; Lemos, Pedro/0000-0002-6782-750X; Deplanque, Dominique/0000-0002-4995-584X; Wijesekera, Vishva/0000-0002-3722-3377; Hankey, Graeme /0000-0002-6044-7328; Ponikowski, Piotr/0000-0002-3391-7064; Fuster, Valentin/0000-0002-9043-9986 FU NHLBI [U01 01HL071988, 01HL092989]; Cordis; Johnson Johnson; Boston Scientific; Sanofi-Aventis; Bristol-Myers Squibb; Eli Lilly FX Supported by grants (U01 01HL071988 and 01HL092989) from the NHLBI. Cordis, Johnson & Johnson, and Boston Scientific provided the stents; Eli Lilly provided abciximab and an unrestricted research grant; and Sanofi-Aventis and Bristol-Myers Squibb provided clopidogrel. NR 21 TC 558 Z9 583 U1 3 U2 127 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 DEC 20 PY 2012 VL 367 IS 25 BP 2375 EP 2384 DI 10.1056/NEJMoa1211585 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 056ZP UT WOS:000312531600005 PM 23121323 ER PT J AU van der Harst, P Zhang, WH Leach, IM Rendon, A Verweij, N Sehmi, J Paul, DS Elling, U Allayee, H Li, XZ Radhakrishnan, A Tan, ST Voss, K Weichenberger, CX Albers, CA Al-Hussani, A Asselbergs, FW Ciullo, M Danjou, F Dina, C Esko, T Evans, DM Franke, L Goegele, M Hartiala, J Hersch, M Holm, H Hottenga, JJ Kanoni, S Kleber, ME Lagou, V Langenberg, C Lopez, LM Lyytikainen, LP Melander, O Murgia, F Nolte, IM O'Reilly, PF Padmanabhan, S Parsa, A Pirastu, N Porcu, E Portas, L Prokopenko, I Ried, JS Shin, SY Tang, CS Teumer, A Traglia, M Ulivi, S Westra, HJ Yang, J Zhao, JH Anni, F Abdellaoui, A Attwood, A Balkau, B Bandinelli, S Bastardot, F Benyamin, B Boehm, BO Cookson, WO Das, D de Bakker, PIW de Boer, RA de Geus, EJC de Moor, MH Dimitriou, M Domingues, FS Doring, A Engstrom, G Eyjolfsson, GI Ferrucci, L Fischer, K Galanello, R Garner, SF Genser, B Gibson, QD Girotto, G Gudbjartsson, DF Harris, SE Hartikainen, AL Hastie, CE Hedblad, B Illig, T Jolley, J Kahonen, M Kema, IP Kemp, JP Liang, LM Lloyd-Jones, H Loos, RJF Meacham, S Medland, SE Meisinger, C Memari, Y Mihailov, E Miller, K Moffatt, MF Nauck, M Novatchkova, M Nutile, T Olafsson, I Onundarson, PT Parracciani, D Penninx, BW Perseu, L Piga, A Pistis, G Pouta, A Puc, U Raitakari, O Ring, SM Robino, A Ruggiero, D Ruokonen, A Saint-Pierre, A Sala, C Salumets, A Sambrook, J Schepers, H Schmidt, CO Sillje, HHW Sladek, R Smit, JH Starr, JM Stephens, J Sulem, P Tanaka, T Thorsteinsdottir, U Tragante, V van Gilst, WH van Pelt, LJ van Veldhuisen, DJ Volker, U Whitfield, JB Willemsen, G Winkelmann, BR Wirnsberger, G Algra, A Cucca, F d'Adamo, AP Danesh, J Deary, IJ Dominiczak, AF Elliott, P Fortina, P Froguel, P Gasparini, P Greinacher, A Hazen, SL Jarvelin, MR Khaw, KT Lehtimaki, T Maerz, W Martin, NG Metspalu, A Mitchell, BD Montgomery, GW Moore, C Navis, G Pirastu, M Pramstaller, PP Ramirez-Solis, R Schadt, E Scott, J Shuldiner, AR Smith, GD Smith, JG Snieder, H Sorice, R Spector, TD Stefansson, K Stumvoll, M Tang, WHW Toniolo, D Tonjes, A Visscher, PM Vollenweider, P Wareham, NJ Wolffenbuttel, BHR Boomsma, DI Beckmann, JS Dedoussis, GV Deloukas, P Ferreira, MA Sanna, S Uda, M Hicks, AA Penninger, JM Gieger, C Kooner, JS Ouwehand, WH Soranzo, N Chambers, JC AF van der Harst, Pim Zhang, Weihua Leach, Irene Mateo Rendon, Augusto Verweij, Niek Sehmi, Joban Paul, Dirk S. Elling, Ulrich Allayee, Hooman Li, Xinzhong Radhakrishnan, Aparna Tan, Sian-Tsung Voss, Katrin Weichenberger, Christian X. Albers, Cornelis A. Al-Hussani, Abtehale Asselbergs, Folkert W. Ciullo, Marina Danjou, Fabrice Dina, Christian Esko, Tonu Evans, David M. Franke, Lude Goegele, Martin Hartiala, Jaana Hersch, Micha Holm, Hilma Hottenga, Jouke-Jan Kanoni, Stavroula Kleber, Marcus E. Lagou, Vasiliki Langenberg, Claudia Lopez, Lorna M. Lyytikainen, Leo-Pekka Melander, Olle Murgia, Federico Nolte, Ilja M. O'Reilly, Paul F. Padmanabhan, Sandosh Parsa, Afshin Pirastu, Nicola Porcu, Eleonora Portas, Laura Prokopenko, Inga Ried, Janina S. Shin, So-Youn Tang, Clara S. Teumer, Alexander Traglia, Michela Ulivi, Sheila Westra, Harm-Jan Yang, Jian Zhao, Jing Hua Anni, Franco Abdellaoui, Abdel Attwood, Antony Balkau, Beverley Bandinelli, Stefania Bastardot, Francois Benyamin, Beben Boehm, Bernhard O. Cookson, William O. Das, Debashish de Bakker, Paul I. W. de Boer, Rudolf A. de Geus, Eco J. C. de Moor, Marleen H. Dimitriou, Maria Domingues, Francisco S. Doering, Angela Engstrom, Gunnar Eyjolfsson, Gudmundur Ingi Ferrucci, Luigi Fischer, Krista Galanello, Renzo Garner, Stephen F. Genser, Bernd Gibson, Quince D. Girotto, Giorgia Gudbjartsson, Daniel Fannar Harris, Sarah E. Hartikainen, Anna-Liisa Hastie, Claire E. Hedblad, Bo Illig, Thomas Jolley, Jennifer Kahonen, Mika Kema, Ido P. Kemp, John P. Liang, Liming Lloyd-Jones, Heather Loos, Ruth J. F. Meacham, Stuart Medland, Sarah E. Meisinger, Christa Memari, Yasin Mihailov, Evelin Miller, Kathy Moffatt, Miriam F. Nauck, Matthias Novatchkova, Maria Nutile, Teresa Olafsson, Isleifur Onundarson, Pall T. Parracciani, Debora Penninx, Brenda W. Perseu, Lucia Piga, Antonio Pistis, Giorgio Pouta, Anneli Puc, Ursula Raitakari, Olli Ring, Susan M. Robino, Antonietta Ruggiero, Daniela Ruokonen, Aimo Saint-Pierre, Aude Sala, Cinzia Salumets, Andres Sambrook, Jennifer Schepers, Hein Schmidt, Carsten Oliver Sillje, Herman H. W. Sladek, Rob Smit, Johannes H. Starr, John M. Stephens, Jonathan Sulem, Patrick Tanaka, Toshiko Thorsteinsdottir, Unnur Tragante, Vinicius van Gilst, Wiek H. van Pelt, L. Joost van Veldhuisen, Dirk J. Voelker, Uwe Whitfield, John B. Willemsen, Gonneke Winkelmann, Bernhard R. Wirnsberger, Gerald Algra, Ale Cucca, Francesco d'Adamo, Adamo Pio Danesh, John Deary, Ian J. Dominiczak, Anna F. Elliott, Paul Fortina, Paolo Froguel, Philippe Gasparini, Paolo Greinacher, Andreas Hazen, Stanley L. Jarvelin, Marjo-Riitta Khaw, Kay Tee Lehtimaki, Terho Maerz, Winfried Martin, Nicholas G. Metspalu, Andres Mitchell, Braxton D. Montgomery, Grant W. Moore, Carmel Navis, Gerjan Pirastu, Mario Pramstaller, Peter P. Ramirez-Solis, Ramiro Schadt, Eric Scott, James Shuldiner, Alan R. Smith, George Davey Smith, J. Gustav Snieder, Harold Sorice, Rossella Spector, Tim D. Stefansson, Kari Stumvoll, Michael Tang, W. H. Wilson Toniolo, Daniela Toenjes, Anke Visscher, Peter M. Vollenweider, Peter Wareham, Nicholas J. Wolffenbuttel, Bruce H. R. Boomsma, Dorret I. Beckmann, Jacques S. Dedoussis, George V. Deloukas, Panos Ferreira, Manuel A. Sanna, Serena Uda, Manuela Hicks, Andrew A. Penninger, Josef Martin Gieger, Christian Kooner, Jaspal S. Ouwehand, Willem H. Soranzo, Nicole Chambers, John C. TI Seventy-five genetic loci influencing the human red blood cell SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; HEMOGLOBIN LEVELS; COMMON VARIANTS; EXPRESSION; DISEASE; PROTEIN; TRAITS; CONSORTIUM; DROSOPHILA; RECEPTOR AB Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function. C1 [Zhang, Weihua; Al-Hussani, Abtehale; O'Reilly, Paul F.; Elliott, Paul; Jarvelin, Marjo-Riitta; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England. [van der Harst, Pim; Leach, Irene Mateo; Verweij, Niek; de Boer, Rudolf A.; Sillje, Herman H. W.; van Gilst, Wiek H.; van Veldhuisen, Dirk J.] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, NL-9700 RB Groningen, Netherlands. [van der Harst, Pim; Franke, Lude; Westra, Harm-Jan] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, NL-9700 RB Groningen, Netherlands. [Zhang, Weihua; Sehmi, Joban; Tan, Sian-Tsung; Miller, Kathy; Kooner, Jaspal S.; Chambers, John C.] Ealing Hosp NHS Trust, Uxbridge UB1 3HW, Middx, England. [Rendon, Augusto; Radhakrishnan, Aparna; Voss, Katrin; Albers, Cornelis A.; Attwood, Antony; Garner, Stephen F.; Jolley, Jennifer; Lloyd-Jones, Heather; Meacham, Stuart; Sambrook, Jennifer; Stephens, Jonathan; Ouwehand, Willem H.] Univ Cambridge, Dept Haematol, Cambridge CB2 0XY, England. [Rendon, Augusto; Radhakrishnan, Aparna; Voss, Katrin; Albers, Cornelis A.; Attwood, Antony; Garner, Stephen F.; Jolley, Jennifer; Lloyd-Jones, Heather; Meacham, Stuart; Sambrook, Jennifer; Stephens, Jonathan; Ouwehand, Willem H.] NHS Blood & Transplant, Cambridge CB2 0PT, England. [Rendon, Augusto] Inst Publ Hlth, MRC Biostat Unit, Cambridge CB2 2SR, England. [Rendon, Augusto; Radhakrishnan, Aparna; Voss, Katrin; Attwood, Antony; Garner, Stephen F.; Jolley, Jennifer; Lloyd-Jones, Heather; Meacham, Stuart; Sambrook, Jennifer; Stephens, Jonathan; Ouwehand, Willem H.] NIHR Cambridge Biomed Res Ctr, Cambridge CB2 0QQ, England. [Sehmi, Joban; Tan, Sian-Tsung; Cookson, William O.; Moffatt, Miriam F.; Scott, James; Kooner, Jaspal S.] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London W12 0NN, England. [Paul, Dirk S.; Radhakrishnan, Aparna; Albers, Cornelis A.; Kanoni, Stavroula; Shin, So-Youn; Attwood, Antony; Meacham, Stuart; Memari, Yasin; Ramirez-Solis, Ramiro; Deloukas, Panos; Ouwehand, Willem H.; Soranzo, Nicole] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. [Elling, Ulrich; Novatchkova, Maria; Puc, Ursula; Wirnsberger, Gerald; Penninger, Josef Martin] Austrian Acad Sci, Inst Mol Biotechnol, A-1030 Vienna, Austria. [Allayee, Hooman; Hartiala, Jaana] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Li, Xinzhong] Univ London Imperial Coll Sci Technol & Med, Inst Clin Sci, London W12 0NN, England. [Li, Xinzhong; Chambers, John C.] Royal Brompton & Harefield NHS Fdn Trust, NIHR Cardiovasc Biomed Res Unit, London SW3 6NP, England. [Li, Xinzhong; Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, London SW3 6NP, England. 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[Parracciani, Debora] Genet Pk Ogliastra, Perdasdefogu, Sardinia, Italy. [Penninx, Brenda W.; Smit, Johannes H.] Vrije Univ Amsterdam Med Ctr, EMGO Inst, Dept Psychiat, NL-1081 BT Amsterdam, Netherlands. [Penninx, Brenda W.] Univ Groningen, Univ Med Ctr Groningen, Dept Psychiat, NL-9700 RB Groningen, Netherlands. [Penninx, Brenda W.] Leiden Univ, Med Ctr, Dept Psychiat, NL-2333 Leiden, Netherlands. [Piga, Antonio] Univ Turin, Dept Clin & Biol Sci, Div Pediat, I-10043 Turin, Italy. [Piga, Antonio] Univ Turin, Dept Clin & Biol Sci, Thalassemia Ctr, I-10043 Turin, Italy. [Pouta, Anneli; Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, FIN-90220 Oulu, Finland. [Pouta, Anneli] Natl Inst Hlth & Welf, FIN-90101 Oulu, Finland. [Raitakari, Olli] Turku Univ Hosp, Dept Clin Physiol & Nucl Med, FIN-20521 Turku, Finland. [Raitakari, Olli] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, FIN-20521 Turku, Finland. [Ring, Susan M.] Univ Bristol, Sch Social & Community Med, Bristol BS8 2PS, Avon, England. [Ruokonen, Aimo] Univ Oulu, Inst Diagnost, FIN-90014 Oulu, Finland. [Salumets, Andres] Competence Ctr Reprod Med & Biol, EE-50410 Tartu, Estonia. [Salumets, Andres] Univ Tartu, Inst Gen & Mol Pathol, EE-51014 Tartu, Estonia. [Schepers, Hein] Univ Groningen, Univ Med Ctr Groningen, Dept Expt Hematol, NL-9700 RB Groningen, Netherlands. [Schepers, Hein] Univ Groningen, Univ Med Ctr Groningen, Dept Stem Cell Biol, NL-9700 RB Groningen, Netherlands. [Schmidt, Carsten Oliver] Univ Med Greifswald, Inst Community Med, D-17475 Greifswald, Germany. [Sladek, Rob] McGill Univ, Fac Med, Dept Human Genet, Montreal, PQ H3A 1B1, Canada. [Sladek, Rob] McGill Univ, Fac Med, Dept Med, Montreal, PQ H3A 1B1, Canada. [Starr, John M.] Univ Edinburgh, Western Gen Hosp, Geriatr Med Unit, Edinburgh EH4 2XU, Midlothian, Scotland. [Winkelmann, Bernhard R.] ClinPhen Study Ctr, D-60594 Frankfurt, Germany. [Algra, Ale] Univ Med Ctr Utrecht, Rudolf Magnus Inst Neurosci, Dept Neurol & Neurosurg, Utrecht Stroke Ctr, NL-3584 CG Utrecht, Netherlands. [Cucca, Francesco] Univ Sassari, Dipartimento Sci Biomed, I-07100 Sassari, Italy. [Danesh, John; Moore, Carmel] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Elliott, Paul; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, MRC HPA Ctr Environm & Hlth, London W2 1PG, England. [Fortina, Paolo] Thomas Jefferson Univ, Coll Med, Dept Canc Biol, Philadelphia, PA 19107 USA. [Fortina, Paolo] Univ Roma La Sapienza, Dipartimento Med Mol, I-00161 Rome, Italy. [Froguel, Philippe] Lille Pasteur Inst, CNRS, UMR 8199, F-59100 Lille, France. [Froguel, Philippe] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London W2 1PG, England. [Greinacher, Andreas] Univ Med Greifswald, Inst Immunol & Transfus Med, D-17487 Greifswald, Germany. [Hazen, Stanley L.; Tang, W. H. Wilson] Cleveland Clin, Lerner Res Inst, Dept Cell Biol, Ctr Cardiovasc Diagnost & Prevent, Cleveland, OH 44195 USA. [Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Lifecourse snd Serv, FIN-90101 Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, FIN-90220 Oulu, Finland. [Khaw, Kay Tee] Addenbrookes Hosp, Clin Gerontol Unit, Cambridge CB2 2QQ, England. [Maerz, Winfried] Synlab Acad, D-68165 Mannheim, Germany. [Navis, Gerjan] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, NL-9700 RB Groningen, Netherlands. [Pramstaller, Peter P.] Gen Cent Hosp, Dept Neurol, I-39100 Bolzano, Italy. [Pramstaller, Peter P.] Med Univ Lubeck, Dept Neurol, D-23538 Lubeck, Germany. [Schadt, Eric] Mt Sinai Sch Med, Inst Genom & Multiscale Biol, New York, NY 10029 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Ctr Geriatr Res Educ & Clin, Baltimore, MD 21201 USA. [Smith, J. Gustav] Lund Univ, Dept Cardiol, S-22185 Lund, Sweden. [Spector, Tim D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England. [Stumvoll, Michael; Toenjes, Anke] Univ Leipzig, Dept Med, D-04103 Leipzig, Germany. [Stumvoll, Michael; Toenjes, Anke] Univ Leipzig, IFB Adipos Dis, D-04103 Leipzig, Germany. [Toniolo, Daniela] CNR, Inst Mol Genet, I-27100 Pavia, Italy. [Wolffenbuttel, Bruce H. R.] Univ Groningen, Univ Med Ctr Groningen, Dept Endocrinol, NL-9700 RB Groningen, Netherlands. [Beckmann, Jacques S.] CHU Vaudois, Serv Med Genet, CH-1011 Lausanne, Switzerland. [Kooner, Jaspal S.; Chambers, John C.] Imperial Coll Healthcare NHS Trust, London W12 0HS, England. RP Chambers, JC (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Biostat, London W2 1PG, England. EM p.van.der.harst@umcg.nl; christian.gieger@helmholtz-muenchen.de; j.kooner@ic.ac.uk; who1000@cam.ac.uk; ns6@sanger.ac.uk; john.chambers@ic.ac.uk RI Prokopenko, Inga/H-3241-2014; Lyytikainen, Leo-Pekka/C-8544-2016; Yang, Jian/A-5852-2010; ruggiero, daniela/K-5638-2016; Franke, Lude/P-7036-2016; Danjou, Fabrice/D-1563-2014; Padmanabhan, Sandosh/S-3963-2016; Verweij, Niek/A-4499-2017; Davey Smith, George/A-7407-2013; Hicks, Andrew/E-9518-2017; de Bakker, Paul/B-8730-2009; Benyamin, Beben/D-9195-2012; Lagou, Vasiliki/N-8451-2013; d'Adamo, Adamo Pio/G-4064-2011; Meisinger, Christine/B-5358-2014; van Veldhuisen, Dirk Jan/E-8967-2014; Pramstaller, Peter/C-2357-2008; Albers, Kees/A-4170-2015; Dina, Christian/D-3535-2015; Boehm, Bernhard/F-8750-2015; Salumets, Andres/J-2278-2015; de Geus, Eco/M-9318-2015; Montgomery, Grant/B-7148-2008; Penninger, Josef/I-6860-2013; Colaus, PsyColaus/K-6607-2013; Deloukas, Panos/B-2922-2013; Wolffenbuttel, Bruce/A-8419-2011; Pirastu, Nicola/G-4358-2011; Medland, Sarah/C-7630-2013; Deary, Ian/C-6297-2009; Beckmann, Jacques S /A-9772-2008; Ferreira, Manuel/D-3609-2013; Ulivi, Sheila/H-3700-2013; Evans, David/H-6325-2013; Tang, Wai Hong/I-1238-2013 OI Padmanabhan, Sandosh/0000-0003-3869-5808; NUTILE, TERESA/0000-0001-7062-8352; Soranzo, Nicole/0000-0003-1095-3852; Gieger, Christian/0000-0001-6986-9554; Verweij, Niek/0000-0002-4303-7685; Meisinger, Christa/0000-0002-9026-6544; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Girotto, Giorgia/0000-0003-4507-6589; Rendon, Augusto/0000-0001-8994-0039; sanna, serena/0000-0002-3768-1749; Gudbjartsson, Daniel/0000-0002-5222-9857; Pirastu, Nicola/0000-0002-5363-3886; Monsalve, Beatriz Elena/0000-0002-5994-866X; Tang, Clara/0000-0003-0265-2638; Esko, Tonu/0000-0003-1982-6569; Prokopenko, Inga/0000-0003-1624-7457; Lyytikainen, Leo-Pekka/0000-0002-7200-5455; Yang, Jian/0000-0003-2001-2474; ruggiero, daniela/0000-0003-3898-7827; Franke, Lude/0000-0002-5159-8802; Danjou, Fabrice/0000-0002-4976-2327; Davey Smith, George/0000-0002-1407-8314; Hicks, Andrew/0000-0001-6320-0411; Sladek, Robert/0000-0002-2730-1204; Engstrom, Gunnar/0000-0002-8618-9152; de Bakker, Paul/0000-0001-7735-7858; Benyamin, Beben/0000-0001-5608-2293; d'Adamo, Adamo Pio/0000-0001-9367-4909; Albers, Kees/0000-0003-4115-3727; Dina, Christian/0000-0002-7722-7348; Salumets, Andres/0000-0002-1251-8160; de Geus, Eco/0000-0001-6022-2666; Montgomery, Grant/0000-0002-4140-8139; Kleber, Marcus/0000-0003-0663-7275; Martin, Nicholas/0000-0003-4069-8020; Memari, Yasin/0000-0002-1747-542X; Visscher, Peter/0000-0002-2143-8760; Kemp, John/0000-0002-9105-2249; Evans, David/0000-0003-0663-4621; Mitchell, Braxton/0000-0003-4920-4744; Ouwehand, Willem/0000-0002-7744-1790; Paul, Dirk/0000-0002-8230-0116; Penninger, Josef/0000-0002-8194-3777; Deloukas, Panos/0000-0001-9251-070X; Wolffenbuttel, Bruce/0000-0001-9262-6921; Medland, Sarah/0000-0003-1382-380X; Beckmann, Jacques S /0000-0002-9741-1900; Ulivi, Sheila/0000-0003-3606-835X; FU British Heart Foundation [RG/08/014/24067, RG/09/012/28096]; Cancer Research UK [14136]; Chief Scientist Office [CZB/4/505, ETM/55]; Department of Health [RP-PG-0310-1002]; Medical Research Council [G0401527, G0600705, G0700704, G0801056, G1000143, G1002084, G9815508, MC_U106179471, MC_U106188470]; NCATS NIH HHS [UL1 TR000439]; NCI NIH HHS [R01 CA165001]; NCRR NIH HHS [K12 RR023250, U54 RR020278, UL1 RR025005]; NHGRI NIH HHS [U01 HG004402]; NHLBI NIH HHS [R01 HL087641, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, P01 HL076491, P01 HL098055, P20 HL113452, R01 HL059367, R01 HL086694, R01 HL087679, R01 HL088119, R01 HL103866, R01 HL103931, U01 HL072515, U01 HL084756]; NIA NIH HHS [N01AG12109, R01 AG018728]; NICHD NIH HHS [R01 HD042157]; NIDA NIH HHS [HHSN271201100005C]; NIDDK NIH HHS [P30 DK072488]; NIGMS NIH HHS [R01 GM053275, U01 GM074518]; NIMH NIH HHS [R01 MH081802, RL1 MH083268, U24 MH068457]; NLM NIH HHS [R01 LM010098]; Wellcome Trust [092731, 097117] NR 47 TC 110 Z9 110 U1 7 U2 104 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 20 PY 2012 VL 492 IS 7429 BP 369 EP + DI 10.1038/nature11677 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 056KQ UT WOS:000312488200044 PM 23222517 ER PT J AU Palys, KE Berger, VW Grant, WC AF Palys, Kaitlin E. Berger, Vance W. Grant, William C. TI Unequal allocation and allocation concealment SO STATISTICS IN MEDICINE LA English DT Letter C1 [Palys, Kaitlin E.] Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. [Berger, Vance W.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, Vance W.] UMBC, Bethesda, MD 20892 USA. [Grant, William C.] James Madison Univ, Dept Econ, Harrisonburg, VA 22807 USA. RP Palys, KE (reprint author), Virginia Polytech Inst & State Univ, Blacksburg, VA 24061 USA. EM palysk@vt.edu NR 7 TC 0 Z9 0 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD DEC 20 PY 2012 VL 31 IS 29 BP 4135 EP 4136 DI 10.1002/sim.5432 PG 2 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 041LH UT WOS:000311402800025 PM 23175158 ER PT J AU Berger, VW AF Berger, Vance W. TI Two-stage randomized trials: outstanding issues SO STATISTICS IN MEDICINE LA English DT Letter C1 [Berger, Vance W.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, Vance W.] UMBC, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Biometry Res Grp, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD DEC 20 PY 2012 VL 31 IS 29 BP 4142 EP 4142 DI 10.1002/sim.5342 PG 1 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 041LH UT WOS:000311402800029 PM 23175161 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI Diversity matters in scientific publishing SO RETROVIROLOGY LA English DT Editorial Material ID IN-VITRO; CELLS; HIV-1; INFECTION; VIRUS; CCR5 AB The importance of geographic diversity in publishing is emphasized in this editorial. C1 NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM kjeang@nih.gov FU Intramural NIH HHS NR 12 TC 0 Z9 0 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD DEC 19 PY 2012 VL 9 AR 109 DI 10.1186/1742-4690-9-109 PG 2 WC Virology SC Virology GA 076MY UT WOS:000313961800001 PM 23253815 ER PT J AU Mitchell, BD Lee, WJ Tolea, MI Shields, K Ashktorab, Z Magder, LS Ryan, KA Pollin, TI McArdle, PF Shuldiner, AR Schaffer, AA AF Mitchell, Braxton D. Lee, Woei-Jyh Tolea, Magdalena I. Shields, Kelsey Ashktorab, Zahra Magder, Laurence S. Ryan, Kathleen A. Pollin, Toni I. McArdle, Patrick F. Shuldiner, Alan R. Schaeffer, Alejandro A. TI Living the Good Life? Mortality and Hospital Utilization Patterns in the Old Order Amish SO PLOS ONE LA English DT Article ID AMERICAN ANABAPTIST GENEALOGY; PHYSICAL-ACTIVITY; LANCASTER COUNTY; CORONARY-ARTERY; RISK-FACTORS; ASSOCIATION; CALCIFICATION; FRAMINGHAM; DISEASE; GENE AB Lifespan increases observed in the United States and elsewhere throughout the developed world, have been attributed in part to improvements in medical care access and technology and to healthier lifestyles. To differentiate the relative contributions of these two factors, we have compared lifespan in the Old Order Amish (OOA), a population with historically low use of medical care, with that of Caucasian participants from the Framingham Heart Study (FHS), focusing on individuals who have reached at least age 30 years. Analyses were based on 2,108 OOA individuals from the Lancaster County, PA community born between 1890 and 1921 and 5,079 FHS participants born approximately the same time. Vital status was ascertained on 96.9% of the OOA cohort through 2011 and through systematic follow-up of the FHS cohort. The lifespan part of the study included an enlargement of the Anabaptist Genealogy Database to 539,822 individuals, which will be of use in other studies of the Amish. Mortality comparisons revealed that OOA men experienced better longevity (p<0.001) and OOA women comparable longevity than their FHS counterparts. We further documented all OOA hospital discharges in Lancaster County, PA during 2002-2004 and compared OOA discharge rates to Caucasian national rates obtained from the National Hospital Discharge Survey for the same time period. Both OOA men and women experienced markedly lower rates of hospital discharges than their non-Amish counterparts, despite the increased lifespan. We speculate that lifestyle factors may predispose the OOA to greater longevity and perhaps to lesser hospital use. Identifying these factors, which might include behaviors such as lesser tobacco use, greater physical activity, and/or enhanced community assimilation, and assessing their transferability to non-Amish communities may produce significant gains to the public health. C1 [Mitchell, Braxton D.; Shields, Kelsey; Ryan, Kathleen A.; Pollin, Toni I.; McArdle, Patrick F.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Lee, Woei-Jyh; Ashktorab, Zahra; Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Dept Hlth & Human Serv, Bethesda, MD 20894 USA. [Tolea, Magdalena I.; Magder, Laurence S.] Univ Maryland, Sch Med, Dept Epidemiol & Publ Hlth, Program Personalized & Genom Med, Baltimore, MD 21201 USA. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. RP Mitchell, BD (reprint author), Univ Maryland, Sch Med, Dept Med, Program Personalized & Genom Med, Baltimore, MD 21201 USA. EM bmitchel@medicine.umaryland.edu OI Mitchell, Braxton/0000-0003-4920-4744 FU National Institutes of Health [R01 HL69313, R01 DK54261, R01 AG1872801, R01 HL088119, R01 AR046838, U01 HL72515]; National Institutes of Health, National Library of Medicine FX This work was supported by research grants R01 HL69313, R01 DK54261, R01 AG1872801, R01 HL088119, R01 AR046838, and U01 HL72515 from the National Institutes of Health. KS was supported by a summer internship made available through the Mid-Atlantic Nutrition and Obesity Research Center (P30 DK072488). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. The authors also gratefully acknowledge the support and helpful discussions with our Amish liaisons and field workers and with our Amish Research Clinic Community Board, including Mr. Davie Stoltzfus, who is in charge of Amish Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 4 Z9 4 U1 1 U2 9 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 DEC 19 PY 2012 VL 7 IS 12 AR e51560 DI 10.1371/journal.pone.0051560 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 059HF UT WOS:000312694300031 PM 23284714 ER PT J AU Lans, I Medina, M Rosta, E Hummer, G Garcia-Viloca, M Lluch, JM Gonzalez-Lafont, A AF Lans, Isaias Medina, Milagros Rosta, Edina Hummer, Gerhard Garcia-Viloca, Mireia Lluch, Jose M. Gonzalez-Lafont, Angels TI Theoretical Study of the Mechanism of the Hydride Transfer between Ferredoxin-NADP(+) Reductase and NADP(+): The Role of Tyr303 SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SITE-DIRECTED MUTAGENESIS; DENSITY DISTRIBUTION ANALYSIS; FREE-ENERGY CALCULATIONS; C-TERMINAL TYROSINE; ANABAENA PCC 7119; CATALYTIC MECHANISM; ELECTRON-DENSITY; COENZYME SPECIFICITY; ENZYMATIC EFFICIENCY; MOLECULAR-DYNAMICS AB During photosynthesis, ferredoxin NADP(+) reductase (FNR) catalyzes the electron transfer from ferredoxin to NADP(+) via its FAD cofactor. The final hydride transfer event between FNR and the nucleotide is a reversible process. Two different transient charge-transfer complexes form prior to and upon hydride transfer, FNRrd-NADP(+) and FNRox-NADPH, regardless of the hydride transfer direction. Experimental structures of the FNRox:NADP(+) interaction have suggested a series of conformational rearrangements that might contribute to attaining the catalytically competent complex, but to date, no direct experimental information about the structure of this complex is available. Recently, a molecular dynamics (MD) theoretical approach was used to provide a putative organization of the active site that might represent a structure close to the transient catalytically competent interaction of Anabaena FNR with its coenzyme, NADP(+). Using this structure, we performed fully microscopic simulations of the hydride transfer processes between Anabaena FNRrd/FNRox and NADP(+)/H, accounting also for the solvation. A dual-level QM/MM hybrid approach was used to describe the potential energy surface of the whole system. MD calculations using the finite-temperature string method combined with the WHAM method provided the potential of mean force for the hydride transfer processes. The results confirmed that the structural model of the reactants evolves to a catalytically competent transition state through very similar free energy barriers for both the forward and reverse reactions, in good agreement with the experimental hydride transfer rate constants reported for this system. This theoretical approach additionally provides subtle structural details of the mechanism in wild-type FNR and provides an explanation why Tyr303 makes possible the photosynthetic reaction, a process that cannot occur when this Tyr is replaced by a Ser. C1 [Lans, Isaias; Medina, Milagros] Univ Zaragoza, Fac Ciencias, Dept Bioquim & Biol Mol & Celular, E-50009 Zaragoza, Spain. [Lans, Isaias; Medina, Milagros] Univ Zaragoza, Inst Biocomputat & Phys Complex Syst BIFI, Joint Unit BIFI IQFR, CSIC, E-50009 Zaragoza, Spain. [Rosta, Edina] Kings Coll London, Dept Chem, London SE1 1UL, England. [Hummer, Gerhard] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Garcia-Viloca, Mireia; Lluch, Jose M.; Gonzalez-Lafont, Angels] Univ Autonoma Barcelona, Dept Quim, Bellaterra 08193, Barcelona, Spain. [Garcia-Viloca, Mireia; Lluch, Jose M.; Gonzalez-Lafont, Angels] Univ Autonoma Barcelona, Inst Biotecnol & Biomed, Bellaterra 08193, Barcelona, Spain. RP Medina, M (reprint author), Univ Zaragoza, Fac Ciencias, Dept Bioquim & Biol Mol & Celular, E-50009 Zaragoza, Spain. EM mmedina@unizar.es; mireia@klingon.uab.cat RI Lluch, Jose M./K-1916-2014; Gonzalez-Lafont, Angels/L-4898-2014; Hummer, Gerhard/A-2546-2013; OI Lluch, Jose M./0000-0002-7536-1869; Gonzalez-Lafont, Angels/0000-0003-0729-2483; Hummer, Gerhard/0000-0001-7768-746X; Medina Trullenque, Maria Milagros/0000-0001-8743-0182; Rosta, Edina/0000-0002-9823-4766 FU Ministerio de Ciencia e Innovacion, Spain [BIO2010-1493]; Gobierno de Aragon [B18]; Ministerio de Economia y Competitividad, Spain [CTQ2011-24292]; Generalitat de Catalunya [2009SGR409]; JAE-CSIC Fellowship; Instituto Quimica-Fisica Rocasolano (CSIC) FX This work was supported by the Ministerio de Ciencia e Innovacion, Spain (Grant BIO2010-1493), the Gobierno de Aragon (Grant B18), the Ministerio de Economia y Competitividad, Spain (Grant CTQ2011-24292), and the Generalitat de Catalunya (2009SGR409). I.L. was the recipient of a JAE-CSIC Fellowship associated with the Instituto Quimica-Fisica Rocasolano (CSIC). NR 45 TC 19 Z9 19 U1 1 U2 69 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 DEC 19 PY 2012 VL 134 IS 50 BP 20544 EP 20553 DI 10.1021/ja310331v PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 055QE UT WOS:000312430700054 PM 23181670 ER PT J AU Prasad, V AF Prasad, Vinay TI Couple Therapy for Posttraumatic Stress Disorder SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID ANXIETY C1 NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Prasad, V (reprint author), NCI, Med Oncol Branch, Bethesda, MD 20892 USA. EM vinayak.prasad@nih.gov NR 5 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 19 PY 2012 VL 308 IS 23 BP 2458 EP 2458 DI 10.1001/jama.2012.14558 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 055TU UT WOS:000312441400015 PM 23288147 ER PT J AU Lada, AG Dhar, A Boissy, RJ Hirano, M Rubel, AA Rogozin, IB Pavlov, YI AF Lada, Artem G. Dhar, Alok Boissy, Robert J. Hirano, Masayuki Rubel, Aleksandr A. Rogozin, Igor B. Pavlov, Youri I. TI AID/APOBEC cytosine deaminase induces genome-wide kataegis SO BIOLOGY DIRECT LA English DT Article DE APOBEC; Deaminase; Mutation; Kataegis; Cancer; Diploid yeast; Hypermutation ID SOMATIC HYPERMUTATION; HUMAN CANCERS; DNA; SPECIFICITY; MUTAGENESIS; EVOLUTION; YEAST AB Clusters of localized hypermutation in human breast cancer genomes, named "kataegis" (from the Greek for thunderstorm), are hypothesized to result from multiple cytosine deaminations catalyzed by AID/APOBEC proteins. However, a direct link between APOBECs and kataegis is still lacking. We have sequenced the genomes of yeast mutants induced in diploids by expression of the gene for PmCDA1, a hypermutagenic deaminase from sea lamprey. Analysis of the distribution of 5,138 induced mutations revealed localized clusters very similar to those found in tumors. Our data provide evidence that unleashed cytosine deaminase activity is an evolutionary conserved, prominent source of genome-wide kataegis events. C1 [Lada, Artem G.; Pavlov, Youri I.] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. [Dhar, Alok] Univ Nebraska Med Ctr, Dept Genet, Cell Biol & Anat & Munroe Meyer Inst, Omaha, NE USA. [Boissy, Robert J.] Univ Nebraska Med Ctr, Dept Internal Med, Omaha, NE USA. [Hirano, Masayuki] Emory Univ, Dept Pathol & Lab Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. [Rubel, Aleksandr A.; Pavlov, Youri I.] St Petersburg Univ, Dept Genet, St Petersburg 199034, Russia. [Rubel, Aleksandr A.] Vavilov Inst Gen Genet, St Petersburg Branch, St Petersburg 199034, Russia. [Rogozin, Igor B.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Rogozin, Igor B.] Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. RP Pavlov, YI (reprint author), Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. EM ypavlov@unmc.edu RI Rubel, Aleksandr/D-2903-2013 OI Rubel, Aleksandr/0000-0001-6203-2006 FU UNMC Eppley Cancer Center; Smoking Disease Research Program DHHS grant [2013-21]; NCI grant [CA129925]; NIH [R01AI072435, R01GM100151]; Russian federal program "Innovative scientific personnel," State [8654]; Human Capital for Science and Education in Innovative Russia; Intramural Research Program of the National Library of Medicine at the National Institutes of Health/DHHS; University of Nebraska Medical Center (UNMC); St. Petersburg University; University of Nebraska Medical Center's DNA Sequencing Core receives from the NCRR [1S10RR027754-01, 5P20RR016469, RR018788-08]; National Institute for General Medical Science (NIGMS) [8P20GM103427, GM103471-09] FX We are grateful to Dr. James D. Eudy, Director of UNMC Sequencing Core Facility, for help with next-generation sequencing and Kristi Berger for expert editing of the manuscript. This work was supported by UNMC Eppley Cancer Center seed grants to YIP in 2010-2011; Smoking Disease Research Program DHHS grant 2013-21 to YIP; NCI grant CA129925 to YIP; by NIH grants R01AI072435 and R01GM100151 to MDC; and by the Russian federal program "Innovative scientific personnel," State contract #8654 to YIP, Federal Grant-in-Aid Program "Human Capital for Science and Education in Innovative Russia 2009-2013". IBR is supported by the Intramural Research Program of the National Library of Medicine at the National Institutes of Health/DHHS. AGL is supported by a Graduate Research Assistantship from the University of Nebraska Medical Center (UNMC). AAR is supported by a research grant from St. Petersburg University. We appreciate the partial support that the University of Nebraska Medical Center's DNA Sequencing Core receives from the NCRR (1S10RR027754-01, 5P20RR016469, RR018788-08) and the National Institute for General Medical Science (NIGMS) (8P20GM103427, GM103471-09). The work was partially carried out at the "Development of Molecular and Cellular Technologies Resource Center" at St. Petersburg University. NR 15 TC 34 Z9 34 U1 0 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD DEC 18 PY 2012 VL 7 AR 47 DI 10.1186/1745-6150-7-47 PG 7 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 100TW UT WOS:000315727600001 PM 23249472 ER PT J AU Spinner, JL Jarrett, CO LaRock, DL Miller, SI Collins, CM Hinnebusch, BJ AF Spinner, Justin L. Jarrett, Clayton O. LaRock, Doris L. Miller, Samuel I. Collins, Carleen M. Hinnebusch, B. Joseph TI Yersinia pestis insecticidal-like toxin complex (Tc) family proteins: characterization of expression, subcellular localization, and potential role in infection of the flea vector SO BMC MICROBIOLOGY LA English DT Article DE Yersinia pestis; Toxin complex proteins; YitA; YipA; YitR; Xenopsylla cheopis ID PHOTORHABDUS-LUMINESCENS; ESCHERICHIA-COLI; PLASMINOGEN-ACTIVATOR; GENE-EXPRESSION; BUBONIC PLAGUE; ORAL TOXICITY; PSEUDOTUBERCULOSIS; TRANSMISSION; EVOLUTION; BACTERIA AB Background: Toxin complex (Tc) family proteins were first identified as insecticidal toxins in Photorhabdus luminescens and have since been found in a wide range of bacteria. The genome of Yersinia pestis, the causative agent of bubonic plague, contains a locus that encodes the Tc protein homologues YitA, YitB, YitC, and YipA and YipB. Previous microarray data indicate that the Tc genes are highly upregulated by Y. pestis while in the flea vector; however, their role in the infection of fleas and pathogenesis in the mammalian host is unclear. Results: We show that the Tc proteins YitA and YipA are highly produced by Y. pestis while in the flea but not during growth in brain heart infusion (BHI) broth at the same temperature. Over-production of the LysR-type regulator YitR from an exogenous plasmid increased YitA and YipA synthesis in broth culture. The increase in production of YitA and YipA correlated with the yitR copy number and was temperature-dependent. Although highly synthesized in fleas, deletion of the Tc proteins did not alter survival of Y. pestis in the flea or prevent blockage of the proventriculus. Furthermore, YipA was found to undergo post-translational processing and YipA and YitA are localized to the outer membrane of Y. pestis. YitA was also detected by immunofluorescence microscopy on the surface of Y. pestis. Both YitA and YipA are produced maximally at low temperature but persist for several hours after transfer to 37 degrees C. Conclusions: Y. pestis Tc proteins are highly expressed in the flea but are not essential for Y. pestis to stably infect or produce a transmissible infection in the flea. However, YitA and YipA localize to the outer membrane and YitA is exposed on the surface, indicating that at least YitA is present on the surface when Y. pestis is transmitted into the mammalian host from the flea. C1 [Spinner, Justin L.; Jarrett, Clayton O.; Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [LaRock, Doris L.; Miller, Samuel I.; Collins, Carleen M.] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. [Miller, Samuel I.] Univ Washington, Dept Genome Sci Immunol & Med, Seattle, WA 98195 USA. RP Spinner, JL (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM Justin.Spinner@nih.gov OI LaRock, Doris/0000-0002-2661-6853 FU NIAID, NIH; NIH [R21 AI067444] FX We thank Madeline Fasen, and the RML visual and medical arts staff for their assistance. We thank Chris Bosio, Jeffrey Shannon, Iman Chouikha, Sophia Dudte, and Aaron Hasenkrug for critical review of the manuscript. This research was supported by the Intramural Research Program of the NIAID, NIH and by the NIH Grant R21 AI067444. NR 38 TC 8 Z9 8 U1 1 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD DEC 18 PY 2012 VL 12 AR 296 DI 10.1186/1471-2180-12-296 PG 14 WC Microbiology SC Microbiology GA 071IF UT WOS:000313584700001 PM 23249165 ER PT J AU Ma, JH Edlich, F Bermejo, GA Norris, KL Youle, RJ Tjandra, N AF Ma, Junhe Edlich, Frank Bermejo, Guillermo A. Norris, Kristi L. Youle, Richard J. Tjandra, Nico TI Structural mechanism of Bax inhibition by cytomegalovirus protein vMIA SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MOLECULAR-STRUCTURE DETERMINATION; MITOCHONDRIA-LOCALIZED INHIBITOR; CELL-DEATH; VIRAL INHIBITOR; XPLOR-NIH; APOPTOSIS; BCL-2; BINDING; FAMILY; FOLD AB The human protein Bax sits at a critical regulatory junction of apoptosis, or programmed cell death. Bax exists in equilibrium between cytosolic and mitochondria-associated forms that shifts toward the latter when Bax is activated by proapoptotic proteins. Activated Bax changes conformation, inserts into the mitochondrial outer membrane (MOM), oligomerizes, and induces MOM permeabilization, causing the release of cytochrome c, which effectively commits the cell to die. Because apoptosis is also a basic defense mechanism against invading pathogens, many viruses have developed counteractive measures. Such is the case of human cytomegalovirus, the replication of which hinges on vMIA (viral mitochondria-localized inhibitor of apoptosis), a virus-encoded protein with a unique, albeit poorly understood antiapoptotic activity by which it binds and recruits Bax to mitochondria. Here we show, via the structure determination of the complex between Bax and a peptide comprising vMIA's Bax-binding domain, that vMIA contacts Bax at a previously unknown regulatory site. Notably, using full-length vMIA, the structure is independently confirmed by assays in human cells that measure Bax subcellular localization and cytochrome c release. Mutants that disrupt key intermolecular interactions disfavor vMIA's mitochondrial recruitment of Bax, and increase cytochrome c release upon apoptosis induction. In a more stringent test, an engineered binding interface that achieves wild-type-like charge complementarity, although in a reversed fashion, recovers wild-type behavior. The structure suggests that by stabilizing key elements in Bax needed to unravel for its MOM insertion and oligomerization, vMIA prevents these important steps in apoptosis. C1 [Ma, Junhe; Bermejo, Guillermo A.; Tjandra, Nico] NHLBI, Lab Mol Biophys, Bethesda, MD 20892 USA. [Edlich, Frank; Norris, Kristi L.; Youle, Richard J.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, Bldg 10, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov FU Leopoldina, National Academy of Sciences, Germany; National Institutes of Health, National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute FX We thank Motoshi Suzuki for assisting in the generation of Bax mutants and providing comments on this manuscript; Yi He for assisting in the fermentations to produce recombinant Bax; Grzegorz Piszczek (Biophysics Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health) for advising on fluorescence anisotropy; and Duck-Yeon Lee (Protein Analysis Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health) for advising on mass spectrometry. F. E. was supported by the Leopoldina, National Academy of Sciences, Germany. This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke (R.J.Y.) and the National Heart, Lung, and Blood Institute (N.T.). NR 26 TC 11 Z9 11 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 18 PY 2012 VL 109 IS 51 BP 20901 EP 20906 DI 10.1073/pnas.1217094110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 065BZ UT WOS:000313123700037 PM 23213219 ER PT J AU Arao, Y Hamilton, KJ Goulding, EH Janardhan, KS Eddy, EM Korach, KS AF Arao, Yukitomo Hamilton, Katherine J. Goulding, Eugenia H. Janardhan, Kyathanahalli S. Eddy, Edward M. Korach, Kenneth S. TI Transactivating function (AF) 2-mediated AF-1 activity of estrogen receptor alpha is crucial to maintain male reproductive tract function SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antagonist reversal; tubule dilation; domain function ID TRANSCRIPTIONAL ACTIVATION; HORMONE RECEPTORS; MALE-FERTILITY; MOUSE; GENE; MICE; SPERMATOGENESIS; INFERTILITY; MUTATIONS; BINDING AB Estrogen receptor alpha (ER alpha) is a ligand-dependent transcription factor containing two transcriptional activation function (AF) domains. AF-1 is in the N terminus of the receptor protein, and AF-2 activity is dependent on helix 12 of the C-terminal ligand-binding domain. We recently showed that two point mutations converting leucines 543 and 544 to alanines in helix 12 (AF2ER) minimized estrogen-dependent AF-2 transcriptional activation. A characteristic feature of AF2ER is that the estrogen antagonists ICI182780 and tamoxifen (TAM) act as agonists through intact AF-1, but not through mutated AF-2. Here we report the reproductive phenotype of male AF2ER knock-in (AF2ERKI) mice and demonstrate the involvement of ER alpha in male fertility. The AF2ERKI male homozygotes are infertile because of seminiferous tubular dysmorphogenesis in the testis, similar to ER alpha KO males. Sperm counts and motility did not differ at age 6 wk in AF2ERKI and WT mice, but a significant testis defect was observed in adult AF2ERKI male mice. The expression of efferent ductal genes involved in fluid reabsorption was significantly lower in AF2ERKI males. TAM treatment for 3 wk beginning at age 21 d activated AF-2-mutated ER alpha (AF2ER) and restored expression of efferent ductule genes. At the same time, the TAM treatment reversed AF2ERKI male infertility compared with the vehicle-treated group. These results indicate that the ER alpha AF-2 mutation results in male infertility, suggesting that the AF-1 is regulated in an AF-2-dependent manner in the male reproductive tract. Activation of ER alpha AF-1 is capable of rescuing AF2ERKI male infertility. C1 [Arao, Yukitomo; Hamilton, Katherine J.; Korach, Kenneth S.] NIEHS, Receptor Biol Grp, Res Triangle Pk, NC 27709 USA. [Goulding, Eugenia H.; Eddy, Edward M.] NIEHS, Gamete Biol Grp, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC 27709 USA. [Janardhan, Kyathanahalli S.] Integrated Lab Syst Inc, Res Triangle Pk, NC 27709 USA. [Janardhan, Kyathanahalli S.] NIEHS, Cellular & Mol Pathol Branch, Res Triangle Pk, NC 27709 USA. RP Korach, KS (reprint author), NIEHS, Receptor Biol Grp, POB 12233, Res Triangle Pk, NC 27709 USA. EM korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU NIEHS Division of Intramural Research Grant [Z01ES70065] FX We thank James Clark, David Monroy, and National Institute of Environmental Health Sciences (NIEHS) Comparative Medicine Branch staff for animal care and operations; the staff of the NIEHS Histology Core and Immunohistochemistry Laboratory; and all members of the NIEHS Receptor Biology Group and the Gamete Biology Group for helpful discussions. This study was funded by NIEHS Division of Intramural Research Grant Z01ES70065 (to K.S.K.). NR 30 TC 9 Z9 10 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 DEC 18 PY 2012 VL 109 IS 51 BP 21140 EP 21145 DI 10.1073/pnas.1216189110 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 065BZ UT WOS:000313123700078 PM 23213263 ER PT J AU Mazor, R Vassall, AN Eberle, JA Beers, R Weldon, JE Venzon, DJ Tsang, KY Benhar, I Pastan, I AF Mazor, Ronit Vassall, Aaron N. Eberle, Jaime A. Beers, Richard Weldon, John E. Venzon, David J. Tsang, Kwong Y. Benhar, Itai Pastan, Ira TI Identification and elimination of an immunodominant T-cell epitope in recombinant immunotoxins based on Pseudomonas exotoxin A SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE deimmunization; immunogenicity; protein engineering; antidrug antibodies ID PHASE-I TRIAL; REDUCED IMMUNOGENICITY; THERAPEUTIC PROTEINS; ANTITUMOR-ACTIVITY; DE-IMMUNIZATION; BINDING; DETERMINANTS; RECOGNITION; VACCINATION; ACTIVATION AB Recombinant immunotoxins (RITs) are chimeric proteins that are being developed for cancer treatment. We have produced RITs that contain PE38, a portion of the bacterial protein Pseudomonas exotoxin A. Because the toxin is bacterial, it often induces neutralizing antibodies, which limit the number of treatment cycles and the effectiveness of the therapy. Because T cells are essential for antibody responses to proteins, we adopted an assay to map the CD4(+) T-cell epitopes in PE38. We incubated peripheral blood mononuclear cells with an immunotoxin to stimulate T-cell expansion, followed by exposure to overlapping peptide fragments of PE38 and an IL-2 ELISpot assay to measure responses. Our observation of T-cell responses in 50 of 50 individuals correlates with the frequency of antibody formation in patients with normal immune systems. We found a single, highly immunodominant epitope in 46% (23/50) of the donors. The immunodominant epitope is DRB1-restricted and was observed in subjects with different HLA alleles, indicating promiscuity. We identified two amino acids that, when deleted or mutated to alanine, eliminated the immunodominant epitope, and we used this information to construct mutant RITs that are highly cytotoxic and do not stimulate T-cell responses in many donors. C1 [Mazor, Ronit; Vassall, Aaron N.; Eberle, Jaime A.; Beers, Richard; Weldon, John E.; Pastan, Ira] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Venzon, David J.] NCI, Biostat & Data Management Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Tsang, Kwong Y.] NCI, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. [Mazor, Ronit; Benhar, Itai] Tel Aviv Univ, Dept Mol Microbiol & Biotechnol, George S Wise Fac Life Sci, IL-69978 Tel Aviv, Israel. RP Pastan, I (reprint author), NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov OI Weldon, John/0000-0002-6516-9064 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; MedImmune, LLC FX We thank Dr. Byungkook Lee for providing the figures showing the structures of the immunotoxins, Dr. Paul Robins for immunological advice, Susan L. Strobl for help in technical troubleshooting, Dr. Alexandro Sette and Carla Ossehof for sharing their epitope-mapping protocol, Dr. Onda Massanori for providing useful reagents, and Dr. Jay Berzofsky, Dawn Walker and Dr. Jon Yewdell for providing helpful comments. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health and by a Cooperative Research and Development Agreement with MedImmune, LLC. NR 42 TC 37 Z9 37 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 DEC 18 PY 2012 VL 109 IS 51 BP E3597 EP E3603 DI 10.1073/pnas.1218138109 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 065BZ UT WOS:000313123700014 PM 23213206 ER PT J AU Wang, R Natarajan, K Revilleza, MJR Boyd, LF Zhi, L Zhao, HY Robinson, H Margulies, DH AF Wang, Rui Natarajan, Kannan Revilleza, Maria Jamela R. Boyd, Lisa F. Zhi, Li Zhao, Huaying Robinson, Howard Margulies, David H. TI Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1 gamma reveals a paradigm for MHC/MHC interaction in immune evasion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE immune recognition; virus evasion; X-ray diffraction ID ACTIVATING IMMUNORECEPTOR NKG2D; NK CELLS; ANTIGEN PRESENTATION; INHIBITORY RECEPTOR; CRYSTAL-STRUCTURE; CANCER PATIENTS; LIGAND MICA; HLA-DM; COMPLEX; GLYCOPROTEIN AB Natural killer (NK) cells are activated by engagement of the NKG2D receptor with ligands on target cells stressed by infection or tumorigenesis. Several human and rodent cytomegalovirus (CMV) immunoevasins down-regulate surface expression of NKG2D ligands. The mouse CMV MHC class I (MHC-I)-like m152/gp40 glycoprotein down-regulates retinoic acid early inducible-1 (RAE1) NKG2D ligands as well as host MHC-I. Here we describe the crystal structure of an m152/RAE1 gamma complex and confirm the intermolecular contacts by mutagenesis. m152 interacts in a pincer-like manner with two sites on the alpha 1 and alpha 2 helices of RAE1 reminiscent of the NKG2D interaction with RAE1. This structure of an MHC-I-like immunoevasin/MHC-I-like ligand complex explains the binding specificity of m152 for RAE1 and allows modeling of the interaction of m152 with classical MHC-I and of related viral immunoevasins. C1 [Wang, Rui; Natarajan, Kannan; Revilleza, Maria Jamela R.; Boyd, Lisa F.; Zhi, Li; Margulies, David H.] NIAID, Mol Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Zhao, Huaying] Natl Inst Biomol Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. [Robinson, Howard] Brookhaven Natl Labs, Natl Synchrotron Light Source, Upton, NY 11973 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 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank Xavier Ambroggio and Michael Dolan for help with docking programs. This research was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 55 TC 13 Z9 13 U1 1 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 DEC 18 PY 2012 VL 109 IS 51 BP E3578 EP E3587 DI 10.1073/pnas.1214088109 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 065BZ UT WOS:000313123700012 PM 23169621 ER PT J AU Spaak, E Bonnefond, M Maier, A Leopold, DA Jensen, O AF Spaak, Eelke Bonnefond, Mathilde Maier, Alexander Leopold, David A. Jensen, Ole TI Layer-Specific Entrainment of Gamma-Band Neural Activity by the Alpha Rhythm in Monkey Visual Cortex SO CURRENT BIOLOGY LA English DT Article ID OSCILLATIONS; PHASE; INHIBITION; FREQUENCY; MODULATION; ATTENTION; CONNECTIONS; INFORMATION; HIPPOCAMPUS; POTENTIALS AB Although the mammalian neocortex has a clear laminar organization, layer-specific neuronal computations remain to be uncovered. Several studies suggest that gamma band activity in primary visual cortex (V1) is produced in granular and superficial layers and is associated with the processing of visual input [1-3]. Oscillatory alpha band activity in deeper layers has been proposed to modulate neuronal excitability associated with changes in arousal and cognitive factors [4-7]. To investigate the layer-specific interplay between these two phenomena, we characterized the coupling between alpha and gamma band activity of the local field potential in V1 of the awake macaque. Using multicontact laminar electrodes to measure spontaneous signals simultaneously from all layers of V1, we found a robust coupling between alpha phase in the deeper layers and gamma amplitude in granular and superficial layers. Moreover, the power in the two frequency bands was anti-correlated. Taken together, these findings demonstrate robust interlaminar cross-frequency coupling in the visual cortex, supporting the view that neuronal activity in the alpha frequency range phasically modulates processing in the cortical microcircuit in a top-down manner [7]. C1 [Spaak, Eelke; Bonnefond, Mathilde; Jensen, Ole] Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6500 HE Nijmegen, Netherlands. [Maier, Alexander; Leopold, David A.] NIMH, Sect Cognit Neurophysiol & Imaging, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. [Maier, Alexander] Vanderbilt Univ, Dept Psychol, Coll Arts & Sci, Nashville, TN 37203 USA. RP Jensen, O (reprint author), Radboud Univ Nijmegen, Donders Inst Brain Cognit & Behav, NL-6500 HE Nijmegen, Netherlands. EM ole.jensen@donders.ru.nl RI Jensen, Ole/D-2120-2010; Bonnefond, Mathilde/J-7572-2012; Maier, Alexander/B-7489-2009; OI Maier, Alexander/0000-0002-7250-502X; Leopold, David/0000-0002-1345-6360 FU Netherlands Organization for Scientific Research (NWO) [453-09-002]; Fyssen Foundation; Intramural Research Programs of the National Institute of Mental Health, National Institute for Neurological Disorders and Stroke; National Eye Institute FX This work was supported by Netherlands Organization for Scientific Research (NWO) VICI Grant #453-09-002 (O.J. and E.S.); the Fyssen Foundation (M.B.); and the Intramural Research Programs of the National Institute of Mental Health, National Institute for Neurological Disorders and Stroke, and the National Eye Institute (D.A.L. and A.M.). NR 44 TC 90 Z9 91 U1 0 U2 18 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 DEC 18 PY 2012 VL 22 IS 24 BP 2313 EP 2318 DI 10.1016/j.cub.2012.10.020 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 060EX UT WOS:000312760400020 PM 23159599 ER PT J AU Hurley, JH Hinshaw, JE AF Hurley, James H. Hinshaw, Jenny E. TI Dynamin: Membrane Scission Meets Physics SO CURRENT BIOLOGY LA English DT Editorial Material ID FISSION C1 [Hurley, James H.] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Hinshaw, Jenny E.] NIDDKD, Lab Cell & Mol Biol, NIH, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM james.hurley@nih.gov; jennyh@helix.nih.gov NR 13 TC 1 Z9 1 U1 0 U2 8 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 DEC 18 PY 2012 VL 22 IS 24 BP R1047 EP R1048 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 060EX UT WOS:000312760400011 PM 23257190 ER PT J AU Golozar, A Fagundes, RB Etemadi, A Schantz, MM Kamangar, F Abnet, CC Dawsey, SM AF Golozar, Asieh Fagundes, Renato B. Etemadi, Arash Schantz, Michele M. Kamangar, Farin Abnet, Christian C. Dawsey, Sanford M. TI Significant Variation in the Concentration of Carcinogenic Polycyclic Aromatic Hydrocarbons in Yerba Mate Samples by Brand, Batch, and Processing Method SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID ESOPHAGEAL CANCER-RISK; WHITE BLOOD-CELLS; ILEX-PARAGUARIENSIS; NORTHEASTERN IRAN; HOT BEVERAGES; DNA ADDUCTS; CONSUMPTION; URINE; CONTRIBUTE; CHEMISTRY AB Drinking mate, common in southern South America, may increase the risk of esophageal squamous cell carcinoma (ESCC). In 2006, we found high but variable polycyclic aromatic hydrocarbon (PAH) content in commercial yerba mate samples from eight Brazilian brands. The PAH content of new samples from the same brands, purchased in 2008, and four brands from a single manufacturer processed in different ways, obtained in 2010, were quantified to determine whether PAH concentration was still high, whether PAH content variation was brand specific, and whether processing method affects PAH content of commercial yerba mate. Concentrations of individual PAHs were quantified using gas chromatography/mass spectrometry with deuterated PAHs as internal standards. Median total PAH concentration was 1500 ng/g (range: 625-3710 ng/g) and 1090 ng/g (621-1990 ng/g) in 2008 and 2010 samples, respectively. Comparing 2006 and 2008 samples, some brands had high PAN concentrations in both years, while PAH concentration changed considerably in others. Benzo[a]pyrene concentrations ranged from 11.9 to 99.3 ng/g and 5.11 to 21.0 ng/g in 2008 and 2010 samples, respectively. The 2010 sample processed without touching smoke had the lowest benzo[a]pyrene content. These results support previous findings of very high total and carcinogenic PAH concentrations in yerba mate, perhaps contributing to the high incidence of ESCC in southern South America. The large PAH content variation by brand, batch, and processing method suggests it may be possible to reduce the content of carcinogenic PAHs in commercial yerba mate, making it a healthier beverage. C1 [Golozar, Asieh; Etemadi, Arash; Kamangar, Farin; Abnet, Christian C.; Dawsey, Sanford M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Fagundes, Renato B.] Univ Fed Santa Maria, Dept Clin Med, Ctr Ciencias Saude, BR-97119900 Santa Maria, RS, Brazil. [Fagundes, Renato B.] Univ Fed Rio Grande do Sul, Fac Med, Programa PG Ciencias Gastroenterol, Porto Alegre, RS, Brazil. [Schantz, Michele M.] NIST, Div Analyt Chem, Gaithersburg, MD 20899 USA. [Kamangar, Farin] Morgan State Univ, Dept Publ Hlth Anal, Sch Community Hlth & Policy, Baltimore, MD 21239 USA. RP Fagundes, RB (reprint author), Ave Grecia 1000,Apt 1002, BR-91350070 Porto Alegre, RS, Brazil. EM fagundesrb@gmail.com RI Abnet, Christian/C-4111-2015; Etemadi, Arash/C-1386-2016 OI Abnet, Christian/0000-0002-3008-7843; Etemadi, Arash/0000-0002-3458-1072 FU intramural program of the National Cancer Institute (NCI), NIH; NIH; National Institute of Standards and Technology (NIST) FX This study was supported in part by funds from the intramural program of the National Cancer Institute (NCI), NIH and in part by an interagency agreement between the NIH and the National Institute of Standards and Technology (NIST). NR 23 TC 5 Z9 5 U1 2 U2 20 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD DEC 18 PY 2012 VL 46 IS 24 BP 13488 EP 13493 DI 10.1021/es303494s PG 6 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA 055QT UT WOS:000312432200058 PM 23101992 ER PT J AU Hakk, H Szabo, DT Huwe, J Diliberto, J Birnbaum, LS AF Hakk, Heldur Szabo, David T. Huwe, Janice Diliberto, Janet Birnbaum, Linda S. TI Novel and Distinct Metabolites Identified Following a Single Oral Dose of alpha- or gamma-Hexabromocyclododecane in Mice SO ENVIRONMENTAL SCIENCE & TECHNOLOGY LA English DT Article ID BROMINATED FLAME RETARDANTS; HYDROXYLATED METABOLITES; TISSUE DISTRIBUTION; REPEATED EXPOSURE; DIPHENYL ETHERS; RAINBOW-TROUT; FOOD-WEB; HBCD; RAT; TOXICOKINETICS AB The metabolism of alpha- and gamma-hexabromocyclododecane (HBCD) was investigated in adult C57BL/6 female mice. alpha- or gamma-[C-14]HBCD (3 mg/kg bw) was orally administered with subsequent urine and feces collection for 4 consecutive days; a separate group of mice was dosed and sacrificed 3 h postexposure to investigate tissue metabolite levels. Extractable and nonextractable HBCD metabolites were quantitated in liver, blood, fat, brain, bile, urine, and feces and characterized by LC/MS (ESI-). Metabolites identified were distinct between the two stereoisomers. In mice exposed to alpha-HBCD, four hydroxylated metabolites were detected in fecal extracts, and one of these metabolite isomers was consistently characterized in liver, brain, and adipose tissue extracts. In contrast, fecal extracts from mice exposed to gamma-HBCD contained multiple isomers of monohydroxy-pentabromocyclododecene, dihydroxy-pentabromocyclododecene, and dihydroxy-pentabromocyclododecadiene, while in liver and adipose tissues extracts only a single monohydroxy-pentabromocyclododecane metabolite was observed. Both stereoisomers were transformed to metabolites which formed covalent bonds to proteins and/or lipids in the gut as suggested by high fecal nonextractables. The presence of tissue- and excreta-specific metabolic products after in vivo exposure to the two main HBCD stereoisomers supports previous toxicokinetic studies indicating that these two stereoisomers are biologically distinct. The distinct metabolic products identified in this study have the potential to aid in the identification of stereoisomer-specific HBCD exposures in future biomonitoring studies. C1 [Hakk, Heldur; Szabo, David T.; Huwe, Janice] ARS, USDA, Biosci Res Lab, Fargo, ND 58102 USA. [Hakk, Heldur; Szabo, David T.; Huwe, Janice] US EPA, Natl Ctr Environm Assessment, Off Res & Dev, Washington, DC 20460 USA. [Diliberto, Janet] US EPA, Off Res & Dev, Natl Hlth & Environm Effects Res Lab, Integrated Syst Toxicol Div, Res Triangle Pk, NC 27711 USA. [Birnbaum, Linda S.] NCI, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Hakk, H (reprint author), ARS, USDA, Biosci Res Lab, 1605 Albrecht Blvd, Fargo, ND 58102 USA. EM heldur.hakk@ars.usda.gov FU University of North Carolina in Chapel Hill; Environmental Protection Agency [CR 833237] FX We thank Colleen Pfaff, Jason Holthusen, Sara Lupton, and Barbara Magelky for technical assistance. This work is funded in part by a cooperative agreement between the University of North Carolina in Chapel Hill and the Environmental Protection Agency CR 833237 predoctoral training grants. This manuscript does not reflect USEPA, NIH, or USDA policy. The use of trade, firm, or corporation names in this publication is for the information and convenience of the reader. Such use does not constitute an official endorsement or approval by the United States Department of Agriculture, the Agricultural Research Service, or the Food Safety and Inspection Service of any product or service to the exclusion of others that may be suitable. USDA is an equal opportunity provider and employer. NR 40 TC 29 Z9 29 U1 3 U2 78 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0013-936X J9 ENVIRON SCI TECHNOL JI Environ. Sci. Technol. PD DEC 18 PY 2012 VL 46 IS 24 BP 13494 EP 13503 DI 10.1021/es303209g PG 10 WC Engineering, Environmental; Environmental Sciences SC Engineering; Environmental Sciences & Ecology GA 055QT UT WOS:000312432200059 PM 23171393 ER PT J AU Grupi, A Minton, AP AF Grupi, Asaf Minton, Allen P. TI Capillary Viscometer for Fully Automated Measurement of the Concentration and Shear Dependence of the Viscosity of Macromolecular Solutions SO ANALYTICAL CHEMISTRY LA English DT Article ID HEMOGLOBIN; RHEOLOGY AB The construction and operation of a novel viscometer/rheometer are described. The instrument is designed to measure the viscosity of a macromolecular solution while automatically varying both solute concentration and shear rate. Viscosity is calculated directly from Poiseuille's law, given the measured difference in pressure between two ends of a capillary tube through which the solution is flowing at a known rate. The instrument requires as little as 0.75 mL of a solution to provide a full profile of viscosity as a function of concentration and shear rate, and it can measure viscosities as high as 500 cP and as low as 1 cP, at shear rates between 10 and 2 x 10(3) s(-1). The results of control experiments are presented to document the accuracy and precision of measurement at both low and high concentration of synthetic polymers and proteins. C1 [Grupi, Asaf; Minton, Allen P.] NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Grupi, A (reprint author), NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. EM grupia@gmail.com; minton@helix.nih.gov OI 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 We thank Paul Smith (NIH) for helpful comments on a draft of the manuscript. This research is supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 18 TC 9 Z9 9 U1 0 U2 42 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD DEC 18 PY 2012 VL 84 IS 24 BP 10732 EP 10736 DI 10.1021/ac302599j PG 5 WC Chemistry, Analytical SC Chemistry GA 055PV UT WOS:000312429800034 PM 23130673 ER PT J AU Martinez, ME Thompson, P Messer, K Ashbeck, EL Lieberman, DA Baron, JA Ahnen, DJ Robertson, DJ Jacobs, ET Greenberg, ER Cross, AJ Atkin, W AF Martinez, Maria Elena Thompson, Patricia Messer, Karen Ashbeck, Erin L. Lieberman, David A. Baron, John A. Ahnen, Dennis J. Robertson, Douglas J. Jacobs, Elizabeth T. Greenberg, E. Robert Cross, Amanda J. Atkin, Wendy TI One-Year Risk for Advanced Colorectal Neoplasia: US Versus UK Risk-Stratification Guidelines SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID PRIMARY-CARE PHYSICIANS; SOCIETY TASK-FORCE; NATIONAL-SURVEY; COLONOSCOPY SURVEILLANCE; ADENOMATOUS POLYPS; CONSENSUS UPDATE; CANCER; POLYPECTOMY; RECOMMENDATIONS; RECURRENCE AB Background: Guidelines from the United Kingdom and the United States on risk stratification after polypectomy differ, as do recommended surveillance intervals. Objective: To compare risk for advanced colorectal neoplasia at 1-year colonoscopy among patients cross-classified by U. S. and U. K. surveillance guidelines. Design: Pooled analysis of 4 prospective studies between 1984 and 1998. Setting: Academic and private clinics in the United States. Patients: 3226 postpolypectomy patients with 6- to 18-month follow-up colonoscopy. Measurements: Rates of advanced neoplasia (an adenoma >= 1 cm, high-grade dysplasia, >25% villous architecture, or invasive cancer) at 1 year, compared across U. S. and U. K. risk categories. Results: Advanced neoplasia was detected 1 year after polypectomy in 3.8% (95% CI, 2.7% to 4.9%) of lower-risk patients and 11.2% (CI, 9.8% to 12.6%) of higher-risk patients by U. S. criteria. According to U. K. criteria, 4.4% (CI, 3.3% to 5.4%) of low-risk patients, 9.9% (CI, 8.3% to 11.5%) of intermediate-risk patients, and 18.7% (CI, 14.8% to 22.5%) of high-risk patients presented with advanced neoplasia; U. K. high-risk patients comprised 12.1% of all patients. All U. S. lower-risk patients were low-risk by U. K. criteria; however, more patients were classified as low-risk, because the U. K. guidelines do not consider histologic features. Higher-risk U. S. patients were distributed across the 3 U. K. categories. Among all patients with advanced neoplasia, 26.3% were reclassified by the U. K. criteria to a higher-risk category and 7.0% to a lower-risk category, with a net 19.0% benefiting from detection 2 years earlier. Overall, substitution of U. K. for U. S. guidelines resulted in an estimated 0.03 additional colonoscopy every 5 years per patient. Limitations: Patients were enrolled 15 to 20 years ago, and quality measures for colonoscopy were unavailable. Patients lacking follow-up colonoscopy or with surveillance colonoscopy after 6 to 18 months and those with cancer or insufficient baseline adenoma characteristics were excluded (2076 of 5302). Conclusion: Application of the U. K. guidelines in the United States could identify a subset of high-risk patients who may warrant a 1-year clearing colonoscopy without substantially increasing rates of colonoscopy. C1 [Martinez, Maria Elena] Univ Calif San Diego, Moores Canc Ctr, Sch Med, La Jolla, CA 92093 USA. Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. Univ Arizona, Coll Med, Tucson, AZ USA. Univ Arizona, Mel & Enid Zuckerman Arizona Coll Publ Hlth, Tucson, AZ USA. Portland VA Med Ctr, Portland, OR USA. Univ N Carolina, Sch Med, Chapel Hill, NC USA. Denver Vet Affairs Med Ctr, Denver, CO USA. Univ Colorado, Sch Med, Denver, CO USA. White River Junct Vet Affairs Med Ctr, White River Jct, VT USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NCI, Rockville, MD USA. Univ London Imperial Coll Sci Technol & Med, London, England. RP Martinez, ME (reprint author), Univ Calif San Diego, Moores Canc Ctr, Sch Med, 3855 Hlth Sci Dr 0901, La Jolla, CA 92093 USA. EM e8martinez@ucsd.edu FU European Union Health Programme [2005317]; International Agency for Research on Cancer; National Cancer Institute [CA-41108, CA-23074, CA95060, CA37287, CA104869, CA23108, CA59005, CA26852]; European Union Public Health Programme FX Grant Support: By the European Union Health Programme (Development of European Guidelines for Quality Assurance of Colorectal Cancer Screening; grant agreement 2005317); the International Agency for Research on Cancer; and the U.S. Public Health Service grants CA-41108, CA-23074, CA95060, CA37287, CA104869, CA23108, CA59005, and CA26852 from the National Cancer Institute.; European Union Public Health Programme. NR 36 TC 18 Z9 18 U1 1 U2 5 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD DEC 18 PY 2012 VL 157 IS 12 BP 856 EP U192 DI 10.7326/0003-4819-157-12-201212180-00005 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 057SB UT WOS:000312583200015 PM 23247939 ER PT J AU Kizer, JR Benkeser, D Arnold, AM Mukamal, KJ Ix, JH Zieman, SJ Siscovick, DS Tracy, RP Mantzoros, CS deFilippi, CR Newman, AB Djousse, L AF Kizer, Jorge R. Benkeser, David Arnold, Alice M. Mukamal, Kenneth J. Ix, Joachim H. Zieman, Susan J. Siscovick, David S. Tracy, Russell P. Mantzoros, Christos S. deFilippi, Christopher R. Newman, Anne B. Djousse, Luc TI Associations of Total and High-Molecular-Weight Adiponectin With All-Cause and Cardiovascular Mortality in Older Persons The Cardiovascular Health Study SO CIRCULATION LA English DT Article DE adiponectin; aging; mortality ID CORONARY-HEART-DISEASE; MYOCARDIAL-INFARCTION; PLASMA ADIPONECTIN; INSULIN-RESISTANCE; RISK; WOMEN; MEN; FAILURE; INFLAMMATION; PARADOX AB Background-Adiponectin shows opposite associations with adverse outcomes in healthy middle-aged populations (lower risk) and cohorts with prevalent cardiovascular disease, heart failure, or advanced age (higher risk). Methods and Results-In a population-based study of older adults, we examined the relationships of total and high-molecular-weight adiponectin with mortality among subgroups defined by baseline cardiovascular status: No cardiovascular disease, heart failure, or atrial fibrillation (group 1); cardiovascular disease but no heart failure/atrial fibrillation (group 2); and heart failure/atrial fibrillation (group 3). We found significant differences in the associations with all-cause mortality across the groups. The association in group 1 was U-shaped; increasing levels of total adiponectin up to 12.4 mg/L were associated with lower mortality after adjustment for confounders (hazard ratio = 0.81 per 1 SD [95% confidence interval, 0.65-0.95]), but above this cut point, higher levels conferred greater risk (hazard ratio = 1.19 [95% confidence interval, 1.12-1.27]). Further adjustment for diabetes mellitus or insulin resistance, protection against which has been proposed to mediate the beneficial relationships of adiponectin with outcome, attenuated the association in the lower range. There was no significant association in group 2, but in group 3, total adiponectin showed a direct adjusted association. Additional adjustment for putative metabolic/inflammatory intermediates suggested a direct association for group 2, and magnified the one for group 3 (hazard ratio = 1.31 [1.15-1.50]). Results were similar for high-molecular-weight adiponectin and for cardiovascular mortality. Conclusions-Adiponectin exhibits distinct associations with mortality in elders, which shift from U-shaped to flat to direct with greater baseline cardiovascular dysfunction but become more consistently adverse after accounting for metabolic/inflammatory factors presumed to be favorably regulated by the adipokine. These findings advance understanding of the adiponectin paradox as it relates to older adults. (Circulation. 2012;126:2951-2961.) C1 [Kizer, Jorge R.] Weill Cornell Med Coll, New York, NY USA. [Benkeser, David; Arnold, Alice M.; Siscovick, David S.] Univ Washington, Seattle, WA 98195 USA. [Mukamal, Kenneth J.; Mantzoros, Christos S.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Mukamal, Kenneth J.; Mantzoros, Christos S.; Djousse, Luc] Harvard Univ, Sch Med, Boston, MA USA. [Ix, Joachim H.] Vet Affairs San Diego Healthcare Syst, San Diego, CA USA. [Ix, Joachim H.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Zieman, Susan J.] NIA, Bethesda, MD 20892 USA. [Tracy, Russell P.] Univ Vermont, Colchester, VT USA. [Mantzoros, Christos S.; Djousse, Luc] Boston Vet Affairs Healthcare Syst, Boston, MA USA. [deFilippi, Christopher R.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Newman, Anne B.] Univ Pittsburgh, Pittsburgh, PA USA. [Djousse, Luc] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Kizer, JR (reprint author), Albert Einstein Coll Med, Cardiovasc Clin Res Unit, 1300 Morris Pk Ave, Bronx, NY 10461 USA. EM jorge.kizer@einstein.yu.edu RI Newman, Anne/C-6408-2013; Djousse, Luc/F-5033-2017 OI Newman, Anne/0000-0002-0106-1150; Djousse, Luc/0000-0002-9902-3047 FU National Heart, Lung, and Blood Institute [R01 HL-094555, HHSN268201200036C, N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01-HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HL080295]; National Institute on Aging [AG-023629, AG-15928, AG-20098, AG-027058]; diaDexus, Inc; Roche Diagnostics FX This work was supported by R01 HL-094555 from the National Heart, Lung, and Blood Institute. The CHS was supported by National Heart, Lung, and Blood Institute contracts HHSN268201200036C, N01-HC-85239, and N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01-HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133; and National Heart, Lung, and Blood Institute grant HL080295, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging. See also http://www.chs-nhlbi.org/pi.htm.; Dr Kizer has received a research grant from diaDexus, Inc and has served on the speakers' bureau for Merck & Co. Dr deFilippi has received a research grant and honoraria from Roche Diagnostics. The other authors report no conflicts. NR 38 TC 41 Z9 44 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 18 PY 2012 VL 126 IS 25 BP 2951 EP U283 DI 10.1161/CIRCULATIONAHA.112.135202 PG 14 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 057FW UT WOS:000312549200017 PM 23159554 ER PT J AU Koveal, D Schuh-Nuhfer, N Ritt, D Page, R Morrison, DK Peti, W AF Koveal, Dorothy Schuh-Nuhfer, Natasha Ritt, Daniel Page, Rebecca Morrison, Deborah K. Peti, Wolfgang TI A CC-SAM, for Coiled Coil-Sterile alpha Motif, Domain Targets the Scaffold KSR-1 to Specific Sites in the Plasma Membrane SO SCIENCE SIGNALING LA English DT Article ID SIGNAL-TRANSDUCTION; PROTEIN STRUCTURES; GENE ENCODES; RAS; DYNAMICS; BINDING; ACTIVATION; NMR; PHOSPHORYLATION; IDENTIFICATION AB Kinase suppressor of Ras-1 (KSR-1) is an essential scaffolding protein that coordinates the assembly of the mitogen-activated protein kinase (MAPK) module, consisting of the MAPK kinase kinase Raf, the MAPK kinase MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), and the MAPK ERK (extracellular signal-regulated kinase) to facilitate activation of MEK and thus ERK. Although KSR-1 is targeted to the cell membrane in part by its atypical C1 domain, which binds to phospholipids, other domains may be involved. We identified another domain in KSR-1 that we termed CC-SAM, which is composed of a coiled coil (CC) and a sterile a motif (SAM). The CC-SAM domain targeted KSR-1 to specific signaling sites at the plasma membrane in growth factor-treated cells, and it bound directly to various micelles and bicelles in vitro, indicating that the CC-SAM functioned as a membrane-binding module. By combining nuclear magnetic resonance spectroscopy and experiments in cultured cells, we found that membrane binding was mediated by helix alpha 3 of the CC motif and that mutating residues in alpha 3 abolished targeting of KSR-1 to the plasma membrane. Thus, in addition to the atypical C1 domain, the CC-SAM domain is required to target KSR-1 to the plasma membrane. C1 [Schuh-Nuhfer, Natasha; Ritt, Daniel; Morrison, Deborah K.] Natl Canc Inst Frederick, SAIC Frederick Inc, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. [Koveal, Dorothy; Page, Rebecca] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02903 USA. [Peti, Wolfgang] Brown Univ, Dept Mol Pharmacol Physiol & Biotechnol, Providence, RI 02903 USA. [Peti, Wolfgang] Brown Univ, Dept Chem, Providence, RI 02903 USA. RP Morrison, DK (reprint author), Natl Canc Inst Frederick, SAIC Frederick Inc, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. EM morrisod@mail.nih.gov; Wolfgang_Peti@brown.edu RI Peti, Wolfgang/L-3492-2014 FU American Cancer Society [RSG-08-067001-LIB]; National Cancer Institute; NIH [R01NS056128, R01GM098482]; NSF/EPSCoR [1004057] FX This research was supported by grant RSG-08-067001-LIB from the American Cancer Society to R. P., federal funds from the National Cancer Institute to D. K. M., and NIH grants R01NS056128 to W. P. and R01GM098482 to R. P. NMR (800 MHz) data were recorded at Brandeis University (NIH S10-RR017269). This research is based in part on work conducted using the Rhode Island NSF Experimental Program to Stimulate Competitive Research (EPSCoR) Proteomics Share Resource Facility, supported in part by the NSF/EPSCoR grant 1004057. NR 46 TC 8 Z9 10 U1 2 U2 9 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 DEC 18 PY 2012 VL 5 IS 255 AR ra94 DI 10.1126/scisignal.2003289 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 059IF UT WOS:000312697000003 PM 23250398 ER PT J AU Kemp, TJ Safaeian, M Hildesheim, A Pan, YJ Penrose, KJ Porras, C Schiller, JT Lowy, DR Herrero, R Pinto, LA AF Kemp, Troy J. Safaeian, Mahboobeh Hildesheim, Allan Pan, Yuanji Penrose, Kerri J. Porras, Carolina Schiller, John T. Lowy, Douglas R. Herrero, Rolando Pinto, Ligia A. TI Kinetic and HPV infection effects on cross-type neutralizing antibody and avidity responses induced by Cervarix (R) SO VACCINE LA English DT Article DE Human papillomavirus; Antibody; Vaccine; Avidity ID PARTICLE VACCINE; DOUBLE-BLIND; WOMEN; EFFICACY; AFFINITY; TRIAL AB Background: We previously demonstrated that Cervarix (R) elicits antibody responses against vaccine-related types for which clinical efficacy was demonstrated (HPV-31 and -45). Here, we evaluated the kinetics of neutralization titers and avidity of Cervarix (R)-induced antibodies up to 36 months of follow-up in unexposed and HPV infected women. Methods: A subset of women who participated in the Cost Rica HPV-16/18 Vaccine Trial had pre- and post-vaccination sera tested for antibody responses to HPV-16, -18, -31, -45, and -58 using a pseudovirion-based neutralization assay, and HPV-16 antibody avidity using an HPV-16 L1 VLP (virus-like particle)-based ELISA developed in our laboratory. Results: In uninfected women, neutralizing antibody titers did not reach significance until after the 3rd dose for HPV-31 (month 12, p = 0.009) and HPV-45 (month 12, p = 0.003), but then persisted up to month 36 (HPV-31, p = 0.01; HPV-45, p = 0.002). Individuals infected with HPV-16 or HPV-31 at enrollment developed a significantly higher median antibody response to the corresponding HPV type after one dose, but there was not a difference between median titers after three doses compared to the HPV negative group. Median HPV-16 antibody avidity and titer increased over time up to month 12; however, the HPV-16 avidity did not correlate well with HPV-16 neutralizing antibody titers at each time point examined, except for month 6. The median avidity levels were higher in HPV-16 infected women at month 1 (p = 0.04) and lower in HPV-16 infected women at month 12 (p = 0.006) compared to the HPV negative women. Conclusions: The persistence of cross-neutralization titers at month 36 suggests cross-reactive antibody responses are likely to persist long-term and are not influenced by infection status at enrollment. However, the weak correlation between avidity and neutralization titers emphasizes the need for examining avidity in efficacy studies to determine if high avidity antibodies play a critical role in protection against infection. (c) 2012 Elsevier Ltd. All rights reserved. C1 [Kemp, Troy J.; Pan, Yuanji; Penrose, Kerri J.; Pinto, Ligia A.] SAIC Frederick Inc, HPV Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Safaeian, Mahboobeh; Hildesheim, Allan] NCI, Infect & Immunoepidemiol Branch, DCEG, NIH, Bethesda, MD 20892 USA. [Schiller, John T.; Lowy, Douglas R.] NCI, Cellular Oncol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Porras, Carolina; Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. [Herrero, Rolando] Int Agcy Res Canc, Prevent & Implementat Grp, F-69372 Lyon, France. RP Pinto, LA (reprint author), SAIC Frederick Inc, HPV Immunol Lab, Frederick Natl Lab Canc Res, Bldg 469,Room 111, Frederick, MD 21702 USA. EM pintol@mail.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NCI; Ministry of Health of Costa Rica; NCI Intramural Research Program; National Institutes of Health Office for Research on Women's Health (ORWH); GSK Bio [FDA BB-IND 7920]; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The Costa Rica HPV Vaccine Trial is a long-standing collaboration between investigators in Costa Rica and the NCI. The trial is sponsored by the NCI, and conducted with support from the Ministry of Health of Costa Rica. The project was funded by the NCI Intramural Research Program and the National Institutes of Health Office for Research on Women's Health (ORWH). Vaccine was provided for our trial by GlaxoSmithKline Biologicals (GSK Bio, Rixensart, Belgium), under a Clinical Trials Agreement with the NCI. GSK Bio also provided support for aspects of the trial associated with regulatory submission needs of the company under grant FDA BB-IND 7920. Laboratory testing was performed at the NCI-sponsored SAIC-Frederick, Inc. HPV Immunology Laboratory in Frederick, MD. The NCI and Costa Rica investigators are responsible for the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation of the manuscript. The NCI and Costa Rica investigators make final editorial decisions on this and subsequent publications; GSK Bio has the right to review and comment. This project has also 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. NR 20 TC 23 Z9 24 U1 0 U2 8 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 DEC 17 PY 2012 VL 31 IS 1 BP 165 EP 170 DI 10.1016/j.vaccine.2012.10.067 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 067PA UT WOS:000313306400023 PM 23123024 ER PT J AU Sciume, G Hirahara, K Takahashi, H Laurence, A Villarino, AV Singleton, KL Spencer, SP Wilhelm, C Poholek, AC Vahedi, G Kanno, Y Belkaid, Y O'Shea, JJ AF Sciume, Giuseppe Hirahara, Kiyoshi Takahashi, Hayato Laurence, Arian Villarino, Alejandro V. Singleton, Kentner L. Spencer, Sean P. Wilhelm, Christoph Poholek, Amanda C. Vahedi, Golnaz Kanno, Yuka Belkaid, Yasmine O'Shea, John J. TI Distinct requirements for T-bet in gut innate lymphoid cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ROR-GAMMA-T; NATURAL-KILLER; INTESTINAL MICROBIOTA; NKP46(+) CELLS; TGF-BETA; HOMEOSTASIS; IMMUNITY; DIFFERENTIATION; PRECURSORS; MATURATION AB Interleukin (IL)-22-producing innate lymphoid cells (ILCs; ILC22) comprise a heterogeneous population of cells that are dependent on the transcription factor retinoid-related orphan gamma t (ROR gamma t) and are critical for barrier function of the intestinal mucosa. A distinct ILC22 subset expresses the natural cytotoxicity receptor NKp46 (NKp46(+) ILC22); however, the factors that contribute to the generation of this population versus other subsets are largely unknown. Herein, we show that T-bet (encoded by Tbx21) was highly expressed in NKp46(+) ILC22, a feature shared by all NKp46(+) cells present in the intestine but not by other IL-22-producing populations. Accordingly, the absence of T-bet resulted in loss of NKp46+ ILC22 in the intestinal lamina propria. The residual NKp46(+) ILC22 present in Tbx21(-/-) mice showed a marked reduction of Ror gamma t expression and impairment in IL-22 production. Generation and functions of gut NK1.1(+) cells were also altered. Bone marrow chimera experiments revealed a cell-intrinsic requirement for T-bet in these subsets and competitive reconstitution experiments revealed roles for T-bet in multiple ILC subsets. Thus, T-bet has a general importance for ILC in the gut and plays a selective and critical role in the generation of NKp46(+) ILC22. C1 [Sciume, Giuseppe; Hirahara, Kiyoshi; Takahashi, Hayato; Laurence, Arian; Villarino, Alejandro V.; Singleton, Kentner L.; Poholek, Amanda C.; Vahedi, Golnaz; Kanno, Yuka; O'Shea, John J.] NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Spencer, Sean P.; Wilhelm, Christoph; Belkaid, Yasmine] NIAID, Mucosal Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov RI Kanno, Yuka/B-5802-2013; Laurence, Arian/A-8770-2009; Sciume, Giuseppe/K-8985-2016; Hirahara, Kiyoshi/E-2460-2017; OI Laurence, Arian/0000-0003-0942-8292; Sciume, Giuseppe/0000-0003-0131-512X; Hirahara, Kiyoshi/0000-0002-9128-9449; Kanno, Yuka/0000-0001-5668-9319; Villarino, Alejandro/0000-0001-8068-2176 FU Intramural Research Programs of NIAMS; Istituto Pasteur-Fondazione Cenci-Bolognetti; Japan Society for Promotion of Sciences Research Fellowship for Japanese Biomedical and Behavioral Researchers at National Institutes of Health; Pharmacology Research Associate Program; National Institute of General Medical Sciences; National Institutes of Health FX This work was supported by the Intramural Research Programs of NIAMS, Istituto Pasteur-Fondazione Cenci-Bolognetti (G. Sciume), the Japan Society for Promotion of Sciences Research Fellowship for Japanese Biomedical and Behavioral Researchers at National Institutes of Health (K. Hirahara and H. Takahashi), Pharmacology Research Associate Program, National Institute of General Medical Sciences, and National Institutes of Health (A.C. Poholek and K.L. Singleton). NR 29 TC 68 Z9 71 U1 0 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 17 PY 2012 VL 209 IS 13 BP 2331 EP 2338 DI 10.1084/jem.20122097 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 057CQ UT WOS:000312539900002 PM 23209316 ER PT J AU Yu, Y Wang, JX Khaled, W Burke, S Li, P Chen, XF Yang, W Jenkins, NA Copeland, NG Zhang, SJ Liu, PT AF Yu, Yong Wang, Juexuan Khaled, Walid Burke, Shannon Li, Peng Chen, Xiongfeng Yang, Wei Jenkins, Nancy A. Copeland, Neal G. Zhang, Shujun Liu, Pentao TI Bcl11a is essential for lymphoid development and negatively regulates p53 SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID B-CELL DEVELOPMENT; HEMATOPOIETIC STEM-CELLS; RECEPTOR-DEFICIENT MICE; MOUSE BONE-MARROW; LINEAGE COMMITMENT; MULTIPOTENT PROGENITORS; GENE REARRANGEMENTS; CRITICAL ROLES; E2A PROTEINS; TRANSCRIPTION AB Transcription factors play important roles in lymphopoiesis. We have previously demonstrated that Bcl11a is essential for normal lymphocyte development in the mouse embryo. We report here that, in the adult mouse, Bcl11a is expressed in most hematopoietic cells and is highly enriched in B cells, early T cell progenitors, common lymphoid progenitors (CLPs), and hematopoietic stem cells (HSCs). In the adult mouse, Bcl11a deletion causes apoptosis in early B cells and CLPs and completely abolishes the lymphoid development potential of HSCs to B, T, and NK cells. Myeloid development, in contrast, is not obviously affected by the loss of Bcl11a. Bcl11a regulates expression of Bcl2, Bcl2-xL, and Mdm2, which inhibits p53 activities. Overexpression of Bcl2 and Mdm2, or p53 deficiency, rescues both lethality and proliferative defects in Bcl11a-deficient early B cells and enables the mutant CLPs to differentiate to lymphocytes. Bcl11a is therefore essential for lymphopoiesis and negatively regulates p53 activities. Deletion of Bcl11a may represent a new approach for generating a mouse model that completely lacks an adaptive immune system. C1 [Yu, Yong; Wang, Juexuan; Khaled, Walid; Burke, Shannon; Li, Peng; Yang, Wei; Liu, Pentao] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England. [Yu, Yong; Zhang, Shujun] Huazhong Agr Univ, Key Lab Agr Anim Genet Breeding & Reprod, Minist Educ, Wuhan 430070, Peoples R China. [Chen, Xiongfeng] NCI, Frederick, MD 21702 USA. [Jenkins, Nancy A.; Copeland, Neal G.] Methodist Hosp, Res Inst, Houston, TX 77030 USA. RP Liu, PT (reprint author), Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England. EM sjxiaozhang@mail.hzau.edu.cn; pl2@sanger.ac.uk FU Wellcome Trust [098051]; China Scholarship Council FX This work is supported by Wellcome Trust (grant number 098051; to P. Liu). Y. Yu is supported by a Fellowship from China Scholarship Council. NR 80 TC 57 Z9 58 U1 1 U2 19 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 DEC 17 PY 2012 VL 209 IS 13 BP 2467 EP 2483 DI 10.1084/jem.20121846 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 057CQ UT WOS:000312539900012 PM 23230003 ER PT J AU Berglund, ED Li, CY Ayala, JE McGuinness, OP Wasserman, DH AF Berglund, Eric D. Li, Candice Y. Ayala, Julio E. McGuinness, Owen P. Wasserman, David H. TI Regulation of Endogenous Glucose Production in Glucose Transporter 4 Over-Expressing Mice SO PLOS ONE LA English DT Article ID TRANSGENIC MICE; CONSCIOUS MOUSE; GLUT4; TRANSPORTER; PROTEIN; GENE; METABOLISM; TOLERANCE AB Strategies to amplify whole-body glucose disposal are key therapies to treat type 2 diabetes. Mice that over-express glucose transporter 4 (Glut4) in skeletal muscle, heart, and adipose tissue (G4Tg) exhibit increased fasting glucose disposal and thus lowered blood glucose. Intriguingly, G4Tg mice also exhibit improved insulin-stimulated suppression of endogenous glucose production even though Glut4 is not present in the liver. It is unclear, however, if hepatic gluco-regulation is altered in G4Tg mice in the basal, non-insulin-stimulated state. The current studies were performed to examine fasting hepatic glucose metabolism in G4Tg mice and to determine whether gluco-regulatory adaptations exist in the non-insulin-stimulated condition. To test this question, phloridzin-glucose clamps were used to match blood glucose and pancreatic hormone levels while tracer dilution techniques were used to measure glucose flux. These techniques were performed in chronically-catheterized, conscious, and un-stressed 5h-fasted G4Tg and wild-type (WT) littermates. Results show reduced blood glucose, hepatic glycogen content, and hepatic glucokinase (GK) activity/expression as well as higher endogenous glucose production, glucose disposal, arterial glucagon, and hepatic glucose-6-phosphatase (G6Pase) activity/expression in G4Tg mice versus WT controls. Clamping blood glucose for 90 min at,115 mg/dLin G4Tg and WT mice normalized nearly all variables. Notably, however, net hepatic glycogen synthetic rates were disproportionately elevated compared to changes in blood glucose. In conclusion, these studies demonstrate that basal improvements in glucose tolerance due to increased uptake in extra-hepatic sites provoke important gluco-regulatory adaptations in the liver. Although changes in blood glucose underlie the majority of these adaptations, net hepatic glycogen synthesis is sensitized. These data emphasize that anti-diabetic therapies that target skeletal muscle, heart, and/or adipose tissue likely positively impact the liver. C1 [Berglund, Eric D.; Li, Candice Y.; Ayala, Julio E.; McGuinness, Owen P.; Wasserman, David H.] Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. [Ayala, Julio E.; McGuinness, Owen P.; Wasserman, David H.] Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37212 USA. RP Berglund, ED (reprint author), Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. EM berglunde@gmail.com FU NIH [DK050277, DK059637] FX This work was funded by NIH DK050277 and DK059637 (awarded to DHW). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 17 TC 4 Z9 5 U1 0 U2 6 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 DEC 17 PY 2012 VL 7 IS 12 AR e52355 DI 10.1371/journal.pone.0052355 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 055RZ UT WOS:000312435900091 PM 23285006 ER PT J AU Chen, MH Huang, J Chen, WM Larson, MG Fox, CS Vasan, RS Seshadri, S O'Donnell, CJ Yang, Q AF Chen, Ming-Huei Huang, Jie Chen, Wei-Min Larson, Martin G. Fox, Caroline S. Vasan, Ramachandran S. Seshadri, Sudha O'Donnell, Christopher J. Yang, Qiong TI Using Family-Based Imputation in Genome-Wide Association Studies with Large Complex Pedigrees: The Framingham Heart Study SO PLOS ONE LA English DT Article ID GENETIC-LOCI; ALZHEIMER-DISEASE; URIC-ACID; FIBRINOGEN; VARIANTS; DESIGN; RISK; MAPS AB Imputation has been widely used in genome-wide association studies (GWAS) to infer genotypes of un-genotyped variants based on the linkage disequilibrium in external reference panels such as the HapMap and 1000 Genomes. However, imputation has only rarely been performed based on family relationships to infer genotypes of un-genotyped individuals. Using 8998 Framingham Heart Study (FHS) participants genotyped with Affymetrix 550K SNPs, we imputed genotypes of same set of SNPs for additional 3121 participants, most of whom were never genotyped due to lack of DNA sample. Prior to imputation, 122 pedigrees were too large to be handled by the imputation software Merlin. Therefore, we developed a novel pedigree splitting algorithm that can maximize the number of genotyped relatives for imputing each un-genotyped individual, while keeping new sub-pedigrees under a pre-specified size. In GWAS of four phenotypes available in FHS (Alzheimer disease, circulating levels of fibrinogen, high-density lipoprotein cholesterol, and uric acid), we compared results using genotyped individuals only with results using both genotyped and imputed individuals. We studied the impact of applying different imputation quality filtering thresholds on the association results and did not found a universal threshold that always resulted in a more significant p-value for previously identified loci. However most of these loci had a lower p-value when we only included imputed genotypes with with >= 60% SNP- and >= 50% person-specific imputation certainty. In summary, we developed a novel algorithm for splitting large pedigrees for imputation and found a plausible imputation quality filtering threshold based on FHS. Further examination may be required to generalize this threshold to other studies. C1 [Chen, Ming-Huei; Larson, Martin G.; Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Chen, Ming-Huei; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Ming-Huei; Huang, Jie; Larson, Martin G.; Fox, Caroline S.; Vasan, Ramachandran S.; Seshadri, Sudha; O'Donnell, Christopher J.; Yang, Qiong] NHLBI, Framingham Heart Study, Framingham, MA USA. [Huang, Jie] Wellcome Trust Sanger Inst, Cambridge, England. [Chen, Wei-Min] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Larson, Martin G.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Hypertens & Diabet, Boston, MA USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med,Div Cardiol, Boston, MA USA. RP Yang, Q (reprint author), Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. EM qyang@bu.edu RI Yang, Qiong/G-5438-2014; OI Yang, Qiong/0000-0002-3658-1375; Larson, Martin/0000-0002-9631-1254; Seshadri, Sudha/0000-0001-6135-2622; Ramachandran, Vasan/0000-0001-7357-5970 FU National Heart, Lung, and Blood Institute [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; NIH [R01 NS017950-28, R01-HL093328-01]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine; Boston Medical Center; [R01HL093328]; [R01HL093029]; [R01NS017950] FX The authors were supported in part by the National Heart, Lung, and Blood Institute's Framingham Heart Study (Con-tract No. N01-HC-25195) and grant numbers R01HL093328, R01HL093029, R01NS017950 and R01HL093029. The research was conducted in part using data and resources from the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (Contract No. N01-HC-25195), its contract with Affymetrix, Inc for genotyping services (Contract No. N02-HL-6-4278) and NIH grants R01 NS017950-28 and R01-HL093328-01. A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 7 Z9 7 U1 1 U2 7 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 DEC 17 PY 2012 VL 7 IS 12 AR e51589 DI 10.1371/journal.pone.0051589 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 055RZ UT WOS:000312435900032 PM 23284720 ER PT J AU Johnson, S Issac, B Zhao, SP Bisht, M Celiku, O Tofilon, P Camphausen, K Shankavaram, U AF Johnson, Seth Issac, Biju Zhao, Shuping Bisht, Mohit Celiku, Orieta Tofilon, Philip Camphausen, Kevin Shankavaram, Uma TI StRAP: An Integrated Resource for Profiling High-Throughput Cancer Genomic Data from Stress Response Studies SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; MICROARRAY DATA; RADIATION-THERAPY; PLATFORMS; RADIOTHERAPY; BIOLOGY; SYSTEMS; TOOL AB The increasing availability and maturity of DNA microarray technology has led to an explosion of cancer profiling studies for identifying cancer biomarkers, and predicting treatment response. Uncovering complex relationships, however, remains the most challenging task as it requires compiling and efficiently querying data from various sources. Here, we describe the Stress Response Array Profiler (StRAP), an open-source, web-based resource for storage, profiling, visualization, and sharing of cancer genomic data. StRAP houses multi-cancer microarray data with major emphasis on radiotherapy studies, and takes a systems biology approach towards the integration, comparison, and cross-validation of multiple cancer profiling studies. The database is a comprehensive platform for comparative analysis of gene expression data. For effective use of arrays, we provide user-friendly and interactive visualization tools that can display the data and query results. StRAP is web-based, platform-independent, and freely accessible at http://strap.nci.nih.gov/. C1 [Johnson, Seth; Zhao, Shuping; Bisht, Mohit; Celiku, Orieta; Tofilon, Philip; Camphausen, Kevin; Shankavaram, Uma] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Johnson, Seth; Zhao, Shuping] SAIC Frederick Inc, Natl Canc Inst Frederick, Frederick, MD USA. [Issac, Biju] Univ Miami, Sylvester Comprehens Canc Ctr, Div Bioinformat, Coral Gables, FL 33124 USA. RP Shankavaram, U (reprint author), NCI, Radiat Oncol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM uma@mail.nih.gov FU National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer 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. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 0 Z9 0 U1 0 U2 8 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 DEC 17 PY 2012 VL 7 IS 12 AR e51693 DI 10.1371/journal.pone.0051693 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 055RZ UT WOS:000312435900045 PM 23284744 ER PT J AU Wei, W Lampe, L Park, S Vangara, BS Waldo, GS Cabantous, S Subaran, SS Yang, DM Lakatta, EG Lin, L AF Wei, Wen Lampe, Leonie Park, Sungha Vangara, Bhavana S. Waldo, Geoffrey S. Cabantous, Stephanie Subaran, Sarah S. Yang, Dongmei Lakatta, Edward G. Lin, Li TI Disulfide Bonds within the C2 Domain of RAGE Play Key Roles in Its Dimerization and Biogenesis SO PLOS ONE LA English DT Article ID GLYCATION END-PRODUCTS; INFLAMMATORY CELL RECRUITMENT; PEPTIDE-N-GLYCANASE; ENDOPLASMIC-RETICULUM; PATTERN-RECOGNITION; ALZHEIMERS-DISEASE; OXIDATIVE STRESS; IMMUNE-RESPONSES; ENDPRODUCTS RAGE; REDOX REGULATION AB Background: The receptor for advanced glycation end products (RAGE) on the cell surface transmits inflammatory signals. A member of the immunoglobulin superfamily, RAGE possesses the V, C1, and C2 ectodomains that collectively constitute the receptor's extracellular structure. However, the molecular mechanism of RAGE biogenesis remains unclear, impeding efforts to control RAGE signaling through cellular regulation. Methodology and Result: We used co-immunoprecipitation and crossing-linking to study RAGE oligomerization and found that RAGE forms dimer-based oligomers. Via non-reducing SDS-polyacrylamide gel electrophoresis and mutagenesis, we found that cysteines 259 and 301 within the C2 domain form intermolecular disulfide bonds. Using a modified tripartite split GFP complementation strategy and confocal microscopy, we also found that RAGE dimerization occurs in the endoplasmic reticulum (ER), and that RAGE mutant molecules without the double disulfide bridges are unstable, and are subjected to the ER-associated degradation. Conclusion: Disulfide bond-mediated RAGE dimerization in the ER is the critical step of RAGE biogenesis. Without formation of intermolecular disulfide bonds in the C2 region, RAGE fails to reach cell surface. Significance: This is the first report of RAGE intermolecular disulfide bond. C1 [Wei, Wen; Lampe, Leonie; Park, Sungha; Vangara, Bhavana S.; Subaran, Sarah S.; Yang, Dongmei; Lakatta, Edward G.; Lin, Li] Natl Inst Aging, Cardiovasc Sci Lab, Baltimore, MD USA. [Waldo, Geoffrey S.; Cabantous, Stephanie] Los Alamos Natl Lab, Biosci Lab, Los Alamos, NM USA. RP Lin, L (reprint author), Natl Inst Aging, Cardiovasc Sci Lab, Baltimore, MD USA. EM linli@mail.nih.gov FU National Institutes of Health, National Institute on Aging; NIH [RO1CA94102]; NIH Protein Structure Initiative [U54 GM074946-01US]; Oak Ridge Institute for Science and Education's Research Associates Program at the NIH; Roland Ernst Foundation; Korea Research Foundation [KRF-2009-013-E00008]; NIH, NIA FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (L. Lin and EGL), the NIH grant RO1CA94102 (L. Lin), and the NIH Protein Structure Initiative (U54 GM074946-01US, "Integrated Center for Structure and Function Innovation") (GSW and SC). WW and DY were supported in part by the Oak Ridge Institute for Science and Education's Research Associates Program at the NIH; L. Lampe was supported in part by the Roland Ernst Foundation; SP was supported in part by the Korea Research Foundation grant (KRF-2009-013-E00008; BV was supported by 2009 and 2010 Summer Student Internship Program of NIH, NIA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 13 Z9 14 U1 2 U2 10 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 DEC 17 PY 2012 VL 7 IS 12 AR e50736 DI 10.1371/journal.pone.0050736 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 055RZ UT WOS:000312435900008 PM 23284645 ER PT J AU Petrie, RJ Yamada, KM AF Petrie, Ryan J. Yamada, Kenneth M. TI At the leading edge of three-dimensional cell migration SO JOURNAL OF CELL SCIENCE LA English DT Article DE Cell migration; Extracellular matrix; Intracellular signaling; Mechanotransduction; Pseudopodia ID FUNDULUS DEEP CELLS; EXTRACELLULAR-MATRIX; FOCAL ADHESIONS; TUMOR-CELLS; COLLAGEN MATRICES; TRANSFORMED-CELLS; SIGNALING COOPERATE; LEUKOCYTE MIGRATION; PROTRUSIVE ACTIVITY; ACTIN CYTOSKELETON AB Cells migrating on flat two-dimensional (2D) surfaces use actin polymerization to extend the leading edge of the plasma membrane during lamellipodia-based migration. This mode of migration is not universal; it represents only one of several mechanisms of cell motility in three-dimensional (3D) environments. The distinct modes of 3D migration are strongly dependent on the physical properties of the extracellular matrix, and they can be distinguished by the structure of the leading edge and the degree of matrix adhesion. How are these distinct modes of cell motility in 3D environments related to each other and regulated? Recent studies show that the same type of cell migrating in 3D extracellular matrix can switch between different leading edge structures. This mode-switching behavior, or plasticity, by a single cell suggests that the apparent diversity of motility mechanisms is integrated by a common intracellular signaling pathway that governs the mode of cell migration. In this Commentary, we propose that the mode of 3D cell migration is governed by a signaling axis involving cell-matrix adhesions, RhoA signaling and actomyosin contractility, and that this might represent a universal mechanism that controls 3D cell migration. C1 [Petrie, Ryan J.; Yamada, Kenneth M.] Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Petrie, RJ (reprint author), Natl Inst Dent & Craniofacial Res, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. EM petrier@mail.nih.gov; kyamada@mail.nih.gov FU Intramural Research Program of the National Institute of Dental and Craniofacial Research [DE000524] FX This work of our laboratory was supported by the Intramural Research Program of the National Institute of Dental and Craniofacial Research [project DE000524]. Deposited in PMC for release after 12 months. NR 116 TC 73 Z9 73 U1 7 U2 78 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD DEC 15 PY 2012 VL 125 IS 24 BP 5917 EP 5926 DI 10.1242/jcs.093732 PG 10 WC Cell Biology SC Cell Biology GA 099AH UT WOS:000315590300002 PM 23378019 ER PT J AU Dickison, VM Richmond, AM Abu Irqeba, A Martak, JG Hoge, SCE Brooks, MJ Othman, MI Khanna, R Mears, AJ Chowdhury, AY Swaroop, A Ogilvie, JM AF Dickison, Virginia M. Richmond, Angela M. Abu Irqeba, Ameair Martak, Joshua G. Hoge, Sean C. E. Brooks, Matthew J. Othman, Mohammed I. Khanna, Ritu Mears, Alan J. Chowdhury, Adnan Y. Swaroop, Anand Ogilvie, Judith Mosinger TI A role for prenylated rab acceptor 1 in vertebrate photoreceptor development SO BMC NEUROSCIENCE LA English DT Article DE Retina; Photoreceptor; Mouse; Retinal degeneration; Photoreceptor development; Rabac1; Prenylated Rab Acceptor 1; Rab6; Vesicular trafficking ID INHERITED RETINAL DEGENERATION; RD MOUSE; RETINITIS-PIGMENTOSA; NITRIC-OXIDE; CELL-DEATH; CGMP-PHOSPHODIESTERASE; SYNAPTIC PLASTICITY; BETA-SUBUNIT; PROTEIN; EXPRESSION AB Background: The rd1 mouse retina is a well-studied model of retinal degeneration where rod photoreceptors undergo cell death beginning at postnatal day (P) 10 until P21. This period coincides with photoreceptor terminal differentiation in a normal retina. We have used the rd1 retina as a model to investigate early molecular defects in developing rod photoreceptors prior to the onset of degeneration. Results: Using a microarray approach, we performed gene profiling comparing rd1 and wild type (wt) retinas at four time points starting at P2, prior to any obvious biochemical or morphological differences, and concluding at P8, prior to the initiation of cell death. Of the 143 identified differentially expressed genes, we focused on Rab acceptor 1 (Rabac1), which codes for the protein Prenylated rab acceptor 1 (PRA1) and plays an important role in vesicular trafficking. Quantitative RT-PCR analysis confirmed reduced expression of PRA1 in rd1 retina at all time points examined. Immunohistochemical observation showed that PRA1-like immunoreactivity (LIR) co-localized with the cis-Golgi marker GM-130 in the photoreceptor as the Golgi translocated from the perikarya to the inner segment during photoreceptor differentiation in wt retinas. Diffuse PRA1-LIR, distinct from the Golgi marker, was seen in the distal inner segment of wt photoreceptors starting at P8. Both plexiform layers contained PRA1 positive punctae independent of GM-130 staining during postnatal development. In the inner retina, PRA1-LIR also colocalized with the Golgi marker in the perinuclear region of most cells. A similar pattern was seen in the rd1 mouse inner retina. However, punctate and significantly reduced PRA1-LIR was present throughout the developing rd1 inner segment, consistent with delayed photoreceptor development and abnormalities in Golgi sorting and vesicular trafficking. Conclusions: We have identified genes that are differentially regulated in the rd1 retina at early time points, which may give insights into developmental defects that precede photoreceptor cell death. This is the first report of PRA1 expression in the retina. Our data support the hypothesis that PRA1 plays an important role in vesicular trafficking between the Golgi and cilia in differentiating and mature rod photoreceptors. C1 [Dickison, Virginia M.; Richmond, Angela M.; Abu Irqeba, Ameair; Martak, Joshua G.; Hoge, Sean C. E.; Chowdhury, Adnan Y.; Ogilvie, Judith Mosinger] St Louis Univ, Dept Biol, St Louis, MO 63103 USA. [Brooks, Matthew J.; Othman, Mohammed I.; Khanna, Ritu; Swaroop, Anand] Univ Michigan, WK Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48109 USA. [Brooks, Matthew J.; Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Mears, Alan J.] Ottawa Hosp Res Inst, Ottawa, ON, Canada. [Mears, Alan J.] Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON, Canada. RP Ogilvie, JM (reprint author), St Louis Univ, Dept Biol, St Louis, MO 63103 USA. EM ogilviej@slu.edu OI Swaroop, Anand/0000-0002-1975-1141; , Ameair/0000-0002-6664-8892 FU National Institutes of Health [EY15113, HD064269]; Foundation Fighting Blindness; National Science Foundation [DBI-0421383]; National Eye Institute FX We would like to thank Sepideh Zareparsi, Judy Speck, Rebecca Gunkel, Garrett Searcy, Ju Zhang, and Cynthia Montana for helpful suggestions and technical support. We would also like to thank Eric Pierce for the generous gift of the RP1 antibody. This research was supported by individual grants from the National Institutes of Health, http://grants.nih.gov/grants/oer.htm (EY15113, HD064269, JMO), and the Foundation Fighting Blindness, http://www.blindness.org/ (JMO), an equipment grant from the National Science Foundation, http://www.nsf.gov/(DBI-0421383), and intramural program of the National Eye Institute. NR 62 TC 8 Z9 8 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD DEC 15 PY 2012 VL 13 AR 152 DI 10.1186/1471-2202-13-152 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 093JU UT WOS:000315188900001 PM 23241222 ER PT J AU Liu, LH Aerbajinai, W Ahmed, SM Rodgers, GP Angers, S Parent, CA AF Liu, Lunhua Aerbajinai, Wulin Ahmed, Syed M. Rodgers, Griffin P. Angers, Stephane Parent, Carole A. TI Radil controls neutrophil adhesion and motility through beta 2-integrin activation SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MEDIATES RAP1-INDUCED ADHESION; CONTROLS CELL-ADHESION; INTEGRIN ACTIVATION; TYROSINE PHOSPHORYLATION; EXTRACELLULAR-MATRIX; LEUKOCYTE ADHESION; RAP1 ACTIVITY; SMALL GTPASE; BETA-GAMMA; MIGRATION AB Integrin activation is required to facilitate multiple adhesion-dependent functions of neutrophils, such as chemotaxis, which is critical for inflammatory responses to injury and pathogens. However, little is known about the mechanisms that mediate integrin activation in neutrophils. We show that Radil, a novel Rap1 effector, regulates beta 1- and beta 2-integrin activation and controls neutrophil chemotaxis. On activation and chemotactic migration of neutrophils, Radil quickly translocates from the cytoplasm to the plasma membrane in a Rap1a-GTP-dependent manner. Cells overexpressing Radil show a substantial increase in cell adhesion, as well as in integrin/focal adhesion kinase (FAK) activation, and exhibit an elongated morphology, with severe tail retraction defects. This phenotype is effectively rescued by treatment with either beta 2-integrin inhibitory antibodies or FAK inhibitors. Conversely, knockdown of Radil causes severe inhibition of cell adhesion, beta 2-integrin activation, and chemotaxis. Furthermore, we found that inhibition of Rap activity by RapGAP coexpression inhibits Radil-mediated integrin and FAK activation, decreases cell adhesion, and abrogates the long-tail phenotype of Radil cells. Overall, these studies establish that Radil regulates neutrophil adhesion and motility by linking Rap1 to beta 2-integrin activation. C1 [Liu, Lunhua; Parent, Carole A.] NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Aerbajinai, Wulin; Rodgers, Griffin P.] NHLBI, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. [Ahmed, Syed M.; Angers, Stephane] Univ Toronto, Leslie Dan Fac Pharm, Dept Pharmaceut Sci, Toronto, ON M5S 3M2, Canada. RP Parent, CA (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM parentc@mail.nih.gov RI Angers, Stephane/E-1432-2014 OI Angers, Stephane/0000-0001-7241-9044 FU Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health; Canadian Breast Cancer Foundation-Ontario Chapter FX We thank Amy Melpolder and the National Institutes of Health Blood Bank for providing human blood from healthy volunteers. We also thank members of the Parent laboratory for excellent discussions and suggestions and, in particular Philippe Afonso and Christina Stuelten for valuable input on the manuscript. This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and by a research grant to S. A. from the Canadian Breast Cancer Foundation-Ontario Chapter. NR 63 TC 9 Z9 9 U1 1 U2 2 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD DEC 15 PY 2012 VL 23 IS 24 BP 4751 EP 4765 DI 10.1091/mbc.E12-05-0408 PG 15 WC Cell Biology SC Cell Biology GA 082PT UT WOS:000314405100009 PM 23097489 ER PT J AU Virtanen, JO Jaffe, H Jacobson, S AF Virtanen, Jussi Oskari Jaffe, Howard Jacobson, Steve TI Identification of virus infection induced or modified cellular proteins as a target for humoral immune response in multiple sclerosis SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Virtanen, Jussi Oskari; Jaffe, Howard; Jacobson, Steve] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 14 EP 14 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800037 ER PT J AU Komori, M Pawlowski, J Shukla, P Romm, E Bielekova, B AF Komori, Mika Pawlowski, Joseph Shukla, Pradeep Romm, Elena Bielekova, Bibiana TI CSF biomarker development for oxidative stress in patients with multiple sclerosis SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Komori, Mika; Pawlowski, Joseph; Shukla, Pradeep; Romm, Elena; Bielekova, Bibiana] NINDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 19 EP 20 PG 2 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800052 ER PT J AU Kosa, P Johnson, K Ni, T Zhu, J Bielekova, B AF Kosa, Peter Johnson, Kory Ni, Ting Zhu, Jun Bielekova, Bibiana TI RNA sequencing analysis of intrathecal exosomes isolated from multiple sclerosis patients SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Kosa, Peter; Bielekova, Bibiana] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Dis Unit, NIH, Bethesda, MD USA. [Johnson, Kory] Natl Inst Neurol Disorders & Stroke, Bioinforrnat Sect, NIH, Bethesda, MD USA. [Ni, Ting; Zhu, Jun] NHLBI, DNA Sequencing & Computat Biol Core, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 20 EP 20 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800053 ER PT J AU Mexhitaj, I Wuest, S Bielekova, B AF Mexhitaj, Ina Wuest, Simone Bielekova, Bibiana TI In vivo achievable concentrations of idebenone are unlikely to inhibit oxidative burst of immune cells SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Mexhitaj, Ina; Wuest, Simone; Bielekova, Bibiana] NINDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 31 EP 31 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800083 ER PT J AU Owen, E Von Korff, A Diamond, A Rosenkrantz, L McCabe, C Keenan, B Chibnik, L Reich, D Bakshi, R Xia, ZQ De Jager, P AF Owen, Emily Von Korff, Alina Diamond, Allison Rosenkrantz, Laura McCabe, Cristin Keenan, Brendan Chibnik, Lori Reich, Daniel Bakshi, Rohit Xia, Zongqi De Jager, Philip TI Integrating genetic and environmental risk scores into an algorithm to predict multiple sclerosis susceptibility SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Owen, Emily; Von Korff, Alina; Diamond, Allison; Rosenkrantz, Laura; Keenan, Brendan; Chibnik, Lori; Bakshi, Rohit; Xia, Zongqi; De Jager, Philip] Brigham & Womens Hosp, Ctr Neurol Dis, Boston, MA 02115 USA. [McCabe, Cristin] Harvard Univ, Broad Inst, MIT, Cambridge, MA 02138 USA. [Reich, Daniel] NINDS, NIH, Bethesda, MD 20892 USA. RI Reich, Daniel/E-5701-2010 OI Reich, Daniel/0000-0002-2628-4334 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 32 EP 32 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800085 ER PT J AU Wuest, SC Kosa, P Mexhitaj, I Romm, E Bielekova, B AF Wuest, Simone Christiane Kosa, Peter Mexhitaj, Ina Romm, Elena Bielekova, Bibiana TI Analysis and comparison of cellular intrathecal and peripheral immune responses in patients with multiple sclerosis SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Wuest, Simone Christiane; Kosa, Peter; Mexhitaj, Ina; Romm, Elena; Bielekova, Bibiana] NINDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 34 EP 34 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800090 ER PT J AU Natrajan, M Guzman, A Huang, J Bielekova, B Franklin, RJM AF Natrajan, Muktha Guzman, Alerie Huang, Jeffrey Bielekova, Bibiana Franklin, Robin J. M. TI Macrophages, myelin debris and the efficiency of CNS remyelination: The problems of growing old SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Natrajan, Muktha; Guzman, Alerie; Franklin, Robin J. M.] Univ Cambridge, Brain Repair Ctr, Dept Clin Neurosci, Cambridge, England. [Huang, Jeffrey] Univ Cambridge, Dept Vet Med, Cambridge, England. [Bielekova, Bibiana] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 41 EP 42 PG 2 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800111 ER PT J AU Leibovitch, E Maggi, P Brunetto, G Motanic, K Wohler, J Macri, SC Westmoreland, S Silva, A Reich, D Jacobson, S AF Leibovitch, Emily Maggi, Pietro Brunetto, Giovanna Motanic, Kelsey Wohler, Jillian Macri, Sheila Cummings Westmoreland, Susan Silva, Afonso Reich, Daniel Jacobson, Steven TI HHV-6A infection enhances EAE severity in the common marmoset SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Leibovitch, Emily; Maggi, Pietro; Brunetto, Giovanna; Motanic, Kelsey; Wohler, Jillian; Silva, Afonso; Reich, Daniel; Jacobson, Steven] NINDS, NIH, Bethesda, MD 20892 USA. [Macri, Sheila Cummings; Westmoreland, Susan] Harvard Univ, Sch Med, NEPRC, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 48 EP 49 PG 2 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800130 ER PT J AU Han, S Perry, JSA Xu, QG Kennedy, LB Bielekova, B AF Han, SungPil Perry, Justin S. A. Xu, Quangang Kennedy, Lucy B. Bielekova, Bibiana TI Inhibitory effects of CD25 blockade on development of pro-inflammatory innate lymphoid cells is associated with decreased intrathecal inflammation in MS SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Han, SungPil; Perry, Justin S. A.; Xu, Quangang; Kennedy, Lucy B.; Bielekova, Bibiana] NINDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 67 EP 67 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800178 ER PT J AU Benhar, I London, A Itskovich, E Kalchenko, V Mack, M Jung, S Caspi, RR Schwartz, M AF Benhar, Inbal London, Anat Itskovich, Elena Kalchenko, Vyacheslav Mack, Matthias Jung, Steffen Caspi, Rachel R. Schwartz, Michal TI Monocyte-derived macrophages orchestrate repair under sterile and immune-mediated neurodegenerative conditions SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Benhar, Inbal; London, Anat; Itskovich, Elena; Schwartz, Michal] Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. [Kalchenko, Vyacheslav] Weizmann Inst Sci, Dept Vet Resources, IL-76100 Rehovot, Israel. [Mack, Matthias] Univ Regensburg, Dept Internal Med, D-93053 Regensburg, Germany. [Jung, Steffen] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel. [Caspi, Rachel R.] NEI, Lab Immunol, NIH, Bethesda, MD 20892 USA. RI Kalchenko, Vyacheslav/F-2924-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 88 EP 88 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800235 ER PT J AU Han, S Salgado, AD Romm, E Bielekova, B AF Han, SungPil Salgado, Alan D. Romm, Elena Bielekova, Bibiana TI Comprehensive monitoring of intrathecal immune cells in patients with multiple sclerosis by 12-color flow cytometric immunophenotyping SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Han, SungPil; Salgado, Alan D.; Romm, Elena; Bielekova, Bibiana] NINDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 98 EP 98 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800262 ER PT J AU Herz, J McGavern, DB AF Herz, Jasmin McGavern, Dorian B. TI Dynamics of memory T cells clearing a persistent CNS infection in the absence of severe tissue Injury SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Herz, Jasmin; McGavern, Dorian B.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 134 EP 135 PG 2 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800362 ER PT J AU Anderson, M Akahata, Y Massoud, R Maric, D Oh, U McCormick, M Jacobson, S AF Anderson, Monique Akahata, Yoshimi Massoud, Raya Maric, Dragan Oh, Unsong McCormick, Matt Jacobson, Steven TI Characterization and behavior of T regulatory cells in HTLV-1 associated myelopathy/tropical spastic paraparesis SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Anderson, Monique; Akahata, Yoshimi; Massoud, Raya; Maric, Dragan; McCormick, Matt; Jacobson, Steven] NINDS, NIH, Bethesda, MD 20892 USA. [Oh, Unsong] Virginia Commonwealth Univ, Dept Neurol, Richmond, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 160 EP 160 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800429 ER PT J AU Rimmerman, N Juknat, A Kozela, E Porat, Z Ben-Hail, D Shoshan-Barmatz, V Daniels, M Vogel, Z AF Rimmerman, Neta Juknat, Ana Kozela, Ewa Porat, Ziv Ben-Hail, Danya Shoshan-Barmatz, Varda Daniels, Mathew Vogel, Zvi TI Cannabinoids affect mitochondrial targets in BV-2 microglial cells SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Meeting Abstract CT 11th International Congress of Neuroimmunology (ISNI) CY NOV 04-08, 2012 CL Boston, MA SP European Sch Neuroimmunol, Int Soc Neuroimmunol (ISNI) C1 [Rimmerman, Neta; Juknat, Ana; Kozela, Ewa; Vogel, Zvi] Tel Aviv Univ, Sch Med, IL-69978 Tel Aviv, Israel. [Porat, Ziv] Weizmann Inst Sci, Flow Cytometry Unit, IL-76100 Rehovot, Israel. [Ben-Hail, Danya; Shoshan-Barmatz, Varda] Ben Gurion Univ Negev, Dept Life Sci, IL-84105 Beer Sheva, Israel. [Daniels, Mathew] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD DEC 15 PY 2012 VL 253 IS 1-2 BP 175 EP 175 PG 1 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 060GP UT WOS:000312764800470 ER PT J AU Sahasrabuddhe, VV Shiels, MS McGlynn, KA Engels, EA AF Sahasrabuddhe, Vikrant V. Shiels, Meredith S. McGlynn, Katherine A. Engels, Eric A. TI The Risk of Hepatocellular Carcinoma Among Individuals With Acquired Immunodeficiency Syndrome in the United States SO CANCER LA English DT Article DE hepatocellular carcinoma; human immunodeficiency virus; acquired immunodeficiency syndrome; epidemiology; hepatitis C virus ID HEPATITIS-C VIRUS; HIV-INFECTED PATIENTS; CANCER-RISK; B-VIRUS; DISEASE PROGRESSION; ALCOHOL-CONSUMPTION; VIRAL-HEPATITIS; LIVER-DISEASE; POPULATION; PREVALENCE AB BACKGROUND: Hepatocellular carcinoma (HCC) is a concern among individuals with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). METHODS: The authors analyzed population-based registry linkage data from the US HIV/AIDS Cancer Match Study (1980-2009) to examine the risk and trends of HCC among individuals with AIDS. Standardized incidence ratios (SIRs) were used to measure HCC risk relative to the general population, and Poisson regression was used to calculate incidence rate ratios (RR) comparing incidence among individuals with AIDS. People with AIDS were categorized according to their HIV risk group into high and low hepatitis C virus (HCV) prevalence groups based on their HIV transmission risk category. RESULTS: Among 615,150 individuals with AIDS, HCC risk was elevated almost 4 times compared with the risk in the general population (N = 366; SIR, 3.8; 95% confidence interval, 3.5-4.3). Although HCC incidence increased steadily across calendar periods (P-trend < .0001; adjusted for sex and age), the excess risk in individuals with AIDS compared with the general population remained somewhat constant (SIRs range, 3.5-3.9) between the monotherapy/dual therapy era (1990-1995) and the recent highly active antiretroviral therapy era (2001-2009). In a multivariate model adjusting for sex, race/ethnicity, and attained calendar period, HCC incidence increased with advancing age (P-trend <.0001) and was associated with HIV risk groups with a known higher prevalence of HCV (adjusted RR, 2.2; 95% confidence interval, 1.8-2.8). CONCLUSIONS: HCC incidence in individuals with AIDS has increased over time despite improved HIV treatment regimens, likely reflecting prolonged survival with chronic liver disease. The high incidence in older adults suggests that this cancer will increase in importance with aging of the HIV-infected population. Cancer 2012; 118:6226-33. Published 2012 by the American Cancer Society*. C1 [Sahasrabuddhe, Vikrant V.; Shiels, Meredith S.; McGlynn, Katherine A.; Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Sahasrabuddhe, VV (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 5032, Rockville, MD 20852 USA. EM vikrant.sahasrabuddhe@nih.gov FU National Cancer Institute at the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Cancer Institute at the National Institutes of Health. NR 45 TC 17 Z9 17 U1 0 U2 7 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD DEC 15 PY 2012 VL 118 IS 24 BP 6226 EP 6233 DI 10.1002/cncr.27694 PG 8 WC Oncology SC Oncology GA 048KZ UT WOS:000311911600028 PM 22736272 ER PT J AU Sin, HS Barski, A Zhang, F Kartashov, AV Nussenzweig, A Chen, JJ Andreassen, PR Namekawa, SH AF Sin, Ho-Su Barski, Artem Zhang, Fan Kartashov, Andrey V. Nussenzweig, Andre Chen, Junjie Andreassen, Paul R. Namekawa, Satoshi H. TI RNF8 regulates active epigenetic modifications and escape gene activation from inactive sex chromosomes in post-meiotic spermatids SO GENES & DEVELOPMENT LA English DT Article DE DNA damage response; epigenetics; escape genes; germ cells; sex chromosomes ID DOUBLE-STRAND BREAKS; DNA-DAMAGE RESPONSE; X-CHROMOSOME; HISTONE UBIQUITINATION; REPAIR PROTEINS; HUMAN GENOME; LIGASE RNF8; GERM-CELLS; LONG ARM; CHROMATIN AB Sex chromosomes are uniquely subject to chromosome-wide silencing during male meiosis, and silencing persists into post-meiotic spermatids. Against this background, a select set of sex chromosome-linked genes escapes silencing and is activated in post-meiotic spermatids. Here, we identify a novel mechanism that regulates escape gene activation in an environment of chromosome-wide silencing in murine germ cells. We show that RNF8-dependent ubiquitination of histone H2A during meiosis establishes active epigenetic modifications, including dimethylation of H3K4 on the sex chromosomes. RNF8-dependent active epigenetic memory, defined by dimethylation of H3K4, persists throughout meiotic division. Various active epigenetic modifications are subsequently established on the sex chromosomes in post-meiotic spermatids. These RNF8-dependent modifications include trimethylation of H3K4, histone lysine crotonylation (Kcr), and incorporation of the histone variant H2AFZ. RNF8-dependent epigenetic programming regulates escape gene activation from inactive sex chromosomes in post-meiotic spermatids. Kcr accumulates at transcriptional start sites of sex-linked genes activated in an RNF8-dependent manner, and a chromatin conformational change is associated with RNF8-dependent epigenetic programming. Furthermore, we demonstrate that this RNF8-dependent pathway is distinct from that which recognizes DNA double-strand breaks. Our results establish a novel connection between a DNA damage response factor (RNF8) and epigenetic programming, specifically in establishing active epigenetic modifications and gene activation. C1 [Sin, Ho-Su; Namekawa, Satoshi H.] Cincinnati Childrens Hosp, Med Ctr, Div Reprod Sci, Perinatal Inst, Cincinnati, OH 45229 USA. [Sin, Ho-Su; Namekawa, Satoshi H.] Cincinnati Childrens Hosp, Med Ctr, Div Dev Biol, Perinatal Inst, Cincinnati, OH 45229 USA. [Sin, Ho-Su; Barski, Artem; Zhang, Fan; Kartashov, Andrey V.; Namekawa, Satoshi H.] Univ Cincinnati, Coll Med, Dept Pediat, Cincinnati, OH 45229 USA. [Barski, Artem; Kartashov, Andrey V.; Andreassen, Paul R.] Cincinnati Childrens Hosp, Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA. [Barski, Artem; Kartashov, Andrey V.; Andreassen, Paul R.] Cincinnati Childrens Hosp, Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA. [Zhang, Fan; Andreassen, Paul R.] Cincinnati Childrens Hosp, Med Ctr, Div Expt Hematol & Canc Biol, Cincinnati, OH 45229 USA. [Nussenzweig, Andre] NCI, Lab Genome Integr, NIH, Bethesda, MD 20892 USA. [Chen, Junjie] Univ Texas MD Anderson Canc Ctr, Dept Expt Radiat Oncol, Houston, TX 77030 USA. RP Namekawa, SH (reprint author), Cincinnati Childrens Hosp, Med Ctr, Div Reprod Sci, Perinatal Inst, Cincinnati, OH 45229 USA. EM satoshi.namekawa@cchmc.org OI Barski, Artem/0000-0002-1861-5316 FU Lalor foundation post-doctoral fellowship; Cincinnati Children's Hospital Medical Center; Basil O'Connor Starter Scholar Award from the March of Dimes Foundation; NCI (NIH) Intramural Research Program; NIH [HL098691, CA092312, HL085587, GM098605] FX We thank Yuya Ogawa, Norishige Yamada, and Kazuteru Hasegawa for discussion and helpful comments regarding the manuscript; Shawn Smith for help with the microarray analysis; Yosuke Ichijima and Misako Ichijima for technical assistance; and Serenity Curtis and Tyler Broering for editing the manuscript. This work was supported by the Lalor foundation post-doctoral fellowship (to H.-S.S.); the Developmental Fund, Trustee Grant and Research Innovation Funding at Cincinnati Children's Hospital Medical Center (to S.H.N.); the Basil O'Connor Starter Scholar Award from the March of Dimes Foundation (to S.H.N.); the NCI (NIH) Intramural Research Program (to A.N.); and NIH grants HL098691 (to A. B.), CA092312 (to J.C.), HL085587 (to P. R. A.), and GM098605 (to S.H.N.). NR 60 TC 35 Z9 37 U1 1 U2 11 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD DEC 15 PY 2012 VL 26 IS 24 BP 2737 EP 2748 DI 10.1101/gad.202713.112 PG 12 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 060KF UT WOS:000312775700008 PM 23249736 ER PT J AU Leary, PJ Barr, RG Bluemke, DA Bristow, MR Hough, CL Kronmal, RA Lima, JA McClelland, RL Tracy, RP Kawut, SM AF Leary, Peter J. Barr, R. Graham Bluemke, David A. Bristow, Michael R. Hough, Catherine L. Kronmal, Richard A. Lima, Joao A. McClelland, Robyn L. Tracy, Russell P. Kawut, Steven M. TI Von Willebrand Factor and the Right Ventricle (the MESA-Right Ventricle Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID PULMONARY ARTERIAL-HYPERTENSION; NITRIC-OXIDE SYNTHASE; CONGESTIVE-HEART-FAILURE; ENDOTHELIAL FUNCTION; SYSTOLIC FUNCTION; ATHEROSCLEROSIS; ANGIOGENESIS; HYPERTROPHY; DYSFUNCTION; ACTIVATION AB Elevation in plasma activity of von Willebrand factor (vWF) reflects endothelial dysfunction and predicts death in pulmonary arterial hypertension. Higher vWF activity is also associated with a lower right ventricular (RV) ejection fraction in pulmonary arterial hypertension. Little is known about the relation between vWF and RV structure and function in adults without cardiovascular disease. The present investigation included 1,976 participants with magnetic resonance imaging assessment of RV structure and function and measurement of vWF activity from the Multi-Ethnic Study of Atherosclerosis. Multivariable linear regression was used to estimate the associations between vWF activity and measures of RV structure and function after adjusting for demographics, anthropometrics, smoking, diabetes mellitus, hypertension, and the corresponding left ventricular parameter. The average vWF activity was 140.7 +/- 57.2%. Elevated vWF activity was independently associated with lower RV mass, RV end-diastolic volume, and RV stroke volume in models with and without adjustment for the corresponding left ventricular parameter (all p values <0.05). There was no association observed between vWF activity and the RV ejection fraction. In conclusion, higher vWF activity is associated with lower RV mass, RV end-diastolic volume, and RV stroke volume. These associations are independent of common cardiovascular risk factors and left ventricular morphologic changes. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:1846-1851) C1 [Kawut, Steven M.] Univ Penn, Dept Med, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Kawut, Steven M.] Univ Penn, Perelman Sch Med, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA. [Leary, Peter J.; Hough, Catherine L.] Univ Washington, Div Pulm & Crit Care Med, Seattle, WA 98195 USA. [Kronmal, Richard A.; McClelland, Robyn L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Barr, R. Graham] Columbia Univ, Dept Med, New York, NY USA. [Barr, R. Graham] Columbia Univ, Dept Epidemiol, New York, NY USA. [Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Bristow, Michael R.] Univ Colorado, Div Cardiol, Denver, CO 80202 USA. [Lima, Joao A.] Johns Hopkins Univ Hosp, Dept Med, Baltimore, MD 21287 USA. [Lima, Joao A.] Johns Hopkins Univ Hosp, Dept Radiol, Baltimore, MD 21287 USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol & Lab Med, Burlington, VT USA. RP Kawut, SM (reprint author), Univ Penn, Dept Med, Perelman Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. EM kawut@upenn.edu OI Bluemke, David/0000-0002-8323-8086; Leary, Peter/0000-0001-5716-248X FU National Institutes of Health [R01-HL086719, K24-HL103844, R01-HL077612, N01-HC95159, HC95165, N01-HC9569] FX This research was supported in part by the National Institutes of Health (grants R01-HL086719, K24-HL103844, R01-HL077612, N01-HC95I59 through HC95165, and N01-HC9569). NR 30 TC 3 Z9 3 U1 0 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD DEC 15 PY 2012 VL 110 IS 12 BP 1846 EP 1851 DI 10.1016/j.amjcard.2012.08.022 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 056TK UT WOS:000312514100022 PM 22995970 ER PT J AU Machiela, MJ Lindstrom, S Allen, NE Haiman, CA Albanes, D Barricarte, A Berndt, SI Bueno-de-Mesquita, HB Chanock, S Gaziano, JM Gapstur, SM Giovannucci, E Henderson, BE Jacobs, EJ Kolonel, LN Krogh, V Ma, J Stampfer, MJ Stevens, VL Stram, DO Tjonneland, A Travis, R Willett, WC Hunter, DJ Le Marchand, L Kraft, P AF Machiela, Mitchell J. Lindstroem, Sara Allen, Naomi E. Haiman, Christopher A. Albanes, Demetrius Barricarte, Aurelio Berndt, Sonja I. Bueno-de-Mesquita, H. Bas Chanock, Stephen Gaziano, J. Michael Gapstur, Susan M. Giovannucci, Edward Henderson, Brian E. Jacobs, Eric J. Kolonel, Laurence N. Krogh, Vittorio Ma, Jing Stampfer, Meir J. Stevens, Victoria L. Stram, Daniel O. Tjonneland, Anne Travis, Ruth Willett, Walter C. Hunter, David J. Le Marchand, Loic Kraft, Peter TI Association of Type 2 Diabetes Susceptibility Variants With Advanced Prostate Cancer Risk in the Breast and Prostate Cancer Cohort Consortium SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE carcinoma; diabetes mellitus; type 2; genetic predisposition to disease; genetics; genome-wide association study; humans; polymorphism; single nucleotide; prostatic neoplasms ID GENOME-WIDE ASSOCIATION; BASE-LINE CHARACTERISTICS; LARGE-SCALE ASSOCIATION; MULTIETHNIC COHORT; COMMON VARIANTS; LOCI; MELLITUS; GENES; METAANALYSIS; IDENTIFICATION AB Observational studies have found an inverse association between type 2 diabetes (T2D) and prostate cancer (PCa), and genome-wide association studies have found common variants near 3 loci associated with both diseases. The authors examined whether a genetic background that favors T2D is associated with risk of advanced PCa. Data from the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium, a genome-wide association study of 2,782 advanced PCa cases and 4,458 controls, were used to evaluate whether individual single nucleotide polymorphisms or aggregations of these 36 T2D susceptibility loci are associated with PCa. Ten T2D markers near 9 loci (NOTCH2, ADCY5, JAZF1, CDKN2A/B, TCF7L2, KCNQ1, MTNR1B, FTO, and HNF1B) were nominally associated with PCa (P < 0.05); the association for single nucleotide polymorphism rs757210 at the HNF1B locus was significant when multiple comparisons were accounted for (adjusted P = 0.001). Genetic risk scores weighted by the T2D log odds ratio and multilocus kernel tests also indicated a significant relation between T2D variants and PCa risk. A mediation analysis of 9,065 PCa cases and 9,526 controls failed to produce evidence that diabetes mediates the association of the HNF1B locus with PCa risk. These data suggest a shared genetic component between T2D and PCa and add to the evidence for an interrelation between these diseases. C1 [Machiela, Mitchell J.; Lindstroem, Sara; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Allen, Naomi E.; Travis, Ruth] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. [Haiman, Christopher A.; Henderson, Brian E.; Stram, Daniel O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Albanes, Demetrius; Berndt, Sonja I.; Chanock, Stephen] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Barricarte, Aurelio] Navarre Publ Hlth Inst, Pamplona, Spain. [Bueno-de-Mesquita, H. Bas] Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. [Bueno-de-Mesquita, H. Bas] Univ Med Ctr Utrecht, Dept Gastroenterol & Hepatol, Utrecht, Netherlands. [Gaziano, J. Michael] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Gaziano, J. Michael] VA Boston Healthcare Syst, Massachusetts Vet Epidemiol Res & Informat Ctr, Boston, MA USA. [Gapstur, Susan M.; Jacobs, Eric J.; Stevens, Victoria L.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Giovannucci, Edward; Stampfer, Meir J.; Willett, Walter C.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Krogh, Vittorio] Ist Nazl Tumori, Fdn IRCCS Ist Ricovero & Cura Carattere Sci, I-20133 Milan, Italy. [Ma, Jing; Stampfer, Meir J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Ma, Jing; Stampfer, Meir J.] Harvard Univ, Sch Med, Boston, MA USA. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. RP Kraft, P (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, 655 Huntington Ave,Bldg 2,Room 207, Boston, MA 02115 USA. EM pkraft@hsph.harvard.edu RI Machiela, Mitchell/F-9781-2013; Albanes, Demetrius/B-9749-2015; Krogh, Vittorio/K-2628-2016 OI Machiela, Mitchell/0000-0001-6538-9705; Krogh, Vittorio/0000-0003-0122-8624 FU National Cancer Institute [U01-CA98233-07, U01-CA98710-06, U01-CA98216-06, U01-CA98758-07]; Intramural Research Program of the National Institutes of Health/National Cancer Institute, Division of Cancer Epidemiology and Genetics; National Institutes of Health [T32-CA09001, T32-GM074897] FX This work was supported by the National Cancer Institute (cooperative agreements U01-CA98233-07 with David J. Hunter, U01-CA98710-06 with Susan M. Gapstur, U01-CA98216-06 with Elio Riboli and Rudolf Kaaks, and U01-CA98758-07 with Brian E. Henderson and the Intramural Research Program of the National Institutes of Health/National Cancer Institute, Division of Cancer Epidemiology and Genetics), as well as National Institutes of Health grants T32-CA09001 and T32-GM074897. NR 54 TC 24 Z9 25 U1 1 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 15 PY 2012 VL 176 IS 12 BP 1121 EP 1129 DI 10.1093/aje/kws191 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 058LI UT WOS:000312634900008 PM 23193118 ER PT J AU Renehan, AG Flood, A Adams, KF Olden, M Hollenbeck, AR Cross, AJ Leitzmann, MF AF Renehan, Andrew G. Flood, Andrew Adams, Kenneth F. Olden, Matthias Hollenbeck, Albert R. Cross, Amanda J. Leitzmann, Michael F. TI Body Mass Index at Different Adult Ages, Weight Change, and Colorectal Cancer Risk in the National Institutes of Health-AARP Cohort SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body mass index; colorectal cancer; weight gain ID POSTMENOPAUSAL BREAST-CANCER; IOWA WOMENS HEALTH; HORMONE REPLACEMENT THERAPY; ENDOMETRIAL CANCER; COLON-CANCER; LIFE-STYLE; PHYSICAL-ACTIVITY; DIABETES-MELLITUS; UNITED-STATES; OLDER WOMEN AB The authors investigated the relations of body mass index at different ages and adult weight change to incident colorectal cancer risk in the prospective National Institutes of HealthAARP Diet and Health Study (19951996), using a subcohort with repeated recall weights (273,679 participants; mean baseline age 62.8 years). During 2,509,662 person-years follow-up, 4076 incident colorectal cancers were ascertained. For men, an increased risk of colon cancer but not rectal cancer was associated with body mass index at baseline age (per 5-kg/m(2) increase, hazard ratio (HR) 1.18, 95 confidence interval (CI): 1.11, 1.25), at age 50 years (HR 1.18, 95 CI: 1.10, 1.26), and at age 35 years (HR 1.16, 95 CI: 1.07, 1.25) but less so at age 18 years. Weight gained between the ages of 18 and 35 years and between 18 years of age and the baseline age was associated with an increased risk of colon cancer in men (per 0.5-kg/year increase, HR 1.18, 95 CI: 1.11, 1.25 and HR 1.29, 95 CI: 1.16, 1.56, respectively). For women, relations throughout were weaker than those observed for men. These findings suggest that weight gains during early to middle adulthood have important influences on colon cancer risk, especially in men. C1 [Renehan, Andrew G.] Univ Manchester, Inst Canc Sci, Manchester, Lancs, England. [Renehan, Andrew G.] Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England. [Flood, Andrew] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Adams, Kenneth F.] HealthPartners Res Fdn, Bloomington, MN USA. [Olden, Matthias; Leitzmann, Michael F.] Univ Regensburg, Dept Epidemiol & Prevent Med, Med Ctr, Regensburg, Germany. [Hollenbeck, Albert R.] AARP, Washington, DC USA. [Cross, Amanda J.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Renehan, AG (reprint author), Christie NHS Fdn Trust, Dept Surg, Wilmslow Rd, Manchester M20 4BX, Lancs, England. EM arenehan@picr.man.ac.uk RI Renehan, Andrew/K-5992-2015 OI Renehan, Andrew/0000-0003-4309-4396 FU United Kingdom Clinical Research Collaboration FX Dr. Renehan holds a senior lectureship award supported by the United Kingdom Clinical Research Collaboration. NR 45 TC 23 Z9 23 U1 2 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 15 PY 2012 VL 176 IS 12 BP 1130 EP 1140 DI 10.1093/aje/kws192 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 058LI UT WOS:000312634900009 PM 23186750 ER PT J AU McCormack, FX Travis, WD Colby, TV Henske, EP Moss, J AF McCormack, Francis X. Travis, William D. Colby, Thomas V. Henske, Elizabeth P. Moss, Joel TI Lymphangioleiomyomatosis Calling It What It Is: A Low-Grade, Destructive, Metastasizing Neoplasm SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID TUBEROUS SCLEROSIS COMPLEX; PULMONARY LYMPHANGIOLEIOMYOMATOSIS; CELLS; TSC2; LAM; LYMPHANGIOGENESIS; TRANSPLANTATION; MECHANISM; GENE C1 [Moss, Joel] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [McCormack, Francis X.] Univ Cincinnati, Dept Internal Med, Div Pulm Crit Care & Sleep Med, Cincinnati, OH USA. [Travis, William D.] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. [Colby, Thomas V.] Mayo Clin, Dept Pathol, Scottsdale, AZ USA. [Henske, Elizabeth P.] Brigham & Womens Hosp, Dept Med, Div Pulm & Crit Care Med, Boston, MA 02115 USA. [Henske, Elizabeth P.] Harvard Univ, Sch Med, Boston, MA USA. RP Moss, J (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov OI McCormack, Francis/0000-0001-7168-9464 NR 28 TC 50 Z9 52 U1 0 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD DEC 15 PY 2012 VL 186 IS 12 BP 1210 EP 1212 DI 10.1164/rccm.201205-0848OE PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 057OZ UT WOS:000312574200006 PM 23250499 ER PT J AU Ren, SX Cheng, ASL To, KF Tong, JHM Li, MS Shen, J Wong, CCM Zhang, L Chan, RLY Wang, XJ Ng, SSM Chiu, LCM Marquez, VE Gallo, RL Chan, FKL Yu, J Sung, JJY Wu, WKK Cho, CH AF Ren, Shun X. Cheng, Alfred S. L. To, Ka F. Tong, Joanna H. M. Li, May S. Shen, Jin Wong, Clover C. M. Zhang, Lin Chan, Ruby L. Y. Wang, Xiao J. Ng, Simon S. M. Chiu, Lawrence C. M. Marquez, Victor E. Gallo, Richard L. Chan, Francis K. L. Yu, Jun Sung, Joseph J. Y. Wu, William K. K. Cho, Chi H. TI Host Immune Defense Peptide LL-37 Activates Caspase-Independent Apoptosis and Suppresses Colon Cancer SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR RECEPTOR; ANTIMICROBIAL PEPTIDE; CATHELICIDIN PEPTIDE; EPITHELIAL-CELLS; ENDONUCLEASE-G; BREAST-CANCER; P53 TARGETS; BAX; DEATH; LL-37/HCAP-18 AB Cathelicidins are a family of bacteriocidal polypeptides secreted by macrophages and polymorphonuclear leukocytes (PMN). LL-37, the only human cathelicidin, has been implicated in tumorigenesis, but there has been limited investigation of its expression and function in cancer. Here, we report that LL-37 activates a p53-mediated, caspase-independent apoptotic cascade that contributes to suppression of colon cancer. LL-37 was expressed strongly in normal colon mucosa but downregulated in colon cancer tissues, where in both settings its expression correlated with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells. Exposure of colon cancer cells to LL-37 induced phosphatidylserine externalization and DNA fragmentation in a manner independent of caspase activation. Apoptogenic function was mediated by nuclear translocation of the proapoptotic factors, apoptosis-inducing factor (AIF) and endonuclease G (EndoG), through p53-dependent upregulation of Bax and Bak and downregulation of Bcl-2 via a pertussis toxin-sensitive G-protein-coupled receptor (GPCR) pathway. Correspondingly, colonic mucosa of cathelicidin-deficient mice exhibited reduced expression of p53, Bax, and Bak and increased expression of Bcl-2 together with a lower basal level of apoptosis. Cathelicidin-deficient mice exhibited an increased susceptibility to azoxymethane-induced colon tumorigenesis, establishing pathophysiologic relevance in colon cancer. Collectively, our findings show that LL-37 activates a GPCR-p53-Bax/Bak/Bcl-2 signaling cascade that triggers AIF/EndoG-mediated apoptosis in colon cancer cells. Cancer Res; 72(24); 6512-23. (c) 2012 AACR. C1 [Ren, Shun X.; Shen, Jin; Wong, Clover C. M.; Zhang, Lin; Chan, Ruby L. Y.; Cho, Chi H.] Chinese Univ Hong Kong, Sch Biomed Sci, Hong Kong, Hong Kong, Peoples R China. [Cheng, Alfred S. L.; To, Ka F.; Li, May S.; Wang, Xiao J.; Chan, Francis K. L.; Yu, Jun; Sung, Joseph J. Y.; Wu, William K. K.; Cho, Chi H.] Chinese Univ Hong Kong, Inst Digest Dis, LKS Inst Hlth, Hong Kong, Hong Kong, Peoples R China. [Cheng, Alfred S. L.; To, Ka F.; Li, May S.; Wang, Xiao J.; Chan, Francis K. L.; Yu, Jun; Sung, Joseph J. Y.; Wu, William K. K.; Cho, Chi H.] Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Hong Kong, Peoples R China. [To, Ka F.; Tong, Joanna H. M.] Chinese Univ Hong Kong, Dept Anat & Cellular Pathol, Hong Kong, Hong Kong, Peoples R China. [Ng, Simon S. M.] Chinese Univ Hong Kong, Dept Surg, Hong Kong, Hong Kong, Peoples R China. [Chiu, Lawrence C. M.] Chinese Univ Hong Kong, Sch Life Sci, Hong Kong, Hong Kong, Peoples R China. [Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Gallo, Richard L.] Univ Calif San Diego, Div Dermatol, San Diego, CA 92103 USA. RP Wu, WKK (reprint author), Chinese Univ Hong Kong, Prince Wales Hosp, Room 701,LKS Med Sci Bldg, Hong Kong, Hong Kong, Peoples R China. EM wukakei@cuhk.edu.hk RI Wu, William K.K./A-3277-2009; Tong, Joanna/J-9327-2013; Cheng, Alfred/C-3327-2014; Yu, Jun /D-8569-2015; ZHANG , Lin/O-9109-2015; Cho, Chi Hin/C-6543-2014; Chan, Francis K. L./F-4851-2010; OI Wu, William K.K./0000-0002-5662-5240; Cheng, Alfred/0000-0003-2345-6951; Cho, Chi Hin/0000-0002-7658-3260; Chan, Francis K. L./0000-0001-7388-2436; Gallo, Richard/0000-0002-1401-7861 FU CUHK Group Research Scheme [3110043]; CUHK Focused Investments Scheme-Sheme C FX This work was supported by research grant from the CUHK Group Research Scheme (3110043) and CUHK Focused Investments Scheme-Sheme C. NR 44 TC 28 Z9 32 U1 1 U2 22 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 DEC 15 PY 2012 VL 72 IS 24 BP 6512 EP 6523 DI 10.1158/0008-5472.CAN-12-2359 PG 12 WC Oncology SC Oncology GA 057VJ UT WOS:000312591900021 PM 23100468 ER PT J AU Suehara, Y Arcila, M Wang, L Hasanovic, A Ang, D Ito, T Kimura, Y Drilon, A Guha, U Rusch, V Kris, MG Zakowski, MF Rizvi, N Khanin, R Ladanyi, M AF Suehara, Yoshiyuki Arcila, Maria Wang, Lu Hasanovic, Adnan Ang, Daphne Ito, Tatsuo Kimura, Yuki Drilon, Alexander Guha, Udayan Rusch, Valerie Kris, Mark G. Zakowski, Maureen F. Rizvi, Naiyer Khanin, Raya Ladanyi, Marc TI Identification of KIF5B-RET and GOPC-ROS1 Fusions in Lung Adenocarcinomas through a Comprehensive mRNA-Based Screen for Tyrosine Kinase Fusions SO CLINICAL CANCER RESEARCH LA English DT Article ID ATOMIC-BOMB SURVIVORS; THYROID-CANCER; PHASE-II; RET; MUTATIONS; REARRANGEMENTS; RADIATION; GENE; GENOME; ALK AB Background: The mutually exclusive pattern of the major driver oncogenes in lung cancer suggests that other mutually exclusive oncogenes exist. We conducted a systematic search for tyrosine kinase fusions by screening all tyrosine kinases for aberrantly high RNA expression levels of the 3' kinase domain (KD) exons relative to more 5' exons. Methods: We studied 69 patients (including five never smokers and 64 current or former smokers) with lung adenocarcinoma negative for all major mutations inKRAS, EGFR, BRAF, MEK1, HER2, and for ALK fusions (termed "pan-negative"). A NanoString-based assay was designed to query the transcripts of 90 tyrosine kinases at two points: 5' to the KD and within the KD or 3' to it. Tumor RNAs were hybridized to the NanoString probes and analyzed for outlier 3' to 5' expression ratios. Presumed novel fusion events were studied by rapid amplification of cDNA ends (RACE) and confirmatory reverse transcriptase PCR (RT-PCR) and FISH. Results: We identified one case each of aberrant 3' to 5' ratios in ROS1 and RET. RACE isolated a GOPC-ROS1 (FIG-ROS1) fusion in the former and a KIF5B-RET fusion in the latter, both confirmed by RT-PCR. The RET rearrangement was also confirmed by FISH. The KIF5B-RET patient was one of only five never smokers in this cohort. Conclusion: The KIF5B-RET fusion defines an additional subset of lung cancer with a potentially targetable driver oncogene enriched in never smokers with "pan-negative" lung adenocarcinomas. We also report in lung cancer the GOPC-ROS1 fusion originally discovered and characterized in a glioma cell line. Clin Cancer Res; 18(24); 6599-608. (C)2012 AACR. C1 [Suehara, Yoshiyuki; Arcila, Maria; Wang, Lu; Hasanovic, Adnan; Ang, Daphne; Ito, Tatsuo; Kimura, Yuki; Zakowski, Maureen F.; Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10065 USA. [Drilon, Alexander; Kris, Mark G.; Rizvi, Naiyer] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10065 USA. [Rusch, Valerie] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA. [Khanin, Raya] Mem Sloan Kettering Canc Ctr, Dept Bioinformat Core, New York, NY 10065 USA. [Ladanyi, Marc] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA. [Guha, Udayan] NCI, Bethesda, MD 20892 USA. RP Ladanyi, M (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pathol, 1275 York Ave, New York, NY 10065 USA. EM ladanyim@mskcc.org OI Kris, Mark/0000-0002-7317-5341 FU NIH [P01 CA129243]; Uniting Against Lung Cancer; International Association for the Study of Lung Cancer Fellowship; Pfizer, Inc.; Boehringer Ingelheim FX The study was supported by NIH P01 CA129243 (to M. Ladanyi and M.G. Kris), Uniting Against Lung Cancer (to M. Ladanyi), and an International Association for the Study of Lung Cancer Fellowship (to A. Drilon).; M.G. Kris has a commercial research grant from Pfizer, Inc. and Boehringer Ingelheim and is a consultant/advisory board member for Pfizer, Inc. M. Ladanyi has been a consultant/advisory board member for NanoString Technologies, Inc. No potential conflicts of interest were disclosed by the other authors. NR 38 TC 66 Z9 68 U1 0 U2 14 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 DEC 15 PY 2012 VL 18 IS 24 BP 6599 EP 6608 DI 10.1158/1078-0432.CCR-12-0838 PG 10 WC Oncology SC Oncology GA 057RC UT WOS:000312580600005 PM 23052255 ER PT J AU Duru, N Fan, M Candas, D Menaa, C Liu, HC Nantajit, D Wen, YF Xiao, K Eldridge, A Chromy, BA Li, SY Spitz, DR Lam, KS Wicha, MS Li, JJ AF Duru, Nadire Fan, Ming Candas, Demet Menaa, Cheikh Liu, Hsin-Chen Nantajit, Danupon Wen, Yunfei Xiao, Kai Eldridge, Angela Chromy, Brett A. Li, Shiyong Spitz, Douglas R. Lam, Kit S. Wicha, Max S. Li, Jian Jian TI HER2-Associated Radioresistance of Breast Cancer Stem Cells Isolated from HER2-Negative Breast Cancer Cells SO CLINICAL CANCER RESEARCH LA English DT Article ID ESTROGEN-RECEPTOR; DNA-REPAIR; INITIATING CELLS; RESISTANCE; ACTIVATION; RADIATION; TRASTUZUMAB; EXPRESSION; HER2; THERAPY AB Purpose: To understand the role of HER2-associated signaling network in breast cancer stem cells (BCSC) using radioresistant breast cancer cells and clinical recurrent breast cancers to evaluate HER2-targeted therapy as a tumor eliminating strategy for recurrent HER2(-/low) breast cancers. Experimental Design: HER2-expressing BCSCs (HER2(+)/CD44(+)/CD24(-/low)) were isolated from radiation-treated breast cancer MCF7 cells and in vivo irradiated MCF7 xenograft tumors. Tumor aggressiveness and radioresistance were analyzed by gap filling, Matrigel invasion, tumor-sphere formation, and clonogenic survival assays. The HER2/CD44 feature was analyzed in 40 primary and recurrent breast cancer specimens. Protein expression profiling in HER2(+)/CD44(+)/CD24(-/low) versus HER2(-)/CD44(+)/CD24(-/low) BCSCs was conducted with two-dimensional difference gel electrophoresis (2-D DIGE) and high-performance liquid chromatography tandem mass spectrometry (HPLC/MS-MS) analysis and HER2-mediated signaling network was generated by MetaCore program. Results: Compared with HER2-negative BCSCs, HER2(+)/CD44(+)/CD24(-/low) cells showed elevated aldehyde dehydrogenase (ALDH) activity and aggressiveness tested by Matrigel invasion, tumor sphere formation, and in vivo tumorigenesis. The enhanced aggressive phenotype and radioresistance of the HER2(+)/CD44(+)/CD24(-/low) cells were markedly reduced by inhibition of HER2 via siRNA or Herceptin treatments. Clinical breast cancer specimens revealed that cells coexpressing HER2 and CD44 were more frequently detected in recurrent (84.6%) than primary tumors (57.1%). In addition, 2-D DIGE and HPLC/ MS-MS of HER2(-)/CD44(+)/CD24(-/low) versus HER2(+)/CD44(+)/CD24(-/low) BCSCs reported a unique HER2-associated protein profile including effectors involved in tumor metastasis, apoptosis, mitochondrial function, and DNA repair. A specific feature of HER2-STAT3 network was identified. Conclusion: This study provides the evidence that HER2-mediated prosurvival signaling network is responsible for the aggressive phenotype of BCSCs that could be targeted to control the therapy-resistant HER2(-/low) breast cancer. Clin Cancer Res; 18(24); 6634-47.+ 2012 AACR. C1 [Duru, Nadire; Fan, Ming; Candas, Demet; Menaa, Cheikh; Liu, Hsin-Chen; Nantajit, Danupon; Eldridge, Angela] Univ Calif Davis, Sch Med, Dept Radiat Oncol, Sacramento, CA 95817 USA. [Xiao, Kai; Lam, Kit S.] Univ Calif Davis, Sch Med, Dept Biochem & Mol Med, Sacramento, CA 95817 USA. [Eldridge, Angela; Chromy, Brett A.] Univ Calif Davis, Sch Med, Dept Pathol & Lab Med, Sacramento, CA 95817 USA. [Lam, Kit S.; Li, Jian Jian] Univ Calif Davis, NCI, Designated Comprehens Canc Ctr, Sacramento, CA 95817 USA. [Chromy, Brett A.] Lawrence Livermore Natl Lab, Phys & Life Sci Directorate, Livermore, CA USA. [Wen, Yunfei] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Li, Shiyong] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Spitz, Douglas R.] Univ Iowa, Free Rad & Radiat Biol Program, Dept Radiat Oncol, Holden Comprehens Canc Ctr, Iowa City, IA USA. [Wicha, Max S.] Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. RP Li, JJ (reprint author), Univ Calif Davis, Sch Med, Dept Radiat Oncol, 1136 Oak Pk Bldg,2700 Stockton Blvd, Sacramento, CA 95817 USA. EM jian-jian.li@ucdmc.ucdavis.edu FU NIH [CA133402, CA152313, CA133114]; Department of Energy Office of Science [DE-SC0001271] FX This work was supported by NIH grants CA133402, CA152313 (to J.J. Li), and CA133114 (to D.R. Spitz) as well as the Department of Energy Office of Science Grant DE-SC0001271 (to J.J. Li). NR 52 TC 54 Z9 55 U1 0 U2 34 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 DEC 15 PY 2012 VL 18 IS 24 BP 6634 EP 6647 DI 10.1158/1078-0432.CCR-12-1436 PG 14 WC Oncology SC Oncology GA 057RC UT WOS:000312580600008 PM 23091114 ER PT J AU Solomon, SB Bellavia, L Sweeney, D Piknova, B Perlegas, A Helms, CC Ferreyra, GA King, SB Raat, NJH Kern, SJ Sun, JF McPhail, LC Schechter, AN Natanson, C Gladwin, MT Kim-Shapiro, DB AF Solomon, Steven B. Bellavia, Landon Sweeney, Daniel Piknova, Barbora Perlegas, Andreas Helms, Christine C. Ferreyra, Gabriela A. King, S. Bruce Raat, Nicolaas J. H. Kern, Steven J. Sun, Junfeng McPhail, Linda C. Schechter, Alan N. Natanson, Charles Gladwin, Mark T. Kim-Shapiro, Daniel B. TI Angeli's salt counteracts the vasoactive effects of elevated plasma hemoglobin SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE Angeli's salt; Cell-free hemoglobin; Methemoglobin; Nitroxyl; Free radicals ID SICKLE-CELL-DISEASE; NITRIC-OXIDE UPTAKE; RED-BLOOD-CELLS; PULMONARY-HYPERTENSION; STORAGE LESION; RELAXING FACTOR; HUMAN-PLATELETS; NITROXYL; NO; SUBSTITUTES AB Plasma hemoglobin (Hb) released during intravascular hemolysis has been associated with numerous deleterious effects that may stem from increased nitric oxide (NO) scavenging, but has also been associated with reactive oxygen species generation and platelet activation. Therapies that convert plasma oxyHb to metHb, or metHb to iron-nitrosyl Hb, could be beneficial because these species do not scavenge NO. In this study, we investigated the effects of Angeli's salt (AS; sodium a-oxyhyponitrite, Na2N2O3), a nitroxyl (HNO) and nitrite (NO2-) donor, on plasma Hb oxidation and formation of iron-nitrosyl Hb from metHb and on the vasoactivity of plasma Hb. We hypothesized that AS could ameliorate hemolysis-associated pathology via its preferential reactivity with plasma Hb, as opposed to red-cell-encapsulated Hb, and through its intrinsic vasodilatory activity. To test this hypothesis, we infused (n=3 per group) (1) cell-free Hb and AS, (2) cell-free Hb+0.9% NaCl, (3) AS+3% albumin, and (4) 3% albumin + 0.9% NaCl (colloid controls for Hb and AS, respectively) in a canine model. Co-infusion of AS and cell-free Hb led to preferential conversion of plasma Hb to metHb, but the extent of conversion was lower than anticipated based on the in vivo concentration of AS relative to plasma Hb. This lower metHb yield was probably due to reactions of nitroxyl-derived AS with plasma components such as thiol-containing compounds. From a physiological and therapeutic standpoint, the infusion of Hb alone led to significant increases in mean arterial pressure (p=0.03) and systemic vascular resistance index (p=0.01) compared to controls. Infusion of AS alone led to significant decreases in these parameters and co-infusion of AS along with Hb had an additive effect in reversing the effects of Hb alone on the systemic circulation. Interestingly, in the pulmonary system, the decrease in pressure when AS was added to Hb was significantly less than would have been expected compared to the effects of Hb and AS alone, suggesting that inactivation of scavenging with AS reduced the direct vasodilatory effects of AS on the vasculature. We also found that AS reduced platelet activation when administered to whole blood in vitro. These data suggest that AS-like compounds could serve as therapeutic agents to counteract the negative vasoconstrictive consequences of hemolysis that occur in hemolytic anemias, transfusion of stored blood, and other diseases. Increases in metHb in the red blood cell, the potential of AS for neurotoxicity, and hypotension would need to be carefully monitored in a clinical trial. Published by Elsevier Inc. C1 [Solomon, Steven B.; Sweeney, Daniel; Ferreyra, Gabriela A.; Kern, Steven J.; Sun, Junfeng; Natanson, Charles] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Bellavia, Landon; Perlegas, Andreas; Helms, Christine C.; Kim-Shapiro, Daniel B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. [King, S. Bruce] Wake Forest Univ, Dept Chem, Winston Salem, NC 27109 USA. [Helms, Christine C.; Kim-Shapiro, Daniel B.] Wake Forest Univ, Translat Sci Ctr, Winston Salem, NC 27109 USA. [Piknova, Barbora; Schechter, Alan N.] NIDDKD, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Raat, Nicolaas J. H.; Gladwin, Mark T.] Univ Pittsburgh, Sch Med, Dept Med, Div Pulm Allergy & Crit Care Med, Pittsburgh, PA 15213 USA. [Raat, Nicolaas J. H.; Gladwin, Mark T.] Univ Pittsburgh, Sch Med, Vasc Med Inst, Dept Med, Pittsburgh, PA 15213 USA. [McPhail, Linda C.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27157 USA. RP Solomon, SB (reprint author), NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. EM ssolomon@cc.nih.gov; shapiro@wfu.edu RI McPhail, Linda/D-9505-2013; OI McPhail, Linda/0000-0002-8670-306X; Schechter, Alan N/0000-0002-5235-9408 FU NIH [HL058091, HL098032] FX The authors are grateful for the assistance of Ms. Jing Feng, Mr. Alan Hilton, and Dr. Melinda Fernandez in the performance of this study and data handling and graphing. S.B.K., D.S., D.K.-S., and M.T.G. are listed as coauthors on a patent application for methods of treating hemolysis. This work was supported by NIH Grants HL058091 and HL098032. NR 58 TC 8 Z9 8 U1 1 U2 15 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD DEC 15 PY 2012 VL 53 IS 12 BP 2229 EP 2239 DI 10.1016/j.freeradbiomed.2012.10.548 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 056UU UT WOS:000312517700004 PM 23099417 ER PT J AU Jin, M Yu, Y Qi, HB Xie, YL Su, N Wang, XF Tan, QY Luo, FT Zhu, Y Wang, Q Du, XL Xian, CJ Liu, P Huang, HY Shen, Y Deng, CX Chen, D Chen, L AF Jin, Min Yu, Ying Qi, Huabing Xie, Yangli Su, Nan Wang, Xiaofeng Tan, Qiaoyan Luo, Fengtao Zhu, Ying Wang, Quan Du, Xiaolan Xian, Cory J. Liu, Peng Huang, Haiyang Shen, Yue Deng, Chu-Xia Chen, Di Chen, Lin TI A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia SO HUMAN MOLECULAR GENETICS LA English DT Article ID GROWTH-FACTOR RECEPTOR-3; ACTIVATING MUTATIONS; MULTIPLE-MYELOMA; BONE-DEVELOPMENT; ATDC5 CELLS; CHONDROGENIC DIFFERENTIATION; CHONDROCYTE PROLIFERATION; HORMONE TREATMENT; ACHONDROPLASIA; DWARFISM AB Gain-of-function mutations in fibroblast growth factor receptor-3 (FGFR3) lead to several types of human skeletal dysplasia syndromes including achondroplasia, hypochondroplasia and thanatophoric dysplasia (TD). Currently, there are no effective treatments for these skeletal dysplasia diseases. In this study, we screened, using FGFR3 as a bait, a random 12-peptide phage library and obtained 23 positive clones that share identical amino acid sequences (VSPPLTLGQLLS), named as peptide P3. This peptide had high binding specificity to the extracellular domain of FGFR3. P3 inhibited tyrosine kinase activity of FGFR3 and its typical downstream molecules, extracellular signal-regulated kinase/mitogen-activated protein kinase. P3 also promoted proliferation and chondrogenic differentiation of cultured ATDC5 chondrogenic cells. In addition, P3 alleviated the bone growth retardation in bone rudiments from mice mimicking human thanatophoric dysplasia type II (TDII). Finally, P3 reversed the neonatal lethality of TDII mice. Thus, this study identifies a novel inhibitory peptide for FGFR3 signaling, which may serve as a potential therapeutic agent for the treatment of FGFR3-related skeletal dysplasia. C1 [Jin, Min; Qi, Huabing; Xie, Yangli; Su, Nan; Wang, Xiaofeng; Tan, Qiaoyan; Luo, Fengtao; Zhu, Ying; Wang, Quan; Du, Xiaolan; Liu, Peng; Huang, Haiyang; Shen, Yue; Chen, Lin] Third Mil Med Univ, State Key Lab Trauma Burns & Combined Injury, Inst Surg Res, Ctr Bone Metab & Repair,Daping Hosp, Chongqing 400042, Peoples R China. [Yu, Ying] Chongqing Univ Technol, Sch Pharm & Bioengn, Chongqing 400050, Peoples R China. [Xian, Cory J.] Univ S Australia, Sch Pharm & Med Sci, Sansom Inst Hlth Res, Adelaide, SA 5001, Australia. [Deng, Chu-Xia] NIDDKD, Genet Dev & Dis Branch, US Natl Inst Hlth, Bethesda, MD 20892 USA. [Chen, Di] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA. RP Chen, L (reprint author), Third Mil Med Univ, State Key Lab Trauma Burns & Combined Injury, Inst Surg Res, Ctr Bone Metab & Repair,Daping Hosp, Chongqing 400042, Peoples R China. EM linchen70@163.com RI Xian, Cory/D-2646-2009; deng, chuxia/N-6713-2016 OI Xian, Cory/0000-0002-8467-2845; FU National Natural Science Foundation of China [81001390, 81030036, 30971607, 81170809, SKLZZ201017]; Special Funds for Major State Basic Research Program of China (973 Program) [2012CB518106, 2011CB964701] FX The work was supported by National Natural Science Foundation of China (No. 81001390, No. 81030036, No. 30971607, No. 81170809, No. SKLZZ201017), the Special Funds for Major State Basic Research Program of China (973 Program) (No. 2012CB518106, No. 2011CB964701). NR 59 TC 18 Z9 19 U1 0 U2 15 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 DEC 15 PY 2012 VL 21 IS 26 BP 5443 EP 5455 DI 10.1093/hmg/dds390 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 056QC UT WOS:000312505000005 PM 23014564 ER PT J AU Foy, RL Chitalia, VC Panchenko, MV Zeng, LL Lopez, D Lee, JW Rana, SV Boletta, A Qian, F Tsiokas, L Piontek, KB Germino, GG Zhou, MNI Cohen, HT AF Foy, Rebecca L. Chitalia, Vipul C. Panchenko, Maria V. Zeng, Liling Lopez, Delia Lee, Jean W. Rana, Shaunak V. Boletta, Alessandra Qian, Feng Tsiokas, Leonidas Piontek, Klaus B. Germino, Gregory G. Zhou, Mina I. Cohen, Herbert T. TI Polycystin-1 regulates the stability and ubiquitination of transcription factor Jade-1 SO HUMAN MOLECULAR GENETICS LA English DT Article ID TUMOR-SUPPRESSOR GENE; KIDNEY-DISEASE; BETA-CATENIN; PKD1 GENE; EPITHELIAL-CELLS; ACETYLTRANSFERASE ACTIVITY; PROTEASOME PATHWAY; CYST FORMATION; IN-VIVO; PROTEIN AB Autosomal-dominant polycystic kidney disease (ADPKD) and von Hippel-Lindau (VHL) disease lead to large kidney cysts that share pathogenetic features. The polycystin-1 (PC1) and pVHL proteins may therefore participate in the same key signaling pathways. Jade-1 is a pro-apoptotic and growth suppressive ubiquitin ligase for beta-catenin and transcriptional coactivator associated with histone acetyltransferase activity that is stabilized by pVHL in a manner that correlates with risk of VHL renal disease. Thus, a relationship between Jade-1 and PC1 was sought. Full-length PC1 bound, stabilized and colocalized with Jade-1 and inhibited Jade-1 ubiquitination. In contrast, the cytoplasmic tail or the naturally occurring C-terminal fragment of PC1 (PC1-CTF) promoted Jade-1 ubiquitination and degradation, suggesting a dominant-negative mechanism. ADPKD-associated PC1 mutants failed to regulate Jade-1, indicating a potential disease link. Jade-1 ubiquitination was mediated by Siah-1, an E3 ligase that binds PC1. By controlling Jade-1 abundance, PC1 and the PC1-CTF differentially regulate Jade-1-mediated transcriptional activity. A key target of PC1, the cyclin-dependent kinase inhibitor p21, is also up-regulated by Jade-1. Through Jade-1, PC1 and PC1 cleaved forms may exert fine control of beta-catenin and canonical Wnt signaling, a critical pathway in cystic renal disease. Thus, Jade-1 is a transcription factor and ubiquitin ligase whose activity is regulated by PC1 in a manner that is physiologic and may correlate with disease. Jade-1 may be an important therapeutic target in renal cystogenesis. C1 [Foy, Rebecca L.; Chitalia, Vipul C.; Panchenko, Maria V.; Zeng, Liling; Lopez, Delia; Lee, Jean W.; Rana, Shaunak V.; Zhou, Mina I.; Cohen, Herbert T.] Boston Univ, Med Ctr, Renal Sect, Boston, MA 02118 USA. [Boletta, Alessandra] Ist Sci San Raffaele, Dulbecco Telethon Inst Dibit, I-20132 Milan, Italy. [Qian, Feng; Piontek, Klaus B.] Johns Hopkins Sch Med, Div Nephrol, Baltimore, MD USA. [Tsiokas, Leonidas] Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, Oklahoma City, OK USA. [Germino, Gregory G.] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Cohen, HT (reprint author), Boston Med Ctr, Renal Sect, Rm X-535,650 Albany St, Boston, MA 02118 USA. EM htcohen@bu.edu OI Chitalia, Vipul/0000-0002-6663-6058; Panchenko, Maria/0000-0001-6247-6598; Cohen, Herbert/0000-0003-1900-8718; Germino, Gregory/0000-0002-3609-5588 FU National Institutes of Health [R01 DK067569, R01 CA079830, T32 DK07053]; National Kidney Foundation; Polycystic Kidney Disease Foundation; Mouse Genetics and Cell Line Core of the George M O'Brien Kidney Center at Yale [P30 DK079310]; Fondazione Telethon FX This work was supported by National Institutes of Health grants to H. T. C. (R01 DK067569 and R01 CA079830), National Institutes of Health training grant for R. L. F. (T32 DK07053), and fellowship grants from the National Kidney Foundation and Polycystic Kidney Disease Foundation to V. C. C. PH and PN cells were provided by the Mouse Genetics and Cell Line Core of the George M O'Brien Kidney Center at Yale (grant P30 DK079310). NR 75 TC 6 Z9 6 U1 1 U2 2 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 DEC 15 PY 2012 VL 21 IS 26 BP 5456 EP 5471 DI 10.1093/hmg/dds391 PG 16 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 056QC UT WOS:000312505000006 PM 23001567 ER PT J AU Hekman, KE Yu, GY Brown, CD Zhu, HP Du, XF Gervin, K Undlien, DE Peterson, A Stevanin, G Clark, HB Pulst, SM Bird, TD White, KP Gomez, CM AF Hekman, Katherine E. Yu, Guo-Yun Brown, Christopher D. Zhu, Haipeng Du, Xiaofei Gervin, Kristina Undlien, Dag Erik Peterson, April Stevanin, Giovanni Clark, H. Brent Pulst, Stefan M. Bird, Thomas D. White, Kevin P. Gomez, Christopher M. TI A conserved eEF2 coding variant in SCA26 leads to loss of translational fidelity and increased susceptibility to proteostatic insult SO HUMAN MOLECULAR GENETICS LA English DT Article ID SPINOCEREBELLAR ATAXIA TYPE-14; UNFOLDED PROTEIN RESPONSE; KINASE-C-GAMMA; ELONGATION FACTOR-II; SACCHAROMYCES-CEREVISIAE; DIPHTHERIA-TOXIN; NEURODEGENERATIVE DISEASE; MOLECULAR PATHOGENESIS; SPECTRIN MUTATIONS; REPEAT EXPANSION AB The autosomal dominant spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of disorders exhibiting cerebellar atrophy and Purkinje cell degeneration whose subtypes arise from 31 distinct genetic loci. Our group previously published the locus for SCA26 on chromosome 19p13.3. In this study, we performed targeted deep sequencing of the critical interval in order to identify candidate causative variants in individuals from the SCA26 family. We identified a single variant that co-segregates with the disease phenotype that produces a single amino acid substitution in eukaryotic elongation factor 2. This substitution, P596H, sits in a domain critical for maintaining reading frame during translation. The yeast equivalent, P580H EF2, demonstrated impaired translocation, detected as an increased rate of 1 programmed ribosomal frameshift read-through in a dual-luciferase assay for observing translational recoding. This substitution also results in a greater susceptibility to proteostatic disruption, as evidenced by a more robust activation of a reporter gene driven by unfolded protein response activation upon challenge with dithiothreitol or heat shock in our yeast model system. Our results present a compelling candidate mutation and mechanism for the pathogenesis of SCA26 and further support the role of proteostatic disruption in neurodegenerative diseases. C1 [Hekman, Katherine E.; Zhu, Haipeng; Du, Xiaofei; Gomez, Christopher M.] Univ Chicago, Dept Neurol, Inst Genom & Syst Biol, Chicago, IL 60637 USA. [Brown, Christopher D.; Peterson, April; White, Kevin P.] Univ Chicago, Dept Human Genet, Inst Genom & Syst Biol, Chicago, IL 60637 USA. [Yu, Guo-Yun] SAIC Frederick Inc, NCI Frederick, Frederick, MD USA. [Yu, Guo-Yun] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Gervin, Kristina; Undlien, Dag Erik] Univ Oslo, Oslo, Norway. [Gervin, Kristina; Undlien, Dag Erik] Oslo Univ Hosp, Dept Med Genet, Oslo, Norway. [Stevanin, Giovanni] Univ Paris 06, Inst Cerveau & Moelle Epiniere, Hop Pitie Salpetriere, CNRS 7225,UMR S 975,EPHE,INSERM,Ctr Rech, Paris, France. [Clark, H. Brent] Univ Minnesota, Dept Lab Med & Pathol Neurol & Neurosurg, Minneapolis, MN 55455 USA. [Pulst, Stefan M.] Univ Utah, Dept Neurol, Salt Lake City, UT 84132 USA. [Bird, Thomas D.] Univ Washington, Dept Neurol, Geriatr Res Ctr, VA Med Ctr, Seattle, WA 98195 USA. RP Gomez, CM (reprint author), Univ Chicago, Dept Neurol, Inst Genom & Syst Biol, 5841 S Maryland Ave, Chicago, IL 60637 USA. EM cgomez@neurology.bsd.uchicago.edu RI Stevanin, Giovanni/E-5038-2016; OI Stevanin, Giovanni/0000-0001-9368-8657 FU Lilly-Life Sciences Research Foundation fellowship; Graduate Training in Growth and Development program at the University of Chicago [T32 HD009007]; Bob Allison Ataxia Research Center; National Ataxia Foundation; Verum Foundation; 'Association Connaitre les Syndromes Cerebelleux' (France); European Union (6th PCRD call: EUROSCA); CTSA [UL1 TR000430]; NIH [R03-NS52582] FX C.D.B. was supported by a Lilly-Life Sciences Research Foundation fellowship. K. E. H. was supported by the Graduate Training in Growth and Development program at the University of Chicago (T32 HD009007). G.-Y.Y. was supported by the Bob Allison Ataxia Research Center and the National Ataxia Foundation. This work was supported financially by the Verum Foundation, the 'Association Connaitre les Syndromes Cerebelleux' (France) and the European Union (6th PCRD call: EUROSCA), CTSA UL1 TR000430, and by NIH (R03-NS52582). NR 94 TC 18 Z9 20 U1 0 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 DEC 15 PY 2012 VL 21 IS 26 BP 5472 EP 5483 DI 10.1093/hmg/dds392 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 056QC UT WOS:000312505000007 PM 23001565 ER PT J AU Lozano, R Naghavi, M Foreman, K Lim, S Shibuya, K Aboyans, V Abraham, J Adair, T Aggarwal, R Ahn, SY Alvarado, M Anderson, HR Anderson, LM Andrews, KG Atkinson, C Baddour, LM Barker-Collo, S Bartels, DH Bell, ML Benjamin, EJ Bennett, D Bhalla, K Bikbov, B Bin Abdulhak, A Birbeck, G Blyth, F Bolliger, I Boufous, SA Bucello, C Burch, M Burney, P Carapetis, J Chen, HL Chou, D Chugh, SS Coffeng, LE Colan, SD Colquhoun, S Colson, KE Condon, J Connor, MD Cooper, LT Corriere, M Cortinovis, M de Vaccaro, KC Couser, W Cowie, BC Criqui, MH Cross, M Dabhadkar, KC Dahodwala, N De Leo, D Degenhardt, L Delossantos, A Denenberg, J Des Jarlais, DC Dharmaratne, SD Dorsey, ER Driscoll, T Duber, H Ebel, B Erwin, PJ Espindola, P Ezzati, M Feigin, V Flaxman, AD Forouzanfar, MH Fowkes, FGR Franklin, R Fransen, M Freeman, MK Gabriel, SE Gakidou, E Gaspari, F Gillum, RF Gonzalez-Medina, D Halasa, YA Haring, D Harrison, JE Havmoeller, R Hay, RJ Hoen, B Hotez, PJ Hoy, D Jacobsen, KH James, SL Jasrasaria, R Jayaraman, S Johns, N Karthikeyan, G Kassebaum, N Keren, A Khoo, JP Knowlton, LM Kobusingye, O Koranteng, A Krishnamurthi, R Lipnick, M Lipshultz, SE Ohno, SL Mabweijano, J MacIntyre, MF Mallinger, L March, L Marks, GB Marks, R Matsumori, A Matzopoulos, R Mayosi, BM McAnulty, JH McDermott, MM McGrath, J Mensah, GA Merriman, TR Michaud, C Miller, M Miller, TR Mock, C Mocumbi, AO Mokdad, AA Moran, A Mulholland, K Nair, MN Naldi, L Narayan, KMV Nasseri, K Norman, P O'Donnell, M Omer, SB Ortblad, K Osborne, R Ozgediz, D Pahari, B Pandian, JD Rivero, AP Padilla, RP Perez-Ruiz, F Perico, N Phillips, D Pierce, K Pope, CA Porrini, E Pourmalek, F Raju, M Ranganathan, D Rehm, JT Rein, DB Remuzzi, G Rivara, FP Roberts, T De Leon, FR Rosenfeld, LC Rushton, L Sacco, RL Salomon, JA Sampson, U Sanman, E Schwebel, DC Segui-Gomez, M Shepard, DS Singh, D Singleton, J Sliwa, K Smith, E Steer, A Taylor, JA Thomas, B Tleyjeh, IM Towbin, JA Truelsen, T Undurraga, EA Venketasubramanian, N Vijayakumar, L Vos, T Wagner, GR Wang, MR Wang, WZ Watt, K Weinstock, MA Weintraub, R Wilkinson, JD Woolf, AD Wulf, S Yeh, PH Yip, P Zabetian, A Zheng, ZJ Lopez, AD Murray, CJL AF Lozano, Rafael Naghavi, Mohsen Foreman, Kyle Lim, Stephen Shibuya, Kenji Aboyans, Victor Abraham, Jerry Adair, Timothy Aggarwal, Rakesh Ahn, Stephanie Y. Alvarado, Miriam Anderson, H. Ross Anderson, Laurie M. Andrews, Kathryn G. Atkinson, Charles Baddour, Larry M. Barker-Collo, Suzanne Bartels, David H. Bell, Michelle L. Benjamin, Emelia J. Bennett, Derrick Bhalla, Kavi Bikbov, Boris Bin Abdulhak, Aref Birbeck, Gretchen Blyth, Fiona Bolliger, Ian Boufous, Soufi Ane Bucello, Chiara Burch, Michael Burney, Peter Carapetis, Jonathan Chen, Honglei Chou, David Chugh, Sumeet S. Coffeng, Luc E. Colan, Steven D. Colquhoun, Samantha Colson, K. Ellicott Condon, John Connor, Myles D. Cooper, Leslie T. Corriere, Matthew Cortinovis, Monica de Vaccaro, Karen Courville Couser, William Cowie, Benjamin C. Criqui, Michael H. Cross, Marita Dabhadkar, Kaustubh C. Dahodwala, Nabila De Leo, Diego Degenhardt, Louisa Delossantos, Allyne Denenberg, Julie Des Jarlais, Don C. Dharmaratne, Samath D. Dorsey, E. Ray Driscoll, Tim Duber, Herbert Ebel, Beth Erwin, Patricia J. Espindola, Patricia Ezzati, Majid Feigin, Valery Flaxman, Abraham D. Forouzanfar, Mohammad H. Fowkes, Francis Gerry R. Franklin, Richard Fransen, Marlene Freeman, Michael K. Gabriel, Sherine E. Gakidou, Emmanuela Gaspari, Flavio Gillum, Richard F. Gonzalez-Medina, Diego Halasa, Yara A. Haring, Diana Harrison, James E. Havmoeller, Rasmus Hay, Roderick J. Hoen, Bruno Hotez, Peter J. Hoy, Damian Jacobsen, Kathryn H. James, Spencer L. Jasrasaria, Rashmi Jayaraman, Sudha Johns, Nicole Karthikeyan, Ganesan Kassebaum, Nicholas Keren, Andre Khoo, Jon-Paul Knowlton, Lisa Marie Kobusingye, Olive Koranteng, Adofo Krishnamurthi, Rita Lipnick, Michael Lipshultz, Steven E. Ohno, Summer Lockett Mabweijano, Jacqueline MacIntyre, Michael F. Mallinger, Leslie March, Lyn Marks, Guy B. Marks, Robin Matsumori, Akira Matzopoulos, Richard Mayosi, Bongani M. McAnulty, John H. McDermott, Mary M. McGrath, John Mensah, George A. Merriman, Tony R. Michaud, Catherine Miller, Matthew Miller, Ted R. Mock, Charles Mocumbi, Ana Olga Mokdad, Ali A. Moran, Andrew Mulholland, Kim Nair, M. Nathan Naldi, Luigi Narayan, K. M. Venkat Nasseri, Kiumarss Norman, Paul O'Donnell, Martin Omer, Saad B. Ortblad, Katrina Osborne, Richard Ozgediz, Doruk Pahari, Bishnu Pandian, Jeyaraj Durai Rivero, Andrea Panozo Padilla, Rogelio Perez Perez-Ruiz, Fernando Perico, Norberto Phillips, David Pierce, Kelsey Pope, C. Arden, III Porrini, Esteban Pourmalek, Farshad Raju, Murugesan Ranganathan, Dharani Rehm, Juergen T. Rein, David B. Remuzzi, Guiseppe Rivara, Frederick P. Roberts, Thomas De Leon, Felipe Rodriguez Rosenfeld, Lisa C. Rushton, Lesley Sacco, Ralph L. Salomon, Joshua A. Sampson, Uchechukwu Sanman, Ella Schwebel, David C. Segui-Gomez, Maria Shepard, Donald S. Singh, David Singleton, Jessica Sliwa, Karen Smith, Emma Steer, Andrew Taylor, Jennifer A. Thomas, Bernadette Tleyjeh, Imad M. Towbin, Jeffrey A. Truelsen, Thomas Undurraga, Eduardo A. Venketasubramanian, N. Vijayakumar, Lakshmi Vos, Theo Wagner, Gregory R. Wang, Mengru Wang, Wenzhi Watt, Kerrianne Weinstock, Martin A. Weintraub, Robert Wilkinson, James D. Woolf, Anthony D. Wulf, Sarah Yeh, Pon-Hsiu Yip, Paul Zabetian, Azadeh Zheng, Zhi-Jie Lopez, Alan D. Murray, Christopher J. L. TI Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010 SO LANCET LA English DT Article ID COMMUNITY-ACQUIRED PNEUMONIA; DIAGNOSTIC GOLD STANDARDS; MILLENNIUM DEVELOPMENT GOALS; RESPIRATORY SYNCYTIAL VIRUS; PUBLIC-HEALTH UTILITY; MATERNAL MORTALITY; VERBAL AUTOPSY; NONCOMMUNICABLE DISEASES; CHILD-MORTALITY; NATIONAL CAUSES AB Background Reliable and timely information on the leading causes of death in populations, and how these are changing, is a crucial input into health policy debates. In the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010), we aimed to estimate annual deaths for the world and 21 regions between 1980 and 2010 for 235 causes, with uncertainty intervals (UIs), separately by age and sex. Methods We attempted to identify all available data on causes of death for 187 countries from 1980 to 2010 from vital registration, verbal autopsy, mortality surveillance, censuses, surveys, hospitals, police records, and mortuaries. We assessed data quality for completeness, diagnostic accuracy, missing data, stochastic variations, and probable causes of death. We applied six different modelling strategies to estimate cause-specific mortality trends depending on the strength of the data. For 133 causes and three special aggregates we used the Cause of Death Ensemble model (CODEm) approach, which uses four families of statistical models testing a large set of different models using different permutations of covariates. Model ensembles were developed from these component models. We assessed model performance with rigorous out-of-sample testing of prediction error and the validity of 95% UIs. For 13 causes with low observed numbers of deaths, we developed negative binomial models with plausible covariates. For 27 causes for which death is rare, we modelled the higher level cause in the cause hierarchy of the GBD 2010 and then allocated deaths across component causes proportionately, estimated from all available data in the database. For selected causes (African trypanosomiasis, congenital syphilis, whooping cough, measles, typhoid and parathyroid, leishmaniasis, acute hepatitis E, and HIV/AIDS), we used natural history models based on information on incidence, prevalence, and case-fatality. We separately estimated cause fractions by aetiology for diarrhoea, lower respiratory infections, and meningitis, as well as disaggregations by subcause for chronic kidney disease, maternal disorders, cirrhosis, and liver cancer. For deaths due to collective violence and natural disasters, we used mortality shock regressions. For every cause, we estimated 95% UIs that captured both parameter estimation uncertainty and uncertainty due to model specification where CODEm was used. We constrained cause-specific fractions within every age-sex group to sum to total mortality based on draws from the uncertainty distributions. Findings In 2010, there were 52.8 million deaths globally. At the most aggregate level, communicable, maternal, neonatal, and nutritional causes were 24.9% of deaths worldwide in 2010, down from 15.9 million (34.1%) of 46.5 million in 1990. This decrease was largely due to decreases in mortality from diarrhoeal disease (from 2.5 to 1.4 million), lower respiratory infections (from 3.4 to 2.8 million), neonatal disorders (from 3.1 to 2.2 million), measles (from 0.63 to 0.13 million), and tetanus (from 0.27 to 0.06 million). Deaths from HIV/AIDS increased from 0.30 million in 1990 to 1.5 million in 2010, reaching a peak of 1.7 million in 2006. Malaria mortality also rose by an estimated 19.9% since 1990 to 1.17 million deaths in 2010. Tuberculosis killed 1.2 million people in 2010. Deaths from non-communicable diseases rose by just under 8 million between 1990 and 2010, accounting for two of every three deaths (34.5 million) worldwide by 2010. 8 million people died from cancer in 2010, 38% more than two decades ago; of these, 1.5 million (19%) were from trachea, bronchus, and lung cancer. Ischaemic heart disease and stroke collectively killed 12.9 million people in 2010, or one in four deaths worldwide, compared with one in five in 1990; 1.3 million deaths were due to diabetes, twice as many as in 1990. The fraction of global deaths due to injuries (5.1 million deaths) was marginally higher in 2010 (9.6%) compared with two decades earlier (8.8%). This was driven by a 46% rise in deaths worldwide due to road traffic accidents (1.3 million in 2010) and a rise in deaths from falls. Ischaemic heart disease, stroke, chronic obstructive pulmonary disease (COPD), lower respiratory infections, lung cancer, and HIV/AIDS were the leading causes of death in 2010. Ischaemic heart disease, lower respiratory infections, stroke, diarrhoeal disease, malaria, and HIV/AIDS were the leading causes of years of life lost due to premature mortality (YLLs) in 2010, similar to what was estimated for 1990, except for HIV/AIDS and preterm birth complications. YLLs from lower respiratory infections and diarrhoea decreased by 45-54% since 1990; ischaemic heart disease and stroke YLLs increased by 17-28%. Regional variations in leading causes of death were substantial. Communicable, maternal, neonatal, and nutritional causes still accounted for 76% of premature mortality in sub-Saharan Africa in 2010. Age standardised death rates from some key disorders rose (HIV/AIDS, Alzheimer's disease, diabetes mellitus, and chronic kidney disease in particular), but for most diseases, death rates fell in the past two decades; including major vascular diseases, COPD, most forms of cancer, liver cirrhosis, and maternal disorders. For other conditions, notably malaria, prostate cancer, and injuries, little change was noted. Interpretation Population growth, increased average age of the world's population, and largely decreasing age-specific, sex-specific, and cause-specific death rates combine to drive a broad shift from communicable, maternal, neonatal, and nutritional causes towards non-communicable diseases. Nevertheless, communicable, maternal, neonatal, and nutritional causes remain the dominant causes of YLLs in sub-Saharan Africa. Overlaid on this general pattern of the epidemiological transition, marked regional variation exists in many causes, such as interpersonal violence, suicide, liver cancer, diabetes, cirrhosis, Chagas disease, African trypanosomiasis, melanoma, and others. Regional heterogeneity highlights the importance of sound epidemiological assessments of the causes of death on a regular basis. C1 [Lozano, Rafael; Naghavi, Mohsen; Lim, Stephen; Ahn, Stephanie Y.; Alvarado, Miriam; Andrews, Kathryn G.; Atkinson, Charles; Bolliger, Ian; Chou, David; Colson, K. 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EM cjlm@uw.edu RI Condon, John/N-2281-2013; Franklin, Richard/H-1731-2012; Adair, Tim/L-1332-2015; , Ivan/D-6804-2012; Undurraga, Eduardo/I-3739-2014; Salomon, Joshua/D-3898-2009; McGrath, John/G-5493-2010; Degenhardt, Louisa/D-4515-2012; Norman, Paul/C-5485-2013; Lopez, Alan/F-1487-2010; Narayan, K.M. Venkat /J-9819-2012; Bikbov, Boris/I-4594-2013; Harrison, James/B-8958-2009; Bolliger, Ian/C-4207-2016; Jacobsen, Kathryn/B-5857-2008; Naldi, Luigi/K-6343-2016 OI Perez-Ruiz, Fernando/0000-0002-5268-1894; Osborne, Richard/0000-0002-9081-2699; Pourmalek, Farshad/0000-0002-2134-0771; Miller, Ted/0000-0002-0958-2639; Mayosi, Bongani/0000-0001-6641-8950; Aboyans, Victor/0000-0002-0322-9818; Merriman, Tony/0000-0003-0844-8726; Chen, Honglei/0000-0003-3446-7779; Condon, John/0000-0003-4952-0990; Aggarwal, Rakesh/0000-0001-9689-494X; Mensah, George/0000-0002-0387-5326; Phillips, David/0000-0003-2569-1015; Johns, Nicole/0000-0003-4513-4582; Benjamin, Emelia/0000-0003-4076-2336; Franklin, Richard/0000-0003-1864-4552; Hotez, Peter/0000-0001-8770-1042; Ebel, Beth/0000-0001-9310-8325; Mock, Charles/0000-0002-0564-568X; Adair, Tim/0000-0002-1562-4452; , Ivan/0000-0002-3108-058X; Undurraga, Eduardo/0000-0002-4425-1253; Cowie, Benjamin/0000-0002-7087-5895; O'Donnell, Martin/0000-0002-7347-7761; Salomon, Joshua/0000-0003-3929-5515; McGrath, John/0000-0002-4792-6068; Degenhardt, Louisa/0000-0002-8513-2218; Norman, Paul/0000-0003-3406-0506; Lopez, Alan/0000-0001-5818-6512; Narayan, K.M. Venkat /0000-0001-8621-5405; Bikbov, Boris/0000-0002-1925-7506; Harrison, James/0000-0001-9893-8491; Bolliger, Ian/0000-0001-8055-297X; Jacobsen, Kathryn/0000-0002-4198-6246; Naldi, Luigi/0000-0002-3160-2835 FU Bill & Melinda Gates Foundation; Medtronic; Lundbeck; Prana Biotechnology; Spanish Health Ministry; Hospital de Cruces Rheumatology Association; US NIH; Dana Foundation; Doris Duke Charitable Foundation; WHO; NIH; National Institute of Environmental Health Sciences; African Programme for Onchocerciasis Control (WHO/APOC); NIH [K23 AG034236]; Parkinson Council; Australian NHMRC; Swedish Research Council [2011-1071]; Australian National Health and Medical Research Council; Bill & Melinda Gates Foundation through the Sabin Institute; National Institutes of Health; Dutch Government; Lily and Ernst Hausmann Research Trust; Harold Amos Medical Faculty Development Award of the Robert Wood Johnson Foundation; Vanderbilt Clinical and Translational Scholars Award; European Center for Injury Prevention, Universidad de Navarra; Department of Health and Ageing; Commonwealth Government of Australia; Institute of Bone and Joint Research (IBJR); University of Sydney (USYD); Department of Rheumatology; Royal North Shore Hospital; St Leonards NSW 2065 Australia; European Chemical Industry Council (CEFIC); CONCAWE (Conservation of Clean Air and Water Europe); General Research Grant at the University of Hong Kong FX E R Dorsey has received consulting fees from Medtronic and Lundbeck and research support from Lundbeck and Prana Biotechnology. M Ezzati chaired a session and gave a talk at the World Cardiology Congress (WCC), with travel cost reimbursed by the World Heart Federation. At the WCC, he also gave a talk at a session organised by PepsiCo with no financial or other renumeration. P J Hotez reports holding several positions: Dean, National School of Tropical Medicine, Baylor College of Medicine; Director, Sabin Vaccine Institute Texas Children's Hospital Center for Vaccine Development; and President, Sabin Vaccine Institute. He also is an inventor on several patents: 5,527,937 "Hookworm Anticoagulant"; 5,753,787 "Nucleic Acids for Ancylostoma Secreted Proteins"; 7,303,752 B2 "Hookworm vaccine"; 12/492,734 "Human Hookworm Vaccine"; 61/077,256 "Multivalent Anthelminthic Vaccine"; and PCT-20100701/0.20.5.18 "Malaria Transmission blocking vaccine". G A Mensah is a former employee of PepsiCo. F Perez-Ruiz was an adviser for Ardea, Menarini, Novartis, and Metabolex; was a member of the Speaker's Bureau for Menarini, Novartis; an adviser for educational issues for Savient; led an investigation grants for the Spanish Health Ministry, Hospital de Cruces Rheumatology Association; and was principal investigator in clinical trials for Ardea.; We would like to thank the countless individuals who have contributed to the Global Burden of Disease 2010 Study in various capacities. We would also like to specifically acknowledge the important contribution to this work from multiple staff members of the WHO. We also wish to thank the following organisations that hosted consultations during the final stages of the analytic process, providing valuable feedback about the results and the data to improve the study's findings overall: Pan American Health Organisation; Eastern Mediterranean Regional Office of WHO; UNAIDS; Ministry of Health, Brazil; China Centers for Disease Control; and the University of Zambia. We would like to thank Cynthia Boschi Pinto for her input into the analyses and estimates. Finally, we would like to acknowledge the extensive support from all staff members at the Institute for Health Metrics and Evaluation and specifically thank: James Bullard, Andrew Ernst, and Serkan Yalcin for their tireless support of the computational infrastructure required to produce the results; Linda A Ettinger for her expert administrative support and facilitating communication and coordination among the authors; Peter Speyer, Abigail McLain, Katherine Leach-Kemon, and Eden Stork for their persistent and invaluable work to gain access to and catalogue as much data as possible to inform the estimates; and Erin C Mullany for her systematic efforts in organising drafts of papers, formatting correspondence with expert groups, and preparing the final manuscript. The following individuals would like to acknowledge various forms of institutional support. J P Abraham acknowledges the World Bank Global Road Safety Facility and Department of Global Health & Population, Harvard School of Public Health, and the WHO Violence and Injury Prevention. K Bhalla was supported by the World Bank Global Road Safety Facility for researcher salaries, to pay for many small projects in Africa to digitise secondary data sources, and supporting several gatherings of the injury expert group over the past 6 years. B Bikbov acknowledges the Moscow State University of Medicine and Dentistry, Moscow, Russia; Academician V I Shumakov Federal Research Centre of Transplantology and Artificial Organs, Moscow, Russia; and International Society of Nephrology. G L Birbeck has received research funding from the US NIH, the Dana Foundation, and the Doris Duke Charitable Foundation; she has also received travel grants from the WHO for related work. H Chen acknowledges his participation in this study was in part supported by the intramural research program of the NIH, the National Institute of Environmental Health Sciences. L E Coffeng received financial support from the African Programme for Onchocerciasis Control (WHO/APOC) for work on onchocerciasis. M Cortinovis, F Gaspari, and N Perico acknowledge the International Society of Nephrology (ISN) on the behalf of the entire Genitourinary Expert Group. M Cross and L March acknowledge the University of Sydney (USYD); Institute of Bone and Joint Research, University of Sydney, Department of Rheumatology, Royal North Shore Hospital, St Leonards NSW 2065 Australia. N Dahodwala was supported by NIH grant K23 AG034236 and the Parkinson Council while working on this project. L Degenhardt is supported by an Australian NHMRC Senior Research Fellowship and funding to support work on illicit drug dependence was provided by the Australian National Drug and Alcohol Research Centre of the University of New South Wales, NSW, Australia.; R Havmoeller is supported by a grant from the Swedish Research Council (#2011-1071). D Hoy was supported by the Bill & Melinda Gates Foundation and the Australian National Health and Medical Research Council. P J Hotez acknowledges grant support from several sources: the Bill & Melinda Gates Foundation regarding human hookworm vaccine through the Sabin Institute (Human Hookworm Vaccine Initiative 1 Human Hookworm Vaccine Initiative; Human Hookworm Vaccine Initiative 3 Clinical Development and Evaluation of the Na-GST-1 and Na-APR-1 Hookworm Vaccine Antigen); the National Institutes of Health (Product development of a membrane tetraspanin vaccine against schistosomiasis; RBD Recombinant Protein-based SARS Vaccine for Biodefense); and the Dutch Government (Product Development Support of the Human Hookworm Vaccine). K H Jacobsen was supported by the WHO for her work on Hepatitis A. B M Mayosi was funded by the Lily and Ernst Hausmann Research Trust. T R Merriman acknowledges the Health Research Council of New Zealand. D Ozgediz is grateful for the collaboration colleagues at Mulago Hospital and Makerere University in Kampala, Uganda. B Pahari would like to thank the Mario Negri Institute. U Sampson was funded in part by The Harold Amos Medical Faculty Development Award of the Robert Wood Johnson Foundation and The Vanderbilt Clinical and Translational Scholars Award. M Segui-Gomez's participation was partly supported by funds of the European Center for Injury Prevention, Universidad de Navarra. E Smith acknowledges Department of Health and Ageing, Commonwealth Government of Australia, Institute of Bone and Joint Research (IBJR), University of Sydney (USYD), Department of Rheumatology, Royal North Shore Hospital, St Leonards NSW 2065 Australia. L Rushton was supported by honorarium for board membership of the European Centre for Ecotoxicology and Toxicology of Chemicals; research grants to Imperial College London (as PI) from the European Chemical Industry Council (CEFIC) and CONCAWE (Conservation of Clean Air and Water Europe). P Yip was supported by a General Research Grant at the University of Hong Kong. NR 110 TC 2988 Z9 3158 U1 224 U2 1385 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD DEC 15 PY 2012 VL 380 IS 9859 BP 2095 EP 2128 PG 34 WC Medicine, General & Internal SC General & Internal Medicine GA 055AL UT WOS:000312387000012 PM 23245604 ER PT J AU Salomon, JA Vos, T Hogan, DR Gagnon, M Naghavi, M Mokdad, A Begum, N Shah, R Karyana, M Kosen, S Farje, MR Moncada, G Dutta, A Sazawal, S Dyer, A Seiler, J Aboyans, V Baker, L Baxter, A Benjamin, EJ Bhalla, K Bin Abdulhak, A Blyth, F Bourne, R Braithwaite, T Brooks, P Brugha, TS Bryan-Hancock, C Buchbinder, R Burney, P Calabria, B Chen, HL Chugh, SS Cooley, R Criqui, MH Cross, M Dabhadkar, KC Dahodwala, N Davis, A Degenhardt, L Diaz-Torne, C Dorsey, ER Driscoll, T Edmond, K Elbaz, A Ezzati, M Feigin, V Ferri, CP Flaxman, AD Flood, L Fransen, M Fuse, K Gabbe, BJ Gillum, RF Haagsma, J Harrison, JE Havmoeller, R Hay, RJ Hel-Baqui, A Hoek, HW Hoffman, H Hogeland, E Hoy, D Jarvis, D Karthikeyan, G Knowlton, LM Lathlean, T Leasher, JL Lim, SS Lipshultz, SE Lopez, AD Lozano, R Lyons, R Malekzadeh, R Marcenes, W March, L Margolis, DJ McGill, N McGrath, J Mensah, GA Meyer, AC Michaud, C Moran, A Mori, R Murdoch, ME Naldi, L Newton, CR Norman, R Omer, SB Osborne, R Pearce, N Perez-Ruiz, F Perico, N Pesudovs, K Phillips, D Pourmalek, F Prince, M Rehm, JT Remuzzi, G Richardson, K Room, R Saha, S Sampson, U Sanchez-Riera, L Segui-Gomez, M Shahraz, S Shibuya, K Singh, D Sliwa, K Smith, E Soerjomataram, I Steiner, T Stolk, WA Stovner, LJ Sudfeld, C Taylor, HR Tleyjeh, IM van der Werf, MJ Watson, WL Weatherall, DJ Weintraub, R Weisskopf, MG Whiteford, H Wilkinson, JD Woolf, AD Zheng, ZJ Murray, CJL AF Salomon, Joshua A. Vos, Theo Hogan, Daniel R. Gagnon, Michael Naghavi, Mohsen Mokdad, Ali Begum, Nazma Shah, Razibuzzaman Karyana, Muhammad Kosen, Soewarta Farje, Mario Reyna Moncada, Gilberto Dutta, Arup Sazawal, Sunil Dyer, Andrew Seiler, Jason Aboyans, Victor Baker, Lesley Baxter, Amanda Benjamin, Emelia J. Bhalla, Kavi Bin Abdulhak, Aref Blyth, Fiona Bourne, Rupert Braithwaite, Tasanee Brooks, Peter Brugha, Traolach S. Bryan-Hancock, Claire Buchbinder, Rachelle Burney, Peter Calabria, Bianca Chen, Honglei Chugh, Sumeet S. Cooley, Rebecca Criqui, Michael H. Cross, Marita Dabhadkar, Kaustubh C. Dahodwala, Nabila Davis, Adrian Degenhardt, Louisa Diaz-Torne, Cesar Dorsey, E. Ray Driscoll, Tim Edmond, Karen Elbaz, Alexis Ezzati, Majid Feigin, Valery Ferri, Cleusa P. Flaxman, Abraham D. Flood, Louise Fransen, Marlene Fuse, Kana Gabbe, Belinda J. Gillum, Richard F. Haagsma, Juanita Harrison, James E. Havmoeller, Rasmus Hay, Roderick J. Hel-Baqui, Abdullah Hoek, Hans W. Hoffman, Howard Hogeland, Emily Hoy, Damian Jarvis, Deborah Karthikeyan, Ganesan Knowlton, Lisa Marie Lathlean, Tim Leasher, Janet L. Lim, Stephen S. Lipshultz, Steven E. Lopez, Alan D. Lozano, Rafael Lyons, Ronan Malekzadeh, Reza Marcenes, Wagner March, Lyn Margolis, David J. McGill, Neil McGrath, John Mensah, George A. Meyer, Ana-Claire Michaud, Catherine Moran, Andrew Mori, Rintaro Murdoch, Michele E. Naldi, Luigi Newton, Charles R. Norman, Rosana Omer, Saad B. Osborne, Richard Pearce, Neil Perez-Ruiz, Fernando Perico, Norberto Pesudovs, Konrad Phillips, David Pourmalek, Farshad Prince, Martin Rehm, Juergen T. Remuzzi, Guiseppe Richardson, Kathryn Room, Robin Saha, Sukanta Sampson, Uchechukwu Sanchez-Riera, Lidia Segui-Gomez, Maria Shahraz, Saeid Shibuya, Kenji Singh, David Sliwa, Karen Smith, Emma Soerjomataram, Isabelle Steiner, Timothy Stolk, Wilma A. Stovner, Lars Jacob Sudfeld, Christopher Taylor, Hugh R. Tleyjeh, Imad M. van der Werf, Marieke J. Watson, Wendy L. Weatherall, David J. Weintraub, Robert Weisskopf, Marc G. Whiteford, Harvey Wilkinson, James D. Woolf, Anthony D. Zheng, Zhi-Jie Murray, Christopher J. L. TI Common values in assessing health outcomes from disease and injury: disability weights measurement study for the Global Burden of Disease Study 2010 SO LANCET LA English DT Article ID ADJUSTED LIFE-YEARS; QUALITY-OF-LIFE; PERSON TRADE-OFFS; RISK-FACTORS; SCHISTOSOMIASIS-JAPONICA; STATE PREFERENCES; CONTROLLED-TRIAL; POPULATION; COUNTRIES; VALUATION AB Background Measurement of the global burden of disease with disability-adjusted life-years (DALYs) requires disability weights that quantify health losses for all non-fatal consequences of disease and injury. There has been extensive debate about a range of conceptual and methodological issues concerning the definition and measurement of these weights. Our primary objective was a comprehensive re-estimation of disability weights for the Global Burden of Disease Study 2010 through a large-scale empirical investigation in which judgments about health losses associated with many causes of disease and injury were elicited from the general public in diverse communities through a new, standardised approach. Methods We surveyed respondents in two ways: household surveys of adults aged 18 years or older (face-to-face interviews in Bangladesh, Indonesia, Peru, and Tanzania; telephone interviews in the USA) between Oct 28, 2009, and June 23, 2010; and an open-access web-based survey between July 26, 2010, and May 16, 2011. The surveys used paired comparison questions, in which respondents considered two hypothetical individuals with different, randomly selected health states and indicated which person they regarded as healthier. The web survey added questions about population health equivalence, which compared the overall health benefits of different life-saving or disease-prevention programmes. We analysed paired comparison responses with probit regression analysis on all 220 unique states in the study. We used results from the population health equivalence responses to anchor the results from the paired comparisons on the disability weight scale from 0 (implying no loss of health) to 1 (implying a health loss equivalent to death). Additionally, we compared new disability weights with those used in WHO's most recent update of the Global Burden of Disease Study for 2004. Findings 13 902 individuals participated in household surveys and 16 328 in the web survey. Analysis of paired comparison responses indicated a high degree of consistency across surveys: correlations between individual survey results and results from analysis of the pooled dataset were 0.9 or higher in all surveys except in Bangladesh (r=0.75). Most of the 220 disability weights were located on the mild end of the severity scale, with 58 (26%) having weights below 0.05. Five (11%) states had weights below 0.01, such as mild anaemia, mild hearing or vision loss, and secondary infertility. The health states with the highest disability weights were acute schizophrenia (0.76) and severe multiple sclerosis (0.71). We identified a broad pattern of agreement between the old and new weights (r=0.70), particularly in the moderate-to-severe range. However, in the mild range below 0.2, many states had significantly lower weights in our study than previously. Interpretation This study represents the most extensive empirical effort as yet to measure disability weights. By contrast with the popular hypothesis that disability assessments vary widely across samples with different cultural environments, we have reported strong evidence of highly consistent results. C1 [Salomon, Joshua A.] Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, Boston, MA 02115 USA. [Knowlton, Lisa Marie] Harvard Univ, Harvard Humanitarian Initiat, Boston, MA 02115 USA. [Vos, Theo; Lopez, Alan D.; Norman, Rosana] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. [Baxter, Amanda; Saha, Sukanta; Whiteford, Harvey] Univ Queensland, Queensland Ctr Mental Hlth Res, Brisbane, Qld, Australia. [McGrath, John] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia. [Naghavi, Mohsen; Mokdad, Ali; Baker, Lesley; Cooley, Rebecca; Flaxman, Abraham D.; Lim, Stephen S.; Lozano, Rafael; Phillips, David; Murray, Christopher J. L.] Univ Washington, Inst Hlth Metr & Evaluat, Seattle, WA 98195 USA. [Shah, Razibuzzaman] Projahnmo Shimantik, Dhaka, Bangladesh. [Karyana, Muhammad; Kosen, Soewarta] Minist Hlth, Natl Inst Hlth Res & Dev, Jakarta, Indonesia. [Farje, Mario Reyna; Moncada, Gilberto] Inst Cuanto, Lima, Peru. [Dutta, Arup; Sazawal, Sunil; Hel-Baqui, Abdullah] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Dyer, Andrew; Seiler, Jason] ICF Int, Fairfax, VA USA. [Aboyans, Victor] Dupuytren Univ Hosp, Dept Cardiol, Limoges, France. [Benjamin, Emelia J.] Boston Univ, Boston, MA 02215 USA. [Bin Abdulhak, Aref] King Fahad Med City, Riyadh, Saudi Arabia. [Fransen, Marlene; Smith, Emma] Univ Sydney, Fac Hlth Sci, No Clin Sch, Dept Rheumatol, Sydney, NSW 2006, Australia. [March, Lyn; Sanchez-Riera, Lidia] Univ Sydney, Inst Bone & Joint Res, Sydney, NSW 2006, Australia. [Driscoll, Tim] Univ Sydney, Sch Populat Hlth, Sydney, NSW 2006, Australia. [Bourne, Rupert] Anglia Ruskin Univ, Vision & Eye Res Unit, Cambridge, England. [Braithwaite, Tasanee] Moorfields Eye Hosp, London, England. [Degenhardt, Louisa] Univ Leicester, Ctr Hlth Policy Programs & Econ, Leicester, Leics, England. [Room, Robin] Univ Leicester, Sch Populat Hlth, Leicester, Leics, England. [Weintraub, Robert] Univ Leicester, Royal Childrens Hosp, Dept Pediat, Leicester, Leics, England. [Brugha, Traolach S.] Univ Leicester, Leicester, Leics, England. [Bryan-Hancock, Claire; Flood, Louise; Harrison, James E.; Lathlean, Tim; Pesudovs, Konrad] Flinders Univ S Australia, Adelaide, SA 5001, Australia. [Buchbinder, Rachelle; Hoy, Damian] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Buchbinder, Rachelle] Cabrini Inst, Malvern, Vic, Australia. [Ezzati, Majid] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Calabria, Bianca; Degenhardt, Louisa; Watson, Wendy L.] Univ New S Wales, Natl Drug & Alcohol Res Ctr, Sydney, NSW, Australia. [Chen, Honglei] NIEHS, Res Triangle Pk, NC 27709 USA. [Chugh, Sumeet S.; Havmoeller, Rasmus] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Criqui, Michael H.] Univ Calif San Diego, San Diego, CA 92103 USA. [Dabhadkar, Kaustubh C.] Emory Univ, Atlanta, GA 30322 USA. [Dahodwala, Nabila; Margolis, David J.] Univ Penn, Philadelphia, PA 19104 USA. [Davis, Adrian] MRC Hearing & Commun Grp, Manchester, Lancs, England. [Diaz-Torne, Cesar] Hosp Santa Creu & St Pablo, Barcelona, Spain. [Edmond, Karen; Pearce, Neil] London Sch Hyg & Trop Med, London WC1, England. [Elbaz, Alexis] INSERM, Paris, France. [Ezzati, Majid] MRC HPA Ctr Environm & Hlth, London, England. [Feigin, Valery] Auckland Univ Technol, Natl Inst Stroke & Appl Neurosci, Auckland, New Zealand. [Ferri, Cleusa P.] Univ Fed Sao Paulo, Sao Paulo, Brazil. [Fuse, Kana] Natl Inst Populat & Social Secur Res, Dept Populat Struct Res, Tokyo, Japan. [Gillum, Richard F.] Howard Univ, Coll Med, Washington, DC USA. [Soerjomataram, Isabelle] Univ Med Ctr Rotterdam, Erasmus MC, Dept Publ Hlth, Rotterdam, Netherlands. [Hay, Roderick J.] Kings Coll Hosp NHS Fdn Trust, London, England. [Prince, Martin] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Havmoeller, Rasmus] Karolinska Univ Hosp, Stockholm, Sweden. [Hoek, Hans W.] Parnassia Psychiat Inst, The Hague, Netherlands. [Hoffman, Howard] NINCDS, NIH, Bethesda, MD 20892 USA. [Hogeland, Emily; Meyer, Ana-Claire] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Karthikeyan, Ganesan] All India Inst Med Sci, New Delhi, India. [Leasher, Janet L.] Nova SE Univ, Ft Lauderdale, FL 33314 USA. [Lipshultz, Steven E.; Wilkinson, James D.] Univ Miami, Leonard M Miller Sch Med, Miami, FL USA. [Lyons, Ronan] Swansea Univ, Swansea, W Glam, Wales. [Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Ctr, Tehran, Iran. [Marcenes, Wagner] Queen Mary Univ London, London, England. [Mensah, George A.] Univ Cape Town, Dept Med, ZA-7925 Cape Town, South Africa. [Sliwa, Karen] Univ Cape Town, Hatter Inst, ZA-7925 Cape Town, South Africa. [Michaud, Catherine] China Med Board, Boston, MA USA. [Moran, Andrew] Columbia Univ, New York, NY USA. [Mori, Rintaro] Natl Ctr Child Hlth & Dev, Tokyo, Japan. [Murdoch, Michele E.] Watford Dist Gen Hosp, Watford, England. [Naldi, Luigi] Centro Studi GISED, Bergamo, Italy. [Newton, Charles R.; Weatherall, David J.] Univ Oxford, Oxford, England. [Omer, Saad B.] Emory Univ, Sch Publ Hlth & Med, Atlanta, GA 30322 USA. [Osborne, Richard] Deakin Univ, Burwood, NSW, Australia. [Perez-Ruiz, Fernando] Hosp Univ Cruces, Baracaldo, Spain. [Perico, Norberto; Remuzzi, Guiseppe] Mario Negri Inst Pharmacol Res, I-24100 Bergamo, Italy. [Pourmalek, Farshad] Univ British Columbia, Fac Med, Sch Populat & Publ Hlth, Vancouver, BC, Canada. [Rehm, Juergen T.] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Room, Robin] Turning Point Alcohol & Drug Ctr, Ctr Alcohol Policy Res, Fitzroy, SA, Australia. [Richardson, Kathryn] Univ Cambridge, Cambridge, England. [Sampson, Uchechukwu] Vanderbilt Univ, Nashville, TN USA. [Sanchez-Riera, Lidia] Inst Invest Biomed Bellvitge, Barcelona, Spain. [Segui-Gomez, Maria] Govt Spain, Minist Interior, Madrid, Spain. [Shahraz, Saeid] Brandeis Univ, Waltham, MA USA. [Shibuya, Kenji] Univ Tokyo, Dept Global Hlth Policy, Tokyo, Japan. [Singh, David] Queens Med Ctr, Honolulu, HI USA. [Stovner, Lars Jacob] Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway. [van der Werf, Marieke J.] KNCV TB Fdn, The Hague, Netherlands. [Weintraub, Robert] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Woolf, Anthony D.] Royal Cornwall Hosp, Truro, England. [Zheng, Zhi-Jie] Shanghai Jiao Tong Univ, Sch Publ Hlth, Shanghai 200030, Peoples R China. RP Salomon, JA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Global Hlth & Populat, 665 Huntington Ave, Boston, MA 02115 USA. EM jsalomon@hsph.harvard.edu RI Baxter, Amanda/E-5449-2011; Prince, Martin/A-9170-2010; Saha, Sukanta/K-3774-2012; Harrison, James/B-8958-2009; McGrath, John/G-5493-2010; NORMAN, ROSANA/F-2774-2010; Buchbinder, Rachelle/G-2952-2011; Jarvis, Deborah/E-6494-2011; Degenhardt, Louisa/D-4515-2012; Lathlean, Tim/K-3653-2013; Stovner, Lars/D-5025-2014; Lopez, Alan/F-1487-2010; Whiteford, Harvey/A-4840-2009; Ferri, Cleusa/B-2922-2010; Naldi, Luigi/K-6343-2016; Salomon, Joshua/D-3898-2009; , Ivan/D-6804-2012; OI Baxter, Amanda/0000-0001-8198-9022; Prince, Martin/0000-0003-1379-7146; Harrison, James/0000-0001-9893-8491; McGrath, John/0000-0002-4792-6068; NORMAN, ROSANA/0000-0002-9742-1957; Degenhardt, Louisa/0000-0002-8513-2218; Lopez, Alan/0000-0001-5818-6512; Benjamin, Emelia/0000-0003-4076-2336; Newton, Charles/0000-0002-6999-5507; Pourmalek, Farshad/0000-0002-2134-0771; Gabbe, Belinda/0000-0001-7096-7688; Taylor, Hugh/0000-0002-9437-784X; Chen, Honglei/0000-0003-3446-7779; Perez-Ruiz, Fernando/0000-0002-5268-1894; Osborne, Richard/0000-0002-9081-2699; Hoek, Hans/0000-0001-6353-5465; Whiteford, Harvey/0000-0003-4667-6623; Ferri, Cleusa/0000-0002-1815-7685; Naldi, Luigi/0000-0002-3160-2835; Salomon, Joshua/0000-0003-3929-5515; , Ivan/0000-0002-3108-058X; O'donnell, Colm/0000-0002-8004-450X; Malekzadeh, Reza/0000-0003-1043-3814; Mensah, George/0000-0002-0387-5326 FU Spanish Health Ministry; Hospital de Cruces Rheumatology Association; Burke Global Health Fellowship Program at the Harvard Global Health Institute; World Bank Global Road Safety Facility; Vision and Eye Research Unit (Postgraduate Medical Institute, Anglia Ruskin University, Cambridge, UK); Department of Health London for the National Health Service Information Centre; University of Leicester for the Estimating the Prevalence of Autism Spectrum Conditions in Adults; Bill & Melinda Gates Foundation; Australian National Health and Medical Research Council (NHMRC); Monash University; Cabrini Health; BUPA Foundation; National Institutes of Health (NIH)-the National Institute of Environmental Health Sciences-USA; Royal North Shore Hospital; Institute of Bone and Joint Research, (University of Sydney); NIH [K23 AG034236]; Parkinson Council; Safework Australia; Swedish Research Council [2011-1071]; Parnassia Psychiatric Institute, The Hague, Netherlands; Department of Psychiatry, University Medical Center Groningen, Netherlands; Department of Epidemiology, Columbia University, New York, NY, USA; Australian National Health and Medical Research Council; Foundation for Alcohol Research and Education; Victorian Department of Health; Harold Amos Medical Faculty Development Award of the Robert Wood Johnson Foundation; Vanderbilt Clinical and Translational Scholars Award; European Center for Injury Prevention, Universidad de Navarra; Africa Programme for Onchocerciasis Control (WHO/APOC); Wellcome Trust UK; Medical Research Council UK; Anthony Cerami and Ann Dunne Research Trust FX A Davis is employed by the UK National Health Service and works for the UK Department of Health as lead adviser on audiology. E R Dorsey has been a consultant to Lundbeck and Medtronic and receives research support from Lundbeck and Prana Biotechnology. M Ezzati chaired a session and gave a talk at the World Cardiology Congress (WCC), with his travel cost reimbursed by the World Heart Federation; he also gave a talk at a session organized by PepsiCo with no financial or other remuneration. H Hoffman is a US Federal Government employee of the National Institutes of Health. G A Mensah is a former employee of PepsiCo. F Perez-Ruiz has been an adviser for Ardea, Menarini, Novartis, Metabolex; has been a member of a speaker's bureau for Menarini and Novartis; has been an adviser on educational issues for Savient; has received investigation grants from the Spanish Health Ministry and Hospital de Cruces Rheumatology Association; and is the principal investigator in clinical trials for Ardea. The other authors declare that they have no conflicts of interest.; We thank all the survey respondents who participated in the study and the survey field staff who did the interviews. We acknowledge institutions that were pivotal in implementation of the survey around the world, providing administrative and logistical support to data collection: Shimantik, Bangladesh; Instituto Cuanto, Peru; the Public Health Laboratory Ivo de Carneri, Pemba Island, Tanzania; ICF International (formerly ICF Macro); and the National Institute of Health Research and Development at the Ministry of Health, Indonesia. We thank the many individuals who have contributed to GBD 2010 in various capacities, and particularly recognise the important contributions to this work from many WHO staff members. We are grateful for guidance and feedback from participants at the Expert Consultation on Disability Weights (Seattle, WA, USA; September, 2008): Laura Damschroder, Dean Jamison, Jennifer Jelsma, Steven Kymes, Donald L Patrick, Michael Schoenbaum, and Michael Wolfson. We give special thanks to Dan Brock, Daniel M Hausman, and Dan Wikler for many enlightening discussions around the topic of disability weights over many years. We thank Colin Mathers and Gretchen Stevens for their particular contributions to many aspects of the study; Farah Chowdhury, Makame H Mohammed, Haidong Wang, Andres I Vecino Ortiz, Rebecca Myerson, and Zhongwei Jia for their assistance in translation of survey instruments; Lebogang Ramma, for insights from adapting the survey in South Africa; Ben Wikler, Jill Oviatt, Corwyn Ellison, and William Heisel for promoting the survey and helping it reach a widespread audience; Emmanuela Gakidou for many helpful suggestions; Erin C Mullany, Kate Muller, and Diana Haring for coordinating, reviewing, and editing the report; and Michael F MacIntyre for his steadfast management of innumerable elements in the overall GBD 2010 enterprise. J A Salomon acknowledges funding from the Burke Global Health Fellowship Program at the Harvard Global Health Institute. K Bhalla's primary source of support was the World Bank Global Road Safety Facility. R Bourne acknowledges support from the Vision and Eye Research Unit (Postgraduate Medical Institute, Anglia Ruskin University, Cambridge, UK). T S Brugha acknowledges funding from the Department of Health London for the National Health Service Information Centre and from the University of Leicester for the Estimating the Prevalence of Autism Spectrum Conditions in Adults: Extending the 2007 Adult Psychiatric Morbidity Survey. C Bryan-Hancock received funding from the Bill & Melinda Gates Foundation to pay for time as a Research Officer on this project. R Buchbinder was partially funded by an Australian National Health and Medical Research Council (NHMRC) Practitioner Fellowship, Monash University, and Cabrini Health. P Burney and D Jarvis acknowledge that the Chronic Respiratory Disease group received funding from the BUPA Foundation; they had no role in study design, data collection, data analysis, data interpretation, decision to submit for publication, or preparation of the report. H Chen acknowledges that his role in the study was partly supported by the intramural research program of the National Institutes of Health (NIH)-the National Institute of Environmental Health Sciences-USA. M Cross and L March acknowledge the support of the Royal North Shore Hospital and the Institute of Bone and Joint Research, (University of Sydney). N Dahodwala was supported by NIH grant K23 AG034236 and the Parkinson Council while working on this project.; L Degenhardt was supported by an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellowship. T Driscoll was supported partly by funding from the National Occupational Health and Safety Commission (now Safework Australia). R Havmoeller was supported by a grant from the Swedish Research Council (#2011-1071). H W Hoek acknowledges support from three institutions: Parnassia Psychiatric Institute, The Hague, Netherlands; the Department of Psychiatry, University Medical Center Groningen, Netherlands; and the Department of Epidemiology, Columbia University, New York, NY, USA. D Hoy was supported by the Bill & Melinda Gates Foundation and the Australian National Health and Medical Research Council. K Pesudovs acknowledges institutional support from Flinders University. R Room's position at the University of Melbourne and Turning Point Alcohol and Drug Centre is funded by the Foundation for Alcohol Research and Education and the Victorian Department of Health. U Sampson was supported by funding by the Harold Amos Medical Faculty Development Award of the Robert Wood Johnson Foundation and the Vanderbilt Clinical and Translational Scholars Award. L Sanchez-Riera acknowledges the Spanish Society of Rheumatology (Sociedad Espanola de Reumatologia). M Segui-Gomez's participation was partly supported by funding from the European Center for Injury Prevention, Universidad de Navarra. E Smith acknowledges the Department of Health and Ageing, Commonwealth Government of Australia, and Institute of Bone and Joint Research (IBJR; University of Sydney). W A Stolk received financial support from the Africa Programme for Onchocerciasis Control (WHO/APOC) for the work on onchocerciasis. D J Weatherall is supported by the Wellcome Trust UK, the Medical Research Council UK, and the Anthony Cerami and Ann Dunne Research Trust. NR 100 TC 357 Z9 375 U1 20 U2 152 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD DEC 15 PY 2012 VL 380 IS 9859 BP 2129 EP 2143 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 055AL UT WOS:000312387000013 PM 23245605 ER PT J AU Vos, T Flaxman, AD Naghavi, M Lozano, R Michaud, C Ezzati, M Shibuya, K Salomon, JA Abdalla, S Aboyans, V Abraham, J Ackerman, I Aggarwal, R Ahn, SY Ali, MK Alvarado, M Anderson, HR Anderson, LM Andrews, KG Atkinson, C Baddour, LM Bahalim, AN Barker-Collo, S Barrero, LH Bartels, DH Basanez, MG Baxter, A Bell, ML Benjamin, EJ Bennett, D Bernabe, E Bhalla, K Bhandari, B Bikbov, B Bin Abdulhak, A Birbeck, G Black, JA Blencowe, H Blore, JD Blyth, F Bolliger, I Bonaventure, A Boufous, SA Bourne, R Boussinesq, M Braithwaite, T Brayne, C Bridgett, L Brooker, S Brooks, P Brugha, TS Bryan-Hancock, C Bucello, C Buchbinder, R Buckle, GR Budke, CM Burch, M Burney, P Burstein, R Calabria, B Campbell, B Canter, CE Carabin, H Carapetis, J Carmona, L Cella, C Charlson, F Chen, HL Cheng, ATA Chou, D Chugh, SS Coffeng, LE Colan, SD Colquhoun, S Colson, KE Condon, J Connor, MD Cooper, LT Corriere, M Cortinovis, M de Vaccaro, KC Couser, W Cowie, BC Criqui, MH Cross, M Dabhadkar, KC Dahiya, M Dahodwala, N Damsere-Derry, J Danaei, G Davis, A De Leo, D Degenhardt, L Dellavalle, R Delossantos, A Denenberg, J Derrett, S Des Jarlais, DC Dharmaratne, SD Dherani, M Diaz-Torne, C Dolk, H Dorsey, ER Driscoll, T Duber, H Ebel, B Edmond, K Elbaz, A Ali, SE Erskine, H Erwin, PJ Espindola, P Ewoigbokhan, SE Farzadfar, F Feigin, V Felson, DT Ferrari, A Ferri, CP Fevre, EM Finucane, MM Flaxman, S Flood, L Foreman, K Forouzanfar, MH Fowkes, FGR Franklin, R Fransen, M Freeman, MK Gabbe, BJ Gabriel, SE Gakidou, E Ganatra, HA Garcia, B Gaspari, F Gillum, RF Gmel, G Gosselin, R Grainger, R Groeger, J Guillemin, F Gunnell, D Gupta, R Haagsma, J Hagan, H Halasa, YA Hall, W Haring, D Haro, JM Harrison, JE Havmoeller, R Hay, RJ Higashi, H Hill, C Hoen, B Hoffman, H Hotez, PJ Hoy, D Huang, JJ Ibeanusi, SE Jacobsen, KH James, SL Jarvis, D Jasrasaria, R Jayaraman, S Johns, N Jonas, JB Karthikeyan, G Kassebaum, N Kawakami, N Keren, A Khoo, JP King, CH Knowlton, LM Kobusingye, O Koranteng, A Krishnamurthi, R Lalloo, R Laslett, LL Lathlean, T Leasher, JL Lee, YY Leigh, J Lim, SS Limb, E Lin, JK Lipnick, M Lipshultz, SE Liu, W Loane, M Ohno, SL Lyons, R Ma, JX Mabweijano, J MacIntyre, MF Malekzadeh, R Mallinger, L Manivannan, S Marcenes, W March, L Margolis, DJ Marks, GB Marks, R Matsumori, A Matzopoulos, R Mayosi, BM McAnulty, JH McDermott, MM McGill, N McGrath, J Medina-Mora, ME Meltzer, M Mensah, GA Merriman, TR Meyer, AC Miglioli, V Miller, M Miller, TR Mitchell, PB Mocumbi, AO Moffitt, TE Mokdad, AA Monasta, L Montico, M Moradi-Lakeh, M Moran, A Morawska, L Mori, R Murdoch, ME Mwaniki, MK Naidoo, K Nair, MN Naldi, L Narayan, KMV Nelson, PK Nelson, RG Nevitt, MC Newton, CR Nolte, S Norman, P Norman, R O'Donnell, M O'Hanlon, S Olives, C Omer, SB Ortblad, K Osborne, R Ozgediz, D Page, A Pahari, B Pandian, JD Rivero, AP Patten, SB Pearce, N Padilla, RP Perez-Ruiz, F Perico, N Pesudovs, K Phillips, D Phillips, MR Pierce, K Pion, S Polanczyk, GV Polinder, S Pope, CA Popova, S Porrini, E Pourmalek, F Prince, M Pullan, RL Ramaiah, KD Ranganathan, D Razavi, H Regan, M Rehm, JT Rein, DB Remuzzi, G Richardson, K Rivara, FP Roberts, T Robinson, C De Leon, FR Ronfani, L Room, R Rosenfeld, LC Rushton, L Sacco, RL Saha, S Sampson, U Sanchez-Riera, L Sanman, E Schwebel, DC Scott, JG Segui-Gomez, M Shahraz, S Shepard, DS Shin, H Shivakoti, R Singh, D Singh, GM Singh, JA Singleton, J Sleet, DA Sliwa, K Smith, E Smith, JL Stapelberg, NJC Steer, A Steiner, T Stolk, WA Stovner, LJ Sudfeld, C Syed, S Tamburlini, G Tavakkoli, M Taylor, HR Taylor, JA Taylor, WJ Thomas, B Thomson, WM Thurston, GD Tleyjeh, IM Tonelli, M Towbin, JRA Truelsen, T Tsilimbaris, MK Ubeda, C Undurraga, EA van der Werf, MJ van Os, J Vavilala, MS Venketasubramanian, N Wang, MR Wang, WZ Watt, K Weatherall, DJ Weinstock, MA Weintraub, R Weisskopf, MG Weissman, MM White, RA Whiteford, H Wiersma, ST Wilkinson, JD Williams, HC Williams, SRM Witt, E Wolfe, F Woolf, AD Wulf, S Yeh, PH Zaidi, AKM Zheng, ZJ Zonies, D Lopez, AD Murray, CJL AF Vos, Theo Flaxman, Abraham D. Naghavi, Mohsen Lozano, Rafael Michaud, Catherine Ezzati, Majid Shibuya, Kenji Salomon, Joshua A. Abdalla, Safa Aboyans, Victor Abraham, Jerry Ackerman, Ilana Aggarwal, Rakesh Ahn, Stephanie Y. Ali, Mohammed K. Alvarado, Miriam Anderson, H. Ross Anderson, Laurie M. Andrews, Kathryn G. Atkinson, Charles Baddour, Larry M. Bahalim, Adil N. Barker-Collo, Suzanne Barrero, Lope H. Bartels, David H. Basanez, Maria-Gloria Baxter, Amanda Bell, Michelle L. Benjamin, Emelia J. Bennett, Derrick Bernabe, Eduardo Bhalla, Kavi Bhandari, Bishal Bikbov, Boris Bin Abdulhak, Aref Birbeck, Gretchen Black, James A. Blencowe, Hannah Blore, Jed D. Blyth, Fiona Bolliger, Ian Bonaventure, Audrey Boufous, Soufi Ane Bourne, Rupert Boussinesq, Michel Braithwaite, Tasanee Brayne, Carol Bridgett, Lisa Brooker, Simon Brooks, Peter Brugha, Traolach S. Bryan-Hancock, Claire Bucello, Chiara Buchbinder, Rachelle Buckle, Geoff Rey Budke, Christine M. Burch, Michael Burney, Peter Burstein, Roy Calabria, Bianca Campbell, Benjamin Canter, Charles E. Carabin, Helene Carapetis, Jonathan Carmona, Loreto Cella, Claudia Charlson, Fiona Chen, Honglei Cheng, Andrew Tai-Ann Chou, David Chugh, Sumeet S. Coffeng, Luc E. Colan, Steven D. Colquhoun, Samantha Colson, K. Ellicott Condon, John Connor, Myles D. Cooper, Leslie T. Corriere, Matthew Cortinovis, Monica de Vaccaro, Karen Courville Couser, William Cowie, Benjamin C. Criqui, Michael H. Cross, Marita Dabhadkar, Kaustubh C. Dahiya, Manu Dahodwala, Nabila Damsere-Derry, James Danaei, Goodarz Davis, Adrian De Leo, Diego Degenhardt, Louisa Dellavalle, Robert Delossantos, Allyne Denenberg, Julie Derrett, Sarah Des Jarlais, Don C. Dharmaratne, Samath D. Dherani, Mukesh Diaz-Torne, Cesar Dolk, Helen Dorsey, E. Ray Driscoll, Tim Duber, Herbert Ebel, Beth Edmond, Karen Elbaz, Alexis Ali, Suad Eltahir Erskine, Holly Erwin, Patricia J. Espindola, Patricia Ewoigbokhan, Stalin E. Farzadfar, Farshad Feigin, Valery Felson, David T. Ferrari, Alize Ferri, Cleusa P. Fevre, Eric M. Finucane, Mariel M. Flaxman, Seth Flood, Louise Foreman, Kyle Forouzanfar, Mohammad H. Fowkes, Francis Gerry R. Franklin, Richard Fransen, Marlene Freeman, Michael K. Gabbe, Belinda J. Gabriel, Sherine E. Gakidou, Emmanuela Ganatra, Hammad A. Garcia, Bianca Gaspari, Flavio Gillum, Richard F. Gmel, Gerhard Gosselin, Richard Grainger, Rebecca Groeger, Justina Guillemin, Francis Gunnell, David Gupta, Ramyani Haagsma, Juanita Hagan, Holly Halasa, Yara A. Hall, Wayne Haring, Diana Maria Haro, Josep Harrison, James E. Havmoeller, Rasmus Hay, Roderick J. Higashi, Hideki Hill, Catherine Hoen, Bruno Hoffman, Howard Hotez, Peter J. Hoy, Damian Huang, John J. Ibeanusi, Sydney E. Jacobsen, Kathryn H. James, Spencer L. Jarvis, Deborah Jasrasaria, Rashmi Jayaraman, Sudha Johns, Nicole Jonas, Jost B. Karthikeyan, Ganesan Kassebaum, Nicholas Kawakami, Norito Keren, Andre Khoo, Jon-Paul King, Charles H. Knowlton, Lisa Marie Kobusingye, Olive Koranteng, Adofo Krishnamurthi, Rita Lalloo, Ratilal Laslett, Laura L. Lathlean, Tim Leasher, Janet L. Lee, Yong Yi Leigh, James Lim, Stephen S. Limb, Elizabeth Lin, John Kent Lipnick, Michael Lipshultz, Steven E. Liu, Wei Loane, Maria Ohno, Summer Lockett Lyons, Ronan Ma, Jixiang Mabweijano, Jacqueline MacIntyre, Michael F. Malekzadeh, Reza Mallinger, Leslie Manivannan, Sivabalan Marcenes, Wagner March, Lyn Margolis, David J. Marks, Guy B. Marks, Robin Matsumori, Akira Matzopoulos, Richard Mayosi, Bongani M. McAnulty, John H. McDermott, Mary M. McGill, Neil McGrath, John Elena Medina-Mora, Maria Meltzer, Michele Mensah, George A. Merriman, Tony R. Meyer, Ana-Claire Miglioli, Valeria Miller, Matthew Miller, Ted R. Mitchell, Philip B. Mocumbi, Ana Olga Moffitt, Terrie E. Mokdad, Ali A. Monasta, Lorenzo Montico, Marcella Moradi-Lakeh, Maziar Moran, Andrew Morawska, Lidia Mori, Rintaro Murdoch, Michele E. Mwaniki, Michael K. Naidoo, Kovin Nair, M. Nathan Naldi, Luigi Narayan, K. M. Venkat Nelson, Paul K. Nelson, Robert G. Nevitt, Michael C. Newton, Charles R. Nolte, Sandra Norman, Paul Norman, Rosana O'Donnell, Martin O'Hanlon, Simon Olives, Casey Omer, Saad B. Ortblad, Katrina Osborne, Richard Ozgediz, Doruk Page, Andrew Pahari, Bishnu Pandian, Jeyaraj Durai Rivero, Andrea Panozo Patten, Scott B. Pearce, Neil Perez Padilla, Rogelio Perez-Ruiz, Fernando Perico, Norberto Pesudovs, Konrad Phillips, David Phillips, Michael R. Pierce, Kelsey Pion, Sebastien Polanczyk, Guilherme V. Polinder, Suzanne Pope, C. Arden, III Popova, Svetlana Porrini, Esteban Pourmalek, Farshad Prince, Martin Pullan, Rachel L. Ramaiah, Kapa D. Ranganathan, Dharani Razavi, Homie Regan, Mathilda Rehm, Juergen T. Rein, David B. Remuzzi, Guiseppe Richardson, Kathryn Rivara, Frederick P. Roberts, Thomas Robinson, Carolyn De Leon, Felipe Rodriguez Ronfani, Luca Room, Robin Rosenfeld, Lisa C. Rushton, Lesley Sacco, Ralph L. Saha, Sukanta Sampson, Uchechukwu Sanchez-Riera, Lidia Sanman, Ella Schwebel, David C. Scott, James Graham Segui-Gomez, Maria Shahraz, Saeid Shepard, Donald S. Shin, Hwashin Shivakoti, Rupak Singh, David Singh, Gitanjali M. Singh, Jasvinder A. Singleton, Jessica Sleet, David A. Sliwa, Karen Smith, Emma Smith, Jennifer L. Stapelberg, Nicolas J. C. Steer, Andrew Steiner, Timothy Stolk, Wilma A. Stovner, Lars Jacob Sudfeld, Christopher Syed, Sana Tamburlini, Giorgio Tavakkoli, Mohammad Taylor, Hugh R. Taylor, Jennifer A. Taylor, William J. Thomas, Bernadette Thomson, W. Murray Thurston, George D. Tleyjeh, Imad M. Tonelli, Marcello Towbin, Jeff Rey A. Truelsen, Thomas Tsilimbaris, Miltiadis K. Ubeda, Clotilde Undurraga, Eduardo A. van der Werf, Marieke J. van Os, Jim Vavilala, Monica S. Venketasubramanian, N. Wang, Mengru Wang, Wenzhi Watt, Kerrianne Weatherall, David J. Weinstock, Martin A. Weintraub, Robert Weisskopf, Marc G. Weissman, Myrna M. White, Richard A. Whiteford, Harvey Wiersma, Steven T. Wilkinson, James D. Williams, Hywel C. Williams, Sean R. M. Witt, Emma Wolfe, Frederick Woolf, Anthony D. Wulf, Sarah Yeh, Pon-Hsiu Zaidi, Anita K. M. Zheng, Zhi-Jie Zonies, David Lopez, Alan D. Murray, Christopher J. L. TI Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010 SO LANCET LA English DT Article ID NEGLECTED TROPICAL DISEASES; ADJUSTED-LIFE-YEARS; IRON-DEFICIENCY ANEMIA; DEVELOPING-COUNTRIES; ANCHORING VIGNETTES; DEPRESSIVE DISORDER; HEARING IMPAIRMENT; COGNITIVE FUNCTION; MENTAL-DISORDERS; RISK-FACTORS AB Background Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). Methods Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. Findings Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350 000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient -0.37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. Interpretation Rates of YLDs per 100 000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. C1 [Baxter, Amanda; Erskine, Holly; Ferrari, Alize; Khoo, Jon-Paul; Saha, Sukanta; Whiteford, Harvey] Univ Queensland, Queensland Ctr Mental Hlth Res, Brisbane, Qld, Australia. 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[Wang, Wenzhi] Capital Med Univ, Beijing Neurosurg Inst, Beijing, Peoples R China. [Weinstock, Martin A.] Brown Univ, Providence, RI 02912 USA. [Weintraub, Robert] Royal Childrens Hosp, Melbourne, Vic, Australia. [Weintraub, Robert] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Williams, Hywel C.] Univ Nottingham, Nottingham NG7 2RD, England. [Williams, Sean R. M.] Univ Western Sydney, Campbelltown, NSW, Australia. [Wolfe, Frederick] Arthrit Res, Wichita, KS USA. [Woolf, Anthony D.] Royal Cornwall Hosp, Truro, England. [Yeh, Pon-Hsiu] London Sch Econ, London WC2A 2AE, England. [Zonies, David] Landstuhl Reg Med Ctr, Landstuhl, Germany. [Nelson, Robert G.] NIDDK, NIH, Bethesda, MD USA. RP Murray, CJL (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, 2301 5th Ave,Suite 600, Seattle, WA 98121 USA. EM cjlm@uw.edu RI Stovner, Lars/D-5025-2014; Moffitt, Terrie/D-5295-2011; Ebel, Beth/F-4544-2014; Lopez, Alan/F-1487-2010; Laslett, Laura/G-3973-2011; Narayan, K.M. Venkat /J-9819-2012; Hall, Wayne/A-3283-2008; Ronfani, Luca/B-6668-2013; Nolte, Sandra/B-7498-2008; Bikbov, Boris/I-4594-2013; Lee, Yong Yi/C-1373-2015; Saha, Sukanta/K-3774-2012; Carmona, Loreto/A-2748-2014; McGrath, John/G-5493-2010; Montico, Marcella/B-5290-2013; Black, James/A-5917-2010; Erskine, Holly/K-5244-2012; NORMAN, ROSANA/F-2774-2010; Buchbinder, Rachelle/G-2952-2011; Polanczyk, Guilherme/C-2345-2012; Jarvis, Deborah/E-6494-2011; Degenhardt, Louisa/D-4515-2012; Norman, Paul/C-5485-2013; Lathlean, Tim/K-3653-2013; Baxter, Amanda/E-5449-2011; Research ID, CTBCC /O-3564-2014; Prince, Martin/A-9170-2010; Charlson, Fiona/F-5290-2011; Harrison, James/B-8958-2009; Whiteford, Harvey/A-4840-2009; Ferri, Cleusa/B-2922-2010; Tonelli, Marcello/B-3028-2009; Haro, Josep Maria/D-1423-2011; Carabin, Helene/B-7600-2016; Patten, Scott/B-4434-2011; Monasta, Lorenzo/B-1388-2012; Bolliger, Ian/C-4207-2016; Boussinesq, Michel/J-7256-2016; Jacobsen, Kathryn/B-5857-2008; Naldi, Luigi/K-6343-2016; Lalloo, Ratilal/O-5624-2014; Scott, James/D-5900-2012; Salomon, Joshua/D-3898-2009; Franklin, Richard/H-1731-2012; Dellavalle, Robert/L-2020-2013; Undurraga, Eduardo/I-3739-2014; Higashi, Hideki/D-3797-2011; OI Moffitt, Terrie/0000-0002-8589-6760; Lopez, Alan/0000-0001-5818-6512; Laslett, Laura/0000-0002-4336-0095; Narayan, K.M. Venkat /0000-0001-8621-5405; Hall, Wayne/0000-0003-1984-0096; Ronfani, Luca/0000-0001-5710-3914; Nolte, Sandra/0000-0001-6185-9423; Bikbov, Boris/0000-0002-1925-7506; Lee, Yong Yi/0000-0003-2359-6823; Carmona, Loreto/0000-0002-4401-2551; McGrath, John/0000-0002-4792-6068; Montico, Marcella/0000-0003-0377-8232; Black, James/0000-0002-2200-3179; NORMAN, ROSANA/0000-0002-9742-1957; Polanczyk, Guilherme/0000-0003-2311-3289; Degenhardt, Louisa/0000-0002-8513-2218; Norman, Paul/0000-0003-3406-0506; Baxter, Amanda/0000-0001-8198-9022; Prince, Martin/0000-0003-1379-7146; Charlson, Fiona/0000-0003-2876-5040; Harrison, James/0000-0001-9893-8491; Whiteford, Harvey/0000-0003-4667-6623; Ferri, Cleusa/0000-0002-1815-7685; Haro, Josep Maria/0000-0002-3984-277X; Patten, Scott/0000-0001-9871-4041; Monasta, Lorenzo/0000-0001-7774-548X; Bolliger, Ian/0000-0001-8055-297X; Boussinesq, Michel/0000-0001-6312-0681; Jacobsen, Kathryn/0000-0002-4198-6246; Naldi, Luigi/0000-0002-3160-2835; Lalloo, Ratilal/0000-0001-5822-1269; Scott, James/0000-0002-0744-0688; Salomon, Joshua/0000-0003-3929-5515; Franklin, Richard/0000-0003-1864-4552; Dellavalle, Robert/0000-0001-8132-088X; Hotez, Peter/0000-0001-8770-1042; Ebel, Beth/0000-0001-9310-8325; Aggarwal, Rakesh/0000-0001-9689-494X; Mock, Charles/0000-0002-0564-568X; Loane, Maria/0000-0002-1206-3637; Undurraga, Eduardo/0000-0002-4425-1253; Cowie, Benjamin/0000-0002-7087-5895; O'Donnell, Martin/0000-0002-7347-7761; O'donnell, Colm/0000-0002-8004-450X; Malekzadeh, Reza/0000-0003-1043-3814; singh, jasvinder/0000-0003-3485-0006; Mensah, George/0000-0002-0387-5326; Higashi, Hideki/0000-0002-5534-0905; Phillips, David/0000-0003-2569-1015; Johns, Nicole/0000-0003-4513-4582; Benjamin, Emelia/0000-0003-4076-2336; Newton, Charles/0000-0002-6999-5507; Leasher, Janet/0000-0002-8779-5162; Weissman, Myrna/0000-0003-3490-3075; Mitchell, Philip/0000-0002-7954-5235; Razavi, Homie/0000-0002-2658-6930; Pourmalek, Farshad/0000-0002-2134-0771; Miller, Ted/0000-0002-0958-2639; Cesar, Diaz-Torne/0000-0001-6275-7699; Fevre, Eric/0000-0001-8931-4986; Pesudovs, Konrad/0000-0002-6322-9369; Mayosi, Bongani/0000-0001-6641-8950; Gabbe, Belinda/0000-0001-7096-7688; Cella, Claudia/0000-0002-9210-0775; Taylor, Hugh/0000-0002-9437-784X; Erskine, Holly/0000-0003-3119-9211; Aboyans, Victor/0000-0002-0322-9818; Merriman, Tony/0000-0003-0844-8726; Chen, Honglei/0000-0003-3446-7779; Perez-Ruiz, Fernando/0000-0002-5268-1894; Osborne, Richard/0000-0002-9081-2699; Bernabe, Eduardo/0000-0002-1858-3713; Moradi-Lakeh, Maziar/0000-0001-7381-5305; King, Charles/0000-0001-8349-9270 FU Berlin Heart Honoraria; Lundbeck; Medtronic; Prana Biotechnology; Safework Australia; Assurance-Maladie (CNAMTS) InVS; Inserm; CHU de Nancy; CHU de Nice; Conseil Regional de Lorraine; Societe Francaise de Negma-Lerads; Pfizer; Pierre Fabre Medicaments; Sanofi-Aventis France; Spanish Health Ministry; Hospital de Cruces Rheumatology Association; Novartis; National Council for Scientific and Technological Development (CNPq, Brazil); European Chemical Industry Council (CEFIC); CONCAWE (Conservation of Clean Air and Water Europe); Takeda; Savient; Ardea; Regeneron; Allergan; URL pharmaceuticals; 36 companies; National Institutes of Arthritis, Musculoskeletal and Skin Diseases (NIAMS); National Institute on Aging (NIA); National Cancer Institute (NCI); Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs); Moscow State University of Medicine and Dentistry, Moscow, Russia; Academician V.I. Shumakov Federal Research Center of Transplantology and Artificial Organs, Moscow, Russia; International Society of Nephrology; Wellcome Trust [098045, 085308]; Department of Health London for the National Health Service Information Centre; University of Leicester; Australian National Health and Medical Research Council (NHMRC); Monash University; Cabrini Health; BUPA Foundation; NIH, the National Institute of Environmental Health Sciences; Africa Programme for Onchocerciasis Control (WHO/APOC); NIH [K23 AG034236]; Parkinson Council; Australian NHMRC; US Department of Veterans Affairs; Health Research Council of New Zealand; University of Otago; National Institute for Stroke and Applied Neurosciences; Swedish Research Council [2011-1071]; Bill and Melinda Gates Foundation; Australian National Health and Medical Research Council; World Health Organization; World Mental Health Japan (WMH-J); Grant for Research on Psychiatric and Neurological Diseases and Mental Health from the Japan Ministry of Health, Labour, and Welfare [H13-SHOGAI-023, H14-TOKUBETSU-026, H16-KOKORO-013]; Australian Government; National Health and Medical Research Council of Australia; Arthritis Foundation of Australia; Tasmanian Community Fund; Masonic Centenary Medical Research Foundation; Royal Hobart Hospital Research Foundation; University of Tasmania; Tehran University of Medical Sciences; South African Medical Research Council Burden of Disease Research Unit; University of Cape Town School of Public Health and Family Medicine; Brien Holden Vision Institute; National Drug and Alcohol Research Centre (UNSW, Australia); Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Biostatistics, Epidemiologic and Bioinformatic Training in Environmental Health Training Grant [ES015459]; Burke Global Health Fellowship; Harold Amos Medical Faculty Development Award of the Robert Wood Johnson Foundation; Vanderbilt Clinical and Translational Scholars Award; European Center for Injury Prevention, Universidad de Navarra; National Institute of Environmental Health Sciences [ES00260]; Wellcome Trust UK; Medical Research Council UK; Anthony Cerami and Ann Dunne Research Trust; AUT University FX C E Canter has worked as an Optum Health consultant, Blue Cross Blue Shield consultant, and received Berlin Heart Honoraria and travel fees. E R Dorsey has received payments for consulting services from Lundbeck and Medtronic and research support from Lundbeck and Prana Biotechnology. T Driscoll was supported in part by funding from the National Occupational Health and Safety Commission (now Safework Australia). M Ezzati chaired a session and gave a talk at the World Cardiology Congress (WCC), with travel cost reimbursed by the World Heart Federation. At the WCC, he also gave a talk at a session organised by PepsiCo with no financial or other remuneration. F Guillemin did a study on osteoarthritis epidemiology in an institution that received grants from public sources: Assurance-Maladie (CNAMTS) InVS, Inserm, CHU de Nancy, CHU de Nice, Conseil Regional de Lorraine, Societe Francaise de Negma-Lerads, Pfizer, Pierre Fabre Medicaments, Sanofi-Aventis France. H J Hoffman is a US Federal Government employee of the National Institutes of Health (NIH). P J Hotez reports holding several positions: Dean, National School of Tropical Medicine, Baylor College of Medicine; Director, Sabin Vaccine Institute Texas Children's Hospital Center for Vaccine Development; and President, Sabin Vaccine Institute. He also is an inventor on several patents: 5,527,937 "Hookworm Anticoagulant"; 5,753,787 "Nucleic Acids for Ancylostoma Secreted Proteins"; 7,303,752 B2 "Hookworm vaccine"; 12/492,734 "Human Hookworm Vaccine"; 61/077,256 "Multivalent Anthelminthic Vaccine"; and PCT-20100701/0.20.5.18 "Malaria Transmission blocking vaccine". G A Mensah is a former employee of PepsiCo. F Perez-Ruiz was an advisor for Ardea, Menarini, Novartis, Metabolex; was a member of the Speaker's Bureau for Menarini, Novartis; an advisor for educational issues for Savient; led investigation grants for the Spanish Health Ministry, Hospital de Cruces Rheumatology Association; and was principal investigator in clinical trials for Ardea. G V Polanczyk has served as a speaker or consultant to Eli-Lily, Novartis, Janssen-Cilag, and Shire Pharmaceuticals, developed educational material for Janssen-Cilag, and received an independent investigator grant from Novartis and from the National Council for Scientific and Technological Development (CNPq, Brazil). L Rushton received honorarium for board membership of the European Centre for Ecotoxicology and Toxicology of Chemicals and received research grants to Imperial College London (as PI) from the European Chemical Industry Council (CEFIC) and CONCAWE (Conservation of Clean Air and Water Europe). J A Singh has received research grants from Takeda and Savient and consultant fees from Savient, Takeda, Ardea, Regeneron, Allergan, URL pharmaceuticals, and Novartis. J A Singh is a member of the executive of OMERACT, an organisation that develops outcome measures in rheumatology and receives arms-length funding from 36 companies; a member of the American College of Rheumatology's Guidelines Subcommittee of the Quality of Care Committee; and a member of the Veterans Affairs Rheumatology Field Advisory Committee. J A Singh is supported by research grants from the National Institutes of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institute on Aging (NIA), National Cancer Institute (NCI) and the Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs) and is also supported by the resources and the use of facilities at the VA Medical Center at Birmingham, Alabama, USA.; We would like to thank the countless individuals who have contributed to the Global Burden of Disease Study 2010 in various capacities. We would also like to specifically acknowledge the important contribution to this work from multiple staff members of the World Health Organization. We also wish to express our gratitude to the following organizations that hosted consultations during the final stages of the analytic process, providing valuable feedback about the results and the data to improve the study's findings overall: Pan American Health Organization; Eastern Mediterranean Regional Office of WHO; UNAIDS; Ministry of Health, Brazil; China Centers for Disease Control; and the University of Zambia. We would like to thank Lori M Newman, Jordis Ott, Poul Erik Petersen, Shekhar Saxena, and Gretchen A Stevens for their collaboration and input into the analyses and estimates. Finally, we would like to acknowledge the extensive support from all staff members at the Institute for Health Metrics and Evaluation and specifically thank: James Bullard, Andrew Ernst, and Serkan Yalcin for their tireless support of the computational infrastructure required to produce the results; Linda A Ettinger for her expert administrative support in order to facilitate communication and coordination amongst the authors; Peter Speyer, Abigail McLain, Katherine Leach-Kemon, and Eden Stork for their persistent and valuable work to gain access to and catalog as much data as possible to inform the estimates; Erin C Mullany for her systematic efforts in organizing drafts of papers, formatting correspondence with expert groups, and preparing the final manuscript; Brad Bell for his review, critiques, and insights about the DisMod-MR software which helped to improve its performance and results; and Jiaji Du for his work developing the user interface for the DisMod-MR software so that multiple expert groups could use it and easily assess the results. The following individuals would like to acknowledge various forms of institutional support. J P Abraham, B Bartels, and P Yeh recognize the support of the World Bank Global Road Safety Facility and Department of Global Health & Population, Harvard School of Public Health, and the World Health Organization Violence and Injury Prevention. B Bikbov acknowledges support from the Moscow State University of Medicine and Dentistry, Moscow, Russia; Academician V.I. Shumakov Federal Research Center of Transplantology and Artificial Organs, Moscow, Russia; International Society of Nephrology. R Bourne acknowledges the Vision & Eye Research Unit, Postgraduate Medical Institute, Anglia Ruskin University, Cambridge, UK. S Brooker is supported by a Wellcome Trust Senior Fellowship in Basic Biomedical Science (098045). T S Brugha received funding from the Department of Health London, for the National Health Service Information Centre, by the University of Leicester. R Buchbinder is partially funded by an Australian National Health and Medical Research Council (NHMRC) Practitioner Fellowship, Monash University and Cabrini Health. P Burney and D Jarvis acknowledge that the Chronic Respiratory Disease Group received support from the BUPA Foundation, who had no role in study design, data collection and analysis, interpretation of data, decision to publish, or preparation of the manuscript. C Cella, M Cortinovis, F Gaspari, V Miglioli, and N Perico on behalf of the entire Genitourinary Expert Group acknowledge the International Society of Nephrology (ISN).; H Chen acknowledges that his participation in this study was in part supported by the intramural research program of the NIH, the National Institute of Environmental Health Sciences. L E Coffeng and W A Stolk received financial support from the Africa Programme for Onchocerciasis Control (WHO/APOC) for their work on onchocerciasis. B C Cowie received institutional support from the Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia. M Cross and L March acknowledge the University of Sydney (USYD); Institute of Bone and Joint Research, University of Sydney, Department of Rheumatology, Royal North Shore Hospital, St Leonards NSW 2065 Australia. N Dahodwala was supported by NIH grant K23 AG034236 and the Parkinson Council while working on this project. L Degenhardt is supported by an Australian NHMRC Senior Research Fellowship and funding to support her work for illicit drug dependence was provided by the Australian National Drug and Alcohol Research Centre of the University of New South Wales, Australia. R Dellavalle was supported by the US Department of Veterans Affairs while contributing to this study. S Derrett acknowledges the Health Research Council of New Zealand and the University of Otago for their support. V Feigin and R Krishnamurthi were supported by the National Institute for Stroke and Applied Neurosciences, AUT University. E Fevre acknowledges the Wellcome Trust for grant 085308. W Hall was supported by an NHMRC Australia Fellowship. R Havmoeller was supported by a grant from the Swedish Research Council (#2011-1071). D Hoy was supported by the Bill and Melinda Gates Foundation and the Australian National Health and Medical Research Council. K H Jacobsen was supported by the World Health Organization for her work on hepatitis A. N Kawakami notes that the collection of data ultimately used in this study was supported by the following grants: The World Mental Health Japan (WMH-J) is supported by the Grant for Research on Psychiatric and Neurological Diseases and Mental Health (H13-SHOGAI-023, H14-TOKUBETSU-026, H16-KOKORO-013) from the Japan Ministry of Health, Labour, and Welfare. He would like to thank staff members, field coordinators, and interviewers of the WMH Japan 2002-2004 Survey. L L Laslett is supported by an Australian Government Australian Postgraduate Award. She also notes that the TasOAC study, the results of which were used in this research, was supported by the National Health and Medical Research Council of Australia; Arthritis Foundation of Australia; Tasmanian Community Fund; Masonic Centenary Medical Research Foundation, Royal Hobart Hospital Research Foundation, and University of Tasmania Institutional Research Grants Scheme. R Malekzadeh funding from research grant of Tehran University of Medical Sciences to do the related studies. R Matzopoulos acknowledges the two institutions that support his research work: South African Medical Research Council Burden of Disease Research Unit; and the University of Cape Town School of Public Health and Family Medicine. T Merriman acknowledges the Health Research Council of New Zealand. K Naidoo was supported by the Brien Holden Vision Institute. P Nelson was supported by the National Drug and Alcohol Research Centre (UNSW, Australia). R G Nelson acknowledges his research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. C Olives was funded in part by the Biostatistics, Epidemiologic and Bioinformatic Training in Environmental Health Training Grant (ES015459).; D Ozgediz acknowledges the staff and collaborators at the Mulago Hospital and Makerere University in Kampala, Uganda. K Pesudovs received institutional support from Flinders University. R Room's position at the University of Melbourne and Turning Point Alcohol and Drug Centre is funded by the Foundation for Alcohol Research and Education and the Victorian Department of Health. J A Salomon received support from the Burke Global Health Fellowship while working on this study. U Sampson received funding support from the Harold Amos Medical Faculty Development Award of the Robert Wood Johnson Foundation and the Vanderbilt Clinical and Translational Scholars Award. L Sanchez-Riera acknowledges the Spanish Society of Rheumatology (Sociedad Espanola de Reumatologia). M Segui-Gomez's participation was partly supported by funds from the European Center for Injury Prevention, Universidad de Navarra. E Smith acknowledges the Department of Health and Ageing, Commonwealth Government of Australia, Institute of Bone and Joint Research (IBJR), University of Sydney (USYD). G D Thurston was supported in part by Center grant ES00260 from the National Institute of Environmental Health Sciences. D J Weatherall was supported by the Wellcome Trust UK, the Medical Research Council UK and the Anthony Cerami and Ann Dunne Research Trust. NR 109 TC 1603 Z9 1678 U1 121 U2 597 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD DEC 15 PY 2012 VL 380 IS 9859 BP 2163 EP 2196 PG 34 WC Medicine, General & Internal SC General & Internal Medicine GA 055AL UT WOS:000312387000015 PM 23245607 ER PT J AU Murray, CJL Vos, T Lozano, R Naghavi, M Flaxman, AD Michaud, C Ezzati, M Shibuya, K Salomon, JA Abdalla, S Aboyans, V Abraham, J Ackerman, I Aggarwal, R Ahn, SY Ali, MK Alvarado, M Anderson, HR Anderson, LM Andrews, KG Atkinson, C Baddour, LM Bahalim, AN Barker-Collo, S Barrero, LH Bartels, DH Basanez, MG Baxter, A Bell, ML Benjamin, EJ Bennett, D Bernabe, E Bhalla, K Bhandari, B Bikbov, B Bin Abdulhak, A Birbeck, G Black, JA Blencowe, H Blore, JD Blyth, F Bolliger, I Bonaventure, A Boufous, SA Bourne, R Boussinesq, M Braithwaite, T Brayne, C Bridgett, L Brooker, S Brooks, P Brugha, TS Bryan-Hancock, C Bucello, C Buchbinder, R Buckle, G Budke, CM Burch, M Burney, P Burstein, R Calabria, B Campbell, B Canter, CE Carabin, H Carapetis, J Carmona, L Cella, C Charlson, F Chen, HL Cheng, ATA Chou, D Chugh, SS Coffeng, LE Colan, SD Colquhoun, S Colson, KE Condon, J Connor, MD Cooper, LT Corriere, M Cortinovis, M De Vaccaro, KC Couser, W Cowie, BC Criqui, MH Cross, M Dabhadkar, KC Dahiya, M Dahodwala, N Damsere-Derry, J Danaei, G Davis, A De Leo, D Degenhardt, L Dellavalle, R Delossantos, A Denenberg, J Derrett, S Des Jarlais, DC Dharmaratne, SD Dherani, M Diaz-Torne, C Dolk, H Dorsey, ER Driscoll, T Duber, H Ebel, B Edmond, K Elbaz, A Ali, SE Erskine, H Erwin, PJ Espindola, P Ewoigbokhan, SE Farzadfar, F Feigin, V Felson, DT Ferrari, A Ferri, CP Fevre, EM Finucane, MM Flaxman, S Flood, L Foreman, K Forouzanfar, MH Fowkes, FGR Fransen, M Freeman, MK Gabbe, BJ Gabriel, SE Gakidou, E Ganatra, HA Garcia, B Gaspari, F Gillum, RF Gmel, G Gonzalez-Medina, D Gosselin, R Grainger, R Grant, B Groeger, J Guillemin, F Gunnell, D Gupta, R Haagsma, J Hagan, H Halasa, YA Hall, W Haring, D Haro, JM Harrison, JE Havmoeller, R Hay, RJ Higashi, H Hill, C Hoen, B Hoffman, H Hotez, PJ Hoy, D Huang, JJ Ibeanusi, SE Jacobsen, KH James, SL Jarvis, D Jasrasaria, R Jayaraman, S Johns, N Jonas, JB Karthikeyan, G Kassebaum, N Kawakami, N Keren, A Khoo, JP King, CH Knowlton, LM Kobusingye, O Koranteng, A Krishnamurthi, R Laden, F Lalloo, R Laslett, LL Lathlean, T Leasher, JL Lee, YY Leigh, J Levinson, D Lim, SS Limb, E Lin, JK Lipnick, M Lipshultz, SE Liu, W Loane, M Ohno, SL Lyons, R Mabweijano, J MacIntyre, MF Malekzadeh, R Mallinger, L Manivannan, S Marcenes, W March, L Margolis, DJ Marks, GB Marks, R Matsumori, A Matzopoulos, R Mayosi, BM McAnulty, JH McDermott, MM McGill, N McGrath, J Medina-Mora, ME Meltzer, M Mensah, GA Merriman, TR Meyer, AC Miglioli, V Miller, M Miller, TR Mitchell, PB Mock, C Mocumbi, AO Moffitt, TE Mokdad, AA Monasta, L Montico, M Moradi-Lakeh, M Moran, A Morawska, L Mori, R Murdoch, ME Mwaniki, MK Naidoo, K Nair, MN Naldi, L Narayan, KMV Nelson, PK Nelson, RG Nevitt, MC Newton, CR Nolte, S Norman, P Norman, R O'Donnell, M O'Hanlon, S Olives, C Omer, SB Ortblad, K Osborne, R Ozgediz, D Page, A Pahari, B Pandian, JD Rivero, AP Patten, SB Pearce, N Padilla, RP Perez-Ruiz, F Perico, N Pesudovs, K Phillips, D Phillips, MR Pierce, K Pion, S Polanczyk, GV Polinder, S Pope, CA Popova, S Porrini, E Pourmalek, F Prince, M Pullan, RL Ramaiah, KD Ranganathan, D Razavi, H Regan, M Rehm, JT Rein, DB Remuzzi, G Richardson, K Rivara, FP Roberts, T Robinson, C De Leon, FR Ronfani, L Room, R Rosenfeld, LC Rushton, L Sacco, RL Saha, S Sampson, U Sanchez-Riera, L Sanman, E Schwebel, DC Scott, JG Segui-Gomez, M Shahraz, S Shepard, DS Shin, H Shivakoti, R Singh, D Singh, GM Singh, JA Singleton, J Sleet, DA Sliwa, K Smith, E Smith, JL Stapelberg, NJC Steer, A Steiner, T Stolk, WA Stovner, LJ Sudfeld, C Syed, S Tamburlini, G Tavakkoli, M Taylor, HR Taylor, JA Taylor, WJ Thomas, B Thomson, WM Thurston, GD Tleyjeh, IM Tonelli, M Towbin, JRA Truelsen, T Tsilimbaris, MK Ubeda, C Undurraga, EA van der Werf, MJ van Os, J Vavilala, MS Venketasubramanian, N Wang, MR Wang, WZ Watt, K Weatherall, DJ Weinstock, MA Weintraub, R Weisskopf, MG Weissman, MM White, RA Whiteford, H Wiebe, N Wiersma, ST Wilkinson, JD Williams, HC Williams, SRM Witt, E Wolfe, F Woolf, AD Wulf, S Yeh, PH Zaidi, AKM Zheng, ZJ Zonies, D Lopez, AD AF Murray, Christopher J. L. Vos, Theo Lozano, Rafael Naghavi, Mohsen Flaxman, Abraham D. Michaud, Catherine Ezzati, Majid Shibuya, Kenji Salomon, Joshua A. Abdalla, Safa Aboyans, Victor Abraham, Jerry Ackerman, Ilana Aggarwal, Rakesh Ahn, Stephanie Y. Ali, Mohammed K. Alvarado, Miriam Anderson, H. Ross Anderson, Laurie M. Andrews, Kathryn G. Atkinson, Charles Baddour, Larry M. Bahalim, Adil N. Barker-Collo, Suzanne Barrero, Lope H. Bartels, David H. Basanez, Maria-Gloria Baxter, Amanda Bell, Michelle L. Benjamin, Emelia J. Bennett, Derrick Bernabe, Eduardo Bhalla, Kavi Bhandari, Bishal Bikbov, Boris Bin Abdulhak, Aref Birbeck, Gretchen Black, James A. Blencowe, Hannah Blore, Jed D. Blyth, Fiona Bolliger, Ian Bonaventure, Audrey Boufous, Soufi Ane Bourne, Rupert Boussinesq, Michel Braithwaite, Tasanee Brayne, Carol Bridgett, Lisa Brooker, Simon Brooks, Peter Brugha, Traolach S. Bryan-Hancock, Claire Bucello, Chiara Buchbinder, Rachelle Buckle, Geoffrey Budke, Christine M. Burch, Michael Burney, Peter Burstein, Roy Calabria, Bianca Campbell, Benjamin Canter, Charles E. Carabin, Helene Carapetis, Jonathan Carmona, Loreto Cella, Claudia Charlson, Fiona Chen, Honglei Cheng, Andrew Tai-Ann Chou, David Chugh, Sumeet S. Coffeng, Luc E. Colan, Steven D. Colquhoun, Samantha Colson, K. Ellicott Condon, John Connor, Myles D. Cooper, Leslie T. Corriere, Matthew Cortinovis, Monica De Vaccaro, Karen Courville Couser, William Cowie, Benjamin C. Criqui, Michael H. Cross, Marita Dabhadkar, Kaustubh C. Dahiya, Manu Dahodwala, Nabila Damsere-Derry, James Danaei, Goodarz Davis, Adrian De Leo, Diego Degenhardt, Louisa Dellavalle, Robert Delossantos, Allyne Denenberg, Julie Derrett, Sarah Des Jarlais, Don C. Dharmaratne, Samath D. Dherani, Mukesh Diaz-Torne, Cesar Dolk, Helen Dorsey, E. Ray Driscoll, Tim Duber, Herbert Ebel, Beth Edmond, Karen Elbaz, Alexis Ali, Suad Eltahir Erskine, Holly Erwin, Patricia J. Espindola, Patricia Ewoigbokhan, Stalin E. Farzadfar, Farshad Feigin, Valery Felson, David T. Ferrari, Alize Ferri, Cleusa P. Fevre, Eric M. Finucane, Mariel M. Flaxman, Seth Flood, Louise Foreman, Kyle Forouzanfar, Mohammad H. Fowkes, Francis Gerry R. Fransen, Marlene Freeman, Michael K. Gabbe, Belinda J. Gabriel, Sherine E. Gakidou, Emmanuela Ganatra, Hammad A. Garcia, Bianca Gaspari, Flavio Gillum, Richard F. Gmel, Gerhard Gonzalez-Medina, Diego Gosselin, Richard Grainger, Rebecca Grant, Bridget Groeger, Justina Guillemin, Francis Gunnell, David Gupta, Ramyani Haagsma, Juanita Hagan, Holly Halasa, Yara A. Hall, Wayne Haring, Diana Maria Haro, Josep Harrison, James E. Havmoeller, Rasmus Hay, Roderick J. Higashi, Hideki Hill, Catherine Hoen, Bruno Hoffman, Howard Hotez, Peter J. Hoy, Damian Huang, John J. Ibeanusi, Sydney E. Jacobsen, Kathryn H. James, Spencer L. Jarvis, Deborah Jasrasaria, Rashmi Jayaraman, Sudha Johns, Nicole Jonas, Jost B. Karthikeyan, Ganesan Kassebaum, Nicholas Kawakami, Norito Keren, Andre Khoo, Jon-Paul King, Charles H. Knowlton, Lisa Marie Kobusingye, Olive Koranteng, Adofo Krishnamurthi, Rita Laden, Francine Lalloo, Ratilal Laslett, Laura L. Lathlean, Tim Leasher, Janet L. Lee, Yong Yi Leigh, James Levinson, Daphna Lim, Stephen S. Limb, Elizabeth Lin, John Kent Lipnick, Michael Lipshultz, Steven E. Liu, Wei Loane, Maria Ohno, Summer Lockett Lyons, Ronan Mabweijano, Jacqueline MacIntyre, Michael F. Malekzadeh, Reza Mallinger, Leslie Manivannan, Sivabalan Marcenes, Wagner March, Lyn Margolis, David J. Marks, Guy B. Marks, Robin Matsumori, Akira Matzopoulos, Richard Mayosi, Bongani M. McAnulty, John H. McDermott, Mary M. McGill, Neil McGrath, John Elena Medina-Mora, Maria Meltzer, Michele Mensah, George A. Merriman, Tony R. Meyer, Ana-Claire Miglioli, Valeria Miller, Matthew Miller, Ted R. Mitchell, Philip B. Mock, Charles Mocumbi, Ana Olga Moffitt, Terrie E. Mokdad, Ali A. Monasta, Lorenzo Montico, Marcella Moradi-Lakeh, Maziar Moran, Andrew Morawska, Lidia Mori, Rintaro Murdoch, Michele E. Mwaniki, Michael K. Naidoo, Kovin Nair, M. Nathan Naldi, Luigi Narayan, K. M. Venkat Nelson, Paul K. Nelson, Robert G. Nevitt, Michael C. Newton, Charles R. Nolte, Sandra Norman, Paul Norman, Rosana O'Donnell, Martin O'Hanlon, Simon Olives, Casey Omer, Saad B. Ortblad, Katrina Osborne, Richard Ozgediz, Doruk Page, Andrew Pahari, Bishnu Pandian, Jeyaraj Durai Panozo Rivero, Andrea Patten, Scott B. Pearce, Neil Perez Padilla, Rogelio Perez-Ruiz, Fernando Perico, Norberto Pesudovs, Konrad Phillips, David Phillips, Michael R. Pierce, Kelsey Pion, Sebastien Polanczyk, Guilherme V. Polinder, Suzanne Pope, C. Arden, III Popova, Svetlana Porrini, Esteban Pourmalek, Farshad Prince, Martin Pullan, Rachel L. Ramaiah, Kapa D. Ranganathan, Dharani Razavi, Homie Regan, Mathilda Rehm, Juergen T. Rein, David B. Remuzzi, Guiseppe Richardson, Kathryn Rivara, Frederick P. Roberts, Thomas Robinson, Carolyn Rodriguez De Leon, Felipe Ronfani, Luca Room, Robin Rosenfeld, Lisa C. Rushton, Lesley Sacco, Ralph L. Saha, Sukanta Sampson, Uchechukwu Sanchez-Riera, Lidia Sanman, Ella Schwebel, David C. Scott, James Graham Segui-Gomez, Maria Shahraz, Saeid Shepard, Donald S. Shin, Hwashin Shivakoti, Rupak Singh, David Singh, Gitanjali M. Singh, Jasvinder A. Singleton, Jessica Sleet, David A. Sliwa, Karen Smith, Emma Smith, Jennifer L. Stapelberg, Nicolas J. C. Steer, Andrew Steiner, Timothy Stolk, Wilma A. Stovner, Lars Jacob Sudfeld, Christopher Syed, Sana Tamburlini, Giorgio Tavakkoli, Mohammad Taylor, Hugh R. Taylor, Jennifer A. Taylor, William J. Thomas, Bernadette Thomson, W. Murray Thurston, George D. Tleyjeh, Imad M. Tonelli, Marcello Towbin, Jeff Rey A. Truelsen, Thomas Tsilimbaris, Miltiadis K. Ubeda, Clotilde Undurraga, Eduardo A. van der Werf, Marieke J. van Os, Jim Vavilala, Monica S. Venketasubramanian, N. Wang, Mengru Wang, Wenzhi Watt, Kerrianne Weatherall, David J. Weinstock, Martin A. Weintraub, Robert Weisskopf, Marc G. Weissman, Myrna M. White, Richard A. Whiteford, Harvey Wiebe, Natasha Wiersma, Steven T. Wilkinson, James D. Williams, Hywel C. Williams, Sean R. M. Witt, Emma Wolfe, Frederick Woolf, Anthony D. Wulf, Sarah Yeh, Pon-Hsiu Zaidi, Anita K. M. Zheng, Zhi-Jie Zonies, David Lopez, Alan D. TI Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010 SO LANCET LA English DT Article ID PUBLIC-HEALTH UTILITY; RISK-FACTORS; ECONOMIC COST; MORTALITY; POPULATION; AUSTRALIA; COUNTRIES; DEATH; LOST; METAANALYSIS AB Background Measuring disease and injury burden in populations requires a composite metric that captures both premature mortality and the prevalence and severity of ill-health. The 1990 Global Burden of Disease study proposed disability-adjusted life years (DALYs) to measure disease burden. No comprehensive update of disease burden worldwide incorporating a systematic reassessment of disease and injury-specific epidemiology has been done since the 1990 study. We aimed to calculate disease burden worldwide and for 21 regions for 1990, 2005, and 2010 with methods to enable meaningful comparisons over time. Methods We calculated DALYs as the sum of years of life lost (YLLs) and years lived with disability (YLDs). DALYs were calculated for 291 causes, 20 age groups, both sexes, and for 187 countries, and aggregated to regional and global estimates of disease burden for three points in time with strictly comparable definitions and methods. YLLs were calculated from age-sex-country-time-specific estimates of mortality by cause, with death by standardised lost life expectancy at each age. YLDs were calculated as prevalence of 1160 disabling sequelae, by age, sex, and cause, and weighted by new disability weights for each health state. Neither YLLs nor YLDs were age-weighted or discounted. Uncertainty around cause-specific DALYs was calculated incorporating uncertainty in levels of all-cause mortality, cause-specific mortality, prevalence, and disability weights. Findings Global DALYs remained stable from 1990 (2.503 billion) to 2010 (2.490 billion). Crude DALYs per 1000 decreased by 23% (472 per 1000 to 361 per 1000). An important shift has occurred in DALY composition with the contribution of deaths and disability among children (younger than 5 years of age) declining from 41% of global DALYs in 1990 to 25% in 2010. YLLs typically account for about half of disease burden in more developed regions (high-income Asia Pacific, western Europe, high-income North America, and Australasia), rising to over 80% of DALYs in sub-Saharan Africa. In 1990, 47% of DALYs worldwide were from communicable, maternal, neonatal, and nutritional disorders, 43% from non-communicable diseases, and 10% from injuries. By 2010, this had shifted to 35%, 54%, and 11%, respectively. Ischaemic heart disease was the leading cause of DALYs worldwide in 2010 (up from fourth rank in 1990, increasing by 29%), followed by lower respiratory infections (top rank in 1990; 44% decline in DALYs), stroke (fifth in 1990; 19% increase), diarrhoeal diseases (second in 1990; 51% decrease), and HIV/AIDS (33rd in 1990; 351% increase). Major depressive disorder increased from 15th to 11th rank (37% increase) and road injury from 12th to 10th rank (34% increase). Substantial heterogeneity exists in rankings of leading causes of disease burden among regions. Interpretation Global disease burden has continued to shift away from communicable to non-communicable diseases and from premature death to years lived with disability. In sub-Saharan Africa, however, many communicable, maternal, neonatal, and nutritional disorders remain the dominant causes of disease burden. The rising burden from mental and behavioural disorders, musculoskeletal disorders, and diabetes will impose new challenges on health systems. Regional heterogeneity highlights the importance of understanding local burden of disease and setting goals and targets for the post-2015 agenda taking such patterns into account. Because of improved definitions, methods, and data, these results for 1990 and 2010 supersede all previously published Global Burden of Disease results. C1 [Baxter, Amanda; Erskine, Holly; Ferrari, Alize; Khoo, Jon-Paul; Saha, Sukanta; Whiteford, Harvey] Univ Queensland, Queensland Ctr Mental Hlth Res, Brisbane, Qld, Australia. [Vos, Theo; Blore, Jed D.; Charlson, Fiona; Higashi, Hideki; Lee, Yong Yi; Norman, Rosana; Page, Andrew; Lopez, Alan D.] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. 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[Nelson, Robert G.] NIDDK, NIH, Bethesda, MD USA. [Hotez, Peter J.] Baylor Coll Med, Natl Sch Trop Med, Waco, TX USA. [Ibeanusi, Sydney E.] Univ Port Harcourt, Port Harcourt, Nigeria. [Jacobsen, Kathryn H.] George Mason Univ, Fairfax, VA 22030 USA. [Jonas, Jost B.] Heidelberg Univ, Med Fac Mannheim, Dept Ophthalmol, Heidelberg, Germany. [Karthikeyan, Ganesan] All India Inst Med Sci, New Delhi, India. [Keren, Andre] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Cardiol, IL-91010 Jerusalem, Israel. [King, Charles H.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Kobusingye, Olive] Makerere Univ, Sch Publ Hlth, Kampala, Uganda. [Kobusingye, Olive] Univ S Africa, Johannesburg, South Africa. [Koranteng, Adofo] Kwame Nkrumah Univ Sci & Technol, Kumasi, Ghana. [Laslett, Laura L.] Univ Tasmania, Hobart, Tas 7001, Australia. [Leasher, Janet L.] Nova SE Univ, Ft Lauderdale, FL 33314 USA. [Levinson, Daphna] Minist Hlth, Jerusalem, Israel. [Lipshultz, Steven E.; Sacco, Ralph L.; Wilkinson, James D.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Lyons, Ronan] Swansea Univ, Swansea, W Glam, Wales. [Mabweijano, Jacqueline] Mulago Hosp, Kampala, Uganda. [Matsumori, Akira] Asian Pacific Soc Cardiol, Kyoto, Japan. [Matzopoulos, Richard] MRC, Tygerberg, South Africa. [Sliwa, Karen] Univ Cape Town, Hatter Inst, ZA-7925 Cape Town, South Africa. [Mensah, George A.] Univ Cape Town, Dept Med, ZA-7925 Cape Town, South Africa. [McAnulty, John H.] Legacy Hlth Syst, Portland, OR USA. [McDermott, Mary M.] Northwestern Univ, Feinberg Sch Med, Evanston, IL USA. [Elena Medina-Mora, Maria] Natl Inst Psychiat Ramon de la Fuente, Mexico City, DF, Mexico. [Meltzer, Michele] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Miller, Ted R.] Pacific Inst Res & Evaluat, Calverton, MD USA. [Mocumbi, Ana Olga] Natl Inst Hlth, Maputo, Mozambique. [Mocumbi, Ana Olga] Univ Eduardo Mondlane, Maputo, Mozambique. [Moffitt, Terrie E.] Duke Univ, Durham, NC USA. [Monasta, Lorenzo; Montico, Marcella; Ronfani, Luca; Tamburlini, Giorgio] IRCCS Burlo Garofolo, Inst Maternal & Child Hlth, Trieste, Italy. [Weissman, Myrna M.] Columbia Univ, Mailman Sch Publ Hlth, New York, NY USA. [Morawska, Lidia] Queensland Univ Technol, Brisbane, Qld 4001, Australia. [Mori, Rintaro] Natl Ctr Child Hlth & Dev, Tokyo, Japan. [Murdoch, Michele E.] Watford Dist Gen Hosp, Watford, England. [Mwaniki, Michael K.] Kemri Wellcome Trust, Kilifi, Kenya. [Naidoo, Kovin] Univ KwaZulu Natal, AVRI, Durban, South Africa. [Naldi, Luigi] Ctr Studi GISED, Bergamo, Italy. [Nolte, Sandra] Charite, D-13353 Berlin, Germany. [O'Donnell, Martin] Natl Univ Ireland Galway, HRB Clin Res Facil, Galway, Ireland. [Osborne, Richard] Deakin Univ, Melbourne, Vic, Australia. [Pahari, Bishnu] BP Koirala Inst Hlth Sci, Dharan, Nepal. [Pandian, Jeyaraj Durai] Betty Cowan Res & Innovat Ctr, Ludhiana, Punjab, India. [Panozo Rivero, Andrea] Hosp Joan 23, La Paz, Bolivia. [Patten, Scott B.] Univ Calgary, Calgary, AB, Canada. [Perez Padilla, Rogelio] Inst Nacl Enfermedades Resp, Mexico City, DF, Mexico. [Perez-Ruiz, Fernando] Hosp Univ Cruces, Baracaldo, Spain. [Phillips, Michael R.] Shanghai Jiao Tong Univ, Shanghai Mental Hlth Ctr, Sch Med, Shanghai 200030, Peoples R China. [Zheng, Zhi-Jie] Shanghai Jiao Tong Univ, Sch Publ Hlth, Shanghai 200030, Peoples R China. [Pope, C. Arden, III] Brigham Young Univ, Provo, UT 84602 USA. [Popova, Svetlana; Rehm, Juergen T.] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Porrini, Esteban] Hosp Univ Canarias, Tenerif, Spain. [Pourmalek, Farshad] Univ British Columbia, Fac Med, Sch Populat & Publ Hlth, Vancouver, BC, Canada. [Ramaiah, Kapa D.] Vector Control Res Ctr, Pondicherry, India. [Razavi, Homie] Ctr Dis Anal, Louisville, CO USA. [Regan, Mathilda] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Rein, David B.] Univ Chicago, NORC, Chicago, IL 60637 USA. [Rodriguez De Leon, Felipe] Complejo Hosp Caja Seguro Social, Panama City, Panama. [Room, Robin] Turning Point Alcohol & Drug Ctr, Ctr Alcohol Policy Res, Fitzroy, SA, Australia. [Sampson, Uchechukwu] Vanderbilt Univ, Nashville, TN USA. [Schwebel, David C.; Singh, Jasvinder A.] Univ Alabama Birmingham, Birmingham, AL USA. [Segui-Gomez, Maria] Minist Interior, Madrid, Spain. [Shin, Hwashin] Hlth Canada, Ottawa, ON K1A 0L2, Canada. [Singh, David] Queens Med Ctr, Honolulu, HI USA. [Stovner, Lars Jacob] Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway. [Syed, Sana; Zaidi, Anita K. M.] Aga Khan Univ, Karachi, Pakistan. [Taylor, Jennifer A.] Drexel Univ, Sch Publ Hlth, Philadelphia, PA 19104 USA. [Tonelli, Marcello] Univ Alberta, Alberta Kidney Dis Network, Edmonton, AB, Canada. [Towbin, Jeff Rey A.] Cincinnati Childrens Hosp, Cincinnati, OH USA. [Truelsen, Thomas] Copenhagen Univ Hosp, Dept Neurol, Herlev, Denmark. [Tsilimbaris, Miltiadis K.] Univ Crete, Sch Med, Iraklion, Greece. [Ubeda, Clotilde] ANLIS, Inst Nacl Epidemiol, Malbran, Argentina. [van der Werf, Marieke J.] KNCV TB Fdn, The Hague, Netherlands. [van Os, Jim] Maastricht Univ, Med Ctr, Maastricht, Netherlands. [Venketasubramanian, N.] Natl Univ Singapore, Singapore 117548, Singapore. [Wang, Wenzhi] Capital Med Univ, Beijing Neurosurg Inst, Beijing, Peoples R China. [Weinstock, Martin A.] Brown Univ, Providence, RI 02912 USA. [Weintraub, Robert] Royal Childrens Hosp, Melbourne, Vic, Australia. [Weintraub, Robert] Murdoch Childrens Res Inst, Melbourne, Vic, Australia. [Williams, Hywel C.] Univ Nottingham, Nottingham NG7 2RD, England. [Williams, Sean R. M.] Hollywood Orthopaed Grp, Perth, WA, Australia. [Wolfe, Frederick] Arthrit Res, Wichita, KS USA. [Woolf, Anthony D.] Royal Cornwall Hosp, Truro, England. [Yeh, Pon-Hsiu] London Sch Econ, London WC2A 2AE, England. [Zonies, David] Landstuhl Reg Med Ctr, Landstuhl, Germany. RP Murray, CJL (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, 2301 5th Ave,Suite 600, Seattle, WA 98121 USA. EM cjlm@uw.edu RI Undurraga, Eduardo/I-3739-2014; Higashi, Hideki/D-3797-2011; Boussinesq, Michel/J-7256-2016; Jacobsen, Kathryn/B-5857-2008; Naldi, Luigi/K-6343-2016; Lalloo, Ratilal/O-5624-2014; Scott, James/D-5900-2012; Salomon, Joshua/D-3898-2009; Dellavalle, Robert/L-2020-2013; Research ID, CTBCC /O-3564-2014; Prince, Martin/A-9170-2010; Charlson, Fiona/F-5290-2011; Harrison, James/B-8958-2009; Whiteford, Harvey/A-4840-2009; Ferri, Cleusa/B-2922-2010; Tonelli, Marcello/B-3028-2009; Haro, Josep Maria/D-1423-2011; Carabin, Helene/B-7600-2016; Patten, Scott/B-4434-2011; Monasta, Lorenzo/B-1388-2012; Bolliger, Ian/C-4207-2016; Stovner, Lars/D-5025-2014; Moffitt, Terrie/D-5295-2011; Lopez, Alan/F-1487-2010; Laslett, Laura/G-3973-2011; Nolte, Sandra/B-7498-2008; Narayan, K.M. Venkat /J-9819-2012; Hall, Wayne/A-3283-2008; Ronfani, Luca/B-6668-2013; Bikbov, Boris/I-4594-2013; Lee, Yong Yi/C-1373-2015; Baxter, Amanda/E-5449-2011; Buchbinder, Rachelle/G-2952-2011; Polanczyk, Guilherme/C-2345-2012; Jarvis, Deborah/E-6494-2011; Degenhardt, Louisa/D-4515-2012; Norman, Paul/C-5485-2013; Lathlean, Tim/K-3653-2013; Carmona, Loreto/A-2748-2014; Saha, Sukanta/K-3774-2012; McGrath, John/G-5493-2010; Montico, Marcella/B-5290-2013; Black, James/A-5917-2010; Erskine, Holly/K-5244-2012; NORMAN, ROSANA/F-2774-2010 OI Moradi-Lakeh, Maziar/0000-0001-7381-5305; Taylor, Hugh/0000-0002-9437-784X; Merriman, Tony/0000-0003-0844-8726; Chen, Honglei/0000-0003-3446-7779; Perez-Ruiz, Fernando/0000-0002-5268-1894; Osborne, Richard/0000-0002-9081-2699; Bernabe, Eduardo/0000-0002-1858-3713; Benjamin, Emelia/0000-0003-4076-2336; Newton, Charles/0000-0002-6999-5507; Weissman, Myrna/0000-0003-3490-3075; Mitchell, Philip/0000-0002-7954-5235; Pourmalek, Farshad/0000-0002-2134-0771; Miller, Ted/0000-0002-0958-2639; Mayosi, Bongani/0000-0001-6641-8950; Gabbe, Belinda/0000-0001-7096-7688; Cella, Claudia/0000-0002-9210-0775; Loane, Maria/0000-0002-1206-3637; Undurraga, Eduardo/0000-0002-4425-1253; Cowie, Benjamin/0000-0002-7087-5895; O'Donnell, Martin/0000-0002-7347-7761; O'donnell, Colm/0000-0002-8004-450X; Malekzadeh, Reza/0000-0003-1043-3814; Aggarwal, Rakesh/0000-0001-9689-494X; Mensah, George/0000-0002-0387-5326; Higashi, Hideki/0000-0002-5534-0905; Boussinesq, Michel/0000-0001-6312-0681; Jacobsen, Kathryn/0000-0002-4198-6246; Naldi, Luigi/0000-0002-3160-2835; Lalloo, Ratilal/0000-0001-5822-1269; Scott, James/0000-0002-0744-0688; Salomon, Joshua/0000-0003-3929-5515; Dellavalle, Robert/0000-0001-8132-088X; Hotez, Peter/0000-0001-8770-1042; Ebel, Beth/0000-0001-9310-8325; Mock, Charles/0000-0002-0564-568X; Prince, Martin/0000-0003-1379-7146; Charlson, Fiona/0000-0003-2876-5040; Harrison, James/0000-0001-9893-8491; Whiteford, Harvey/0000-0003-4667-6623; Ferri, Cleusa/0000-0002-1815-7685; Haro, Josep Maria/0000-0002-3984-277X; Patten, Scott/0000-0001-9871-4041; Monasta, Lorenzo/0000-0001-7774-548X; Bolliger, Ian/0000-0001-8055-297X; Moffitt, Terrie/0000-0002-8589-6760; Lopez, Alan/0000-0001-5818-6512; Laslett, Laura/0000-0002-4336-0095; Nolte, Sandra/0000-0001-6185-9423; Narayan, K.M. Venkat /0000-0001-8621-5405; Hall, Wayne/0000-0003-1984-0096; Ronfani, Luca/0000-0001-5710-3914; Bikbov, Boris/0000-0002-1925-7506; Lee, Yong Yi/0000-0003-2359-6823; Baxter, Amanda/0000-0001-8198-9022; Polanczyk, Guilherme/0000-0003-2311-3289; Degenhardt, Louisa/0000-0002-8513-2218; Norman, Paul/0000-0003-3406-0506; Carmona, Loreto/0000-0002-4401-2551; McGrath, John/0000-0002-4792-6068; Montico, Marcella/0000-0003-0377-8232; Black, James/0000-0002-2200-3179; NORMAN, ROSANA/0000-0002-9742-1957 FU Berlin Heart Honoraria; Lundbeck; Medtronic; Prana Biotechnology; Safework Australia; Assurance-Maladie (CNAMTS) InVS; Inserm; CHU de Nancy; CHU de Nice; Conseil Regional de Lorraine; Societe Francaise de Negma-Lerads; Pfizer; Pierre Fabre Medicaments; Sanofi-Afentis France; Spanish Health Ministry; Hospital de Cruces Rheumatology Association; Novartis; National Council for Scientific and Technological Development (CNPq, Brazil); Takeda; Savient; Ardea; Regeneron; Allergan; URL pharmaceuticals; 36 companies; National Institutes of Arthritis, Musculoskeletal and Skin Diseases (NIAMS); National Institutes of Aging (NIA); National Cancer Institute (NCI); Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs); Wellcome Trust [098045, 085308]; Department of Health London for the National Health Service Information Centre; University of Leicester; Australian National Health and Medical Research Council (NHMRC); Monash University; Cabrini Health; BUPA Foundation; NIH; National Institute of Environmental Health Sciences; Africa Programme for Onchocerciasis Control (WHO/APOC); Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia; NIH [K23 AG034236]; Parkinson Council; Australian NHMRC; US Department of Veterans Affairs; Health Research Council of New Zealand; University of Otago; National Institute for Stroke and Applied Neurosciences; AUT University; NHMRC; Swedish Research Council [2011-1071]; Bill and Melinda Gates Foundation; Australian National Health and Medical Research Council; World Health Organization; World Mental Health Japan (WMH-J); Japan Ministry of Health, Labour, and Welfare [H13-SHOGAI-023, H14-TOKUBETSU-026, H16-KOKORO-013]; Australian Government; National Health and Medical Research Council of Australia; Arthritis Foundation of Australia; Tasmanian Community Fund; Masonic Centenary Medical Research Foundation; Royal Hobart Hospital Research Foundation; University of Tasmania; Tehran University of Medical Sciences; South African Medical Research Council Burden of Disease Research Unit; University of Cape Town School of Public Health and Family Medicine; Brien Holden Vision Institute; National Drug and Alcohol Research Centre (UNSW, Australia); Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; Biostatistics, Epidemiologic and Bioinformatic Training in Environmental Health Training Grant [ES015459]; Foundation for Alcohol Research and Education; Victorian Department of Health; Burke Global Health Fellowship; Harold Amos Medical Faculty Development Award of the Robert Wood Johnson Foundation; Vanderbilt Clinical and Translational Scholars Award; Spanish Society of Rheumatology (Sociedad Espanola de Reumatologia); European Center for Injury Prevention, Universidad de Navarra; Department of Health and Ageing; Commonwealth Government of Australia; Institute of Bone and Joint Research (IBJR); University of Sydney (USYD); National Institute of Environmental Health Sciences [ES00260]; Wellcome Trust UK; Medical Research Council UK; Anthony Cerami and Ann Dunne Research Trust FX C E Canter has worked as an Optum Health consultant, Blue Cross Blue Shield consultant, and received Berlin Heart Honoraria and travel fees. E R Dorsey has received payments for consulting services from Lundbeck and Medtronic and research support from Lundbeck and Prana Biotechnology. T Driscoll was supported in part by funding from the National Occupational Health and Safety Commission (now Safework Australia). M Ezzati chaired a session and gave a talk at the World Cardiology Congress (WCC), with travel cost reimbursed by the World Heart Federation. At the WCC, he also gave a talk at a session organised by PepsiCo with no financial or other remuneration. F Guillemin conducted a study on osteoarthritis epidemiology in an institution that received grants from public sources: Assurance-Maladie (CNAMTS) InVS, Inserm, CHU de Nancy, CHU de Nice, Conseil Regional de Lorraine, Societe Francaise de Negma-Lerads, Pfizer, Pierre Fabre Medicaments, Sanofi-Afentis France. H J Hoffman is a US Federal Government employee of the National Institutes of Health (NIH). P J Hotez reports holding several positions: Dean, National School of Tropical Medicine, Baylor College of Medicine; Director, Sabin Vaccine Institute Texas Children's Hospital Center for Vaccine Development; and President, Sabin Vaccine Institute. He also is an inventor on several patents: 5,527,937 "Hookworm Anticoagulant"; 5,753,787 "Nucleic Acids for Ancylostoma Secreted Proteins"; 7,303,752 B2 "Hookworm vaccine"; 12/492,734 "Human Hookworm Vaccine"; 61/077,256 "Multivalent Anthelminthic Vaccine"; and PCT-20100701/0.20.5.18 "Malaria Transmission blocking vaccine". G Mensah is a former employee of PepsiCo. F Perez-Ruiz was an advisor for Ardea, Menarini, Novartis, Metabolex; was a member of the Speaker's Bureau for Menarini, Novartis; an advisor for educational issues for Savient; led investigation grants for the Spanish Health Ministry, Hospital de Cruces Rheumatology Association; and was principal investigator in clinical trials for Ardea. G V Polanczyk has served as a speaker and/or consultant to Eli-Lily, Novartis, Janssen-Cilag, and Shire Pharmaceuticals, developed educational material for Janssen-Cilag, and received an independent investigator grant from Novartis and from the National Council for Scientific and Technological Development (CNPq, Brazil). L Rushton received honorarium for board membership of the European Centre for Ecotoxicology and Toxicology of Chemicals and received research grants to Imperial College London (as PI) from the European Chemical Industry Council (CEFIC) and CONCAWE (Conservation of Clean Air and Water Europe). J A Singh has received research grants from Takeda and Savient and consultant fees from Savient, Takeda, Ardea, Regeneron, Allergan, URL pharmaceuticals and Novartis. J A Singh is a member of the executive of OMERACT, an organisation that develops outcome measures in rheumatology and receives arms-length funding from 36 companies; a member of the American College of Rheumatology's Guidelines Subcommittee of the Quality of Care Committee; and a member of the Veterans Affairs Rheumatology Field Advisory Committee. J A Singh is supported by research grants from the National Institutes of Arthritis, Musculoskeletal and Skin Diseases (NIAMS), National Institutes of Aging (NIA), National Cancer Institute (NCI), and the Agency for Health Quality and Research Center for Education and Research on Therapeutics (CERTs) and is also supported by the resources and the use of facilities at the VA Medical Center at Birmingham, AL, USA.; We would like to thank the countless individuals who have contributed to the Global Burden of Disease 2010 study in various capacities. We would like to specifically acknowledge the important contribution to this work from multiple staff members of the World Health Organization. We also wish to express our gratitude to the following organisations that hosted consultations during the final stages of the analytic process, providing valuable feedback about the results and the data to improve the study's findings overall: Pan American Health Organization; Eastern Mediterranean Regional Office of WHO; UNAIDS; Ministry of Health, Brazil; China Centers for Disease Control; and the University of Zambia. We would like to thank Lori M Newman, Jordis Ott, Poul Erik Petersen, Shekhar Saxena, and Gretchen A Stevens for their collaboration and input into the analyses and estimates. Finally, we would like to acknowledge the extensive support from all staff members at the Institute for Health Metrics and Evaluation and specifically thank: James Bullard, Andrew Ernst, and Serkan Yalcin for their tireless support of the computational infrastructure required to produce the results; Linda A Ettinger for her expert administrative support in order to facilitate communication and coordination amongst the authors; Peter Speyer, Abigail McLain, Katherine Leach-Kemon, and Eden Stork for their persistent and valuable work to gain access to and catalog as much data as possible to inform the estimates; and Erin C Mullany for her systematic efforts in organising drafts of papers, formatting correspondence with expert groups, and preparing the final manuscript. The following individuals would like to acknowledge various forms of institutional support. J P Abraham, B Bartels, and P Yeh recognise the support of the World Bank Global Road Safety Facility and Department of Global Health & Population, Harvard School of Public Health, and the World Health Organization Violence and Injury Prevention. B Bikbov acknowledges support from the Moscow State University of Medicine and Dentistry, Moscow, Russia; Academician V I Shumakov Federal Research Center of Transplantology and Artificial Organs, Moscow, Russia; International Society of Nephrology. R Bourne acknowledges the Vision & Eye Research Unit, Postgraduate Medical Institute, Anglia Ruskin University, Cambridge, UK. S Brooker is supported by a Wellcome Trust Senior Fellowship in Basic Biomedical Science (098045). T S Brugha received funding from the Department of Health London, for the National Health Service Information Centre, by the University of Leicester. R Buchbinder is partially funded by an Australian National Health and Medical Research Council (NHMRC) Practitioner Fellowship, Monash University, and Cabrini Health. P Burney and D Jarvis acknowledge the Chronic Respiratory Disease group received funding from the BUPA Foundation. They had no role in study design, data collection and analysis, interpretation of data, decision to publish, or preparation of the manuscript. C Cella, M Cortinovis, F Gaspari, V Miglioli, and N Perico, on behalf of the entire Genitourinary Expert Group, acknowledge the International Society of Nephrology (ISN). H Chen acknowledges that his participation in this study was in part supported by the intramural research program of the NIH, the National Institute of Environmental Health Sciences. L E Coffeng, and W A Stolk received financial support from the Africa Programme for Onchocerciasis Control (WHO/APOC) for their work on onchocerciasis.; B C Cowie received institutional support from the Victorian Infectious Diseases Reference Laboratory, Melbourne, Australia. M Cross and L March acknowledge the University of Sydney (USYD); Institute of Bone and Joint Research, University of Sydney, Department of Rheumatology, Royal North Shore Hospital, St Leonards NSW 2065 Australia. N Dahodwala was supported by NIH grant K23 AG034236 and the Parkinson Council while working on this project. L Degenhardt is supported by an Australian NHMRC Senior Research Fellowship and funding to support her work for illicit drug dependence was provided by the Australian National Drug and Alcohol Research Centre of the University of New South Wales, Australia. R Dellavalle was supported by the US Department of Veterans Affairs while contributing to this study. S Derrett acknowledges the Health Research Council of New Zealand and the University of Otago for their support. V Feigin and R Krishnamurthi were supported by the National Institute for Stroke and Applied Neurosciences, AUT University. E Fevre acknowledges the Wellcome Trust for grant 085308. W Hall was supported by an NHMRC Australia Fellowship. R Havmoeller was supported by a grant from the Swedish Research Council (#2011-1071). D Hoy was supported by the Bill and Melinda Gates Foundation and the Australian National Health and Medical Research Council. K H Jacobsen was supported by the World Health Organization for her work on hepatitis A. N Kawakami notes that the collection of data ultimately used in this study was supported by the following grants: The World Mental Health Japan (WMH-J) is supported by the Grant for Research on Psychiatric and Neurological Diseases and Mental Health (H13-SHOGAI-023, H14-TOKUBETSU-026, H16-KOKORO-013) from the Japan Ministry of Health, Labour, and Welfare. He would like to thank staff members, field coordinators, and interviewers of the WMH Japan 2002-2004 Survey. L L Laslett is supported by an Australian Government Australian Postgraduate Award. She also notes that the TasOAC study, the results of which were used in this research, was supported by the National Health and Medical Research Council of Australia; Arthritis Foundation of Australia; Tasmanian Community Fund; Masonic Centenary Medical Research Foundation, Royal Hobart Hospital Research Foundation, and University of Tasmania Institutional Research Grants Scheme. R Malekzadeh received funding from a research grant of Tehran University of Medical Sciences to do the related studies. R Matzopoulos acknowledges the two institutions that support his research work: South African Medical Research Council Burden of Disease Research Unit; and the University of Cape Town School of Public Health and Family Medicine. T Merriman acknowledges the Health Research Council of New Zealand. K Naidoo was supported by the Brien Holden Vision Institute. P Nelson was supported by the National Drug and Alcohol Research Centre (UNSW, Australia). R G Nelson acknowledges his research was supported in part by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. C Olives was funded in part by the Biostatistics, Epidemiologic and Bioinformatic Training in Environmental Health Training Grant (ES015459). D Ozgediz acknowledges the staff and collaborators at the Mulago Hospital and Makerere University in Kampala, Uganda. K Pesudovs received institutional support from Flinders University.; R Room's position at the University of Melbourne and Turning Point Alcohol and Drug Centre is funded by the Foundation for Alcohol Research and Education and the Victorian Department of Health. J A Salomon received support from the Burke Global Health Fellowship while working on this study. U Sampson received funding support from the Harold Amos Medical Faculty Development Award of the Robert Wood Johnson Foundation and the Vanderbilt Clinical and Translational Scholars Award. L Sanchez-Riera acknowledges the Spanish Society of Rheumatology (Sociedad Espanola de Reumatologia). M Segui-Gomez's participation was partly supported by funds from the European Center for Injury Prevention, Universidad de Navarra. E Smith acknowledges the Department of Health and Ageing, Commonwealth Government of Australia, Institute of Bone and Joint Research (IBJR), University of Sydney (USYD). G D Thurston was supported in part by Center grant ES00260 from the National Institute of Environmental Health Sciences. D J Weatherall was supported by the Wellcome Trust UK, the Medical Research Council UK and the Anthony Cerami and Ann Dunne Research Trust. NR 112 TC 2073 Z9 2153 U1 93 U2 725 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD DEC 15 PY 2012 VL 380 IS 9859 BP 2197 EP 2223 PG 27 WC Medicine, General & Internal SC General & Internal Medicine GA 055AL UT WOS:000312387000016 PM 23245608 ER PT J AU Lim, SS Vos, T Flaxman, AD Danaei, G Shibuya, K Adair-Rohani, H Amann, M Anderson, HR Andrews, KG Aryee, M Atkinson, C Bacchus, LJ Bahalim, AN Balakrishnan, K Balmes, J Barker-Collo, S Baxter, A Bell, ML Blore, JD Blyth, F Bonner, C Borges, G Bourne, R Boussinesq, M Brauer, M Brooks, P Bruce, NG Brunekreef, B Bryan-Hancock, C Bucello, C Buchbinder, R Bull, F Burnett, RT Byers, TE Calabria, B Carapetis, J Carnahan, E Chafe, Z Charlson, F Chen, HL Chen, JS Cheng, ATA Child, JC Cohen, A Colson, KE Cowie, BC Darby, S Darling, S Davis, A Degenhardt, L Dentener, F Des Jarlais, DC Devries, K Dherani, M Ding, EL Dorsey, ER Driscoll, T Edmond, K Ali, SE Engell, RE Erwin, PJ Fahimi, S Falder, G Farzadfar, F Ferrari, A Finucane, MM Flaxman, S Fowkes, FGR Freedman, G Freeman, MK Gakidou, E Ghosh, S Giovannucci, E Gmel, G Graham, K Grainger, R Grant, B Gunnell, D Gutierrez, HR Hall, W Hoek, HW Hogan, A Hosgood, HD Hoy, D Hu, H Hubbell, BJ Hutchings, SJ Ibeanusi, SE Jacklyn, GL Jasrasaria, R Jonas, JB Kan, HD Kanis, JA Kassebaum, N Kawakami, N Khang, YH Khatibzadeh, S Khoo, JP Kok, C Laden, F Lalloo, R Lan, Q Lathlean, T Leasher, JL Leigh, J Li, Y Lin, JK Lipshultz, SE London, S Lozano, R Lu, Y Mak, J Malekzadeh, R Mallinger, L Marcenes, W March, L Marks, R Martin, R McGale, P McGrath, J Mehta, S Mensah, GA Merriman, TR Micha, R Michaud, C Mishra, V Hanafiah, KM Mokdad, AA Morawska, L Mozaffarian, D Murphy, T Naghavi, M Neal, B Nelson, PK Nolla, JM Norman, R Olives, C Omer, SB Orchard, J Osborne, R Ostro, B Page, A Pandey, KD Parry, CDH Passmore, E Patra, J Pearce, N Pelizzari, PM Petzold, M Phillips, MR Pope, D Pope, CA Powles, J Rao, M Razavi, H Rehfuess, EA Rehm, JT Ritz, B Rivara, FP Roberts, T Robinson, C Rodriguez-Portales, JA Romieu, I Room, R Rosenfeld, LC Roy, A Rushton, L Salomon, JA Sampson, U Sanchez-Riera, L Sanman, E Sapkota, A Seedat, S Shi, PL Shield, K Shivakoti, R Singh, GM Sleet, DA Smith, E Smith, KR Stapelberg, NJC Steenland, K Stockl, H Stovner, LJ Straif, K Straney, L Thurston, GD Tran, JH Van Dingenen, R van Donkelaar, A Veerman, JL Vijayakumar, L Weintraub, R Weissman, MM White, RA Whiteford, H Wiersma, ST Wilkinson, JD Williams, HC Williams, W Wilson, N Woolf, AD Yip, P Zielinski, JM Lopez, AD Murray, CJL Ezzati, M AF Lim, Stephen S. Vos, Theo Flaxman, Abraham D. Danaei, Goodarz Shibuya, Kenji Adair-Rohani, Heather Amann, Markus Anderson, H. Ross Andrews, Kathryn G. Aryee, Martin Atkinson, Charles Bacchus, Loraine J. Bahalim, Adil N. Balakrishnan, Kalpana Balmes, John Barker-Collo, Suzanne Baxter, Amanda Bell, Michelle L. Blore, Jed D. Blyth, Fiona Bonner, Carissa Borges, Guilherme Bourne, Rupert Boussinesq, Michel Brauer, Michael Brooks, Peter Bruce, Nigel G. Brunekreef, Bert Bryan-Hancock, Claire Bucello, Chiara Buchbinder, Rachelle Bull, Fiona Burnett, Richard T. Byers, Tim E. Calabria, Bianca Carapetis, Jonathan Carnahan, Emily Chafe, Zoe Charlson, Fiona Chen, Honglei Chen, Jian Shen Cheng, Andrew Tai-Ann Child, Jennifer Christine Cohen, Aaron Colson, K. Ellicott Cowie, Benjamin C. Darby, Sarah Darling, Susan Davis, Adrian Degenhardt, Louisa Dentener, Frank Des Jarlais, Don C. Devries, Karen Dherani, Mukesh Ding, Eric L. Dorsey, E. Ray Driscoll, Tim Edmond, Karen Ali, Suad Eltahir Engell, Rebecca E. Erwin, Patricia J. Fahimi, Saman Falder, Gail Farzadfar, Farshad Ferrari, Alize Finucane, Mariel M. Flaxman, Seth Fowkes, Francis Gerry R. Freedman, Greg Freeman, Michael K. Gakidou, Emmanuela Ghosh, Santu Giovannucci, Edward Gmel, Gerhard Graham, Kathryn Grainger, Rebecca Grant, Bridget Gunnell, David Gutierrez, Hialy R. Hall, Wayne Hoek, Hans W. Hogan, Anthony Hosgood, H. Dean, III Hoy, Damian Hu, Howard Hubbell, Bryan J. Hutchings, Sally J. Ibeanusi, Sydney E. Jacklyn, Gemma L. Jasrasaria, Rashmi Jonas, Jost B. Kan, Haidong Kanis, John A. Kassebaum, Nicholas Kawakami, Norito Khang, Young-Ho Khatibzadeh, Shahab Khoo, Jon-Paul Kok, Cindy Laden, Francine Lalloo, Ratilal Lan, Qing Lathlean, Tim Leasher, Janet L. Leigh, James Li, Yang Lin, John Kent Lipshultz, Steven E. London, Stephanie Lozano, Rafael Lu, Yuan Mak, Joelle Malekzadeh, Reza Mallinger, Leslie Marcenes, Wagner March, Lyn Marks, Robin Martin, Randall McGale, Paul McGrath, John Mehta, Sumi Mensah, George A. Merriman, Tony R. Micha, Renata Michaud, Catherine Mishra, Vinod Hanafiah, Khayriyyah Mohd Mokdad, Ali A. Morawska, Lidia Mozaffarian, Dariush Murphy, Tasha Naghavi, Mohsen Neal, Bruce Nelson, Paul K. Miquel Nolla, Joan Norman, Rosana Olives, Casey Omer, Saad B. Orchard, Jessica Osborne, Richard Ostro, Bart Page, Andrew Pandey, Kiran D. Parry, Charles D. H. Passmore, Erin Patra, Jayadeep Pearce, Neil Pelizzari, Pamela M. Petzold, Max Phillips, Michael R. Pope, Dan Pope, C. Arden, III Powles, John Rao, Mayuree Razavi, Homie Rehfuess, Eva A. Rehm, Juergen T. Ritz, Beate Rivara, Frederick P. Roberts, Thomas Robinson, Carolyn Rodriguez-Portales, Jose A. Romieu, Isabelle Room, Robin Rosenfeld, Lisa C. Roy, Ananya Rushton, Lesley Salomon, Joshua A. Sampson, Uchechukwu Sanchez-Riera, Lidia Sanman, Ella Sapkota, Amir Seedat, Soraya Shi, Peilin Shield, Kevin Shivakoti, Rupak Singh, Gitanjali M. Sleet, David A. Smith, Emma Smith, Kirk R. Stapelberg, Nicolas J. C. Steenland, Kyle Stoeckl, Heidi Stovner, Lars Jacob Straif, Kurt Straney, Lahn Thurston, George D. Tran, Jimmy H. Van Dingenen, Rita van Donkelaar, Aaron Veerman, J. Lennert Vijayakumar, Lakshmi Weintraub, Robert Weissman, Myrna M. White, Richard A. Whiteford, Harvey Wiersma, Steven T. Wilkinson, James D. Williams, Hywel C. Williams, Warwick Wilson, Nicholas Woolf, Anthony D. Yip, Paul Zielinski, Jan M. Lopez, Alan D. Murray, Christopher J. L. Ezzati, Majid TI A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010 SO LANCET LA English DT Article ID CORONARY-HEART-DISEASE; LUNG-CANCER RISK; FINE PARTICULATE MATTER; ASIA-PACIFIC REGION; LONG-TERM EXPOSURE; BODY-MASS INDEX; RANDOMIZED CONTROLLED-TRIAL; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; AIR-POLLUTION AB Background Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. Methods We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. Findings In 2010, the three leading risk factors for global disease burden were high blood pressure (7.0% [95% uncertainty interval 6.2-7.7] of global DALYs), tobacco smoking including second-hand smoke (6.3% [5.5-7.0]), and alcohol use (5.5% [5.0-5.9]). In 1990, the leading risks were childhood underweight (7.9% [6.8-9.4]), household air pollution from solid fuels (HAP; 7.0% [5.6-8.3]), and tobacco smoking including second-hand smoke (6.1% [5.4-6.8]). Dietary risk factors and physical inactivity collectively accounted for 10.0% (95% UI 9.2-10.8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water and sanitation accounting for 0.9% (0.4-1.6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. Interpretation Worldwide, the contribution of different risk factors to disease burden has changed substantially, with a shift away from risks for communicable diseases in children towards those for non-communicable diseases in adults. These changes are related to the ageing population, decreased mortality among children younger than 5 years, changes in cause-of-death composition, and changes in risk factor exposures. New evidence has led to changes in the magnitude of key risks including unimproved water and sanitation, vitamin A and zinc deficiencies, and ambient particulate matter pollution. The extent to which the epidemiological shift has occurred and what the leading risks currently are varies greatly across regions. In much of sub-Saharan Africa, the leading risks are still those associated with poverty and those that affect children. C1 [Lim, Stephen S.; Flaxman, Abraham D.; Andrews, Kathryn G.; Atkinson, Charles; Carnahan, Emily; Colson, K. 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[Yip, Paul] Univ Hong Kong, Ctr Suicide Res & Prevent, Hong Kong, Hong Kong, Peoples R China. RP Lim, SS (reprint author), Univ Washington, Inst Hlth Metr & Evaluat, 2301 5th Ave,Suite 600, Seattle, WA 98121 USA. EM stevelim@uw.edu RI Balakrishnan, Kalpana/B-6653-2015; Lopez, Alan/F-1487-2010; Hall, Wayne/A-3283-2008; Stockwell, Tim/B-6662-2012; Baxter, Amanda/E-5449-2011; Ritz, Beate/E-3043-2015; Charlson, Fiona/F-5290-2011; Whiteford, Harvey/A-4840-2009; Boussinesq, Michel/J-7256-2016; Bacchus, Loraine/J-9996-2016; Lalloo, Ratilal/O-5624-2014; Salomon, Joshua/D-3898-2009; Martin, Randall/C-1205-2014; Pope, Daniel/C-3054-2014; Stovner, Lars/D-5025-2014; Sapkota, Amir/A-5968-2011; McGrath, John/G-5493-2010; Orchard, Jessica/E-2078-2013; NORMAN, ROSANA/F-2774-2010; Buchbinder, Rachelle/G-2952-2011; Degenhardt, Louisa/D-4515-2012; Bull, Fiona/G-4148-2012; Veerman, Lennert/A-9973-2011; Lathlean, Tim/K-3653-2013; Parry, Charles/A-2906-2009; OI Chen, Honglei/0000-0003-3446-7779; Osborne, Richard/0000-0002-9081-2699; London, Stephanie/0000-0003-4911-5290; Hoek, Hans/0000-0001-6353-5465; brunekreef, bert/0000-0001-9908-0060; Powles, John/0000-0002-0766-7989; Stockl, Heidi/0000-0002-0907-8483; Hu, Howard/0000-0002-3676-2707; Balakrishnan, Kalpana/0000-0002-5905-1801; Cowie, Benjamin/0000-0002-7087-5895; O'donnell, Colm/0000-0002-8004-450X; Malekzadeh, Reza/0000-0003-1043-3814; Mensah, George/0000-0002-0387-5326; Jacklyn, Gemma/0000-0002-4814-3241; Lopez, Alan/0000-0001-5818-6512; Hall, Wayne/0000-0003-1984-0096; Baxter, Amanda/0000-0001-8198-9022; Charlson, Fiona/0000-0003-2876-5040; Whiteford, Harvey/0000-0003-4667-6623; Boussinesq, Michel/0000-0001-6312-0681; Bacchus, Loraine/0000-0002-9966-8208; Lalloo, Ratilal/0000-0001-5822-1269; Salomon, Joshua/0000-0003-3929-5515; Ghosh, Santu/0000-0003-1358-3471; Martin, Randall/0000-0003-2632-8402; McGrath, John/0000-0002-4792-6068; Orchard, Jessica/0000-0002-5702-7277; NORMAN, ROSANA/0000-0002-9742-1957; Degenhardt, Louisa/0000-0002-8513-2218; Veerman, Lennert/0000-0002-3206-8232; Parry, Charles/0000-0001-9787-2785; Devries, Karen/0000-0001-8935-2181; Weissman, Myrna/0000-0003-3490-3075; Borges, Guilherme/0000-0002-3269-0507; Khang, Young-Ho/0000-0002-9585-8266; Brauer, Michael/0000-0002-9103-9343; Merriman, Tony/0000-0003-0844-8726 FU Lundbeck; Prana Biotechnology; Abbott; Amgen; AstraZeneca; George Clinical; GlaxoSmithKline; Novartis; PepsiCo; Pfizer; Pharmacy Guild of Australia; Roche; Sanofi-Aventis; Seervier; Tanabe; Australian Food and Grocery Council; Bupa Australia; Johnson and Johnson; Merck Schering-Plough; Servier; United Healthcare Group; Imperial College London (as PI) from the European Chemical Industry Council; CONCAWE; USEPA; Shell Foundation; Fight for Sight; Australian National Health and Medical Research Council; Monash University; Cabrini Health; Health Effects Institute; William and Flora Hewlett Foundation; Cancer Research UK; Safework Australia; Johns Hopkins Vaccine Initiative Scholarship; WHO; Parnassia Psychiatric Institute, The Hague, Netherlands; Department of Psychiatry, University Medical Center Groningen, University of Groningen, Netherlands; World Mental Health Japan; Grant for Research on Psychiatric and Neurological Diseases and Mental Health from the Japan Ministry of Health, Labour, and Welfare [H13-SHOGAI-023, H14-TOKUBETSU-026, H16-KOKORO-013]; Intramural Research Program of the NIH (National Cancer Institute); Division of Intramural Research, National Institute of Environmental Health Sciences, USA; Australian Research Council Future Fellowship; National Health and Medical Research Council of Australia Senior Research Fellowship; Munich Centre of Health Sciences; Foundation for Alcohol Research and Education; Victorian Department of Health; Burke Global Health Fellowship; Harold Amos Medical Faculty Development Award of the Robert Wood Johnson Foundation; Vanderbilt Clinical and Translational Scholars Award; Spanish Society of Rheumatology; South African Research Chairs Initiative; National Research Foundation; National Institute of Environmental Health Sciences [ES00260]; UK Medical Research Council (MRC); National Institute for Health Research Comprehensive Biomedical research Centre at Imperial College Healthcare NHS Trust; Nutrition Impact Model Study (NIMS); Bill & Melinda Gates Foundation; Spanish Rheumatology Association; Institute of Bone and Joint Research; University of Sydney FX A Davis is employed by the NHS on works for the UK Dept of Health as lead adviser on audiology. E R Dorsey has been a consultant for Medtronic and Lundbeck and has received grant support from Lundbeck and Prana Biotechnology. M Ezzati chaired a session and gave a talk at the World Cardiology Congress (WCC), with travel cost reimbursed by the World Heart Federation. At the WCC, he also gave a talk at a session organised by Pepsico with no financial remuneration. G A Mensah is a former employee of PepsiCo. D Mozaffarian has received: ad hoc travel reimbursement and/or honoraria for one-time specific presentations on diet and cardiometabolic diseases from Nutrition Impact (9/10), the International Life Sciences Institute (12/10), Bunge (11/11), Pollock Institute (3/12), and Quaker Oats (4/12; modest); and Unilever's North America Scientific Advisory Board (modest). B Neal is the Chair of the Australian Division of World Action on Salt and Health. He has consulted to Roche and Takeda. He has received lecture fees, travel fees, or reimbursements from Abbott, Amgen, AstraZeneca, George Clinical, GlaxoSmithKline, Novartis, PepsiCo, Pfizer, Pharmacy Guild of Australia, Roche, Sanofi-Aventis, Seervier, and Tanabe. He holds research support from the Australian Food and Grocery Council, Bupa Australia, Johnson and Johnson, Merck Schering-Plough, Roche, Servier, and United Healthcare Group. He is not employed by a commercial entity and has no equity ownership or stock options, patents or royalties, or any other financial or non-financial support that might be viewed as a conflict of interest. L Rushton received honorarium for board membership of the European Centre for Ecotoxicology and Toxicology of Chemicals and research grants to Imperial College London (as PI) from the European Chemical Industry Council and CONCAWE.; We thank the countless individuals who have contributed to the Global Burden of Disease Study 2010 in various capacities. We specifically acknowledge the important contribution to this work from multiple staff members of the World Health Organization. We also thank the following organisations that hosted consultations during the final stages of the analytical process, providing valuable feedback about the results and the data to improve the study's findings overall: Pan American Health Organization; Eastern Mediterranean Regional Office of WHO; UNAIDS; Ministry of Health, Brazil; China Centers for Disease Control; and the University of Zambia. We thank Regina Guthold, Jordis Ott, Annette Pruss-Ustun, and Gretchen A Stevens for their collaboration and input into the analyses and estimates. Finally, we acknowledge the extensive support from all staff members at the Institute for Health Metrics and Evaluation and specifically thank: James Bullard, Andrew Ernst, and Serkan Yalcin for their tireless support of the computational infrastructure required to produce the results; Linda A Ettinger for her expert administrative support to facilitate communication and coordination amongst the authors; Peter Speyer, Abigail McLain, Katherine Leach-Kemon, and Eden Stork for their persistent and valuable work to gain access to and catalogue as much data as possible to inform the estimates; and Erin C Mullany for her systematic efforts in organising drafts of papers, formatting correspondence with expert groups, and preparing the final manuscript. J Balmes, Z Chafe, and K R Smith acknowledge that their aspects of the research were also supported by USEPA and the Shell Foundation, neither of which had any role in design, data collection, analysis, interpretation, or decisions related to publication. R Bourne acknowledges Institutional Support: Vision & Eye Research Unit, Postgraduate Medical Institute, Anglia Ruskin University, Cambridge, UK. Funding support: Fight for Sight (Dr Hans and Mrs Gertrude Hirsch award). R Buchbinder was partially supported by an Australian National Health and Medical Research Council Practitioner Fellowship, Monash University, and Cabrini Health. A J Cohen received support from the Health Effects Institute and The William and Flora Hewlett Foundation. S Darby was supported by Cancer Research UK. L Degenhardt was supported by an Australian National Health and Medical Research Council Senior Research Fellowship. T Driscoll was supported in part by funding from the National Occupational Health and Safety Commission (now Safework Australia). K M Hanafiah's work for the GBD hepatitis C prevalence study was funded partly by Johns Hopkins Vaccine Initiative Scholarship and partly by WHO. H W Hoek acknowledges the support of: the Parnassia Psychiatric Institute, The Hague, Netherlands; the Department of Psychiatry, University Medical Center Groningen, University of Groningen, Netherlands; and the Department of Epidemiology, Columbia University, New York, USA. D Hoy was supported by the Bill & Melinda Gates Foundation and the Australian National Health and Medical Research Council. N Kawakami notes that data used in the study was collected through support from the following grants: The World Mental Health Japan is supported by the Grant for Research on Psychiatric and Neurological Diseases and Mental Health (H13-SHOGAI-023, H14-TOKUBETSU-026, H16-KOKORO-013) from the Japan Ministry of Health, Labour, and Welfare. He thanks staff members, filed coordinators, and interviewers of the WMH Japan 2002-2004 Survey.; Q Lan was supported in part by the Intramural Research Program of the NIH (National Cancer Institute). S London is supported by the Division of Intramural Research, National Institute of Environmental Health Sciences, USA. T R Merriman acknowledges the Health Research Council of New Zealand. B Neal was supported in his contribution to this work by an Australian Research Council Future Fellowship and a National Health and Medical Research Council of Australia Senior Research Fellowship. C Olives was supported in his contribution to this work by an Australian Research Council Future Fellowship and a National Health and Medical Research Council of Australia Senior Research Fellowship. E A Rehfuess acknowledges financial support from the Munich Centre of Health Sciences. R Room's position at the University of Melbourne and Turning Point Alcohol and Drug Centre is funded by the Foundation for Alcohol Research and Education and the Victorian Department of Health. J A Salomon received support from the Burke Global Health Fellowship while working on this study. U Sampson was supported in part by: The Harold Amos Medical Faculty Development Award of the Robert Wood Johnson Foundation; The Vanderbilt Clinical and Translational Scholars Award. L Sanchez-Riera acknowledges the Spanish Society of Rheumatology for their funds. S Seedat is supported by the South African Research Chairs Initiative, hosted by the Department of Science and Technology and the National Research Foundation. G D Thurston was supported in part by grant ES00260 from the National Institute of Environmental Health Sciences. J M Zielinski acknowledges institutional support from: Health Canada, University of Ottawa, and WHO (International Radon Project). M Ezzati's research is supported by a Strategic Award from the UK Medical Research Council (MRC) and by the National Institute for Health Research Comprehensive Biomedical research Centre at Imperial College Healthcare NHS Trust. Work on micronutrient deficiencies was supported by the Nutrition Impact Model Study (NIMS) funded by the Bill & Melinda Gates Foundation. The GBD Osteoporosis Expert Group was supported by the Spanish Rheumatology Association, Institute of Bone and Joint Research, University of Sydney. The GBD Osteoporosis Expert Group also acknowledges the contributions made by Professor Philip Sambrook who passed away in April, 2012. NR 192 TC 2676 Z9 2777 U1 212 U2 1309 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 EI 1474-547X J9 LANCET JI Lancet PD DEC 15 PY 2012 VL 380 IS 9859 BP 2224 EP 2260 PG 37 WC Medicine, General & Internal SC General & Internal Medicine GA 055AL UT WOS:000312387000017 PM 23245609 ER PT J AU Sherwood, JE Mesner, OC Weintrob, AC Hadigan, CM Wilkins, KJ Crum-Cianflone, NF Aronson, NE AF Sherwood, Jeffrey E. Mesner, Octavio C. Weintrob, Amy C. Hadigan, Colleen M. Wilkins, Kenneth J. Crum-Cianflone, Nancy F. Aronson, Naomi E. TI Vitamin D Deficiency and Its Association With Low Bone Mineral Density, HIV-Related Factors, Hospitalization, and Death in a Predominantly Black HIV-Infected Cohort SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; RANDOMIZED CONTROLLED-TRIALS; HUMAN-IMMUNODEFICIENCY-VIRUS; D INSUFFICIENCY; DISEASE PROGRESSION; AFRICAN-AMERICANS; FREE TESTOSTERONE; POSITIVE PATIENTS; HIGH PREVALENCE; RISK-FACTORS AB Background. Low bone mineral density (BMD) is common among patients infected with human immunodeficiency virus (HIV) and present in higher rates in black subjects. This study assessed vitamin D levels in HIV cases versus noninfected matched controls to determine if deficiency was associated with BMD and HIV clinical outcomes. Methods. In total, 271 military beneficiaries with HIV underwent dual energy x-ray absorptiometry (DEXA) screening in 2001-2. Serum 25OH-vitamin D levels were determined using stored serum from the time of DEXA and 6-18 months prior. Two non-HIV-infected controls for each active duty case (n = 205) were matched on age, sex, race, zip code, and season using the Department of Defense Serum Repository (DoDSR). Vitamin D levels <20 ng/mL were considered deficient. HIV-related factors and clinical outcomes were assessed using data collected in the DoD HIV Natural History study. Results. In total, 165 of 205 (80.5%) active duty HIV cases had 2 matched controls available. HIV cases had greater odds of for vitamin D deficiency (VDD) compared with controls (demographics adjusted paired data odds ratio [OR], 1.46, 95% confidence interval [CI], .87-2.45), but this was not statistically significant. Blacks were disproportionately deficient (P < .001) but not relative to HIV status or BMD. Low BMD was associated with typical risk factors (low body mass index and exercise levels, alcohol use); given limited available data the relationship between tenofovir exposure and VDD or low BMD could not be determined. Analysis of HIV-specific factors and outcomes such as exposure to antiretrovirals, HIV progression, hospitalizations, and death revealed no significant associations with vitamin D levels. Conclusions. VDD was highly prevalent in black HIV-infected persons but did not explain the observed racial disparity in BMD. Vitamin D deficiency was not more common among HIV-infected persons, nor did it seem associated with HIV-related factors/clinical outcomes. C1 [Weintrob, Amy C.; Aronson, Naomi E.] Uniformed Serv Univ Hlth Sci, Dept Med, Bethesda, MD 20814 USA. [Sherwood, Jeffrey E.] William Beaumont Army Med Ctr, Dept Med, El Paso, TX 79920 USA. [Mesner, Octavio C.; Weintrob, Amy C.; Wilkins, Kenneth J.; Crum-Cianflone, Nancy F.] Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Infect Dis Clin Res Program, Bethesda, MD 20814 USA. [Weintrob, Amy C.; Aronson, Naomi E.] Walter Reed Natl Mil Med Ctr, Dept Med, Bethesda, MD USA. [Hadigan, Colleen M.] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. [Crum-Cianflone, Nancy F.] USN, San Diego Med Ctr, Infect Dis Clin, San Diego, CA USA. RP Aronson, NE (reprint author), Uniformed Serv Univ Hlth Sci, Dept Med, Rm A3058,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM naomi.aronson@usuhs.edu FU Infectious Disease Clinical Research Program (IDCRP), a Department of Defense program through the Uniformed Services University of the Health Sciences [IDCRP-000-03]; National Institute of Allergy and Infectious Diseases, National Institutes of Health [Y1-AI-5072] FX Support for this work (IDCRP-000-03) was provided by the Infectious Disease Clinical Research Program (IDCRP), a Department of Defense program executed through the Uniformed Services University of the Health Sciences. This project has been funded in whole, or in part, with federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under Inter-Agency Agreement Y1-AI-5072. NR 36 TC 8 Z9 8 U1 1 U2 10 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2012 VL 55 IS 12 BP 1727 EP 1736 DI 10.1093/cid/cis785 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 044SF UT WOS:000311643000021 PM 22972869 ER PT J AU Prasad, P Sun, JF Danner, RL Natanson, C AF Prasad, Paritosh Sun, Junfeng Danner, Robert L. Natanson, Charles TI Patient-Level Data Provide Additional Insight for Tigecycline All-Cause Mortality Meta-analysis Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Prasad, Paritosh; Sun, Junfeng; Danner, Robert L.; Natanson, Charles] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Prasad, P (reprint author), NIH, Dept Crit Care Med, Ctr Clin, 9000 Rockville Pike,Bldg 10,Rm 2C145, Bethesda, MD 20892 USA. EM paritosh.prasad@nih.gov NR 3 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2012 VL 55 IS 12 BP 1740 EP 1741 DI 10.1093/cid/cis768 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 044SF UT WOS:000311643000024 ER PT J AU Chasman, DI Fuchsberger, C Pattaro, C Teumer, A Boger, CA Endlich, K Olden, M Chen, MH Tin, A Taliun, D Li, M Gao, XY Gorski, M Yang, Q Hundertmark, C Foster, MC O'Seaghdha, CM Glazer, N Isaacs, A Liu, CT Smith, AV O'Connell, JR Struchalin, M Tanaka, T Li, G Johnson, AD Gierman, HJ Feitosa, MF Hwang, SJ Atkinson, EJ Lohman, K Cornelis, MC Johansson, A Tonjes, A Dehghan, A Lambert, JC Holliday, EG Sorice, R Kutalik, Z Lehtimaki, T Esko, T Deshmukh, H Ulivi, S Chu, AY Murgia, F Trompet, S Imboden, M Coassin, S Pistis, G Harris, TB Launer, LJ Aspelund, T Eiriksdottir, G Mitchell, BD Boerwinkle, E Schmidt, H Cavalieri, M Rao, M Hu, F Demirkan, A Oostra, BA de Andrade, M Turner, ST Ding, JZ Andrews, JS Freedman, BI Giulianini, F Koenig, W Illig, T Meisinger, C Gieger, C Zgaga, L Zemunik, T Boban, M Minelli, C Wheeler, HE Igl, W Zaboli, G Wild, SH Wright, AF Campbell, H Ellinghaus, D Nothlings, U Jacobs, G Biffar, R Ernst, F Homuth, G Kroemer, HK Nauck, M Stracke, S Volker, U Volzke, H Kovacs, P Stumvoll, M Magi, R Hofman, A Uitterlinden, AG Rivadeneira, F Aulchenko, YS Polasek, O Hastie, N Vitart, V Helmer, C Wang, JJ Stengel, B Ruggiero, D Bergmann, S Kahonen, M Viikari, J Nikopensius, T Province, M Ketkar, S Colhoun, H Doney, A Robino, A Kramer, BK Portas, L Ford, I Buckley, BM Adam, M Thun, GA Paulweber, B Haun, M Sala, C Mitchell, P Ciullo, M Kim, SK Vollenweider, P Raitakari, O Metspalu, A Palmer, C Gasparini, P Pirastu, M Jukema, JW Probst-Hensch, NM Kronenberg, F Toniolo, D Gudnason, V Shuldiner, AR Coresh, J Schmidt, R Ferrucci, L Siscovick, DS van Duijn, CM Borecki, IB Kardia, SLR Liu, YM Curhan, GC Rudan, I Gyllensten, U Wilson, JF Franke, A Pramstaller, PP Rettig, R Prokopenko, I Witteman, J Hayward, C Ridker, PM Parsa, A Bochud, M Heid, IM Kao, WHL Fox, CS Kottgen, A AF Chasman, Daniel I. Fuchsberger, Christian Pattaro, Cristian Teumer, Alexander Boeger, Carsten A. Endlich, Karlhans Olden, Matthias Chen, Ming-Huei Tin, Adrienne Taliun, Daniel Li, Man Gao, Xiaoyi Gorski, Mathias Yang, Qiong Hundertmark, Claudia Foster, Meredith C. O'Seaghdha, Conall M. Glazer, Nicole Isaacs, Aaron Liu, Ching-Ti Smith, Albert V. O'Connell, Jeffrey R. Struchalin, Maksim Tanaka, Toshiko Li, Guo Johnson, Andrew D. Gierman, Hinco J. Feitosa, Mary F. Hwang, Shih-Jen Atkinson, Elizabeth J. Lohman, Kurt Cornelis, Marilyn C. Johansson, Asa Toenjes, Anke Dehghan, Abbas Lambert, Jean-Charles Holliday, Elizabeth G. Sorice, Rossella Kutalik, Zoltan Lehtimaeki, Terho Esko, Tonu Deshmukh, Harshal Ulivi, Sheila Chu, Audrey Y. Murgia, Federico Trompet, Stella Imboden, Medea Coassin, Stefan Pistis, Giorgio Harris, Tamara B. Launer, Lenore J. Aspelund, Thor Eiriksdottir, Gudny Mitchell, Braxton D. Boerwinkle, Eric Schmidt, Helena Cavalieri, Margherita Rao, Madhumathi Hu, Frank Demirkan, Ayse Oostra, Ben A. de Andrade, Mariza Turner, Stephen T. Ding, Jingzhong Andrews, Jeanette S. Freedman, Barry I. Giulianini, Franco Koenig, Wolfgang Illig, Thomas Meisinger, Christa Gieger, Christian Zgaga, Lina Zemunik, Tatijana Boban, Mladen Minelli, Cosetta Wheeler, Heather E. Igl, Wilmar Zaboli, Ghazal Wild, Sarah H. Wright, Alan F. Campbell, Harry Ellinghaus, David Noethlings, Ute Jacobs, Gunnar Biffar, Reiner Ernst, Florian Homuth, Georg Kroemer, Heyo K. Nauck, Matthias Stracke, Sylvia Voelker, Uwe Voelzke, Henry Kovacs, Peter Stumvoll, Michael Maegi, Reedik Hofman, Albert Uitterlinden, Andre G. Rivadeneira, Fernando Aulchenko, Yurii S. Polasek, Ozren Hastie, Nick Vitart, Veronique Helmer, Catherine Wang, Jie Jin Stengel, Benedicte Ruggiero, Daniela Bergmann, Sven Kahonen, Mika Viikari, Jorma Nikopensius, Tiit Province, Michael Ketkar, Shamika Colhoun, Helen Doney, Alex Robino, Antonietta Kraemer, Bernhard K. Portas, Laura Ford, Ian Buckley, Brendan M. Adam, Martin Thun, Gian-Andri Paulweber, Bernhard Haun, Margot Sala, Cinzia Mitchell, Paul Ciullo, Marina Kim, Stuart K. Vollenweider, Peter Raitakari, Olli Metspalu, Andres Palmer, Colin Gasparini, Paolo Pirastu, Mario Jukema, J. Wouter Probst-Hensch, Nicole M. Kronenberg, Florian Toniolo, Daniela Gudnason, Vilmundur Shuldiner, Alan R. Coresh, Josef Schmidt, Reinhold Ferrucci, Luigi Siscovick, David S. van Duijn, Cornelia M. Borecki, Ingrid B. Kardia, Sharon L. R. Liu, Yongmei Curhan, Gary C. Rudan, Igor Gyllensten, Ulf Wilson, James F. Franke, Andre Pramstaller, Peter P. Rettig, Rainer Prokopenko, Inga Witteman, Jacqueline Hayward, Caroline Ridker, Paul M. Parsa, Afshin Bochud, Murielle Heid, Iris M. Kao, W. H. Linda Fox, Caroline S. Koettgen, Anna CA CARDIoGRAM Consortium ICBP Consortium CARe Consortium WTCCC2 TI Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function SO HUMAN MOLECULAR GENETICS LA English DT Article ID GLOMERULAR-FILTRATION-RATE; COMMUNITY-BASED POPULATION; SERUM CREATININE; RENAL-FUNCTION; R PACKAGE; DISEASE; EXPRESSION; LOCI; TRAITS; SNPS AB In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general. C1 [Chasman, Daniel I.; Chu, Audrey Y.; Giulianini, Franco; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02215 USA. [Chasman, Daniel I.; O'Seaghdha, Conall M.; Curhan, Gary C.; Ridker, Paul M.; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Fuchsberger, Christian] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Pattaro, Cristian; Taliun, Daniel; Minelli, Cosetta; Pramstaller, Peter P.] Med Univ Lubeck, Affiliated Inst, European Acad Bozen Bolzano, Ctr Biomed, I-39100 Bolzano, Italy. [Teumer, Alexander; Homuth, Georg; Voelker, Uwe] Ernst Moritz Arndt Univ Greifswald, Interfac Inst Genet & Funct Genom, D-17487 Greifswald, Germany. [Boeger, Carsten A.; Olden, Matthias] Univ Hosp Regensburg, Dept Internal Med 2, D-93042 Regensburg, Germany. [Olden, Matthias; Gorski, Mathias; Heid, Iris M.] Univ Hosp Regensburg, Dept Epidemiol & Prevent Med, D-93042 Regensburg, Germany. [Endlich, Karlhans] Ernst Moritz Arndt Univ Greifswald, Inst Anat & Cell Biol, D-17487 Greifswald, Germany. [Chen, Ming-Huei] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Chen, Ming-Huei; Yang, Qiong] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Tin, Adrienne; Li, Man; Coresh, Josef; Kao, W. H. Linda; Koettgen, Anna] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Gao, Xiaoyi; Feitosa, Mary F.; Province, Michael; Ketkar, Shamika; Borecki, Ingrid B.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO 63108 USA. [Gorski, Mathias; Illig, Thomas; Heid, Iris M.] Univ Munich, Inst Med Informat Biometry & Epidemiol, D-85764 Neuherberg, Germany. [Gorski, Mathias; Illig, Thomas; Heid, Iris M.] Univ Munich, Inst Epidemiol, D-85764 Neuherberg, Germany. [Hundertmark, Claudia; Koettgen, Anna] Freiburg Univ Clin, Div Renal, D-79110 Freiburg, Germany. [Foster, Meredith C.; Johnson, Andrew D.; Hwang, Shih-Jen; Fox, Caroline S.] NHLBI Framingham Heart Study, Ctr Populat Studies, Framingham, MA 01702 USA. [O'Seaghdha, Conall M.] Brigham & Womens Hosp, Div Nephrol, Boston, MA 02115 USA. [Glazer, Nicole] Boston Univ, Sch Med, Sect Prevent Med & Epidemiol, Dept Med, Boston, MA 02118 USA. [Isaacs, Aaron; Dehghan, Abbas; Demirkan, Ayse; Oostra, Ben A.; Hofman, Albert; Aulchenko, Yurii S.; van Duijn, Cornelia M.; Witteman, Jacqueline] Erasmus MC, Dept Epidemiol, NL-3000 CA Rotterdam, Netherlands. [Isaacs, Aaron; Demirkan, Ayse; Oostra, Ben A.] Leiden Univ, Ctr Med Syst Biol, Leiden, Netherlands. [Liu, Ching-Ti] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Smith, Albert V.; Aspelund, Thor; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Res Inst, IS-201 Kopavogur, Iceland. [Smith, Albert V.; Aspelund, Thor; Gudnason, Vilmundur] Univ Iceland, IS-101 Reykjavik, Iceland. [O'Connell, Jeffrey R.; Mitchell, Braxton D.; Shuldiner, Alan R.] Univ Maryland, Sch Med, Dept Med, Baltimore, MD 21201 USA. [Parsa, Afshin] Univ Maryland, Sch Med, Div Nephrol, Baltimore, MD 21201 USA. [Struchalin, Maksim] Univ Rotterdam, Dept Epidemiol & Biostat, Rotterdam, Netherlands. [Struchalin, Maksim] Univ Rotterdam, Dept Forens Mol Biol, Rotterdam, Netherlands. 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[Biffar, Reiner] Ernst Moritz Arndt Univ Greifswald, Clin Prosthodont Dent Gerostomatol & Mat Sci, D-17475 Greifswald, Germany. [Kroemer, Heyo K.] Ernst Moritz Arndt Univ Greifswald, Inst Pharmacol, D-17487 Greifswald, Germany. [Nauck, Matthias] Ernst Moritz Arndt Univ Greifswald, Inst Clin Chem & Lab Med, D-17475 Greifswald, Germany. [Stracke, Sylvia] Ernst Moritz Arndt Univ Greifswald, Clin Internal Med A, D-17475 Greifswald, Germany. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, D-17487 Greifswald, Germany. [Maegi, Reedik] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford OX3 7LJ, England. [Maegi, Reedik; Prokopenko, Inga] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. [Uitterlinden, Andre G.; Rivadeneira, Fernando; Prokopenko, Inga] Erasmus MC, Dept Internal Med, NL-3000 DR Rotterdam, Netherlands. [Helmer, Catherine] Univ Bordeaux 2, ISPED Case 11, INSERM U897, F-33076 Bordeaux, France. [Wang, Jie Jin; Mitchell, Paul] Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Ctr Vis Res, Sydney, NSW 2145, Australia. [Wang, Jie Jin] Univ Melbourne, CERA, Melbourne, Vic 3002, Australia. [Stengel, Benedicte] Univ Paris 11, INSERM UMRS CESP Team 10 1018, Villejuif, France. [Kahonen, Mika] Univ Tampere, Dept Clin Physiol, Tampere 33521, Finland. [Viikari, Jorma; Raitakari, Olli] Univ Turku, Dept Clin Physiol, Turku Univ Hosp, Res Ctr Appl & Prevent Cardiovasc Med, Turku 20521, Finland. [Robino, Antonietta; Gasparini, Paolo] Univ Trieste, Trieste, Italy. [Kraemer, Bernhard K.] Univ Med Ctr Mannheim, Dept Med, D-68167 Mannheim, Germany. [Ford, Ian] Univ Glasgow, Robertson Ctr Biostat, Glasgow, Lanark, Scotland. [Buckley, Brendan M.] Natl Univ Ireland Univ Coll Cork, Dept Pharmacol & Therapeut, Cork, Ireland. [Paulweber, Bernhard] Paracelsus Med Univ, Dept Internal Med 1, A-5020 Salzburg, Austria. [Vollenweider, Peter] CHU Vaudois, Dept Internal Med, CH-1011 Lausanne, Switzerland. [Vollenweider, Peter] Univ Lausanne, CH-1011 Lausanne, Switzerland. [Palmer, Colin] Univ Dundee, Biomed Res Inst, Ninewells Hosp Dundee, Dundee DD1 9SY, Scotland. [Jukema, J. Wouter] Durrer Ctr Cardiogenet Res, Amsterdam, Netherlands. [Jukema, J. Wouter] ICIN, Utrecht, Netherlands. [Jukema, J. Wouter] Einthoven Lab Expt Vasc Med, Leiden, Netherlands. [Shuldiner, Alan R.] Vet Adm Med Ctr, Geriatr Res & Educ Clin Ctr, Baltimore, MD 21218 USA. [Coresh, Josef; Kao, W. H. Linda] Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21287 USA. [Schmidt, Reinhold] Med Univ Graz, Univ Clin Neurol, Dept Special Neurol, A-8036 Graz, Austria. [Kardia, Sharon L. R.] Univ Med, Dept Epidemiol, Ann Arbor, MI 48109 USA. [Kardia, Sharon L. R.] Univ Med, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Curhan, Gary C.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Rettig, Rainer] Ernst Moritz Arndt Univ Greifswald, Inst Physiol, D-17487 Greifswald, Germany. [Bochud, Murielle] CHU Vaudois, Univ Inst Social & Prevent Med, CH-1066 Epalinges, Switzerland. [Bochud, Murielle] Univ Lausanne, CH-1066 Epalinges, Switzerland. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. RP Chasman, DI (reprint author), Brigham & Womens Hosp, Div Prevent Med, 900 Commonwealth Ave E, Boston, MA 02215 USA. EM dchasman@rics.bwh.harvard.edu; cfuchsb@umich.edu RI Smith, Albert/K-5150-2015; ruggiero, daniela/K-5638-2016; Bochud, Murielle/A-3981-2010; Hayward, Caroline/M-8818-2016; Franke, Andre/B-2151-2010; Boban, Mladen/E-2777-2017; Feitosa, Mary/K-8044-2012; Johansson, Asa/G-5270-2011; EHRET, Georg/A-9532-2009; Wang, Jie Jin/P-1499-2014; Kronenberg, Florian/B-1736-2008; Mitchell, Paul/P-1498-2014; lambert, jean-charles/F-8787-2013; HELMER, Catherine/I-6581-2015; Gudnason, Vilmundur/K-6885-2015; Wilson, James F/A-5704-2009; Polasek, Ozren/B-6002-2011; Prokopenko, Inga/H-3241-2014; Stengel, Benedicte/G-5730-2015; Rudan, Igor/I-1467-2012; Johnson, Andrew/G-6520-2013; Ulivi, Sheila/H-3700-2013; Aspelund, Thor/C-5983-2008; Colaus, PsyColaus/K-6607-2013; Aulchenko, Yurii/M-8270-2013; Lambert, jean-charles/A-9553-2014; Meisinger, Christine/B-5358-2014; Yang, Qiong/G-5438-2014; Pramstaller, Peter/C-2357-2008; Ellinghaus, David/G-4467-2012; Nothlings, Ute/B-2713-2010; Endlich, Karlhans/G-5485-2013 OI Magi, Reedik/0000-0002-2964-6011; Esko, Tonu/0000-0003-1982-6569; Gieger, Christian/0000-0001-6986-9554; Rivadeneira, Fernando/0000-0001-9435-9441; Palmer, Colin/0000-0002-6415-6560; Meisinger, Christa/0000-0002-9026-6544; Smith, Albert/0000-0003-1942-5845; ruggiero, daniela/0000-0003-3898-7827; Bochud, Murielle/0000-0002-5727-0218; Hayward, Caroline/0000-0002-9405-9550; Franke, Andre/0000-0003-1530-5811; Feitosa, Mary/0000-0002-0933-2410; Thun, Gian Andri/0000-0003-4436-3455; Fuchsberger, Christian/0000-0002-5918-8947; Zgaga, Lina/0000-0003-4089-9703; Wheeler, Heather/0000-0003-1365-9667; Johansson, Asa/0000-0002-2915-4498; EHRET, Georg/0000-0002-5730-0675; Wang, Jie Jin/0000-0001-9491-4898; Kronenberg, Florian/0000-0003-2229-1120; HELMER, Catherine/0000-0002-5169-7421; Gudnason, Vilmundur/0000-0001-5696-0084; Wilson, James F/0000-0001-5751-9178; Polasek, Ozren/0000-0002-5765-1862; Prokopenko, Inga/0000-0003-1624-7457; Rudan, Igor/0000-0001-6993-6884; Colhoun, Helen/0000-0002-8345-3288; Mitchell, Braxton/0000-0003-4920-4744; Bergmann, Sven/0000-0002-6785-9034; Dehghan, Abbas/0000-0001-6403-016X; Ulivi, Sheila/0000-0003-3606-835X; Aspelund, Thor/0000-0002-7998-5433; Aulchenko, Yurii/0000-0002-7899-1575; Lambert, jean-charles/0000-0003-0829-7817; FU Chief Scientist Office [CZB/4/710]; Medical Research Council [MC_U127561128]; NCI NIH HHS [F32 CA165823, R01 CA047988]; NHLBI NIH HHS [N01 HC025195, R01 HL043851, R01 HL080467, T32 HL007575]; NIA NIH HHS [R01 AG025941]; NIDDK NIH HHS [P30 DK079637] NR 68 TC 28 Z9 28 U1 2 U2 41 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 DEC 15 PY 2012 VL 21 IS 24 BP 5329 EP 5343 DI 10.1093/hmg/dds369 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 049ES UT WOS:000311965600009 PM 22962313 ER PT J AU Siddiq, A Couch, FJ Chen, GK Lindstrom, S Eccles, D Millikan, RC Michailidou, K Stram, DO Beckmann, L Rhie, SK Ambrosone, CB Aittomaki, K Amiano, P Apicella, C Baglietto, L Bandera, EV Beckmann, MW Berg, CD Bernstein, L Blomqvist, C Brauch, H Brinton, L Bui, QM Buring, JE Buys, SS Campa, D Carpenter, JE Chasman, DI Chang-Claude, J Chen, C Clavel-Chapelon, F Cox, A Cross, SS Czene, K Deming, SL Diasio, RB Diver, WR Dunning, AM Durcan, L Ekici, AB Fasching, PA Feigelson, HS Fejerman, L Figueroa, JD Fletcher, O Flesch-Janys, D Gaudet, MM Gerty, SM Rodriguez-Gil, JL Giles, GG van Gils, CH Godwin, AK Graham, N Greco, D Hall, P Hankinson, SE Hartmann, A Hein, R Heinz, J Hoover, RN Hopper, JL Hu, JJ Huntsman, S Ingles, SA Irwanto, A Isaacs, C Jacobs, KB John, EM Justenhoven, C Kaaks, R Kolonel, LN Coetzee, GA Lathrop, M Marchand, L Lee, AM Lee, IM Lesnick, T Lichtner, P Liu, JJ Lund, E Makalic, E Martin, NG McLean, CA Meijers-Heijboer, H Meindl, A Miron, P Monroe, KR Montgomery, GW Muller-Myhsok, B Nickels, S Nyante, SJ Olswold, C Overvad, K Palli, D Park, DJ Palmer, JR Pathak, H Peto, J Pharoah, P Rahman, N Rivadeneira, F Schmidt, DF Schmutzler, RK Slager, S Southey, MC Stevens, KN Sinn, HP Press, MF Ross, E Riboli, E Ridker, PM Schumacher, FR Severi, G Silva, ID Stone, J Sund, M Tapper, WJ Thun, MJ Travis, RC Turnbull, C Uitterlinden, AG Waisfisz, Q Wang, XS Wang, ZM Weaver, J Schulz-Wendtland, R Wilkens, LR Van Den Berg, D Zheng, W Ziegler, RG Ziv, E Nevanlinna, H Easton, DF Hunter, DJ Henderson, BE Chanock, SJ Garcia-Closas, M Kraft, P Haiman, CA Vachon, CM AF Siddiq, Afshan Couch, Fergus J. Chen, Gary K. Lindstrom, Sara Eccles, Diana Millikan, Robert C. Michailidou, Kyriaki Stram, Daniel O. Beckmann, Lars Rhie, Suhn Kyong Ambrosone, Christine B. Aittomaki, Kristiina Amiano, Pilar Apicella, Carmel Baglietto, Laura Bandera, Elisa V. Beckmann, Matthias W. Berg, Christine D. Bernstein, Leslie Blomqvist, Carl Brauch, Hiltrud Brinton, Louise Bui, Quang M. Buring, Julie E. Buys, Saundra S. Campa, Daniele Carpenter, Jane E. Chasman, Daniel I. Chang-Claude, Jenny Chen, Constance Clavel-Chapelon, Francoise Cox, Angela Cross, Simon S. Czene, Kamila Deming, Sandra L. Diasio, Robert B. Diver, W. Ryan Dunning, Alison M. Durcan, Lorraine Ekici, Arif B. Fasching, Peter A. Feigelson, Heather Spencer Fejerman, Laura Figueroa, Jonine D. Fletcher, Olivia Flesch-Janys, Dieter Gaudet, Mia M. Gerty, Susan M. Rodriguez-Gil, Jorge L. Giles, Graham G. van Gils, Carla H. Godwin, Andrew K. Graham, Nikki Greco, Dario Hall, Per Hankinson, Susan E. Hartmann, Arndt Hein, Rebecca Heinz, Judith Hoover, Robert N. Hopper, John L. Hu, Jennifer J. Huntsman, Scott Ingles, Sue A. Irwanto, Astrid Isaacs, Claudine Jacobs, Kevin B. John, Esther M. Justenhoven, Christina Kaaks, Rudolf Kolonel, Laurence N. Coetzee, Gerhard A. Lathrop, Mark Le Marchand, Loic Lee, Adam M. Lee, I-Min Lesnick, Timothy Lichtner, Peter Liu, Jianjun Lund, Eiliv Makalic, Enes Martin, Nicholas G. McLean, Catriona A. Meijers-Heijboer, Hanne Meindl, Alfons Miron, Penelope Monroe, Kristine R. Montgomery, Grant W. Mueller-Myhsok, Bertram Nickels, Stefan Nyante, Sarah J. Olswold, Curtis Overvad, Kim Palli, Domenico Park, Daniel J. Palmer, Julie R. Pathak, Harsh Peto, Julian Pharoah, Paul Rahman, Nazneen Rivadeneira, Fernando Schmidt, Daniel F. Schmutzler, Rita K. Slager, Susan Southey, Melissa C. Stevens, Kristen N. Sinn, Hans-Peter Press, Michael F. Ross, Eric Riboli, Elio Ridker, Paul M. Schumacher, Fredrick R. Severi, Gianluca Silva, Isabel dos Santos Stone, Jennifer Sund, Malin Tapper, William J. Thun, Michael J. Travis, Ruth C. Turnbull, Clare Uitterlinden, Andre G. Waisfisz, Quinten Wang, Xianshu Wang, Zhaoming Weaver, JoEllen Schulz-Wendtland, Ruediger Wilkens, Lynne R. Van Den Berg, David Zheng, Wei Ziegler, Regina G. Ziv, Elad Nevanlinna, Heli Easton, Douglas F. Hunter, David J. Henderson, Brian E. Chanock, Stephen J. Garcia-Closas, Montserrat Kraft, Peter Haiman, Christopher A. Vachon, Celine M. CA Australian Breast Canc Tissue Bank Familial Breast Canc Study GENICA Consortium TI A meta-analysis of genome-wide association studies of breast cancer identifies two novel susceptibility loci at 6q14 and 20q11 SO HUMAN MOLECULAR GENETICS LA English DT Article ID BRCA1 MUTATION CARRIERS; TUMOR SUBTYPES; RISK; POPULATION; CONSORTIUM; MELANOMA AB Genome-wide association studies (GWAS) of breast cancer defined by hormone receptor status have revealed loci contributing to susceptibility of estrogen receptor (ER)-negative subtypes. To identify additional genetic variants for ER-negative breast cancer, we conducted the largest meta-analysis of ER-negative disease to date, comprising 4754 ER-negative cases and 31 663 controls from three GWAS: NCI Breast and Prostate Cancer Cohort Consortium (BPC3) (2188 ER-negative cases; 25 519 controls of European ancestry), Triple Negative Breast Cancer Consortium (TNBCC) (1562 triple negative cases; 3399 controls of European ancestry) and African American Breast Cancer Consortium (AABC) (1004 ER-negative cases; 2745 controls). We performed in silico replication of 86 SNPs at P 1 10(-5) in an additional 11 209 breast cancer cases (946 with ER-negative disease) and 16 057 controls of Japanese, Latino and European ancestry. We identified two novel loci for breast cancer at 20q11 and 6q14. SNP rs2284378 at 20q11 was associated with ER-negative breast cancer (combined two-stage OR 1.16; P 1.1 10(8)) but showed a weaker association with overall breast cancer (OR 1.08, P 1.3 10(6)) based on 17 869 cases and 43 745 controls and no association with ER-positive disease (OR 1.01, P 0.67) based on 9965 cases and 22 902 controls. Similarly, rs17530068 at 6q14 was associated with breast cancer (OR 1.12; P 1.1 10(9)), and with both ER-positive (OR 1.09; P 1.5 10(5)) and ER-negative (OR 1.16, P 2.5 10(7)) disease. We also confirmed three known loci associated with ER-negative (19p13) and both ER-negative and ER-positive breast cancer (6q25 and 12p11). Our results highlight the value of large-scale collaborative studies to identify novel breast cancer risk loci. C1 [Couch, Fergus J.; Lesnick, Timothy; Olswold, Curtis; Slager, Susan; Stevens, Kristen N.; Vachon, Celine M.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN 55905 USA. [Couch, Fergus J.; Wang, Xianshu] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Diasio, Robert B.; Lee, Adam M.] Mayo Clin, Dept Pharmacol, Rochester, MN 55905 USA. [Siddiq, Afshan; Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Genom Common Dis, London, England. [Chen, Gary K.; Stram, Daniel O.; Rhie, Suhn Kyong; Ingles, Sue A.; Coetzee, Gerhard A.; Monroe, Kristine R.; Schumacher, Fredrick R.; Van Den Berg, David; Henderson, Brian E.; Haiman, Christopher A.] Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Press, Michael F.] Univ So Calif, Keck Sch Med, Kenneth Norris Jr Comprehens Canc Ctr, Dept Pathol, Los Angeles, CA 90033 USA. [Coetzee, Gerhard A.] Univ So Calif, Keck Sch Med, Dept Urol, Los Angeles, CA 90089 USA. [Lindstrom, Sara; Chen, Constance; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Eccles, Diana; Durcan, Lorraine; Gerty, Susan M.; Graham, Nikki; Tapper, William J.] Univ Southampton, Fac Med, Southampton SO9 5NH, Hants, England. [Millikan, Robert C.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Millikan, Robert C.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Michailidou, Kyriaki] Univ Cambridge, Dept Publ Hlth & Primary Care, Ctr Canc Genet Epidemiol, Cambridge, England. [Dunning, Alison M.; Pharoah, Paul; Easton, Douglas F.] Univ Cambridge, Ctr Canc Genet Epidemiol, Dept Oncol, Cambridge, England. [Beckmann, Lars] IQWiG, Inst Qual & Efficiency Hlth Care, Cologne, Germany. [Ambrosone, Christine B.] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA. [Aittomaki, Kristiina] Univ Helsinki, Dept Clin Genet, Helsinki, Finland. [Greco, Dario; Nevanlinna, Heli] Univ Helsinki, Dept Obstet & Gynecol, Helsinki, Finland. [Blomqvist, Carl] Helsinki Univ Cent Hosp, Dept Oncol, Helsinki, Finland. [Amiano, Pilar] Consortium Biomed Res Epidemiol & Publ Hlth CIBER, Madrid, Spain. [Apicella, Carmel; Baglietto, Laura; Bui, Quang M.; Giles, Graham G.; Hopper, John L.; Makalic, Enes; Schmidt, Daniel F.; Severi, Gianluca; Stone, Jennifer] Univ Melbourne, Ctr Mol Environm Genet & Analyt Epidemiol, Melbourne Sch Populat Hlth, Melbourne, Vic 3010, Australia. [Park, Daniel J.; Southey, Melissa C.] Univ Melbourne, Genet Epidemiol Lab, Dept Pathol, Melbourne, Vic 3010, Australia. [Baglietto, Laura; Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Melbourne, Vic, Australia. [Australian Breast Canc Tissue Bank] Univ Sydney, ABCTB, Sydney, NSW 2006, Australia. [Carpenter, Jane E.] Univ Sydney, Westmead Millennium Inst, Australian Breast Canc Tissue Bank, Sydney, NSW 2006, Australia. [Bandera, Elisa V.] Canc Inst New Jersey, New Brunswick, NJ USA. [Beckmann, Matthias W.; Fasching, Peter A.] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Univ Breast Ctr Franconia, Dept Gynecol & Obstet, Erlangen, Germany. [Hartmann, Arndt] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Pathol, Erlangen, Germany. [Schulz-Wendtland, Ruediger] Univ Erlangen Nurnberg, Univ Hosp Erlangen, Inst Diagnost Radiol, Erlangen, Germany. [Berg, Christine D.] NCI, Early Detect Res Grp, Canc Prevent Div, Rockville, MD USA. [Brinton, Louise; Figueroa, Jonine D.; Hoover, Robert N.; Jacobs, Kevin B.; Nyante, Sarah J.; Wang, Zhaoming; Ziegler, Regina G.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Bernstein, Leslie] Beckman Res Inst, Dept Populat Sci, Div Canc Etiol, City Of Hope, CA USA. Univ Tubingen, Dr Margarete Fischer Bosch Inst Clin Pharmacol, Gene Environm Interact & Breast Canc Germany GENI, Stuttgart, Germany. [Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.; Chasman, Daniel I.; Hankinson, Susan E.; Lee, I-Min; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA USA. [Buys, Saundra S.] Univ Utah, Huntsman Canc Inst, Salt Lake City, UT USA. [Campa, Daniele] German Canc Res Ctr, Genom Epidemiol Grp, D-6900 Heidelberg, Germany. [Chang-Claude, Jenny; Hein, Rebecca; Kaaks, Rudolf; Nickels, Stefan] German Canc Res Ctr, Div Canc Epidemiol, D-6900 Heidelberg, Germany. Deutsch Krebsforschungszentrum DKFZ, Heidelberg, Germany. [Clavel-Chapelon, Francoise] Hop Paul Brousse, INSERM UMR 1018, Team Nutr Hormones & Sante Desfemmes 9, Ctr Rech Epidemiol & Sante Populat, Villejuif, France. [Cox, Angela] Univ Sheffield, Inst Canc Studies, Dept Oncol, Sheffield, S Yorkshire, England. [Cross, Simon S.] Univ Sheffield, Acad Unit Pathol, Dept Neurosci, Fac Med Dent & Hlth, Sheffield, S Yorkshire, England. [Czene, Kamila; Hall, Per] Karolinska Inst, S-17177 Stockholm, Sweden. [Deming, Sandra L.; Zheng, Wei] Vanderbilt Univ Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol, Dept Med, Nashville, TN USA. [Deming, Sandra L.; Zheng, Wei] Vanderbilt Univ Sch Med, Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Diver, W. Ryan; Gaudet, Mia M.; Thun, Michael J.] Amer Canc Soc, Epidemiol Res Program, Atlanta, GA 30329 USA. [Ekici, Arif B.] Univ Erlangen Nurnberg, Inst Human Genet, Erlangen, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, Dept Med, David Geffen Sch Med, Div Hematol & Oncol, Los Angeles, CA 90024 USA. [Rahman, Nazneen; Turnbull, Clare; Familial Breast Canc Study] Inst Canc Res, Sect Canc Genet, Sutton, Surrey, England. [Garcia-Closas, Montserrat] Inst Canc Res, Sect Epidemiol & Genet, Sutton, Surrey, England. [Feigelson, Heather Spencer; Huntsman, Scott] Kaiser Permanente, Inst Hlth Res, Denver, CO USA. [Fejerman, Laura; Ziv, Elad] Univ Calif San Francisco, Dept Med, Div Gen Internal Med, Inst Human Genet, San Francisco, CA USA. [Fejerman, Laura; Ziv, Elad] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Fletcher, Olivia] Breakthrough Breast Canc Res Ctr, Inst Canc Res, London, England. [Flesch-Janys, Dieter; Heinz, Judith] UCCH, Dept Canc Epidemiol, Clin Canc Registry, Hamburg, Germany. [Flesch-Janys, Dieter; Heinz, Judith] Univ Med Ctr Hamburg Eppendorf, Dept Med Biometr & Epidemiol, Hamburg, Germany. Evangel Kliniken Bonn gGmbH, Dept Internal Med, Bonn, Germany. Univ Bonn, Fac Med, Inst Pathol, Bonn, Germany. German Social Accid Insurance IPA, Inst Prevent & Occupat Med, Bochum, Germany. Saarland Univ Med Ctr, Inst & Outpatient Clin Occupat Med, Homburg, Germany. [GENICA Consortium] Saarland Univ Fac Med, Homburg, Germany. [Rodriguez-Gil, Jorge L.; Hu, Jennifer J.] Univ Miami Miller Sch Med, Sylvester Comprehens Canc Ctr, Miami, FL USA. [Rodriguez-Gil, Jorge L.; Hu, Jennifer J.] Univ Miami Miller Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL USA. [van Gils, Carla H.] Univ Med Ctr, Julius Ctr, Utrecht, Netherlands. [Godwin, Andrew K.; Pathak, Harsh] Kansas Univ Med Ctr, Dept Pathol & Lab Med, Kansas City, KS USA. [Hein, Rebecca] Univ Cologne, PMV Res Grp, Dept Child & Adolescent Psychiat & Psychotherapy, D-50931 Cologne, Germany. [Schmutzler, Rita K.] Univ Cologne, Div Mol Gynaecooncol, Dept Obstet & Gynaecol, D-50931 Cologne, Germany. [Irwanto, Astrid; Liu, Jianjun] Genome Inst Singapore, Div Human Genet, Singapore, Singapore. [Isaacs, Claudine] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Jacobs, Kevin B.; Wang, Zhaoming] NCI Frederick, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD USA. [Jacobs, Kevin B.] Bioinformed Consulting Serv, Gaithersburg, MD USA. [John, Esther M.] Canc Prevent Inst Calif, Fremont, CA USA. [John, Esther M.] Stanford Univ Sch Med, Stanford Canc Inst, Stanford, CA USA. [Kolonel, Laurence N.; Le Marchand, Loic; Wilkens, Lynne R.] Univ Hawaii Canc Ctr, Program Epidemiol, Honolulu, HI USA. [Lathrop, Mark] Ctr Natl Genotypage, Evry, France. [Lathrop, Mark] Fdn Jean Dausset, CEPH, Paris, France. [Lichtner, Peter] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany. [Lund, Eiliv] Univ Tromso, Inst Community Med, Tromso, Norway. [Martin, Nicholas G.; Montgomery, Grant W.] Queensland Inst Med Res, QIMR GWAS Collect, Brisbane, Qld 4006, Australia. [McLean, Catriona A.] Alfred Hosp, Melbourne, Vic, Australia. [Meijers-Heijboer, Hanne; Waisfisz, Quinten] Vrije Univ Amsterdam Med Ctr, Sect Oncogenet, Dept Clin Genet, Amsterdam, Netherlands. [Meindl, Alfons] Tech Univ Munich, Div Gynaecol Tumor Genet, Clin Gynaecol & Obstet, Munich, Germany. [Miron, Penelope] Dana Farber Canc Inst, Boston, MA 02115 USA. [Mueller-Myhsok, Bertram] Max Planck Inst Psychiat, D-8000 Munich, Germany. [Overvad, Kim] Aarhus Univ Hosp, Aalborg Hosp, Ctr Cardiovasc Res, Dept Cardiol, Aalborg, Denmark. [Palli, Domenico] ISPO, Canc Res & Prevent Inst, Mol & Nutr Epidemiol Unit, Florence, Italy. [Palmer, Julie R.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. [Peto, Julian; Silva, Isabel dos Santos] London Sch Hyg & Trop Med, Noncommunicable Dis Epidemiol Dept, London WC1, England. [Rivadeneira, Fernando; Uitterlinden, Andre G.] Erasmus MC, Dept Internal Med & Epidemiol, Rotterdam, Netherlands. [Sinn, Hans-Peter] Univ Heidelberg Hosp, Dept Pathol, Heidelberg, Germany. [Ross, Eric] Fox Chase Canc Ctr, Dept Biostat, Philadelphia, PA 19111 USA. [Sund, Malin] Umea Univ, Dept Surg, Umea, Sweden. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. RP Vachon, CM (reprint author), Mayo Clin, Dept Hlth Sci Res, 200 1st St SW,Charlton 6-239, Rochester, MN 55905 USA. EM christopher.haiman@med.usc.edu; vachon.celine@mayo.edu RI Bandera, Elisa/M-4169-2014; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Montgomery, Grant/B-7148-2008; Campa, Daniele/K-1617-2016; Rahman, Nazneen/D-2802-2013; Muller-Myhsok, Bertram/A-3289-2013; Ekici, Arif/C-3971-2013; Clavel-Chapelon, Francoise/G-6733-2014; Berg , Christine/K-1047-2014; Ziv, Elad/L-5396-2014 OI Giles, Graham/0000-0003-4946-9099; Martin, Nicholas/0000-0003-4069-8020; Czene, Kamila/0000-0002-3233-5695; Palmer, Julie/0000-0002-6534-335X; Sund, Malin/0000-0002-7516-9543; Cross, Simon/0000-0003-2044-1754; Fejerman, Laura/0000-0003-3179-1151; Dunning, Alison Margaret/0000-0001-6651-7166; Rivadeneira, Fernando/0000-0001-9435-9441; Nevanlinna, Heli/0000-0002-0916-2976; Cox, Angela/0000-0002-5138-1099; PALLI, Domenico/0000-0002-5558-2437; Park, Daniel/0000-0002-6354-0931; Bandera, Elisa/0000-0002-8789-2755; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Montgomery, Grant/0000-0002-4140-8139; Campa, Daniele/0000-0003-3220-9944; Rahman, Nazneen/0000-0003-4376-0440; Greco, Dario/0000-0001-9195-9003; FU Department of Defense [W81XWH-08-1-0383]; Norris Foundation; MEC (National Institutes of Health) [R01-CA63464, R37-CA54281]; CARE (National Institute for Child Health and Development) [NO1-HD-3-3175]; WCHS (U.S. Army Medical Research and Material Command (USAMRMC) [DAMD-17-01-0-0334]; National Institutes of Health [R01-CA100598, CA 65725, CA87969, CA49449, CA67262, CA50385, 5UO1CA098233, CA109147, CA132839, CA54281, CA63464, CA120120]; Breast Cancer Research Foundation; SFBCS (National Institutes of Health) [R01-CA77305]; SFBCS (United States Army Medical Research Program) [DAMD17-96-6071]; NC-BCFR (National Institutes of Health) [U01-CA69417]; CBCS (National Institutes of Health Specialized Program of Research Excellence in Breast Cancer [P50-CA58223]; Center for Environmental Health and Susceptibility, National Institute of Environmental Health Sciences, National Institutes of Health [P30-ES10126]; PLCO (Intramural Research Program, National Cancer Institute, National Institutes of Health); NBHS (National Institutes of Health) [R01-CA100374]; WFBC (National Institutes of Health) [R01-CA73629]; National Cancer Institute, National Institutes of Health [RFA CA-06-503]; MCBCS (National Institutes of Health) [CA122340]; Specialized Program of Research Excellence (SPORE) in Breast Cancer [CA116201]; Breast Cancer Research Foundation (BCRF); MARIE (Deutsche Krebshilfe e.V.) [70-2892-BR I]; Hamburg Cancer Society; German Cancer Research Center (DKFZ); Federal Ministry of Education and Research (BMBF) Germany [01KH0402]; GENICA (Federal Ministry of Education and Research (BMBF) Germany [01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114]; Robert Bosch Foundation Stuttgart, Germany; MCCS (Australian NHMRC) [209057, 251553, 504711]; SBCS [Breast Cancer Campaign) [2004Nov49]; Yorkshire Cancer Research; DFCI (DFCI Breast Cancer SPORE NIH) [P50 CA089393]; POSH (Cancer Research UK); DEMOKRITOS [Hellenic Cooperative Oncology Group] [HR R_BG/04]; Greek General Secretary for Research and Technology (GSRT) Program; European Union; BBCC (Dr Mildred Scheel Stiftung of the Deutsche Krebshilfe e.V.); BBCS (Cancer Research UK); Breakthrough Breast Cancer; NHS; National Cancer Research Network (NCRN); LMBC (European Union) [LSHC-CT-2003-503297]; Stichting tegen Kanker [232-2008]; OBCS (Finnish Cancer Foundation); Sigrid Juselius Foundation; University of Finland; Oulu University Hospital; HEBCS (Helsinki University Central Hospital Research Fund); Academy of Finland [132473]; Finnish Cancer Society; Nordic Cancer Union; FCCC [U01CA69631, 5U01CA113916]; University of Kansas Cancer Center; Kansas Bioscience Authority Eminent Scholar Program; RPCI (RPCI DataBank and BioRepository (DBBR); Cancer Center Support Grant Shared Resource [P30 CA016056-32]; SKKDKFZS (Deutsches Krebsforschungszentrum); BIGGS (National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre; Guy's & St. Thomas' NHS Foundation Trust; King's College London and King's College Hospital NHS Foundation Trust; ABCTB (National Health and Medical Research Council of Australia); Cancer Institute NSW; National Breast Cancer Foundation; ABCS (Dutch Cancer Society [2009-4363]; KARBAC (The Stockholm Cancer Society); US National Institutes of Health, National Cancer Institute [U01-CA98233, U01-CA98710, U01-CA98216, U01-CA98758]; NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics (PLCO); National Heart, Lung, and Blood Institute [HL043851, HL080467]; National Cancer Institute [CA 047988]; Donald W. Reynolds Foundation; Fondation Leducq; Amgen; Wellcome Trust; Cancer Research UK; CR-UK [C1287/A10118, C1287/A12014]; European Community [223175 (HEALTH-F2-2009-223175)]; European Union [BM0606]; National Health and Medical Research Council of Australia; New South Wales Cancer Council; Victorian Health Promotion Foundation (Australia); Institut National de Cancer; Netherlands Organisation for Scientific Research (NWO) as part of a ZonMw/VIDI [91756341]; Deutsche Krebshilfe [107054]; Dietmar-Hopp Foundation; Helmholtz society; e German Cancer Research Centre (DKFZ); German Cancer Aid [107352]; Deutsche Krebshilfe e.V. [70-2892-BR I]; German Cancer Research Center; Agency for Science, Technology and Research of Singapore (A*STAR); US National Institute of Health (NIH); Susan G. Komen Breast Cancer Foundation; Helsinki University Central Hospital Research Fund; Nordic Center of Excellence in Disease Genetics FX AABC was supported by a Department of Defense Breast Cancer Research Program Era of Hope Scholar Award to C. A. H. (W81XWH-08-1-0383) and the Norris Foundation. Each of the participating AABC studies was supported by the following grants: MEC (National Institutes of Health grants R01-CA63464 and R37-CA54281); CARE (National Institute for Child Health and Development grant NO1-HD-3-3175), WCHS (U.S. Army Medical Research and Material Command (USAMRMC) grant DAMD-17-01-0-0334, the National Institutes of Health grant R01-CA100598 and the Breast Cancer Research Foundation, SFBCS (National Institutes of Health grant R01-CA77305 and United States Army Medical Research Program grant DAMD17-96-6071), NC-BCFR (National Institutes of Health grant U01-CA69417), CBCS (National Institutes of Health Specialized Program of Research Excellence in Breast Cancer, grant number P50-CA58223, and Center for Environmental Health and Susceptibility, National Institute of Environmental Health Sciences, National Institutes of Health, grant number P30-ES10126), PLCO (Intramural Research Program, National Cancer Institute, National Institutes of Health) and NBHS (National Institutes of Health grant R01-CA100374), WFBC (National Institutes of Health grant R01-CA73629). The NC-BCFR is one of six sites participating in The Breast Cancer Family Registry (BCFR) which was supported by the National Cancer Institute, National Institutes of Health under RFA CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry and Principal Investigators. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR.; The TNBCC studies were supported by the following grants: MCBCS (National Institutes of Health Grants CA122340 and a Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201) and the Breast Cancer Research Foundation (BCRF); MARIE (Deutsche Krebshilfe e.V., grant number 70-2892-BR I, the Hamburg Cancer Society, the German Cancer Research Center (DKFZ) and the Federal Ministry of Education and Research (BMBF) Germany grant 01KH0402); GENICA (Federal Ministry of Education and Research (BMBF) Germany grants 01KW9975/5, 01KW9976/8, 01KW9977/0, 01KW0114, and the Robert Bosch Foundation Stuttgart, Germany; MCCS (Australian NHMRC grants 209057, 251553 and 504711 and infrastructure provided by the Cancer Council Victoria); SBCS [Breast Cancer Campaign (grant 2004Nov49 to A. C.), and by Yorkshire Cancer Research core funding]; DFCI (DFCI Breast Cancer SPORE NIH P50 CA089393); POSH (Cancer Research UK); DEMOKRITOS [Hellenic Cooperative Oncology Group research grant (HR R_BG/04) and the Greek General Secretary for Research and Technology (GSRT) Program, Research Excellence II, funded at 75% by the European Union]; BBCC (Dr Mildred Scheel Stiftung of the Deutsche Krebshilfe e.V.); BBCS (Cancer Research UK and Breakthrough Breast Cancer and NHS funding to the NIHR biomedical Research Centre and the National Cancer Research Network (NCRN); LMBC (European Union Framework Programme 6 Project LSHC-CT-2003-503297 (the Cancerdegradome) and by the 'Stichting tegen Kanker' (232-2008); OBCS (Finnish Cancer Foundation, the Sigrid Juselius Foundation, the Academy of Finland, the University of Finland, and Oulu University Hospital); HEBCS (Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation); FCCC (U01CA69631, 5U01CA113916, the University of Kansas Cancer Center and the Kansas Bioscience Authority Eminent Scholar Program); RPCI (RPCI DataBank and BioRepository (DBBR), a Cancer Center Support Grant Shared Resource (P30 CA016056-32)); SKKDKFZS (Deutsches Krebsforschungszentrum); BIGGS (National Institute for Health Research (NIHR) Comprehensive Biomedical Research Centre, Guy's & St. Thomas' NHS Foundation Trust in partnership with King's College London and King's College Hospital NHS Foundation Trust); ABCTB (National Health and Medical Research Council of Australia, The Cancer Institute NSW and the National Breast Cancer Foundation); ABCS (Dutch Cancer Society grant number 2009-4363); KARBAC (The Stockholm Cancer Society).; BPC3 is supported by the US National Institutes of Health, National Cancer Institute under cooperative agreements U01-CA98233 (NHS, NHSII, WHS), U01-CA98710 (CPS2), U01-CA98216 (EPIC), U01-CA98758 (MEC) and Intramural Research Program of NIH/National Cancer Institute, Division of Cancer Epidemiology and Genetics (PLCO). The authors thank Drs Christine Berg and Philip Prorok, Division of Cancer Prevention, NCI, the screening center investigators and staff of the PLCO Cancer Screening Trial, Mr Thomas Riley and staff at Information Management Services, Inc., and Ms Barbara O'Brien and staff at Westat, Inc. for their contributions to the PLCO Cancer Screening Trial.; The WHS is supported by HL043851 and HL080467 from the National Heart, Lung, and Blood Institute and CA 047988 from the National Cancer Institute, the Donald W. Reynolds Foundation and the Fondation Leducq, with collaborative scientific support and funding for genotyping provided by Amgen.; The UK2 GWAS was funded by Wellcome Trust and Cancer Research UK. The WTCCC was funded by the Wellcome Trust. BCAC is funded by CR-UK (C1287/A10118, C1287/A12014) and by the European Community's Seventh Framework Programme under grant agreement no. 223175 (HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). The ABCFS study was supported by the National Health and Medical Research Council of Australia, the New South Wales Cancer Council, the Victorian Health Promotion Foundation (Australia) and the National Cancer Institute, National Institutes of Health under RFA-CA-06-503 and through cooperative agreements with members of the Breast Cancer Family Registry (BCFR) and the Principle Investigators. The University of Melbourne (U01 CA69638) contributed data to this study. The content of this manuscript does not necessarily reflect the views or the policies of the National Cancer Institute or any of the collaborating centers in the BCFR, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government or the BCFR. We extend our thanks to the many women and their families that generously participated in the Australian Breast Cancer Family Study and consented to us accessing their pathology material. J.L.H. is a National Health and Medical Research Council Australia Fellow. M. C. S. is a National Health and Medical Research Council Senior Research Fellow. J.L.H. and M. C. S. are both group leaders of the Victoria Breast Cancer Research Consortium. The BBCS is funded by Cancer Research UK and Breakthrough Breast Cancer and acknowledges NHS funding to the NIHR Biomedical Research Centre, and the National Cancer Research Network (NCRN). The BBCS GWAS received funding from The Institut National de Cancer. The DFBBCS GWAS was funded by The Netherlands Organisation for Scientific Research (NWO) as part of a ZonMw/VIDI grant number 91756341. We thank Muriel Adank for selecting the samples and Margreet Ausems, Christi van Asperen, Senno Verhoef and Rogier van Oldenburg for providing samples from their Clinical Genetic centers. The GC-HBOC was supported by Deutsche Krebshilfe (107054), the Dietmar-Hopp Foundation, the Helmholtz society and the German Cancer Research Centre (DKFZ). The GC-HBOC GWAS was supported by the German Cancer Aid (grant no. 107352). The MARIE study was supported by the Deutsche Krebshilfe e.V. (70-2892-BR I), the Hamburg Cancer Society, the German Cancer Research Center and the genotype work in part by the Federal Ministry of Education and Research (BMBF) Germany (01KH0402). MARIE would like to thank Tracy Slanger and Elke Mutschelknauss for their valuable contributions, and S. Behrens, R. Birr, M. Celik, U. Eilber, B. Kaspereit, N. Knese and K. Smit for their excellent technical assistance. The SASBAC study was supported by funding from the Agency for Science, Technology and Research of Singapore (A*STAR), the US National Institute of Health (NIH) and the Susan G. Komen Breast Cancer Foundation. CGEMS. The Nurses' Health Studies are supported by NIH grants CA 65725, CA87969, CA49449, CA67262, CA50385 and 5UO1CA098233. The HEBCS study has been financially supported by the Helsinki University Central Hospital Research Fund, Academy of Finland (132473), the Finnish Cancer Society, The Nordic Cancer Union and the Sigrid Juselius Foundation.; The population allele and genotype frequencies were obtained from the data source funded by the Nordic Center of Excellence in Disease Genetics based on samples regionally selected from Finland, Sweden and Denmark. We thank Drs Kirsimari Aaltonen, Paivi Heikkila and Tuomas Heikkinen and RN Hanna Jantti and Irja Erkkila for their help with the HEBCS data and samples.; The biofeature analysis was supported by NIH grant CA109147.; The breast cancer GWAS in Japanese and Latinos in the MEC (MEC-LAT and MEC-JPT) were supported by NIH grants CA132839, CA54281 and CA63464. Genotyping of the Latino breast cancer cases and controls from SFBCS and NC-BCFR was supported by NIH grant CA120120. NR 28 TC 82 Z9 82 U1 1 U2 41 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 DEC 15 PY 2012 VL 21 IS 24 BP 5373 EP 5384 DI 10.1093/hmg/dds381 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 049ES UT WOS:000311965600012 PM 22976474 ER PT J AU Mangino, M Hwang, SJ Spector, TD Hunt, SC Kimura, M Fitzpatrick, AL Christiansen, L Petersen, I Elbers, CC Harris, T Chen, W Srinivasan, SR Kark, JD Benetos, A El Shamieh, S Visvikis-Siest, S Christensen, K Berenson, GS Valdes, AM Vinuela, A Garcia, M Arnett, DK Broeckel, U Province, MA Pankow, JS Kammerer, C Liu, YM Nalls, M Tishkoff, S Thomas, F Ziv, E Psaty, BM Bis, JC Rotter, JI Taylor, KD Smith, E Schork, NJ Levy, D Aviv, A AF Mangino, Massimo Hwang, Shih-Jen Spector, Timothy D. Hunt, Steven C. Kimura, Masayuki Fitzpatrick, Annette L. Christiansen, Lene Petersen, Inge Elbers, Clara C. Harris, Tamara Chen, Wei Srinivasan, Sathanur R. Kark, Jeremy D. Benetos, Athanase El Shamieh, Said Visvikis-Siest, Sophie Christensen, Kaare Berenson, Gerald S. Valdes, Ana M. Vinuela, Ana Garcia, Melissa Arnett, Donna K. Broeckel, Ulrich Province, Michael A. Pankow, James S. Kammerer, Candace Liu, Yongmei Nalls, Michael Tishkoff, Sarah Thomas, Fridtjof Ziv, Elad Psaty, Bruce M. Bis, Joshua C. Rotter, Jerome I. Taylor, Kent D. Smith, Erin Schork, Nicholas J. Levy, Daniel Aviv, Abraham TI Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans SO HUMAN MOLECULAR GENETICS LA English DT Article ID PULMONARY-FIBROSIS; ZINC FINGERS; HYPERTENSIVE SUBJECTS; ASSOCIATION ANALYSIS; TERT-CLPTM1L LOCUS; COMMON VARIANTS; QUADRUPLEX DNA; GENOTYPE DATA; HTERT GENE; TGF-BETA AB Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P 9.1 10(11)) and with the telomerase RNA component TERC (rs1317082, P 1.1 10(8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P 3.6 10(8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P 3.3 10(8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population. C1 [Kimura, Masayuki; Aviv, Abraham] Univ Med & Dent New Jersey, New Jersey Med Sch, Ctr Human Dev & Aging, Newark, NJ 07103 USA. [Mangino, Massimo; Spector, Timothy D.; Valdes, Ana M.; Vinuela, Ana] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Hwang, Shih-Jen; Levy, Daniel] Framingham Heart Dis Epidemiol Study, Framingham, MA 01701 USA. [Hwang, Shih-Jen; Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. [Hunt, Steven C.] Univ Utah, Dept Med, Cardiovasc Genet Div, Salt Lake City, UT 84108 USA. [Fitzpatrick, Annette L.; Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.; Bis, Joshua C.] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Christiansen, Lene; Petersen, Inge; Christensen, Kaare] Univ So Denmark, Inst Publ Hlth, Dept Epidemiol, Odense, Denmark. [Elbers, Clara C.; Tishkoff, Sarah] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Harris, Tamara; Garcia, Melissa] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Nalls, Michael] NIA, Neurogenet Lab, Intramural Res Program, Bethesda, MD 20892 USA. [Chen, Wei; Srinivasan, Sathanur R.; Berenson, Gerald S.] Tulane Univ, Ctr Cardiovasc Hlth, New Orleans, LA 70118 USA. [Kark, Jeremy D.] Hebrew Univ Jerusalem, Hadassah Sch Publ Hlth, Jerusalem, Israel. [Benetos, Athanase] Univ Lorraine, INSERM, U961, Dept Geriatr, Nancy, France. [El Shamieh, Said; Visvikis-Siest, Sophie] Univ Lorraine, Fac Pharm, Unite Rech Genet Cardiovasc EA 4373, Nancy, France. [Arnett, Donna K.] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35233 USA. [Broeckel, Ulrich] Med Coll Wisconsin, Individualized Med Inst, Milwaukee, WI 53226 USA. [Province, Michael A.] Washington Univ Sch Med, Ctr Genome Sci & Syst Biol, Div Stat Genom, St Louis, MO 63110 USA. [Pankow, James S.] Univ Minnesota Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55455 USA. [Kammerer, Candace] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA 15213 USA. [Liu, Yongmei] Wake Forest Sch Med, Dept Epidemiol, Winston Salem, NC 27150 USA. [Thomas, Fridtjof] Univ Tennessee Hlth Sci Ctr, Dept Prevent Med, Memphis, TN 38105 USA. [Ziv, Elad] Univ Calif San Francisco, Dept Internal Med, San Francisco, CA 94143 USA. [Psaty, Bruce M.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98101 USA. [Rotter, Jerome I.; Taylor, Kent D.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Smith, Erin] Univ Calif San Diego, La Jolla, CA 92093 USA. [Schork, Nicholas J.] Scripps Res Inst, Dept Mol & Expt Med, San Diego, CA 92101 USA. RP Aviv, A (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Ctr Human Dev & Aging, 185 S Orange Ave, Newark, NJ 07103 USA. EM avivab@umdnj.edu RI Vinuela, Ana/J-9326-2012; Visvikis-Siest, Sophie/H-2324-2014; Ziv, Elad/L-5396-2014; mangino, massimo/F-5134-2011; Christensen, Kaare/C-2360-2009; OI Pankow, James/0000-0001-7076-483X; Visvikis-Siest, Sophie/0000-0001-8104-8425; mangino, massimo/0000-0002-2167-7470; Christensen, Kaare/0000-0002-5429-5292; Vinuela, Ana/0000-0003-3771-8537 FU Wellcome Trust; European Community [HEALTH-F4-2007-201413]; Dept of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre; ERC; National Eye Institute via an NIH/CIDR; National Institute of Child Health and Human Development [HD-061437, HD-062783]; National Institute on Aging [AG-16592]; NIH [N01-HC-25195]; National Heart, Lung, and Blood Institute; Center for Population Studies of the NHLBI; NHLBI [1 R01 HL80698-01, N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C, HL080295, HL087652, HL105756]; NIA [AG-23629, AG-15928, AG-20098, AG-027058, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Center of Advancing Translational Technologies CTSI [UL1TR000124]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; Cedars-Sinai Board of Governors' Chair in Medical Genetics; NIH: Human Telomere Genetics [R01AG20132]; Telomeres Vascular Aging [R01AG21593]; Leukocyte Telomere Dynamics, Gender, Menopause, Insulin Resistance [R01AG030678]; US-Israel Binational Science Foundation; Israel Science Foundation; French Fondation pour la Recherche Medicale [FRM DCV2007-0409250]; Plan Pluriformation [PPF815 PSVT-2005]; National Institutes of Health [HHSN268200782096C]; NIH, National Institute on Aging; [HL54471]; [HL54472]; [HL54473]; [HL54495]; [HL54496]; [HL54509]; [HL54515]; [HL055673] FX TwinsUK. The study was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013), ENGAGE project grant agreement (HEALTH-F4-2007-201413). The study also receives support from the Dept of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy's & St Thomas' NHS Foundation Trust in partnership with King's College London. T. D. S. is an NIHR senior Investigator and is holder of an ERC Advanced Principal Investigator award. Genotyping was performed by The Wellcome Trust Sanger Institute, support of the National Eye Institute via an NIH/CIDR genotyping project.; The Bogalusa Heart Study. This study was supported by grants HD-061437 and HD-062783 from the National Institute of Child Health and Human Development, and AG-16592 from the National Institute on Aging.; The Framingham Heart Study. Supported by NIH contract N01-HC-25195. This project was supported in part by intramural funding from the National Heart, Lung, and Blood Institute and the Center for Population Studies of the NHLBI.; CHS. This CHS research was supported by NHLBI grant 1 R01 HL80698-01 and contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C and NHLBI grants HL080295, HL087652, HL105756 with additional contribution from NINDS. Additional support was provided through AG-23629, AG-15928, AG-20098 and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping were supported in part by National Center of Advancing Translational Technologies CTSI grant UL1TR000124 and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center and Cedars-Sinai Board of Governors' Chair in Medical Genetics (J.I.R.).; The Center of Human Development and Aging. A. A. grant support: NIH: Human Telomere Genetics R01AG20132; Telomeres & Vascular Aging, R01AG21593; Leukocyte Telomere Dynamics, Gender, Menopause, Insulin Resistance, R01AG030678.; Jerusalem LRC Longitudinal Study The study was funded by the US-Israel Binational Science Foundation and the Israel Science Foundation.; ADELAHYDE-Nancy study and ERA-France study. The study received support from the French Fondation pour la Recherche Medicale (FRM DCV2007-0409250) and the Plan Pluriformation (PPF815 PSVT-2005). Special thanks to Ms Cynthia hiriot (INSERM U961, Nancy France) for her contribution to the geotyping of French cohorts.; HyperGEN. HyperGEN was supported by cooperative agreements HL54471, HL54472, HL54473, HL54495, HL54496, HL54509, HL54515 and grant HL055673. HyperGEN investigators and institutions can be found at http://www.biostat.wustl.edu/hypergen/hypergen.shtml.; Health ABC. This research was supported by NIA contracts N01AG62101, N01AG62103 and N01AG62106. The GWAS was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences and 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 HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. Funding to pay the Open Access publication charges for this article was provided by the Wellcome Trust. NR 75 TC 66 Z9 67 U1 3 U2 15 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 DEC 15 PY 2012 VL 21 IS 24 BP 5385 EP 5394 DI 10.1093/hmg/dds382 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 049ES UT WOS:000311965600013 PM 23001564 ER PT J AU Balamayooran, G Batra, S Theivanthiran, B Cai, SS Pacher, P Jeyaseelan, S AF Balamayooran, Gayathriy Batra, Sanjay Theivanthiran, Balamayooran Cai, Shanshan Pacher, Pal Jeyaseelan, Samithamby TI Intrapulmonary G-CSF Rescues Neutrophil Recruitment to the Lung and Neutrophil Release to Blood in Gram-Negative Bacterial Infection in MCP-1(-/-) Mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; MONOCYTE CHEMOATTRACTANT PROTEIN-1; ESCHERICHIA-COLI PNEUMONIA; PULMONARY HOST-DEFENSE; MACROPHAGE INFLAMMATORY PROTEIN-2; NF-KAPPA-B; PNEUMOCOCCAL PNEUMONIA; PROTECTS MICE; FUNCTIONAL-CHARACTERIZATION; STREPTOCOCCUS-PNEUMONIAE AB We previously demonstrated that MCP-1 is important for E. coli-induced neutrophil migration to the lungs. However, E. coli neither disseminates nor induces death in mice. Furthermore, the cell types and the host defense mechanisms that contribute to MCP-1-dependent neutrophil trafficking have not been defined. In this study, we sought to explore the cell types and the mechanisms associated with Klebsiella pneumoniae-mediated MCP-1-dependent neutrophil influx. MCP-1(-/-) mice are more susceptible to pulmonary K. pneumoniae infection and show higher bacterial burden in the lungs and dissemination. MCP-1(-/-) mice also display attenuated neutrophil influx, cytokine/chemokine production, and activation of NF-kappa B and MAPKs following intratracheal K pneumoniae infection. rMCP-1 treatment in MCP-1(-/-) mice following K. pneumoniae infection rescued impairment in survival, bacterial clearance, and neutrophil accumulation in the lung. Neutrophil numbers in the blood of MCP-1(-/-) mice were associated with G-CSF concentrations in bronchoalveolar lavage fluid and blood. Bone marrow or resident cell-derived MCP-1 contributed to bacterial clearance, neutrophil accumulation, and cytokine/chemokine production in the lungs following infection. Furthermore, exogenous MCP-1 dose dependently increased neutrophil counts and G-CSF concentrations in the blood. Intriguingly, administration of intratracheal rG-CSF to MCP-1(-/-) mice after K. pneumoniae infection rescued survival, bacterial clearance and dissemination, and neutrophil influx in MCP-1(-/-) mice. Collectively, these novel findings unveil an unrecognized role of MCP-1 in neutrophil-mediated host immunity during K. pneumoniae pneumonia and illustrate that G-CSF could be used to rescue impairment in host immunity in individuals with absent or malfunctional MCP-1. The Journal of Immunology, 2012,189: 5849-5859. C1 [Balamayooran, Gayathriy; Batra, Sanjay; Theivanthiran, Balamayooran; Cai, Shanshan; Jeyaseelan, Samithamby] Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Lab Lung Biol, Baton Rouge, LA 70803 USA. [Pacher, Pal] NIAAA, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Jeyaseelan, Samithamby] Louisiana State Univ, Hlth Sci Ctr, Dept Med, Pulm & Crit Care Med Sect, New Orleans, LA 70112 USA. RP Jeyaseelan, S (reprint author), Louisiana State Univ, Sch Vet Med, Dept Pathobiol Sci, Lab Lung Biol, Skip Bertman Dr, Baton Rouge, LA 70803 USA. EM jey@lsu.edu RI Pacher, Pal/B-6378-2008 OI Pacher, Pal/0000-0001-7036-8108 FU Flight Attendant Medical Research Institute Scientist Award [YCSA-062466]; National Institutes of Health via the American Recovery and Reinvestment Act [R01 HL-091958, R01 HL-09195851] FX This work was supported by Flight Attendant Medical Research Institute Scientist Award YCSA-062466 as well as by National Institutes of Health Grants R01 HL-091958 and R01 HL-09195851 (via the American Recovery and Reinvestment Act) (to S.J.). NR 81 TC 19 Z9 19 U1 1 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2012 VL 189 IS 12 BP 5849 EP 5859 DI 10.4049/jimmunol.1200585 PG 11 WC Immunology SC Immunology GA 049PM UT WOS:000311995800040 PM 23129755 ER PT J AU Romagnoli, R Baraldi, PG Salvador, MK Camacho, ME Preti, D Tabrizi, MA Bassetto, M Brancale, A Hamel, E Bortolozzi, R Basso, G Viola, G AF Romagnoli, Romeo Baraldi, Pier Giovanni Salvador, Maria Kimatrai Camacho, M. Encarnacion Preti, Delia Tabrizi, Mojgan Aghazadeh Bassetto, Marcella Brancale, Andrea Hamel, Ernest Bortolozzi, Roberta Basso, Giuseppe Viola, Giampietro TI Synthesis and biological evaluation of 2-substituted-4-(3 ',4 ',5 '-trimethoxyphenyl)-5-aryl thiazoles as anticancer agents SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Tubulin; Thiazole; Combretastatin-A4; Colchicine site; Apoptosis ID ANTIMITOTIC AGENTS; NATURAL-PRODUCTS; CELL-DEATH; INDUCED APOPTOSIS; CANCER-THERAPY; TUBULIN; ANALOGS; COLCHICINE; BINDING; COMBRETASTATIN-A-4 AB Antitumor agents that bind to tubulin and disrupt microtubule dynamics have attracted considerable attention in the last few years. To extend our knowledge of the thiazole ring as a suitable mimic for the cis-olefin present in combretastatin A-4, we fixed the 3,4,5-trimethoxyphenyl at the C4-position of the thiazole core. We found that the substituents at the C2- and C5-positions had a profound effect on antiproliferative activity. Comparing compounds with the same substituents at the C5-position of the thiazole ring, the moiety at the C2-position influenced antiproliferative activities, with the order of potency being NHCH3 > Me >> N(CH3)(2). The N-methylamino substituent significantly improved antiproliferative activity on MCF-7 cells with respect to C2-amino counterparts. Increasing steric bulk at the C2-position from N-methylamino to N, N-dimethylamino caused a 1-2 log decrease in activity. The 2-N-methylamino thiazole derivatives 3b, 3d and 3e were the most active compounds as antiproliferative agents, with IC50 values from low micromolar to single digit nanomolar, and, in addition, they are also active on multidrug-resistant cell lines over-expressing P-glycoprotein. Antiproliferative activity was probably caused by the compounds binding to the colchicines site of tubulin polymerization and disrupting microtubule dynamics. Moreover, the most active compound 3e induced apoptosis through the activation of caspase-2, -3 and -8, but 3e did not cause mitochondrial depolarization. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Salvador, Maria Kimatrai; Camacho, M. Encarnacion; Preti, Delia; Tabrizi, Mojgan Aghazadeh] Univ Ferrara, Dipartimento Sci Farmaceut, I-44121 Ferrara, Italy. [Bassetto, Marcella; Brancale, Andrea] Cardiff Univ, Sch Pharm & Pharmaceut Sci, Cardiff CF10 3NB, S Glam, Wales. [Hamel, Ernest] NCI, Screening Technol Branch, Dev Therapeut Program,NIH, Div Canc Treatment & Diag,Frederick Natl Lab Canc, Frederick, MD 21702 USA. [Bortolozzi, Roberta; Basso, Giuseppe; Viola, Giampietro] Univ Padua, Lab Oncoematol, Dipartimento Salute Donna & Bambino, I-35131 Padua, Italy. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, Via Fossato Mortara 17-19, I-44121 Ferrara, Italy. EM rmr@unife.it; baraldi@unife.it; giampietro.viola1@unipd.it RI Viola, Giampietro/I-4095-2012; Aghazadeh Tabrizi, Mojgan/I-9169-2014; Brancale, Andrea/N-9445-2014; Bortolozzi, Roberta/D-4950-2015; Camacho, M. Encarnacion/G-7916-2015; preti, delia/G-9916-2015; Romagnoli, Romeo/G-9887-2015; Baraldi, Pier Giovanni/B-7933-2017; OI Viola, Giampietro/0000-0001-9329-165X; Brancale, Andrea/0000-0002-9728-3419; Bortolozzi, Roberta/0000-0002-3357-4815; Camacho, M. Encarnacion/0000-0003-1214-5103; preti, delia/0000-0002-1075-3781; Bassetto, Marcella/0000-0002-2491-5868; BASSO, GIUSEPPE/0000-0002-2634-9302 FU Intramural NIH HHS [Z99 CA999999] NR 43 TC 24 Z9 25 U1 1 U2 32 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 DEC 15 PY 2012 VL 20 IS 24 BP 7083 EP 7094 DI 10.1016/j.bmc.2012.10.001 PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 041SK UT WOS:000311421300018 PM 23117171 ER PT J AU Qian, WJ Park, JE Lee, KS Burke, TR AF Qian, Wen-Jian Park, Jung-Eun Lee, Kyung S. Burke, Terrence R., Jr. TI Non-proteinogenic amino acids in the pThr-2 position of a pentamer peptide that confer high binding affinity for the polo box domain (PBD) of polo-like kinase 1 (Plk1) SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Polo-like kinase; Polo box domain; Non-proteogenic amino acids; Peptide ligands; Signal transduction ID RECOGNITION; DISCOVERY; CANCER AB We report herein that incorporating long-chain alkylphenyl-containing non-proteinogenic amino acids in place of His at the pT-2 position of the parent polo-like kinase 1 (Plk1) polo box domain (PBD)-binding pentapeptide, PLHSpT (1a) increases affinity. For certain analogs, approximately two orders-of-magnitude improvement in affinity was observed. Although, none of the new analogs was as potent as our previously described peptide 1b, in which the pT-2 histidine imidazole ring is alkylated at its pi nitrogen (N3), our current finding that the isomeric His(N1)-analog (1c) binds with approximately 50-fold less affinity than 1b, indicates the positional importance of attachment to the His imidazole ring. Our demonstration that a range of modified residues at the pT-2 position can enhance binding affinity, should facilitate the development of minimally-sized Plk1 PBD-binding antagonists. Published by Elsevier Ltd. C1 [Park, Jung-Eun; Lee, Kyung S.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Qian, Wen-Jian; Burke, Terrence R., Jr.] NCI, Biol Chem Lab, Mol Discovery Program, Frederick Natl Lab Canc Res,Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Lee, KS (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kyunglee@mail.nih.gov; burkete@helix.nih.gov RI Burke, Terrence/N-2601-2014 FU NIH, Center for Cancer Research, Frederick National Laboratory for Cancer Research; National Cancer Institute, National Institutes of Health FX This work was supported by the Intramural Research Program of the NIH, Center for Cancer Research, Frederick National Laboratory for Cancer Research and the National Cancer Institute, National Institutes of Health. NR 20 TC 7 Z9 8 U1 1 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD DEC 15 PY 2012 VL 22 IS 24 BP 7306 EP 7308 DI 10.1016/j.bmcl.2012.10.093 PG 3 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 041UA UT WOS:000311425500003 PM 23159568 ER PT J AU Zhao, XZ Maddali, K Smith, SJ Metifiot, M Johnson, BC Marchand, C Hughes, SH Pommier, Y Burke, TR AF Zhao, Xue Zhi Maddali, Kasthuraiah Smith, Steven J. Metifiot, Mathieu Johnson, Barry C. Marchand, Christophe Hughes, Stephen H. Pommier, Yves Burke, Terrence R., Jr. TI 6,7-Dihydroxy-1-oxoisoindoline-4-sulfonamide-containing HIV-1 integrase inhibitors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE HIV-1 integrase; Inhibit; Raltegravir; Sulfonamide ID STRAND TRANSFER; RALTEGRAVIR; RESISTANCE; POTENT; INFECTION; DESIGN AB Although an extensive body of scientific and patent literature exists describing the development of HIV-1 integrase (IN) inhibitors, Merck's raltegravir and Gilead's elvitegravir remain the only IN inhibitors FDA-approved for the treatment of AIDS. The emergence of raltegravir-resistant strains of HIV-1 containing mutated forms of IN underlies the need for continued efforts to enhance the efficacy of IN inhibitors against resistant mutants. We have previously described bicyclic 6,7-dihydroxyoxoisoindolin-1-ones that show good IN inhibitory potency. This report describes the effects of introducing substituents into the 4- and 5-positions of the parent 6,7-dihydroxyoxoisoindolin-1-one platform. We have developed several sulfonamide-containing analogs that enhance potency in cell-based HIV assays by more than two orders-of-magnitude and we describe several compounds that are more potent than raltegravir against the clinically relevant Y143R IN mutant. Published by Elsevier Ltd. C1 [Zhao, Xue Zhi; Burke, Terrence R., Jr.] NIH, Biol Chem Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Maddali, Kasthuraiah; Metifiot, Mathieu; Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Smith, Steven J.; Johnson, Barry C.; Hughes, Stephen H.] NIH, HIV Drug Resistance Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Zhao, XZ (reprint author), NIH, Biol Chem Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM xuezhi.zhao@nih.gov; burkete@helix.nih.gov RI Zhao, Xue Zhi/N-9594-2014; Burke, Terrence/N-2601-2014 OI Zhao, Xue Zhi/0000-0003-1006-6364; FU NIH, Center for Cancer Research, Frederick National Laboratory for Cancer Research; National Cancer Institute, National Institutes of Health; Joint Science and Technology Office of the Department of Defense FX This work was supported in part by the Intramural Research Program of the NIH, Center for Cancer Research, Frederick National Laboratory for Cancer Research and the National Cancer Institute, National Institutes of Health and the Joint Science and Technology Office of the Department of Defense. 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. NR 29 TC 12 Z9 13 U1 0 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD DEC 15 PY 2012 VL 22 IS 24 BP 7309 EP 7313 DI 10.1016/j.bmcl.2012.10.088 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 041UA UT WOS:000311425500004 PM 23149229 ER PT J AU Ahsan, MJ Govindasamy, J Khalilullah, H Mohan, G Stables, JP AF Ahsan, Mohamed Jawed Govindasamy, Jeyabalan Khalilullah, Habibullah Mohan, Govind Stables, James P. TI POMA analyses as new efficient bioinformatics' platform to predict and optimise bioactivity of synthesized 3a,4-dihydro-3H-indeno[1,2-c]pyrazole-2-carboxamide/carbothioamide analogues (vol 22, pg 7029, 2012) SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Correction C1 [Ahsan, Mohamed Jawed; Govindasamy, Jeyabalan; Khalilullah, Habibullah] Alwar Pharm Coll, Dept Med Chem, Alwar 301030, Rajasthan, India. [Ahsan, Mohamed Jawed; Mohan, Govind] Nims Univ, Nims Inst Pharm, Dept Pharmaceut Chem, Jaipur 303121, Rajasthan, India. [Stables, James P.] NIH, Preclin Pharmacol Sect, Epilepsy Branch, Bethesda, MD 20892 USA. RP Ahsan, MJ (reprint author), Alwar Pharm Coll, Dept Med Chem, Alwar 301030, Rajasthan, India. EM jawedpharma@gmail.com OI Ahsan, Mohamed Jawed/0000-0002-6919-5489 NR 1 TC 0 Z9 0 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD DEC 15 PY 2012 VL 22 IS 24 BP 7748 EP 7748 DI 10.1016/j.bmcl.2012.10.113 PG 1 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 041UA UT WOS:000311425500093 ER PT J AU Blackwelder, WC Biswas, K Wu, YK Kotloff, KL Farag, TH Nasrin, D Graubard, BI Sommerfelt, H Levine, MM AF Blackwelder, William C. Biswas, Kousick Wu, Yukun Kotloff, Karen L. Farag, Tamer H. Nasrin, Dilruba Graubard, Barry I. Sommerfelt, Halvor Levine, Myron M. TI Statistical Methods in the Global Enteric Multicenter Study (GEMS) SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID ATTRIBUTABLE RISK; DIARRHEA; CHILDREN; ENTEROPATHOGENS; ETIOLOGY; DISEASE AB The Global Enteric Multicenter Study (GEMS) is an investigation of the burden (number of cases and incidence) of moderate-to-severe diarrhea (MSD) in children < 60 months of age at 7 sites in sub-Saharan Africa and South Asia. The population attributable fraction for a putative pathogen, either unadjusted or adjusted for other pathogens, is estimated using the proportion of MSD cases from whom the pathogen was isolated and the odds ratio for MSD and the pathogen from conditional logistic regression modeling. The adjusted attributable fraction, proportion of MSD cases taken to a sentinel health center (SHC), number of cases presenting to an SHC, and the site's population are used to estimate the annual number of MSD cases and MSD incidence rate attributable to a pathogen or group of pathogens. Associations with death and nutritional outcomes, ascertained at follow-up visits to case and control households, are evaluated both in MSD cases and in the population. C1 [Blackwelder, William C.; Wu, Yukun; Kotloff, Karen L.; Farag, Tamer H.; Nasrin, Dilruba; Levine, Myron M.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. [Biswas, Kousick] Vet Adm, Perry Point, MD USA. [Graubard, Barry I.] NCI, Bethesda, MD 20892 USA. [Sommerfelt, Halvor] Univ Bergen, Ctr Int Hlth, Oslo, Norway. [Sommerfelt, Halvor] Norwegian Inst Publ Hlth, Div Infect Dis Control, Oslo, Norway. RP Blackwelder, WC (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, 685 W Baltimore St, Baltimore, MD 21201 USA. EM wblackwe@medicine.umaryland.edu RI kotloff, karen/E-7768-2012 OI kotloff, karen/0000-0003-1808-6431 FU Bill & Melinda Gates Foundation [38874] FX This work was supported by the Bill & Melinda Gates Foundation (grant number 38874). NR 29 TC 27 Z9 27 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2012 VL 55 SU 4 BP S246 EP S253 DI 10.1093/cid/cis788 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 044QP UT WOS:000311637600004 PM 23169937 ER PT J AU Kotloff, KL Blackwelder, WC Nasrin, D Nataro, JP Farag, TH van Eijk, A Adegbola, RA Alonso, PL Breiman, RF Faruque, ASG Saha, D Sow, SO Sur, D Zaidi, AKM Biswas, K Panchalingam, S Clemens, JD Cohen, D Glass, RI Mintz, ED Sommerfelt, H Levine, MM AF Kotloff, Karen L. Blackwelder, William C. Nasrin, Dilruba Nataro, James P. Farag, Tamer H. van Eijk, Annemieke Adegbola, Richard A. Alonso, Pedro L. Breiman, Robert F. Faruque, Abu Syed Golam Saha, Debasish Sow, Samba O. Sur, Dipika Zaidi, Anita K. M. Biswas, Kousick Panchalingam, Sandra Clemens, John D. Cohen, Dani Glass, Roger I. Mintz, Eric D. Sommerfelt, Halvor Levine, Myron M. TI The Global Enteric Multicenter Study (GEMS) of Diarrheal Disease in Infants and Young Children in Developing Countries: Epidemiologic and Clinical Methods of the Case/Control Study SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID SUB-SAHARAN AFRICA; ROTAVIRUS DIARRHEA; RURAL BANGLADESH; EPISODES; VACCINE; DEATHS; POPULATION; INFECTIONS; MORTALITY; COMMUNITY AB Background. Diarrhea is a leading cause of illness and death among children aged <5 years in developing countries. This paper describes the clinical and epidemiological methods used to conduct the Global Enteric Multicenter Study (GEMS), a 3-year, prospective, age-stratified, case/control study to estimate the population-based burden, microbiologic etiology, and adverse clinical consequences of acute moderate-to-severe diarrhea (MSD) among a censused population of children aged 0-59 months seeking care at health centers in sub-Saharan Africa and South Asia. Methods. GEMS was conducted at 7 field sites, each serving a population whose demography and healthcare utilization practices for childhood diarrhea were documented. We aimed to enroll 220 MSD cases per year from selected health centers serving each site in each of 3 age strata (0-11, 12-23, and 24-59 months), along with 1-3 matched community controls. Cases and controls supplied clinical, epidemiologic, and anthropometric data at enrollment and again approximately 60 days later, and provided enrollment stool specimens for identification and characterization of potential diarrheal pathogens. Verbal autopsy was performed if a child died. Analytic strategies will calculate the fraction of MSD attributable to each pathogen and the incidence, financial costs, nutritional consequences, and case fatality overall and by pathogen. Conclusions. When completed, GEMS will provide estimates of the incidence, etiology, and outcomes of MSD among infants and young children in sub-Saharan Africa and South Asia. This information can guide development and implementation of public health interventions to diminish morbidity and mortality from diarrheal diseases. C1 [Kotloff, Karen L.; Nataro, James P.; Levine, Myron M.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Dept Pediat, Baltimore, MD 21201 USA. [Kotloff, Karen L.; Blackwelder, William C.; Nasrin, Dilruba; Nataro, James P.; Farag, Tamer H.; Panchalingam, Sandra; Levine, Myron M.] Univ Maryland, Sch Med, Ctr Vaccine Dev, Dept Med, Baltimore, MD 21201 USA. [van Eijk, Annemieke] Univ Liverpool, Liverpool Sch Trop Med, Child & Reprod Hlth Grp, Liverpool L69 3BX, Merseyside, England. [Adegbola, Richard A.; Saha, Debasish] Med Res Council United Kingdom Unit, Fajara, Gambia. [Alonso, Pedro L.] Univ Barcelona, Hosp Clin, Ctr Recerca Salut Int Barcelona, E-08007 Barcelona, Spain. [Breiman, Robert F.] US Ctr Dis Control & Prevent, Kenya Off, Global Dis Detect Div, Nairobi, Kenya. [Faruque, Abu Syed Golam] Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. [Sow, Samba O.] Ctr Dev Vaccins, Bamako, Mali. [Sur, Dipika] Natl Inst Cholera & Enter Dis, Kolkata, India. [Zaidi, Anita K. M.] Aga Khan Univ, Dept Paediat & Child Hlth, Karachi, Pakistan. [Biswas, Kousick] Cooperat Studies Program Coordinating Ctr, Dept Vet Affairs, Perry Point, MD USA. [Clemens, John D.] Int Vaccine Inst, Seoul, South Korea. [Cohen, Dani] Tel Aviv Univ, Sackler Fac Med, Sch Publ Hlth, Dept Epidemiol & Prevent Med, Ramat Aviv, Israel. [Glass, Roger I.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Mintz, Eric D.] US Ctr Dis Control & Prevent, Div Foodborne Waterborne & Environm Dis, Atlanta, GA USA. [Sommerfelt, Halvor] Univ Bergen, Ctr Int Hlth, Oslo, Norway. [Sommerfelt, Halvor] Norwegian Inst Publ Hlth, Div Infect Dis Control, Oslo, Norway. RP Kotloff, KL (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, Dept Pediat, 685 W Baltimore St,HSF 480, Baltimore, MD 21201 USA. EM kkotloff@medicine.umaryland.edu RI kotloff, karen/E-7768-2012 OI kotloff, karen/0000-0003-1808-6431 FU Bill & Melinda Gates Foundation [38874] FX This work was supported by the Bill & Melinda Gates Foundation (grant number 38874). NR 43 TC 68 Z9 68 U1 2 U2 15 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2012 VL 55 SU 4 BP S232 EP S245 DI 10.1093/cid/cis753 PG 14 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 044QP UT WOS:000311637600003 PM 23169936 ER PT J AU Ernst, S Liu, K Agarwala, S Moratscheck, N Avci, ME Nogare, DD Chitnis, AB Ronneberger, O Lecaudey, V AF Ernst, Sandra Liu, Kun Agarwala, Sobhika Moratscheck, Nicola Avci, Mehmet Ender Nogare, Damian Dalle Chitnis, Ajay B. Ronneberger, Olaf Lecaudey, Virginie TI Shroom3 is required downstream of FGF signalling to mediate proneuromast assembly in zebrafish SO DEVELOPMENT LA English DT Article DE Lateral line; Apical constriction; Rosette; Shroom3; Rho kinase; Collective cell migration; Morphogenesis; Zebrafish ID LATERAL-LINE SYSTEM; EPITHELIAL-CELL SHAPE; RHO-ASSOCIATED KINASE; APICAL CONSTRICTION; FAMILY PROTEINS; CRANIAL GANGLIA; MYOSIN-II; MORPHOGENESIS; MIGRATION; EXPRESSION AB During development, morphogenetic processes require a precise coordination of cell differentiation, cell shape changes and, often, cell migration. Yet, how pattern information is used to orchestrate these different processes is still unclear. During lateral line (LL) morphogenesis, a group of cells simultaneously migrate and assemble radially organized cell clusters, termed rosettes, that prefigure LL sensory organs. This process is controlled by Fibroblast growth factor (FGF) signalling, which induces cell fate changes, cell migration and cell shape changes. However, the exact molecular mechanisms induced by FGF activation that mediate these changes on a cellular level are not known. Here, we focus on the mechanisms by which FGFs control apical constriction and rosette assembly. We show that apical constriction in the LL primordium requires the activity of non-muscle myosin. We demonstrate further that shroom3, a well-known regulator of non-muscle myosin activity, is expressed in the LL primordium and that its expression requires FGF signalling. Using gain-and loss-of-function experiments, we demonstrate that Shroom3 is the main organizer of cell shape changes during rosette assembly, probably by coordinating Rho kinase recruitment and non-muscle myosin activation. In order to quantify morphogenesis in the LL primordium in an unbiased manner, we developed a unique trainable 'rosette detector'. We thus propose a model in which Shroom3 drives rosette assembly in the LL downstream of FGF in a Rho kinase-and non-muscle myosin-dependent manner. In conclusion, we uncovered the first mechanistic link between patterning and morphogenesis during LL sensory organ formation. C1 [Ernst, Sandra; Liu, Kun; Agarwala, Sobhika; Moratscheck, Nicola; Avci, Mehmet Ender; Ronneberger, Olaf; Lecaudey, Virginie] Univ Freiburg, Ctr Biol Signalling Studies BIOSS, D-79104 Freiburg, Germany. [Ernst, Sandra; Agarwala, Sobhika; Moratscheck, Nicola; Avci, Mehmet Ender; Lecaudey, Virginie] Univ Freiburg, Fac Biol, Dept Dev Biol, D-79104 Freiburg, Germany. [Liu, Kun; Ronneberger, Olaf] Univ Freiburg, Inst Comp Sci, Image Anal Lab, D-79110 Freiburg, Germany. [Nogare, Damian Dalle; Chitnis, Ajay B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Genom Differentiat, NIH, Bethesda, MD USA. RP Lecaudey, V (reprint author), Univ Freiburg, Ctr Biol Signalling Studies BIOSS, Schanzlestr 18, D-79104 Freiburg, Germany. EM virginie.lecaudey@bioss.uni-freiburg.de RI Lecaudey, Virginie/A-8696-2013 FU German Research Foundation (DFG) [EXC 294-BIOSS, SFB 850-TP A2, GRK 1104]; Ministry of Science, Research and Art of Baden-Wurttemberg; Marie Curie Reintegration Grant [PERG06-GA-2009-256292] FX This work was supported by the German Research Foundation (DFG) [EXC 294-BIOSS to S. E., K. L., O.R. and V. L.; SFB 850-TP A2 to M. E. A. and V. L; GRK 1104 to S. A. and V. L.], the 'Juniorprofessuren Programm' of the Ministry of Science, Research and Art of Baden-Wurttemberg (fellowship to N.M.) and a Marie Curie Reintegration Grant [PERG06-GA-2009-256292 Morphogenesis to V.L.]. NR 49 TC 22 Z9 22 U1 1 U2 6 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 DEC 15 PY 2012 VL 139 IS 24 BP 4571 EP 4581 DI 10.1242/dev.083253 PG 11 WC Developmental Biology SC Developmental Biology GA 041PO UT WOS:000311413900009 PM 23136387 ER PT J AU Zhang, DY Lozier, J Chang, R Sachdev, V Chen, MY Audibert, JL Horvath, KA Rosing, DR AF Zhang, David Yi Lozier, Jay Chang, Richard Sachdev, Vandana Chen, Marcus Y. Audibert, Jennifer L. Horvath, Keith A. Rosing, Douglas R. TI Case study and review: Treatment of tricuspid prosthetic valve thrombosis SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Review DE Tricuspid valve; Prosthetic valve; Thrombosis, thrombolysis, fibrinolysis; Ebstein anomaly; Recombinant tissue plasminogen activator (tPa); Pannus ID VALVULAR HEART-DISEASE; PLASMINOGEN-ACTIVATOR; THROMBOLYTIC TREATMENT; PULMONARY-EMBOLISM; MECHANICAL VALVE; TASK-FORCE; MANAGEMENT; THERAPY; OBSTRUCTION; GUIDELINES AB Prosthetic valve thrombosis (PVT) is a severe and life-threatening complication of heart valve replacement. Conventional therapy is surgical thrombectomy or valve replacement. Medical thrombolysis is another emerging option. We report the case of a 57 year old woman with a history of Ebstein anomaly who underwent successful treatment of tricuspid prosthetic valve thrombosis with intra-atrial infusion of very low dose recombinant tissue plasminogen activator (tPA). We review the presentation, etiology, diagnosis, and treatment of tricuspid PVT emphasizing a modified medical option as a safe, minimally invasive alternative to surgical intervention or conventional medical therapy for tricuspid valve thrombosis. Published by Elsevier Ireland Ltd. C1 [Sachdev, Vandana; Chen, Marcus Y.; Audibert, Jennifer L.; Rosing, Douglas R.] NHLBI, Cardiovasc & Pulm Branch, NIH, Bethesda, MD 20892 USA. [Zhang, David Yi] Univ Miami, Miller Sch Med, Div Internal Med, Miami, FL 33136 USA. [Lozier, Jay] NIH, Hematol Serv, Ctr Clin, Bethesda, MD 20892 USA. [Chang, Richard] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Horvath, Keith A.] NHLBI, Off Director, NIH, Bethesda, MD 20892 USA. RP Rosing, DR (reprint author), NHLBI, Cardiovasc & Pulm Branch, NIH, Bldg 10,CRC 5-3330, Bethesda, MD 20892 USA. FU National Heart, Lung, and Blood Institute (NHLBI); Clinical Center (CC) of the National Institutes of Health FX Supported by the Intramural Research Programs of the National Heart, Lung, and Blood Institute (NHLBI) and Clinical Center (CC) of the National Institutes of Health. NR 34 TC 4 Z9 4 U1 0 U2 6 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 DEC 15 PY 2012 VL 162 IS 1 BP 14 EP 19 DI 10.1016/j.ijcard.2011.09.081 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 042SI UT WOS:000311490900013 PM 22000268 ER PT J AU Aebi, S Gelber, S Lang, I Anderson, SJ Robidoux, A Martin, M Nortier, JWR Mamounas, EP Geyer, CE Maibach, R Gelber, RD Wolmark, N Wapnir, I AF Aebi, S. Gelber, S. Lang, I. Anderson, S. J. Robidoux, A. Martin, M. Nortier, J. W. R. Mamounas, E. P. Geyer, C. E., Jr. Maibach, R. Gelber, R. D. Wolmark, N. Wapnir, I. TI Chemotherapy prolongs survival for isolated local or regional recurrence of breast cancer: The CALOR trial (Chemotherapy as Adjuvant for Locally Recurrent breast cancer; IBCSG 27-02, NSABP B-37, BIG 1-02) SO CANCER RESEARCH LA English DT Meeting Abstract C1 Int Breast Canc Study Grp, Bern, Switzerland. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Breast Int Grp, Brussels, Belgium. NR 0 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA S3-2 DI 10.1158/0008-5472.SABCS12-S3-2 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900007 ER PT J AU Cobleigh, MA Anderson, SJ Julian, TB Siziopikou, KP Arthur, DW Rabinovitch, R Zheng, P Mamounas, EP Wolmark, N AF Cobleigh, M. A. Anderson, S. J. Julian, T. B. Siziopikou, K. P. Arthur, D. W. Rabinovitch, R. Zheng, P. Mamounas, E. P. Wolmark, N. TI NSABP B-43: A phase III clinical trial to compare trastuzumab (T) given concurrently with radiation therapy (RT) to RT alone for women with HER2+DCIS resected by lumpectomy (Lx) SO CANCER RESEARCH LA English DT Meeting Abstract C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Rush Univ, Med Ctr, Chicago, IL 60612 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Virginia Commonwealth Univ, Richmond, VA USA. Univ Colorado, Aurora, CO USA. Aultman Hosp, Canton, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA OT1-2-01 DI 10.1158/0008-5472.SABCS12-OT1-2-01 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900094 ER PT J AU Cortazar, P Zhang, L Untch, M Mehta, K Costantino, J Wolmark, N Bonnefoi, H Cameron, D Gianni, L Valagussa, P Zujewski, JA Justice, R Loibl, S Wickerham, L Bogaerts, J Baselga, J Perou, C Blumenthal, G Blohmer, J Mamounas, E Bergh, J Semiglazov, V Prowell, T Eidtmann, H Paik, S Piccart, M Sridhara, R Fasching, P Swain, SM Slaets, L Tang, S Gerber, B Geyer, C Pazdur, R Ditsch, N Rastogi, P Eiermann, W von Mincwitz, G AF Cortazar, P. Zhang, L. Untch, M. Mehta, K. Costantino, J. Wolmark, N. Bonnefoi, H. Cameron, D. Gianni, L. Valagussa, P. Zujewski, J. A. Justice, R. Loibl, S. Wickerham, L. Bogaerts, J. Baselga, J. Perou, C. Blumenthal, G. Blohmer, J. Mamounas, E. Bergh, J. Semiglazov, V. Prowell, T. Eidtmann, H. Paik, S. Piccart, M. Sridhara, R. Fasching, P. Swain, S. M. Slaets, L. Tang, S. Gerber, B. Geyer, C. Pazdur, R. Ditsch, N. Rastogi, P. Eiermann, W. von Mincwitz, G. TI Meta-analysis Results from the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) SO CANCER RESEARCH LA English DT Meeting Abstract C1 US FDA, Rockville, MD 20857 USA. HELIOS Klinikum Berlin Buch, Berlin, Germany. NSABP, Pittsburgh, PA USA. Univ Pittsburgh, Pittsburgh, PA USA. INSERM, Inst Bergonie, U916, Bordeaux, France. Univ Bordeaux Segalen, Bordeaux, France. Univ Edinburgh, Edinburgh, Midlothian, Scotland. Ist Sci San Raffaele, I-20132 Milan, Italy. Fdn Michelangelo, Milan, Italy. NCI, Bethesda, MD 20892 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. GBG Forsch GmbH, Berlin, Germany. Washington Hosp Ctr, Washington, DC 20010 USA. St Gertrauden Hosp, Berlin, Germany. Univ Womens Hosp, Kiel, Germany. Univ Womens Hosp, Erlangen, Germany. Univ Womens Hosp, Rostock, Germany. Univ Womens Hosp, Munich, Germany. Karolinska Inst, Stockholm, Sweden. St Gorans Univ Hosp, S-11281 Stockholm, Sweden. EORTC Headquarters, Brussels, Belgium. Mem Sloan Kettering Canc Ctr, 1275 York Ave, New York, NY 10021 USA. NN Petrov Res Inst Oncol, St Petersburg, Russia. Inst Jules Bordet, B-1000 Brussels, Belgium. NR 0 TC 22 Z9 24 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA S1-11 DI 10.1158/0008-5472.SABCS12-S1-11 PG 2 WC Oncology SC Oncology GA V43TY UT WOS:000209704900090 ER PT J AU De Mukhopadhyay, K Elkahloun, AG Hinck, AP Yoon, K Cornell, JE Shu, L Yang, J Sun, L AF De Mukhopadhyay, K. Elkahloun, A. G. Hinck, A. P. Yoon, K. Cornell, J. E. Shu, L. Yang, J. Sun, L. TI Determining the molecular mechanism of the breast cancer-induced brain metastasis and a role of a novel pan-TGF-beta inhibitor as a potential therapy for brain metastasis in a mouse xenograft model SO CANCER RESEARCH LA English DT Meeting Abstract C1 Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. NHGRI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P1-05-18 DI 10.1158/0008-5472.SABCS12-P1-05-18 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900175 ER PT J AU Dillenburg, PP Patel, VT Dorsam, R Masedunskas, A Amornphimoltham, P Weigert, R Molinolo, A Gutkind, JS AF Dillenburg, Pilla P. Patel, V. T. Dorsam, R. Masedunskas, A. Amornphimoltham, P. Weigert, R. Molinolo, A. Gutkind, J. S. TI Blockade of mTORC1 decreases CXCR4-mediated migration and metastasis SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Dillenburg, Pilla P.; Patel, V. T.; Dorsam, R.; Masedunskas, A.; Amornphimoltham, P.; Weigert, R.; Molinolo, A.; Gutkind, J. S.] NIH, Bethesda, MD 20892 USA. OI Masedunskas, Andrius/0000-0002-4533-5467 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P1-05-23 DI 10.1158/0008-5472.SABCS12-P1-05-23 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900180 ER PT J AU Fabris, L Berton, S Massarut, S D'Andrea, S Roncadin, M Perin, T Calin, G Belletti, B Baldassarre, G AF Fabris, L. Berton, S. Massarut, S. D'Andrea, S. Roncadin, M. Perin, T. Calin, G. Belletti, B. Baldassarre, G. TI Radiotherapy-induced miR expression influences the formation of local recurrence in breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Natl Canc Inst, CRO, Bethesda, MD USA. Univ Texas MD Anderson Canc Ctr, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P5-10-17 DI 10.1158/0008-5472.SABCS-P5-10-17 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704901295 ER PT J AU Gatti-Mays, M Kallakury, BVS Makariou, E Venzon, D Permaul, E Isaacs, C Cohen, P Warren, R Gallagher, A Eng-Wong, J AF Gatti-Mays, M. Kallakury, B. V. S. Makariou, E. Venzon, D. Permaul, E. Isaacs, C. Cohen, P. Warren, R. Gallagher, A. Eng-Wong, J. TI Down-regulation of trefoil protein 1(TFF1) in normal breast tissue of postmenopausal women at increased risk for breast cancer on exemestane SO CANCER RESEARCH LA English DT Meeting Abstract C1 Georgetown Univ Hosp, Washington, DC 20007 USA. NCI, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. Georgetown Univ Hosp, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P1-09-04 DI 10.1158/0008-5472.SABCS12-P1-09-04 PG 2 WC Oncology SC Oncology GA V43TY UT WOS:000209704902124 ER PT J AU Home, HN Sherman, ME Garcia-Closas, M Pharoah, PD Blows, FM Yang, XR Lissowska, J Brinton, LA Chanock, SJ Figueroa, JD AF Home, H. N. Sherman, M. E. Garcia-Closas, M. Pharoah, P. D. Blows, F. M. Yang, X. R. Lissowska, J. Brinton, L. A. Chanock, S. J. Figueroa, J. D. TI Common variants at 10p14 and 1p11.2 display heterogeneity in breast cancer associations by E-cadherin tumor tissue expression in two independent datasets SO CANCER RESEARCH LA English DT Meeting Abstract C1 NCI, Rockville, MD USA. Inst Canc Res, Sutton, Surrey, England. Univ Cambridge, Cambridge CB2 1TN, England. M Sklodowska Curie Mem Canc Ctr & Inst Oncol, Warsaw, Poland. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P3-08-02 DI 10.1158/0008-5472.SABCS12-P3-08-02 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900354 ER PT J AU Hunsberger, S AF Hunsberger, S. TI Clinical Trial Designs for New Therapies: When Should We Randomize? SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Hunsberger, S.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA ES3-4 DI 10.1158/0008-5472.SABCS12-ES3-4 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900051 ER PT J AU Jin, L Simone, B Sano, Y Lim, M Zhao, S Savage, JE Baserga, R Camphausen, K Simone, NL AF Jin, L. Simone, B. Sano, Y. Lim, M. Zhao, S. Savage, J. E. Baserga, R. Camphausen, K. Simone, N. L. TI Decreasing the metastatic potential in Triple Negative Breast Cancer through the miR-17 cluster SO CANCER RESEARCH LA English DT Meeting Abstract C1 Thomas Jefferson Univ, Philadelphia, PA 19107 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P6-01-03 DI 10.1158/0008-5472.SABCS12-P8-01-03 PG 2 WC Oncology SC Oncology GA V43TY UT WOS:000209704902070 ER PT J AU Kesarwala, AH Pfalzer, LA O'Meara, WP Stout, NL AF Kesarwala, A. H. Pfalzer, L. A. O'Meara, W. P. Stout, N. L. TI Symptoms, Physical Impairments, and Function in Breast Cancer Patients with Negative Axillary Lymph Nodes SO CANCER RESEARCH LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Univ Michigan Flint, Flint, MI USA. Lahey Clin Fdn, Burlington, MA USA. Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P2-11-14 DI 10.1158/0008-5472.SABCS12-P2-11-14 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900255 ER PT J AU Kesarwala, AH Pfalzer, LA O'Meara, WP Stout, NL AF Kesarwala, A. H. Pfalzer, L. A. O'Meara, W. P. Stout, N. L. TI The Effect of Positive Axillary Lymph Nodes on Symptoms, Physical Impairments, and Function SO CANCER RESEARCH LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Univ Michigan Flint, Flint, MI USA. Lahey Clin Fdn, Burlington, MA USA. Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P2-11-13 DI 10.1158/0008-5472.SABCS12-P2-11-13 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900254 ER PT J AU Kim, S Taylor, JA Sandler, DP AF Kim, S. Taylor, J. A. Sandler, D. P. TI Urinary levels of prostaglandin E-2 metabolite and postmenopausal breast cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 Georgia Hlth Sci Univ, Augusta, GA USA. NIEHS, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P3-08-03 DI 10.1158/0008-5472.SABCS12-P3-08-03 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900355 ER PT J AU Lee, O Chatterton, RT Muzzio, M Page, K Jovanovic, B Helenowski, I Dunn, B Heckman-Stoddard, B Foster, K Shklovskaya, J Skripkauskas, S Bergan, R Khan, SA AF Lee, O. Chatterton, R. T. Muzzio, M. Page, K. Jovanovic, B. Helenowski, I. Dunn, B. Heckman-Stoddard, B. Foster, K. Shklovskaya, J. Skripkauskas, S. Bergan, R. Khan, S. A. TI Topical 4-OHT trial in women with DCIS of the breast: report of plasma and breast tissue concentration of tamoxifen metabolites SO CANCER RESEARCH LA English DT Meeting Abstract C1 Northwestern Univ, Chicago, IL 60611 USA. IIT, Res Inst, Chicago, IL 60616 USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P1-09-07 DI 10.1158/0008-5472.SABCS12-P1-09-07 PG 2 WC Oncology SC Oncology GA V43TY UT WOS:000209704902127 ER PT J AU Lu, J Jacobs, SA Buyse, ME Paik, S Wolmark, N AF Lu, J. Jacobs, S. A. Buyse, M. E. Paik, S. Wolmark, N. TI NSABP FB-7 Trial: A Phase II Randomized Clinical Trial Evaluating Neoadjuvant Therapy Regimens with Weekly Paclitaxel and Neratinib or Trastuzumab or Neratinib and Trastuzumab Followed by Doxorubicin and Cyclophosphamide with Postoperative Trastuzumab in Women with Locally Advanced HER2-Positive Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract C1 SUNY Stony Brook, Stony Brook, NY 11794 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA OT1-1-12 DI 10.1158/0008-5472.SABCS12-OT1-1-12 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900087 ER PT J AU Lubet, R Vedell, P Grubbs, C Bernard, P You, M AF Lubet, R. Vedell, P. Grubbs, C. Bernard, P. You, M. TI Gene expression changes in methylnitrosourea (MNU)-induced ER+ mammary cancers following short-term treatment of rats with SERMs (Tamoxifen and Arzoxifene) SO CANCER RESEARCH LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Med Sch Wisconsin, Milwaukee, WI USA. Hunstman Canc Ctr, Salt Lake City, UT USA. Univ Alabama Birmingham, Birmingham, AL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P1-08-02 DI 10.1158/0008-5472.SABCS12-P1-08-02 PG 2 WC Oncology SC Oncology GA V43TY UT WOS:000209704902132 ER PT J AU Lubet, RA Ellis, MJ Grubbs, CJ AF Lubet, R. A. Ellis, M. J. Grubbs, C. J. TI Effects Of An Allosteric AKT Inhibitor (MK2206) Administered With Or Without The Aromatase Inhibitor Vorozole In An ER+ Rat Mammary Cancer Model: Preventive And Therapeutic Effects SO CANCER RESEARCH LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Washington Univ, St Louis, MO USA. Univ Alabama Birmingham, Birmingham, AL USA. NR 0 TC 0 Z9 0 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 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P1-08-01 DI 10.1158/0008-5472.SABCS12-P1-08-01 PG 2 WC Oncology SC Oncology GA V43TY UT WOS:000209704902130 ER PT J AU Mamounas, EP Tang, G Paik, S Baehner, FL Liu, Q Jeong, JH Kim, SR Butler, SM Jamshidian, F Cherbavaz, DB Sing, AP Shak, S Julian, TB Lembersky, BC Wickerham, DL Costantino, JP Wolmark, N AF Mamounas, E. P. Tang, G. Paik, S. Baehner, F. L. Liu, Q. Jeong, J-H Kim, S-R Butler, S. M. Jamshidian, F. Cherbavaz, D. B. Sing, A. P. Shak, S. Julian, T. B. Lembersky, B. C. Wickerham, D. L. Costantino, J. P. Wolmark, N. TI Association between the 21-gene recurrence score (RS) and benefit from adjuvant paclitaxel (Pac) in node-positive (N plus ), ER-positive breast cancer patients (pts): Results from NSABP B-28 SO CANCER RESEARCH LA English DT Meeting Abstract C1 Natl Surg Adjuvant Breast & Bowel Project, Operat Ctr, Pittsburgh, PA USA. Natl Surg Adjuvant Breast & Bowel Project, Biostat Ctr, Pittsburgh, PA USA. Aultman Hosp, Canton, OH USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15260 USA. Genom Hlth Inc, Redwood City, CA USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA S1-10 DI 10.1158/0008-5472.SABCS12-S1-10 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900079 ER PT J AU Nielsen, TO Polley, MY Leung, SCY Mastropasqua, MG Zabaglo, LA Bartlett, JMS Viale, G McShane, LM Hayes, DF Dowsett, M AF Nielsen, T. O. Polley, M-Yc Leung, S. C. Y. Mastropasqua, M. G. Zabaglo, L. A. Bartlett, J. M. S. Viale, G. McShane, L. M. Hayes, D. F. Dowsett, M. CA BIG-NABCG Collaboration TI An international Ki67 reproducibility study SO CANCER RESEARCH LA English DT Meeting Abstract C1 Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. NCI, Bethesda, MD 20892 USA. European Inst Oncol, Milan, Italy. Inst Canc Res, London SW3 6JB, England. Ontario Inst Canc Res, Toronto, ON, Canada. Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Royal Marsden Hosp, London SW3 6JJ, England. North Amer Breast Canc Grp Collaborat, Breast Int Grp, Brussels, Belgium. NR 0 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA S4-6 DI 10.1158/0008-5472.SABCS12-S4-6 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900020 ER PT J AU Nyante, SJ Gierach, GL Dallal, CM Park, Y Hollenbeck, AR Brinton, LA AF Nyante, S. J. Gierach, G. L. Dallal, C. M. Park, Y. Hollenbeck, A. R. Brinton, L. A. TI Cigarette smoking and postmenopausal breast cancer risk: results from the NIH-AARP Diet and Health Study SO CANCER RESEARCH LA English DT Meeting Abstract C1 NCI, Rockville, MD USA. AARP, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P3-07-04 DI 10.1158/0008-5472.SABCS12-P3-07-04 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900389 ER PT J AU Oesterreich, S Kitchens, C Gavin, P Wu, CC Riehle, K Coarfa, C Edwards, D Schiff, R Milosavljevic, A Lee, A AF Oesterreich, S. Kitchens, C. Gavin, P. Wu, C-C Riehle, K. Coarfa, C. Edwards, D. Schiff, R. Milosavljevic, A. Lee, A. TI Lack of Frequent Estrogen Receptor Mutation in Primary Breast Tumors SO CANCER RESEARCH LA English DT Meeting Abstract C1 Univ Pittsburgh, Canc Institure, Pittsburgh, PA USA. Baylor Coll Med, Houston, TX 77030 USA. NSABP, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P6-05-12 DI 10.1158/0008-5472.SABCS12-P6-05-12 PG 2 WC Oncology SC Oncology GA V43TY UT WOS:000209704902062 ER PT J AU Puhalla, SL Appleman, LJ Beumer, JH Tawbi, H Stoller, RG Owonikoko, TK Ramalingam, SS Belani, CP Brufsky, AM Abraham, J Shepherd, SP Giranda, V Chen, AP Chu, E AF Puhalla, S. L. Appleman, L. J. Beumer, J. H. Tawbi, H. Stoller, R. G. Owonikoko, T. K. Ramalingam, S. S. Belani, C. P. Brufsky, A. M. Abraham, J. Shepherd, S. P. Giranda, V. Chen, A. P. Chu, E. TI Two phase I trials exploring different dosing schedules of carboplatin (C), paclitaxel (P), and the poly-ADP-ribose polymerase (PARP) inhibitor, veliparib (ABT-888) (V) with activity in triple negative breast cancer (TNBC) SO CANCER RESEARCH LA English DT Meeting Abstract C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA. Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. W Virginia Univ, Ctr Canc, Morgantown, WV 26506 USA. Penn State Hershey Canc Inst, Hershey, PA USA. NCI, Bethesda, MD 20892 USA. Abbott Labs, Abbott Pk, IL 60064 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA PD09-06 DI 10.1158/0008-5472.SABCS12-PD09-06 PG 2 WC Oncology SC Oncology GA V43TY UT WOS:000209704901423 ER PT J AU Romond, E Suman, VJ Jeong, JH Sledge, GW Geyer, CE Martino, S Rastogi, P Gralow, J Swain, SM Winer, E Colon-Otero, G Hudis, C Paik, S Davidson, N Mamounas, EP Zujewski, JA Wolmark, N Perez, EA AF Romond, E. Suman, V. J. Jeong, J-H Sledge, G. W., Jr. Geyer, C. E., Jr. Martino, S. Rastogi, P. Gralow, J. Swain, S. M. Winer, E. Colon-Otero, G. Hudis, C. Paik, S. Davidson, N. Mamounas, E. P. Zujewski, J. A. Wolmark, N. Perez, E. A. CA Natl Surg Adjuvant Breast Bowel Pr TI Trastuzumab plus adjuvant chemotherapy for HER2-positive breast cancer: Final planned joint analysis of overall survival (OS) from NSABP B-31 and NCCTG N9831 SO CANCER RESEARCH LA English DT Meeting Abstract C1 Univ Kentucky, Lexington, KY 40506 USA. Mayo Clin, Rochester, MN USA. Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15260 USA. IU Simon Canc Ctr, Indianapolis, IN USA. Univ Texas Southwestern Med Ctr, Dallas, TX USA. Angeles Clin & Res Inst, Santa Monica, CA USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. Univ Washington, Seattle, WA 98195 USA. Medstar Washington Hosp Ctr, Washington, DC USA. Dana Farber Canc Inst, Boston, MA USA. Mem Sloan Kettering Canc Ctr, New York, NY USA. Aultman Hosp, Canton, OH USA. NCI, Canc Therapy Evaluat Program, NIH, DHHS, Bethesda, MD 20892 USA. Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA S5-5 DI 10.1158/0008-5472.SABCS12-S5-5 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900026 ER PT J AU Virador, VM Casagrange, G Raafat, A Callahan, R Kohn, E AF Virador, V. M. Casagrange, G. Raafat, A. Callahan, R. Kohn, E. TI Targeted Expression of the Human Chaperone BAG3 to the Murine Mammary Gland Dysregulates Mammary Gland Development and Differentiation By Unrestricted Expansion of Lumina! Cells SO CANCER RESEARCH LA English DT Meeting Abstract C1 [Virador, V. M.; Casagrange, G.; Raafat, A.; Callahan, R.; Kohn, E.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P2-04-08 DI 10.1158/0008-5472.SABCS12-P2-04-08 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704900294 ER PT J AU Wapnir, IL Gelber, S Lang, I Anderson, SJ Robidoux, A Martin, M Nortier, JWR Mamounas, EP Geyer, CE Maibach, R Gelber, RD Wolmark, N Aebi, S AF Wapnir, I. L. Gelber, S. Lang, I. Anderson, S. J. Robidoux, A. Martin, M. Nortier, J. W. R. Mamounas, E. P. Geyer, C. E., Jr. Maibach, R. Gelber, R. D. Wolmark, N. Aebi, S. TI Patterns of locoregional failure in the CALOR (Chemotheraphy as Adjuvant for Locally Recurrent Breast Cancer) Trial SO CANCER RESEARCH LA English DT Meeting Abstract C1 Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Int Breast Canc Study Grp, Pittsburgh, PA USA. Breast Int Grp, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P6-07-06 DI 10.1158/0008-5472.SABCS12-P6-07-06 PG 2 WC Oncology SC Oncology GA V43TY UT WOS:000209704901325 ER PT J AU Zhan, M Li, F Zhu, Y Ma, J Landua, J Wei, W Vadakkan, T Zhang, M Dickinson, M Lewis, M Rosen, J Wong, S AF Zhan, M. Li, F. Zhu, Y. Ma, J. Landua, J. Wei, W. Vadakkan, T. Zhang, M. Dickinson, M. Lewis, M. Rosen, J. Wong, S. TI Quantitative Characterization of 3D Vasculature Spatial Patterns Within Tumor Microenvironment of Breast Cancer Stem Cells SO CANCER RESEARCH LA English DT Meeting Abstract C1 Methodist Hosp, NCI Ctr Modeling Canc Dev, Houston, TX 77030 USA. Baylor Coll Med, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2012 VL 72 SU 24 MA P4-02-08 DI 10.1158/0008-5472.SABCS12-P4-02-08 PG 1 WC Oncology SC Oncology GA V43TY UT WOS:000209704901013 ER PT J AU Esber, GR Roesch, MR Bali, S Trageser, J Bissonette, GB Puche, AC Holland, PC Schoenbaum, G AF Esber, Guillem R. Roesch, Matthew R. Bali, Shreya Trageser, Jason Bissonette, Gregory B. Puche, Adam C. Holland, Peter C. Schoenbaum, Geoffrey TI Attention-Related Pearce-Kaye-Hall Signals in Basolateral Amygdala Require the Midbrain Dopaminergic System SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Attention; dopamine; prediction error; rat; salience; schizophrenia ID SURPRISE-INDUCED ENHANCEMENT; ANTERIOR CINGULATE CORTEX; REWARD PREDICTION ERRORS; ORBITOFRONTAL CORTEX; CENTRAL NUCLEUS; NEURONS ENCODE; LATERAL AMYGDALA; DIFFERENT ROLES; RESPONSES; PSYCHOSIS AB Background: Neural activity in basolateral amygdala has recently been shown to reflect surprise or attention as predicted by the Pearce-Kaye-Hall model (PKH)-an influential model of associative learning. Theoretically, a PKH attentional signal originates in prediction errors of the kind associated with phasic firing of dopamine neurons. This requirement for prediction errors, coupled with projections from the midbrain dopamine system into basolateral amygdala, suggests that the PKH signal in amygdala may depend on dopaminergic input. Methods: To test this, we recorded single unit activity in basolateral amygdala in rats with 6-hydroxydopamine or sham lesions of the ipsilateral midbrain region. Neurons were recorded as the rats performed a task previously used to demonstrate both dopaminergic reward prediction errors and attentional signals in basolateral amygdala neurons. Results: We found that neurons recorded in sham lesioned rats exhibited the same attention-related PKH signal observed in previous studies. By contrast, neurons recorded in rats with ipsilateral 6-hydroxydopamine lesions failed to show attentional signaling. Conclusions: These results indicate a linkage between the neural instantiations of the basolateral complex of the amygdala attentional signal and dopaminergic prediction errors. Such a linkage would have important implications for understanding both normal and aberrant learning and behavior, particularly in diseases thought to have a primary effect on dopamine systems, such as addiction and schizophrenia. C1 [Esber, Guillem R.; Schoenbaum, Geoffrey] NIDA, Intramural Res Program, Baltimore, MD 21224 USA. [Roesch, Matthew R.; Bissonette, Gregory B.] Univ Maryland, Dept Psychol, College Pk, MD 20742 USA. [Roesch, Matthew R.] Univ Maryland, Program Neurosci & Cognit Sci, College Pk, MD 20742 USA. [Bali, Shreya] Univ Bristol, Fac Med & Dent, Bristol, Avon, England. [Trageser, Jason; Holland, Peter C.] Johns Hopkins Univ, Dept Psychol & Brain Sci, Baltimore, MD 21218 USA. [Puche, Adam C.; Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. RP Schoenbaum, G (reprint author), NIDA, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM geoffrey.schoenbaum@nih.gov OI Bissonette, Gregory/0000-0003-4478-652X FU National Institute on Drug Abuse [R01-DA015718, K01DA021609, R01DA031695]; National Institute on Aging [R01-AG027097]; National Institute on Drug Abuse-Intramural Research Program FX This work was supported by grants from the National Institute on Drug Abuse (R01-DA015718, GS; K01DA021609, MRR; R01DA031695, MRR) and National Institute on Aging (R01-AG027097, GS) and the National Institute on Drug Abuse-Intramural Research Program (GS). This article was prepared, in part, while GS was employed at University of Maryland School of Medicine, Baltimore, Maryland. The opinions expressed in this article are the author's own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. NR 68 TC 12 Z9 14 U1 0 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD DEC 15 PY 2012 VL 72 IS 12 BP 1012 EP 1019 DI 10.1016/j.biopsych.2012.05.023 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 037AS UT WOS:000311074000007 PM 22763185 ER PT J AU Walker, L Gozzi, M Lenroot, R Thurm, A Behseta, B Swedo, S Pierpaoli, C AF Walker, Lindsay Gozzi, Marta Lenroot, Rhoshel Thurm, Audrey Behseta, Babak Swedo, Susan Pierpaoli, Carlo TI Diffusion Tensor Imaging in Young Children with Autism: Biological Effects and Potential Confounds SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Autism; diffusion tensor imaging; fractional anisotropy; mean diffusivity; MRI; white matter ID HIGH-FUNCTIONING AUTISM; WHITE-MATTER COMPROMISE; VOXEL-BASED MORPHOMETRY; SPECTRUM DISORDERS; SPATIAL-STATISTICS; CORPUS-CALLOSUM; FRONTAL-LOBE; HUMAN BRAIN; ASPERGER-SYNDROME; CONNECTIVITY MRI AB Background: Diffusion tensor imaging (DTI) has been used over the past decade to study structural differences in the brains of children with autism compared with typically developing children. These studies generally find reduced fractional anisotropy (FA) and increased mean diffusivity (MD) in children with autism; however, the regional pattern of findings varies greatly. Methods: We used DTI to investigate the brains of sedated children with autism (n = 39) and naturally asleep typically developing children (n = 39) between 2 and 8 years of age. Tract based spatial statistics and whole brain voxel-wise analysis were performed to investigate the regional distribution of differences between groups. Results: In children with autism, we found significantly reduced FA in widespread regions and increased MD only in posterior brain regions. Significant age x group interaction was found, indicating a difference in developmental trends of FA and MD between children with autism and typically developing children. The magnitude of the measured differences between groups was small, on the order of approximately 1%-2%. Subjects and control subjects showed distinct regional differences in imaging artifacts that can affect DTI measures. Conclusions: We found statistically significant differences in DTI metrics between children with autism and typically developing children, including different developmental trends of these metrics. However, this study indicates that between-group differences in DTI studies of autism should be interpreted with caution, because their small magnitude make these measurements particularly vulnerable to the effects of artifacts and confounds, which might lead to false positive and/or false negative biological inferences. C1 [Walker, Lindsay; Pierpaoli, Carlo] NICHHD, Program Pediat Imaging & Tissue Sci, NIH, Bethesda, MD 20892 USA. [Gozzi, Marta; Thurm, Audrey; Behseta, Babak; Swedo, Susan] NIMH, Pediat & Dev Neurosci Branch, NIH, Bethesda, MD 20892 USA. [Walker, Lindsay] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Lenroot, Rhoshel] Univ New S Wales, Sch Psychiat, Sydney, NSW, Australia. RP Walker, L (reprint author), NICHD, NIH, Program Pediat Imaging & Tissue Sci, 13 South Dr,Bldg 13,Room 3W16D, Bethesda, MD 20892 USA. EM walkerlin@mail.nih.gov RI Walker, Lindsay/A-7122-2012 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; National Institute of Mental Health, National Institutes of Health; Department of Defense through the Center for Neuroscience and Regenerative Medicine FX This research was supported by the Intramural Research Programs of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health, National Institutes of Health. Support for this work included funding from the Department of Defense through the Center for Neuroscience and Regenerative Medicine. We wish to thank Madison Berl for her advice and insights in the interpretation of the statistical analysis. These data were previously published in abstracts at the International Society for Magnetic Resonance in Medicine (ISMRM), Melbourne, Australia, 2012, and the International Meeting for Autism Research (IMFAR), Toronto, Ontario, Canada, 2012. We would also like to thank the Henry M. Jackson Foundation (HJF) for their administrative support. NR 68 TC 31 Z9 31 U1 4 U2 37 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD DEC 15 PY 2012 VL 72 IS 12 BP 1043 EP 1051 DI 10.1016/j.biopsych.2012.08.001 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 037AS UT WOS:000311074000011 PM 22906515 ER PT J AU Tanaka, NK Suzuki, E Dye, L Ejima, A Stopfer, M AF Tanaka, Nobuaki K. Suzuki, Emiko Dye, Louis Ejima, Aki Stopfer, Mark TI Dye fills reveal additional olfactory tracts in the protocerebrum of wild-type Drosophila SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE olfactory circuit; olfaction; mushroom body; lateral horn; antennal lobe ID ANTENNAL LOBE; MUSHROOM BODY; PROJECTION NEURONS; APIS-MELLIFERA; MELANOGASTER; BRAIN; REPRESENTATION; ORGANIZATION; CONNECTIONS; PATHWAYS AB The antennal lobe (AL) is the primary olfactory center in insect brains. It receives sensory input from the olfactory sensory neurons (OSNs) and sends, through its projection neurons (PNs), reformatted output to secondary olfactory centers, including the mushroom body (MB) calyx and the lateral horn (LH) in the protocerebrum. By injecting dye into the AL of wild-type Drosophila, we identified previously unknown direct pathways between the AL and the ventrolateral, superior medial, and posterior lateral protocerebra. We found that most of these areas in the protocerebrum are connected with the AL through multiple tracts, suggesting that these areas are sites of convergence for olfactory information. Furthermore, areas such as the superior medial protocerebrum now appear to receive olfactory output both directly from the AL and indirectly from lobes of the MB and the LH, suggesting a degree of functional interaction among these areas. We also analyzed the length and number of fibers in each tract. We compare our results obtained from wild-type flies with recent results from transgenic strains and discuss how information about odorants is distributed to multiple protocerebral areas. J. Comp. Neurol. 520:41314140, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Dye, Louis; Stopfer, Mark] NICHHD, Microscopy & Imaging Core, Bethesda, MD 20892 USA. [Tanaka, Nobuaki K.] Japan Sci & Technol Agcy JST, Kawaguchi, Saitama 3320012, Japan. [Tanaka, Nobuaki K.; Ejima, Aki] Kyoto Univ, Career Path Promot Unit Young Life Scientists, Kyoto 6068501, Japan. [Suzuki, Emiko] Grad Univ Adv Studies, Natl Inst Genet, Struct Biol Ctr, Mishima, Shizuoka 4118540, Japan. [Suzuki, Emiko] Grad Univ Adv Studies, Dept Genet, Mishima, Shizuoka 4118540, Japan. RP Stopfer, M (reprint author), NICHHD, Microscopy & Imaging Core, 35 Lincoln Dr,Msc 3715, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov FU JSPS [22770068]; JST PREST Program; NIG Cooperative Research Program [2010-A83, 2011-A60]; National Institute of Child Health and Human Development FX Grant sponsor: JSPS; Grant number: 22770068; Grant sponsor: JST PREST Program (to N.K.T.); Grant sponsor: NIG Cooperative Research Program; Grant number: 2010-A83; Grant number: 2011-A60 (to N.K.T., E. S., A. E.); Grant sponsor: National Institute of Child Health and Human Development (to M.S.). NR 37 TC 7 Z9 7 U1 0 U2 13 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD DEC 15 PY 2012 VL 520 IS 18 BP 4131 EP 4140 DI 10.1002/cne.23149 PG 10 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 023YF UT WOS:000310073200003 PM 22592823 ER PT J AU Fera, A Dosemeci, A Sousa, AA Yang, C Leapman, RD Reese, TS AF Fera, Andrea Dosemeci, Ayse Sousa, Alioscka A. Yang, Charlotte Leapman, Richard D. Reese, Thomas S. TI Direct visualization of CaMKII at postsynaptic densities by electron microscopy tomography SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE postsynaptic densities; CaMKII; tomography; negative staining; electron microscopy ID PROTEIN-KINASE-II; DENDRITIC SPINES; ORGANIZATION; TRANSLOCATION; SYNAPSES; CORE; NEURONS; REGIONS; PSD-95; BRAIN AB Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a major component of postsynaptic densities (PSDs) involved in synaptic regulation. It has been previously shown that upon activity CaMKII from the spine reversibly aggregates at the cytoplasmic surfaces of PSDs, where it encounters various targets for phosphorylation. Targets for CaMKII are also present within the PSD, but there has been no reliable method to pinpoint whether, or where, CaMKII is located inside the PSD. Here we show that CaMKII can be mapped molecule-by-molecule within isolated PSDs using negative stain electron microscopy tomography. CaMKII molecules found in the core of the PSD may represent a pool distinct from the CaMKII residing at the cytoplasmic surface. J. Comp. Neurol. 520:42184225, 2012. (c) 2012 Wiley Periodicals, Inc. C1 [Fera, Andrea; Dosemeci, Ayse; Yang, Charlotte; Reese, Thomas S.] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Sousa, Alioscka A.; Leapman, Richard D.] Natl Inst Biomed Imaging & Bioengn, Lab Cellular Imaging & Macromol Biophys, NIH, Bethesda, MD 20892 USA. RP Fera, A (reprint author), NINDS, Neurobiol Lab, NIH, Bldg 49,Rm 3A60, Bethesda, MD 20892 USA. EM feraandr@ninds.nih.gov FU Intramural Research Programs of National Institute of Neurological Disorders and Stroke (NINDS); National Institute of Bio-medical Imaging and Bio-Engineering (NIBIB), National Institutes of Health (NIH) FX Grant sponsor: Intramural Research Programs of National Institute of Neurological Disorders and Stroke (NINDS) and National Institute of Bio-medical Imaging and Bio-Engineering (NIBIB), National Institutes of Health (NIH). NR 36 TC 4 Z9 4 U1 2 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD DEC 15 PY 2012 VL 520 IS 18 BP 4218 EP 4225 DI 10.1002/cne.23151 PG 8 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 023YF UT WOS:000310073200009 PM 22627922 ER PT J AU De Flora, S Balansky, R D'Agostini, F Cartiglia, C Longobardi, M Steele, VE Izzotti, A AF De Flora, Silvio Balansky, Roumen D'Agostini, Francesco Cartiglia, Cristina Longobardi, Mariagrazia Steele, Vernon E. Izzotti, Alberto TI Smoke-induced microRNA and related proteome alterations. Modulation by chemopreventive agents SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cigarette smoke; microRNAs; proteome; chemopreventive agents ID ENVIRONMENTAL CIGARETTE-SMOKE; N-ACETYLCYSTEINE; LUNG-CANCER; PHENETHYL ISOTHIOCYANATE; NEONATAL MICE; RESPIRATORY-TRACT; GENE-EXPRESSION; END-POINTS; MOUSE LUNG; RATS AB Dysregulation of microRNAs (miRNAs) has important consequences on gene and protein expression since a single miRNA targets a number of genes simultaneously. This article provides a review of published data and ongoing studies regarding the effects of cigarette smoke (CS), either mainstream (MCS) or environmental (ECS), on the expression of miRNAs and related proteins. The results generated in mice, rats, and humans provided evidence that exposure to CS results in an intense dysregulation of miRNA expression in the respiratory tract, which is mainly oriented in the sense of downregulation. In parallel, there was an upregulation of proteins targeted by the downregulated miRNAs. These trends reflect an attempt to defend the respiratory tract by means of antioxidant mechanisms, detoxification of carcinogens, DNA repair, anti-inflammatory pathways, apoptosis, etc. However, a long-lasting exposure to CS causes irreversible miRNA alterations that activate carcinogenic mechanisms, such as modulation of oncogenes and oncosuppressor genes, cell proliferation, recruitment of undifferentiated stem cells, inflammation, inhibition of intercellular communications, angiogenesis, invasion, and metastasis. The miRNA alterations induced by CS in the lung of mice and rats are similar to those observed in the human respiratory tract. Since a number of miRNAs that are modulated by CS and/or chemopreventive agents are subjected to single nucleotide polymorphisms in humans, they can be evaluated according to toxicogenomic/pharmacogenomics approaches. A variety of cancer chemopreventive agents tested in our laboratory modulated both baseline and CS-related miRNA and proteome alterations, thus contributing to evaluate both safety and efficacy of dietary and pharmacological agents. C1 [De Flora, Silvio; Balansky, Roumen; D'Agostini, Francesco; Cartiglia, Cristina; Longobardi, Mariagrazia; Izzotti, Alberto] Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. [Balansky, Roumen] Natl Oncol Ctr, BU-1157 Sofia, Bulgaria. [Steele, Vernon E.] NCI, Rockville, MD USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM sdf@unige.it OI izzotti, alberto/0000-0002-8588-0347 FU U.S. National Cancer Institute (NCI) [N01-CN53301]; Associazione Italiana per la Ricerca sul Cancro (AIRC) [8909] FX Grant sponsor: U.S. National Cancer Institute (NCI); Grant number: N01-CN53301; Grant sponsor: Associazione Italiana per la Ricerca sul Cancro (AIRC); Grant number: 8909 NR 55 TC 27 Z9 27 U1 3 U2 11 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 DEC 15 PY 2012 VL 131 IS 12 BP 2763 EP 2773 DI 10.1002/ijc.27814 PG 11 WC Oncology SC Oncology GA 029GH UT WOS:000310482300005 PM 22945459 ER PT J AU Hosui, A Klover, P Tatsumi, T Uemura, A Nagano, H Doki, Y Mori, M Hiramatsu, N Kanto, T Hennighausen, L Hayashi, N Takehara, T AF Hosui, Atsushi Klover, Peter Tatsumi, Tomohide Uemura, Akio Nagano, Hiroaki Doki, Yuichiro Mori, Masaki Hiramatsu, Naoki Kanto, Tatsuya Hennighausen, Lothar Hayashi, Norio Takehara, Tetsuo TI Suppression of signal transducers and activators of transcription 1 in hepatocellular carcinoma is associated with tumor progression SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE STAT1; VEGF; HCC; HIF-1; IFN alpha ID ENDOTHELIAL GROWTH-FACTOR; INTERFERON-ALPHA; GENE-EXPRESSION; HEPATITIS-C; LIVER; PATHWAY; CANCER; INVASION; CELLS; STAT3 AB Signal transducers and activators of transcription (STAT) 1 plays a pivotal role in cell-cycle and cell-fate determination, and vascular endothelial growth factor (VEGF) also contributes tumor growth. Recently, interferon (IFN) alpha has been reported to be effective for prevention of hepatocellular carcinomas (HCCs) recurrence, but the detailed mechanisms remain elusive. In vitro, cobalt chloridetreated VEGF induction and hypoxia responsive element (HRE) promoter activity were inhibited by IFNs and this abrogation was cancelled by introduction of small interfering RNA for STAT1. Immunoprecipitation/chromatin immunoprecipitation analyses showed STAT1 bound to hypoxia-inducible factor (HIF)-1 alpha and dissociated HIF-complex from HRE promoter lesion. In a xenograft model using Balb/c nude mice, tumor growth was suppressed by IFN alpha through inhibition of VEGF expression and it was oppositely enhanced when STAT1-deleted cells were injected. This augmentation was due to upregulation of VEGF and hyaluronan synthase 2. In human samples, 29 HCCs were resected, divided into two groups based on STAT1 activation in tumor and the clinical features were investigated. Patients with suppressed STAT1 activity had a shorter recurrence-free survival. Histological and reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed portal vein microinvasion and increased VEGF levels in tumors from suppressed STAT1 group. These human samples also showed a reverse correlation between VEGF and STAT1-regulated genes expression. These results in vitro and in vivo suggested that IFN alpha are potential candidates for prevention of vessel invasion acting through inhibition of VEGF expression and need to be properly used when STAT1 expression is suppressed. C1 [Hosui, Atsushi; Tatsumi, Tomohide; Uemura, Akio; Hiramatsu, Naoki; Kanto, Tatsuya; Takehara, Tetsuo] Osaka Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, Suita, Osaka 5650871, Japan. [Klover, Peter; Hennighausen, Lothar] NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Nagano, Hiroaki; Doki, Yuichiro; Mori, Masaki] Osaka Univ, Grad Sch Med, Dept Surg, Suita, Osaka 5650871, Japan. [Hayashi, Norio] Kansai Rosai Hosp, Amagasaki, Hyogo, Japan. RP Takehara, T (reprint author), Osaka Univ, Grad Sch Med, Dept Gastroenterol & Hepatol, 2-2 Yamadaoka, Suita, Osaka 5650871, Japan. EM takehara@gh.med.osaka-u.ac.jp FU Ministry of Education, Culture, Sports, Science, and Technology, Japan FX Grant sponsor: Ministry of Education, Culture, Sports, Science, and Technology, Japan NR 22 TC 0 Z9 0 U1 0 U2 5 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 DEC 15 PY 2012 VL 131 IS 12 BP 2774 EP 2784 DI 10.1002/ijc.27580 PG 11 WC Oncology SC Oncology GA 029GH UT WOS:000310482300006 PM 22488367 ER PT J AU Gage, JC Ajenifuja, KO Wentzensen, N Adepiti, AC Stoler, M Eder, PS Bell, L Shrestha, N Eklund, C Reilly, M Hutchinson, M Wacholder, S Castle, PE Burk, RD Schiffman, M AF Gage, Julia C. Ajenifuja, Kayode O. Wentzensen, Nicolas Adepiti, Akinfolarin C. Stoler, Mark Eder, Paul S. Bell, Laura Shrestha, Niwashin Eklund, Claire Reilly, Mary Hutchinson, Martha Wacholder, Sholom Castle, Philip E. Burk, Robert D. Schiffman, Mark TI Effectiveness of a simple rapid human papillomavirus DNA test in rural Nigeria SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE screening; cervical cancer prevention; HPV DNA testing; test accuracy ID INVASIVE CERVICAL-CANCER; INTERNATIONAL INCIDENCE RATES; INTRAEPITHELIAL NEOPLASIA; TRIAL AB Success of the new human papillomavirus (HPV) DNA test for low-resource settings (careHPV (TM) test; QIAGEN Gaithersburg Inc., Gaithersburg, MD) requires good test performance when operated by personnel with limited laboratory experience. We evaluated the transferability, reliability, and accuracy of the careHPV test nested within a cervical screening project in a large Nigerian village. CareHPV testing was performed on screen-positive (n = 345) and screen-negative (n = 42) women attending colposcopy (68.3% of referred). Biopsies of abnormal-appearing areas were processed and read in the U.S. CareHPV specimens taken immediately before colposcopy were processed up to four times (in the field) by two secondary school graduates without laboratory experience, trained for this study. Specifically, QIAGEN Gaithersburg trained a laboratory-inexperienced U.S. researcher, who trained the first local technician who, in turn, trained the second. Residual specimens were sent to the U.S. for MY09/MY11 PCR testing for 13 carcinogenic genotypes (HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68) plus HPV66 (included in careHPV). Intrarater agreement was 98.8% (? = 0.97) and 98.9% (kappa = 0.97) for Technicians 1 and 2, respectively, while inter-rater agreement was 96.3% (kappa = 0.90). Agreement with MY09/MY11 PCR (virologic reference standard) was 89.3% (kappa = 0.73) with 74.2% sensitivity and 95.7% specificity. The careHPV test detected 12 (80%) of 15 histologically confirmed cervical intraepithelial neoplasia Grade 2 (CIN2) or worse lesions, with an estimated 83.0% specificity to detect -/- B6 mice, Michael Reth for providing Mb1-cre mice, Trairak Pisitkun for providing the technical support for isolation of single cell suspensions from kidneys, and Lily Koo and Steven M. Becker for help with fluorescence microscopy. We are most thankful to Rachel Caspi and Silvia Bolland for critical reading of the manuscript and suggestions and James E. Balow for discussion. We greatly appreciate the constructive inputs provided by members of the Siebenlist laboratory and we are grateful to Anthony S. Fauci for continued support. This research was supported by the Intramural Research Programs of NIAID and NIDCR, NIH. NR 49 TC 60 Z9 64 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD DEC 14 PY 2012 VL 37 IS 6 BP 1104 EP 1115 DI 10.1016/j.immuni.2012.08.014 PG 12 WC Immunology SC Immunology GA 057PH UT WOS:000312575000017 PM 23123062 ER PT J AU Buehler, E Chen, YC Martin, S AF Buehler, Eugen Chen, Yu-Chi Martin, Scott TI C911: A Bench-Level Control for Sequence Specific siRNA Off-Target Effects SO PLOS ONE LA English DT Article ID RNAI SCREENS AB Small interfering RNAs (siRNAs) have become a ubiquitous experimental tool for down-regulating mRNAs. Unfortunately, off-target effects are a significant source of false positives in siRNA experiments and an effective control for them has not previously been identified. We introduce two methods of mismatched siRNA design for negative controls based on changing bases in the middle of the siRNA to their complement bases. To test these controls, a test set of 20 highly active siRNAs (10 true positives and 10 false positives) was identified from a genome-wide screen performed in a cell-line expressing a simple, constitutively expressed luciferase reporter. Three controls were then synthesized for each of these 20 siRNAs, the first two using the proposed mismatch design methods and the third being a simple random permutation of the sequence (scrambled siRNA). When tested in the original assay, the scrambled siRNAs showed significantly reduced activity in comparison to the original siRNAs, regardless of whether they had been identified as true or false positives, indicating that they have little utility as experimental controls. In contrast, one of the proposed mismatch design methods, dubbed C911 because bases 9 through 11 of the siRNA are replaced with their complement, was able to completely distinguish between the two groups. False positives due to off-target effects maintained most of their activity when the C911 mismatch control was tested, whereas true positives whose phenotype was due to on-target effects lost most or all of their activity when the C911 mismatch was tested. The ability of control siRNAs to distinguish between true and false positives, if widely adopted, could reduce erroneous results being reported in the literature and save research dollars spent on expensive follow-up experiments. C1 [Buehler, Eugen; Chen, Yu-Chi; Martin, Scott] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. RP Buehler, E (reprint author), NIH, Natl Ctr Adv Translat Sci, Bldg 10, Bethesda, MD 20892 USA. EM eugen.buehler@nih.gov OI Buehler, Eugen/0000-0001-7167-676X FU Intramural Research Program of the National Institutes of Health, National Center for Advancing Translational Sciences FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Center for Advancing Translational Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 14 TC 39 Z9 39 U1 0 U2 6 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 DEC 14 PY 2012 VL 7 IS 12 AR e51942 DI 10.1371/journal.pone.0051942 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 055AJ UT WOS:000312386800112 PM 23251657 ER PT J AU Ran, WQ Higgs, PG AF Ran, Wenqi Higgs, Paul G. TI Contributions of Speed and Accuracy to Translational Selection in Bacteria SO PLOS ONE LA English DT Article ID CODON USAGE BIAS; ESCHERICHIA-COLI; GENE-EXPRESSION; PROTEIN EXPRESSION; ADAPTATION INDEX; TRANSFER-RNAS; EVOLUTION; GENOME; GROWTH; YEAST AB Among bacteria, we have previously shown that species that are capable of rapid growth have stronger selection on codon usage than slow growing species, and possess higher numbers of rRNA and tRNA genes. This suggests that fast-growers are adapted for fast protein synthesis. There is also considerable evidence that codon usage is influenced by accuracy of translation, and some authors have argued that accuracy is more important than speed. Here we compare the strength of the two effects by studying the codon usages in high and low expression genes and on conserved and variable sites within high expression genes. We introduce a simple statistical method that can be used to assess the significance and the strength of the two types of bias in the same sets of sequences. We compare our statistical measure of codon bias to the common used codon adaptation index, and show that the new measure is preferable for three reasons for the purposes of this analysis. Across a large sample of bacterial genomes, both effects from speed and accuracy are clearly visible, although the speed effect appears to be much stronger than the accuracy effect and is found to be significant in a larger proportion of genomes. It is also difficult to explain the correlation of codon bias in the high expression genes with growth rates and numbers of copies of tRNA and rRNA genes on the basis of selection for accuracy. Hence we conclude that selection for translational speed is a dominant effect in driving codon usage bias in fast-growing bacteria, with selection for accuracy playing a small supplementary role. Citation: Ran W, Higgs PG (2012) Contributions of Speed and Accuracy to Translational Selection in Bacteria. PLoS ONE 7(12): e51652. doi:10.1371/journal.pone. 0051652 C1 [Ran, Wenqi; Higgs, Paul G.] McMaster Univ, Dept Phys & Astron, Hamilton, ON L8S 4M1, Canada. [Ran, Wenqi] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Ran, WQ (reprint author), McMaster Univ, Dept Phys & Astron, Hamilton, ON L8S 4M1, Canada. EM wenqi.ran@nih.gov; higgsp@mcmaster.ca FU Natural Sciences and Engineering Research Council of Canada; Intramural Program of National Library of Medicine, National Center for Biotechnology Information, National Institutes of Health FX This work was supported by the Natural Sciences and Engineering Research Council of Canada. Wenqi Ran is supported by The Intramural Program of National Library of Medicine, National Center for Biotechnology Information, 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 29 TC 15 Z9 15 U1 2 U2 19 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 DEC 14 PY 2012 VL 7 IS 12 AR e51652 DI 10.1371/journal.pone.0051652 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 055AJ UT WOS:000312386800060 PM 23272132 ER PT J AU Donaldson, MM Kao, SF Eslamizar, L Gee, C Koopman, G Lifton, M Schmitz, JE Sylwester, AW Wilson, A Hawkins, N Self, SG Roederer, M Foulds, KE AF Donaldson, Mitzi M. Kao, Shing-Fen Eslamizar, Leila Gee, Connie Koopman, Gerrit Lifton, Michelle Schmitz, Joern E. Sylwester, Andrew W. Wilson, Aaron Hawkins, Natalie Self, Steve G. Roederer, Mario Foulds, Kathryn E. TI Optimization and qualification of an 8-color intracellular cytokine staining assay for quantifying T cell responses in rhesus macaques for pre-clinical vaccine studies SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Flow cytometry; Immune assays; Phenotype; Memory; Antigen-specific ID MONKEYS; QUALITY AB Vaccination and SW challenge of macaque species is the best animal model for evaluating candidate HIV vaccines in pre-clinical studies. As such, robust assays optimized for use in nonhuman primates are necessary for reliable ex vivo measurement of immune responses and identification of potential immune correlates of protection. We optimized and qualified an 8-color intracellular cytokine staining assay for the measurement of IFN gamma, IL-2, and TNF from viable CD4 and CD8 T cells from cryopreserved rhesus macaque PBMC stimulated with peptides. After optimization, five laboratories tested assay performance using the same reagents and PBMC samples: similar results were obtained despite the use of flow cytometers with different configurations. The 8-color assay was then subjected to a pre-qualification study to quantify specificity and precision. These data were used to set positivity thresholds and to design the qualification protocol. Upon completion of the qualification study, the assay was shown to be highly reproducible with low inter-aliquot, inter-day, and inter-operator variability according to the qualification criteria with an overall variability of 20-40% for each outcome measurement. Thus, the 8-color ICS assay was formally qualified according to the ICH guidelines Q2 (R1) for specificity and precision indicating that it is considered a standardized/robust assay acceptable for use in pre-clinical trial immunogenicity testing. Published by Elsevier B.V. C1 [Donaldson, Mitzi M.; Kao, Shing-Fen; Roederer, Mario; Foulds, Kathryn E.] NIAID, Nonhuman Primate Immunogen Core, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Eslamizar, Leila; Gee, Connie; Lifton, Michelle; Schmitz, Joern E.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Sch Med, Boston, MA 02215 USA. [Koopman, Gerrit] Biomed Primate Res Ctr, Dept Virol, Rijswijk, Netherlands. [Sylwester, Andrew W.] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Beaverton, OR 97006 USA. [Wilson, Aaron] Int AIDS Vaccine Initiat, Design Lab, New York, NY 10038 USA. [Hawkins, Natalie; Self, Steve G.] Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98109 USA. RP Foulds, KE (reprint author), NIAID, Nonhuman Primate Immunogen Core, Vaccine Res Ctr, NIH, 40 Convent Dr,Room 5507, Bethesda, MD 20892 USA. EM fouldsk@mail.nih.gov FU NIAID, NIH; Bill & Melinda Gates Foundation [OPP1032325] FX We thank Drs. Joanne Yu and Pratip Chattopadhyay for custom antibody conjugation, and members of the ImmunoTechnology Section, Flow Cytometry Core, and Immunology Core at the Vaccine Research Center for advice and assistance. We thank Gail Levine and Anna Sambor of the Foundation for the NIH for management support and logistical support. This work was supported by the Intramural Research Program of the NIAID, NIH, and by the Collaboration for AIDS Vaccine Discovery (CAVD), grant #OPP1032325, from the Bill & Melinda Gates Foundation. NR 15 TC 13 Z9 14 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD DEC 14 PY 2012 VL 386 IS 1-2 BP 10 EP 21 DI 10.1016/j.jim.2012.08.011 PG 12 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 037UU UT WOS:000311132800002 PM 22955212 ER PT J AU Psaki, S Bhutta, ZA Ahmed, T Ahmed, S Bessong, P Islam, M John, S Kosek, M Lima, A Nesamvuni, C Shrestha, P Svensen, E McGrath, M Richard, S Seidman, J Caulfield, L Miller, M Checkley, W AF Psaki, Stephanie Bhutta, Zulfiqar A. Ahmed, Tahmeed Ahmed, Shamsir Bessong, Pascal Islam, Munirul John, Sushil Kosek, Margaret Lima, Aldo Nesamvuni, Cebisa Shrestha, Prakash Svensen, Erling McGrath, Monica Richard, Stephanie Seidman, Jessica Caulfield, Laura Miller, Mark Checkley, William CA MALED Network Investigators TI Household food access and child malnutrition: results from the eight-country MAL-ED study SO POPULATION HEALTH METRICS LA English DT Article ID BURKINA-FASO; INSECURITY; UNDERNUTRITION; HEALTH; CONSEQUENCES; EXPENDITURE; EXPERIENCE; COMMUNITY AB Background: Stunting results from decreased food intake, poor diet quality, and a high burden of early childhood infections, and contributes to significant morbidity and mortality worldwide. Although food insecurity is an important determinant of child nutrition, including stunting, development of universal measures has been challenging due to cumbersome nutritional questionnaires and concerns about lack of comparability across populations. We investigate the relationship between household food access, one component of food security, and indicators of nutritional status in early childhood across eight country sites. Methods: We administered a socioeconomic survey to 800 households in research sites in eight countries, including a recently validated nine-item food access insecurity questionnaire, and obtained anthropometric measurements from children aged 24 to 60 months. We used multivariable regression models to assess the relationship between household food access insecurity and anthropometry in children, and we assessed the invariance of that relationship across country sites. Results: Average age of study children was 41 months. Mean food access insecurity score (range: 0-27) was 5.8, and varied from 2.4 in Nepal to 8.3 in Pakistan. Across sites, the prevalence of stunting (42%) was much higher than the prevalence of wasting (6%). In pooled regression analyses, a 10-point increase in food access insecurity score was associated with a 0.20 SD decrease in height-for-age Z score (95% CI 0.05 to 0.34 SD; p = 0.008). A likelihood ratio test for heterogeneity revealed that this relationship was consistent across countries (p = 0.17). Conclusions: Our study provides evidence of the validity of using a simple household food access insecurity score to investigate the etiology of childhood growth faltering across diverse geographic settings. Such a measure could be used to direct interventions by identifying children at risk of illness and death related to malnutrition. C1 [Psaki, Stephanie; McGrath, Monica; Richard, Stephanie; Seidman, Jessica; Miller, Mark; Checkley, William] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Psaki, Stephanie; Kosek, Margaret; McGrath, Monica; Richard, Stephanie; Seidman, Jessica; Caulfield, Laura; Checkley, William] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Program Global Dis Epidemiol & Control, Baltimore, MD USA. [Psaki, Stephanie; Kosek, Margaret; McGrath, Monica; Richard, Stephanie; Seidman, Jessica; Caulfield, Laura; Checkley, William] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Div Human Nutr, Baltimore, MD USA. [Bhutta, Zulfiqar A.] Aga Khan Univ, Div Women & Child Hlth, Karachi, Pakistan. [Ahmed, Tahmeed; Ahmed, Shamsir; Islam, Munirul] Int Ctr Diarrhoeal Dis Res, Matlab, Bangladesh. [Bessong, Pascal; Nesamvuni, Cebisa] Univ Venda, Thohoyandou, South Africa. [John, Sushil] Christian Med Coll & Hosp, Vellore, Tamil Nadu, India. [Shrestha, Prakash] Inst Med, Kathmandu, Nepal. [Svensen, Erling] Univ Bergen, Bergen, Norway. [Lima, Aldo] Univ Fed Ceara, Fortaleza, Ceara, Brazil. [Checkley, William] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care, Baltimore, MD 21212 USA. RP Checkley, W (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM wcheckl1@jhmi.edu OI Bessong, Pascal/0000-0003-0561-272X NR 29 TC 20 Z9 20 U1 5 U2 34 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-7954 J9 POPUL HEALTH METR JI Popul. Health Metr. PD DEC 13 PY 2012 VL 10 AR 24 DI 10.1186/1478-7954-10-24 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 098SG UT WOS:000315568400001 PM 23237098 ER PT J AU Soleimanifard, S Abd-Elmoniem, KZ Sasano, T Agarwal, HK Abraham, MR Abraham, TP Prince, JL AF Soleimanifard, Sahar Abd-Elmoniem, Khaled Z. Sasano, Tetsuo Agarwal, Harsh K. Abraham, M. Roselle Abraham, Theodore P. Prince, Jerry L. TI Three-dimensional regional strain analysis in porcine myocardial infarction: a 3T magnetic resonance tagging study SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Article DE Magnetic resonance tagging; Harmonic phase analysis; Three-dimensional regional strain; Myocardial infarction; Diagnostic accuracy ID VENTRICULAR-TACHYCARDIA; STIMULATED ECHOES; WALL-MOTION; HEART WALL; MRI; CONTRAST; MODEL; DENSE; QUANTIFICATION; DYSSYNCHRONY AB Background: Previous studies of mechanical strain anomalies in myocardial infarction (MI) have been largely limited to analysis of one-dimensional (1D) and two-dimensional (2D) strain parameters. Advances in cardiovascular magnetic resonance (CMR) methods now permit a complete three-dimensional (3D) interrogation of myocardial regional strain. The aim of this study was to investigate the incremental value of CMR-based 3D strain and to test the hypothesis that 3D strain is superior to 1D or 2D strain analysis in the assessment of viability using a porcine model of infarction. Methods: Infarction was induced surgically in 20 farm pigs. Cine, late gadolinium enhancement, and CMR tagging images were acquired at 11 days before (baseline), and 11 days (early) and 1 month (late) after induction of infarct. Harmonic phase analysis was performed to measure circumferential, longitudinal, and radial strains in myocardial segments, which were defined based on the transmurality of delayed enhancement. Univariate, bivariate, and multivariate logistic regression models of strain parameters were created and analyzed to compare the overall diagnostic accuracy of 3D strain analysis with 1D and 2D analyses in identifying the infarct and its adjacent regions from healthy myocardium. Results: 3D strain differed significantly in infarct, adjacent, and remote segments (p < 0.05) at early and late post-MI. In univariate, bivariate, and multivariate analyses, circumferential, longitudinal, and radial strains were significant factors (p < 0.001) in differentiation of infarct and adjacent segments from baseline values. In identification of adjacent segments, receiver operating characteristic analysis using the 3D strain multivariate model demonstrated a significant improvement (p < 0.01) in overall diagnostic accuracy in comparison with 2D (circumferential and radial) and 1D (circumferential) models (3D: 96%, 2D: 81%, and 1D: 71%). A similar trend was observed in identification of infarct segments. Conclusions: Cumulative 3D strain information accurately identifies infarcts and their neighboring regions from healthy myocardium. The 3D interrogation of myocardial contractility provides incremental diagnostic accuracy in delineating the dysfunctional and nonviable myocardium in comparison with 1D or 2D quantification of strain. The infarct neighboring regions are the major beneficiaries of the 3D assessment of regional strain. C1 [Soleimanifard, Sahar; Prince, Jerry L.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [Abd-Elmoniem, Khaled Z.] NIDDK, NIH, Bethesda, MD USA. [Sasano, Tetsuo; Abraham, M. Roselle; Abraham, Theodore P.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Agarwal, Harsh K.] Philips Res North Amer, Briarcliff Manor, NY USA. [Prince, Jerry L.] Johns Hopkins Univ, Dept Radiol & Radiol Sci, Baltimore, MD 21218 USA. RP Prince, JL (reprint author), Johns Hopkins Univ, Dept Elect & Comp Engn, 3400 N Charles St,Clark Hall 201, Baltimore, MD 21218 USA. EM prince@jhu.edu RI Abd-Elmoniem, Khaled/B-9289-2008; Prince, Jerry/A-3281-2010 OI Abd-Elmoniem, Khaled/0000-0002-1001-1702; Prince, Jerry/0000-0002-6553-0876 FU NIH/NHLBI [R01HL47405] FX We thank Evert-Jan Vonken, MD, PhD, and Michael Schar, PhD for kindly providing the technical expertise with CMR acquisitions, and Amr Youssef, MD for help with animal studies. This work was supported in part by NIH/NHLBI research grant R01HL47405. NR 37 TC 8 Z9 8 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1097-6647 J9 J CARDIOVASC MAGN R JI J. Cardiov. Magn. Reson. PD DEC 13 PY 2012 VL 14 AR 85 DI 10.1186/1532-429X-14-85 PG 12 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 096AY UT WOS:000315377300002 PM 23237210 ER PT J AU Stewart, PE Carroll, JA Dorward, DW Stone, HH Sarkar, A Picardeau, M Rosa, PA AF Stewart, Philip E. Carroll, James A. Dorward, David W. Stone, Hunter H. Sarkar, Amit Picardeau, Mathieu Rosa, Patricia A. TI Characterization of the Bat proteins in the oxidative stress response of Leptospira biflexa SO BMC MICROBIOLOGY LA English DT Article ID INTERROGANS SEROVAR LAI; ESCHERICHIA-COLI; BORRELIA-BURGDORFERI; ANTIOXIDANT DEFENSE; POSITIVE CONTROL; OUTER-MEMBRANE; CATALASE; TEMPERATURE; GROWTH; HTPG AB Background: Leptospires lack many of the homologs for oxidative defense present in other bacteria, but do encode homologs of the Bacteriodes aerotolerance (Bat) proteins, which have been proposed to fulfill this function. Bat homologs have been identified in all families of the phylum Spirochaetes, yet a specific function for these proteins has not been experimentally demonstrated. Results: We investigated the contribution of the Bat proteins in the model organism Leptospira biflexa for their potential contributions to growth rate, morphology and protection against oxidative challenges. A genetically engineered mutant strain in which all bat ORFs were deleted did not exhibit altered growth rate or morphology, relative to the wild-type strain. Nor could we demonstrate a protective role for the Bat proteins in coping with various oxidative stresses. Further, pre-exposing L. biflexa to sublethal levels of reactive oxygen species did not appear to induce a general oxidative stress response, in contrast to what has been shown in other bacterial species. Differential proteomic analysis of the wild-type and mutant strains detected changes in the abundance of a single protein only - HtpG, which is encoded by the gene immediately downstream of the bat loci. Conclusion: The data presented here do not support a protective role for the Leptospira Bat proteins in directly coping with oxidative stress as previously proposed. L. biflexa is relatively sensitive to reactive oxygen species such as superoxide and H2O2, suggesting that this spirochete lacks a strong, protective defense against oxidative damage despite being a strict aerobe. C1 [Stewart, Philip E.; Stone, Hunter H.; Sarkar, Amit; Rosa, Patricia A.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Carroll, James A.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Dorward, David W.] NIAID, Res Technol Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Picardeau, Mathieu] Inst Pasteur, Unite Biol Spirochetes, F-75015 Paris, France. RP Stewart, PE (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM pestewart@niaid.nih.gov FU Intramural Research Program of the NIH, NIAID FX The authors gratefully acknowledge the generous gifts of strains and advice from David Haake and Marije Pinne. We also thank Joe Hinnebusch and Frank Gherardini for critical reading of the manuscript; Dan Sturdevant, Kevin Lawrence and Julie Boylan for technical advice and helpful discussions, Jeff Skinner at Bioinformatics and Computational Biosciences Branch for statistical analysis, and Scott Samuels' lab for technical advice on RNA isolation. This research was supported by the Intramural Research Program of the NIH, NIAID. NR 49 TC 6 Z9 6 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2180 J9 BMC MICROBIOL JI BMC Microbiol. PD DEC 13 PY 2012 VL 12 AR 290 DI 10.1186/1471-2180-12-290 PG 13 WC Microbiology SC Microbiology GA 079EK UT WOS:000314153000001 PM 23234440 ER PT J AU Birmann, BM Neuhouser, ML Rosner, B Albanes, D Buring, JE Giles, GG Lan, Q Lee, IM Purdue, MP Rothman, N Severi, G Yuan, JM Anderson, KC Pollak, M Rifai, N Hartge, P Landgren, O Lessin, L Virtamo, J Wallace, RB Manson, JE Colditz, GA AF Birmann, Brenda M. Neuhouser, Marian L. Rosner, Bernard Albanes, Demetrius Buring, Julie E. Giles, Graham G. Lan, Qing Lee, I-Min Purdue, Mark P. Rothman, Nathaniel Severi, Gianluca Yuan, Jian-Min Anderson, Kenneth C. Pollak, Michael Rifai, Nader Hartge, Patricia Landgren, Ola Lessin, Lawrence Virtamo, Jarmo Wallace, Robert B. Manson, Joann E. Colditz, Graham A. TI Prediagnosis biomarkers of insulin-like growth factor-1, insulin, and interleukin-6 dysregulation and multiple myeloma risk in the Multiple Myeloma Cohort Consortium SO BLOOD LA English DT Article ID UNDETERMINED SIGNIFICANCE MGUS; SINGAPORE CHINESE HEALTH; BODY-MASS INDEX; MONOCLONAL GAMMOPATHY; CANCER-RISK; WOMENS HEALTH; BREAST-CANCER; CELL-GROWTH; DISEASE; MEN AB Insulin-like growth factor-1 (IGF-1), insulin, and IL-6 are dysregulated in multiple myeloma pathogenesis and may also contribute to multiple myeloma etiology. To examine their etiologic role, we prospectively analyzed concentrations of serologic markers in 493 multiple myeloma cases and 978 controls from 8 cohorts in the Multiple Myeloma Cohort Consortium. We computed odds ratios (ORs) and 95% confidence intervals (CIs) for multiple myeloma per 1-SD increase in biomarker concentration using conditional logistic regression. We examined heterogeneity by time since blood collection (<= 3, 4- <= 6, and > 6 years) in stratified models. Fasting IGF binding protein-1 concentration was associated with multiple myeloma risk within 3 years (OR, 95% CI per 1-SD increase: 2.3, 1.4-3.8, P = .001) and soluble IL-6 receptor level was associated within 6 years after blood draw (OR (<= 3 years), 95% CI, 1.4, 1.1-1.9, P = .01; OR4- (<= 6 years), 95% CI, 1.4, 1.1-1.7, P = .002). No biomarker was associated with longer-term multiple myeloma risk (ie, > 6 years). Interactions with time were statistically significant (IGF binding protein-1, P-heterogeneity = .0016; sIL6R, P-heterogeneity = .016). The time-restricted associations probably reflect the bioactivity of tumor and microenvironment cells in transformation from monoclonal gammopathy of undetermined significance or smoldering multiple myeloma to clinically manifest multiple myeloma. (Blood. 2012; 120(25): 4929-4937) C1 [Birmann, Brenda M.; Rosner, Bernard] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA 02115 USA. [Birmann, Brenda M.; Rosner, Bernard; Buring, Julie E.; Lee, I-Min; Rifai, Nader; Manson, Joann E.] Harvard Univ, Sch Med, Boston, MA USA. [Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Neuhouser, Marian L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Neuhouser, Marian L.] Univ Washington, Grad Program Nutr Sci, Seattle, WA 98195 USA. [Albanes, Demetrius; Lan, Qing; Purdue, Mark P.; Rothman, Nathaniel; Hartge, Patricia; Landgren, Ola] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Buring, Julie E.; Lee, I-Min; Manson, Joann E.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Buring, Julie E.; Lee, I-Min; Manson, Joann E.; Colditz, Graham A.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Giles, Graham G.; Severi, Gianluca] Canc Council Victoria, Canc Epidemiol Ctr, Carlton, Australia. [Giles, Graham G.; Severi, Gianluca] Univ Melbourne, Sch Populat Hlth, Ctr Mol Environm Genet & Analyt Epidemiol, Parkville, Vic 3052, Australia. [Giles, Graham G.] Monash Univ, Dept Epidemiol & Prevent Med, Melbourne, Vic 3004, Australia. [Yuan, Jian-Min] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA. [Yuan, Jian-Min] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Yuan, Jian-Min] Univ Pittsburgh, Inst Canc, Div Canc Control & Populat Sci, Pittsburgh, PA USA. [Yuan, Jian-Min] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Anderson, Kenneth C.] Dana Farber Canc Inst, Dept Med Oncol, Jerome Lipper Multiple Myeloma Ctr, Boston, MA 02115 USA. [Pollak, Michael] McGill Univ, Jewish Gen Hosp, Lady Davis Res Inst, Dept Oncol, Montreal, PQ H3T 1E2, Canada. [Rifai, Nader] Childrens Hosp, Dept Lab Med, Boston, MA 02115 USA. [Landgren, Ola] NCI, Multiple Myeloma Sect, Metab Branch,Ctr Canc Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Lessin, Lawrence] Howard Univ, MedStar Res Inst, Washington, DC 20059 USA. [Lessin, Lawrence] Washington Hosp Ctr, Washington Canc Inst, Dept Med Oncol & Hematol, Washington, DC 20010 USA. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Wallace, Robert B.] Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. [Colditz, Graham A.] Washington Univ, Sch Med, Dept Surg, St Louis, MO 63110 USA. [Colditz, Graham A.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. [Colditz, Graham A.] Barnes Jewish Hosp, St Louis, MO 63110 USA. RP Birmann, BM (reprint author), Brigham & Womens Hosp, Channing Div Network Med, Dept Med, 181 Longwood Ave, Boston, MA 02115 USA. EM brenda.birmann@channing.harvard.edu RI Albanes, Demetrius/B-9749-2015; Purdue, Mark/C-9228-2016; Colditz, Graham/A-3963-2009; OI Purdue, Mark/0000-0003-1177-3108; Colditz, Graham/0000-0002-7307-0291; Giles, Graham/0000-0003-4946-9099 FU National Institutes of Health [R01 CA127435, K07 CA115687, P01 CA87969, R01 CA49449, P01 CA055075, P50 CA100707, CA047988, HL043851, HL080467, R01CA080205, R01CA144034]; National Cancer Institute Division of Cancer Epidemiology and Genetics; National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221] FX This work was supported by the National Institutes of Health (R01 CA127435, K07 CA115687, B.M.B.; P01 CA87969, R01 CA49449, P01 CA055075, P50 CA100707, CA047988, HL043851, HL080467, R01CA080205, and R01CA144034) and the National Cancer Institute Division of Cancer Epidemiology and Genetics (intramural funds). The WHI program is supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services (contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221). NR 50 TC 17 Z9 17 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 13 PY 2012 VL 120 IS 25 BP 4929 EP 4937 DI 10.1182/blood-2012-03-417253 PG 9 WC Hematology SC Hematology GA 065BR UT WOS:000313122800009 PM 23074271 ER PT J AU Unnisa, Z Clark, JP Roychoudhury, J Thomas, E Tessarollo, L Copeland, NG Jenkins, NA Grimes, HL Kumar, AR AF Unnisa, Zeenath Clark, Jason P. Roychoudhury, Jayeeta Thomas, Elizabeth Tessarollo, Lino Copeland, Neal G. Jenkins, Nancy A. Grimes, H. Leighton Kumar, Ashish R. TI Meis1 preserves hematopoietic stem cells in mice by limiting oxidative stress SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; DEFINITIVE HEMATOPOIESIS; IN-VIVO; HYPOXIA; EXPRESSION; GENES; QUIESCENCE; HIF-1-ALPHA; HOMEOSTASIS; MUTATIONS AB The transcription factor Meis1 is expressed preferentially in hematopoietic stem cells (HSCs) and overexpressed in certain leukemias. However, the functions of Meis1 in hematopoiesis remain largely unknown. In the present study, we found that Meis1 is required for the maintenance of hematopoiesis under stress and over the long term, whereas steady-state hematopoiesis was sustained in the absence of Meis1 in inducible knock-out mice. BM cells of Meis1-deficient mice showed reduced colony formation and contained significantly fewer numbers of long-term HSCs, which exhibited loss of quiescence. Further, we found that Meis1 deletion led to the accumulation of reactive oxygen species in HSCs and decreased expression of genes implicated in hypoxia response. Finally, reactive oxygen species scavenging by N-acetyl cysteine or stabilization of hypoxia signaling by knockdown of the von-Hippel-Lindau (VHL) protein led to reversal of the effects of Meis1 deletion. The results of the present study demonstrate that Meis1 protects and preserves HSCs by restricting oxidative metabolism. (Blood. 2012; 120(25): 4973-4981) C1 [Unnisa, Zeenath; Clark, Jason P.; Roychoudhury, Jayeeta; Thomas, Elizabeth; Grimes, H. Leighton; Kumar, Ashish R.] Cincinnati Childrens Hosp Med Ctr, Canc & Blood Dis Inst, Cincinnati, OH 45236 USA. [Tessarollo, Lino] NCI, Ctr Canc Res, Frederick, MD 21701 USA. [Copeland, Neal G.; Jenkins, Nancy A.] Methodist Hosp, Res Inst, Houston, TX 77030 USA. RP Kumar, AR (reprint author), Cincinnati Childrens Hosp Med Ctr, Canc & Blood Dis Inst, 3333 Burnet Ave, Cincinnati, OH 45236 USA. EM ashish.kumar@cchmc.org OI Grimes, H. Leighton/0000-0001-8162-6758 FU National Institutes of Health [K08-CA122191]; Cincinnati Children's Hospital Medical Center; Cancer Free Kids FX This research was supported by grants from the National Institutes of Health (K08-CA122191), Cincinnati Children's Hospital Medical Center (trustee award), and Cancer Free Kids. The research flow cytometry core, comprehensive mouse and cancer core, and gene-expression microarray core facilities at Cincinnati Children's Hospital Medical Center provided valuable support. NR 35 TC 27 Z9 28 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 13 PY 2012 VL 120 IS 25 BP 4973 EP 4981 DI 10.1182/blood-2012-06-435800 PG 9 WC Hematology SC Hematology GA 065BR UT WOS:000313122800014 PM 23091297 ER PT J AU Daridon, C Loddenkemper, C Spieckermann, S Kuhl, AA Salama, A Burmester, GR Lipsky, PE Dorner, T AF Daridon, Capucine Loddenkemper, Christoph Spieckermann, Simone Kuehl, Anja A. Salama, Abdulgabar Burmester, Gerd R. Lipsky, Peter E. Doerner, Thomas TI Splenic proliferative lymphoid nodules distinct from germinal centers are sites of autoantigen stimulation in immune thrombocytopenia SO BLOOD LA English DT Article ID FOLLICULAR DENDRITIC CELLS; CLASS SWITCH RECOMBINATION; REGULATORY T-CELLS; B-CELLS; ANTIBODY-RESPONSES; PURPURA; SPLEEN; DYNAMICS; BCL6; DIFFERENTIATION AB To understand more specific abnormalities of humoral autoimmunity, we studied 31 spleens from immune thrombocytopenia (ITP) patients and 36 control spleens. Detailed analysis identified at least 2 different splenic structures accommodating proliferating B cells, classic germinal centers (GCs), and proliferative lymphoid nodules (PLNs). PLNs were characterized by proliferating Ki67(+) B cells close to follicular dendritic cells (FDCs) and lacked polarization into dark and light zones. As opposed to cells in GCs, proliferating B cells in PLN lacked expression of Bcl6. In both PLNs and GCs of ITP spleens, the density of T cells was significantly reduced. Both T follicular helper cells (T-FH) and regulatory T cells were reduced within PLNs of ITP spleens suggesting a defect of tolerance related to a loss of T-cell control. Within PLNs of ITP, but not controls, abundant platelet glycoprotein (GP) IIb/IIIa autoantigens was found in IgM containing immune complexes tightly bound to FDCs and closely approximated to proliferating B cells. GPIV was found less often, but not in the same PLNs as GPIIb/IIIa. Autoantigens were not found in the GCs of ITP or controls indicating that PLNs are the sites of autoantigen stimulation in ITP potentially related to a lack of control by T cells and/or the present autoantigen. (Blood. 2012; 120(25): 5021-5031) C1 [Daridon, Capucine; Burmester, Gerd R.; Doerner, Thomas] Charite, Dept Med Rheumatol & Clin Immunol CC12, D-13353 Berlin, Germany. [Daridon, Capucine; Burmester, Gerd R.; Doerner, Thomas] Charite, Deutsch Rheumaforsch Zentrum DRFZ, D-13353 Berlin, Germany. [Loddenkemper, Christoph; Spieckermann, Simone; Kuehl, Anja A.] Charite, Dept Gastroenterol Infectiol & Rheumatol CC13, D-13353 Berlin, Germany. [Kuehl, Anja A.] Res Ctr ImmunoSci RCIS, Berlin, Germany. [Salama, Abdulgabar] Charite, Inst Transfus Med CC14, D-13353 Berlin, Germany. [Lipsky, Peter E.] NIH, Natl Inst Arthrit & Musculoskeletal & Skin Dis, Bethesda, MD 20892 USA. RP Dorner, T (reprint author), Charite, Deutsch Rheumaforsch Zentrum DRFZ, D-13353 Berlin, Germany. EM thomas.doerner@charite.de FU Deutsche Forschungsgemeinschaft (DFG) [SFB650/TP16]; DFG [Do491/7-2] FX This work was supported by the Deutsche Forschungsgemeinschaft (DFG) through grants SFB650/TP16 (T.D., A.S., G.R.B.) and DFG project Do491/7-2 (T.D.). NR 44 TC 20 Z9 20 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 13 PY 2012 VL 120 IS 25 BP 5021 EP 5031 DI 10.1182/blood-2012-04-424648 PG 11 WC Hematology SC Hematology GA 065BR UT WOS:000313122800019 PM 22955923 ER PT J AU Celli, J AF Celli, Jean TI LRSAM1, an E3 Ubiquitin Ligase with a Sense for Bacteria SO CELL HOST & MICROBE LA English DT Editorial Material ID AUTOPHAGY; SALMONELLA; IMMUNITY; PROTEINS; ADAPTER; NDP52 AB Antimicrobial autophagy is a host cellular process that captures and delivers intracellular parasites to lysosomes following their targeting as cargo via ubiquitination. Huett et al. (2012) show that the LRR- and RING-domain-containing E3 ubiquitin ligase LRSAM1 recognizes various bacteria and generates a ubiquitin signal that initiates the autophagic cascade. C1 NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Celli, J (reprint author), NIAID, Intracellular Parasites Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM jcelli@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000954-03] NR 10 TC 3 Z9 3 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD DEC 13 PY 2012 VL 12 IS 6 BP 735 EP 736 DI 10.1016/j.chom.2012.11.007 PG 2 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 069AF UT WOS:000313406600003 PM 23245317 ER PT J AU Bart, BA Goldsmith, SR Lee, KL Givertz, MM O'Connor, CM Bull, DA Redfield, MM Deswal, A Rouleau, JL LeWinter, MM Ofili, EO Stevenson, LW Semigran, MJ Felker, GM Chen, HH Hernandez, AF Anstrom, KJ McNulty, SE Velazquez, EJ Ibarra, JC Mascette, AM Braunwald, E AF Bart, Bradley A. Goldsmith, Steven R. Lee, Kerry L. Givertz, Michael M. O'Connor, Christopher M. Bull, David A. Redfield, Margaret M. Deswal, Anita Rouleau, Jean L. LeWinter, Martin M. Ofili, Elizabeth O. Stevenson, Lynne W. Semigran, Marc J. Felker, G. Michael Chen, Horng H. Hernandez, Adrian F. Anstrom, Kevin J. McNulty, Steven E. Velazquez, Eric J. Ibarra, Jenny C. Mascette, Alice M. Braunwald, Eugene CA Heart Failure Clinical Res Network TI Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID WORSENING RENAL-FUNCTION; HOSPITALIZED-PATIENTS; DIURETICS; CONGESTION; OVERLOAD AB BACKGROUND Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function. METHODS We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days. RESULTS Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P = 0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04 +/- 0.53 mg per deciliter (-3.5 +/- 46.9 mu mol per liter) in the pharmacologictherapy group, as compared with +0.23 +/- 0.70 mg per deciliter (20.3 +/- 61.9 mu mol per liter) in the ultrafiltration group (P = 0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5 +/- 5.1 kg [12.1 +/- 11.3 lb] and 5.7 +/- 3.9 kg [12.6 +/- 8.5 lb], respectively; P = 0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P = 0.03). CONCLUSIONS In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491.) C1 [Bart, Bradley A.; Goldsmith, Steven R.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Redfield, Margaret M.; Chen, Horng H.] Mayo Clin, Rochester, MN USA. [Lee, Kerry L.; Hernandez, Adrian F.; Anstrom, Kevin J.; McNulty, Steven E.; Velazquez, Eric J.; Ibarra, Jenny C.] Duke Clin Res Inst, Durham, NC USA. [O'Connor, Christopher M.; Felker, G. Michael] Duke Univ, Med Ctr, Durham, NC USA. [O'Connor, Christopher M.; Felker, G. Michael] Duke Univ, Med Ctr, Duke Heart Ctr, Durham, NC 27710 USA. [Givertz, Michael M.; Stevenson, Lynne W.; Braunwald, Eugene] Brigham & Womens Hosp, Boston, MA 02115 USA. [Semigran, Marc J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bull, David A.] Univ Utah, Salt Lake City, UT USA. [Deswal, Anita] Michael E DeBakey VA Med Ctr, Houston, TX USA. [Deswal, Anita] Baylor Coll Med, Houston, TX 77030 USA. [Rouleau, Jean L.] Univ Montreal, Montreal, PQ, Canada. [Rouleau, Jean L.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [LeWinter, Martin M.] Univ Vermont, Burlington, VT 05405 USA. [Ofili, Elizabeth O.] Morehouse Sch Med, Atlanta, GA 30310 USA. [Mascette, Alice M.] NHLBI, Bethesda, MD 20892 USA. RP Bart, BA (reprint author), O5 HCMC,701 Pk Ave S, Minneapolis, MN 55410 USA. EM bartx006@umn.edu RI Hernandez, Adrian F./A-7818-2016 OI Hernandez, Adrian F./0000-0003-3387-9616 FU National Heart, Lung, and Blood Institute [U10HL084904, U10HL084861, U10HL084875, U10HL084877, U10HL084889, U10HL084890, U10HL084891, U10HL084899, U10HL084907, U10HL084931] FX Supported by grants from the National Heart, Lung, and Blood Institute (U10HL084904 [for the data coordinating center], U10HL084861, U10HL084875, U10HL084877, U10HL084889, U10HL084890, U10HL084891, U10HL084899, U10HL084907, and U10HL084931 [for the clinical centers]). NR 24 TC 233 Z9 256 U1 3 U2 24 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 DEC 13 PY 2012 VL 367 IS 24 BP 2296 EP 2304 DI 10.1056/NEJMoa1210357 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 052HF UT WOS:000312187700003 PM 23131078 ER PT J AU Bernstein, HD AF Bernstein, Harris D. TI CELL BIOLOGY All clear for ribosome landing SO NATURE LA English DT Editorial Material ID SIGNAL-RECOGNITION PARTICLE; CRYSTAL-STRUCTURE; SRP RNA; RECEPTOR; COMPLEX C1 NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Bernstein, HD (reprint author), NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. EM harris_bernstein@nih.gov NR 10 TC 0 Z9 0 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 13 PY 2012 VL 492 IS 7428 BP 189 EP 191 PG 3 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 053GM UT WOS:000312259300024 PM 23235870 ER PT J AU Narayan, N Lee, IH Borenstein, R Sun, JH Wong, R Tong, G Fergusson, MM Liu, J Rovira, II Cheng, HL Wang, GH Gucek, M Lombard, D Alt, FW Sack, MN Murphy, E Cao, L Finkel, T AF Narayan, Nisha Lee, In Hye Borenstein, Ronen Sun, Junhui Wong, Renee Tong, Guang Fergusson, Maria M. Liu, Jie Rovira, Ilsa I. Cheng, Hwei-Ling Wang, Guanghui Gucek, Marjan Lombard, David Alt, Fredrick W. Sack, Michael N. Murphy, Elizabeth Cao, Liu Finkel, Toren TI The NAD-dependent deacetylase SIRT2 is required for programmed necrosis (Retracted article. See vol. 506, pg. 516, 2014) SO NATURE LA English DT Article; Retracted Publication ID INDUCED CELL-DEATH; RIP1; APOPTOSIS; AUTOPHAGY; PHOSPHORYLATION; IDENTIFICATION; NECROPTOSIS; ACTIVATION; MECHANISMS; REGULATOR AB Although initially viewed as unregulated, increasing evidence suggests that cellular necrosis often proceeds through a specific molecular program. In particular, death ligands such as tumour necrosis factor (TNF)-alpha activate necrosis by stimulating the formation of a complex containing receptor-interacting protein 1 (RIP1) and receptor-interacting protein 3 (RIP3). Relatively little is known regarding how this complex formation is regulated. Here, we show that the NAD-dependent deacetylase SIRT2 binds constitutively to RIP3 and that deletion or knockdown of SIRT2 prevents formation of the RIP1-RIP3 complex in mice. Furthermore, genetic or pharmacological inhibition of SIRT2 blocks cellular necrosis induced by TNF-alpha. We further demonstrate that RIP1 is a critical target of SIRT2-dependent deacetylation. Using gain- and loss-of-function mutants, we demonstrate that acetylation of RIP1 lysine 530 modulates RIP1-RIP3 complex formation and TNF-alpha-stimulated necrosis. In the setting of ischaemia-reperfusion injury, RIP1 is deacetylated in a SIRT2-dependent fashion. Furthermore, the hearts of Sirt2(-/-) mice, or wild-type mice treated with a specific pharmacological inhibitor of SIRT2, show marked protection from ischaemic injury. Taken together, these results implicate SIRT2 as an important regulator of programmed necrosis and indicate that inhibitors of this deacetylase may constitute a novel approach to protect against necrotic injuries, including ischaemic stroke and myocardial infarction. C1 [Narayan, Nisha; Lee, In Hye; Borenstein, Ronen; Fergusson, Maria M.; Liu, Jie; Rovira, Ilsa I.; Sack, Michael N.; Finkel, Toren] NHLBI, Ctr Mol Med, NIH, Bethesda, MD 20892 USA. [Sun, Junhui; Wong, Renee; Tong, Guang; Murphy, Elizabeth] NHLBI, Syst Biol Ctr, NIH, Bethesda, MD 20892 USA. [Tong, Guang] Fourth Mil Med Univ, Xijing Hosp, Dept Cardiovasc Surg, Xian 710032, Peoples R China. [Cheng, Hwei-Ling; Alt, Fredrick W.] Childrens Hosp, Howard Hughes Med Inst, Program Cellular & Mol Med, Boston, MA 02115 USA. [Cheng, Hwei-Ling; Alt, Fredrick W.] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. [Cheng, Hwei-Ling; Alt, Fredrick W.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Wang, Guanghui; Gucek, Marjan] NHLBI, Prote Core, NIH, Bethesda, MD 20892 USA. [Lombard, David] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. [Lombard, David] Univ Michigan, Inst Gerontol, Ann Arbor, MI 48109 USA. [Cao, Liu] China Med Univ, Key Lab Med Cell Biol, Shenyang 110001, Peoples R China. RP Finkel, T (reprint author), NHLBI, Ctr Mol Med, NIH, Bldg 10, Bethesda, MD 20892 USA. EM finkelt@nih.gov FU NIH FX We are grateful to M. Lenardo for providing the RIP1-deficient Jurkat cell line, X. Wang for the Flag-tagged RIP3 plasmid and Y. Zhao for helpful discussions. This work was supported by NIH Intramural funds. F.W.A. is an Investigator of the Howard Hughes Medical Institute. NR 32 TC 81 Z9 85 U1 3 U2 86 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD DEC 13 PY 2012 VL 492 IS 7428 BP 199 EP + DI 10.1038/nature11700 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 053GM UT WOS:000312259300031 PM 23201684 ER PT J AU Besnard, J Ruda, GF Setola, V Abecassis, K Rodriguiz, RM Huang, XP Norval, S Sassano, MF Shin, AI Webster, LA Simeons, FRC Stojanovski, L Prat, A Seidah, NG Constam, DB Bickerton, GR Read, KD Wetsel, WC Gilbert, IH Roth, BL Hopkins, AL AF Besnard, Jeremy Ruda, Gian Filippo Setola, Vincent Abecassis, Keren Rodriguiz, Ramona M. Huang, Xi-Ping Norval, Suzanne Sassano, Maria F. Shin, Antony I. Webster, Lauren A. Simeons, Frederick R. C. Stojanovski, Laste Prat, Annik Seidah, Nabil G. Constam, Daniel B. Bickerton, G. Richard Read, Kevin D. Wetsel, William C. Gilbert, Ian H. Roth, Bryan L. Hopkins, Andrew L. TI Automated design of ligands to polypharmacological profiles SO NATURE LA English DT Article ID DE-NOVO DESIGN; DRUG-DISCOVERY; MEDIAN MOLECULES; ADME PROPERTIES; IN-SILICO; OPTIMIZATION; INHIBITORS; IDENTIFICATION; SCHIZOPHRENIA; FINGERPRINTS AB The clinical efficacy and safety of a drug is determined by its activity profile across many proteins in the proteome. However, designing drugs with a specific multi-target profile is both complex and difficult. Therefore methods to design drugs rationally a priori against profiles of several proteins would have immense value in drug discovery. Here we describe a new approach for the automated design of ligands against profiles of multiple drug targets. The method is demonstrated by the evolution of an approved acetylcholinesterase inhibitor drug into brain-penetrable ligands with either specific polypharmacology or exquisite selectivity profiles for G-protein-coupled receptors. Overall, 800 ligand-target predictions of prospectively designed ligands were tested experimentally, of which 75% were confirmed to be correct. We also demonstrate target engagement in vivo. The approach can be a useful source of drug leads when multi-target profiles are required to achieve either selectivity over other drug targets or a desired polypharmacology. C1 [Besnard, Jeremy; Ruda, Gian Filippo; Abecassis, Keren; Norval, Suzanne; Webster, Lauren A.; Simeons, Frederick R. C.; Stojanovski, Laste; Bickerton, G. Richard; Read, Kevin D.; Gilbert, Ian H.; Hopkins, Andrew L.] Univ Dundee, Coll Life Sci, Div Biol Chem & Drug Discovery, Dundee DD1 5EH, Scotland. [Setola, Vincent; Huang, Xi-Ping; Roth, Bryan L.] Univ N Carolina Chapel Hill, Sch Med, Dept Pharmacol, NIMH Psychoact Drug Screening Program, Chapel Hill, NC 27759 USA. [Rodriguiz, Ramona M.; Shin, Antony I.; Wetsel, William C.] Duke Univ, Sch Med, Mouse Behav & Neuroendocrine Anal Core Facil, Durham, NC 27710 USA. [Sassano, Maria F.; Roth, Bryan L.] Univ N Carolina Chapel Hill, Sch Med, Div Chem Biol & Med Chem, Chapel Hill, NC 27759 USA. [Prat, Annik; Seidah, Nabil G.] Univ Montreal, Clin Res Inst Montreal IRCM, Lab Biochem Neuroendocrinol, Montreal, PQ H2W 1R7, Canada. [Constam, Daniel B.] Ecole Polytech Fed Lausanne EPFL SV ISREC, CH-1015 Lausanne, Switzerland. [Wetsel, William C.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. [Wetsel, William C.] Duke Univ, Sch Med, Dept Cell Biol, Durham, NC 27710 USA. [Wetsel, William C.] Duke Univ, Sch Med, Dept Neurobiol, Durham, NC 27710 USA. RP Hopkins, AL (reprint author), Univ Dundee, Coll Life Sci, Div Biol Chem & Drug Discovery, Dundee DD1 5EH, Scotland. EM bryan_roth@med.unc.edu; a.hopkins@dundee.ac.uk RI sassano, maria/G-4941-2013; Seidah, Nabil/I-3596-2013; Roth, Bryan/F-3928-2010; Hopkins, Andrew/H-5138-2011; OI Seidah, Nabil/0000-0001-6503-9342; Hopkins, Andrew/0000-0003-1977-018X; Ruda, Gian Filippo/0000-0001-6150-2715; Besnard, Jeremy/0000-0001-5452-8183; Constam, Daniel B./0000-0002-6256-3891; Gilbert, Ian/0000-0002-5238-1314; /0000-0001-6426-0598 FU SULSA [HR07019]; BBSRC Doctoral Training Programme; BBSRC Pathfinder [BB/FOF/PF/15/09]; BBSRC [BB/J010510/1]; University of Dundee's Pump Priming Fund for Translational Medical Research; National Institutes of Health (NIH) [MH082441]; Wellcome Trust [WT 083481]; North Carolina Biotechnology Center; Michael Hooker Chair of Pharmacology FX This work is supported by SULSA (HR07019), the BBSRC Doctoral Training Programme, the BBSRC Pathfinder (BB/FOF/PF/15/09) and the BBSRC Follow On Fund schemes (BB/J010510/1) (A.L.H.), the University of Dundee's Pump Priming Fund for Translational Medical Research (I.H.G. and A.L.H.) and by grants from the National Institutes of Health (NIH) supporting drug discovery receptor pharmacology (B.L.R.) and the NIH grant MH082441 (W.C.W.). The chemical synthesis and informatics benefits from the infrastructure investments from the Wellcome Trust Strategic Award (WT 083481). We thank J. Overington for StARlite and ChEMBL. We wish to thank D. Murugesan for compound purification and C. Means and T. Rhodes for helping with the open field, hole-board and zero-maze tests. We also wish to thank C. Elms and J. Zhou for their support in the husbandry and generation of the mice used for behavioural testing. We also wish to thank F. Y. Li for customizing the software configuration for the hole-board tests. Some of the equipment used in the behavioural testing was purchased with a grant from the North Carolina Biotechnology Center. B.L.R. also received support from the Michael Hooker Chair of Pharmacology. NR 58 TC 199 Z9 199 U1 9 U2 105 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 13 PY 2012 VL 492 IS 7428 BP 215 EP + DI 10.1038/nature11691 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 053GM UT WOS:000312259300034 PM 23235874 ER PT J AU Reichert, T Chowell, G McCullers, JA AF Reichert, Tom Chowell, Gerardo McCullers, Jonathan A. TI The age distribution of mortality due to influenza: pandemic and peri-pandemic SO BMC MEDICINE LA English DT Article DE Pandemic influenza; mortality due to influenza; recycling; pandemic attack rates; vaccination; protective immunity ID ORIGINAL ANTIGENIC SIN; HONG-KONG INFLUENZA; H1N1 INFLUENZA; UNITED-STATES; A-VIRUS; EPIDEMIOLOGIC EVIDENCE; PROTECTIVE IMMUNITY; ELDERLY-PEOPLE; VACCINATION; ANTIBODIES AB Background: Pandemic influenza is said to 'shift mortality' to younger age groups; but also to spare a subpopulation of the elderly population. Does one of these effects dominate? Might this have important ramifications? Methods: We estimated age-specific excess mortality rates for all-years for which data were available in the 20th century for Australia, Canada, France, Japan, the UK, and the USA for people older than 44 years of age. We modeled variation with age, and standardized estimates to allow direct comparison across age groups and countries. Attack rate data for four pandemics were assembled. Results: For nearly all seasons, an exponential model characterized mortality data extremely well. For seasons of emergence and a variable number of seasons following, however, a subpopulation above a threshold age invariably enjoyed reduced mortality. 'Immune escape', a stepwise increase in mortality among the oldest elderly, was observed a number of seasons after both the A(H2N2) and A(H3N2) pandemics. The number of seasons from emergence to escape varied by country. For the latter pandemic, mortality rates in four countries increased for younger age groups but only in the season following that of emergence. Adaptation to both emergent viruses was apparent as a progressive decrease in mortality rates, which, with two exceptions, was seen only in younger age groups. Pandemic attack rate variation with age was estimated to be similar across four pandemics with very different mortality impact. Conclusions: In all influenza pandemics of the 20th century, emergent viruses resembled those that had circulated previously within the lifespan of then-living people. Such individuals were relatively immune to the emergent strain, but this immunity waned with mutation of the emergent virus. An immune subpopulation complicates and may invalidate vaccine trials. Pandemic influenza does not 'shift' mortality to younger age groups; rather, the mortality level is reset by the virulence of the emerging virus and is moderated by immunity of past experience. In this study, we found that after immune escape, older age groups showed no further mortality reduction, despite their being the principal target of conventional influenza vaccines. Vaccines incorporating variants of pandemic viruses seem to provide little benefit to those previously immune. If attack rates truly are similar across pandemics, it must be the case that immunity to the pandemic virus does not prevent infection, but only mitigates the consequences. C1 [Reichert, Tom] Entropy Res Inst, Lincoln, MA 01773 USA. [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Tempe, AZ 85287 USA. [Chowell, Gerardo] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [McCullers, Jonathan A.] St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38104 USA. [McCullers, Jonathan A.] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38104 USA. RP Reichert, T (reprint author), Entropy Res Inst, 345 S Great Rd, Lincoln, MA 01773 USA. EM treichert@entropyresearch.org RI Chowell, Gerardo/F-5038-2012 OI Chowell, Gerardo/0000-0003-2194-2251 FU Multinational lnfluenza Seasonal Mortality Study (MISMS); Fogarty lnternational Center; US NlH; American Lebanese-Syrian Associated Charities (ALSAC); Entropy Research Institute FX Access to literature search and copies for TR was provided by the Boston Medical Library. This study was supported, in part, by the Multinational lnfluenza Seasonal Mortality Study (MISMS) effort within the Fogarty lnternational Center and the US NlH (to GC), and by the American Lebanese-Syrian Associated Charities (ALSAC) (to JMcC). Funding for the conversion of the Japanese all-cause mortality data to machine-readable form was provided by a special grant from the Entropy Research Institute. NR 58 TC 4 Z9 5 U1 1 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD DEC 12 PY 2012 VL 10 AR 162 DI 10.1186/1741-7015-10-162 PG 15 WC Medicine, General & Internal SC General & Internal Medicine GA 103YR UT WOS:000315956000001 PM 23234604 ER PT J AU Kimura, S Paiz, J Yoneda, M Kido, T Vinson, C Ward, JM AF Kimura, Shioko Paiz, Jorge Yoneda, Mitsuhiro Kido, Taketomo Vinson, Charles Ward, Jerrold M. TI Deficiency of CCAAT/enhancer binding protein family DNA binding prevents malignant conversion of adenoma to carcinoma in NNK-induced lung carcinogenesis in the mouse SO MOLECULAR CANCER LA English DT Article DE C/EBPs; Lung chemical carcinogenesis bioassay; Dominant negative; A-C/EBP; Transgenic mouse; 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; NNK ID ACUTE MYELOID-LEUKEMIA; C/EBP TRANSCRIPTION FACTORS; TUMOR-SUPPRESSOR; GENE-EXPRESSION; DOWN-REGULATION; BREAST-CANCER; ALPHA; CELLS; PROLIFERATION; CLASSIFICATION AB Background: The CCAAT/enhancer binding proteins (C/EBPs) play important roles in carcinogenesis of many tumors including the lung. Since multiple C/EBPs are expressed in lung, the combinatorial expression of these C/EBPs on lung carcinogenesis is not known. Methods: A transgenic mouse line expressing a dominant negative A-C/EBP under the promoter of lung epithelial Clara cell secretory protein (CCSP) gene in doxycycline dependent fashion was subjected to 4-(methylnitrosamino)1-(3-pyridyl)-1-butanone (NNK)-induced lung carcinogenesis bioassay in the presence and absence of doxycycline, and the effect of abolition of DNA binding activities of C/EBPs on lung carcinogenesis was examined. Results: A-C/EBP expression was found not to interfere with tumor development; however, it suppressed the malignant conversion of adenoma to carcinoma during NNK-induced lung carcinogenesis. The results suggested that Ki67 may be used as a marker for lung carcinomas in mouse. Conclusions: The DNA binding of C/EBP family members can be used as a potential molecular target for lung cancer therapy. C1 [Kimura, Shioko; Paiz, Jorge; Yoneda, Mitsuhiro; Kido, Taketomo; Vinson, Charles] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Ward, Jerrold M.] Global VetPathol, Montgomery Village, MD 20866 USA. RP Kimura, S (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM kimuras@mail.nih.gov FU Intramural Research Program of the National Cancer Institute, Center for Cancer Research FX We would like to thank Frank J. Gonzalez for his critical review of the manuscript and Eric Nimako for the maintenance of mice. This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research. NR 35 TC 1 Z9 1 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD DEC 12 PY 2012 VL 11 AR 90 DI 10.1186/1476-4598-11-90 PG 7 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 077TX UT WOS:000314052100001 PM 23234329 ER PT J AU Schneider, A David, VA Johnson, WE O'Brien, SJ Barsh, GS Menotti-Raymond, M Eizirik, E AF Schneider, Alexsandra David, Victor A. Johnson, Warren E. O'Brien, Stephen J. Barsh, Gregory S. Menotti-Raymond, Marilyn Eizirik, Eduardo TI How the Leopard Hides Its Spots: ASIP Mutations and Melanism in Wild Cats SO PLOS ONE LA English DT Article ID AGOUTI SIGNALING PROTEIN; COAT-COLOR; GENETICS; PIGMENTATION; EVOLUTION; INHERITANCE; EXTENSION; PATTERNS; RECEPTOR; GENES AB The occurrence of melanism (darkening of the background coloration) is documented in 13 felid species, in some cases reaching high frequencies at the population level. Recent analyses have indicated that it arose multiple times in the Felidae, with three different species exhibiting unique mutations associated with this trait. The causative mutations in the remaining species have so far not been identified, precluding a broader assessment of the evolutionary dynamics of melanism in the Felidae. Among these, the leopard (Panthera pardus) is a particularly important target for research, given the iconic status of the 'black panther' and the extremely high frequency of melanism observed in some Asian populations. Another felid species from the same region, the Asian golden cat (Pardofelis temminckii), also exhibits frequent records of melanism in some areas. We have sequenced the coding region of the Agouti Signaling Protein (ASIP) gene in multiple leopard and Asian golden cat individuals, and identified distinct mutations strongly associated with melanism in each of them. The single nucleotide polymorphism (SNP) detected among the P. pardus individuals was caused by a nonsense mutation predicted to completely ablate ASIP function. A different SNP was identified in P. temminckii, causing a predicted amino acid change that should also induce loss of function. Our results reveal two additional cases of species-specific mutations implicated in melanism in the Felidae, and indicate that ASIP mutations may play an important role in naturally-occurring coloration polymorphism. C1 [Schneider, Alexsandra; Eizirik, Eduardo] Pontificia Univ Catolica Rio Grande Sul PUCRS, Lab Biol Genom & Mol, Fac Biociencias, Porto Alegre, RS, Brazil. [David, Victor A.; Johnson, Warren E.; O'Brien, Stephen J.; Menotti-Raymond, Marilyn] Frederick Natl Lab Canc Res, Lab Genom Div, Frederick, MD USA. [O'Brien, Stephen J.] St Petersburg State Univ, Theodosius Dobzhansky Ctr Genome Informat, St Petersburg, Russia. [Barsh, Gregory S.] HudsonAlpha Inst Biotechnol, Huntsville, AL USA. [Eizirik, Eduardo] Inst Procarnivoros, Sao Paulo, Brazil. RP Schneider, A (reprint author), Pontificia Univ Catolica Rio Grande Sul PUCRS, Lab Biol Genom & Mol, Fac Biociencias, Porto Alegre, RS, Brazil. EM ale-schneider@live.com; eduardo.eizirik@pucrs.br RI Eizirik, Eduardo/K-8034-2012; Johnson, Warren/D-4149-2016; OI Eizirik, Eduardo/0000-0002-9658-0999; Johnson, Warren/0000-0002-5954-186X; O'Brien, Stephen J./0000-0001-7353-8301 FU Brazilian National Research Council/CNPq; CAPES/Brazil; USA federal funds from the National Cancer Institute, National Institutes of Health [HHSN26120080001E] FX This work was funded by the Brazilian National Research Council/CNPq (www.cnpq.br), CAPES/Brazil (www.capes.gov.br), and USA federal funds from the National Cancer Institute, National Institutes of Health (www.nih.gov), under contract HHSN26120080001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does its 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 50 TC 8 Z9 8 U1 11 U2 74 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 DEC 12 PY 2012 VL 7 IS 12 AR e50386 DI 10.1371/journal.pone.0050386 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 066QV UT WOS:000313236200028 PM 23251368 ER PT J AU Scimemi, A Diamond, JS AF Scimemi, Annalisa Diamond, Jeffrey S. TI The Number and Organization of Ca2+ Channels in the Active Zone Shapes Neurotransmitter Release from Schaffer Collateral Synapses SO JOURNAL OF NEUROSCIENCE LA English DT Article ID PROBABILITY FLUCTUATION ANALYSIS; OPTICAL QUANTAL ANALYSIS; SINGLE CALCIUM CHANNELS; SYNAPTIC-TRANSMISSION; TRANSMITTER RELEASE; CA3-CA1 SYNAPSES; N-TYPE; NERVE-TERMINALS; OMEGA-CONOTOXIN; TERM PLASTICITY AB Fast synaptic transmission requires tight colocalization of Ca2+ channels and neurotransmitter vesicles. It is generally thought that Ca2+ channels are expressed abundantly in presynaptic active zones, that vesicles within the same active zone have similar release properties, and that significant vesicle depletion only occurs at synapses with high release probability. Here we show, at excitatory CA3 -> CA1 synapses in mouse hippocampus, that release from individual vesicles is generally triggered by only one Ca2+ channel and that only few functional Ca2+ channels may be spread in the active zone at variable distances to neighboring neurotransmitter vesicles. Using morphologically realistic Monte Carlo simulations, we show that this arrangement leads to a widely heterogeneous distribution of release probability across the vesicles docked at the active zone, and that depletion of the vesicles closest to Ca2+ channels can account for the Ca2+ dependence of short-term plasticity at these synapses. These findings challenge the prevailing view that efficient synaptic transmission requires numerous presynaptic Ca2+ channels in the active zone, and indicate that the relative arrangement of Ca2+ channels and vesicles contributes to the heterogeneity of release probability within and across synapses and to vesicle depletion at small central synapses with low average release probability. C1 [Scimemi, Annalisa; Diamond, Jeffrey S.] NINDS, Synapt Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Scimemi, A (reprint author), NINDS, Synapt Physiol Sect, NIH, 35 Convent Dr 3C1006, Bethesda, MD 20892 USA. EM scimemia@ninds.nih.gov RI Scimemi, Annalisa/O-5396-2014; Diamond, Jeffrey/C-1835-2015 OI Scimemi, Annalisa/0000-0003-4975-093X; Diamond, Jeffrey/0000-0002-1770-2629 FU National Institute of Neurological Disorders and Stroke Intramural Research Program [NS002986] FX This work was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program (NS002986). We thank J.M. Kerr, D. M. Kullmann, C.J. McBain, A. Poleg-Polsky, and L. G. Wu for comments on this manuscript; M. Dittrich for help with MCell; and T. Prustel and I. Scimemi for help with error propagation analysis. NR 59 TC 23 Z9 23 U1 0 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 12 PY 2012 VL 32 IS 50 BP 18157 EP 18176 DI 10.1523/JNEUROSCI.3827-12.2012 PG 20 WC Neurosciences SC Neurosciences & Neurology GA 055GY UT WOS:000312404700022 PM 23238730 ER PT J AU Ko, F Vitale, S Chou, CF Cotch, MF Saaddine, J Friedman, DS AF Ko, Fang Vitale, Susan Chou, Chiu-Fang Cotch, Mary Frances Saaddine, Jinan Friedman, David S. TI Prevalence of Nonrefractive Visual Impairment in US Adults and Associated Risk Factors, 1999-2002 and 2005-2008 SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID TYPE-2 DIABETES-MELLITUS; UNITED-STATES; TEMPORAL TRENDS; RETINOPATHY; CHILDREN; ADOLESCENTS; PERSPECTIVE; HEALTH AB Context Over the past decade, chronic illnesses with ophthalmic sequelae such as diabetes and diabetic retinopathy have increased. Objectives To estimate prevalence of nonrefractive visual impairment and to describe its relationship with demographic and systemic risk factors including diagnosed diabetes. Design, Setting, and Participants The National Health and Nutrition Examination Survey (NHANES) examined a representative sample of the US noninstitutionalized population. In 1999-2002 and 2005-2008, 9471 and 10 480 participants aged 20 years or older received questionnaires, laboratory tests, and physical examinations. Visual acuity of less than 20/40 aided by autorefractor was classified as nonrefractive visual impairment. Main Outcome Measure Nonrefractive visual impairment. Results Weighted prevalence of nonrefractive visual impairment increased 21% among US adults aged 20 years and older from 1.4% in 1999-2002 to 1.7% in 2005-2008 (P=.03); and increased 40% among non-Hispanic whites aged 20-39 years from 0.5% to 0.7% (P=.008). In multivariable analyses, statistically significant risk factors for nonrefractive visual impairment in 1999-2002 included age (per year odds ratio [OR], 1.07; 95% CI, 1.05-1.09), poverty (OR, 2.18; 95% CI, 1.31-3.64), lack of insurance (OR, 1.85; 95% CI, 1.16-2.95), and diabetes with 10 or more years since diagnosis (OR, 1.93; 95% CI, 1.15-3.25). In 2005-2008, risk factors included age (OR, 1.05; 95% CI, 1.04-1.07), poverty (OR, 2.23; 95% CI, 1.55-3.22), education less than high school (OR, 2.11; 95% CI, 1.54-2.90), and diabetes with 10 or more years since diagnosis (OR, 2.67; 95% CI, 1.64-4.37). Prevalence of diabetes with 10 or more years since diagnosis increased 22% overall from 2.8% to 3.6% (P=.02); and 133% among non-Hispanic whites aged 20-39 years from 0.3% to 0.7% (P<.001). Conclusion Prevalence of nonrefractive visual impairment was significantly higher in 2005-2008 than in 1999-2002 and may be attributable, in part, to higher prevalence of diabetes, an associated risk factor that increased in prevalence during this time period. JAMA. 2012;308(22):2361-2368 www.jama.com C1 [Ko, Fang; Friedman, David S.] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Dana Ctr Prevent Ophthalmol, Baltimore, MD 21205 USA. [Friedman, David S.] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Vitale, Susan; Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Chou, Chiu-Fang; Saaddine, Jinan] Ctr Dis Control & Prevent, Div Diabet Translat, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. RP Friedman, DS (reprint author), Wilmer 120,600 N Wolfe St, Baltimore, MD 21287 USA. EM david.friedman@jhu.edu OI Cotch, Mary Frances/0000-0002-2046-4350 FU National Eye Institute (ARVO); Pepose; David Friedman Research Grant Award; Centers for Disease Control and Prevention (CDC) [1U58DP002653-01]; National Center for Health Statistics (NCHS); CDC; National Institutes of Health (NIH) [Z01EY000402] FX All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Friedman reports having consulted for Alcon, Bausch and Lomb, Merck, Pfizer, Allergan, Nidek, and QLT. Dr Ko reports receipt of support for travel to meetings for the study or other purposes from the National Eye Institute (ARVO travel grant), a Pepose travel grant, and a David Friedman Research Grant Award for provision of writing assistance, medicines, equipment, or administratrive support. The remaining authors report no disclosures.; This study was supported by the Centers for Disease Control and Prevention (CDC) grant 1U58DP002653-01 and the David Friedman Research Grant Award. The National Health and Nutrition Examination Survey (NHANES) is sponsored by the National Center for Health Statistics (NCHS), CDC. Funding for the vision component was provided by the National Eye Institute (NEI), National Institutes of Health (NIH), Intramural Research Program grant Z01EY000402. NR 37 TC 29 Z9 30 U1 0 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 12 PY 2012 VL 308 IS 22 BP 2361 EP 2368 DI 10.1001/jama.2012.85685 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 051MW UT WOS:000312132400026 PM 23232894 ER PT J AU Traverse, JH Henry, TD Pepine, CJ Willerson, JT Zhao, DXM Ellis, SG Forder, JR Anderson, RD Hatzopoulos, AK Penn, MS Perin, EC Chambers, J Baran, KW Raveendran, G Lambert, C Lerman, A Simon, DI Vaughan, DE Lai, DJ Gee, AP Taylor, DA Cogle, CR Thomas, JD Olson, RE Bowman, S Francescon, J Geither, C Handberg, E Kappenman, C Westbrook, L Piller, LB Simpson, LM Baraniuk, S Loghin, C Aguilar, D Richman, S Zierold, C Spoon, DB Bettencourt, J Sayre, SL Vojvodic, RW Skarlatos, SI Gordon, DJ Ebert, RF Kwak, M Moye, LA Simari, RD AF Traverse, Jay H. Henry, Timothy D. Pepine, Carl J. Willerson, James T. Zhao, David X. M. Ellis, Stephen G. Forder, John R. Anderson, R. David Hatzopoulos, Antonis K. Penn, Marc S. Perin, Emerson C. Chambers, Jeffrey Baran, Kenneth W. Raveendran, Ganesh Lambert, Charles Lerman, Amir Simon, Daniel I. Vaughan, Douglas E. Lai, Dejian Gee, Adrian P. Taylor, Doris A. Cogle, Christopher R. Thomas, James D. Olson, Rachel E. Bowman, Sherry Francescon, Judy Geither, Carrie Handberg, Eileen Kappenman, Casey Westbrook, Lynette Piller, Linda B. Simpson, Lara M. Baraniuk, Sarah Loghin, Catalin Aguilar, David Richman, Sara Zierold, Claudia Spoon, Daniel B. Bettencourt, Judy Sayre, Shelly L. Vojvodic, Rachel W. Skarlatos, Sonia I. Gordon, David J. Ebert, Ray F. Kwak, Minjung Moye, Lemuel A. Simari, Robert D. CA CCTRN TI Effect of the Use and Timing of Bone Marrow Mononuclear Cell Delivery on Left Ventricular Function After Acute Myocardial Infarction The TIME Randomized Trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID REDUCED NEOVASCULARIZATION CAPACITY; CARDIOSPHERE-DERIVED CELLS; THERAPY RESEARCH NETWORK; ISCHEMIC-HEART-DISEASE; PROGENITOR CELLS; STEM-CELLS; INTRACORONARY INFUSION; DOUBLE-BLIND; REPAIR; REGENERATION AB Context While the delivery of cell therapy after ST-segment elevation myocardial infarction (STEMI) has been evaluated in previous clinical trials, the influence of the timing of cell delivery on the effect on left ventricular function has not been analyzed. Objectives To determine the effect of intracoronary autologous bone marrow mononuclear cell (BMC) delivery after STEMI on recovery of global and regional left ventricular function and whether timing of BMC delivery (3 days vs 7 days after reperfusion) influences this effect. Design, Setting, and Patients A randomized, 2 x 2 factorial, double-blind, placebo-controlled trial, Timing In Myocardial infarction Evaluation (TIME) enrolled 120 patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] <= 45%) after successful primary percutaneous coronary intervention (PCI) of anterior STEMI between July 17, 2008, and November 15, 2011, as part of the Cardiovascular Cell Therapy Research Network sponsored by the National Heart, Lung, and Blood Institute. Interventions Intracoronary infusion of 150 x 10(6) BMCs or placebo (randomized 2: 1) within 12 hours of aspiration and cell processing administered at day 3 or day 7 (randomized 1: 1) after treatment with PCI. Main Outcome Measures The primary end points were change in global (LVEF) and regional (wall motion) left ventricular function in infarct and border zones at 6 months measured by cardiac magnetic resonance imaging and change in left ventricular function as affected by timing of treatment on day 3 vs day 7. The secondary end points included major adverse cardiovascular events as well as changes in left ventricular volumes and infarct size. Results The mean (SD) patient age was 56.9 (10.9) years and 87.5% of participants were male. At 6 months, there was no significant increase in LVEF for the BMC group (45.2% [95% CI, 42.8% to 47.6%] to 48.3% [95% CI, 45.3% to 51.3%) vs the placebo group (44.5% [95% CI, 41.0% to 48.0%] to 47.8% [95% CI, 43.4% to 52.2%]) (P=.96). There was no significant treatment effect on regional left ventricular function observed in either infarct or border zones. There were no significant differences in change in global left ventricular function for patients treated at day 3 (-0.9% [95% CI, -6.6% to 4.9%], P=.76) or day 7 (1.1% [95% CI, -4.7% to 6.9%], P=.70). The timing of treatment had no significant effect on regional left ventricular function recovery. Major adverse events were rare among all treatment groups. Conclusion Among patients with STEMI treated with primary PCI, the administration of intracoronary BMCs at either 3 days or 7 days after the event had no significant effect on recovery of global or regional left ventricular function compared with placebo. C1 [Traverse, Jay H.; Henry, Timothy D.; Olson, Rachel E.] Abbott NW Hosp, Minneapolis Heart Inst, Minneapolis, MN 55407 USA. [Traverse, Jay H.; Henry, Timothy D.; Raveendran, Ganesh; Zierold, Claudia] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Pepine, Carl J.; Forder, John R.; Anderson, R. David; Lambert, Charles; Cogle, Christopher R.; Handberg, Eileen] Univ Florida, Coll Med, Gainesville, FL USA. [Willerson, James T.; Perin, Emerson C.; Taylor, Doris A.; Kappenman, Casey; Westbrook, Lynette] St Lukes Episcopal Hosp, Texas Heart Inst, Houston, TX USA. [Zhao, David X. M.; Hatzopoulos, Antonis K.; Bowman, Sherry; Francescon, Judy] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Ellis, Stephen G.; Thomas, James D.; Geither, Carrie] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Penn, Marc S.] NE Ohio Med Univ, Rootstown, OH USA. [Chambers, Jeffrey] Mercy Hosp, Metropolitan Heart & Vasc Inst, Minneapolis, MN USA. [Baran, Kenneth W.] United Hosp, St Paul Heart Clin, St Paul, MN USA. [Lambert, Charles] Florida Hosp Pepin Heart Inst, Tampa, FL USA. [Lerman, Amir; Spoon, Daniel B.; Simari, Robert D.] Mayo Clin, Rochester, MN USA. [Simon, Daniel I.] Univ Hosp Case Med Ctr, Cleveland, OH USA. [Vaughan, Douglas E.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Lai, Dejian; Piller, Linda B.; Simpson, Lara M.; Baraniuk, Sarah; Bettencourt, Judy; Sayre, Shelly L.; Vojvodic, Rachel W.; Moye, Lemuel A.] Univ Texas Houston, Sch Publ Hlth, Houston, TX 77030 USA. [Loghin, Catalin] Univ Texas Houston, Sch Med, Houston, TX 77030 USA. [Gee, Adrian P.; Aguilar, David; Richman, Sara] Baylor Coll Med, Houston, TX 77030 USA. [Skarlatos, Sonia I.; Gordon, David J.; Ebert, Ray F.; Kwak, Minjung] NHLBI, Bethesda, MD USA. RP Bettencourt, J (reprint author), Univ Texas Houston, Sch Publ Hlth, 1200 Herman Pressler,Room W-838, Houston, TX 77030 USA. EM judith.l.bettencourt@uth.tmc.edu RI Hatzopoulos, Antonis/D-2049-2010; Cogle, Christopher/H-1746-2016 OI Cogle, Christopher/0000-0001-5422-6863 FU Capricor; Osiris; NHLBI; Athersys; Abbott Vascular; American Heart Association; National Space Biomedical Research Institute/National Aeronautics and Space Administration; Amorcyte; Baxter; BDI Pharma; National Heart, Lung, and Blood Institute [5 U01 HL087318-04] FX The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Henry reported serving as a consultant for Capricor; and receiving grant funding from Capricor and Osiris. Dr Pepine reported receiving funding for writing assistance, medicines, equipment, or administrative support from the National, Heart, Lung and Blood Institute (NHLBI) and Biosafe. Dr Willerson reported receiving funding from the NHLBI for participation in review activities. Dr Ellis reported receiving travel support from Abbott Vascular and Boston Scientific. Dr Hatzopoulos reported receiving funding from the NHLBI for writing and reviewing manuscripts, and participating in review activities. Dr Penn reported serving as a consultant to Aastrom and Juventas; receiving grant funding from Athersys; and having patents, receiving royalties, and owning stock/stock options in Juventas Therapeutics; and receiving reimbursement for travel expenses from Juventas Therapeutics. Dr Perin reported serving as a consultant to Cytori, Celgene, Biosense Webster, and Cephalon. Dr Simon reported serving as a consultant to Cordis/Johnson & Johnson, Medtronic Vascular, Merck, the Medicines Company, and Portola; serving as an expert witness for Cordis/Johnson & Johnson; and receiving payment for lectures from Abbott Vascular. Dr Taylor reported receiving payment for lectures from the American Heart Association. Dr Thomas reported that he served as president of the American Society of Echocardiography in 2011-2012; and received grant funding from the National Space Biomedical Research Institute/National Aeronautics and Space Administration. Dr Handberg reported receiving grant funding from Amorcyte, Baxter, and BDI Pharma. Ms Westbrook reported receiving travel reimbursement from Barnett International. All of the authors reported receiving research grant funding and support for travel expenses to meetings for the Cardiovascular Cell Therapy Research Network from the NHLBI.; Funding for this trial was provided by the National Heart, Lung, and Blood Institute under cooperative agreement 5 U01 HL087318-04. NR 26 TC 162 Z9 165 U1 2 U2 20 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 12 PY 2012 VL 308 IS 22 BP 2380 EP 2389 DI 10.1001/jama.2012.28726 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 051MW UT WOS:000312132400028 PM 23129008 ER PT J AU Rabin, BA Purcell, P Naveed, S Moser, RP Henton, MD Proctor, EK Brownson, RC Glasgow, RE AF Rabin, Borsika A. Purcell, Peyton Naveed, Sana Moser, Richard P. Henton, Michelle D. Proctor, Enola K. Brownson, Ross C. Glasgow, Russell E. TI Advancing the application, quality and harmonization of implementation science measures SO IMPLEMENTATION SCIENCE LA English DT Article DE Implementation; Dissemination; Measures; Constructs; Quality of measurement; Harmonization; Technology-mediated social participation ID HEALTH-SERVICES AB Background: The field of implementation science (IS) encompasses a broad range of constructs and uses measures from a variety of disciplines. However, there has been little standardization of measures or agreement on definitions of constructs across different studies, fields, authors, or research groups. Methods: We describe a collaborative, web-based activity using the United States National Cancer Institute's (NCI) Grid-Enabled Measures (GEM) portal that uses a wiki platform to focus discussion and engage the research community to enhance the quality and harmonization of measures for IS health-related research and practice. We present the history, process, and preliminary data from the GEM Dissemination & Implementation (D&I) Campaign on IS measurement. Results: The GEM D&I Campaign has been ongoing for eight weeks as of this writing, and has used a combination of expert opinion and crowd-sourcing approaches. To date it has listed definitions for 45 constructs and summarized information on 120 measures. Usage of the website peaked at a rate of 124 views from 89 visitors on week seven. Users from seven countries have contributed measures and/or constructs, shared experience in using different measures, contributed comments, and identified research gaps and needs. Conclusion: Thus far, this campaign has provided information about different IS measures, their associated characteristics, and comments. The next step is to rate these measures for quality and practicality. This resource and ongoing activity have potential to advance the quality and harmonization of IS measures and constructs, and we invite readers to contribute to the process. C1 [Rabin, Borsika A.; Henton, Michelle D.] Kaiser Permanente Colorado, CRN Canc Commun Res Ctr, Inst Hlth Res, Denver, CO USA. [Purcell, Peyton; Naveed, Sana; Moser, Richard P.; Glasgow, Russell E.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Proctor, Enola K.] Washington Univ, George Warren Brown Sch Social Work, St Louis, MO 63130 USA. [Brownson, Ross C.] Washington Univ, Prevent Res Ctr St Louis, Brown Sch, St Louis, MO 63110 USA. [Brownson, Ross C.] Washington Univ, Sch Med, Div Publ Hlth Sci, St Louis, WA USA. [Brownson, Ross C.] Washington Univ, Sch Med, Alvin J Siteman Canc Ctr, St Louis, WA USA. RP Rabin, BA (reprint author), Kaiser Permanente Colorado, CRN Canc Commun Res Ctr, Inst Hlth Res, Legacy Highlands Bldg,10065 E Harvard Ave,Suite 3, Denver, CO USA. EM borsika.a.rabin@gmail.com FU National Cancer Institute Centers of Excellence in Cancer Communication Research [P20CA137219]; National Cancer Institute at the National Institutes of Health [1R01CA124404-01]; Centers for Disease Control and Prevention, Prevention Research Centers Program [U48/DP001903]; Washington University Dissemination and Implementation Research Core (DIRC); NIH Clinical and Translational Science Award (CTSA); WU calls its Institute of Clinical and Translational Sciences (ICTS) [5UL1RR02499205, 06/09-05/11]; National Cancer Institute Centers for Transdisciplinary Research on Energetics and Cancer (TREC) [U54CA155496] FX The preparation of this manuscript was funded through National Cancer Institute Centers of Excellence in Cancer Communication Research (award number P20CA137219), the National Cancer Institute at the National Institutes of Health grant number 1R01CA124404-01, the Centers for Disease Control and Prevention, Prevention Research Centers Program cooperative agreement number U48/DP001903, the Washington University Dissemination and Implementation Research Core (DIRC), through its NIH Clinical and Translational Science Award (CTSA), which WU calls its Institute of Clinical and Translational Sciences (ICTS, 5UL1RR02499205, 06/09-05/11), and the National Cancer Institute Centers for Transdisciplinary Research on Energetics and Cancer (TREC) (U54CA155496) - Dissemination and Implementation Research Core. NR 24 TC 24 Z9 24 U1 1 U2 16 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1748-5908 J9 IMPLEMENT SCI JI Implement. Sci. PD DEC 11 PY 2012 VL 7 AR 119 DI 10.1186/1748-5908-7-119 PG 11 WC Health Care Sciences & Services; Health Policy & Services SC Health Care Sciences & Services GA 104BA UT WOS:000315962900001 PM 23231885 ER PT J AU Elleder, D Baiga, TJ Russell, RL Naughton, JA Hughes, SH Noel, JP Young, JAT AF Elleder, Daniel Baiga, Thomas J. Russell, Rebecca L. Naughton, John A. Hughes, Stephen H. Noel, Joseph P. Young, John A. T. TI Identification of a 3-aminoimidazo[1,2-a]pyridine inhibitor of HIV-1 reverse transcriptase SO VIROLOGY JOURNAL LA English DT Article DE HIV-1; NNRTI; Inhibitor ID IMMUNODEFICIENCY-VIRUS TYPE-1; DRUG DISCOVERY; REPLICATION; INFECTION; NNRTIS AB Background: Despite the effectiveness of highly active antiretroviral therapy (HAART), there remains an urgent need to develop new human immunodeficiency virus type 1 (HIV-1) inhibitors with better pharmacokinetic properties that are well tolerated, and that block common drug resistant virus strains. Methods: Here we screened an in-house small molecule library for novel inhibitors of HIV-1 replication. Results: An active compound containing a 3-aminoimidazo[1,2-a]pyridine scaffold was identified and quantitatively characterized as a non-nucleoside reverse transcriptase inhibitor (NNRTI). Conclusions: The potency of this compound coupled with its inexpensive chemical synthesis and tractability for downstream SAR analysis make this inhibitor a suitable lead candidate for further development as an antiviral drug. C1 [Elleder, Daniel; Naughton, John A.; Young, John A. T.] Salk Inst Biol Studies, Nomis Ctr Immunobiol & Microbial Pathogenesis, La Jolla, CA 92037 USA. [Baiga, Thomas J.; Russell, Rebecca L.; Noel, Joseph P.] Salk Inst Biol Studies, Howard Hughes Med Inst, Jack H Skirball Ctr Chem Biol & Prote, La Jolla, CA 92037 USA. [Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Baiga, Thomas J.] EMD Millipore Corp, Biosci Business Unit, Pacific Ctr Court 10394, San Diego, CA 92121 USA. RP Young, JAT (reprint author), Salk Inst Biol Studies, Nomis Ctr Immunobiol & Microbial Pathogenesis, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM jyoung@salk.edu RI Elleder, Daniel/G-3551-2014 FU Nomis Foundation; James B. Pendleton Charitable Trust; NIH [P30 CA014195-38]; Intramural Research Program of NIH, National Cancer Institute FX This work was supported by the Nomis Foundation, the James B. Pendleton Charitable Trust (JATY) and NIH Grant P30 CA014195-38 (JATY and JPN). JPN is an investigator with the Howard Hughes Medical Institute. This research was supported [in part] by the Intramural Research Program of NIH, National Cancer Institute (SH). We thank members of the Noel and Young labs for helpful discussions. We thank Justin Ramsey for assistance in preparing the Salk in-house library and Kevin Olivieri, Lars Pache, and Sumit Chanda (Sanford-Burnham Medical Research Institute) for providing the NL4-3 Nef+ IRES rluc virus construct. We thank Dr. David Smith and the UCSD Center for AIDS Research for providing PBMC samples. NR 19 TC 10 Z9 10 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD DEC 11 PY 2012 VL 9 AR 305 DI 10.1186/1743-422X-9-305 PG 7 WC Virology SC Virology GA 081IO UT WOS:000314312600001 PM 23231773 ER PT J AU Cole, SW Conti, G Arevalo, JMG Ruggiero, AM Heckman, JJ Suomi, SJ AF Cole, Steven W. Conti, Gabriella Arevalo, Jesusa M. G. Ruggiero, Angela M. Heckman, James J. Suomi, Stephen J. TI Transcriptional modulation of the developing immune system by early life social adversity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE stress; social genomics; gene regulation ID CHILDHOOD SOCIOECONOMIC-STATUS; GENE-EXPRESSION; INDIVIDUAL-DIFFERENCES; DNA METHYLATION; HOST-RESISTANCE; MATERNAL-CARE; STRESS; RESPONSES; ADULTHOOD; HEALTH AB To identify molecular mechanisms by which early life social conditions might influence adult risk of disease in rhesus macaques (Macaca mulatta), we analyze changes in basal leukocyte gene expression profiles in 4-mo-old animals reared under adverse social conditions. Compared with the basal condition of maternal rearing (MR), leukocytes from peer-reared (PR) animals and PR animals provided with an inanimate surrogate mother (surrogate/peer reared, SPR) show enhanced expression of genes involved in inflammation, cytokine signaling, and T-lymphocyte activation, and suppression of genes involved in several innate antimicrobial defenses including type I interferon (IFN) antiviral responses. Promoter-based bioinformatic analyses implicate increased activity of CREB and NF-kappa B transcription factors and decreased activity of IFN response factors (IRFs) in structuring the observed differences in gene expression. Transcript origin analyses identify monocytes and CD4(+) T lymphocytes as primary cellular mediators of transcriptional up-regulation and B lymphocytes as major sources of down-regulated genes. These findings show that adverse social conditions can become embedded within the basal transcriptome of primate immune cells within the first 4 mo of life, and they implicate sympathetic nervous system-linked transcription control pathways as candidate mediators of those effects and potential targets for health-protective intervention. C1 [Cole, Steven W.; Arevalo, Jesusa M. G.] Univ Calif Los Angeles, Sch Med, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. [Cole, Steven W.; Arevalo, Jesusa M. G.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Conti, Gabriella] Univ Chicago, Harris Sch Publ Policy Studies, Chicago, IL 60637 USA. [Ruggiero, Angela M.; Suomi, Stephen J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Comparat Ethol, NIH, Bethesda, MD 20892 USA. [Heckman, James J.] Univ Chicago, Dept Econ, Chicago, IL 60637 USA. [Heckman, James J.] Amer Bar Fdn, Chicago, IL 60611 USA. [Heckman, James J.] Univ Coll Dublin, Geary Inst, Dublin 4, Ireland. RP Cole, SW (reprint author), Univ Calif Los Angeles, Sch Med, Dept Med, Div Hematol Oncol, Los Angeles, CA 90095 USA. EM coles@ucla.edu; jjh@uchicago.edu FU National Institutes of Health [P30AG107265, P60AG010415, R01HD054702, P30AG012857, R01AG034679, R01CA116778, R37-HD065072]; Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development; American Bar Foundation; European Research Council FX We thank Weihong Yan for parsing the Macaca mulatta genome to provide RefSeq promoter sequences, Kuan Chen and Yilan Chen for help in clustering the gene lists by GO biological function, and the National Institute of Aging (NIA) for catalyzing this research collaboration through the 2008 NIA Workshop on Genetic Methods and the Life Course. This research was supported by National Institutes of Health Grants P30AG107265, P60AG010415, R01HD054702, P30AG012857, R01AG034679, R01CA116778, and R37-HD065072; by funds from the Division of Intramural Research, Eunice Kennedy Shriver National Institute of Child Health and Human Development; and by the American Bar Foundation. We acknowledge the support of a European Research Council grant hosted by University College Dublin, DEVHEALTH 269874. NR 66 TC 55 Z9 56 U1 1 U2 31 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 DEC 11 PY 2012 VL 109 IS 50 BP 20578 EP 20583 DI 10.1073/pnas.1218253109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 058AF UT WOS:000312605600089 PM 23184974 ER PT J AU Rajagopalan, S Long, EO AF Rajagopalan, Sumati Long, Eric O. TI Cellular senescence induced by CD158d reprograms natural killer cells to promote vascular remodeling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE KIR2DL4; microarray ID HLA-G; NK CELLS; PREGNANCY; RECEPTOR; HETEROCHROMATIN; BIOMARKER; FIBROSIS; SURVIVAL; PATHWAY; STRESS AB Natural killer (NK) cells, which have an essential role in immune defense, also contribute to reproductive success. NK cells are abundant at the maternal-fetal interface, where soluble HLA-G is produced by fetal trophoblast cells during early pregnancy. Soluble HLA-G induces a proinflammatory response in primary, resting NK cells on endocytosis into early endosomes where its receptor, CD158d, resides. CD158d initiates signaling through DNA-PKcs, Akt, and NF-kappa B for a proinflammatory and proangiogenic response. The physiological relevance of this endosomal signaling pathway, and how activation of CD158d through soluble ligands regulates NK cell fate and function is unknown. We show here that CD158d agonists trigger a DNA damage response signaling pathway involving cyclin-dependent kinase inhibitor p21 expression and heterochromatin protein HP1-gamma phosphorylation. Sustained activation through CD158d induced morphological changes in NK cell shape and size, and survival in the absence of cell-cycle entry, all hallmarks of senescence, and a transcriptional signature of a senescence-associated secretory phenotype (SASP). SASP is a program that can be induced by oncogenes or DNA damage, and promotes growth arrest and tissue repair. The secretome of CD158d-stimulated senescent NK cells promoted vascular remodeling and angiogenesis as assessed by functional readouts of vascular permeability and endothelial cell tube formation. Retrospective analysis of the decidual NK cell transcriptome revealed a strong senescence signature. We propose that a positive function of senescence in healthy tissue is to favor reproduction through the sustained activation of NK cells to remodel maternal vasculature in early pregnancy. C1 [Rajagopalan, Sumati; Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Rajagopalan, S (reprint author), NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM sumi@nih.gov; eLong@nih.gov RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 FU Intramural Research Program of the NIAID, NIH FX We thank D. E. Geraghty (Fred Hutchinson Cancer Research Center) for 721.221-HLA-G5 cells and D. Sturdevant and the Genomics Branch of the Research Technologies Section (Rocky Mountain Laboratories, NIAID, NIH) for microarray analysis. This research was supported by the Intramural Research Program of the NIAID, NIH. NR 36 TC 37 Z9 40 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 DEC 11 PY 2012 VL 109 IS 50 BP 20596 EP 20601 DI 10.1073/pnas.1208248109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 058AF UT WOS:000312605600092 PM 23184984 ER PT J AU Busser, BW Huang, D Rogacki, KR Lane, EA Shokri, L Ni, T Gamble, CE Gisselbrecht, SS Zhu, J Bulyk, ML Ovcharenko, I Michelson, AM AF Busser, Brian W. Huang, Di Rogacki, Kevin R. Lane, Elizabeth A. Shokri, Leila Ni, Ting Gamble, Caitlin E. Gisselbrecht, Stephen S. Zhu, Jun Bulyk, Martha L. Ovcharenko, Ivan Michelson, Alan M. TI Integrative analysis of the zinc finger transcription factor Lame duck in the Drosophila myogenic gene regulatory network SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID MESODERM DEVELOPMENT; MYOBLAST FUSION; GENOME; MEF2; SPECIFICITY; ACTIVATION; EXPRESSION; PROTEIN; MAP AB Contemporary high-throughput technologies permit the rapid identification of transcription factor (TF) target genes on a genome-wide scale, yet the functional significance of TFs requires knowledge of target gene expression patterns, cooperating TFs, and cis-regulatory element (CRE) structures. Here we investigated the myogenic regulatory network downstream of the Drosophila zinc finger TF Lame duck (Lmd) by combining both previously published and newly performed genomic data sets, including ChIP sequencing (ChIP-seq), genome-wide mRNA profiling, cell-specific expression patterns of putative transcriptional targets, analysis of histone mark signatures, studies of TF cooccupancy by additional mesodermal regulators, TF binding site determination using protein binding microarrays (PBMs), and machine learning of candidate CRE motif compositions. Our findings suggest that Lmd orchestrates an extensive myogenic regulatory network, a conclusion supported by the identification of Lmd-dependent genes, histone signatures of Lmd-bound genomic regions, and the relationship of these features to cell-specific gene expression patterns. The heterogeneous cooccupancy of Lmd-bound regions with additional mesodermal regulators revealed that different transcriptional inputs are used to mediate similar myogenic gene expression patterns. Machine learning further demonstrated diverse combinatorial motif patterns within tissue-specific Lmd-bound regions. PBM analysis established the complete spectrum of Lmd DNA binding specificities, and site-directed mutagenesis of Lmd and additional newly discovered motifs in known enhancers demonstrated the critical role of these TF binding sites in supporting full enhancer activity. Collectively, these findings provide insights into the transcriptional codes regulating muscle gene expression and offer a generalizable approach for similar studies in other systems. C1 [Huang, Di; Ovcharenko, Ivan; Michelson, Alan M.] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Busser, Brian W.; Rogacki, Kevin R.; Lane, Elizabeth A.; Ni, Ting; Gamble, Caitlin E.; Zhu, Jun] NHLBI, Lab Dev Syst Biol, Bethesda, MD 20892 USA. [Shokri, Leila; Gisselbrecht, Stephen S.; Bulyk, Martha L.] Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA. [Bulyk, Martha L.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Bulyk, Martha L.] Harvard Univ, Sch Med, Harvard Mit Div Hlth Sci & Technol, Boston, MA 02115 USA. RP Ovcharenko, I (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM ovcharen@nih.gov; michelsonam@nhlbi.nih.gov OI Gisselbrecht, Stephen/0000-0001-8723-902X FU NHLBI Division of Intramural Research; Intramural Research Program of the National Institutes of Health (NIH) [RO1 HG005287]; National Library of Medicine; NIH Grant National Research Service [F32 GM090645] FX We thank E. Furlong, H. Nguyen, and A. Nose for providing fly strains and antibodies; C. Sonnenbrot for technical assistance; M. Berger for initial PBM analyses of Lmd (Division of Genetics, Brigham and Women's Hospital); and P. McCoy [Flow Cytometry Core Facility, National Heart Lung and Blood Institute (NHLBI) Division of Intramural Research] for performing cell purifications. This work was funded by the NHLBI Division of Intramural Research (A.M.M.), the Intramural Research Program of the National Institutes of Health (NIH), National Library of Medicine (I.O.), NIH Grant RO1 HG005287 (to M.L.B.), and NIH Grant National Research Service Award F32 GM090645 (to L.S.). NR 43 TC 17 Z9 17 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 11 PY 2012 VL 109 IS 50 BP 20768 EP 20773 DI 10.1073/pnas.1210415109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 058AF UT WOS:000312605600121 PM 23184988 ER PT J AU Young, RM Staudt, LM AF Young, Ryan M. Staudt, Louis M. TI A New "Brew" of MALT1 Inhibitors SO CANCER CELL LA English DT Editorial Material ID B-CELL LYMPHOMA; CARD11 MUTATIONS; PROTEASE AB The activated B cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL) is an aggressive lymphoma that is addicted to NF-kappa B signaling through the CARD11-BCL10-MALT1 complex. In this issue of Cancer Cell, Nagel and colleagues and Fontan and colleagues describe MALT1 inhibitors suitable for clinical use that are selectively toxic to this malignancy. C1 [Young, Ryan M.; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov FU Intramural NIH HHS [ZIA BC011008-06] NR 10 TC 6 Z9 6 U1 1 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD DEC 11 PY 2012 VL 22 IS 6 BP 706 EP 707 DI 10.1016/j.ccr.2012.11.011 PG 2 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 056CW UT WOS:000312467000004 PM 23238011 ER PT J AU Rienstra, M Lubitz, SA Mahida, S Sinner, MF Ellinor, PT Van Gelder, IC Magnani, JW Fontes, JD Benjamin, EJ AF Rienstra, Michiel Lubitz, Steven A. Mahida, Saagar Sinner, Moritz F. Ellinor, Patrick T. Van Gelder, Isabelle C. Magnani, Jared W. Fontes, Joao D. Benjamin, Emelia J. TI Response to Letter Regarding Article, "Symptoms and Functional Status of Patients With Atrial Fibrillation: State of the Art and Future Research Opportunities" SO CIRCULATION LA English DT Letter ID VENTRICULAR DIASTOLIC DYSFUNCTION C1 [Rienstra, Michiel; Lubitz, Steven A.; Mahida, Saagar; Sinner, Moritz F.; Ellinor, Patrick T.] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. [Van Gelder, Isabelle C.] Univ Groningen, Dept Cardiol, Univ Med Ctr Groningen, Groningen, Netherlands. [Magnani, Jared W.; Fontes, Joao D.; Benjamin, Emelia J.] NHLBI, Framingham, MA USA. [Magnani, Jared W.; Fontes, Joao D.; Benjamin, Emelia J.] Boston Univ, Framingham Heart Study, Framingham, MA USA. RP Rienstra, M (reprint author), Massachusetts Gen Hosp, Cardiovasc Res Ctr, Charlestown, MA 02129 USA. OI Benjamin, Emelia/0000-0003-4076-2336; Rienstra, Michiel/0000-0002-2581-070X NR 5 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 DEC 11 PY 2012 VL 126 IS 24 BP E350 EP E350 DI 10.1161/CIRCULATIONAHA.112.145185 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 053MK UT WOS:000312275600004 ER PT J AU Sengupta, P Van Engelenburg, S Lippincott-Schwartz, J AF Sengupta, Prabuddha Van Engelenburg, Schuyler Lippincott-Schwartz, Jennifer TI Visualizing Cell Structure and Function with Point-Localization Superresolution Imaging SO DEVELOPMENTAL CELL LA English DT Review ID OPTICAL RECONSTRUCTION MICROSCOPY; SINGLE-MOLECULE LOCALIZATION; GENETICALLY EXPRESSED PROBES; GREEN FLUORESCENT PROTEIN; HIGH-DENSITY LOCALIZATION; PAIR-CORRELATION-ANALYSIS; HAND-OVER-HAND; LIVING CELLS; NANOSCALE ORGANIZATION; DIFFRACTION-LIMIT AB Fundamental to the success of cell and developmental biology is the ability to tease apart molecular organization in cells and tissues by localizing specific proteins with respect to one another in a native cellular context. However, many key cellular structures (from mitochondrial cristae to nuclear pores) lie below the diffraction limit of visible light, precluding analysis of their organization by conventional approaches. Point-localization superresolution microscopy techniques, such as PALM and STORM, are poised to resolve, with unprecedented clarity, the organizational principles of macromolecular complexes within cells, thus leading to deeper insights into cellular function in both health and disease. C1 [Sengupta, Prabuddha; Van Engelenburg, Schuyler; Lippincott-Schwartz, Jennifer] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM lippincj@mail.nih.gov OI Sengupta, Prabuddha/0000-0001-7094-6967 FU Intramural NIH HHS [Z01 HD008850-01, Z99 HD999999] NR 86 TC 52 Z9 52 U1 6 U2 68 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD DEC 11 PY 2012 VL 23 IS 6 BP 1092 EP 1102 DI 10.1016/j.devcel.2012.09.022 PG 11 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 055PP UT WOS:000312429200003 PM 23237943 ER PT J AU He, Y Beatty, A Han, XM Ji, YW Ma, XF Adelstein, RS Yates, JR Kemphues, K Qi, L AF He, Yin Beatty, Alexander Han, Xuemei Ji, Yewei Ma, Xuefei Adelstein, Robert S. Yates, John R., III Kemphues, Kenneth Qi, Ling TI Nonmuscle Myosin IIB Links Cytoskeleton to IRE1 alpha Signaling during ER Stress SO DEVELOPMENTAL CELL LA English DT Article ID UNFOLDED-PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; CAENORHABDITIS-ELEGANS; SENSOR IRE1-ALPHA; MAMMALIAN-CELLS; MESSENGER-RNAS; IRE1; ACTIVATION; PATHWAY; KINASE AB Here we identify and characterize a cytoskeletal myosin protein required for IRE1 alpha oligomerization, activation, and signaling. Proteomic screening identified nonmuscle myosin heavy chain IIB (NMHCIIB), a subunit of nonmuscle myosin IIB (NMIIB), as an ER stress-dependent interacting protein specific to IRE1 alpha. Loss of NMIIB compromises XBP1s and UPR target gene expression with no effect on the PERK pathway. Mechanistically, NMIIB is required for IRE1 alpha aggregation and foci formation under ER stress. The NMIIB-mediated effect on IRE1 alpha signaling is in part dependent on the phosphorylation of myosin regulatory light chain and the actomyosin contractility of NMIIB. Biologically, the function of NMIIB in ER stress response is conserved as both mammalian cells and C. elegans lacking NMIIB exhibit hypersensitivity to ER stress. Thus, optimal IRE1 alpha activation and signaling require concerted coordination between the ER and cytoskeleton. C1 [He, Yin; Kemphues, Kenneth; Qi, Ling] Cornell Univ, Grad Program Genet Genom & Dev, Ithaca, NY 14853 USA. [Beatty, Alexander; Kemphues, Kenneth; Qi, Ling] Cornell Univ, Grad Program Biochem Mol & Cell Biol, Ithaca, NY 14853 USA. [He, Yin; Beatty, Alexander; Kemphues, Kenneth] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. [He, Yin; Ji, Yewei; Qi, Ling] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Han, Xuemei; Yates, John R., III] Scripps Res Inst, Dept Physiol Chem, La Jolla, CA 92037 USA. [Ma, Xuefei; Adelstein, Robert S.] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Qi, L (reprint author), Cornell Univ, Grad Program Genet Genom & Dev, Ithaca, NY 14853 USA. EM lq35@cornell.edu RI Ji, Yewei/F-5040-2014 OI Ji, Yewei/0000-0002-4249-6812 FU American Diabetes Association (ADA) [1-12-CD-04]; NIH [HL004228, R01GM079112, P41 GM 103533, R21AA020351, R01DK082582] FX We thank Drs. C. Hetz, D. Ron, P. Walter, M. Montminy, L. Glimcher, L. Kraus, F. Hu, A. Bretscher, and V. Vogt for reagents and equipment; A. Bretscher for suggestions; M. Montminy, J.T. Lis, and M.A. Conti for reading of the manuscript; D. Garbett and R. Dick for assistance with sucrose gradient; D. Morton for assistance with C. elegans experiments; S. Sun for the drawing of the graphical abstract; and members of the Qi laboratory for technical assistance and discussions. L.Q. is the recipient of the Junior Faculty and Career Development Awards from American Diabetes Association (ADA). This study is supported by the NIH (HL004228 to X.M. and R.S.A.; R01GM079112 to K.K.; P41 GM 103533 to J.R.Y.; and R21AA020351 and R01DK082582 to L.Q.) and the ADA (1-12-CD-04 to L.Q.). NR 44 TC 16 Z9 16 U1 0 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD DEC 11 PY 2012 VL 23 IS 6 BP 1141 EP 1152 DI 10.1016/j.devcel.2012.11.006 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 055PP UT WOS:000312429200011 PM 23237951 ER PT J AU Huebner, AJ Dai, D Morasso, M Schmidt, EE Schafer, M Werner, S Roop, DR AF Huebner, Aaron J. Dai, Daisy Morasso, Maria Schmidt, Edward E. Schaefer, Matthias Werner, Sabine Roop, Dennis R. TI Amniotic Fluid Activates the Nr12/Keap1 Pathway to Repair an Epidermal Barrier Defect In Utero SO DEVELOPMENTAL CELL LA English DT Article ID PROLINE-RICH PROTEINS; CORNIFIED ENVELOPE; NRF2 ACTIVATION; LORICRIN; GENE; MICE; KERATINOCYTES; EXPRESSION; DIFFERENTIATION; PRECURSOR AB The loss of loricrin, a major component of the cornified envelope, results in a delay of epidermal barrier formation. Therefore, the living layers of the epidermis are aberrantly exposed to late-stage amniotic fluid, which may serve as the signal to upregulate genes that functionally compensate for the loss of loricrin. Consistent with this hypothesis, metabolomic studies revealed marked changes in amniotic fluid between E14.5 and E16.5 days postcoitum. In addition, we discovered that the Nrf2/Keap1 pathway detects these compositional changes and directly upregulates the expression of genes involved in the compensatory response, thus ensuring postnatal survival. In support of this finding, we demonstrate that genetically blocking the Nrf2 pathway abolishes the compensatory response and that preemptively activating Nrf2 pharmacologically rescues the delay in barrier formation in utero. Our findings reveal that the functions of Nrf2 and the composition of amniotic fluid have coevolved to ensure the formation of a functional barrier. C1 [Huebner, Aaron J.; Dai, Daisy; Roop, Dennis R.] Univ Colorado, Dept Dermatol, Denver, CO 80045 USA. [Huebner, Aaron J.; Dai, Daisy; Roop, Dennis R.] Univ Colorado, Charles C Gates Ctr Regenerat Med & Stem Cell Bio, Denver, CO 80045 USA. [Huebner, Aaron J.] Univ Colorado, Cell Biol Stem Cells & Dev Grad Program, Denver, CO 80045 USA. [Morasso, Maria] NIAMS, Dev Skin Biol Sect, NIH, Bethesda, MD 20892 USA. [Schmidt, Edward E.] Montana State Univ, Dept Immunol & Infect Dis, Bozeman, MT 59717 USA. [Schaefer, Matthias; Werner, Sabine] Swiss Fed Inst Technol, Inst Mol Hlth Sci, Dept Biol, CH-8093 Zurich, Switzerland. RP Roop, DR (reprint author), Univ Colorado, Dept Dermatol, Denver, CO 80045 USA. EM dennis.roop@ucdenver.edu RI Schafer, Matthias/K-1911-2012 OI Schafer, Matthias/0000-0001-6754-0448 FU Skin Diseases Research Core Center [AR057212]; National Institutes of Health (NIH) [AR060388]; Swiss National Science Foundation [310030_132884/1] FX We would like to thank Dr. Daniel Hohl (University of Lausanne, Switzerland) for the Sprr2 antibody and Dr. Jeffrey Johnson (University of Wisconsin) for the ARE reporter mouse line. We would also like to acknowledge the assistance of the mouse transgenic core facility and the morphology and phenotyping core facility, which are both supported by a Skin Diseases Research Core Center grant awarded to the University of Colorado, Denver (AR057212). Lastly, we would like to acknowledge the Mass Spectrometry, Proteomics, and Metabolomics core facility at Montana State University for their help with the metabolomics studies. This work was supported by a National Institutes of Health (NIH) grant (AR060388) awarded to D.R.R. and a grant from the Swiss National Science Foundation (310030_132884/1) awarded to S.W. NR 35 TC 20 Z9 20 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD DEC 11 PY 2012 VL 23 IS 6 BP 1238 EP 1246 DI 10.1016/j.devcel.2012.11.002 PG 9 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 055PP UT WOS:000312429200019 PM 23237955 ER PT J AU Bae, C Kalia, J Song, I Yu, J Kim, HH Swartz, KJ Kim, JI AF Bae, Chanhyung Kalia, Jeet Song, Inhye Yu, JeongHeon Kim, Ha Hyung Swartz, Kenton J. Kim, Jae Il TI High Yield Production and Refolding of the Double-Knot Toxin, an Activator of TRPV1 Channels SO PLOS ONE LA English DT Article ID FUNNEL-WEB SPIDER; 3-DIMENSIONAL SOLUTION STRUCTURE; OMEGA-CONOTOXIN TXVII; CALCIUM-CHANNEL; DISULFIDE BRIDGES; POTASSIUM CHANNEL; ESCHERICHIA-COLI; AGATOXIN-IVA; VENOM; INHIBITOR AB A unique peptide toxin, named double-knot toxin (DkTx), was recently purified from the venom of the tarantula Ornithoctonus huwena and was found to stably activate TRPV1 channels by targeting the outer pore domain. DkTx has been shown to consist of two inhibitory cysteine-knot (ICK) motifs, referred to as K1 and K2, each containing six cysteine residues. Beyond this initial characterization, however, the structural and functional details about DkTx remains elusive in large part due to the lack of a high yielding methodology for the synthesis and folding of this cysteine-rich peptide. Here, we overcome this obstacle by generating pure DkTx in quantities sufficient for structural and functional analyses. Our methodology entails expression of DkTx in E. coli followed by oxidative folding of the isolated linear peptide. Upon screening of various oxidative conditions for optimizing the folding yield of the toxin, we observed that detergents were required for efficient folding of the linear peptide. Our synthetic DkTx co-eluted with the native toxin on HPLC, and irreversibly activated TRPV1 in a manner identical to native DkTx. Interestingly, we find that DkTx has two interconvertible conformations present in a 1: 6 ratio at equilibrium. Kinetic analysis of DkTx folding suggests that the K1 and K2 domains influence each other during the folding process. Moreover, the CD spectra of the toxins shows that the secondary structures of K1 and K2 remains intact even after separating the two knots. These findings provide a starting point for detailed studies on the structural and functional characterization of DkTx and utilization of this toxin as a tool to explore the elusive mechanisms underlying the polymodal gating of TRPV1. Citation: Bae C, Kalia J, Song I, Yu J, Kim HH, et al. (2012) High Yield Production and Refolding of the Double-Knot Toxin, an Activator of TRPV1 Channels. PLoS ONE 7(12): e51516. doi:10.1371/journal.pone.0051516 C1 [Bae, Chanhyung; Song, Inhye; Yu, JeongHeon; Kim, Jae Il] Gwangju Inst Sci & Technol GIST, Sch Life Sci, Kwangju, South Korea. [Kalia, Jeet; Swartz, Kenton J.] NINDS, Mol Physiol & Biophys Sect, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Kim, Ha Hyung] Chung Ang Univ, Coll Pharm, Seoul 156756, South Korea. RP Kim, JI (reprint author), Gwangju Inst Sci & Technol GIST, Sch Life Sci, Kwangju, South Korea. EM jikim@gist.ac.kr FU Next-Generation BioGreen 21 Program [PJ008158]; Rural Development Administration, Republic of Korea; National Research Foundation of Korea grant; Korean Government (MEST) [NRF-C1ABA001-2011-0018559]; Brain Research Center of the 21st Century Frontier Research Program [M103KV010005-06K2201-00610]; BioImaging Research Center at the Gwangju Institute of Science and Technology; Basic Research Projects in High-tech Industrial Technology; Gwangju Institute of Science and Technology; Intramural Research Program of the NINDS, NIH; NINDS competitive fellowship FX This research was supported by grants from the Next-Generation BioGreen 21 Program (PJ008158); the Rural Development Administration, Republic of Korea; a National Research Foundation of Korea grant funded by the Korean Government (MEST) (NRF-C1ABA001-2011-0018559); the Brain Research Center of the 21st Century Frontier Research Program (M103KV010005-06K2201-00610); the BioImaging Research Center at the Gwangju Institute of Science and Technology and Basic Research Projects in High-tech Industrial Technology funded by the Gwangju Institute of Science and Technology in 2011; the Intramural Research Program of the NINDS, NIH, and by an NINDS competitive fellowship to Jeet Kalia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 8 Z9 8 U1 2 U2 14 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 DEC 11 PY 2012 VL 7 IS 12 AR e51516 DI 10.1371/journal.pone.0051516 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 053RN UT WOS:000312290800072 PM 23240036 ER PT J AU Babu, SS Wojtowicz, A Freichel, M Birnbaumer, L Hecker, M Cattaruzza, M AF Babu, Sahana Suresh Wojtowicz, Agnieszka Freichel, Marc Birnbaumer, Lutz Hecker, Markus Cattaruzza, Marco TI Mechanism of Stretch-Induced Activation of the Mechanotransducer Zyxin in Vascular Cells SO SCIENCE SIGNALING LA English DT Article ID SMOOTH-MUSCLE-CELLS; ATRIAL-NATRIURETIC-PEPTIDE; CYCLASE-A RECEPTOR; HUMAN ENDOTHELIAL-CELLS; CARDIOVASCULAR PATHOPHYSIOLOGY; TRANSCRIPTION FACTORS; VOLUME EXPANSION; GENE-EXPRESSION; TRP CHANNELS; SHEAR-STRESS AB Vascular cells respond to supraphysiological amounts of stretch with a characteristic phenotypic change that results in dysfunctional remodeling of the affected arteries. Although the pathophysiological consequences of stretch-induced signaling are well characterized, the mechanism of mechanotransduction is unclear. We focused on the mechanotransducer zyxin, which translocates to the nucleus to drive gene expression in response to stretch. In cultured human endothelial cells and perfused femoral arteries isolated from wild-type and several knockout mouse strains, we characterized a multistep signaling pathway whereby stretch led to a transient receptor potential channel 3-mediated release of the endothelial vasoconstrictor peptide endothelin-1 (ET-1). ET-1, through autocrine activation of its B-type receptor, elicited the release of pro-atrial natriuretic peptide (ANP), which caused the autocrine activation of the ANP receptor guanylyl cyclase A (GC-A). Activation of GC-A, in turn, led to protein kinase G-mediated phosphorylation of zyxin at serine 142, thereby triggering the translocation of zyxin to the nucleus, where it was required for stretch-induced gene expression. Thus, we have identified a stretch-induced signaling pathway in vascular cells that leads to the activation of zyxin, a cytoskeletal protein specifically involved in transducing mechanical stimuli. C1 [Babu, Sahana Suresh; Wojtowicz, Agnieszka; Hecker, Markus; Cattaruzza, Marco] Univ Heidelberg, Inst Physiol & Pathophysiol, Div Cardiovasc Physiol, D-69120 Heidelberg, Germany. [Freichel, Marc] Univ Heidelberg, Inst Pharmacol, D-69120 Heidelberg, Germany. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Hecker, M (reprint author), Univ Heidelberg, Inst Physiol & Pathophysiol, Div Cardiovasc Physiol, D-69120 Heidelberg, Germany. EM hecker@physiologie.uni-hd.de FU German Research Foundation [CA 262/1-3]; European Commission (Marie Curie Initial Training Network SmArt); Intramural Research Program of the NIH [Z01-ES101684] FX This work was supported in part by the German Research Foundation (grant CA 262/1-3 to M.C.), the European Commission (Marie Curie Initial Training Network SmArt to M.H.), and the Intramural Research Program of the NIH (Z01-ES101684 to L.B.). NR 45 TC 14 Z9 14 U1 0 U2 14 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 DEC 11 PY 2012 VL 5 IS 254 AR ra91 DI 10.1126/scisignal.2003173 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 054YT UT WOS:000312382300003 ER PT J AU Tsao, CW Preis, SR Peloso, GM Hwang, SJ Kathiresan, S Fox, CS Cupples, LA Hoffmann, U O'Donnell, CJ AF Tsao, Connie W. Preis, Sarah Rosner Peloso, Gina M. Hwang, Shih-Jen Kathiresan, Sekar Fox, Caroline S. Cupples, L. Adrienne Hoffmann, Udo O'Donnell, Christopher J. TI Relations of Long-Term and Contemporary Lipid Levels and Lipid Genetic Risk Scores With Coronary Artery Calcium in the Framingham Heart Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE coronary artery calcium; genetic risk score; lipids ID GENOME-WIDE ASSOCIATION; LOW-DENSITY-LIPOPROTEIN; CARDIOVASCULAR RISK; COMPUTED-TOMOGRAPHY; YOUNG-ADULTS; DISEASE; CALCIFICATION; ATHEROSCLEROSIS; PREDICTION; LOCI AB Objectives This study evaluated the association of timing of lipid levels and lipid genetic risk score (GRS) with subclinical atherosclerosis. Background Atherosclerosis is a slowly progressive disorder influenced by suboptimal lipid levels. Long-term versus contemporary lipid levels may more strongly impact the development of coronary artery calcium (CAC). Methods Framingham Heart Study (FHS) Offspring Cohort participants (n = 1,156, 44% male, 63 +/- 9 years) underwent serial fasting lipids (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein, and triglycerides), Exam 1 (1971 to 1975) to Exam 7 (1998 to 2001). FHS Third Generation Cohort participants (n = 1,954, 55% male, 45 +/- 6 years) had fasting lipid profiles assessed, 2002 to 2005. Computed tomography (2002 to 2005) measured CAC. Lipid GRSs were computed from significantly associated single-nucleotide polymorphisms. The association between early, long-term average, and contemporary lipids, and lipid GRS with elevated CAC was assessed using logistic regression. Results In FHS Offspring, Exam 1 and long-term average as compared with Exam 7 lipid measurements, including untreated lipid levels, were strongly associated with elevated CAC. In the FHS Third Generation, contemporary lipids were associated with CAC. The LDL-C GRS was associated with CAC (age-/sex-adjusted odds ratio: 1.14, 95% confidence interval: 1.00 to 1.29, p = 0.04). However, addition of the GRS to the lipid models did not result in a significant increase in the odds ratio or C-statistic for any lipid measure. Conclusions Early and long-term average lipid levels, as compared with contemporary measures, are more strongly associated with elevated CAC. Lipid GRS was associated with lipid levels but did not predict elevated CAC. Adult early and long-term average lipid levels provide important information when assessing subclinical atherosclerosis and cardiovascular risk. (J Am Coll Cardiol 2012;60:2364-71) (C) 2012 by the American College of Cardiology Foundation C1 [Tsao, Connie W.; Preis, Sarah Rosner; Peloso, Gina M.; Hwang, Shih-Jen; Fox, Caroline S.; Cupples, L. Adrienne; O'Donnell, Christopher J.] Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. [Tsao, Connie W.] Harvard Univ, Beth Israel Deaconess Med Ctr, Div Cardiovasc, Dept Med,Sch Med, Boston, MA 02215 USA. [Preis, Sarah Rosner; Peloso, Gina M.; Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Kathiresan, Sekar; O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA USA. [Fox, Caroline S.] Harvard Univ, Brigham & Womens Hosp, Div Endocrinol & Metab, Sch Med, Boston, MA 02115 USA. [Hoffmann, Udo] Harvard Univ, Sch Med, Dept Radiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Tsao, CW (reprint author), Natl Heart Lung & Blood Inst Framingham Heart Stu, Framingham, MA USA. OI Preis, Sarah/0000-0002-9360-4166; Cupples, L. Adrienne/0000-0003-0273-7965 FU National Heart, Lung, and Blood Institute [N01-HC-25195]; Affymetrix, Inc [N02-HL-6-4278]; ACCF; Merck; Pfizer FX The Framingham Heart Study (FHS) is supported by the National Heart, Lung, and Blood Institute (contract N01-HC-25195). This work was partially supported by the National Heart, Lung, and Blood Institute's contract with Affymetrix, Inc, for genotyping services (contract N02-HL-6-4278). Analyses are partially based on resources from Framingham Heart Study investigators in the SNP Health Association Resource project. Dr. Tsao is partially supported by an award from the ACCF. Dr. Kathiresan is a member of the Scientific Advisory Board for Merck; and has received research grants from Merck and Pfizer. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Tsao and Preis contributed equally to this work. NR 32 TC 8 Z9 8 U1 0 U2 6 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 DEC 11 PY 2012 VL 60 IS 23 BP 2364 EP 2371 DI 10.1016/j.jacc.2012.09.007 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 048ZS UT WOS:000311952400004 PM 23141485 ER PT J AU Wei, A Mehtala, JG Patri, AK AF Wei, Alexander Mehtala, Jonathan G. Patri, Anil K. TI Challenges and opportunities in the advancement of nanomedicines SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE Nanomedicine; Drug delivery; Size analysis; Ligand density; Active targeting; Passive uptake ID COATED GOLD NANOPARTICLES; DYNAMIC LIGHT-SCATTERING; FIELD-FLOW FRACTIONATION; CELL LUNG-CANCER; IN-VIVO; MASS-SPECTROMETRY; ANALYTICAL ULTRACENTRIFUGATION; TARGETED NANOPARTICLES; 2-PHOTON LUMINESCENCE; PHOTOTHERMAL THERAPY AB Nanomedicine-based approaches to cancer treatment face several challenges that differ from those encountered by conventional medicines during clinical development. A systematic exploration of these issues has led us to identify the following needs and opportunities for further development: (1) robust and general methods for the accurate characterization of nanoparticle size, shape, and composition; (2) scalable approaches for producing nanomedicines with optimized bioavailability and excretion profiles; (3) particle engineering for maintaining low levels of nonspecific cytotoxicity and sufficient stability during storage; (4) optimization of surface chemistries for maximum targeted delivery and minimum nonspecific adsorption; (5) practical methods for quantifying ligand density and distributions on multivalent nanocarriers; and (6) the design of multifunctional nanomedicines for novel combination therapies with supportable levels of bioaccumulation. (C) 2012 Elsevier B.V. All rights reserved. C1 [Wei, Alexander; Mehtala, Jonathan G.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Patri, Anil K.] SAIC Frederick Inc, Nanotechnol Characterizat Lab, Adv Technol Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Wei, A (reprint author), Purdue Univ, Dept Chem, 560 Oval Dr, W Lafayette, IN 47907 USA. EM alexwei@purdue.edu; patria@mail.nih.gov RI Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Cancer Institute [RC1 CA-147096]; Lilly Endowment (College of Pharmacy); Purdue University Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX The authors gratefully acknowledge support from the National Cancer Institute (RC1 CA-147096), the Lilly Endowment (College of Pharmacy), and the Purdue University Center for Cancer Research. We thank Henry Havel and David Thompson for helpful discussions and suggestions. 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. 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. NR 169 TC 35 Z9 37 U1 2 U2 82 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 EI 1873-4995 J9 J CONTROL RELEASE JI J. Control. Release PD DEC 10 PY 2012 VL 164 IS 2 BP 236 EP 246 DI 10.1016/j.jconrel.2012.10.007 PG 11 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 062UG UT WOS:000312947500016 PM 23064314 ER PT J AU Carter, HB Partin, AW Walsh, PC Trock, BJ Veltri, RW Nelson, WG Coffey, DS Singer, EA Epstein, JI AF Carter, H. Ballentine Partin, Alan W. Walsh, Patrick C. Trock, Bruce J. Veltri, Robert W. Nelson, William G. Coffey, Donald S. Singer, Eric A. Epstein, Jonathan I. TI Gleason Score 6 Adenocarcinoma: Should It Be Labeled As Cancer? SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID LOCALIZED PROSTATE-CANCER; 2005 INTERNATIONAL-SOCIETY; RADICAL PROSTATECTOMY; ACTIVE SURVEILLANCE; GRADING SYSTEM; NEEDLE-BIOPSY; MEN; PATHOLOGY; TRENDS; DIAGNOSIS C1 [Carter, H. Ballentine; Partin, Alan W.; Walsh, Patrick C.; Trock, Bruce J.; Veltri, Robert W.; Nelson, William G.; Coffey, Donald S.; Epstein, Jonathan I.] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Carter, H. Ballentine; Partin, Alan W.; Walsh, Patrick C.; Trock, Bruce J.; Veltri, Robert W.; Nelson, William G.; Coffey, Donald S.; Epstein, Jonathan I.] Johns Hopkins Univ Hosp, Baltimore, MD 21287 USA. [Singer, Eric A.] NCI, NIH, Bethesda, MD 20892 USA. RP Carter, HB (reprint author), Johns Hopkins Univ, Baltimore, MD 21218 USA. NR 30 TC 86 Z9 87 U1 0 U2 9 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 DEC 10 PY 2012 VL 30 IS 35 BP 4294 EP 4296 DI 10.1200/JCO.2012.44.0586 PG 3 WC Oncology SC Oncology GA 052KG UT WOS:000312195900008 PM 23032616 ER PT J AU Weischer, M Nordestgaard, BG Pharoah, P Bolla, MK Nevanlinna, H van't Veer, LJ Garcia-Closas, M Hopper, JL Hall, P Andrulis, IL Devilee, P Fasching, PA Anton-Culver, H Lambrechts, D Hooning, M Cox, A Giles, GG Burwinkel, B Lindblom, A Couch, FJ Mannermaa, A Alnaes, GG John, EM Dork, T Flyger, H Dunning, AM Wang, Q Muranen, TA van Hien, R Figueroa, J Southey, MC Czene, K Knight, JA Tollenaar, RAEM Beckmann, MW Ziogas, A Christiaens, MR Collee, JM Reed, MWR Severi, G Marme, F Margolin, S Olson, JE Kosma, VM Kristensen, VN Miron, A Bogdanova, N Shah, M Blomqvist, C Broeks, A Sherman, M Phillips, KA Li, JM Liu, JJ Glendon, G Seynaeve, C Ekici, AB Leunen, K Kriege, M Cross, SS Baglietto, L Sohn, C Wang, XS Kataja, V Borresen-Dale, AL Meyer, A Easton, DF Schmidt, MK Bojesen, SE AF Weischer, Maren Nordestgaard, Borge G. Pharoah, Paul Bolla, Manjeet K. Nevanlinna, Heli van't Veer, Laura J. Garcia-Closas, Montserrat Hopper, John L. Hall, Per Andrulis, Irene L. Devilee, Peter Fasching, Peter A. Anton-Culver, Hoda Lambrechts, Diether Hooning, Maartje Cox, Angela Giles, Graham G. Burwinkel, Barbara Lindblom, Annika Couch, Fergus J. Mannermaa, Arto Alnaes, Grethe Grenaker John, Esther M. Doerk, Thilo Flyger, Henrik Dunning, Alison M. Wang, Qin Muranen, Taru A. van Hien, Richard Figueroa, Jonine Southey, Melissa C. Czene, Kamila Knight, Julia A. Tollenaar, Rob A. E. M. Beckmann, Matthias W. Ziogas, Argyrios Christiaens, Marie-Rose Collee, Johanna Margriet Reed, Malcolm W. R. Severi, Gianluca Marme, Frederik Margolin, Sara Olson, Janet E. Kosma, Veli-Matti Kristensen, Vessela N. Miron, Alexander Bogdanova, Natalia Shah, Mitul Blomqvist, Carl Broeks, Annegien Sherman, Mark Phillips, Kelly-Anne Li, Jingmei Liu, Jianjun Glendon, Gord Seynaeve, Caroline Ekici, Arif B. Leunen, Karin Kriege, Mieke Cross, Simon S. Baglietto, Laura Sohn, Christof Wang, Xianshu Kataja, Vesa Borresen-Dale, Anne-Lise Meyer, Andreas Easton, Douglas F. Schmidt, Marjanka K. Bojesen, Stig E. TI CHEK2*1100delC Heterozygosity in Women With Breast Cancer Associated With Early Death, Breast Cancer-Specific Death, and Increased Risk of a Second Breast Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID TUMOR CHARACTERISTICS; MENDELIAN RANDOMIZATION; GERMLINE MUTATION; CHEK2; SUSCEPTIBILITY; PROGNOSIS; SURVIVAL; VARIANT; GENE AB Purpose We tested the hypotheses that CHEK2*1100delC heterozygosity is associated with increased risk of early death, breast cancer-specific death, and risk of a second breast cancer in women with a first breast cancer. Patients and Methods From 22 studies participating in the Breast Cancer Association Consortium, 25,571 white women with invasive breast cancer were genotyped for CHEK2*1100delC and observed for up to 20 years (median, 6.6 years). We examined risk of early death and breast cancer-specific death by estrogen receptor status and risk of a second breast cancer after a first breast cancer in prospective studies. Results CHEK2*1100delC heterozygosity was found in 459 patients (1.8%). In women with estrogen receptor-positive breast cancer, multifactorially adjusted hazard ratios for heterozygotes versus noncarriers were 1.43 (95% CI, 1.12 to 1.82; log-rank P = .004) for early death and 1.63 (95% CI, 1.24 to 2.15; log-rank P < .001) for breast cancer-specific death. In all women, hazard ratio for a second breast cancer was 2.77 (95% CI, 2.00 to 3.83; log-rank P < .001) increasing to 3.52 (95% CI, 2.35 to 5.27; log-rank P < .001) in women with estrogen receptor-positive first breast cancer only. Conclusion Among women with estrogen receptor-positive breast cancer, CHEK2*1100delC heterozygosity was associated with a 1.4-fold risk of early death, a 1.6-fold risk of breast cancer-specific death, and a 3.5-fold risk of a second breast cancer. This is one of the few examples of a genetic factor that influences long-term prognosis being documented in an extensive series of women with breast cancer. J Clin Oncol 30: 4308-4316. (C) 2012 by American Society of Clinical Oncology C1 [Weischer, Maren; Nordestgaard, Borge G.; Flyger, Henrik; Bojesen, Stig E.] Univ Copenhagen, Copenhagen, Denmark. [Pharoah, Paul; Bolla, Manjeet K.; Dunning, Alison M.; Wang, Qin; Shah, Mitul; Easton, Douglas F.] Univ Cambridge, Cambridge, England. [Garcia-Closas, Montserrat] Inst Canc Res, London SW3 6JB, England. [Cox, Angela; Reed, Malcolm W. R.; Cross, Simon S.] Univ Sheffield, Sheffield, S Yorkshire, England. [Nevanlinna, Heli; Muranen, Taru A.; Blomqvist, Carl] Univ Helsinki, Helsinki, Finland. [Nevanlinna, Heli; Muranen, Taru A.; Blomqvist, Carl] Univ Helsinki, Cent Hosp, Helsinki, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa] Univ Eastern Finland, Kuopio, Finland. [Mannermaa, Arto; Kosma, Veli-Matti; Kataja, Vesa] Kuopio Univ Hosp, SF-70210 Kuopio, Finland. [van't Veer, Laura J.; van Hien, Richard; Broeks, Annegien; Schmidt, Marjanka K.] Netherlands Canc Inst, Amsterdam, Netherlands. [Devilee, Peter; Tollenaar, Rob A. E. M.] Leiden Univ, Med Ctr, Leiden, Netherlands. [Hooning, Maartje; Collee, Johanna Margriet; Kriege, Mieke] Erasmus Univ, Med Ctr, Rotterdam, Netherlands. [Seynaeve, Caroline] Erasmus MC, Daniel den Hoed Canc Ctr, Rotterdam, Netherlands. [Hopper, John L.; Giles, Graham G.; Southey, Melissa C.; Severi, Gianluca; Baglietto, Laura] Univ Melbourne, Melbourne, Vic, Australia. [Giles, Graham G.; Severi, Gianluca; Baglietto, Laura] Canc Council Victoria, Melbourne, Vic, Australia. [Phillips, Kelly-Anne] Peter MacCallum Canc Ctr, Melbourne, Vic, Australia. [Phillips, Kelly-Anne] Univ Melbourne, Melbourne, Vic, Australia. [Hall, Per; Lindblom, Annika; Czene, Kamila; Margolin, Sara] Karolinska Inst, Stockholm, Sweden. [Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord] Mt Sinai Hosp, Toronto, ON M5G 1X5, Canada. [Fasching, Peter A.; Beckmann, Matthias W.; Ekici, Arif B.] Univ Erlangen Nurnberg, D-91054 Erlangen, Germany. [Fasching, Peter A.; Beckmann, Matthias W.] Comprehens Canc Ctr Erlangen Nuremberg, Erlangen, Germany. [Burwinkel, Barbara; Marme, Frederik; Sohn, Christof] Univ Heidelberg, Heidelberg, Germany. [Burwinkel, Barbara] German Canc Res Ctr, D-6900 Heidelberg, Germany. [Doerk, Thilo; Bogdanova, Natalia; Meyer, Andreas] Hannover Med Sch, D-3000 Hannover, Germany. [Fasching, Peter A.] Univ Calif Los Angeles, Los Angeles, CA USA. [Anton-Culver, Hoda; Ziogas, Argyrios] Univ Calif Irvine, Irvine, CA USA. [John, Esther M.; Kristensen, Vessela N.] Canc Prevent Inst Calif, Fremont, CA USA. [Lambrechts, Diether] VIB, Vesalius Res Ctr, Louvain, Belgium. [Christiaens, Marie-Rose; Leunen, Karin] Katholieke Univ Leuven, Univ Hosp Leuven, Louvain, Belgium. [Couch, Fergus J.; Olson, Janet E.; Wang, Xianshu] Mayo Clin, Rochester, MN USA. [Alnaes, Grethe Grenaker; Borresen-Dale, Anne-Lise] Univ Oslo, Norwegian Radium Hosp, Oslo Univ Hosp, Oslo, Norway. [Figueroa, Jonine; Sherman, Mark] NCI, Bethesda, MD 20892 USA. [Miron, Alexander] Dana Farber Canc Inst, Boston, MA 02115 USA. [Li, Jingmei; Liu, Jianjun] Genome Inst Singapore, Singapore, Singapore. RP Bojesen, SE (reprint author), Copenhagen Univ Hosp, Herlev Hosp, Dept Clin Biochem, Herlev Ringvej 75, DK-2730 Herlev, Denmark. EM stig.egil.bojesen@regionh.dk RI Verdrengh, Evelien/H-4571-2012; Li, Jingmei/I-2904-2012; Ekici, Arif/C-3971-2013; Andrulis, Irene/E-7267-2013; Knight, Julia/A-6843-2012; Dork, Thilo/J-8620-2012; Garcia-Closas, Montserrat /F-3871-2015; OI Cox, Angela/0000-0002-5138-1099; Dunning, Alison Margaret/0000-0001-6651-7166; Giles, Graham/0000-0003-4946-9099; Muranen, Taru/0000-0002-5895-1808; Phillips, Kelly-Anne/0000-0002-0475-1771; Nevanlinna, Heli/0000-0002-0916-2976; Li, Jingmei/0000-0001-8587-7511; Garcia-Closas, Montserrat /0000-0003-1033-2650; Czene, Kamila/0000-0002-3233-5695; Cross, Simon/0000-0003-2044-1754 FU Cancer Research UK [10118, 10119, 10124]; NCI NIH HHS [P50 CA116201, R01 CA122340] NR 20 TC 39 Z9 39 U1 0 U2 10 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 DEC 10 PY 2012 VL 30 IS 35 BP 4308 EP 4316 DI 10.1200/JCO.2012.42.7336 PG 9 WC Oncology SC Oncology GA 052KG UT WOS:000312195900011 PM 23109706 ER PT J AU Burstein, HJ Piccart-Gebhart, MJ Perez, EA Hortobagyi, GN Wolmark, N Albain, KS Norton, L Winer, EP Hudis, CA AF Burstein, Harold J. Piccart-Gebhart, Martine J. Perez, Edith A. Hortobagyi, Gabriel N. Wolmark, Norman Albain, Kathy S. Norton, Larry Winer, Eric P. Hudis, Clifford A. TI Ongoing Debate: Anthracyclines and Adjuvant Treatment of Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Burstein, Harold J.; Winer, Eric P.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Piccart-Gebhart, Martine J.] Inst Jules Bordet, B-1000 Brussels, Belgium. [Perez, Edith A.] Mayo Clin, Jacksonville, FL 32224 USA. [Hortobagyi, Gabriel N.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Wolmark, Norman] Allegheny Gen Hosp, Pittsburgh, PA 15212 USA. [Wolmark, Norman] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. [Albain, Kathy S.] Loyola Univ Chicago Stritch Sch Med, Maywood, IL USA. [Norton, Larry; Hudis, Clifford A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Burstein, HJ (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. OI Norton, Larry/0000-0003-3701-9250 NR 2 TC 0 Z9 0 U1 0 U2 1 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 DEC 10 PY 2012 VL 30 IS 35 BP 4446 EP 4446 DI 10.1200/JCO.2012.45.9677 PG 1 WC Oncology SC Oncology GA 052KG UT WOS:000312195900032 ER PT J AU Tang, LL Liu, AY Schisterman, EF Zhou, XH Liu, CCL AF Tang, Liansheng Larry Liu, Aiyi Schisterman, Enrique F. Zhou, Xiao-Hua Liu, Catherine Chun-Ling TI Homogeneity tests of clustered diagnostic markers with applications to the BioCycle Study SO STATISTICS IN MEDICINE LA English DT Article DE ROC curve; biomarker; homogeneity test; sample size ID OPERATING CHARACTERISTIC CURVES AB Diagnostic trials often require the use of a homogeneity test among several markers. Such a test may be necessary to determine the power both during the design phase and in the initial analysis stage. However, no formal method is available for the power and sample size calculation when the number of markers is greater than two and marker measurements are clustered in subjects. This article presents two procedures for testing the accuracy among clustered diagnostic markers. The first procedure is a test of homogeneity among continuous markers based on a global null hypothesis of the same accuracy. The result under the alternative provides the explicit distribution for the power and sample size calculation. The second procedure is a simultaneous pairwise comparison test based on weighted areas under the receiver operating characteristic curves. This test is particularly useful if a global difference among markers is found by the homogeneity test. We apply our procedures to the BioCycle Study designed to assess and compare the accuracy of hormone and oxidative stress markers in distinguishing women with ovulatory menstrual cycles from those without. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Tang, Liansheng Larry] George Mason Univ, Dept Stat, Fairfax, VA 22030 USA. [Liu, Aiyi; Schisterman, Enrique F.] NICHHD, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. [Zhou, Xiao-Hua] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Liu, Catherine Chun-Ling] Hong Kong Polytech Univ, Dept Appl Math, Hong Kong, Hong Kong, Peoples R China. RP Tang, LL (reprint author), George Mason Univ, Dept Stat, Fairfax, VA 22030 USA. EM ltang1@gmu.edu RI Liu, Chunling/A-4827-2015; OI Liu, Chunling/0000-0003-3410-445X; Liu, Aiyi/0000-0002-6618-5082; Schisterman, Enrique/0000-0003-3757-641X FU National Cancer Institute [R15CA150698]; National Security Agency [H98230-11-1-0196]; Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service [XVA 61-036]; American Chemistry Council; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The authors thank anonymous referees, the associate editor, and the editor for their constructive comments and useful suggestions. The work was supported in part with funding from the American Chemistry Council and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The project described here was supported by Award Number R15CA150698 from the National Cancer Institute under the American Recovery and Reinvestment Act of 2009, by Award Number H98230-11-1-0196 from the National Security Agency, and by Department of Veterans Affairs, Veterans Health Administration, Health Services Research and Development Service, project grant #XVA 61-036. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, the National Institutes of Health, or the Department of Veterans Affairs. NR 16 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD DEC 10 PY 2012 VL 31 IS 28 BP 3638 EP 3648 DI 10.1002/sim.5391 PG 11 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 041LC UT WOS:000311402300014 PM 22733707 ER PT J AU Cheon, K Albert, PS Zhang, ZW AF Cheon, Kyeongmi Albert, Paul S. Zhang, Zhiwei TI The impact of random-effect misspecification on percentile estimation for longitudinal growth data SO STATISTICS IN MEDICINE LA English DT Article DE distributional misspecification; percentile estimation; longitudinal data ID LINEAR MIXED MODELS; FETAL-GROWTH; REFERENCE INTERVALS; RISK-FACTORS; CURVES; BIRTH AB Identifying unusual growth-related measurements or longitudinal patterns in growth is often the focus in fetal and pediatric medicine. For example, the goal of the ongoing National Fetal Growth Study is to develop both cross-sectional and longitudinal reference curves for ultrasound fetal growth measurements that can be used for this purpose. Current methodology for estimating cross-sectional and longitudinal reference curves relies mainly on the linear mixed model. The focus of this paper is on examining the robustness of percentile estimation to the assumptions with respect to the Gaussian random-effect assumption implicitly made in the standard linear mixed model. We also examine a random-effects distribution based on mixtures of normals and compare the two approaches under both correct and misspecified random-effects distributions. In general, we find that the standard linear mixed model is relatively robust for cross-sectional percentile estimation but less robust for longitudinal or personalized reference curves based on the conditional distribution given prior ultrasound measurements. The methodology is illustrated with data from a longitudinal fetal growth study. Published 2012. This article is a US Government work and is in the public domain in the USA. C1 [Cheon, Kyeongmi; Albert, Paul S.; Zhang, Zhiwei] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. RP Albert, PS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd, Rockville, MD 20852 USA. EM albertp@mail.nih.gov FU National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX The authors thank the editor and the reviewers for helpful comments and the Center for Information Technology, National Institutes of Health, for providing the high-performance computational capabilities of the Biowulf cluster computer system. This study was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 23 TC 2 Z9 2 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD DEC 10 PY 2012 VL 31 IS 28 BP 3708 EP 3718 DI 10.1002/sim.5437 PG 11 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 041LC UT WOS:000311402300020 PM 22786788 ER PT J AU Valberg, M Grotmol, T Tretli, S Veierod, MB Devesa, SS Aalen, OO AF Valberg, Morten Grotmol, Tom Tretli, Steinar Veierod, Marit B. Devesa, Susan S. Aalen, Odd O. TI Frailty modeling of age-incidence curves of osteosarcoma and Ewing sarcoma among individuals younger than 40 years SO STATISTICS IN MEDICINE LA English DT Article DE frailty; osteosarcoma; Ewing sarcoma; growth spurt; susceptibility; survival analysis ID CANCER INCIDENCE; RATES; EPIDEMIOLOGY; COHORT; RISK AB The ArmitageDoll model with random frailty can fail to describe incidence rates of rare cancers influenced by an accelerated biological mechanism at some, possibly short, period of life. We propose a new model to account for this influence. Osteosarcoma and Ewing sarcoma are primary bone cancers with characteristic ageincidence patterns that peak in adolescence. We analyze Surveillance, Epidemiology and End Result program incidence data for whites younger than 40?years diagnosed during the period 1975-2005, with an ArmitageDoll model with compound Poisson frailty. A new model treating the adolescent growth spurt as the accelerated mechanism affecting cancer development is a significant improvement over that model. We also model the incidence rate conditioning on the event of having developed the cancers before the age of 40?years and compare the results with those predicted by the ArmitageDoll model. Our results support existing evidence of an underlying susceptibility for the two cancers among a very small proportion of the population. In addition, the modeling results suggest that susceptible individuals with a rapid growth spurt acquire the cancers sooner than they otherwise would have if their growth had been slower. The new model is suitable for modeling incidence rates of rare diseases influenced by an accelerated biological mechanism. Copyright (C) 2012 John Wiley & Sons, Ltd. C1 [Valberg, Morten; Veierod, Marit B.; Aalen, Odd O.] Univ Oslo, Inst Basic Med Sci, Dept Biostat, N-0317 Oslo, Norway. [Grotmol, Tom; Tretli, Steinar] Canc Registry Norway, Inst Populat Based Canc Res, Oslo, Norway. [Devesa, Susan S.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Valberg, M (reprint author), Univ Oslo, Inst Basic Med Sci, Dept Biostat, POB 1122 Blindern, N-0317 Oslo, Norway. EM morten.valberg@medisin.uio.no OI Veierod, Marit B./0000-0002-2083-2758 FU Norwegian Cancer Society [171851]; Division of Cancer Epidemiology and Genetics Intramural Research Program, National Cancer Institute, USA FX This work was supported by the Norwegian Cancer Society, project/grant number 171851, and the Division of Cancer Epidemiology and Genetics Intramural Research Program, National Cancer Institute, USA. NR 33 TC 3 Z9 3 U1 2 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 J9 STAT MED JI Stat. Med. PD DEC 10 PY 2012 VL 31 IS 28 BP 3731 EP 3747 DI 10.1002/sim.5441 PG 17 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 041LC UT WOS:000311402300022 PM 22744906 ER PT J AU Fay, MP Shih, JH AF Fay, Michael P. Shih, Joanna H. TI Weighted logrank tests for interval censored data when assessment times depend on treatment SO STATISTICS IN MEDICINE LA English DT Article DE interval censoring; multiple imputation; rank test; permutation test; survival analysis; within cluster resampling ID COMPLEX CLUSTERED DATA; NONPARAMETRIC TEST; REGRESSION-ANALYSIS; RANK-TESTS; INFERENCE; SURVIVAL; CONSISTENCY; IMPUTATION; MODEL AB We consider weighted logrank tests for interval censored data when assessment times may depend on treatment, and for each individual, we only use the two assessment times that bracket the event of interest. It is known that treating finite right endpoints as observed events can substantially inflate the type I error rate under assessmenttreatment dependence (ATD), but the validity of several other implementations of weighted logrank tests (score tests, permutation tests, multiple imputation tests) has not been studied in this situation. With a bounded number of unique assessment times, the score test under the grouped continuous model retains the type I error rate asymptotically under ATD; however, although the approximate permutation test based on the permutation central limit theorem is not asymptotically valid under every ATD scenario, we show through simulation that in many ATD scenarios, it retains the type I error rate better than the score test. We show a case where the approximate permutation test retains the type I error rate when the exact permutation test does not. We study and modify the multiple imputation logrank tests of Huang, Lee, and Yu (2008, Statistics in Medicine, 27: 32173226), showing that the distribution of the rank-like scores asymptotically does not depend on the assessment times. We show through simulations that our modifications of the multiple imputation logrank tests retain the type I error rate in all cases studied, even with ATD and a small number of individuals in each treatment group. Simulations were performed using the interval R package. Published 2012. This article is a US Government work and is in the public domain in the USA. C1 [Fay, Michael P.] NIAID, Bethesda, MD 20892 USA. [Shih, Joanna H.] NCI, Bethesda, MD 20892 USA. RP Fay, MP (reprint author), NIAID, 6700-B Rockledge Dr,MSC 7630, Bethesda, MD 20892 USA. EM mfay@niaid.nih.gov OI Fay, Michael P./0000-0002-8643-9625 FU Intramural NIH HHS [Z99 AI999999] NR 28 TC 4 Z9 4 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0277-6715 EI 1097-0258 J9 STAT MED JI Stat. Med. PD DEC 10 PY 2012 VL 31 IS 28 BP 3760 EP 3772 DI 10.1002/sim.5447 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 041LC UT WOS:000311402300024 PM 22786795 ER PT J AU Liu, H Kato, Y Erzinger, SA Kiriakova, GM Qian, YZ Palmieri, D Steeg, PS Price, JE AF Liu, Hui Kato, Yukinari Erzinger, Stephanie A. Kiriakova, Galina M. Qian, Yongzhen Palmieri, Diane Steeg, Patricia S. Price, Janet E. TI The role of MMP-1 in breast cancer growth and metastasis to the brain in a xenograft model SO BMC CANCER LA English DT Article DE Breast cancer; Brain metastasis; MMP-1; TGF alpha; EGFR ID MATRIX METALLOPROTEINASE-1; ENDOTHELIAL-CELLS; GENE-EXPRESSION; POOR-PROGNOSIS; MELANOMA-CELLS; TUMOR-GROWTH; IN-VIVO; PROMOTES; MICROENVIRONMENT; ASTROCYTES AB Background: Brain metastasis is an increasingly common complication for breast cancer patients; approximately 15-30% of breast cancer patients develop brain metastasis. However, relatively little is known about how these metastases form, and what phenotypes are characteristic of cells with brain metastasizing potential. In this study, we show that the targeted knockdown of MMP-1 in breast cancer cells with enhanced brain metastatic ability not only reduced primary tumor growth, but also significantly inhibited brain metastasis. Methods: Two variants of the MDA-MB-231 human breast cancer cell line selected for enhanced ability to form brain metastases in nude mice (231-BR and 231-BR3 cells) were found to express high levels of matrix metalloproteinase-1 (MMP-1). Short hairpin RNA-mediated stable knockdown of MMP-1 in 231-BR and 231-BR3 cells were established to analyze tumorigenic ability and metastatic ability. Results: Short hairpin RNA-mediated stable knockdown of MMP-1 inhibited the invasive ability of MDA-MB 231 variant cells in vitro, and inhibited breast cancer growth when the cells were injected into the mammary fat pad of nude mice. Reduction of MMP-1 expression significantly attenuated brain metastasis and lung metastasis formation following injection of cells into the left ventricle of the heart and tail vein, respectively. There were significantly fewer proliferating cells in brain metastases of cells with reduced MMP-1 expression. Furthermore, reduced MMP-1 expression was associated with decreased TGF alpha release and phospho-EGFR expression in 231-BR and BR3 cells. Conclusions: Our results show that elevated expression of MMP-1 can promote the local growth and the formation of brain metastases by breast cancer cells. C1 [Liu, Hui; Kato, Yukinari; Erzinger, Stephanie A.; Kiriakova, Galina M.; Price, Janet E.] Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. [Qian, Yongzhen; Palmieri, Diane; Steeg, Patricia S.] NCI, Womens Canc Sect, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Liu, H (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. EM hliu5@mdanderson.org; janprice11@gmail.com RI Palmieri, Diane/B-4258-2015 FU US Department of Defense Breast Cancer Research Program [W81-XWH-062-0033]; Cancer Fighters of America; Cancer Center Support Grant from the National Cancer Institute [CA16672] FX This research is supported in part by the US Department of Defense Breast Cancer Research Program, W81-XWH-062-0033, Cancer Fighters of America, and Cancer Center Support Grant CA16672 from the National Cancer Institute. STR DNA fingerprinting was done by the University of Texas MD Anderson Cancer Center Characterized Cell Line Core, supported by CA16672. We thank Donna Reynolds for expert assistance with immunohistochemistry. NR 53 TC 35 Z9 37 U1 2 U2 14 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD DEC 7 PY 2012 VL 12 AR 583 DI 10.1186/1471-2407-12-583 PG 11 WC Oncology SC Oncology GA 059QT UT WOS:000312720800001 PM 23217186 ER PT J AU Chowell, G Nishiura, H Viboud, C AF Chowell, Gerardo Nishiura, Hiroshi Viboud, Cecile TI Modeling rapidly disseminating infectious disease during mass gatherings SO BMC MEDICINE LA English DT Review DE Model; mathematical; epidemic; outbreaks; epidemiology; mass gathering; school closure; clustering; reactive vaccination; movement; social networks ID INFLUENZA-A H1N1; 2009 PANDEMIC H1N1; SOCIAL NETWORKS; SEASONAL INFLUENZA; UNITED-STATES; AIRLINE TRANSPORTATION; BIOTERRORIST SMALLPOX; INTERNATIONAL SPREAD; COMMERCIAL AIRLINER; MIXING PATTERNS AB We discuss models for rapidly disseminating infectious diseases during mass gatherings (MGs), using influenza as a case study. Recent innovations in modeling and forecasting influenza transmission dynamics at local, regional, and global scales have made influenza a particularly attractive model scenario for MG. We discuss the behavioral, medical, and population factors for modeling MG disease transmission, review existing model formulations, and highlight key data and modeling gaps related to modeling MG disease transmission. We argue that the proposed improvements will help integrate infectious-disease models in MG health contingency plans in the near future, echoing modeling efforts that have helped shape influenza pandemic preparedness plans in recent years. C1 [Chowell, Gerardo] Arizona State Univ, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. [Chowell, Gerardo; Viboud, Cecile] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Nishiura, Hiroshi] Univ Hong Kong, Sch Publ Hlth, Pokfulam, Hong Kong, Peoples R China. [Nishiura, Hiroshi] Japan Sci & Technol Agcy, PRESTO Precursory Res Embryon Sci & Technol, Kawaguchi, Saitama 3320012, Japan. RP Chowell, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, 900 S Cady Mall, Tempe, AZ 85287 USA. EM gchowell@asu.edu RI Chowell, Gerardo/F-5038-2012; OI Chowell, Gerardo/0000-0003-2194-2251; Nishiura, Hiroshi/0000-0003-0941-8537 FU NIGMS NIH HHS [R01 GM100471] NR 124 TC 9 Z9 9 U1 2 U2 19 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7015 J9 BMC MED JI BMC Med. PD DEC 7 PY 2012 VL 10 AR 159 DI 10.1186/1741-7015-10-159 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 064DY UT WOS:000313052500001 PM 23217051 ER PT J AU Rinaldi, C Grunseich, C Sevrioukova, IF Schindler, A Horkayne-Szakaly, I Lamperti, C Landoure, G Kennerson, ML Burnett, BG Bonnemann, C Biesecker, LG Ghezzi, D Zeviani, M Fischbeck, KH AF Rinaldi, Carlo Grunseich, Christopher Sevrioukova, Irina F. Schindler, Alice Horkayne-Szakaly, Iren Lamperti, Costanza Landoure, Guida Kennerson, Marina L. Burnett, Barrington G. Boennemann, Carsten Biesecker, Leslie G. Ghezzi, Daniele Zeviani, Massimo Fischbeck, Kenneth H. TI Cowchock Syndrome Is Associated with a Mutation in Apoptosis-Inducing Factor SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID MARIE-TOOTH-DISEASE; MOTOR-SENSORY NEUROPATHY; MENTAL-RETARDATION; CELL-DEATH; FACTOR AIF; DEAFNESS AB Cowchock syndrome (CMTX4) is a slowly progressive X-linked recessive disorder with axonal neuropathy, deafness, and cognitive impairment. The disease locus was previously mapped to an 11 cM region at chromosome X: q24-q26. Exome sequencing of an affected individual from the originally described family identified a missense change c.1478A>T (p.Glu493Val) in AIFM1, the gene encoding apoptosis-inducing factor (AIF) mitochondrion-associated 1. The change is at a highly conserved residue and cosegregated with the phenotype in the family. AIF is an FAD-dependent NADH oxidase that is imported into mitochondria. With apoptotic insults, a N-terminal transmembrane linker is cleaved off, producing a soluble fragment that is released into the cytosol and then transported into the nucleus, where it triggers caspase-independent apoptosis. Another AIFM1 mutation that predicts p.Arg201del has recently been associated with severe mitochondrial encephalomyopathy in two infants by impairing oxidative phosphorylation. The c.1478A>T (p.Glu493Val) mutation found in the family reported here alters the redox properties of the AIF protein and results in increased cell death via apoptosis, without affecting the activity of the respiratory chain complexes. Our findings expand the spectrum of AIF-related disease and provide insight into the effects of AIFM1 mutations. C1 [Rinaldi, Carlo; Grunseich, Christopher; Schindler, Alice; Landoure, Guida; Burnett, Barrington G.; Boennemann, Carsten; Fischbeck, Kenneth H.] NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Sevrioukova, Irina F.] Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. [Horkayne-Szakaly, Iren] Joint Pathol Ctr Neuropathol & Ophthalm Pathol, Silver Spring, MD 20910 USA. [Lamperti, Costanza; Ghezzi, Daniele; Zeviani, Massimo] Ist Ricovero & Cura Carattere Sci, Carlo Resta Neurol Inst Fdn, Div Mol Neurogenet, I-20126 Milan, Italy. [Landoure, Guida] Ctr Hosp Univ Point G, Serv Neurol, Bamako, Mali. [Kennerson, Marina L.] Univ Sydney, ANZAC Res Inst, Northcott Neurosci Lab, Concord, NSW 2139, Australia. [Kennerson, Marina L.] Concord Hosp, Mol Med Lab, Concord, NSW 2139, Australia. [Biesecker, Leslie G.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Biesecker, Leslie G.] NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA. RP Rinaldi, C (reprint author), NINDS, Neurogenet Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM rinaldic@ninds.nih.gov RI Kennerson, Marina/B-5058-2014; Zeviani, Massimo/K-2891-2014; Ghezzi, Daniele/J-7873-2016 OI Ghezzi, Daniele/0000-0002-6564-3766; FU NINDS; NHGRI; National Institutes of Health [GM67637]; Pierfranco and Luisa Mariani Foundation, Italy; Fondazione Telethon [GGP11011, GPP10005]; CARIPLO [2011/0526]; Italian Association of Mitochondrial Disease Patients and Families (Mitocon) FX We are grateful to the family members for their participation and to Justin Y. Kwan, at NINDS, for performing the muscle biopsy. This work was supported in part by NINDS and NHGRI intramural research funding; National Institutes of Health Grant GM67637; the Pierfranco and Luisa Mariani Foundation, Italy; Fondazione Telethon grants GGP11011 and GPP10005; CARIPLO grant 2011/0526; and the Italian Association of Mitochondrial Disease Patients and Families (Mitocon). NR 23 TC 43 Z9 45 U1 0 U2 10 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD DEC 7 PY 2012 VL 91 IS 6 BP 1095 EP 1102 DI 10.1016/j.ajhg.2012.10.008 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 055LI UT WOS:000312417400013 PM 23217327 ER PT J AU Zane, L Jeang, KT AF Zane, Linda Jeang, Kuan-Teh TI The importance of ubiquitination and sumoylation on the transforming activity of HTLV Tax-1 and Tax-2 SO RETROVIROLOGY LA English DT Article DE HTLV-1; HTLV-2; Tax; ATL; Cell transformation; NF-kappa B; Sumoylation; Ubiquitination ID ACTIVATION; CANCER AB Human T-cell Leukemia Virus type 1 (HTLV-1) and 2 (HTLV-2) are two closely related human retroviruses. HTLV-1 is associated with an aggressive Adult T-cell Leukemia (ATL) while there is no evidence for an association of HTLV-2 with any human malignancies. The two viruses encode transactivator proteins, Tax-1 and Tax-2 respectively. In ATL, Tax-1 is thought to play a central role in the transformation of a normal T-cell into a leukemic cell; however, it has not been entirely clear how post-translational modifications of Tax-1 influence its transforming activity. Here, we discuss three recent papers that report on the ubiquitination and sumoylation of Tax-1 and Tax-2. We comment on their divergent findings implicating the importance (or lack of importance) of these modifications and other events on Tax activation of NF-kappa B as related to cellular transformation. C1 [Zane, Linda; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, 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 KJEANG@nih.gov FU Intramural NIAID funding; Office of the Director, NIH; Bill and Melinda Gates Foundation FX Research in KTJ's laboratory is supported by Intramural NIAID funding, the IATAP program from the Office of the Director, NIH, and by the Bill and Melinda Gates Foundation. We thank Swathi Nuli for assistance with the figure. NR 15 TC 9 Z9 9 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD DEC 7 PY 2012 VL 9 AR 103 DI 10.1186/1742-4690-9-103 PG 4 WC Virology SC Virology GA 057RT UT WOS:000312582400001 PM 23217176 ER PT J AU Ivanic, J Schmidt, MW Luke, B AF Ivanic, Joseph Schmidt, Michael W. Luke, Brian TI High-level theoretical study of the NO dimer and tetramer: Has the tetramer been observed? SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID NITRIC-OXIDE DIMER; 2ND-ORDER PERTURBATION-THEORY; CORRELATED MOLECULAR CALCULATIONS; SELF-CONSISTENT-FIELD; GAUSSIAN-BASIS SETS; WAVE-FUNCTIONS; RAMAN-SPECTRA; OPEN-SHELL; ELECTRONIC STATES; FORCE-FIELD AB The ground-state properties of (NO)(2) and (NO)(4) have been investigated using multireference second-order perturbation theory (MRMP2) and include a two-tier extrapolation to the complete basis set (CBS) limit. For the NO dimer the MRMP2(18,14)/CBS predicted structure, binding energy (with respect to 2NO; D-e = 3.46 kcal/mol), and dipole moment (u(e) = 0.169 D) are in excellent agreement with experimental measurements (D-e = 2.8-3.8 kcal/mol; u(e) = 0.171 D). Additionally, three of four intermolecular anharmonic MRMP2(18,14)/CBS-estimated frequencies (143 cm(-1), 238 cm(-1), 421 cm(-1)) are in excellent agreement with recent gas-phase experimental measurements (135 cm(-1), 239 cm(-1), 429/428 cm(-1)); however, the predicted value of 151 cm(-1) for the out-of-plane torsion (A(2)) is elevated compared to recent experimental estimates of 97-117 cm(-1). Our finding that this infrared-forbidden vibration is also predicted to have an extremely low Raman activity (0.04 angstrom/amu at the MP2/QZ level of theory) conflicts with Raman measurements of a strong intensity for a low frequency band; however, these studies were performed for low temperature solid and liquid phases. Probing the possibility of the presence of higher order clusters we investigated the stability of (NO)(4) and discovered three isomers, each resembling pairs of dimers, that were stable to dissociation to 2(NO)(2), with the lowest-energy isomer (C-i structure) having a predicted binding energy almost identical to that of the dimer. Computed vibrational frequencies of the C-i isomer indicate that the 12 highest-frequency modes resemble barely shifted NO dimer-combined bands while the 13th highest-frequency mode at similar to 100 cm(-1) is exclusive to (NO)(4). Moreover, this tetramer-unique vibration is infrared inactive but has a very high predicted Raman activity of some 24 angstrom/amu. Guided by the theoretical results, we reexamined and reassigned experimental Raman and infrared data going back to 1951 and determined that our best predictions of vibrational frequencies of (NO)(2) and (NO)(4) are consistent with experimental observations. We thus postulate the existence and observation of (NO)(4). [http://dx.doi.org/10.1063/1.4769226] C1 [Ivanic, Joseph; Luke, Brian] SAIC Frederick Inc, Adv Biomed Comp Ctr, Informat Syst Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Schmidt, Michael W.] Iowa State Univ, Dept Chem & Ames Lab US DOE, Ames, IA 50011 USA. RP Ivanic, J (reprint author), SAIC Frederick Inc, Adv Biomed Comp Ctr, Informat Syst Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. EM ivanicj@mail.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Department of Energy 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 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. M.W.S. acknowledges support by the Department of Energy Chemical Physics program. NR 71 TC 4 Z9 4 U1 2 U2 32 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 DEC 7 PY 2012 VL 137 IS 21 AR 214316 DI 10.1063/1.4769226 PG 10 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 053EH UT WOS:000312252900030 PM 23231240 ER PT J AU Reiner, JE Balijepalli, A Robertson, JWF Drown, BS Burden, DL Kasianowicz, JJ AF Reiner, Joseph E. Balijepalli, Arvind Robertson, Joseph W. F. Drown, Bryon S. Burden, Daniel L. Kasianowicz, John J. TI The effects of diffusion on an exonuclease/nanopore-based DNA sequencing engine SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID IRREVERSIBLE ELECTRICAL BREAKDOWN; BETA-CYCLODEXTRIN; PROTEIN NANOPORE; MEMBRANE CHANNEL; PORE; MOLECULE; DYNAMICS; GENOME; IDENTIFICATION; DEVICE AB Over 15 years ago, the ability to electrically detect and characterize individual polynucleotides as they are driven through a single protein ion channel was suggested as a potential method for rapidly sequencing DNA, base-by-base, in a ticker tape-like fashion. More recently, a variation of this method was proposed in which a nanopore would instead detect single nucleotides cleaved sequentially by an exonuclease enzyme in close proximity to one pore entrance. We analyze the exonuclease/nanopore-based DNA sequencing engine using analytical theory and computer simulations that describe nucleotide transport. The available data and analytical results suggest that the proposed method will be limited to reading <80 bases, imposed, in part, by the short lifetime each nucleotide spends in the vicinity of the detection element within the pore and the ability to accurately discriminate between the four mononucleotides. (C) 2012 American Institute of Physics. [http://dx.doi.org/10.1063/1.4766363] C1 [Balijepalli, Arvind; Robertson, Joseph W. F.; Kasianowicz, John J.] NIST, Phys Measurement Lab, Semicond & Dimens Metrol Div, CMOS & Reliabil Grp, Gaithersburg, MD 20899 USA. [Reiner, Joseph E.] Virginia Commonwealth Univ, Dept Phys, Richmond, VA 23284 USA. [Balijepalli, Arvind] NHLBI, Lab Computat Biol, NIH, Rockville, MD 20892 USA. [Drown, Bryon S.; Burden, Daniel L.] Wheaton Coll, Dept Chem, Wheaton, IL 60187 USA. RP Kasianowicz, JJ (reprint author), NIST, Phys Measurement Lab, Semicond & Dimens Metrol Div, CMOS & Reliabil Grp, Gaithersburg, MD 20899 USA. EM john.kasianowicz@nist.gov RI Reiner, Joseph/B-7893-2013; OI Reiner, Joseph/0000-0002-1056-8703; Drown, Bryon/0000-0002-5631-512X FU National Institute of Standards and Technology (NIST) Office of Law Enforcement Standards; Wheaton College Alumni Foundation; National Science Foundation (NSF); NRC/NIST NIH FX This work was supported in part by grants from National Institute of Standards and Technology (NIST) Office of Law Enforcement Standards (J.J.K., J.W.F.R., J.E.R.), the Wheaton College Alumni Foundation (D. L. B., B. S. D.), the National Science Foundation (NSF) (D. L. B.), and NRC/NIST NIH Research Fellowship (A. B.). We thank Dr. James Russo at Columbia University for helpful comments on the paper. NR 41 TC 15 Z9 15 U1 2 U2 42 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 DEC 7 PY 2012 VL 137 IS 21 AR 214903 DI 10.1063/1.4766363 PG 7 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 053EH UT WOS:000312252900049 PM 23231259 ER PT J AU Elbers, CC Guo, YR Tragante, V van Iperen, EPA Lanktree, MB Castillo, BA Chen, F Yanek, LR Wojczynski, MK Li, YR Ferwerda, B Ballantyne, CM Buxbaum, SG Chen, YDI Chen, WM Cupples, LA Cushman, M Duan, YA Duggan, D Evans, MK Fernandes, JK Fornage, M Garcia, M Garvey, WT Glazer, N Gomez, F Harris, TB Halder, I Howard, VJ Keller, MF Kamboh, MI Kooperberg, C Kritchevsky, SB LaCroix, A Liu, K Liu, YM Musunuru, K Newman, AB Onland-Moret, NC Ordovas, J Peter, I Post, W Redline, S Reis, SE Saxena, R Schreiner, PJ Volcik, KA Wang, XB Yusuf, S Zonderland, AB Anand, SS Becker, DM Psaty, B Rader, DJ Reiner, AP Rich, SS Rotter, JI Sale, MM Tsai, MY Borecki, IB Hegele, RA Kathiresan, S Nalls, MA Taylor, HA Hakonarson, H Sivapalaratnam, S Asselbergs, FW Drenos, F Wilson, JG Keating, BJ AF Elbers, Clara C. Guo, Yiran Tragante, Vinicius van Iperen, Erik P. A. Lanktree, Matthew B. Castillo, Berta Almoguera Chen, Fang Yanek, Lisa R. Wojczynski, Mary K. Li, Yun R. Ferwerda, Bart Ballantyne, Christie M. Buxbaum, Sarah G. Chen, Yii-Der Ida Chen, Wei-Min Cupples, L. Adrienne Cushman, Mary Duan, Yanan Duggan, David Evans, Michele K. Fernandes, Jyotika K. Fornage, Myriam Garcia, Melissa Garvey, W. Timothy Glazer, Nicole Gomez, Felicia Harris, Tamara B. Halder, Indrani Howard, Virginia J. Keller, Margaux F. Kamboh, M. Ilyas Kooperberg, Charles Kritchevsky, Stephen B. LaCroix, Andrea Liu, Kiang Liu, Yongmei Musunuru, Kiran Newman, Anne B. Onland-Moret, N. Charlotte Ordovas, Jose Peter, Inga Post, Wendy Redline, Susan Reis, Steven E. Saxena, Richa Schreiner, Pamela J. Volcik, Kelly A. Wang, Xingbin Yusuf, Salim Zonderland, Alan B. Anand, Sonia S. Becker, Diane M. Psaty, Bruce Rader, Daniel J. Reiner, Alex P. Rich, Stephen S. Rotter, Jerome I. Sale, Michele M. Tsai, Michael Y. Borecki, Ingrid B. Hegele, Robert A. Kathiresan, Sekar Nalls, Michael A. Taylor, Herman A., Jr. Hakonarson, Hakon Sivapalaratnam, Suthesh Asselbergs, Folkert W. Drenos, Fotios Wilson, James G. Keating, Brendan J. TI Gene-Centric Meta-Analysis of Lipid Traits in African, East Asian and Hispanic Populations SO PLOS ONE LA English DT Article ID INTERCELLULAR-ADHESION MOLECULE-1; DENSITY-LIPOPROTEIN-CHOLESTEROL; SINGLE-NUCLEOTIDE POLYMORPHISM; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; CHAIN FATTY-ACIDS; METABOLIC SYNDROME; ASSOCIATION RESOURCE; NATURAL-SELECTION; YOUNG-ADULTS AB Meta-analyses of European populations has successfully identified genetic variants in over 100 loci associated with lipid levels, but our knowledge in other ethnicities remains limited. To address this, we performed dense genotyping of similar to 2,000 candidate genes in 7,657 African Americans, 1,315 Hispanics and 841 East Asians, using the IBC array, a custom similar to 50,000 SNP genotyping array. Meta-analyses confirmed 16 lipid loci previously established in European populations at genome-wide significance level, and found multiple independent association signals within these lipid loci. Initial discovery and in silico follow-up in 7,000 additional African American samples, confirmed two novel loci: rs5030359 within ICAM1 is associated with total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (p = 8.8x10(-7) and p = 1.5x10(-6) respectively) and a nonsense mutation rs3211938 within CD36 is associated with high-density lipoprotein cholesterol (HDL-C) levels (p = 13.5x10(-1)2). The rs3211938-G allele, which is nearly absent in European and Asian populations, has been previously found to be associated with CD36 deficiency and shows a signature of selection in Africans and African Americans. Finally, we have evaluated the effect of SNPs established in European populations on lipid levels in multi-ethnic populations and show that most known lipid association signals span across ethnicities. However, differences between populations, especially differences in allele frequency, can be leveraged to identify novel signals, as shown by the discovery of ICAM1 and CD36 in the current report. C1 [Elbers, Clara C.; Ferwerda, Bart; Gomez, Felicia] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. [Elbers, Clara C.; Tragante, Vinicius; Onland-Moret, N. Charlotte; Asselbergs, Folkert W.] Univ Med Ctr, Dept Med Genet, Utrecht, Netherlands. [Elbers, Clara C.; Onland-Moret, N. Charlotte; Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Guo, Yiran; Castillo, Berta Almoguera; Li, Yun R.; Hakonarson, Hakon; Keating, Brendan J.] Childrens Hosp Philadelphia, Abramson Res Ctr, Ctr Appl Gen, Philadelphia, PA 19104 USA. [Guo, Yiran] BGI Shenzhen, Shenzhen, Peoples R China. [Tragante, Vinicius; Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Div Heart & Lungs, Dept Cardiol, Utrecht, Netherlands. [van Iperen, Erik P. A.] Univ Amsterdam, Acad Med Ctr, Dept Clin Epidemiol Biostat & Bioinformat, NL-1105 AZ Amsterdam, Netherlands. [Lanktree, Matthew B.] Univ Western Ontario, Dept Med, Schulich Sch Med & Dent, London, ON, Canada. [Lanktree, Matthew B.] Univ Western Ontario, Dept Biochem, Schulich Sch Med & Dent, London, ON, Canada. [Chen, Fang; Chen, Wei-Min; Rich, Stephen S.; Sale, Michele M.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Yanek, Lisa R.; Becker, Diane M.] Johns Hopkins Sch Med, GeneSTAR Res Program, Div Gen Internal Med, Baltimore, MD USA. [Wojczynski, Mary K.] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA. [Ballantyne, Christie M.] Baylor Coll Med, Houston, TX 77030 USA. [Buxbaum, Sarah G.] Jackson State Univ, Jackson Heart Study, Jackson, MS USA. [Chen, Yii-Der Ida; Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Chen, Wei-Min] Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. [Cupples, L. Adrienne; Glazer, Nicole] Boston Univ, Boston, MA 02215 USA. [Cupples, L. Adrienne] NHLBI, Framingham Heart Study, Framingham, MA USA. [Wojczynski, Mary K.; Duan, Yanan; Borecki, Ingrid B.] Washington Univ, Sch Med, Div Stat Genom, St Louis, MO USA. [Wojczynski, Mary K.; Duan, Yanan; Borecki, Ingrid B.] Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. [Duggan, David] Translat Genom Res Inst, Phoenix, AZ USA. [Garcia, Melissa; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Reis, Steven E.] Univ Pittsburgh, Sch Med, Pittsburgh, PA USA. [Kooperberg, Charles; LaCroix, Andrea; Reiner, Alex P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Kritchevsky, Stephen B.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Sticht Ctr Aging, Winston Salem, NC 27109 USA. [Liu, Kiang] Northwestern Univ, Dept Prevent Med, Feinberg Sch Med, Chicago, IL 60611 USA. [Liu, Yongmei] Wake Forest Univ, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Kamboh, M. Ilyas; Wang, Xingbin] Univ Pittsburgh, Dept Human Genet, Pittsburgh, PA USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Ordovas, Jose] Tufts Univ, JM USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Peter, Inga] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY USA. [Post, Wendy] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. [Redline, Susan] Brigham & Womens Hosp, Boston, MA 02115 USA. [Redline, Susan] Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Boston, MA 02215 USA. [Saxena, Richa] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Saxena, Richa] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Schreiner, Pamela J.] Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. [Volcik, Kelly A.] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Div Epidemiol Human Genet & Environm Sci, Houston, TX USA. [Yusuf, Salim; Anand, Sonia S.] McMaster Univ, Hamilton Hlth Sci, Populat Hlth Res Inst, Hamilton, ON, Canada. [Psaty, Bruce] Univ Washington, Cardiovasc Hlth Res Unit, Dept Med, Seattle, WA 98195 USA. [Psaty, Bruce] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA USA. [Rader, Daniel J.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA USA. [Sale, Michele M.] Univ Virginia, Dept Biochem & Mol Genet, Charlottesville, VA USA. [Sale, Michele M.] Univ Virginia, Dept Med, Charlottesville, VA USA. [Tsai, Michael Y.] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. [Hegele, Robert A.] Univ Western Ontario, Robarts Res Inst, London, ON, Canada. [Keller, Margaux F.; Nalls, Michael A.] NIA, Neurogenet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. [Taylor, Herman A., Jr.] Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. [Taylor, Herman A., Jr.] Jackson State Univ, Tougaloo Coll, Jackson, MS USA. [Sivapalaratnam, Suthesh] Univ Amsterdam, Acad Med Ctr, Dept Vasc Med, NL-1105 AZ Amsterdam, Netherlands. [Drenos, Fotios] UCL, Fac Populat Hlth Sci, Inst Cardiovasc Sci, Ctr Cardiovasc Genet, London, England. [Wilson, James G.] Univ Mississippi, Med Ctr, Dept Physiol & Biophys, Jackson, MS 39216 USA. [Cushman, Mary] Univ Vermont, Dept Med, Thrombosis & Hemostasis Program, Burlington, VT USA. [Fernandes, Jyotika K.] Med Univ S Carolina, Coll Med, Div Endocrinol Diabet & Med Genet, Charleston, SC 29425 USA. [Garvey, W. Timothy] Univ Alabama Birmingham, Dept Nutr Sci, Birmingham, AL 35294 USA. [Howard, Virginia J.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. [Zonderland, Alan B.] NIA, Lab Personal & Cognit, NIH, Bethesda, MD 20892 USA. [Evans, Michele K.] NIA, Hlth Dispar Unit, NIH, Baltimore, MD 21224 USA. [Halder, Indrani] Univ Pittsburgh, Inst Heart & Vasc, Sch Med, Pittsburgh, PA USA. [Buxbaum, Sarah G.] Jackson State Univ, Sch Hlth Sci, Dept Epidemiol & Biostat, Jackson, MS USA. RP Elbers, CC (reprint author), Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. EM bkeating@mail.med.upenn.edu RI Newman, Anne/C-6408-2013; Reis, Steven/J-3957-2014; Guo, Yiran/H-4120-2011; Onland-Moret, N. Charlotte/G-9185-2011; Hegele, Robert/G-3301-2011; Buxbaum, Sarah/E-1970-2013 OI Newman, Anne/0000-0002-0106-1150; Lanktree, Matthew/0000-0002-5750-6286; Kritchevsky, Stephen/0000-0003-3336-6781; van Iperen, Erik/0000-0001-7107-3168; Guo, Yiran/0000-0002-6549-8589; Cupples, L. Adrienne/0000-0003-0273-7965; Kamboh, M. Ilyas/0000-0002-3453-1438; Buxbaum, Sarah/0000-0002-4886-3564 FU National Heart, Lung, and Blood Institute; Massachusetts Institute of Technology - Broad Institute [N01-HC-65226]; Netherlands Organization for Scientific Research (NWO); Netherlands Organisation for Health Research and Development (ZonMw) [90700342] FX The CARe Consortium wishes to acknowledge the support of the National Heart, Lung, and Blood Institute and the contributions of the research institutions, study investigators, field staff and study participants in creating this resource for biomedical research. The following nine parent studies have contributed parent study data, ancillary study data, and DNA samples through the Massachusetts Institute of Technology - Broad Institute (N01-HC-65226) to create this genotype/phenotype database for wide dissemination to the biomedical research community: the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), the Cleveland Family Study (CFS), the Cooperative Study of Sickle Cell Disease (CSSCD), the Coronary Artery Risk Development in Young Adults (CARDIA) study, the Framingham Heart Study (FHS), the Jackson Heart Study (JHS), the Multi-Ethnic Study of Atherosclerosis (MESA), and the Sleep Heart Health Study (SHHS). C. C. E is supported by a Rubicon grant from the Netherlands Organization for Scientific Research (NWO). F. W. A. is supported by a clinical fellowship from the Netherlands Organisation for Health Research and Development (ZonMw grant 90700342). Additional funding information can be found in the Supporting Information S1. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 52 TC 16 Z9 16 U1 2 U2 21 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 DEC 7 PY 2012 VL 7 IS 12 AR e50198 DI 10.1371/journal.pone.0050198 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 050OT UT WOS:000312064100013 PM 23236364 ER PT J AU Ene, CI Edwards, L Riddick, G Baysan, M Woolard, K Kotliarova, S Lai, C Belova, G Cam, M Walling, J Zhou, M Stevenson, H Kim, HS Killian, K Veenstra, T Bailey, R Song, H Zhang, W Fine, HA AF Ene, Chibawanye I. Edwards, Lincoln Riddick, Gregory Baysan, Mehmet Woolard, Kevin Kotliarova, Svetlana Lai, Chen Belova, Galina Cam, Maggie Walling, Jennifer Zhou, Ming Stevenson, Holly Kim, Hong Sug Killian, Keith Veenstra, Timothy Bailey, Rolanda Song, Hua Zhang, Wei Fine, Howard A. TI Histone Demethylase Jumonji D3 (JMJD3) as a Tumor Suppressor by Regulating p53 Protein Nuclear Stabilization SO PLOS ONE LA English DT Article ID INITIATING CELLS; GENOME BROWSER; HUMAN GLIOBLASTOMA; H3K27 DEMETHYLASE; DNA METHYLATION; STEM-CELLS; DIFFERENTIATION; PATHWAY; REPRESSION; UCSC AB Histone methylation regulates normal stem cell fate decisions through a coordinated interplay between histone methyltransferases and demethylases at lineage specific genes. Malignant transformation is associated with aberrant accumulation of repressive histone modifications, such as polycomb mediated histone 3 lysine 27 (H3K27me3) resulting in a histone methylation mediated block to differentiation. The relevance, however, of histone demethylases in cancer remains less clear. We report that JMJD3, a H3K27me3 demethylase, is induced during differentiation of glioblastoma stem cells (GSCs), where it promotes a differentiation-like phenotype via chromatin dependent (INK4A/ARF locus activation) and chromatin independent (nuclear p53 protein stabilization) mechanisms. Our findings indicate that deregulation of JMJD3 may contribute to gliomagenesis via inhibition of the p53 pathway resulting in a block to terminal differentiation. C1 [Fine, Howard A.] NYU, Ctr Canc, Langone Med Ctr, New York, NY 10003 USA. [Ene, Chibawanye I.; Edwards, Lincoln; Riddick, Gregory; Baysan, Mehmet; Woolard, Kevin; Kotliarova, Svetlana; Lai, Chen; Belova, Galina; Cam, Maggie; Walling, Jennifer; Kim, Hong Sug; Bailey, Rolanda; Song, Hua; Zhang, Wei] NINDS, Neurooncol Branch, Ctr Canc Res, NCI,NIH, Bethesda, MD 20892 USA. [Ene, Chibawanye I.] NIH, NIH Oxford Cambridge Res Scholars Program, Bethesda, MD 20892 USA. [Zhou, Ming; Veenstra, Timothy] NCI, Lab Prote & Analyt Technol, Frederick Natl Lab Canc Res, NIH, Frederick, MD 21701 USA. [Stevenson, Holly; Killian, Keith] NCI, Mol Profiling Core, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), NYU, Ctr Canc, Langone Med Ctr, New York, NY 10003 USA. EM Howard.Fine@nyumc.org FU Howard Hughes Medical Institute National Cancer Institute, National Institute of Health FX This study was supported by the Howard Hughes Medical Institute National Cancer Institute, National Institute of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 33 Z9 34 U1 0 U2 9 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 DEC 7 PY 2012 VL 7 IS 12 AR e51407 DI 10.1371/journal.pone.0051407 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 050OT UT WOS:000312064100115 PM 23236496 ER PT J AU Fujino, K Horie, M Honda, T Nakamura, S Matsumoto, Y Francischetti, IMB Tomonaga, K AF Fujino, Kan Horie, Masayuki Honda, Tomoyuki Nakamura, Shoko Matsumoto, Yusuke Francischetti, Ivo M. B. Tomonaga, Keizo TI Evolutionarily Conserved Interaction between the Phosphoproteins and X Proteins of Bornaviruses from Different Vertebrate Species SO PLOS ONE LA English DT Article ID BORNA-DISEASE VIRUS; PROVENTRICULAR DILATATION DISEASE; NUCLEAR-LOCALIZATION; AVIAN BORNAVIRUS; RNA; IMPORT; CANADA; DOMAIN; SIGNAL; GEESE AB Bornavirus, a non-segmented, negative-strand RNA viruses, is currently classified into several genetically distinct genotypes, such as Borna disease virus (BDV) and avian bornaviruses (ABVs). Recent studies revealed that bornavirus genotypes show unique sequence variability in the putative 5' untranslated region (5' UTR) of X/P mRNA, a bicistronic mRNA for the X protein and phosphoprotein (P). In this study, to understand the evolutionary relationship among the bornavirus genotypes, we investigated the functional interaction between the X and P proteins of four bornavirus genotypes, BDV, ABV genotype 4 and 5 and reptile bornavirus (RBV), the putative 5' UTRs of which exhibit variation in the length. Immunofluorescence and immunoprecipitation analyses using mammalian and avian cell lines revealed that the X proteins of bornaviruses conserve the ability to facilitate the export of P from the nucleus to the cytoplasm via interaction with P. Furthermore, we showed that inter-genotypic interactions may occur between X and P among the genotypes, except for X of RBV. In addition, a BDV minireplicon assay demonstrated that the X and P proteins of ABVs, but not RBV, can affect the polymerase activity of BDV. This study demonstrates that bornaviruses may have conserved the fundamental function of a regulatory protein during their evolution, whereas RBV has evolved distinctly from the other bornavirus genotypes. C1 [Fujino, Kan; Horie, Masayuki; Honda, Tomoyuki; Nakamura, Shoko; Matsumoto, Yusuke; Tomonaga, Keizo] Kyoto Univ, Inst Virus Res, Dept Viral Oncol, Kyoto 606, Japan. [Francischetti, Ivo M. B.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Tomonaga, K (reprint author), Kyoto Univ, Inst Virus Res, Dept Viral Oncol, Kyoto 606, Japan. EM tomonaga@virus.kyoto-u.ac.jp OI Matsumoto, Yusuke/0000-0003-3500-2279 FU Japan Society for the Promotion of Science (JSPS); Takeda Science Foundation; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This study was supported in part by Funding Program for Next Generation World-Leading Researchers (NEXT program) from Japan Society for the Promotion of Science (JSPS) (KT), Research Grants from Takeda Science Foundation (KT) and the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health (IMBF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 6 Z9 7 U1 0 U2 13 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 DEC 7 PY 2012 VL 7 IS 12 AR e51161 DI 10.1371/journal.pone.0051161 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 050OT UT WOS:000312064100074 PM 23236446 ER PT J AU Sol, EM Wagner, SA Weinert, BT Kumar, A Kim, HS Deng, CX Choudhary, C AF Sol, Eri Maria Wagner, Sebastian A. Weinert, Brian T. Kumar, Amit Kim, Hyun-Seok Deng, Chu-Xia Choudhary, Chunaram TI Proteomic Investigations of Lysine Acetylation Identify Diverse Substrates of Mitochondrial Deacetylase Sirt3 SO PLOS ONE LA English DT Article ID FATTY-ACID OXIDATION; MASS-SPECTROMETRY; SIGNALING NETWORKS; C-TRAP; SIRTUINS; FRACTIONATION; RESTRICTION; STRESS; PHOSPHORYLATION; IDENTIFICATION AB Lysine acetylation is a posttranslational modification that is dynamically regulated by the activity of acetyltransferases and deacetylases. The human and mouse genomes encode 18 different lysine deacetylases (KDACs) which are key regulators of many cellular processes. Identifying substrates of KDACs and pinpointing the regulated acetylation sites on target proteins may provide important information about the molecular basis of their functions. Here we apply quantitative proteomics to identify endogenous substrates of the mitochondrial deacetylase Sirtuin 3 (Sirt3) by comparing site-specific acetylation in wild-type murine embryonic fibroblasts to Sirt3 knockout cells. We confirm Sirt3-regulated acetylation of several mitochondrial proteins in human cells by comparing acetylation in U2OS cells overexpressing Sirt3 to U2OS cells in which Sirt3 expression was reduced by shRNA. Our data demonstrate that ablation of Sirt3 significantly increases acetylation at dozens of sites on mitochondrial proteins. Substrates of Sirt3 are implicated in various metabolic pathways, including fatty acid metabolism and the tricarboxylic acid cycle. These results imply broader regulatory roles of Sirt3 in the mitochondria by modulating acetylation on diverse substrates. The experimental strategy described here is generic and can be applied to identify endogenous substrates of other lysine deacetylases. C1 [Sol, Eri Maria; Wagner, Sebastian A.; Weinert, Brian T.; Kumar, Amit; Choudhary, Chunaram] Univ Copenhagen, Dept Prote, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth Sci, Copenhagen, Denmark. [Kim, Hyun-Seok; Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. [Kim, Hyun-Seok] Ewha Womans Univ, Dept Life Sci, Div Life & Pharmaceut Sci, Coll Nat Sci, Seoul, South Korea. RP Choudhary, C (reprint author), Univ Copenhagen, Dept Prote, Novo Nordisk Fdn Ctr Prot Res, Fac Hlth Sci, Copenhagen, Denmark. EM chuna.choudhary@cpr.ku.dk RI deng, chuxia/N-6713-2016; OI Weinert, Brian/0000-0002-1335-9915 FU European Commission [INFRASTRUCTURES-F7-2010-262067/PRIME-XS]; Lundbeck Foundation [R48-A4649]; Novo Nordisk Foundation; Swedish Research Council [20097387]; Danish Council for Independent Research [FSS: 10-085134] FX This work is supported in part by the European Commission's 7th Framework Programme grant Proteomics Research Infrastructure Maximising knowledge EXchange and access (XS) (INFRASTRUCTURES-F7-2010-262067/PRIME-XS), and the Lundbeck Foundation (R48-A4649). The Center for Protein Research is funded by a generous grant from the Novo Nordisk Foundation. EMS is supported by a postdoctoral fellowship from Swedish Research Council (20097387). SAW is supported by a postdoctoral grant from Danish Council for Independent Research (FSS: 10-085134). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 51 TC 49 Z9 49 U1 0 U2 21 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 DEC 7 PY 2012 VL 7 IS 12 AR e50545 DI 10.1371/journal.pone.0050545 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 050OT UT WOS:000312064100019 PM 23236377 ER PT J AU Wigelsworth, DJ Ruthel, G Schnell, L Herrlich, P Blonder, J Veenstra, TD Carman, RJ Wilkins, TD Guy, TVN Pauillac, S Gibert, M Sauvonnet, N Stiles, BG Popoff, MR Barth, H AF Wigelsworth, Darran J. Ruthel, Gordon Schnell, Leonie Herrlich, Peter Blonder, Josip Veenstra, Timothy D. Carman, Robert J. Wilkins, Tracy D. Guy Tran Van Nhieu Pauillac, Serge Gibert, Maryse Sauvonnet, Nathalie Stiles, Bradley G. Popoff, Michel R. Barth, Holger TI CD44 Promotes Intoxication by the Clostridial Iota-Family Toxins SO PLOS ONE LA English DT Article ID BOTULINUM C2 TOXIN; LIPID RAFTS; BIOLOGICAL-ACTIVITY; SPIROFORME TOXIN; BINDING DOMAIN; ANTHRAX TOXIN; VERO CELLS; RECEPTOR; ACTIN; PROTEINS AB Various pathogenic clostridia produce binary protein toxins associated with enteric diseases of humans and animals. Separate binding/translocation (B) components bind to a protein receptor on the cell surface, assemble with enzymatic (A) component(s), and mediate endocytosis of the toxin complex. Ultimately there is translocation of A component(s) from acidified endosomes into the cytosol, leading to destruction of the actin cytoskeleton. Our results revealed that CD44, a multifunctional surface protein of mammalian cells, facilitates intoxication by the iota family of clostridial binary toxins. Specific antibody against CD44 inhibited cytotoxicity of the prototypical Clostridium perfringens iota toxin. Versus CD44(+) melanoma cells, those lacking CD44 bound less toxin and were dose-dependently resistant to C. perfringens iota, as well as Clostridium difficile and Clostridium spiroforme iota-like, toxins. Purified CD44 specifically interacted in vitro with iota and iota-like, but not related Clostridium botulinum C2, toxins. Furthermore, CD44 knockout mice were resistant to iota toxin lethality. Collective data reveal an important role for CD44 during intoxication by a family of clostridial binary toxins. C1 [Stiles, Bradley G.] Wilson Coll, Dept Biol, Chambersburg, PA 17201 USA. [Ruthel, Gordon] Univ Penn, Core Imaging Facil, Sch Vet Med, Philadelphia, PA 19104 USA. [Schnell, Leonie; Barth, Holger] Univ Ulm, Inst Pharmacol & Toxicol, Med Ctr, Ulm, Germany. [Wigelsworth, Darran J.] USA, Med Res Inst Infect Dis, Integrated Toxicol Div, Frederick, MD USA. [Herrlich, Peter] Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany. [Blonder, Josip; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Frederick, MD 21701 USA. [Carman, Robert J.; Wilkins, Tracy D.] TechLab Inc, Blacksburg, VA USA. [Guy Tran Van Nhieu] Coll France, Dept Intracellular Commun & Infect Microorgan, F-75231 Paris, France. [Pauillac, Serge; Gibert, Maryse; Popoff, Michel R.] Inst Pasteur, Unite Bacteries Anaerobies & Toxines, Paris, France. [Sauvonnet, Nathalie] Inst Pasteur, Unite Biol Interact Cellulaires, Paris, France. RP Stiles, BG (reprint author), Wilson Coll, Dept Biol, Chambersburg, PA 17201 USA. EM bstiles@wilson.edu; mpopoff@pasteur.fr; holger.barth@uni-ulm.de RI Barth, Holger/E-7920-2013; Popoff, Michel/O-7719-2016 OI Popoff, Michel/0000-0001-9305-8989 FU Institut Pasteur; Faculty Fund for Research at Wilson College; Faculty of Medicine at the University of Ulm plus Deutsche Forschungsgemeinschaft (DFG) [BA 2087/2-1] FX Funding was provided in part by the Institut Pasteur (MRP), Faculty Fund for Research at Wilson College (BGS), as well as the Faculty of Medicine at the University of Ulm plus Deutsche Forschungsgemeinschaft (DFG grant BA 2087/2-1) to HB. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 60 TC 13 Z9 13 U1 0 U2 12 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 DEC 7 PY 2012 VL 7 IS 12 AR e51356 DI 10.1371/journal.pone.0051356 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 050OT UT WOS:000312064100104 PM 23236484 ER PT J AU Gao, L Shao, L Higgins, CD Poulton, JS Peifer, M Davidson, MW Wu, XF Goldstein, B Betzig, E AF Gao, Liang Shao, Lin Higgins, Christopher D. Poulton, John S. Peifer, Mark Davidson, Michael W. Wu, Xufeng Goldstein, Bob Betzig, Eric TI Noninvasive Imaging beyond the Diffraction Limit of 3D Dynamics in Thickly Fluorescent Specimens SO CELL LA English DT Article ID STRUCTURED ILLUMINATION MICROSCOPY; PLANE ILLUMINATION; ADAPTIVE OPTICS; MOUSE-BRAIN; C. ELEGANS; RESOLUTION; CELLS; LIVE; BIOLOGY; LIGHT AB Optical imaging of the dynamics of living specimens involves tradeoffs between spatial resolution, temporal resolution, and phototoxicity, made more difficult in three dimensions. Here, however, we report that rapid three-dimensional (3D) dynamics can be studied beyond the diffraction limit in thick or densely fluorescent living specimens over many time points by combining ultrathin planar illumination produced by scanned Bessel beams with super-resolution structured illumination microscopy. We demonstrate in vivo karyotyping of chromosomes during mitosis and identify different dynamics for the actin cytoskeleton at the dorsal and ventral surfaces of fibroblasts. Compared to spinning disk confocal microscopy, we demonstrate substantially reduced photodamage when imaging rapid morphological changes in D. discoideum cells, as well as improved contrast and resolution at depth within developing C. elegans embryos. Bessel beam structured plane illumination thus promises new insights into complex biological phenomena that require 4D subcellular spatiotemporal detail in either a single or multicellular context. C1 [Gao, Liang; Shao, Lin; Betzig, Eric] Howard Hughes Med Inst, Ashburn, VA 20147 USA. [Higgins, Christopher D.; Poulton, John S.; Peifer, Mark; Goldstein, Bob] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. [Wu, Xufeng] NHLBI, 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. RP Betzig, E (reprint author), Howard Hughes Med Inst, Janelia Farm Res Campus, Ashburn, VA 20147 USA. EM betzige@janelia.hhmi.org OI Goldstein, Bob/0000-0001-6961-675X; Peifer, Mark/0000-0003-1412-3987 FU NIH [R01-GM083071, R01-GM67236] FX We thank the following Janelia Farm researchers: Thomas Planchon and Bi-Chang Chen for their help with the instrument; Helen White and Sarah Winfrey for cell culture and transfection; Aliosha Nern and Phuson Hulamm for the D. melanogaster brain sample; and Hanchuan Peng for the C. elegans L1 larva. We also thank Dan Milkie of Coleman Technologies, Chadds Ford, PA for custom instrument control software; Goeh Jung of the NHLBI/NIH for the D. discoideum specimen; and Jennifer Lippincott-Schwartz and John Hammer of the NIH for valuable suggestions. B.G. acknowledges the support of NIH R01-GM083071. J.S.P. and M.P. acknowledge the support of NIH R01-GM67236. NR 28 TC 133 Z9 134 U1 2 U2 157 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 7 PY 2012 VL 151 IS 6 BP 1370 EP 1385 DI 10.1016/j.cell.2012.10.008 PG 16 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 049RA UT WOS:000311999900024 PM 23217717 ER PT J AU Kormendi, V Szyk, A Piszczek, G Roll-Mecak, A AF Kormendi, Vasilisa Szyk, Agnieszka Piszczek, Grzegorz Roll-Mecak, Antonina TI Crystal Structures of Tubulin Acetyltransferase Reveal a Conserved Catalytic Core and the Plasticity of the Essential N Terminus SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHLAMYDOMONAS ALPHA-TUBULIN; AXON REGENERATION; ACETYLATION; MICROTUBULES; LYSINE; SUPERFAMILY; SOFTWARE; FLAGELLA; PROTEIN; MEC-17 AB Tubulin acetyltransferase (TAT) acetylates Lys-40 of alpha-tubulin in the microtubule lumen. TAT is inefficient, and its activity is enhanced when tubulin is incorporated in microtubules. Acetylation is associated with stable microtubules and regulates the binding of microtubule motors and associated proteins. TAT is important in neuronal polarity and mechanosensation, and decreased tubulin acetylation levels are associated with axonal transport defects and neurodegeneration. We present the first structure of TAT in complex with acetyl-CoA (Ac-CoA) at 2.7 angstrom resolution. The structure reveals a conserved stable catalytic core shared with other GCN5 superfamily acetyltransferases consisting of a central beta-sheet flanked by alpha-helices and a C-terminal beta-hairpin unique to TAT. Structure-guided mutagenesis establishes the molecular determinants for Ac-CoA and tubulin substrate recognition. The wild-type TAT construct is a monomer in solution. We identify a metastable interface between the conserved core and N-terminal domain that modulates the oligomerization of TAT in solution and is essential for activity. The 2.45 angstrom resolution structure of an inactive TAT construct with an active site point mutation near this interface reveals a domain-swapped dimer in which the functionally essential N terminus shows evidence of marked structural plasticity. The sequence segment corresponding to this structurally plastic region in TAT has been implicated in substrate recognition in other GCN5 superfamily acetyltransferases. Our structures provide a rational platform for the mechanistic dissection of TAT activity and the design of TAT inhibitors with therapeutic potential in neuronal regeneration. C1 [Roll-Mecak, Antonina] NINDS, Cell Biol & Biophys Unit, Porter Neurosci Res Ctr, NIH, Bethesda, MD 20892 USA. [Piszczek, Grzegorz; Roll-Mecak, Antonina] NHLBI, NIH, Bethesda, MD 20892 USA. RP Roll-Mecak, A (reprint author), NINDS, Cell Biol & Biophys Unit, Porter Neurosci Res Ctr, NIH, Bldg 35,Rm 3B-203,35 Convent Dr,MSC 3700, Bethesda, MD 20892 USA. EM Antonina@mail.nih.gov FU National Institutes of Health FX This work was supported, in whole or in part, by the intramural program of the National Institutes of Health (to A. R. M.). NR 31 TC 17 Z9 18 U1 0 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 DEC 7 PY 2012 VL 287 IS 50 BP 41569 EP 41575 DI 10.1074/jbc.C112.421222 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 051CT UT WOS:000312103000001 PM 23105108 ER PT J AU Xiao, CY Wang, RH Lahusen, TJ Park, O Bertola, A Maruyama, T Reynolds, D Chen, Q Xu, XL Young, HA Chen, WJ Gao, B Deng, CX AF Xiao, Cuiying Wang, Rui-Hong Lahusen, Tyler J. Park, Ogyi Bertola, Adeline Maruyama, Takashi Reynolds, Della Chen, Qiang Xu, Xiaoling Young, Howard A. Chen, Wan-Jun Gao, Bin Deng, Chu-Xia TI Progression of Chronic Liver Inflammation and Fibrosis Driven by Activation of c-JUN Signaling in Sirt6 Mutant Mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DEPENDENT GENE-EXPRESSION; TUMOR-SUPPRESSOR; DEVELOPMENTAL DEFECTS; MAMMALIAN SIRTUINS; TRANSCRIPTION 3; EFFECTOR-CELLS; LIFE-SPAN; CANCER; METABOLISM; DISEASE AB The human body has a remarkable ability to regulate inflammation, a biophysical response triggered by virus infection and tissue damage. Sirt6 is critical for metabolism and lifespan; however, its role in inflammation is unknown. Here we show that Sirt6-null (Sirt6(-/-)) mice developed chronic liver inflammation starting at similar to 2 months of age, and all animals were affected by 7-8 months of age. Deletion of Sirt6 in T cells or myeloid-derived cells was sufficient to induce liver inflammation and fibrosis, albeit to a lesser degree than that in the global Sirt6(-/-) mice, suggesting that Sirt6 deficiency in the immune cells is the cause. Consistently, macrophages derived from the bone marrow of Sirt6(-/-) mice showed increased MCP-1, IL-6, and TNF alpha expression levels and were hypersensitive to LPS stimulation. Mechanistically, SIRT6 interacts with c-JUN and deacetylates histone H3 lysine 9 (H3K9) at the promoter of proinflammatory genes whose expression involves the c-JUN signaling pathway. Sirt6-deficient macrophages displayed hyperacetylation of H3K9 and increased occupancy of c-JUN in the promoter of these genes, leading to their elevated expression. These data suggest that Sirt6 plays an anti-inflammatory role in mice by inhibiting c-JUN-dependent expression of proinflammatory genes. C1 [Xiao, Cuiying; Wang, Rui-Hong; Lahusen, Tyler J.; Chen, Qiang; Xu, Xiaoling; Deng, Chu-Xia] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Xiao, Cuiying; Park, Ogyi; Bertola, Adeline; Gao, Bin] NIAAA, Lab Liver Dis, NIH, Bethesda, MD 20892 USA. [Maruyama, Takashi; Chen, Wan-Jun] Natl Inst Dent & Craniofacial Res, Mucosal Immunol Sect, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. [Reynolds, Della; Young, Howard A.] Frederick Natl Lab Canc Res, Expt Immunol Lab, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016; OI Bertola, Adeline/0000-0002-4885-8423 FU National Institutes of Health Intramural Research Program FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program. NR 56 TC 40 Z9 40 U1 1 U2 10 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 7 PY 2012 VL 287 IS 50 BP 41903 EP 41913 DI 10.1074/jbc.M112.415182 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 051CT UT WOS:000312103000030 PM 23076146 ER PT J AU Thiyagarajan, N Pham, TTK Stinson, B Sundriyal, A Tumbale, P Lizotte-Waniewski, M Brew, K Acharya, KR AF Thiyagarajan, Nethaji Pham, Tram T. K. Stinson, Brittany Sundriyal, Amit Tumbale, Percy Lizotte-Waniewski, Michelle Brew, Keith Acharya, K. Ravi TI Structure of a metal-independent bacterial glycosyltransferase that catalyzes the synthesis of histo-blood group A antigen SO SCIENTIFIC REPORTS LA English DT Article ID GROUP-B GLYCOSYLTRANSFERASES; MOLECULAR REPLACEMENT; RETAINING GLYCOSYLTRANSFERASE; DIFFERENTIAL RECOGNITION; CONFORMATIONAL-CHANGES; ESCHERICHIA-COLI; ALPHA-1,3-GALACTOSYLTRANSFERASE; SPECIFICITY; SYNTHASE; BINDING AB Histo-blood group antigens (HBGAs) are a source of antigenic variation between individuals that modulates resistance and susceptibility to pathogens and is a barrier to the spread of enveloped viruses. HBGAs are also produced by a few prokaryotes where they are synthesized by glycosyltransferases (GTs) related to human HBGA synthases. Here we report the first structure of a bacterial GT of this family, from an intestinal resident, Bacteroides ovatus. Unlike its mammalian homologues and other GTs with similar folds, this protein lacks a metal-binding Asp-X-Asp motif and is fully active in the absence of divalent metal ions, yet is strikingly similar in structure and in its interactions with substrates to structurally characterized mammalian metal-dependent mammalian homologues. This shows how an apparently major divergence in catalytic properties can be accommodated by minor structural adjustments and illustrates the structural underpinnings of horizontal transfer of a functional gene from prokaryotes to vertebrates. C1 [Stinson, Brittany; Tumbale, Percy; Lizotte-Waniewski, Michelle; Brew, Keith] Florida Atlantic Univ, Dept Biomed Sci, Charles E Schmidt Coll Med, Boca Raton, FL 33431 USA. [Thiyagarajan, Nethaji; Pham, Tram T. K.; Sundriyal, Amit; Acharya, K. Ravi] Univ Bath, Dept Biol & Biochem, Bath BA2 7AY, Avon, England. [Sundriyal, Amit] Univ Basel, Dept Struct Biol, Biozentrum, CH-4056 Basel, Switzerland. [Tumbale, Percy] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Brew, K (reprint author), Florida Atlantic Univ, Dept Biomed Sci, Charles E Schmidt Coll Med, 777 Glades Rd, Boca Raton, FL 33431 USA. EM kbrew@fau.edu; bsskra@bath.ac.uk RI Brew, Keith/A-6746-2009 OI Brew, Keith/0000-0003-1306-1032 FU Wellcome Trust (UK) equipment grant [088464]; University of Bath; NIH (USA) [AR40994]; National Science Foundation (USA) [GK-12] FX This work was supported by a Wellcome Trust (UK) equipment grant (number 088464) to K.R.A. We thank Professor Eleanor Dodson (University of York, UK) for help with 'molecular replacement' used in the structure determination of apo BoGT6a and the scientists at Diamond Light Source, Didcot, Oxon (UK) for their support during X-ray diffraction data collection. T.T.K.P. wishes to thank Biotechnology Center of Ho Chi Minh City, Vietnam and University of Bath for a post-graduate studentship. K.B. was supported by NIH (USA) grant AR40994 and P.T. and B.S. were partly funded by the National Science Foundation (USA) GK-12 Program. NR 44 TC 5 Z9 5 U1 2 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 7 PY 2012 VL 2 AR 940 DI 10.1038/srep00940 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 049MZ UT WOS:000311988400002 PM 23230506 ER PT J AU Liu, Y Rutlin, M Huang, SY Barrick, CA Wang, F Jones, KR Tessarollo, L Ginty, DD AF Liu, Yin Rutlin, Michael Huang, Siyi Barrick, Colleen A. Wang, Fan Jones, Kevin R. Tessarollo, Lino Ginty, David D. TI Sexually Dimorphic BDNF Signaling Directs Sensory Innervation of the Mammary Gland SO SCIENCE LA English DT Article ID CELL-DEATH; NERVOUS-SYSTEM; IN-VIVO; TRKB; RECEPTOR; NEURONS; MOUSE; DIFFERENTIATION; ORGANIZATION; GENE AB How neural circuits associated with sexually dimorphic organs are differentially assembled during development is unclear. Here, we report a sexually dimorphic pattern of mouse mammary gland sensory innervation and the mechanism of its formation. Brain-derived neurotrophic factor (BDNF), emanating from mammary mesenchyme and signaling through its receptor TrkB on sensory axons, is required for establishing mammary gland sensory innervation of both sexes at early developmental stages. Subsequently, in males, androgens promote mammary mesenchymal expression of a truncated form of TrkB, which prevents BDNF-TrkB signaling in sensory axons and leads to a rapid loss of mammary gland innervation independent of neuronal apoptosis. Thus, sex hormone regulation of a neurotrophic factor signal directs sexually dimorphic axonal growth and maintenance, resulting in generation of a sex-specific neural circuit. C1 [Liu, Yin; Rutlin, Michael; Huang, Siyi; Ginty, David D.] Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. [Barrick, Colleen A.; Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Wang, Fan] Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. [Jones, Kevin R.] Univ Colorado, Dept Mol Cellular & Dev Biol, Boulder, CO 80309 USA. RP Ginty, DD (reprint author), Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. EM dginty@jhmi.edu FU NIH [NS34814, EY014998, DE019440] FX We thank members of the Ginty laboratory for assistance and discussions throughout the course of this project, and A. Kolodkin and R. Kuruvilla for comments on the manuscript. This work was supported by NIH grants NS34814 (D. D. G.), EY014998 (K.R.J.), and DE019440 (F. W.). D. D. G. is an investigator of the Howard Hughes Medical Institute. BDNFlox mice are covered under U. S. patent no. 4,959,317, which is licensed to Bristol-Myer Squibb Company, with the right to grant sublicenses. The mice are available for noncommercial biomedical research under a Material Transfer Agreement with the University of Colorado. NR 21 TC 22 Z9 22 U1 0 U2 22 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 DEC 7 PY 2012 VL 338 IS 6112 BP 1357 EP 1360 DI 10.1126/science.1228258 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 049NZ UT WOS:000311991200071 PM 23224557 ER PT J AU Liu, X Houzet, L Jeang, KT AF Liu, Xiang Houzet, Laurent Jeang, Kuan-Teh TI Tombusvirus P19 RNA silencing suppressor (RSS) activity in mammalian cells correlates with charged amino acids that contribute to direct RNA-binding SO CELL AND BIOSCIENCE LA English DT Article ID SMALL INTERFERING RNA; DOUBLE-STRANDED-RNA; BUSHY-STUNT-VIRUS; SYSTEMIC INVASION; HIV-1 REPLICATION; VIRAL-INFECTIONS; PROTEIN; MICRORNA; DICER; EXPRESSION AB Background: Tombusvirus P19 is a protein encoded by tomato bushy stunt virus and related tombusviruses. Earlier studies have demonstrated that P19 is an RNA silencing suppressor (RSS) in plant cells. However, it has not been systematically investigated how P19 suppresses RNA interference in various mammalian cell settings. Results: We have studied the RSS effect of P19 in mammalian cells, HEK293T, HeLa, and mouse embryonic fibroblasts. We have individually mutated 18 positively charged residues in P19 and found that 6 of these charged residues in P19 reduce its ability to suppress RNA interference. In each case, the reduction of silencing of RNA interference correlated with the reduced ability by these P19 mutants to bind siRNAs (small interfering RNAs). Conclusions: Our findings characterize a class of RNA-binding proteins that function as RSS moieties. We find a tight correlation between positively charged residues in P19 accounting for siRNA-binding and their RSS activity. Because P19's activity is conserved in plant and animal cells, we conclude that its RSS function unlikely requires cell type-specific co-factors and likely arises from direct RNA-binding. C1 [Liu, Xiang; Houzet, Laurent; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, 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 kjeang@niaid.nih.gov RI Liu, Xiang/F-5731-2014 FU NIAID intramural research funds; IATAP program from the Office of the Director, NIH FX We are grateful to Alicia Buckler-White and Ronald Plishka for sequencing and analyses. We thank our laboratory members for critical readings of the manuscript. This work was supported by NIAID intramural research funds and funding from the IATAP program from the Office of the Director, NIH. NR 59 TC 6 Z9 6 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 2045-3701 J9 CELL BIOSCI JI Cell Biosci. PD DEC 6 PY 2012 VL 2 AR 41 DI 10.1186/2045-3701-2-41 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 068HP UT WOS:000313357400001 PM 23216864 ER PT J AU Wiestner, A AF Wiestner, Adrian TI Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia SO BLOOD LA English DT Review ID B-CELL-RECEPTOR; NON-HODGKIN-LYMPHOMA; TYROSINE KINASE; ANTIGEN RECEPTOR; FOSTAMATINIB DISODIUM; THERAPEUTIC TARGET; AUTOIMMUNE-DISEASE; SYK INHIBITOR; ACTIVATION; SURVIVAL AB Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that depend on host factors in the tissue microenvironment for survival and proliferation. In vitro, CLL cells rapidly undergo apoptosis unless microenvironmental factors are provided that support their survival. Signaling pathways activated in the microenvironment in vivo include the B-cell receptor (BCR) and NF-kappa B pathways. Thus, CLL is a disease "addicted to the host" and is dependent on pathways that pro-mote normal B-cell development, expansion, and survival; this is particularly true in the case of the BCR signaling cascade. Small-molecule inhibitors of kinases that are essential for BCR signal transduction abrogate the stimulating effects of the microenvironment on CLL cells. The orally administered tyrosine kinase inhibitors fostamatinib and ibrutinib and the phosphatidylinositol 3-kinase inhibitor GS1101 have induced impressive responses in relapsed and refractory CLL patients, mostly with moderate side effects. Reductions in lymphadenopathy and splenomegaly are seen within weeks and are frequently accompanied by a transient rise in absolute lymphocyte count that is asymptomatic and probably the result of changes in CLL cell trafficking. This review discusses the biologic basis for kinase inhibitors as targeted therapy of CLL and summarizes the exciting early clinical experience with these agents. (Blood. 2012;120(24):4684-4691) C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10,CRC 3-5140, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov FU Heart, Lung, and Blood Institute, National Institutes of Health FX A.W. is supported by the intramural research program of the Heart, Lung, and Blood Institute, National Institutes of Health. NR 80 TC 82 Z9 85 U1 0 U2 17 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD DEC 6 PY 2012 VL 120 IS 24 BP 4684 EP 4691 DI 10.1182/blood-2012-05-423194 PG 8 WC Hematology SC Hematology GA 064ZO UT WOS:000313115300009 PM 22875912 ER PT J AU Moir, S De Ravin, SS Santich, BH Kim, JY Posada, JG Ho, J Buckner, CM Wang, W Kardava, L Garofalo, M Marciano, BE Manischewitz, J King, LR Khurana, S Chun, TW Golding, H Fauci, AS Malech, HL AF Moir, Susan De Ravin, Suk See Santich, Brian H. Kim, Jin Young Posada, Jacqueline G. Ho, Jason Buckner, Clarisa M. Wang, Wei Kardava, Lela Garofalo, Mary Marciano, Beatriz E. Manischewitz, Jody King, Lisa R. Khurana, Surender Chun, Tae-Wook Golding, Hana Fauci, Anthony S. Malech, Harry L. TI Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells SO BLOOD LA English DT Article ID HIV-INFECTION; EXPRESSION; ANTIBODIES; BINDING; RECEPTORS; RESPONSES AB CD27(+) memory B cells are reduced in the blood of patients with chronic granulomatous disease (CGD) for reasons and consequences that remain unclear. Here we confirm not only decreased CD27(+) but also IgG(+) B cells in the blood of CGD patients compared with healthy donors (HDs). However, among IgG(+) B cells, the ratio of CD27(-) to CD27(+) was significantly higher in CGD patients compared with HDs. Similar to conventional memory B cells, CD27(-)IgG(+) B cells of CGD patients expressed activation markers and had undergone somatic hypermutation, albeit at levels lower than their CD27(+) counterparts. Functional analyses revealed slight reductions in frequencies of total IgG but not influenza-specific memory B-cell responses, as measured by Elispot in CGD patients compared with HDs. Serum IgG levels and influenza-specific antibodies were also normal in these CGD patients. Finally, we provide evidence that influenza-specific memory B cells can be present within the CD27(-)IgG(+) B-cell compartment. Together, these findings show that, despite reduced circulating CD27(+) memory B cells, CGD patients maintain an intact humoral immunologic memory, with potential contribution from CD27(-) B cells. (Blood. 2012;120(24):4850-4858) C1 [De Ravin, Suk See; Garofalo, Mary; Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Moir, Susan; Santich, Brian H.; Kim, Jin Young; Posada, Jacqueline G.; Ho, Jason; Buckner, Clarisa M.; Wang, Wei; Kardava, Lela; Chun, Tae-Wook; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Marciano, Beatriz E.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Manischewitz, Jody; King, Lisa R.; Khurana, Surender; Golding, Hana] US FDA, Ctr Biol Evaluat & Res, Div Viral Prod, Bethesda, MD USA. RP De Ravin, SS (reprint author), NIAID, Host Def Lab, NIH, 10-CRC-5W-3816,10 Ctr Dr, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov; sderavin@niaid.nih.gov OI Malech, Harry/0000-0001-5874-5775 FU NIAID, National Institutes of Health FX This work was supported by the Intramural Research Program of NIAID, National Institutes of Health. NR 29 TC 22 Z9 23 U1 0 U2 12 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 DEC 6 PY 2012 VL 120 IS 24 BP 4850 EP 4858 DI 10.1182/blood-2012-05-430959 PG 9 WC Hematology SC Hematology GA 064ZO UT WOS:000313115300028 PM 23074274 ER PT J AU Huang, J Sabater-Lleal, M Asselbergs, FW Tregouet, D Shin, SY Ding, JZ Baumert, J Oudot-Mellakh, T Folkersen, L Johnson, AD Smith, NL Williams, SM Ikram, MA Kleber, ME Becker, DM Truong, V Mychaleckyj, JC Tang, WH Yang, Q Sennblad, B Moore, JH Williams, FMK Dehghan, A Silbernagel, G Schrijvers, EMC Smith, S Karakas, M Tofler, GH Silveira, A Navis, GJ Lohman, K Chen, MH Peters, A Goel, A Hopewell, JC Chambers, JC Saleheen, D Lundmark, P Psaty, BM Strawbridge, RJ Boehm, BO Carter, AM Meisinger, C Peden, JF Bis, JC McKnight, B Ohrvik, J Taylor, K Franzosi, MG Seedorf, U Collins, R Franco-Cereceda, A Syvanen, AC Goodall, AH Yanek, LR Cushman, M Muller-Nurasyid, M Folsom, AR Basu, S Matijevic, N van Gilst, WH Kooner, JS Hofman, A Danesh, J Clarke, R Meigs, JB Kathiresan, S Reilly, MP Klopp, N Harris, TB Winkelmann, BR Grant, PJ Hillege, HL Watkins, H Spector, TD Becker, LC Tracy, RP Marz, W Uitterlinden, AG Eriksson, P Cambien, F Morange, PE Koenig, W Soranzo, N van der Harst, P Liu, YM O'Donnell, CJ Hamsten, A AF Huang, Jie Sabater-Lleal, Maria Asselbergs, Folkert W. Tregouet, David Shin, So-Youn Ding, Jingzhong Baumert, Jens Oudot-Mellakh, Tiphaine Folkersen, Lasse Johnson, Andrew D. Smith, Nicholas L. Williams, Scott M. Ikram, Mohammad A. Kleber, Marcus E. Becker, Diane M. Vinh Truong Mychaleckyj, Josyf C. Tang, Weihong Yang, Qiong Sennblad, Bengt Moore, Jason H. Williams, Frances M. K. Dehghan, Abbas Silbernagel, Guenther Schrijvers, Elisabeth M. C. Smith, Shelly Karakas, Mahir Tofler, Geoffrey H. Silveira, Angela Navis, Gerjan J. Lohman, Kurt Chen, Ming-Huei Peters, Annette Goel, Anuj Hopewell, Jemma C. Chambers, John C. Saleheen, Danish Lundmark, Per Psaty, Bruce M. Strawbridge, Rona J. Boehm, Bernhard O. Carter, Angela M. Meisinger, Christa Peden, John F. Bis, Joshua C. McKnight, Barbara Ohrvik, John Taylor, Kent Franzosi, Maria Grazia Seedorf, Udo Collins, Rory Franco-Cereceda, Anders Syvaenen, Ann-Christine Goodall, Alison H. Yanek, Lisa R. Cushman, Mary Mueller-Nurasyid, Martina Folsom, Aaron R. Basu, Saonli Matijevic, Nena van Gilst, Wiek H. Kooner, Jaspal S. Hofman, Albert Danesh, John Clarke, Robert Meigs, James B. Kathiresan, Sekar Reilly, Muredach P. Klopp, Norman Harris, Tamara B. Winkelmann, Bernhard R. Grant, Peter J. Hillege, Hans L. Watkins, Hugh Spector, Timothy D. Becker, Lewis C. Tracy, Russell P. Maerz, Winfried Uitterlinden, Andre G. Eriksson, Per Cambien, Francois Morange, Pierre-Emmanuel Koenig, Wolfgang Soranzo, Nicole van der Harst, Pim Liu, Yongmei O'Donnell, Christopher J. Hamsten, Anders CA DIAGRAM Consortium CARDIoGRAM Consortium C4D Consortium CARDIOGENICS Consortium TI Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation SO BLOOD LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; CORONARY-ARTERY-DISEASE; MYOCARDIAL-INFARCTION; GENETIC-VARIATION; SUSCEPTIBILITY LOCI; TYPE-1 EXPRESSION; CIRCADIAN CLOCK; PLASMA-LEVELS; TISSUE; RISK AB We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 x 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 x 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 x 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, dis-covery P = 2.9 x 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1. (Blood. 2012;120(24):4873-4881) C1 [Huang, Jie; Johnson, Andrew D.; Yang, Qiong; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [Hamsten, Anders] Karolinska Inst, Atherosclerosis Res Unit, Ctr Mol Med, Karolinska Univ Hosp Solna,Dept Med, S-17176 Stockholm, Sweden. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Dept Cardiol, Div Heart & Lungs, Utrecht, Netherlands. [Asselbergs, Folkert W.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. [Asselbergs, Folkert W.] Univ Med Ctr, Dept Med Genet, Utrecht, Netherlands. [Tregouet, David; Oudot-Mellakh, Tiphaine; Vinh Truong; Cambien, Francois] Univ Paris 06, INSERM, UMR S 937, ICAN Inst, Paris, France. [Shin, So-Youn; Soranzo, Nicole] Wellcome Trust Sanger Inst, Hinxton, England. [Ding, Jingzhong] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Baumert, Jens; Peters, Annette; Meisinger, Christa] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 2, Neuherberg, Germany. [Johnson, Andrew D.; O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [Smith, Nicholas L.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Smith, Nicholas L.; Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Smith, Nicholas L.] Seattle Epidemiol Res & Informat Ctr, VA Off Res & Dev, Seattle, WA USA. [Williams, Scott M.] Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. [Ikram, Mohammad A.; Dehghan, Abbas; Schrijvers, Elisabeth M. C.; Hofman, Albert] Erasmus Med Ctr MC Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Ikram, Mohammad A.; Uitterlinden, Andre G.] Erasmus MC Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Kleber, Marcus E.] Ludwigshafen Risk & Cardiovasc Hlth LURIC Study N, Freiburg, Germany. [Kleber, Marcus E.; Maerz, Winfried] Heidelberg Univ, Fac Med, Mannheim Inst Publ Hlth, Mannheim, Germany. [Becker, Diane M.; Yanek, Lisa R.] Johns Hopkins Sch Med, Div Internal Med, Baltimore, MD USA. [Mychaleckyj, Josyf C.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Tang, Weihong; Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Yang, Qiong; Chen, Ming-Huei] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Moore, Jason H.] Dartmouth Med Sch, Dept Genet, Lebanon, NH USA. [Moore, Jason H.] Dartmouth Med Sch, Dept Community & Family Med, Lebanon, NH USA. [Williams, Frances M. K.; Spector, Timothy D.; Soranzo, Nicole] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Dehghan, Abbas; Schrijvers, Elisabeth M. C.; Hofman, Albert; Uitterlinden, Andre G.] Netherlands Consortium Hlth Aging, Leiden, Netherlands. [Silbernagel, Guenther] Univ Tubingen, Dept Internal Med, Div Endocrinol Diabetol Nephrol Vasc Dis & Clin C, Tubingen, Germany. [Smith, Shelly; Liu, Yongmei] Wake Forest Univ, Bowman Gray Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Karakas, Mahir; Koenig, Wolfgang] Univ Ulm, Med Ctr, Dept Internal Med Cardiol 2, D-89069 Ulm, Germany. [Tofler, Geoffrey H.] Univ Sydney, Royal N Shore Hosp, Sydney, NSW 2006, Australia. [Navis, Gerjan J.] Univ Groningen, Univ Med Ctr Groningen, Dept Internal Med, Groningen, Netherlands. [Lohman, Kurt] Wake Forest Univ, Bowman Gray Sch Med, Dept Biostat Sci, Winston Salem, NC USA. [Goel, Anuj; Peden, John F.; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford, England. [Goel, Anuj; Peden, John F.; Watkins, Hugh] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Hopewell, Jemma C.; Collins, Rory; Clarke, Robert] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Chambers, John C.] Univ London Imperial Coll Sci Technol & Med, London, England. [Saleheen, Danish] Ctr Noncommunicable Dis Pakistan, Karachi, Pakistan. [Saleheen, Danish; Danesh, John] Univ Cambridge, Strangeways Res Lab, Dept Publ Hlth & Primary Care, Cambridge, England. [Lundmark, Per; Syvaenen, Ann-Christine] Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden. [Psaty, Bruce M.; Bis, Joshua C.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Boehm, Bernhard O.] Univ Ulm, Grad Sch Mol Diabetol & Endocrinol, Div Endocrinol Diabet & Metab, D-89069 Ulm, Germany. [Carter, Angela M.; Grant, Peter J.] Univ Leeds, Div Cardiovasc & Diabet Res, Leeds, W Yorkshire, England. [McKnight, Barbara] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Taylor, Kent] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Franzosi, Maria Grazia] Ist Mario Negri, Dept Cardiovasc Res, Milan, Italy. [Seedorf, Udo] Univ Munster, LIFA, Gesell Arterioskleroseforsch 5, D-48149 Munster, Germany. [Franco-Cereceda, Anders] Karolinska Inst, Dept Mol Med & Surg, Cardiothorac Surg Unit, S-17176 Stockholm, Sweden. [Goodall, Alison H.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Cushman, Mary] Univ Vermont, Dept Med, Burlington, VT USA. [Cushman, Mary] Univ Vermont, Dept Pathol, Burlington, VT 05405 USA. [Mueller-Nurasyid, Martina] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Genet Epidemiol, Neuherberg, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Inst Med Informat Biometry & Epidemiol, Chair Epidemiol, Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Chair Genet Epidemiol, Munich, Germany. [Mueller-Nurasyid, Martina] Univ Munich, Univ Hosp Grosshadern, Dept Med 1, Munich, Germany. [Basu, Saonli] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Matijevic, Nena] Univ Texas Hlth Sci Ctr Houston, Hemostasis Lab, Houston, TX USA. [van Gilst, Wiek H.; Hillege, Hans L.; van der Harst, Pim] Univ Groningen, Univ Med Ctr Groningen, Dept Cardiol, Groningen, Netherlands. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [Meigs, James B.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA. [Kathiresan, Sekar] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kathiresan, Sekar] Broad Inst Harvard & Massachusetts Inst Technol M, Program Med & Populat Genet, Cambridge, MA USA. [Reilly, Muredach P.] Univ Penn, Perelman Sch Med, Cardiovasc Inst, Philadelphia, PA 19104 USA. [Klopp, Norman] German Resrarch Ctr Environm Hlth, Helmholtz Zentrum Munchen, Div Mol Epidemiol, Neuherberg, Germany. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. [Winkelmann, Bernhard R.] Cardiol Team Sachsenhausen, Frankfurt, Germany. [Becker, Lewis C.] Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA. [Tracy, Russell P.] Univ Vermont, Coll Med, Dept Pathol & Biochem, Burlington, VT USA. [Maerz, Winfried] Synlab Acad, Mannheim, Germany. [Maerz, Winfried] Med Univ Graz, Clin Inst Med & Chem Lab Diagnost, Graz, Austria. [Morange, Pierre-Emmanuel] Univ Aix Marseille 2, UMR S 626, INSERM, Marseille, France. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA. RP Hamsten, A (reprint author), Karolinska Inst, Atherosclerosis Res Unit, Ctr Mol Med, Karolinska Univ Hosp Solna,Dept Med, Bldg L8-03, S-17176 Stockholm, Sweden. EM odonnellc@nhlbi.nih.gov; anders.hamsten@ki.se RI Meisinger, Christine/B-5358-2014; Yang, Qiong/G-5438-2014; Strawbridge, Rona/H-5422-2012; Boehm, Bernhard/F-8750-2015; Peters, Annette/A-6117-2011; Tregouet, David-Alexandre/E-3961-2016; Williams, Scott/B-9491-2012; Johnson, Andrew/G-6520-2013; Sabater-Lleal, Maria/I-5832-2013; OI Strawbridge, Rona/0000-0001-8506-3585; Williams, Frances/0000-0002-2998-2744; Ikram, Mohammad Arfan/0000-0003-0372-8585; Seedorf, Udo/0000-0003-4652-5358; Folkersen, Lasse/0000-0003-0708-9530; Soranzo, Nicole/0000-0003-1095-3852; Meisinger, Christa/0000-0002-9026-6544; Watkins, Hugh/0000-0002-5287-9016; Ouwehand, Willem/0000-0002-7744-1790; Kleber, Marcus/0000-0003-0663-7275; Dehghan, Abbas/0000-0001-6403-016X; Sabater Lleal, Maria/0000-0002-0128-379X FU Biotechnology and Biological Sciences Research Council; British Heart Foundation [, RG/08/014/24067]; Department of Health; Intramural NIH HHS; Medical Research Council [, G0700931, MC_U137686857]; NCATS NIH HHS [UL1 TR000124]; NCRR NIH HHS [M01 RR00052, RR-024156, RR018787, UL1-RR-025005]; NHGRI NIH HHS [U01-HG-004402]; NHLBI NIH HHS [N01-HC-85084, 1U01 HL072518, HL080295, HL087652, HL105756, HL65234, HL67466, N01 HC-15103, N01 HC-55222, N01 HC085086, N01 HC095166, N01-HC-25195, N01-HC-35129, N01-HC-45133, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, N01-HC-75150, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85085, N01-HC-85086, N01-HC-85239, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, N02-HL-6-4278, P01 HL074940, R01 HL095603, R01 HL095796, R01 HL59684, R01-HL-086694, R01-HL-087641, R01-HL-59367, R01-HL59367, R01HL071051, R01HL071205, R01HL071250, R01HL071251, R01HL071252, R01HL071258, R01HL071259, U01 HL072518]; NIA NIH HHS [1R01AG032098-01A1, AG-023629, AG-027058, AG-15928, AG-20098, N01AG62101, N01AG62103, N01AG62106]; NIDDK NIH HHS [DK063491, K24 DK080140]; NIGMS NIH HHS [P20 GM103534, T32 GM080178]; NLM NIH HHS [LM010098, R01 LM010098]; PHS HHS [HHSN268200625226C, HHSN268200782096C, HHSN268201200036C]; Wellcome Trust [, 090532] NR 37 TC 26 Z9 27 U1 0 U2 17 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 DEC 6 PY 2012 VL 120 IS 24 BP 4873 EP 4881 DI 10.1182/blood-2012-06-436188 PG 9 WC Hematology SC Hematology GA 064ZO UT WOS:000313115300031 PM 22990020 ER PT J AU Kim, SH Cho, YR Kim, HJ Oh, JS Ahn, EK Ko, HJ Hwang, BJ Lee, SJ Cho, Y Kim, YK Stetler-Stevenson, WG Seo, DW AF Kim, Soo Hyeon Cho, Young-Rak Kim, Hyeon-Ju Oh, Joa Sub Ahn, Eun-Kyung Ko, Hye-Jin Hwang, Byung Joon Lee, Seo-Jin Cho, Yongwan Kim, Yong Kee Stetler-Stevenson, William G. Seo, Dong-Wan TI Antagonism of VEGF-A-induced increase in vascular permeability by an integrin alpha 3 beta 1-Shp-1-cAMP/PKA pathway SO BLOOD LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TYROSINE-PHOSPHATASE TCPTP; TISSUE INHIBITOR; BETA-CATENIN; CELL JUNCTIONS; CADHERIN; TIMP-2; ANGIOGENESIS; METALLOPROTEINASE-2; PROTEIN AB In cancer, VEGF-induced increase in vascular permeability results in increased interstitial pressure, reducing perfusion and increasing hypoxia, which reduce delivery of chemotherapeutic agents and increase resistance to ionizing radiation. Here, we show that both TIMP-2 and Ala + TIMP-2, a TIMP-2 mutant without matrix metalloproteinase inhibitory activity, antagonize the VEGF-A-induced increase in vascular permeability, both in vitro and in vivo. Like other agents known to preserve endothelial barrier function, TIMP-2 elevates cytosolic levels of cAMP and increases cytoskeletal-associated vascular endothelial cadherin in human microvascular endothelial cells. All of these effects are completely ablated by selective knockdown of integrin alpha 3 beta 1 expression, expression of a dominant negative protein tyrosine phosphatase Shp-1 mutant, administration of the protein tyrosine phosphatase inhibitor orthovanadate, or the adenylate cyclase inhibitor SQ22536. This TIMP-2-mediated inhibition of vascular permeability involves an integrin alpha 3 beta 1-Shp-1-cAMP/protein kinase A-dependent vascular endothelial cadherin cytoskeletal association, as evidenced by using siRNAs to integrin alpha 3 beta 1 and Shp-1, or treatment with Shp-1 inhibitor NSC87877 and protein kinase A inhibitor H89. Our results demonstrate the potential utility for TIMP-2 in cancer therapy through "normalization" of vascular permeability in addition to previously described antiangiogenic effects. (Blood. 2012;120(24):4892-4902) C1 [Kim, Soo Hyeon; Hwang, Byung Joon] Kangwon Natl Univ, Coll Biomed Sci, Dept Mol Biosci, Chunchon, South Korea. [Seo, Dong-Wan] Dankook Univ, Coll Pharm, Biochem Lab, Cheonan 330714, South Korea. [Ahn, Eun-Kyung; Ko, Hye-Jin] Gyeonggi Inst Sci & Technol Promot, Nat Prod Res Inst, Suwon, South Korea. [Lee, Seo-Jin] Shingyeong Univ, Dept Life Sci & Biotechnol, Hwaseong, South Korea. [Cho, Yongwan] Proteogen Inc, Proteinchip Res Ctr, Chunchon, South Korea. [Kim, Yong Kee] Sookmyung Womens Univ, Coll Pharm, Seoul, South Korea. [Stetler-Stevenson, William G.] NCI, Extracellular Matrix Pathol Sect, Radiat Oncol Branch, Ctr Canc Res,NIH,Adv Technol Ctr, Bethesda, MD 20892 USA. RP Stetler-Stevenson, WG (reprint author), NCI, Extracellular Matrix Pathol Sect, Radiat Oncol Branch, Ctr Canc Res,NIH,Adv Technol Ctr, Rm 115D, Bethesda, MD 20892 USA. EM sstevenw@mail.nih.gov; dwseomb@dankook.ac.kr RI Stetler-Stevenson, William/H-6956-2012; OI Stetler-Stevenson, William/0000-0002-5500-5808; Oh, Joa Sub/0000-0002-6367-5174; Seo, Dong-Wan/0000-0003-4971-834X FU National Cancer Institute, Center for Cancer Research [Z01SC 009179]; National Research Foundation of Korea from the Ministry of Education, Science and Technology [KRF-2008-313-C00555, 2010-0021913] FX This work was supported by the National Cancer Institute, Center for Cancer Research Project (intramural research funds Z01SC 009179, W.G.S.-S.), and Basic Science Research Program through the National Research Foundation of Korea from the Ministry of Education, Science and Technology (KRF-2008-313-C00555 and 2010-0021913, D.-W.S.). NR 50 TC 23 Z9 23 U1 0 U2 5 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 DEC 6 PY 2012 VL 120 IS 24 BP 4892 EP 4902 DI 10.1182/blood-2012-05-428243 PG 11 WC Hematology SC Hematology GA 064ZO UT WOS:000313115300033 PM 23074279 ER PT J AU Zhao, K Ishida, Y Oleksyk, TK Winkler, CA Roca, AL AF Zhao, Kai Ishida, Yasuko Oleksyk, Taras K. Winkler, Cheryl A. Roca, Alfred L. TI Evidence for selection at HIV host susceptibility genes in a West Central African human population SO BMC EVOLUTIONARY BIOLOGY LA English DT Article DE HIV dependency factors; Single nucleotide polymorphisms; Biaka pygmies; Mbuti pygmies ID IMMUNODEFICIENCY-VIRUS TYPE-1; WORLDWIDE HUMAN-POPULATIONS; RECENT POSITIVE SELECTION; PYGMY HUNTER-GATHERERS; CHEMOKINE RECEPTOR; NONHUMAN-PRIMATES; NATURAL-SELECTION; AIDS PROGRESSION; MILLION SNPS; FOAMY VIRUS AB Background: HIV-1 derives from multiple independent transfers of simian immunodeficiency virus (SIV) strains from chimpanzees to human populations. We hypothesized that human populations in west central Africa may have been exposed to SIV prior to the pandemic, and that previous outbreaks may have selected for genetic resistance to immunodeficiency viruses. To test this hypothesis, we examined the genomes of Biaka Western Pygmies, who historically resided in communities within the geographic range of the central African chimpanzee subspecies (Pan troglodytes troglodytes) that carries strains of SIV ancestral to HIV-1. Results: SNP genotypes of the Biaka were compared to those of African human populations who historically resided outside the range of P. t. troglodytes, including the Mbuti Eastern Pygmies. Genomic regions showing signatures of selection were compared to the genomic locations of genes reported to be associated with HIV infection or pathogenesis. In the Biaka, a strong signal of selection was detected at CUL5, which codes for a component of the vif-mediated APOBEC3 degradation pathway. A CUL5 allele protective against AIDS progression was fixed in the Biaka. A signal of selection was detected at TRIM5, which codes for an HIV post-entry restriction factor. A protective mis sense mutation in TRIM5 had the highest frequency in Biaka compared to other African populations, as did a protective allele for APOBEC3G, which codes for an anti-HIV-1 restriction factor. Alleles protective against HIV-1 for APOBEC3H, CXCR6 and HLA-C were at higher frequencies in the Biaka than in the Mbuti. Biaka genomes showed a strong signal of selection at TSG101, an inhibitor of HIV-1 viral budding. Conclusions: We found protective alleles or evidence for selection in the Biaka at a number of genes associated with HIV-1 infection or progression. Pygmies have also been reported to carry genotypes protective against HIV-1 for the genes CCR5 and CCL3L1. Our hypothesis that HIV-1 may have shaped the genomes of some human populations in West Central Africa appears to merit further investigation. C1 [Zhao, Kai; Ishida, Yasuko; Roca, Alfred L.] Univ Illinois, Dept Anim Sci, Urbana, IL 61801 USA. [Oleksyk, Taras K.] Univ Puerto Rico, Dept Biol, Mayaguez, PR 00681 USA. [Winkler, Cheryl A.] NCI, Basic Res Lab, Ctr Canc Res, SAIC Frederick,Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Roca, Alfred L.] Univ Illinois, Inst Genom Biol, Urbana, IL 61801 USA. RP Roca, AL (reprint author), Univ Illinois, Dept Anim Sci, Urbana, IL 61801 USA. EM roca@illinois.edu RI Taras, Oleksyk/J-8805-2013 OI Taras, Oleksyk/0000-0002-8148-3918 FU Bill & Melinda Gates Foundation through the Grand Challenges Exploration Initiative; federal funds from National Cancer Institute, National Institutes of Health [HHSN26120080001E] FX Funded by a grant from the Bill & Melinda Gates Foundation through the Grand Challenges Exploration Initiative. 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 project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract HHSN26120080001E. NR 83 TC 9 Z9 9 U1 1 U2 31 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD DEC 6 PY 2012 VL 12 AR 237 DI 10.1186/1471-2148-12-237 PG 13 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 067HP UT WOS:000313285200001 PM 23217182 ER PT J AU Mancini, G D'Annessa, I Coletta, A Chillemi, G Pommier, Y Cushman, M Desideri, A AF Mancini, Giordano D'Annessa, Ilda Coletta, Andrea Chillemi, Giovanni Pommier, Yves Cushman, Mark Desideri, Alessandro TI Binding of an Indenoisoquinoline to the Topoisomerase-DNA Complex Induces Reduction of Linker Mobility and Strengthening of Protein-DNA Interaction SO PLOS ONE LA English DT Article ID PARTICLE MESH EWALD; MOLECULAR-DYNAMICS; CATALYTIC MECHANISM; CLEAVAGE COMPLEXES; COVALENT COMPLEX; I INHIBITORS; CAMPTOTHECIN; SIMULATIONS; RESISTANCE; IDENTIFICATION AB Long-duration comparative molecular dynamics simulations of the DNA-topoisomerase binary and DNA-topoisomerase-indenoisoquinoline ternary complexes have been carried out. The analyses demonstrated the role of the drug in conformationally stabilizing the protein-DNA interaction. In detail, the protein lips, clamping the DNA substrate, interact more tightly in the ternary complex than in the binary one. The drug also reduces the conformational space sampled by the protein linker domain through an increased interaction with the helix bundle proximal to the active site. A similar alteration of linker domain dynamics has been observed in a precedent work for topotecan but the molecular mechanisms were different if compared to those described in this work. Finally, the indenoisoquinoline keeps Lys532 far from the DNA, making it unable to participate in the religation reaction, indicating that both short- and long-range interactions contribute to the drug poisoning effect. Citation: Mancini G, D'Annessa I, Coletta A, Chillemi G, Pommier Y, et al. (2012) Binding of an Indenoisoquinoline to the Topoisomerase-DNA Complex Induces Reduction of Linker Mobility and Strengthening of Protein-DNA Interaction. PLoS ONE 7(12): e51354. doi:10.1371/journal.pone.0051354 C1 [D'Annessa, Ilda; Coletta, Andrea; Desideri, Alessandro] Univ Roma Tor Vergata, Dept Biol, I-00173 Rome, Italy. [D'Annessa, Ilda; Coletta, Andrea; Desideri, Alessandro] Univ Roma Tor Vergata, Ctr Bioinformat & Biostat, I-00173 Rome, Italy. [Mancini, Giordano; Chillemi, Giovanni] CASPUR Interuniv Consortium Applicat Super Comp U, Rome, Italy. [Pommier, Yves] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Cushman, Mark] Purdue Univ, Dept Med Chem & Mol Pharmacol, Coll Pharm, W Lafayette, IN 47907 USA. [Cushman, Mark] Purdue Univ, Purdue Ctr Canc Res, W Lafayette, IN 47907 USA. RP Desideri, A (reprint author), Univ Roma Tor Vergata, Dept Biol, Via Ric Sci, I-00173 Rome, Italy. EM desideri@uniroma2.it RI Chillemi, Giovanni/E-5201-2010; Coletta, Andrea/H-9856-2012; OI Chillemi, Giovanni/0000-0003-3901-6926; Coletta, Andrea/0000-0003-4032-394X; D'Annessa, Ilda/0000-0002-6174-6899 FU Associazione Italiana Ricerca Cancro AIRC [10121] FX AD thanks the Associazione Italiana Ricerca Cancro AIRC (www.airc.it), which supported the work with project number 10121. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 44 TC 12 Z9 13 U1 1 U2 17 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 DEC 6 PY 2012 VL 7 IS 12 AR e51354 DI 10.1371/journal.pone.0051354 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 057UO UT WOS:000312589700038 PM 23236483 ER PT J AU Merbah, M Arakelyan, A Edmonds, T Ochsenbauer, C Kappes, JC Shattock, RJ Grivel, JC Margolis, LB AF Merbah, Melanie Arakelyan, Anush Edmonds, Tara Ochsenbauer, Christina Kappes, John C. Shattock, Robin J. Grivel, Jean-Charles Margolis, Leonid B. TI HIV-1 Expressing the Envelopes of Transmitted/Founder or Control/Reference Viruses Have Similar Infection Patterns of CD4 T-Cells in Human Cervical Tissue Ex Vivo SO PLOS ONE LA English DT Article ID HUMAN LYMPHOID-TISSUE; SIMIAN IMMUNODEFICIENCY VIRUS; SEXUAL TRANSMISSION; CXCR4-TROPIC HIV-1; TYPE-1 INFECTION; MOLECULAR CLONES; PATHOGENESIS; CCR5; DISSEMINATION; DETERMINANTS AB Recently, it was found that 80% of sexual HIV-1 transmissions are established by a single virion/viral genome. To investigate whether the transmitted/founder (T/F) viruses have specific biological properties favoring sexual transmission, we inoculated human cervical tissue explants with isogenic HIV-1 viruses encoding Env sequences from T/F and control reference (C/R) HIV-1 variants as well as with full length T/F HIV-1 and compared their replication efficiencies, T cell depletion, and the activation status of infected cells. We found that all the HIV-1 variants were capable of transmitting infection to cervical tissue ex vivo and in this system preferentially replicate in activated CD4 T cells and deplete these cells. There was no difference in the biological properties of T/F and C/R HIV-1 variants as evaluated in ex vivo cervical tissue. Citation: Merbah M, Arakelyan A, Edmonds T, Ochsenbauer C, Kappes JC, et al. (2012) HIV-1 Expressing the Envelopes of Transmitted/Founder or Control/Reference Viruses Have Similar Infection Patterns of CD4 T-Cells in Human Cervical Tissue Ex Vivo. PLoS ONE 7(12): e50839. doi:10.1371/journal.pone.0050839 C1 [Merbah, Melanie; Arakelyan, Anush; Grivel, Jean-Charles; Margolis, Leonid B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Intercellular Interact, Program Phys Biol, NIH, Bethesda, MD 20892 USA. [Edmonds, Tara; Ochsenbauer, Christina; Kappes, John C.] Univ Alabama Birmingham, Birmingham, AL USA. [Shattock, Robin J.] Univ London Imperial Coll Sci Technol & Med, London, England. RP Grivel, JC (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Intercellular Interact, Program Phys Biol, NIH, Bethesda, MD 20892 USA. EM grigri@helix.nih.gov FU Intramural NICHD Program; Center for HIV/AIDS Vaccine Immunology (CHAVI) [U19 AI067854-05] FX The work of MM, AA, J-CG and LBM was supported by the Intramural NICHD Program. RS, CO, TGE and JCK were supported by the Center for HIV/AIDS Vaccine Immunology (CHAVI) # U19 AI067854-05. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 7 Z9 7 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 DEC 6 PY 2012 VL 7 IS 12 AR e50839 DI 10.1371/journal.pone.0050839 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 057UO UT WOS:000312589700019 PM 23236398 ER PT J AU Cavanaugh, J Monosov, IE McAlonan, K Berman, R Smith, MK Cao, V Wang, KH Boyden, ES Wurtz, RH AF Cavanaugh, James Monosov, Ilya E. McAlonan, Kerry Berman, Rebecca Smith, Mitchell K. Cao, Vania Wang, Kuan H. Boyden, Edward S. Wurtz, Robert H. TI Optogenetic Inactivation Modifies Monkey Visuomotor Behavior SO NEURON LA English DT Article ID SACCADIC EYE-MOVEMENTS; SUPERIOR COLLICULUS; NEURONS; SIGNALS; SPREAD; BRAIN; FIELD AB A critical technique for understanding how neuronal activity contributes to behavior is determining whether perturbing it changes behavior. The advent of optogenetic techniques allows the immediately reversible alteration of neuronal activity in contrast to chemical approaches lasting minutes to hours. Modification of behavior using optogenetics has had substantial success in rodents but has not been as successful in monkeys. Here, we show how optogenetic inactivation of superior colliculus neurons in awake monkeys leads to clear and repeatable behavioral deficits in the metrics of saccadic eye movements. We used our observations to evaluate principles governing the use of optogenetic techniques in the study of the neuronal bases of behavior in monkeys, particularly how experimental design must address relevant parameters, such as the application of light to subcortical structures, the spread of viral injections, and the extent of neuronal inactivation with light. C1 [Cavanaugh, James; Monosov, Ilya E.; McAlonan, Kerry; Berman, Rebecca; Smith, Mitchell K.; Wurtz, Robert H.] NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20982 USA. [Cao, Vania; Wang, Kuan H.] NIMH, Unit Neural Circuits & Adapt Behav, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Boyden, Edward S.] MIT, Dept Biol Engn & Brain & Cognit Sci, Cambridge, MA USA. RP Cavanaugh, J (reprint author), NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20982 USA. EM jrc@lsr.nei.nih.gov RI Wang, Kuan Hong/J-1150-2016 OI Wang, Kuan Hong/0000-0002-2249-5417 FU Intramural NIH HHS [ZIA EY000109-33] NR 16 TC 46 Z9 46 U1 2 U2 22 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD DEC 6 PY 2012 VL 76 IS 5 BP 901 EP 907 DI 10.1016/j.neuron.2012.10.016 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 053OX UT WOS:000312283400007 PM 23217739 ER PT J AU Stavreva, DA George, AA Klausmeyer, P Varticovski, L Sack, D Voss, TC Schiltz, RL Blazer, VS Iwanowicz, LR Hager, GL AF Stavreva, Diana A. George, Anuja A. Klausmeyer, Paul Varticovski, Lyuba Sack, Daniel Voss, Ty C. Schiltz, R. Louis Blazer, Vicki S. Iwanowicz, Luke R. Hager, Gordon L. TI Prevalent Glucocorticoid and Androgen Activity in US Water Sources SO SCIENTIFIC REPORTS LA English DT Article ID BASS MICROPTERUS-DOLOMIEU; WASTE-WATER; ENDOCRINE DISRUPTORS; REPRODUCTIVE HEALTH; LIVING CELLS; RECEPTOR; POTOMAC; RIVER; QUANTIFICATION; CONTAMINANTS AB Contamination of the environment with endocrine disrupting chemicals (EDCs) is a major health concern. The presence of estrogenic compounds in water and their deleterious effect are well documented. However, detection and monitoring of other classes of EDCs is limited. Here we utilize a high-throughput live cell assay based on sub-cellular relocalization of GFP-tagged glucocorticoid and androgen receptors (GFP-GR and GFP-AR), in combination with gene transcription analysis, to screen for glucocorticoid and androgen activity in water samples. We report previously unrecognized glucocorticoid activity in 27%, and androgen activity in 35% of tested water sources from 14 states in the US. Steroids of both classes impact body development, metabolism, and interfere with reproductive, endocrine, and immune systems. This prevalent contamination could negatively affect wildlife and human populations. C1 [Stavreva, Diana A.; George, Anuja A.; Varticovski, Lyuba; Sack, Daniel; Voss, Ty C.; Schiltz, R. Louis; Hager, Gordon L.] NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. [Klausmeyer, Paul] SAIC Frederick Inc, Nat Prod Support Grp, Frederick Natl Lab Canc Res, Ft Detrick, MD 21702 USA. [Blazer, Vicki S.; Iwanowicz, Luke R.] USGS BRD Leetown Sci Ctr, Kearneysville, WV 25430 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,B602 41 Lib Dr, Bethesda, MD 20892 USA. EM stavrevd@mail.nih.gov; luke_iwanowicz@usgs.gov; hagerg@exchange.nih.gov RI George, Anuja/C-5963-2017; OI George, Anuja/0000-0003-2643-6307; Iwanowicz, Luke/0000-0002-1197-6178 FU USGS; Fish and Wildlife Contaminants program; Great Lakes Research Initiative; West Virginia Departments of Natural Resources and Environmental Protection; Virginia Department of Game and Inland Fisheries; Maryland Department of Natural Resources; Pennsylvania Fish and Boat Commission; NIH, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NCI High Throughput Facility FX Collection and extraction of environmental samples was funded by the Chesapeake Bay Priority Ecosystems Science, Toxic Substances Hydrology, Fisheries and Contaminant programs of USGS, the Fish and Wildlife Contaminants program, the Great Lakes Research Initiative, West Virginia Departments of Natural Resources and Environmental Protection, Virginia Department of Game and Inland Fisheries, Maryland Department of Natural Resources and Pennsylvania Fish and Boat Commission. 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 also 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. We acknowledge the assistance of Tatiana Karpova and Jim McNally, LRBGE Fluorescence Imaging Facility. We also acknowledge the support of the NCI High Throughput Facility. NR 42 TC 16 Z9 16 U1 2 U2 49 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2045-2322 J9 SCI REP-UK JI Sci Rep PD DEC 6 PY 2012 VL 2 AR 937 DI 10.1038/srep00937 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 048TJ UT WOS:000311935700006 PM 23226835 ER PT J AU Haspel, N Laurent, AD Zanuy, D Nussinov, R Aleman, C Puiggali, J Revilla-Lopez, G AF Haspel, Nurit Laurent, Adele D. Zanuy, David Nussinov, Ruth Aleman, Carlos Puiggali, Jordi Revilla-Lopez, Guillem TI Conformational Exploration of Two Peptides and Their Hybrid Polymer Conjugates: Potentialities As Self-Aggregating Materials SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID MOLECULAR-DYNAMICS; PEG CRYSTALLIZATION; BLOCK-COPOLYMERS; AMYLOIDS; FRAGMENT; SYSTEM AB In this work we elucidate the conformational preferences of two amyloid-forming peptides, Arginine-Vasopressin and Neuromedin-K, and two new biomacromolecular conjugates obtained by linking the two peptides to a polyester (poly(R-lactic acid)) chain. The conformational properties of the new hybrid conjugates have been assessed through molecular dynamics simulations and compared to those of their individual components Our results suggest that the free unconjugated peptides tend to,adopt backbone arrangements. which resemble a beta-hairpin shape, a conformation which has been reported to facilitate amyloid self-aggregation. The backbone conformational preferences of the unlinked peptides are maintained in the peptide-polymer hybrid. Yet significant differences in the side chains nonbonding interactions patterns were detected between the two states. This suggests that the conformational profile of the peptides backbones is preserved when linked to the polymer, maintaining the amyloid precursor like structure. Additionally, several hydrodynamic parameters Were computed for both the polylactic acid and for the conjugates: no significant differences were observed, which suggests that the peptide moiety of the hybrid does not significantly affect the conformational tendencies of the polymer chain. Combined, our results provide a conformational exploration of two amyloid-forming peptides and first steps toward the design of two feasible self aggregating hybrid materials C1 [Haspel, Nurit] Univ Massachusetts, Dept Compuer Sci, Boston, MA 02125 USA. [Laurent, Adele D.; Zanuy, David; Aleman, Carlos; Puiggali, Jordi; Revilla-Lopez, Guillem] Univ Politecn Cataluna, Dept Engn Quim, ETS Engn Ind Barcelona, E-08028 Barcelona, Spain. [Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick, Ctr Canc Res,Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. [Aleman, Carlos] Univ Politecn Cataluna, Ctr Res Nanoengn, E-08028 Barcelona, Spain. RP Haspel, N (reprint author), Univ Massachusetts, Dept Compuer Sci, Harbor Campus, Boston, MA 02125 USA. EM nurit.haspel@umb.edu; guillermo.revilla@upc.edu RI Zanuy, David/G-3930-2014; Laurent, Adele/G-5190-2011; Haspel, Nurit/D-1961-2017; OI Zanuy, David/0000-0001-7704-2178; Laurent, Adele/0000-0001-9553-9014; Puiggali, Jordi/0000-0002-0640-4474 FU MICINN; FEDER [MAT2009-09138, MAT2009-11503]; Generalitat de Catalunya [2009-SGR-925, 2009SGR-1208]; UMass Boston proposal development grant; Barcelona Supercumpt-ing Center (BSC) [QCM-2011-2-0020]; Generalitat de Catalunya; National Science Foundation [TG-MCB100025]; Federal funds from the National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research FX This work has been supported by MICINN and FEDER (Grants MAT2009-09138 and MAT2009-11503), by the Generalitat de Catalunya (Grants 2009-SGR-925, 2009SGR-1208, and XRQTC), and by the UMass Boston proposal development grant (N.H). The authors are indebted for the computational resources provided by "Centre de Super-computacio de Catalunya" (CESCA), Barcelona Supercumpt-ing Center (BSC, Project QCM-2011-2-0020) and the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. (http://biowulf.nih.gov). Part of the calculations were carried out on the supercomputing facilities in the College of Science and Mathematics at UMass Boston. Support for the research of C.A. was received through the prize "ICREA Academia" for excellence in research funded by the Generalitat de Catalunya. The research was supported in part by the National Science Foundation through TeraGrid resources provided by the Texas Advanced Computing Center (TACC) under Grant No. TG-MCB100025 (N.H.). 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. 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. NR 45 TC 4 Z9 4 U1 1 U2 29 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 DEC 6 PY 2012 VL 116 IS 48 BP 13941 EP 13952 DI 10.1021/jp3043363 PG 12 WC Chemistry, Physical SC Chemistry GA 048OL UT WOS:000311921700001 PM 23157485 ER PT J AU Lee, GS Subramanian, N Kim, AI Aksentijevich, I Goldbach-Mansky, R Sacks, DB Germain, RN Kastner, DL Chae, JJ AF Lee, Geun-Shik Subramanian, Naeha Kim, Andrew I. Aksentijevich, Ivona Goldbach-Mansky, Raphaela Sacks, David B. Germain, Ronald N. Kastner, Daniel L. Chae, Jae Jin TI The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP SO NATURE LA English DT Article ID NALP3 INFLAMMASOME; MURINE MACROPHAGES; ACTIVATION; ATP; CRYSTALS; LIPOPOLYSACCHARIDE; MUTATIONS; SECRETION; RELEASE AB Mutations in the gene encoding NLRP3 cause a spectrum of auto-inflammatory diseases known as cryopyrin-associated periodic syndromes (CAPS)(1). NLRP3 is a key component of one of several distinct cytoplasmic multiprotein complexes (inflammasomes) that mediate the maturation of the proinflammatory cytokine interleukin-1 beta (IL-1 beta) by activating caspase-1. Although several models for inflammasome activation, such as K+ efflux(2), generation of reactive oxygen species(3) and lysosomal destabilization(4), have been proposed, the precise molecular mechanism of NLRP3 inflammasome activation, as well as the mechanism by which CAPS-associated mutations activate NLRP3, remain to be elucidated. Here we show that the murine calcium-sensing receptor (CASR) activates the NLRP3 inflammasome, mediated by increased intracellular Ca2+ and decreased cellular cyclic AMP(cAMP). Ca2+ or other CASR agonists activate the NLRP3 inflammasome in the absence of exogenous ATP, whereas knockdown of CASR reduces inflammasome activation in response to known NLRP3 activators. CASR activates the NLRP3 inflammasome through phospholipase C, which catalyses inositol-1,4,5-trisphosphate production and thereby induces release of Ca2+ from endoplasmic reticulum stores. The increased cytoplasmic Ca2+ promotes the assembly of inflammasome components, and intracellular Ca2+ is required for spontaneous inflammasome activity in cells from patients with CAPS. CASR stimulation also results in reduced intracellular cAMP, which independently activates the NLRP3 inflammasome. cAMP binds to NLRP3 directly to inhibit inflammasome assembly, and downregulation of cAMP relieves this inhibition. The binding affinity of cAMP for CAPS-associated mutant NLRP3 is substantially lower than for wild-type NLRP3, and the uncontrolled mature IL-1 beta production from CAPS patients' peripheral blood mononuclear cells is attenuated by increasing cAMP. Taken together, these findings indicate that Ca2+ and cAMP are two key molecular regulators of the NLRP3 inflammasome that have critical roles in the molecular pathogenesis of CAPS. C1 [Lee, Geun-Shik; Kim, Andrew I.; Aksentijevich, Ivona; Kastner, Daniel L.; Chae, Jae Jin] NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Lee, Geun-Shik] Kangwon Natl Univ, Coll Vet Med, Chunchon 200701, Gangwon, South Korea. [Subramanian, Naeha; Germain, Ronald N.] NIAID, Lab Syst Biol, NIH, Bethesda, MD 20892 USA. [Goldbach-Mansky, Raphaela] NIAMSD, Translat Autoinflammatory Dis Sect, NIH, Bethesda, MD 20892 USA. [Sacks, David B.] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kastner, DL (reprint author), NHGRI, Inflammatory Dis Sect, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM kastnerd@mail.nih.gov; chaej@mail.nih.gov OI Sacks, David/0000-0003-3100-0735 FU NIAMS; NHGRI; NIAID, NIH FX This work was supported by the Intramural Research Programs of the NIAMS, NHGRI, and NIAID, NIH. We thank E. Remmers for discussion and a thorough review of this manuscript. NR 24 TC 215 Z9 228 U1 4 U2 70 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 6 PY 2012 VL 492 IS 7427 BP 123 EP + DI 10.1038/nature11588 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 048EQ UT WOS:000311893400058 PM 23143333 ER PT J AU Reddy, UM Page, GP Saade, GR Silver, RM Thorsten, VR Parker, CB Pinar, H Willinger, M Stoll, BJ Heim-Hall, J Varner, MW Goldenberg, RL Bukowski, R Wapner, RJ Drews-Botsch, CD O'Brien, BM Dudley, DJ Levy, B AF Reddy, Uma M. Page, Grier P. Saade, George R. Silver, Robert M. Thorsten, Vanessa R. Parker, Corette B. Pinar, Halit Willinger, Marian Stoll, Barbara J. Heim-Hall, Josefine Varner, Michael W. Goldenberg, Robert L. Bukowski, Radek Wapner, Ronald J. Drews-Botsch, Carolyn D. O'Brien, Barbara M. Dudley, Donald J. Levy, Brynn CA NICHD Stillbirth Collaborative Res TI Karyotype versus Microarray Testing for Genetic Abnormalities after Stillbirth SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; COPY-NUMBER VARIANTS; MICRODUPLICATION 22Q11.2; CONGENITAL-ANOMALIES; INDIVIDUALS; DEATHS AB BACKGROUND Genetic abnormalities have been associated with 6 to 13% of stillbirths, but the true prevalence may be higher. Unlike karyotype analysis, microarray analysis does not require live cells, and it detects small deletions and duplications called copy-number variants. METHODS The Stillbirth Collaborative Research Network conducted a population-based study of stillbirth in five geographic catchment areas. Standardized postmortem examinations and karyotype analyses were performed. A single-nucleotide polymorphism array was used to detect copy-number variants of at least 500 kb in placental or fetal tissue. Variants that were not identified in any of three databases of apparently unaffected persons were then classified into three groups: probably benign, clinical significance unknown, or pathogenic. We compared the results of karyotype and microarray analyses of samples obtained after delivery. RESULTS In our analysis of samples from 532 stillbirths, microarray analysis yielded results more often than did karyotype analysis (87.4% vs. 70.5%, P<0.001) and provided better detection of genetic abnormalities (aneuploidy or pathogenic copy-number variants, 8.3% vs. 5.8%; P = 0.007). Microarray analysis also identified more genetic abnormalities among 443 antepartum stillbirths (8.8% vs. 6.5%, P = 0.02) and 67 stillbirths with congenital anomalies (29.9% vs. 19.4%, P = 0.008). As compared with karyotype analysis, microarray analysis provided a relative increase in the diagnosis of genetic abnormalities of 41.9% in all stillbirths, 34.5% in antepartum stillbirths, and 53.8% in stillbirths with anomalies. CONCLUSIONS Microarray analysis is more likely than karyotype analysis to provide a genetic diagnosis, primarily because of its success with nonviable tissue, and is especially valuable in analyses of stillbirths with congenital anomalies or in cases in which karyotype results cannot be obtained. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.) C1 [Reddy, Uma M.; Willinger, Marian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. [Page, Grier P.; Thorsten, Vanessa R.; Parker, Corette B.] RTI Int, Res Triangle Pk, NC USA. [Saade, George R.; Bukowski, Radek] Univ Texas Med Branch Galveston, Galveston, TX USA. [Silver, Robert M.; Varner, Michael W.] Univ Utah, Sch Med, Salt Lake City, UT USA. [Silver, Robert M.; Varner, Michael W.] Intermt Hlth Care, Salt Lake City, UT USA. [Pinar, Halit; O'Brien, Barbara M.] Brown Univ, Sch Med, Providence, RI 02912 USA. [Stoll, Barbara J.] Emory Univ, Sch Med, Atlanta, GA USA. [Stoll, Barbara J.] Childrens Healthcare Atlanta, Atlanta, GA USA. [Drews-Botsch, Carolyn D.] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Heim-Hall, Josefine; Dudley, Donald J.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Goldenberg, Robert L.; Wapner, Ronald J.; Levy, Brynn] Columbia Univ, Med Ctr, New York, NY USA. RP Reddy, UM (reprint author), NICHD, Pregnancy & Perinatol Branch, 6100 Execut Blvd,Rm 4B03,MSC 7510, Bethesda, MD 20892 USA. EM reddyu@mail.nih.gov RI Drews-Botsch, Carolyn/M-8560-2016; Varner, Michael/K-9890-2013 OI Drews-Botsch, Carolyn/0000-0002-8763-7404; Varner, Michael/0000-0001-9455-3973 FU NICHD [HD45925, HD45944, HD45952, HD45953, HD45954, HD45955]; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX Supported by grants (HD45925, HD45944, HD45952, HD45953, HD45954, and HD45955) from the NICHD.; Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development NR 29 TC 56 Z9 61 U1 0 U2 9 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 DEC 6 PY 2012 VL 367 IS 23 BP 2185 EP 2193 DI 10.1056/NEJMoa1201569 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 048DO UT WOS:000311890600005 PM 23215556 ER PT J AU Landgren, O Staudt, L AF Landgren, Ola Staudt, Louis TI MYD88 L265P Somatic Mutation in IgM MGUS SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 [Landgren, Ola; Staudt, Louis] NCI, Bethesda, MD 20892 USA. RP Landgren, O (reprint author), NCI, Bethesda, MD 20892 USA. NR 5 TC 43 Z9 45 U1 1 U2 3 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 6 PY 2012 VL 367 IS 23 BP 2255 EP 2256 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 048DO UT WOS:000311890600020 PM 23215570 ER PT J AU Wu, CH Arighi, CN Cohen, KB Hirschman, L Krallinger, M Lu, ZY Mattingly, C Valencia, A Wiegers, TC Wilbur, WJ AF Wu, Cathy H. Arighi, Cecilia N. Cohen, Kevin B. Hirschman, Lynette Krallinger, Martin Lu, Zhiyong Mattingly, Carolyn Valencia, Alfonso Wiegers, Thomas C. Wilbur, W. John TI BioCreative-2012 Virtual Issue SO DATABASE-THE JOURNAL OF BIOLOGICAL DATABASES AND CURATION LA English DT Editorial Material ID INTERACTION DATABASE; BIOLOGY C1 [Wu, Cathy H.; Arighi, Cecilia N.] Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19711 USA. [Cohen, Kevin B.] Univ Colorado Denver, Sch Med, Ctr Computat Pharmacol, Aurora, CO 80045 USA. [Hirschman, Lynette] Mitre Corp, Bedford, MA 01730 USA. [Krallinger, Martin; Valencia, Alfonso] Spanish Natl Canc Res Ctr, Struct & Computat Biol Grp, E-28029 Madrid, Spain. [Lu, Zhiyong; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Mattingly, Carolyn; Wiegers, Thomas C.] N Carolina State Univ, Dept Biol, Raleigh, NC 27695 USA. RP Wu, CH (reprint author), Univ Delaware, Ctr Bioinformat & Computat Biol, Newark, DE 19711 USA. EM wuc@udel.edu RI Crozier, Laura/A-4821-2010; Valencia, Alfonso/I-3127-2015; OI Valencia, Alfonso/0000-0002-8937-6789; Arighi, Cecilia/0000-0002-0803-4817 NR 15 TC 12 Z9 12 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1758-0463 J9 DATABASE-OXFORD JI Database PD DEC 5 PY 2012 AR bas049 DI 10.1093/database/bas049 PG 3 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 106AS UT WOS:000316114400001 ER PT J AU Johnson, BC Pauly, GT Rai, G Patel, D Bauman, JD Baker, HL Das, K Schneider, JP Maloney, DJ Arnold, E Thomas, CJ Hughes, SH AF Johnson, Barry C. Pauly, Gary T. Rai, Ganesha Patel, Disha Bauman, Joseph D. Baker, Heather L. Das, Kalyan Schneider, Joel P. Maloney, David J. Arnold, Eddy Thomas, Craig J. Hughes, Stephen H. TI A comparison of the ability of rilpivirine (TMC278) and selected analogues to inhibit clinically relevant HIV-1 reverse transcriptase mutants SO RETROVIROLOGY LA English DT Article DE HIV; Reverse transcriptase; Rilpivirine ID NONNUCLEOSIDE INHIBITORS; HIV-1-INFECTED PATIENTS; RESISTANCE MUTATIONS; DOUBLE-BLIND; WILD-TYPE; DESIGN; DRUG; ETRAVIRINE; PHASE-3; POTENT AB Background: The recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast to earlier NNRTIs, rilpivirine retains potency against well-characterized, clinically relevant RT mutants. Many structural analogues of rilpivirine are described in the patent literature, but detailed analyses of their antiviral activities have not been published. This work addresses the ability of several of these analogues to inhibit the replication of wild-type (WT) and drug-resistant HIV-1. Results: We used a combination of structure activity relationships and X-ray crystallography to examine NNRTIs that are structurally related to rilpivirine to determine their ability to inhibit WT RT and several clinically relevant RT mutants. Several analogues showed broad activity with only modest losses of potency when challenged with drug-resistant viruses. Structural analyses (crystallography or modeling) of several analogues whose potencies were reduced by RT mutations provide insight into why these compounds were less effective. Conclusions: Subtle variations between compounds can lead to profound differences in their activities and resistance profiles. Compounds with larger substitutions replacing the pyrimidine and benzonitrile groups of rilpivirine, which reorient pocket residues, tend to lose more activity against the mutants we tested. These results provide a deeper understanding of how rilpivirine and related compounds interact with the NNRTI binding pocket and should facilitate development of novel inhibitors. C1 [Johnson, Barry C.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Pauly, Gary T.; Schneider, Joel P.] Frederick Natl Lab Canc Res, Canc Biol Lab, Frederick, MD USA. [Rai, Ganesha; Baker, Heather L.; Maloney, David J.; Thomas, Craig J.] NIH, Chem Genom Ctr, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Patel, Disha; Bauman, Joseph D.; Das, Kalyan; Arnold, Eddy] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Patel, Disha; Bauman, Joseph D.; Das, Kalyan; Arnold, Eddy] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Frederick Natl Lab Canc Res, POB BBldg 539,Room 130A, Frederick, MD 21702 USA. EM hughesst@mail.nih.gov RI Schneider, Joel/N-2610-2014 FU Intramural Research Programs of the National Cancer Institute; National Human Genome Research Institute; National Center for Advancing Translational Sciences; Intramural AIDS Targeted Antiviral Program (IATAP); R37 Merit Award [AI 27690] FX This research was supported by the Intramural Research Programs of the National Cancer Institute, the National Human Genome Research Institute, the National Center for Advancing Translational Sciences, the Intramural AIDS Targeted Antiviral Program (IATAP), and an R37 Merit Award AI 27690 to E.A. We acknowledge the Cornell High Energy Synchrotron Source (CHESS) for X-ray diffraction data collection. NR 31 TC 19 Z9 19 U1 1 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD DEC 5 PY 2012 VL 9 AR 99 DI 10.1186/1742-4690-9-99 PG 11 WC Virology SC Virology GA 076NF UT WOS:000313962500001 PM 23217210 ER PT J AU Hall, FS Perona, MTG AF Hall, F. Scott Perona, Maria T. G. TI Have studies of the developmental regulation of behavioral phenotypes revealed the mechanisms of gene-environment interactions? SO PHYSIOLOGY & BEHAVIOR LA English DT Review DE Environmental enrichment; Social isolation; Maternal deprivation; Gene-environment interaction; Epigenetic mechanisms ID EARLY MATERNAL SEPARATION; MEDIAL PREFRONTAL CORTEX; ISOLATION-REARED RATS; NERVE GROWTH-FACTOR; HIPPOCAMPAL GLUCOCORTICOID-RECEPTOR; PITUITARY-ADRENAL AXIS; EARLY SOCIAL-ISOLATION; INFANT RHESUS-MONKEYS; EARLY-LIFE STRESS; LONG-EVANS RATS AB This review addresses the recent convergence of our long-standing knowledge of the regulation of behavioral phenotypes by developmental experience with recent advances in our understanding of mechanisms regulating gene expression. This review supports a particular perspective on the developmental regulation of behavioral phenotypes: That the role of common developmental experiences (e.g. maternal interactions, peer interactions, exposure to a complex environment, etc.) W to fit individuals to the circumstances of their lives within bounds determined by long-standing (evolutionary) mechanisms that have shaped responses to critical and fundamental types of experience via those aspects of gene structure that regulate gene expression. The phenotype of a given species is not absolute for a given genotype but rather variable within bounds that is determined by mechanisms regulated by experience (e.g. epigenetic mechanisms). This phenotypic variation is not necessarily random, or evenly distributed along a continuum of description or measurement, but often highly disjointed, producing distinct, even opposing, phenotypes. The potentiality for these varying phenotypes is itself the product of evolution, the potential for alternative phenotypes itself conveying evolutionary advantage. Examples of such phenotypic variation, resulting from environmental or experiential influences, have a long history of study in neurobiology, and a number of these will be discussed in this review: neurodevelopmental experiences that produce phenotypic variation in visual perception, cognitive function, and emotional behavior. Although other examples will be discussed, particular emphasis will be made on the role of social behavior on neurodevelopment and phenotypic determination. It will be argued that an important purpose of some aspects of social behavior is regulation of neurobehavioral phenotypes by experience via genetic regulatory mechanisms. Published by Elsevier Inc. C1 [Hall, F. Scott; Perona, Maria T. G.] NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Hall, FS (reprint author), NIDA, Mol Neurobiol Branch, Intramural Res Program, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM shall@intra.nida.nih.gov RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 FU Intramural Research Program of the National Institute on Drug Abuse (USA) FX This work was supported by funding from the Intramural Research Program of the National Institute on Drug Abuse (USA). NR 405 TC 12 Z9 12 U1 3 U2 44 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD DEC 5 PY 2012 VL 107 IS 5 SI SI BP 623 EP 640 DI 10.1016/j.physbeh.2012.05.014 PG 18 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 067PW UT WOS:000313308600003 PM 22643448 ER PT J AU Yang, M Abrams, DN Zhang, JY Weber, MD Katz, AM Clarke, AM Silverman, JL Crawley, JN AF Yang, Mu Abrams, Danielle N. Zhang, James Y. Weber, Michael D. Katz, Adam M. Clarke, Andrew M. Silverman, Jill L. Crawley, Jacqueline N. TI Low sociability in BTBR T plus tf/J mice is independent of partner strain SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Autism; Mouse models; Mouse social behaviors; Inbred strains; Three-chambered social approach task; Reciprocal social interaction; BTBR T plus tf/J; Social partner; Olfactory habituation/dishabituation; Repetitive behaviors ID INBRED MOUSE STRAINS; SOCIAL APPROACH BEHAVIORS; AUTISM SPECTRUM DISORDERS; VISIBLE BURROW SYSTEM; C57BL/6J MICE; MUTANT MICE; ULTRASONIC COMMUNICATION; REPETITIVE BEHAVIOR; INSULIN-RESISTANCE; T+TF/J MICE AB Inbred mouse strains differ greatly in social behaviors, making them a valuable resource to study genetic and non-genetic mechanisms underlying social deficits relevant to autism spectrum disorders. A hallmark symptom of autism is a lack of ability to understand other people's thoughts and intentions, which leads to impairments in adjusting behaviors in response to ever-changing social situations in daily life. We compared the ability of BTBR T + tf/J (BTBR), a strain with low sociability, and C57BL/6J (B6), a strain with high sociability, for their abilities to modulate responses to social cues from different partners in the reciprocal social interaction test. Results indicate that BTBR exhibited low sociability toward different partners and displayed minimal ability to modify behaviors toward different partners. In contrast, B6 showed high sociability toward different partners and was able to modify social behaviors toward different partners. Consistent results were found in two independent cohorts of different ages, and in both sexes. In the three-chambered test, high sociability in B6 and low sociability in BTBR were independent of strain of the novel mouse. Since social deficits in BTBR could potentially be caused by physical disabilities in detecting social olfactory cues, or in cognitive abilities, we tested BTBR and B6 mice on measures of olfaction and cognition. BTBR mice displayed more sniffing of social odors emitted by soiled bedding than of an odorless novel object, but failed to show a preference for a live novel mouse over a novel object. On olfactory habituation/dishabituation to a sequence of odors, BTBR displayed discrimination abilities across three non-social and two social odors. However, as compared to B6, BTBR displayed less sniff time for both non-social and social odors, and no significant dishabituation between cage odors from two different novel mouse strains, findings that will be important to investigate further. BTBR was generally normal in spatial acquisition on the Morris water maze test, but showed deficits in reversal learning. Time spent freezing on contextual and cued fear conditioning was lower in BTBR than in B6. Our findings suggest that BTBR has poor abilities to modulate its responses to different social partners, which may be analogous to social cognition deficits in autism, adding to the value of this strain as a mouse model of autism. Published by Elsevier Inc. C1 [Yang, Mu] NIMH, Lab Behav Neurosci, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Yang, M (reprint author), NIMH, Lab Behav Neurosci, Intramural Res Program, NIH, Bldg 35,Room 1C-909,Mail Code 3730, Bethesda, MD 20892 USA. EM yangmu@mail.nih.gov FU National Institute of Mental Health Intramural Research Program FX This work was supported by the National Institute of Mental Health Intramural Research Program. NR 89 TC 36 Z9 36 U1 0 U2 11 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD DEC 5 PY 2012 VL 107 IS 5 SI SI BP 649 EP 662 DI 10.1016/j.physbeh.2011.12.025 PG 14 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 067PW UT WOS:000313308600005 PM 22245067 ER PT J AU Kavaliers, M Clipperton-Allen, A Cragg, CL Gustafsson, JA Korach, KS Muglia, L Choleris, E AF Kavaliers, Martin Clipperton-Allen, Amy Cragg, Cheryl L. Gustafsson, Jan-Ake Korach, Kenneth S. Muglia, Louis Choleris, Elena TI Male risk taking, female odors, and the role of estrogen receptors SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE Boldness; Decision making; Predator odor; Anxiety; Fear; Social behavior; Social recognition; Sexual behavior; Oxytocin ID ANTIPREDATOR DEFENSIVE BEHAVIOR; PLASMA TESTOSTERONE LEVELS; MAJOR URINARY PROTEINS; ALPHA GENE DISRUPTION; COPULATING MALE RATS; BETA KNOCKOUT MICE; SEXUAL AROUSAL; SOCIAL RECOGNITION; MUS-MUSCULUS; OXYTOCIN RECEPTOR AB Male risk-taking and decision making are affected by sex-related cues, with men making riskier choices and decisions after exposure to either women or stimuli associated with women. In non-human species females and, or their cues can also increase male risk taking. Under the ecologically relevant condition of predation threat, brief exposure of male mice to the odors of a sexually receptive novel female reduces the avoidance of, and aversive responses to, a predator. We briefly review evidence showing that estrogen receptors (ERs), ER alpha and ER beta, are associated with the mediation of these risk taking responses. We show that ERs influence the production of the female odors that affect male risk taking, with the odors of wild type (ER alpha WT, ER beta WT), oxytocin (OT) wildtype (OTWT), gene-deleted 'knock-out' ER ER beta (ER beta KO), but not ER beta KO or oxytocin (OT) OTKO or ovariectomized (OVX) female mice reducing the avoidance responses of male mice to cat odor. We further show that administration of specific ER alpha and ER beta agonists to OVX females results in their odors increasing male risk taking and boldness towards a predator. We also review evidence that ERs are involved in the mediation of the responses of males to female cues, with ER alpha being associated with the sexual and both ER beta and ER alpha with the sexual and social mechanisms underlying the effects of female cues on male risk taking. The implications and relations of these findings with rodents to ERs and the regulation of human risk taking are briefly considered. (C) 2012 Elsevier Inc. All rights reserved. C1 [Kavaliers, Martin] Univ Western Ontario, Dept Psychol, London, ON N6A 5C2, Canada. [Clipperton-Allen, Amy; Cragg, Cheryl L.; Choleris, Elena] Univ Guelph, Dept Psychol, Guelph, ON N1G 2W1, Canada. [Gustafsson, Jan-Ake] Ctr Nucl Receptors & Cell Signaling, Houston, TX 77004 USA. [Korach, Kenneth S.] NIEHS, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Muglia, Louis] Cincinnati Childrens Hosp Med Ctr, Perinatal Inst, Cincinnati, OH USA. RP Kavaliers, M (reprint author), Univ Western Ontario, Dept Psychol, London, ON N6A 5C2, Canada. EM kavalier@uwo.ca OI Korach, Kenneth/0000-0002-7765-418X FU NSERC; Swedish Cancer Fund FX MK and EC were supported by NSERC. Support for J-AG was provided by the Swedish Cancer Fund. Portions of this work were carried out in the Laboratory of the Neurobiology of Behaviors at The Rockefeller University. NR 145 TC 8 Z9 8 U1 5 U2 45 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD DEC 5 PY 2012 VL 107 IS 5 SI SI BP 751 EP 761 DI 10.1016/j.physbeh.2012.03.017 PG 11 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 067PW UT WOS:000313308600017 PM 22472459 ER PT J AU Alexandre, BM Charro, N Blonder, J Lopes, C Azevedo, P de Almeida, AB Chan, KC Prieto, DA Issaq, H Veenstra, TD Penque, D AF Alexandre, Bruno M. Charro, Nuno Blonder, Josip Lopes, Carlos Azevedo, Pilar de Almeida, Antonio Bugalho Chan, King C. Prieto, DaRue A. Issaq, Haleem Veenstra, Timothy D. Penque, Deborah TI Profiling the erythrocyte membrane proteome isolated from patients diagnosed with chronic obstructive pulmonary disease SO JOURNAL OF PROTEOMICS LA English DT Article DE O-16/O-18 stable isotopic labeling; Chronic obstructive pulmonary disease; Membrane proteins; Red blood cells; LC-MS/MS ID RED-BLOOD-CELL; TANDEM MASS-SPECTROMETRY; OXIDATIVE STRESS; KINESIN SUPERFAMILY; IN-VIVO; COPD; IDENTIFICATION; PROTEINS; PEPTIDE; FUTURE AB Structural and metabolic alterations in erythrocytes play an important role in the pathophysiology of Chronic Obstructive Pulmonary Disease (COPD). Whether these dysfunctions are related to the modulation of erythrocyte membrane proteins in patients diagnosed with COPD remains to be determined. Herein, a comparative proteomic profiling of the erythrocyte membrane fraction isolated from peripheral blood of smokers diagnosed with COPD and smokers with no COPD was performed using differential O-16/O-18 stable isotope labeling. A total of 219 proteins were quantified as being significantly differentially expressed within the erythrocyte membrane proteomes of smokers with COPD and healthy smokers. Functional pathway analysis showed that the most enriched biofunctions were related to cell-to-cell signaling and interaction, hematological system development, immune response, oxidative stress and cytoskeleton. Chorein (VPS13A), a cytoskeleton related protein whose defects had been associated with the presence of cell membrane deformation of circulating erythrocytes was found to be down-regulated in the membrane fraction of erythrocytes obtained from COPD patients. Methemoglobin reductase (CYB5R3) was also found to be underexpressed in these cells, suggesting that COPD patients may be at higher risk for developing methemoglobinemia. This article is part of a Special Issue entitled: Integrated omics. (C) 2012 Elsevier B.V. All rights reserved. C1 [Alexandre, Bruno M.; Charro, Nuno; Penque, Deborah] INSA, Lab Prote, Dept Genet, Inst Nacl Saude Dr Ricardo Jorge,IP, P-1649016 Lisbon, Portugal. [Alexandre, Bruno M.; Charro, Nuno; Blonder, Josip; Chan, King C.; Prieto, DaRue A.; Issaq, Haleem; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Lopes, Carlos; Azevedo, Pilar; de Almeida, Antonio Bugalho] Univ Lisbon, Clin Univ Pneumol, HSM, Lisbon, Portugal. RP Penque, D (reprint author), INSA, Lab Prote, Dept Genet, Inst Nacl Saude Dr Ricardo Jorge,IP, Edificio INSA 2,Ave Padre Cruz, P-1649016 Lisbon, Portugal. EM deborah.penque@insa.min-saude.pt RI Penque, Deborah/F-4830-2013; Alexandre, Bruno/A-9028-2016 OI Penque, Deborah/0000-0002-4527-7148; Alexandre, Bruno/0000-0002-7381-9258 FU Fundacao para a Ciencia e a Tecnologia (FCT)/FEDER [POCTI/SAU-MMO/56163/2004]; FCT/Poly-Annual Funding Program; FEDER/Saude XXI Program (Portugal); FCT [SFRH/BD/31415/2006, SFRH/BD/27906/2006] FX The authors would like to thank all patients and healthy individuals who voluntarily participated in this study. Also to Maria Teresa Seixas and colleagues from Laboratorio de Hematologia, Instituto Nacional de Saude Dr. Ricardo Jorge (INSA) for complete blood count (CBC), Pedro Loureiro, Arminda Vilares and Ana Cardoso for blood collection, colleagues from Laboratorio de Proteomica (INSA) and National Cancer Institute at Frederick (NCI-SAIC), and Dr Patricia Gomes-Alves for assistance with densitometry including the respective statistical analysis. This work was partially supported by the Fundacao para a Ciencia e a Tecnologia (FCT)/FEDER (POCTI/SAU-MMO/56163/2004), the FCT/Poly-Annual Funding Program and the FEDER/Saude XXI Program (Portugal). BMA and NC are recipients of FCT Doctoral Fellowship (SFRH/BD/31415/2006 and SFRH/BD/27906/2006). NR 52 TC 4 Z9 4 U1 0 U2 15 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-3919 J9 J PROTEOMICS JI J. Proteomics PD DEC 5 PY 2012 VL 76 SI SI BP 259 EP 269 DI 10.1016/j.jprot.2012.04.008 PG 11 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 068UG UT WOS:000313391100025 PM 22538302 ER PT J AU Dong, SW Qin, T Hamel, E Beutler, JA Porco, JA AF Dong, Suwei Qin, Tian Hamel, Ernest Beutler, John A. Porco, John A., Jr. TI Synthesis of Chamaecypanone C Analogues from in Situ-Generated Cyclopentadienones and Their Biological Evaluation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ONE-STEP SYNTHESIS; ENANTIOSELECTIVE SYNTHESIS; MICROTUBULE INHIBITOR; OXIDATION; DERIVATIVES; SKELETON; KETONES; MANZAMENONES; DIMERIZATION; CATALYST AB A rhodium-catalyzed dehydrogenation protocol for the conversion of 3,5-diarylcyclopentenones to the corresponding 2,4-diarylcyclopentadienones has been developed. With this protocol, analogues of the cytotoxic agent chamaecypanone C have been synthesized via Diels-Alder cycloaddition between the cyclopentadienones and in situ-generated o-quinols. Biological evaluation of these analogues revealed a compound with higher activity as a microtubule inhibitor and cytotoxic agent in comparison with the parent structure. C1 [Dong, Suwei; Qin, Tian; Porco, John A., Jr.] Boston Univ, Dept Chem, Boston, MA 02215 USA. [Dong, Suwei; Qin, Tian; Porco, John A., Jr.] Boston Univ, Ctr Chem Methodol & Lib Dev CMLD BU, Boston, MA 02215 USA. [Hamel, Ernest] NCI, Screening Technol Branch, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. [Beutler, John A.] NCI, Mol Targets Lab, Frederick Natl Lab Canc Res, Frederick, MD 21702 USA. RP Porco, JA (reprint author), Boston Univ, Dept Chem, 590 Commonwealth Ave, Boston, MA 02215 USA. EM porco@bu.edu RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 FU NIH [GM-073855]; NIGMS CMLD Initiative [P50 GM067041]; Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research; Developmental Therapeutics Program, Division of Cancer Diagnosis and Treatment; Vertex Pharmaceuticals, Inc. FX Financial support from the NIH (GM-073855 to J.A.P.) and the NIGMS CMLD Initiative (P50 GM067041 to J.A.P.) is gratefully acknowledged. T.Q thanks Vertex Pharmaceuticals, Inc. for a graduate fellowship. This research was also supported in part by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research and by the Developmental Therapeutics Program, Division of Cancer Diagnosis and Treatment. We thank Drs. Jeffrey Bacon (Boston University) and Charles Campana (Bruker AXS) for X-ray crystal stricture analyses and Drs. Yingju Xu and Mark McLaughlin (Department of Process Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, NJ) for their kind donation of diarylcyclopentenones. NR 48 TC 10 Z9 10 U1 2 U2 19 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 DEC 5 PY 2012 VL 134 IS 48 BP 19782 EP 19787 DI 10.1021/ja3084708 PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 047VM UT WOS:000311869600047 PM 23110297 ER PT J AU Qi, QY Guerra, CA Moyes, CL Elyazar, IRF Gething, PW Hay, SI Tatem, AJ AF Qi, Qiuyin Guerra, Carlos A. Moyes, Catherine L. Elyazar, Iqbal R. F. Gething, Peter W. Hay, Simon I. Tatem, Andrew J. TI The effects of urbanization on global Plasmodium vivax malaria transmission SO MALARIA JOURNAL LA English DT Article DE Plasmodium vivax; Urbanization; Dominant Anopheles vectors; Mapping ID DOMINANT ANOPHELES VECTORS; SUB-SAHARAN AFRICA; DUFFY-BLOOD-GROUP; URBAN AGRICULTURE; DISTRIBUTION MAPS; BIONOMIC PRECIS; FALCIPARUM MALARIA; RISK-FACTORS; HEALTH; POPULATION AB Background: Many recent studies have examined the impact of urbanization on Plasmodium falciparum malaria endemicity and found a general trend of reduced transmission in urban areas. However, none has examined the effect of urbanization on Plasmodium vivax malaria, which is the most widely distributed malaria species and can also cause severe clinical syndromes in humans. In this study, a set of 10,003 community-based P. vivax parasite rate (PvPR) surveys are used to explore the relationships between PvPR in urban and rural settings. Methods: The PvPR surveys were overlaid onto a map of global urban extents to derive an urban/rural assignment. The differences in PvPR values between urban and rural areas were then examined. Groups of PvPR surveys inside individual city extents (urban) and surrounding areas (rural) were identified to examine the local variations in PvPR values. Finally, the relationships of PvPR between urban and rural areas within the ranges of 41 dominant Anopheles vectors were examined. Results: Significantly higher PvPR values in rural areas were found globally. The relationship was consistent at continental scales when focusing on Africa and Asia only, but in the Americas, significantly lower values of PvPR in rural areas were found, though the numbers of surveys were small. Moreover, except for the countries in the Americas, the same trends were found at national scales in African and Asian countries, with significantly lower values of PvPR in urban areas. However, the patterns at city scales among 20 specific cities where sufficient data were available were less clear, with seven cities having significantly lower PvPR values in urban areas and two cities showing significantly lower PvPR in rural areas. The urban-rural PvPR differences within the ranges of the dominant Anopheles vectors were generally, in agreement with the regional patterns found. Conclusions: Except for the Americas, the patterns of significantly lower P. vivax transmission in urban areas have been found globally, regionally, nationally and by dominant vector species here, following trends observed previously for P. falciparum. To further understand these patterns, more epidemiological, entomological and parasitological analyses of the disease at smaller spatial scales are needed. C1 [Qi, Qiuyin; Tatem, Andrew J.] Univ Florida, Dept Geog, Gainesville, FL 32611 USA. [Qi, Qiuyin; Tatem, Andrew J.] Univ Florida, Emerging Pathogens Inst, Gainesville, FL USA. [Guerra, Carlos A.; Moyes, Catherine L.; Gething, Peter W.; Hay, Simon I.] Univ Oxford, Dept Zool, Spatial Ecol & Epidemiol Grp, Oxford OX1 3PS, England. [Elyazar, Iqbal R. F.] Eijkman Oxford Clin Res Unit, Jakarta 10430, Indonesia. [Tatem, Andrew J.] Univ Southampton, Dept Geog & Environm, Southampton, Hants, England. [Hay, Simon I.; Tatem, Andrew J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Qi, QY (reprint author), Univ Florida, Dept Geog, Gainesville, FL 32611 USA. EM qiuyinqi@ufl.edu RI Hay, Simon/F-8967-2015; OI Hay, Simon/0000-0002-0611-7272; Gething, Peter/0000-0001-6759-5449; Moyes, Catherine/0000-0002-8028-4079 FU Bill and Melinda Gates Foundation [49446, 1032350]; NIH/NIAID [U19AI089674]; Wellcome Trust [095066]; Biomedical Resources Grant from the Wellcome Trust [091835]; University of Oxford-Li Ka Shing Foundation Global Health Program; Oxford Tropical Network; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; Wellcome Trust, UK FX The large global assembly of parasite prevalence data was critically dependent on the generous contributions of data made by a large number of people in the malaria research and control communities and these individuals are listed on the MAP website (http://www.map.ac.uk/acknowledgements.html). AJT is supported by grants from the Bill and Melinda Gates Foundation (#49446 and #1032350) (http://www.gatesfoundation.org) and NIH/NIAID (U19AI089674). SIH is funded by a Senior Research Fellowship from the Wellcome Trust (#095066) that also supports PWG. CLM is funded by a Biomedical Resources Grant from the Wellcome Trust (#091835). IRFE is funded by grants from the University of Oxford-Li Ka Shing Foundation Global Health Program and the Oxford Tropical Network. AJT and SIH also acknowledge support from the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (http://www.fic.nih.gov). This work forms part of the output of the Malaria Atlas Project (MAP, http://www.map.ox.ac.uk), principally funded by the Wellcome Trust, UK (http://www.wellcome.ac.uk). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 9 Z9 10 U1 0 U2 20 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD DEC 5 PY 2012 VL 11 AR 403 DI 10.1186/1475-2875-11-403 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 058TO UT WOS:000312657300001 PM 23217010 ER PT J AU Switzer, WM Tang, SH Ahuka-Mundeke, S Shankar, A Hanson, DL Zheng, HQ Ayouba, A Wolfe, ND LeBreton, M Djoko, CF Tamoufe, U Esteban, A Heneine, W Peeters, M Wright, LL Muyembe-Tamfum, JJ Wemakoy, EO Mulembakani, P Hoff, NA Rimoin, AW AF Switzer, William M. Tang, Shaohua Ahuka-Mundeke, Steve Shankar, Anupama Hanson, Debra L. Zheng, HaoQiang Ayouba, Ahidjo Wolfe, Nathan D. LeBreton, Matthew Djoko, Cyrille F. Tamoufe, Ubald Esteban, Amandine Heneine, Walid Peeters, Martine Wright, Linda L. Muyembe-Tamfum, Jean Jacques Wemakoy, Emile Okitolonda Mulembakani, Prime Hoff, Nicole A. Rimoin, Anne W. TI Novel simian foamy virus infections from multiple monkey species in women from the Democratic Republic of Congo SO RETROVIROLOGY LA English DT Article DE Simian foamy virus; Retrovirus; Zoonosis; Africa; Women; Transmission; Public health; Emerging ID IMMUNODEFICIENCY-VIRUS; NONHUMAN-PRIMATES; CENTRAL-AFRICA; TRANSMISSION; HIV-1; CAMEROON; HUMANS; RETROVIRUS; EMERGENCE; BUSHMEAT AB Background: Zoonotic transmission of simian retroviruses in Central Africa is ongoing and can result in pandemic human infection. While simian foamy virus (SFV) infection was reported in primate hunters in Cameroon and Gabon, little is known about the distribution of SFV in Africa and whether human-to-human transmission and disease occur. We screened 3,334 plasmas from persons living in rural villages in central Democratic Republic of Congo (DRC) using SFV-specific EIA and Western blot (WB) tests. PCR amplification of SFV polymerase sequences from DNA extracted from buffy coats was used to measure proviral loads. Phylogenetic analysis was used to define the NHP species origin of SFV. Participants completed questionnaires to capture NHP exposure information. Results: Sixteen (0.5%) samples were WB-positive; 12 of 16 were from women (75%, 95% confidence limits 47.6%, 92.7%). Sequence analysis detected SFV in three women originating from Angolan colobus or red-tailed monkeys; both monkeys are hunted frequently in DRC. NHP exposure varied and infected women lived in distant villages suggesting a wide and potentially diverse distribution of SFV infections across DRC. Plasmas from 22 contacts of 8 WB-positive participants were all WB negative suggesting no secondary viral transmission. Proviral loads in the three women ranged from 14 - 1,755 copies/10(5) cells. Conclusions: Our study documents SFV infection in rural DRC for the first time and identifies infections with novel SFV variants from Colobus and red-tailed monkeys. Unlike previous studies, women were not at lower risk for SFV infection in our population, providing opportunities for spread of SFV both horizontally and vertically. However, limited testing of close contacts of WB-positive persons did not identify human-to-human transmission. Combined with the broad behavioral risk and distribution of NHPs across DRC, our results suggest that SFV infection may have a wider geographic distribution within DRC. These results also reinforce the potential for an increased SFV prevalence throughout the forested regions of Africa where humans and simians co-exist. Our finding of endemic foci of SFV infection in DRC will facilitate longitudinal studies to determine the potential for person-to-person transmissibility and pathogenicity of these zoonotic retroviral infections. C1 [Switzer, William M.; Tang, Shaohua; Shankar, Anupama; Hanson, Debra L.; Zheng, HaoQiang; Heneine, Walid] Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA 30333 USA. [Ahuka-Mundeke, Steve; Ayouba, Ahidjo; Esteban, Amandine; Peeters, Martine] Inst Rech Dev, Montpellier, France. [Ahuka-Mundeke, Steve; Muyembe-Tamfum, Jean Jacques] Inst Natl Rech Biomed, Kinshasa, Zaire. [Wolfe, Nathan D.; LeBreton, Matthew; Djoko, Cyrille F.; Tamoufe, Ubald] Global Viral Forecasting Initiat, San Francisco, CA 94104 USA. [Wright, Linda L.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD 20892 USA. [Wemakoy, Emile Okitolonda; Mulembakani, Prime] Univ Kinshasa, Kinshasa Sch Publ Hlth, Kinshasa, Zaire. [Hoff, Nicole A.; Rimoin, Anne W.] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. RP Switzer, WM (reprint author), Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA 30333 USA. EM bswitzer@cdc.gov RI Valle, Ruben/A-7512-2013 FU Faucett Family Foundation; Rawji Foundation; Global Viral Forecasting [ANRS12182/12255, NIH RO1 AI50529]; U.S. Agency for International Development (USAID) [GHN-A-OO-09-00010-00] FX We are grateful to Corey Clemons and Anisha Patel for their help with generating many of the new Cercopithecus SFV pol sequences from Cameroon while guest researchers at CDC. Funding for this study was provided by the Faucett Family and Rawji Foundations and Global Viral Forecasting (ANRS12182/12255 and NIH RO1 AI50529), graciously supported by the U.S. Department of Defense Armed Forces Health Surveillance Center, Division of Global Emerging Infections, Surveillance Operations (AFHSC GEIS), the Defense Threat Reduction Agency Cooperative Biological Engagement Program (DTRA-CBEP), Department of Defense HIV/AIDS Prevention Program (DHAPP), Google.org, the Skoll Foundation, and the U.S. Agency for International Development (USAID) Emerging Pandemic Threats Program, PREDICT project, under the terms of Cooperative Agreement Number GHN-A-OO-09-00010-00. Use of trade names is for identification only and does not imply endorsement by the U. S. Department of Health and Human Services, the Public Health Service, or the Centers for Disease Control and Prevention (CDC). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the CDC. NR 45 TC 17 Z9 17 U1 0 U2 21 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD DEC 5 PY 2012 VL 9 AR 100 DI 10.1186/1742-4690-9-100 PG 15 WC Virology SC Virology GA 056BL UT WOS:000312461800001 PM 23217108 ER PT J AU Mattson, MP AF Mattson, Mark P. TI Energy Intake and Exercise as Determinants of Brain Health and Vulnerability to Injury and Disease SO CELL METABOLISM LA English DT Review ID BODY-MASS INDEX; HIGH-FAT DIET; NEUROTROPHIC FACTOR LEVELS; GENE-EXPRESSION PROFILE; TRANSGENIC MOUSE MODEL; AGED RHESUS-MONKEYS; A-BETA-DEPOSITION; CALORIC RESTRICTION; ALZHEIMERS-DISEASE; INSULIN-RESISTANCE AB Evolution favored individuals with superior cognitive and physical abilities under conditions of limited food sources, and brain function can therefore be optimized by intermittent dietary energy restriction (ER) and exercise. Such energetic challenges engage adaptive cellular stress-response signaling pathways in neurons involving neurotrophic factors, protein chaperones, DNA-repair proteins, autophagy, and mitochondrial biogenesis. By suppressing adaptive cellular stress responses, overeating and a sedentary lifestyle may increase the risk of Alzheimer's and Parkinson's diseases, stroke, and depression. Intense concerted efforts of governments, families, schools, and physicians will be required to successfully implement brain-healthy lifestyles that incorporate ER and exercise. C1 [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mattson, MP (reprint author), NIA, Neurosci Lab, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institute on Aging. NR 183 TC 96 Z9 100 U1 12 U2 86 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD DEC 5 PY 2012 VL 16 IS 6 BP 706 EP 722 DI 10.1016/j.cmet.2012.08.012 PG 17 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 055ML UT WOS:000312420600005 PM 23168220 ER PT J AU Soroceanu, A Sidhwa, F Aarabi, S Kaufman, A Glazebrook, M AF Soroceanu, Alexandra Sidhwa, Feroze Aarabi, Shahram Kaufman, Annette Glazebrook, Mark TI Surgical Versus Nonsurgical Treatment of Acute Achilles Tendon Rupture A Meta-Analysis of Randomized Trials SO JOURNAL OF BONE AND JOINT SURGERY-AMERICAN VOLUME LA English DT Article ID NONOPERATIVE TREATMENT; SURGERY AB Background: Surgical repair is a common method of treatment of acute Achilles rupture in North America because, despite a higher risk of overall complications, it has been believed to offer a reduced risk of rerupture. However, more recent trials, particularly those using functional bracing with early range of motion, have challenged this belief. The aim of this meta-analysis was to compare surgical treatment and conservative treatment with regard to the rerupture rate, the overall rate of other complications, return to work, calf circumference, and functional outcomes, as well as to examine the effects of early range of motion on the rerupture rate. Methods: A literature search, data extraction, and quality assessment were conducted by two independent reviewers. Publication bias was assessed with use of the Egger and Begg tests. Heterogeneity was assessed with use of the 12 test, and fixed or random-effect models were used accordingly. Pooled results were expressed as risk ratios, risk differences, and weighted or standardized mean differences, as appropriate. Meta-regression was employed to identify causes of heterogeneity. Subgroup analysis was performed to assess the effect of early range of motion. Results: Ten studies met the inclusion criteria. If functional rehabilitation with early range of motion was employed, rerupture rates were equal for surgical and nonsurgical patients (risk difference = 1.7%, p = 0.45). If such early range of motion was not employed, the absolute risk reduction achieved by surgery was 8.8% (p = 0.001 in favor of surgery). Surgery was associated with an absolute risk increase of 15.8% (p = 0.016 in favor of nonoperative management) for complications other than rerupture. Surgical patients returned to work 19.16 days sooner (p = 0.0014). There was no significant difference between the two treatments with regard to calf circumference (p = 0.357), strength (p = 0.806), or functional outcomes (p = 0.226). Conclusions: The results of the meta-analysis demonstrate that conservative treatment should be considered at centers using functional rehabilitation. This resulted in rerupture rates similar to those for surgical treatment while offering the advantage of a decrease in other complications. Surgical repair should be preferred at centers that do not employ early-range-of-motion protocols as it decreased the rerupture risk in such patients. C1 [Soroceanu, Alexandra] Dalhousie Univ, Queen Elizabeth II Hlth Sci Ctr, Div Orthopaed Surg, Halifax, NS B3H 4M8, Canada. [Kaufman, Annette] NCI, Canc Prevent Fellowship Program, Rockville, MD 20852 USA. RP Soroceanu, A (reprint author), Dalhousie Univ, Queen Elizabeth II Hlth Sci Ctr, Div Orthopaed Surg, 1796 Summer St, Halifax, NS B3H 4M8, Canada. EM markglazebr@ns.sympatico.ca FU Intramural NIH HHS [Z99 CA999999] NR 23 TC 71 Z9 77 U1 2 U2 32 PU JOURNAL BONE JOINT SURGERY INC PI NEEDHAM PA 20 PICKERING ST, NEEDHAM, MA 02192 USA SN 0021-9355 J9 J BONE JOINT SURG AM JI J. Bone Joint Surg.-Am. Vol. PD DEC 5 PY 2012 VL 94A IS 23 BP 2136 EP 2143 DI 10.2106/JBJS.K.00917 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 047YD UT WOS:000311876500004 PM 23224384 ER PT J AU Bartesaghi, A Lecumberry, F Sapiro, G Subramaniam, S AF Bartesaghi, Alberto Lecumberry, Federico Sapiro, Guillermo Subramaniam, Sriram TI Protein Secondary Structure Determination by Constrained Single-Particle Cryo-Electron Tomography SO STRUCTURE LA English DT Article ID ELECTRON CRYOMICROSCOPY; RESOLUTION; MICROSCOPY; REFINEMENT; RECONSTRUCTIONS; CLASSIFICATION; VISUALIZATION; ASSEMBLIES; ALIGNMENT AB Cryo-electron microscopy (cryo-EM) is a powerful technique for 3D structure determination of protein complexes by averaging information from individual molecular images. The resolutions that can be achieved with single-particle cryo-EM are frequently limited by inaccuracies in assigning molecular orientations based solely on 2D projection images. Tomographic data collection schemes, however, provide powerful constraints that can be used to more accurately determine molecular orientations necessary for 3D reconstruction. Here, we propose "constrained single-particle tomography" as a general strategy for 3D structure determination in cryo-EM. A key component of our approach is the effective use of images recorded in tilt series to extract high-resolution information and correct for the contrast transfer function. By incorporating geometric constraints into the refinement to improve orientational accuracy of images, we reduce model bias and overrefinement artifacts and demonstrate that protein structures can be determined at resolutions of similar to 8 angstrom starting from low-dose tomographic tilt series. C1 [Bartesaghi, Alberto; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lecumberry, Federico] Univ Republica, Fac Ingn, Inst Ingn Elect, Montevideo 11300, Uruguay. [Sapiro, Guillermo] Duke Univ, Dept Elect & Comp Engn, Durham, NC 27707 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM ss1@nih.gov FU Center for Cancer Research, National Cancer Institute; NIH IATAP program; SNI; ANII; NSF; ONR; NSSEFF FX We thank Bridget Carragher for providing purified GroEL, David Schauder and Katherine Klymko for assistance with data collection, and members of our laboratory for helpful comments. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD (http://biowulf.nih.gov) and was supported by funds from the Center for Cancer Research, National Cancer Institute, and the NIH IATAP program. The work of F.L. was performed in part while visiting the University of Minnesota and NIH and is partially supported by SNI and ANII. G.S. is partially supported by NSF, ONR, and NSSEFF. NR 35 TC 27 Z9 27 U1 0 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD DEC 5 PY 2012 VL 20 IS 12 BP 2003 EP 2013 DI 10.1016/j.str.2012.10.016 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 050MO UT WOS:000312057600005 PM 23217682 ER PT J AU Liu, S Chen, YH Li, J Huang, T Tarasov, S King, A Weissman, AM Byrd, RA Das, R AF Liu, Shan Chen, Yinghua Li, Jess Huang, Tao Tarasov, Sergey King, Aaren Weissman, Allan M. Byrd, R. Andrew Das, Ranabir TI Promiscuous Interactions of gp78 E3 Ligase CUE Domain with Polyubiquitin Chains SO STRUCTURE LA English DT Article ID CONJUGATING ENZYME; UBIQUITIN-BINDING; RING FINGER; UBA DOMAIN; RECOGNITION; DEGRADATION; DIUBIQUITIN; PROTEINS; COMPLEX; UBIQUITYLATION AB Recognition of ubiquitin and polyubiquitin chains by ubiquitin-binding domains (UBDs) is vital for ubiquitin-mediated signaling pathways. The endoplasmic reticulum resident RING finger ubiquitin ligase (E3) gp78 regulates critical proteins via the ubiquitin-proteasome system to maintain cellular homeostasis and includes a UBD known as the CUE domain, which is essential for function. A probable role of this domain is to recognize ubiquitin-modified substrates, enabling gp78 to assemble polyubiquitin chains on these substrates and mark them for degradation. Here, we report the molecular details of the interaction of gp78CUE domain with ubiquitin and diubiquitin. The gp78CUE domain exhibits a well-defined set of interactions with ubiquitin and a dynamic, promiscuous interaction with diubiquitin chains. This leads to a model in which the CUE domain functions to both facilitate substrate binding and enable switching between adjacent ubiquitin molecules of a growing chain to enable processivity in ubiquitination. C1 [Liu, Shan; Chen, Yinghua; Li, Jess; Huang, Tao; Tarasov, Sergey; King, Aaren; Byrd, R. Andrew; Das, Ranabir] NCI, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. RP Byrd, RA (reprint author), NCI, Struct Biophys Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM byrdra@mail.nih.gov; dasranabir@mail.nih.gov RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 FU Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 41 TC 9 Z9 9 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD DEC 5 PY 2012 VL 20 IS 12 BP 2138 EP 2150 DI 10.1016/j.str.2012.09.020 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 050MO UT WOS:000312057600016 PM 23123110 ER PT J AU Papaneri, AB Wirblich, C Cann, JA Cooper, K Jahrling, PB Schnell, MJ Blaney, JE AF Papaneri, Amy B. Wirblich, Christoph Cann, Jennifer A. Cooper, Kurt Jahrling, Peter B. Schnell, Matthias J. Blaney, Joseph E. TI A replication-deficient rabies virus vaccine expressing Ebola virus glycoprotein is highly attenuated for neurovirulence SO VIROLOGY LA English DT Article DE Ebola virus; Rabies virus; Vaccine; Neurovirulence; Mice ID SAD B19; IMMUNIZATION; PROTECTION; CHALLENGE; VECTORS; MORTALITY; GORILLAS; SAFETY; LIVE AB We are developing inactivated and live-attenuated rabies virus (RABV) vaccines expressing Ebola virus (EBOV) glycoprotein for use in humans and endangered wildlife, respectively. Here, we further characterize the pathogenesis of the live-attenuated RABV/EBOV vaccine candidates in mice in an effort to define their growth properties and potential for safety. RABV vaccines expressing GP (RV-GP) or a replication-deficient derivative with a deletion of the RABV G gene (RV Delta G-GP) are both avirulent after intracerebral inoculation of adult mice. Furthermore, RV Delta G-GP is completely avirulent upon intracerebral inoculation of suckling mice unlike parental RABV vaccine or RV-GP. Analysis of RV Delta G-GP in the brain by quantitative PCR, determination of virus titer, and immunohistochemistry indicated greatly restricted virus replication. In summary, our findings indicate that RV-GP retains the attenuation phenotype of the live-attenuated RABV vaccine, and RV Delta G-GP would appear to be an even safer alternative for use in wildlife or consideration for human use. Published by Elsevier Inc. C1 [Papaneri, Amy B.; Jahrling, Peter B.; Blaney, Joseph E.] NIAID, Emerging Viral Pathogens Sect, NIH, Ft Detrick, MD 21702 USA. [Wirblich, Christoph; Schnell, Matthias J.] Thomas Jefferson Univ, Jefferson Med Coll, Dept Microbiol & Immunol, Philadelphia, PA 19107 USA. [Schnell, Matthias J.] Thomas Jefferson Univ, Jefferson Med Coll, Jefferson Vaccine Ctr, Philadelphia, PA 19107 USA. [Cann, Jennifer A.; Cooper, Kurt; Jahrling, Peter B.] NIAID, Integrated Res Facil, NIH, Ft Detrick, MD 21702 USA. RP Blaney, JE (reprint author), NIAID, EVPS, NIH Integrated Res Facil, 8200 Res Plaza, Ft Detrick, MD 21702 USA. EM matthias.schnell@jefferson.edu; jblaney@niaid.nih.gov OI Papaneri, Amy/0000-0003-2144-2441 FU NIAID Division of Intramural Research FX These studies were supported in part by the NIAID Division of Intramural Research. We thank Nicholas Oberlander for contribution to the animal studies and Fabian de Kok-Mercado for assistance in preparation of figures. NR 28 TC 12 Z9 14 U1 0 U2 20 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 DEC 5 PY 2012 VL 434 IS 1 BP 18 EP 26 DI 10.1016/j.virol.2012.07.020 PG 9 WC Virology SC Virology GA 038OF UT WOS:000311183300004 PM 22889613 ER PT J AU Tang, YJ Liu, Z Ding, S Lin, CH Ca, YQ Rodriguez, FA Sayer, JM Jerina, DM Amin, S Broyde, S Geacintov, NE AF Tang, Yijin Liu, Zhi Ding, Shuang Lin, Chin H. Ca, Yuqin Rodriguez, Fabian A. Sayer, Jane M. Jerina, Donald M. Amin, Shantu Broyde, Suse Geacintov, Nicholas E. TI Nuclear Magnetic Resonance Solution Structure of an N-2-Guanine DNA Adduct Derived from the Potent Tumorigen Dibenzo[a,l]pyrene: Intercalation from the Minor Groove with Ruptured Watson-Crick Base Pairing SO BIOCHEMISTRY LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; NUCLEOTIDE EXCISION-REPAIR; RAT MAMMARY-GLAND; HAMSTER V79 CELLS; FEMALE CD RATS; FJORD-REGION; SOLUTION CONFORMATION; DIOL EPOXIDES; MOUSE SKIN; OPPOSITE DT AB The most potent tumorigen identified among the polycyclic aromatic hydrocarbons (PAH) is the nonplanar fjord region dibenzo[a,l]-pyrene (DB[a,l]P). It is metabolically activated in vivo through the widely studied diol epoxide (DE) pathway to form covalent adducts with DNA bases, predominantly guanine and adenine. The (+)-11S,12R,13R,145 DE enantiomer forms adducts via its C14 position with the exocyclic amino group of guanine. Here, we present the first nuclear magnetic resonance solution structure of a DB[a,l]P-derived adduct, the 14R-(+)-trans-anti-DB[a,l]P-N-2-dG (DB[a,l]P-dg) lesion in double-stranded DNA. In contrast to the stereochemically identical benzo[a]pyrene-derived N-2-dG adduct (B[a]P-dG) in which the B[a]P rings reside in the B-DNA minor groove on the 3'-side of the modifed deoxyguanosine, in the DB[a,l]P-derived adduct the DB[a,l]P rings intercalate into the duplex on the 3'-side of the modified base from the sterically crowded minor groove. Watson-Crick base pairing of the modified guanine with the partner cytosine is broken, but these bases retain some stacking with the bulky DB[a,l]P ring system. This new theme in PAN DE-DNA adduct conformation differs from (1) the classical intercalation motif in which Watson-Crick base pairing is intact at the lesion site and (2) the base-displaced intercalation motif in which the damaged base and its partner are extruded from the helix. The structural considerations that lead to the intercalated conformation of the DB[a,l]P-dG lesion in contrast to the minor groove alignment of the B[a]P-dG adduct, and the implications of the DB[a,l]P-dG conformational motif for the recognition of such DNA lesions by the human nucleotide excision repair apparatus, are discussed. C1 [Tang, Yijin; Liu, Zhi; Lin, Chin H.; Rodriguez, Fabian A.; Geacintov, Nicholas E.] NYU, Dept Chem, New York, NY 10003 USA. [Ding, Shuang; Ca, Yuqin; Broyde, Suse] NYU, Dept Biol, New York, NY 10003 USA. [Sayer, Jane M.; Jerina, Donald M.] NIDDK, Bioorgan Chem Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. [Amin, Shantu] Penn State Coll Med, Dept Pharmacol, Hershey, PA 17033 USA. RP Geacintov, NE (reprint author), NYU, Dept Chem, New York, NY 10003 USA. EM ng1@nyu.edu FU National Cancer Institute of the National Institutes of Health [CA-099194, CA-28038]; National Institutes of Health (NIH) [CA-75449]; NCI [NO2-03-81013-74]; National Science Foundation [MCB060037]; Research Facilities Improvement Grant from the National Center for Research Resources (NIH) [C06 RR-16572]; New York State Office of Science, Technology and Academic Research; NIH Grant [P41 GM66354] FX This research was supported by the National Cancer Institute of the National Institutes of Health via Grants CA-099194 (N.E.G.) and CA-28038 (S.B.). Computational infrastructure and systems management was partially supported by National Institutes of Health (NIH) Grant CA-75449 to S.B. This study was supported in part by NCI Contract NO2-03-81013-74 (S.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.; The dibenzo[a,l]pyrene diol epoxide used in some of the experiments was obtained from Dr. S. Amin at the NCI Chemical Carcinogen Storage Facility at Pennsylvania State University (Hershey, PA). The major fraction of the sitespecifically modified oligonucleotides used in this work was supplied by Dr. Haruhiko Yagi and Dr. Albrecht Seidel which is gratefully acknowledged. This work used computational resources of the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation Grant MCB060037. Components of this work were conducted in the Shared Instrumentation Facility at New York University that was constructed with support from Research Facilities Improvement Grant C06 RR-16572 from the National Center for Research Resources (NIH). Furthermore, NMR resources were also used at the New York Structural Biology Center (NYSBC) where N.E.G. is an affiliated Principal Investigator. The NYSBC is a STAR site supported by the New York State Office of Science, Technology and Academic Research, and its NMR resources are supported by NIH Grant P41 GM66354. NR 67 TC 9 Z9 9 U1 0 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 4 PY 2012 VL 51 IS 48 BP 9751 EP 9762 DI 10.1021/bi3013577 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 047UI UT WOS:000311866600016 PM 23121427 ER PT J AU Barr, B Taylor-Robinson, D Whitehead, M AF Barr, Ben Taylor-Robinson, David Whitehead, Margaret TI Impact on health inequalities of rising prosperity in England 1998-2007, and implications for performance incentives: longitudinal ecological study SO BRITISH MEDICAL JOURNAL LA English DT Article ID MORTALITY; UNEMPLOYMENT; DEPRIVATION; MECHANISMS; CHALLENGES; RECESSION; MIGRATION; CRISES AB Objective To investigate whether the uneven rise in prosperity between 1999 and 2008 accounted for differential increases in life expectancy in English local authorities. Design Longitudinal ecological study. Setting 324 local authorities in England, classified by their baseline level of deprivation. Main outcome measures Multivariable regression was used to investigate the association between trends in prosperity between 1998 and 2007 and trends in life expectancy. Trends in health inequalities were assessed by comparing the experience of Spearhead local authorities (the 70 most deprived in 1998) with the average for all English local authorities. Results Those local authorities that experienced the greatest improvement in prosperity experienced greater increases in life expectancy. With each 1% absolute decline in unemployment, life expectancy increased by 2.2 (95% confidence interval 0.5 to 3.8) months in men and by 1.7 (0.4 to 3.1) months in women. With each 1000 pound increase in average household income in a local authority, life expectancy increased by 1.4 (0.3 to 2.5) months in men and by 1.1 (0.2 to 1.9) months in women. The more deprived a local authority was in 1998, the lower the rate at which life expectancy improved. Conclusion Decreases in unemployment and increases in average income in an area explained, to a large extent, why some local authorities "performed" better than others. Health inequalities between Spearhead and all local authorities widened during the period of rising prosperity, but they would have widened to an even greater extent had unemployment not fallen at a faster rate in more deprived areas. With worsening economic trends over the next 10 years, this research suggests that increases in life expectancy are likely to be smaller and health inequalities may widen at a faster rate than in the previous decade. Allocating resources to local authorities on the basis of their "performance" at increasing life expectancy is likely to reward more affluent areas rather than disadvantaged areas with greater needs, exacerbating the problem. C1 [Barr, Ben; Taylor-Robinson, David; Whitehead, Margaret] Univ Liverpool, Inst Psychol Hlth & Soc, Dept Publ Hlth & Policy, Liverpool L69 3GB, Merseyside, England. [Barr, Ben] NIH, Bethesda, MD USA. [Taylor-Robinson, David] MRC, London W1N 4AL, England. RP Barr, B (reprint author), Univ Liverpool, Inst Psychol Hlth & Soc, Dept Publ Hlth & Policy, Liverpool L69 3GB, Merseyside, England. EM benbarr@liverpool.ac.uk FU NIHR [DRF-2009-02-12]; MRC [G0802448] FX BB is supported by an NIHR doctoral research fellowship (DRF-2009-02-12). DT-R is supported by an MRC population health scientist fellowship (G0802448). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 40 TC 5 Z9 5 U1 1 U2 23 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BRIT MED J JI Br. Med. J. PD DEC 4 PY 2012 VL 345 AR e7831 DI 10.1136/bmj.e7831 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 052HY UT WOS:000312189700002 PM 23212879 ER PT J AU Yeboah, J Rodriguez, CJ Stacey, B Lima, JA Liu, ST Carr, JJ Hundley, WG Herrington, DM AF Yeboah, Joseph Rodriguez, Carlos J. Stacey, Brandon Lima, Joao A. Liu, Songtao Carr, J. Jeffrey Hundley, W. Gregory Herrington, David M. TI Prognosis of Individuals With Asymptomatic Left Ventricular Systolic Dysfunction in the Multi-Ethnic Study of Atherosclerosis (MESA) SO CIRCULATION LA English DT Article DE heart failure; death; cardiovascular events; cardiovascular imaging; asymptomatic left ventricular systolic dysfunction ID HEART-FAILURE; MYOCARDIAL-INFARCTION; NATRIURETIC PEPTIDES; POPULATION; COMMUNITY; SURVIVAL; PLASMA; HYPERTROPHY; MORTALITY; ADULTS AB Background-Limited data exist on the prevalence, associations, and prognosis of individuals with asymptomatic left ventricular systolic dysfunction (ALVSD), especially in populations without previous clinical cardiovascular disease (CVD). Methods and Results-Kaplan-Meier and Cox proportional hazard analyses were used to assess the association between ALVSD, defined as left ventricular ejection fraction < 50%, and adjudicated incident congestive heart failure (CHF), all-cause mortality, and CVD events. Of 5004 participants, 112 participants had CHF, 321 had a CVD event, and 278 died after 9 years of follow-up. The overall prevalence of ALVSD was 1.7%, with a higher prevalence in blacks (2.6%). ALVSD had a worse cardiovascular risk profile and was also associated with increased risk in unadjusted and adjusted models for incident CHF (HR [hazard ratio] [95% CI {confidence interval}]: 12.0 [7.04-20.3], P < 0.0001 and 8.69 [4.89-15.45], P < 0.001 respectively), CVD (HR [95% CI]: 3.32 [1.98-5.58], P < 0.001 and 2.21 [1.30-3.73], P = 0.003 respectively), and all-cause mortality (HR [95% CI]: 3.47 [2.03-5.94], P < 0.0001 and 2.00 [1.13-3.54], P = 0.017, respectively). A 10% decrement in left ventricular ejection fraction at baseline was associated with an increase in risk in unadjusted and adjusted models for clinical CHF (HR [95% CI]: 2.17 [1.82-2.63], P < 0.0001 and 2.13 [1.73-2.51], P < 0.001, respectively) and all-cause mortality (HR [95% CI]: 1.22 [1.05-1.41], P = 0.009 and 1.17 [1.00-1.36], P = 0.047, respectively). Among the subset of participants with ALVSD, the left ventricular mass index was particularly informative about risk for incident CHF (c-index = 0.74). Conclusions-ALVSD is uncommon in individuals without previous clinical CVD, but it is associated with high risk for CHF, CVD, and all-cause mortality. The left ventricular mass index had good discrimination for incident CHF in Multi-Ethnic Study of Atherosclerosis (MESA) participants with ALVSD. (Circulation. 2012;126:2713-2719.) C1 [Yeboah, Joseph; Rodriguez, Carlos J.; Stacey, Brandon; Carr, J. Jeffrey; Hundley, W. Gregory; Herrington, David M.] Wake Forest Sch Med, Dept Internal Med Cardiol, Winston Salem, NC 27157 USA. [Yeboah, Joseph; Rodriguez, Carlos J.; Carr, J. Jeffrey] Wake Forest Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27157 USA. [Lima, Joao A.] Johns Hopkins Univ, Baltimore, MD USA. [Liu, Songtao] NIH, Bethesda, MD 20892 USA. [Carr, J. Jeffrey; Hundley, W. Gregory] Wake Forest Sch Med, Div Radiol Sci, Winston Salem, NC 27157 USA. RP Yeboah, J (reprint author), Wake Forest Sch Med, Dept Internal Med Cardiol, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jyeboah@wakehealth.edu RI Carr, John/A-1938-2012 OI Carr, John/0000-0002-4398-8237 FU [N01-HC-95159]; [N01-HC-95167]; [R01HL098445] FX This research was supported by contracts N01-HC-95159 through N01-HC-95167 and a Diversity Supplement to R01HL098445 (principle investigator: Dr Carr). A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. NR 26 TC 20 Z9 20 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 DEC 4 PY 2012 VL 126 IS 23 BP 2713 EP 2719 DI 10.1161/CIRCULATIONAHA.112.112201 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048TY UT WOS:000311937200012 PM 23124035 ER PT J AU Lamas, GA Boineau, R Goertz, C Mark, DB Rozema, TC Nahin, RL Rosenberg, Y Stylianou, M Drisko, J Lee, KL AF Lamas, Gervasio A. Boineau, Robin Goertz, Christine Mark, Daniel B. Rozema, Theodore C. Nahin, Richard L. Rosenberg, Yves Stylianou, Mario Drisko, Jeanne Lee, Kerry L. TI Results of the Trial to Assess Chelation Therapy SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association CY NOV 03-07, 2012 CL Los Angeles, CA SP Amer Heart Assoc DE Coronary artery disease; Myocardial infarction; Prevention; Pharmacology; Vitamins C1 [Lamas, Gervasio A.] Mt Sinai Med Cntr, Miami, FL USA. [Goertz, Christine] Palmer Coll Chiropract, Davenport, IA USA. [Boineau, Robin; Rosenberg, Yves; Stylianou, Mario] Natl Heart Lung & Blood Inst, Bethesda, MD USA. [Mark, Daniel B.; Lee, Kerry L.] Duke Clin Rsch Inst, Durham, NC USA. [Rozema, Theodore C.] Biogenesis Med Cntr, Landrum, SC USA. [Nahin, Richard L.] Natl Cntr Complementary & Alternat Med, Bethesda, MD USA. [Drisko, Jeanne] Univ Kansas, Med Cntr, Kansas City, KS USA. NR 0 TC 0 Z9 0 U1 1 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 DEC 4 PY 2012 VL 126 IS 23 BP 2778 EP 2779 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048TY UT WOS:000311937200023 ER PT J AU Mark, DB Anstrom, KJ Boineau, R Goertz, C Rozema, TC Knight, JD Clapp-Channing, NE Liu, DM Nahin, RL Rosenberg, Y Drisko, J Lee, KL Lamas, GA AF Mark, Daniel B. Anstrom, Kevin J. Boineau, Robin Goertz, Christine Rozema, Theodore C. Knight, J. David Clapp-Channing, Nancy E. Liu, Diane M. Nahin, Richard L. Rosenberg, Yves Drisko, Jeanne Lee, Kerry L. Lamas, Gervasio A. TI Quality of Life Outcomes in the Trial to Assess Chelation Therapy (TACT) SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association CY NOV 03-07, 2012 CL Los Angeles, CA SP Amer Heart Assoc DE Cardiovascular disease; Quality of life; Vitamins; Coronary artery disease; Evidence-based medicine C1 [Mark, Daniel B.] Duke Univ, Med Cntr, Durham, NC USA. [Anstrom, Kevin J.; Knight, J. David; Clapp-Channing, Nancy E.; Liu, Diane M.; Lee, Kerry L.] Duke Clin Rsch Inst, Durham, NC USA. [Boineau, Robin; Rosenberg, Yves] NHLBI, Bethesda, MD 20892 USA. [Goertz, Christine] Palmer Coll Chiropract, Davenport, IA USA. [Rozema, Theodore C.] Biogenesis Med Cntr, Landrum, SC USA. [Nahin, Richard L.] Nat Cntr Complementary & Alternat Med, Bethesda, MD USA. [Drisko, Jeanne] Univ Kansas, Med Cntr, Kansas City, KS USA. [Lamas, Gervasio A.] Mt Sinai Med Cntr, Miami, FL 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 DEC 4 PY 2012 VL 126 IS 23 BP 2779 EP 2780 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048TY UT WOS:000311937200027 ER PT J AU Traverse, JH Henry, TD Pepine, CJ Willerson, JT Zhao, DX Ellis, SG Piller, LB Perin, EC Penn, MS Chambers, J Baran, KW Raveendran, G Lambert, C Gee, AP Forder, JR Taylor, DA Cogle, CR Thomas, JD Ebert, RF Skarlatos, SI Moye, LA Simari, RD AF Traverse, Jay H. Henry, Timothy D. Pepine, Carl J. Willerson, James T. Zhao, David X. Ellis, Stephen G. Piller, Linda B. Perin, Emerson C. Penn, Marc S. Chambers, Jeffrey Baran, Kenneth W. Raveendran, Ganesh Lambert, Charles Gee, Adrian P. Forder, John R. Taylor, Doris A. Cogle, Christopher R. Thomas, James D. Ebert, Ray F. Skarlatos, Sonia I. Moye, Lemuel A. Simari, Robert D. TI The Effect of Timing of Stem Cell Delivery Following Acute Myocardial Infarction: The NHLBI and CCTRN TIME Trial SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association CY NOV 03-07, 2012 CL Los Angeles, CA SP Amer Heart Assoc DE Stem cell therapy; Myocardial infarction; STEMI; Clinical trials; Cardiac MRI C1 [Traverse, Jay H.; Henry, Timothy D.] Abbott NW Hosp, Minneapolis Heart Inst, Minneapolis, MN 55407 USA. [Pepine, Carl J.; Forder, John R.; Cogle, Christopher R.] Univ Florida, Coll Med, Gainesville, FL USA. [Willerson, James T.; Perin, Emerson C.] St Lukes Episcopal Hosp, Texas Heart Inst, Houston, TX USA. [Zhao, David X.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Ellis, Stephen G.; Thomas, James D.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Piller, Linda B.; Moye, Lemuel A.] Univ Texas Houston, Sch Publ Hlth, Houston, TX USA. [Penn, Marc S.] Summa Cardiovasc Inst, Rootstown, OH USA. [Chambers, Jeffrey] Mercy Hosp, Coon Rapids, MN USA. [Baran, Kenneth W.] United Hosp, St Paul Heart Clin, St Paul, MN USA. [Raveendran, Ganesh] Univ Minnesota, Lillehei Heart Inst, Minneapolis, MN 55455 USA. [Lambert, Charles] Pepin Heart Hosp, Patel Rsch Inst, Tampa, FL USA. [Gee, Adrian P.] Baylor Coll Med, Houston, TX 77030 USA. [Taylor, Doris A.] St Lukes Episcopal Hosp, Texas Heart Inst, Minneapolis, MN USA. [Ebert, Ray F.; Skarlatos, Sonia I.] NHLBI, Bethesda, MD 20892 USA. [Simari, Robert D.] Mayo Clin, Rochester, MN USA. NR 0 TC 1 Z9 1 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 DEC 4 PY 2012 VL 126 IS 23 BP 2783 EP 2784 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048TY UT WOS:000311937200039 ER PT J AU Bart, BA Goldsmith, SR Lee, KL Stevenson, LW O'Connor, CM Bull, DA Redfield, MM Deswal, A Rouleau, JL LeWinter, MM Ofili, EO Givertz, MM Semigran, MJ Felker, GM Chen, HH Hernandez, AF Anstrom, KJ McNulty, SE Velazquez, EJ Mascette, AM Braunwald, E AF Bart, Bradley A. Goldsmith, Steven R. Lee, Kerry L. Stevenson, Lynne W. O'Connor, Christopher M. Bull, David A. Redfield, Margaret M. Deswal, Anita Rouleau, Jean L. LeWinter, Martin M. Ofili, Elizabeth O. Givertz, Micheal M. Semigran, Marc J. Felker, G. M. Chen, Horng H. Hernandez, Adrian F. Anstrom, Kevin J. McNulty, Steven E. Velazquez, Eric J. Mascette, Alice M. Braunwald, Eugene TI Cardiorenal Rescue Study in Acute Decompensated Heart Failure: Results of CARRESS-HF, for the Heart Failure Clinical Research Network SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association CY NOV 03-07, 2012 CL Los Angeles, CA SP Amer Heart Assoc DE Acute heart failure; Diuretics; Renal function; Device C1 [Bart, Bradley A.; Goldsmith, Steven R.] Hennepin Cty Med Ctr, Minneapolis, MN 55415 USA. [Lee, Kerry L.; O'Connor, Christopher M.; Felker, G. M.; Hernandez, Adrian F.; Anstrom, Kevin J.; McNulty, Steven E.; Velazquez, Eric J.] Duke Univ, Durham, NC USA. [Stevenson, Lynne W.; Givertz, Micheal M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Bull, David A.] Univ Utah, Salt Lake City, UT USA. [Redfield, Margaret M.; Chen, Horng H.] Mayo Clin, Rochester, MN USA. [Deswal, Anita] Baylor Coll Med, Houston, TX 77030 USA. [Deswal, Anita] VA Med Cntr, Houston, TX USA. [Rouleau, Jean L.] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [LeWinter, Martin M.] Univ Vermont, Berlington, VT USA. [Ofili, Elizabeth O.] Morehouse Sch Med, Atlanta, GA 30310 USA. [Semigran, Marc J.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Mascette, Alice M.] NHLBI, Bethesda, MD 20892 USA. [Braunwald, Eugene] Harvard Univ, Sch Med, Boston, MA USA. 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 DEC 4 PY 2012 VL 126 IS 23 BP 2786 EP 2786 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048TY UT WOS:000311937200046 ER PT J AU Idris, AH Guffey, D Pepe, PE Brown, SP Aufderheide, TP Brooks, SC Callaway, CW Christenson, J Davis, DP Daya, MR Gray, R Kudenchuk, PJ Larsen, J Lin, S Menegazzi, JJ Sheehan, K Sopko, G Stiell, IG Nichol, G AF Idris, Ahamed H. Guffey, Danielle Pepe, Paul E. Brown, Siobhan P. Aufderheide, Tom P. Brooks, Steven C. Callaway, Clifton W. Christenson, Jim Davis, Dan P. Daya, Mohamud R. Gray, Randal Kudenchuk, Peter J. Larsen, Jonathan Lin, Steve Menegazzi, James J. Sheehan, Kellie Sopko, George Stiell, Ian G. Nichol, Graham CA ROC Investigators TI The Interaction of Chest Compression Rates With the Impedance Threshold Device and Association With Survival Following Out-of-Hospital Cardiac Arrest SO CIRCULATION LA English DT Meeting Abstract CT Scientific Sessions of the American-Heart-Association CY NOV 03-07, 2012 CL Los Angeles, CA SP Amer Heart Assoc DE Cardiac arrest; Cardiopulmonary resuscitation; Emergency care C1 [Idris, Ahamed H.; Pepe, Paul E.] UT SW Med Ctr, Dallas, TX USA. [Guffey, Danielle; Brown, Siobhan P.; Kudenchuk, Peter J.; Sheehan, Kellie; Nichol, Graham] Univ Washington, Seattle, WA 98195 USA. [Aufderheide, Tom P.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Callaway, Clifton W.; Menegazzi, James J.] Univ Pittsburgh, Pittsburgh, PA USA. [Brooks, Steven C.] Queens Univ, Toronto, ON, Canada. [Christenson, Jim] Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. [Davis, Dan P.] UCSD Med Cntr, San Diego, CA USA. [Daya, Mohamud R.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Gray, Randal] Univ Alabama Birmingham, Birmingham, AL USA. [Larsen, Jonathan] Seattle Fire Dept, Seattle, WA USA. [Lin, Steve] St Michaels Hosp, Li Ka Shing Knowledge Inst, Toronto, ON M5B 1W8, Canada. [Sopko, George] NIH, Bethesda, MD 20892 USA. [Stiell, Ian G.] Univ Ottawa, Ottawa, ON, Canada. NR 0 TC 0 Z9 0 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 DEC 4 PY 2012 VL 126 IS 23 BP 2796 EP 2796 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048TY UT WOS:000311937200072 ER PT J AU Wilson, JR Marshall, RJ Shanbhag, SM Sanai, R Corcoran, P Arai, AE Bandettini, WP AF Wilson, Joel R. Marshall, Robert J. Shanbhag, Sujata M. Sanai, Reza Corcoran, Philip Arai, Andrew E. Bandettini, W. Patricia TI Multimodality Imaging of a Dissecting Intramyocardial Hematoma Extending into the Left Atrial Wall Following Myocardial Infarction SO CIRCULATION LA English DT Editorial Material C1 [Shanbhag, Sujata M.; Arai, Andrew E.; Bandettini, W. Patricia] NHLBI, Adv Cardiovasc Imaging Lab, NIH, Bethesda, MD 20892 USA. [Wilson, Joel R.] Univ Calif San Diego, Sulpizio Cardiovasc Ctr, La Jolla, CA 92093 USA. [Corcoran, Philip] NHLBI, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. [Marshall, Robert J.; Sanai, Reza] CardioCare LLC, Chevy Chase, MD USA. [Marshall, Robert J.] Meritus Med Ctr, Hagerstown, MD USA. [Sanai, Reza; Corcoran, Philip] Suburban Hosp, Bethesda, MD USA. RP Bandettini, WP (reprint author), NHLBI, Adv Cardiovasc Imaging Lab, NIH, 10 Ctr Dr,Bldg 10,Rm B1D-416,MSC 1061, Bethesda, MD 20892 USA. EM ingkanisorn@nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 4 TC 2 Z9 2 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD DEC 4 PY 2012 VL 126 IS 23 BP E339 EP E341 DI 10.1161/CIRCULATIONAHA.112.117390 PG 3 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 048TY UT WOS:000311937200001 PM 23212999 ER PT J AU Tsuji, PA Carlson, BA Naranjo-Suarez, S Yoo, MH Xu, XM Fomenko, DE Gladyshev, VN Hatfield, DL Davis, CD AF Tsuji, Petra A. Carlson, Bradley A. Naranjo-Suarez, Salvador Yoo, Min-Hyuk Xu, Xue-Ming Fomenko, Dmitri E. Gladyshev, Vadim N. Hatfield, Dolph L. Davis, Cindy D. TI Knockout of the 15 kDa Selenoprotein Protects against Chemically-Induced Aberrant Crypt Formation in Mice SO PLOS ONE LA English DT Article ID GUANYLATE-BINDING PROTEIN-1; INFLAMMATORY CYTOKINES; ENDOTHELIAL-CELLS; CANCER RISK; SELENIUM; EXPRESSION; COLON; SEP15; INHIBITION; GROWTH AB Evidence suggests that selenium has cancer preventive properties that are largely mediated through selenoproteins. Our previous observations demonstrated that targeted down-regulation of the 15 kDa selenoprotein (Sep15) in murine colon cancer cells resulted in the reversal of the cancer phenotype. The present study investigated the effect of Sep15 knockout in mice using a chemically-induced colon cancer model. Homozygous Sep15 knockout mice, and wild type littermate controls were given four weekly subcutaneous injections of azoxymethane (10 mg/kg). Sep15 knockout mice developed significantly (p<0.001) fewer aberrant crypt foci than controls demonstrating that loss of Sep15 protects against aberrant crypt foci formation. Dietary selenium above adequate levels did not significantly affect aberrant crypt foci formation in Sep15 knockout mice. To investigate molecular targets affected by loss of Sep15, gene expression patterns in colonic mucosal cells of knockout and wild type mice were examined using microarray analysis. Subsequent analyses verified that guanylate binding protein-1 (GBP-1) mRNA and protein expression were strongly upregulated in Sep15 knockout mice. GBP-1, which is expressed in response to interferon-c, is considered to be an activation marker during inflammatory diseases, and upregulation of GBP-1 in humans has been associated with a highly significant, increased five-year survival rate in colorectal cancer patients. In agreement with these studies, we observed a higher level of interferon-c in plasma of Sep15 knockout mice. Overall, our results demonstrate for the first time, that Sep15 knockout mice are protected against chemically-induced aberrant crypt foci formation and that Sep15 appears to have oncogenic properties in colon carcinogenesis in vivo. Citation: Tsuji PA, Carlson BA, Naranjo-Suarez S, Yoo M-H, Xu X-M, et al. (2012) Knockout of the 15 kDa Selenoprotein Protects against Chemically-Induced Aberrant Crypt Formation in Mice. PLoS ONE 7(12): e50574. doi:10.1371/journal.pone.0050574 C1 [Tsuji, Petra A.] Towson Univ, Dept Biol Sci, Towson, MD USA. [Tsuji, Petra A.; Carlson, Bradley A.; Naranjo-Suarez, Salvador; Yoo, Min-Hyuk; Xu, Xue-Ming; Hatfield, Dolph L.] NIH, Mol Biol Selenium Sect, Lab Canc Prevent, Bethesda, MD 20892 USA. [Davis, Cindy D.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Fomenko, Dmitri E.] Univ Nebraska, Dept Biochem, Lincoln, NE 68583 USA. [Gladyshev, Vadim N.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. RP Tsuji, PA (reprint author), Towson Univ, Dept Biol Sci, Towson, MD USA. EM ptsuji@towson.edu RI Gladyshev, Vadim/A-9894-2013 FU National Cancer Institute (NCI) Intramural; Cancer Prevention Fellowship Program; Division of Cancer Prevention, National Institutes of Health (NIH) [CA080946]; Towson University FX This work was funded by National Cancer Institute (NCI) Intramural support, the Cancer Prevention Fellowship Program, the Division of Cancer Prevention, National Institutes of Health (NIH) CA080946, and Towson University. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 38 TC 10 Z9 11 U1 2 U2 10 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 DEC 4 PY 2012 VL 7 IS 12 AR e50574 DI 10.1371/journal.pone.0050574 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 051EQ UT WOS:000312108500019 PM 23226526 ER PT J AU Zhang, Q Rahim, MMA Allan, DSJ Tu, MM Belanger, S Abou-Samra, E Ma, J Sekhon, HS Fairhead, T Zein, HS Carlyle, JR Anderson, SK Makrigiannis, AP AF Zhang, Qiang Rahim, Mir Munir A. Allan, David S. J. Tu, Megan M. Belanger, Simon Abou-Samra, Elias Ma, Jaehun Sekhon, Harman S. Fairhead, Todd Zein, Haggag S. Carlyle, James R. Anderson, Stephen K. Makrigiannis, Andrew P. TI Mouse Nkrp1-Clr Gene Cluster Sequence and Expression Analyses Reveal Conservation of Tissue-Specific MHC-Independent Immunosurveillance SO PLOS ONE LA English DT Article ID C-TYPE LECTIN; MISSING-SELF-RECOGNITION; KILLER-CELL RECEPTORS; NK1.1(+) T-CELLS; NK CELLS; LY49 CLUSTER; ENDOGENOUS RETROVIRUSES; DENDRITIC CELLS; IMMUNE-SYSTEM; HUMAN NKR-P1A AB The Nkrp1 (Klrb1)-Clr (Clec2) genes encode a receptor-ligand system utilized by NK cells as an MHC-independent immunosurveillance strategy for innate immune responses. The related Ly49 family of MHC-I receptors displays extreme allelic polymorphism and haplotype plasticity. In contrast, previous BAC-mapping and aCGH studies in the mouse suggest the neighboring and related Nkrp1-Clr cluster is evolutionarily stable. To definitively compare the relative evolutionary rate of Nkrp1-Clr vs. Ly49 gene clusters, the Nkrp1-Clr gene clusters from two Ly49 haplotype-disparate inbred mouse strains, BALB/c and 129S6, were sequenced. Both Nkrp1-Clr gene cluster sequences are highly similar to the C57BL/6 reference sequence, displaying the same gene numbers and order, complete pseudogenes, and gene fragments. The Nkrp1-Clr clusters contain a strikingly dissimilar proportion of repetitive elements compared to the Ly49 clusters, suggesting that certain elements may be partly responsible for the highly disparate Ly49 vs. Nkrp1 evolutionary rate. Focused allelic polymorphisms were found within the Nkrp1b/d (Klrb1b), Nkrp1c (Klrb1c), and Clr-c (Clec2f) genes, suggestive of possible immune selection. Cell-type specific transcription of Nkrp1-Clr genes in a large panel of tissues/organs was determined. Clrb (Clec2d) and Clr-g (Clec2i) showed wide expression, while other Clr genes showed more tissue-specific expression patterns. In situ hybridization revealed specific expression of various members of the Clr family in leukocytes/hematopoietic cells of immune organs, various tissue-restricted epithelial cells (including intestinal, kidney tubular, lung, and corneal progenitor epithelial cells), as well as myocytes. In summary, the Nkrp1-Clr gene cluster appears to evolve more slowly relative to the related Ly49 cluster, and likely regulates innate immunosurveillance in a tissue-specific manner. Citation: Zhang Q, Rahim MMA, Allan DSJ, Tu MM, Belanger S, et al. (2012) Mouse Nkrp1-Clr Gene Cluster Sequence and Expression Analyses Reveal Conservation of Tissue-Specific MHC-Independent Immunosurveillance. PLoS ONE 7(12): e50561. doi:10.1371/journal.pone.0050561 C1 [Allan, David S. J.; Ma, Jaehun; Carlyle, James R.] Univ Toronto, Dept Immunol, Sunnybrook Res Inst, Toronto, ON, Canada. [Zhang, Qiang; Rahim, Mir Munir A.; Tu, Megan M.; Belanger, Simon; Abou-Samra, Elias; Zein, Haggag S.; Makrigiannis, Andrew P.] Univ Ottawa, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada. [Sekhon, Harman S.] Ottawa Hosp, Dept Pathol & Lab Med, Ottawa, ON, Canada. [Fairhead, Todd] Ottawa Hosp, Kidney Res Ctr, Res Inst, Ottawa, ON, Canada. [Zein, Haggag S.] Cairo Univ, Dept Genet, Giza, Egypt. [Anderson, Stephen K.] SAIC Frederick Inc, Basic Sci Program, Expt Immunol Lab, Frederick Natl Lab Canc Res, Frederick, MD USA. RP Carlyle, JR (reprint author), Univ Toronto, Dept Immunol, Sunnybrook Res Inst, Toronto, ON, Canada. EM james.carlyle@utoronto.ca; andersonst@mail.nih.gov; amakrigi@uottawa.ca FU Canadian Institutes of Health Research [CIHR 86630]; Early Researcher Award from the Ontario Ministry of Research and Innovation; Intramural Research Program of National Institutes of Health (NIH); Frederick National Lab, Center for Cancer Research; Frederick National Laboratory for Cancer Research, NIH [HHSN261200800001E] FX This work was supported by an operating grant from the Canadian Institutes of Health Research (CIHR 86630; to A.P.M. & J.R.C), and an Early Researcher Award from the Ontario Ministry of Research and Innovation (to J.R.C). A.P.M. holds a Canada Research Chair in Innate Pathogen Resistance. J.R.C. holds a CIHR New Investigator Award and an Investigator in the Pathogenesis of Infectious Disease Award from the Burroughs Wellcome Fund, United States of America. This research was supported in part by the Intramural Research Program of National Institutes of Health (NIH), Frederick National Lab, Center for Cancer Research. This project has been funded in part with federal funds from the Frederick National Laboratory for Cancer Research, NIH, under contract 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 United States government. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 48 TC 10 Z9 10 U1 2 U2 6 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 DEC 4 PY 2012 VL 7 IS 12 AR e50561 DI 10.1371/journal.pone.0050561 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 051EQ UT WOS:000312108500018 PM 23226525 ER PT J AU Zhou, ZJ Huang, DT Bao, JF Chen, QL Liu, G Chen, Z Chen, XY Gao, JH AF Zhou, Zijian Huang, Dengtong Bao, Jianfeng Chen, Qiaoli Liu, Gang Chen, Zhong Chen, Xiaoyuan Gao, Jinhao TI A Synergistically Enhanced T-1-T-2 Dual-Modal Contrast Agent SO ADVANCED MATERIALS LA English DT Article DE T-1-T-2 dual-modal; synergistic enhancement; molecular imaging; accuracy; liver tumor ID IRON-OXIDE NANOPARTICLES; MULTIFUNCTIONAL MAGNETIC NANOPARTICLES; SIZE-CONTROLLED SYNTHESIS; MRI CONTRAST; GADOLINIUM; LIVER; T-1; NANOCRYSTALS; RELAXATION; SURFACE AB Monodisperse Gd2O3-embedded iron oxide (GdIO) nanoparticles can simultaneously enhance the local magnetic field intensities of each other under an external magnetic field and result in synergistic enhancement of T-1 and T-2 effects. GdIO nanoparticles have the unique property to be both T-1 and T-2 contrast agents and can potentially lead to higher accuracy in cancer diagnosis, particularly liver tumors. C1 [Zhou, Zijian; Huang, Dengtong; Chen, Qiaoli; Gao, Jinhao] Xiamen Univ, Key Lab Chem Biol Fujian Prov, State Key Lab Phys Chem Solid Surfaces, Xiamen 361005, Peoples R China. [Zhou, Zijian; Huang, Dengtong; Chen, Qiaoli; Gao, Jinhao] Xiamen Univ, Dept Biol Chem, Coll Chem & Chem Engn, Xiamen 361005, Peoples R China. [Bao, Jianfeng; Chen, Zhong] Xiamen Univ, Dept Elect Sci, Xiamen 361005, Peoples R China. [Bao, Jianfeng; Chen, Zhong] Xiamen Univ, Fujian Key Lab Plasma & Magnet Resonance, Xiamen 361005, Peoples R China. [Liu, Gang; Chen, Xiaoyuan; Gao, Jinhao] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. [Chen, Xiaoyuan] Natl Inst Biomed Imaging & Bioengn, Lab Mol Imaging & Nanomed, NIH, Bethesda, MD 20892 USA. RP Gao, JH (reprint author), Xiamen Univ, Key Lab Chem Biol Fujian Prov, State Key Lab Phys Chem Solid Surfaces, Xiamen 361005, Peoples R China. EM jhgao@xmu.edu.cn RI SKL, PCOSS/D-4395-2013; Gao, Jinhao/F-5092-2010; Chen, Zhong/G-4601-2010 OI Gao, Jinhao/0000-0003-3215-7013; FU National Science Foundation of China [21021061, 81000662, 21222106, J1030415]; Fundamental Research Funds for the Central Universities [2010121012]; Program for New Century Excellent Talents in University [NCET-10-0709] FX This work was supported by the National Science Foundation of China (21021061, 81000662, 21222106, and J1030415), the Fundamental Research Funds for the Central Universities (2010121012), and the Program for New Century Excellent Talents in University (NCET-10-0709). NR 44 TC 85 Z9 87 U1 15 U2 134 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 0935-9648 EI 1521-4095 J9 ADV MATER JI Adv. Mater. PD DEC 4 PY 2012 VL 24 IS 46 BP 6223 EP 6228 DI 10.1002/adma.201203169 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 051MF UT WOS:000312130600017 PM 22972529 ER PT J AU Lorieau, JL Louis, JM Schwieters, CD Bax, A AF Lorieau, Justin L. Louis, John M. Schwieters, Charles D. Bax, Adriaan TI pH-triggered, activated-state conformations of the influenza hemagglutinin fusion peptide revealed by NMR SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE conformational ensemble; dynamics; membrane proteins; RDC; relaxation dispersion ID MEMBRANE-FUSION; VIRUS HEMAGGLUTININ; BACKBONE MOTION; CHEMICAL-SHIFTS; LIPID-BILAYERS; T4 LYSOZYME; RELAXATION; DYNAMICS; MUTANT; DOMAIN AB The highly conserved first 23 residues of the influenza hemagglutinin HA2 subunit constitute the fusion domain, which plays a pivotal role in fusing viral and host-cell membranes. At neutral pH, this peptide adopts a tight helical hairpin wedge structure, stabilized by aliphatic hydrogen bonding and charge-dipole interactions. We demonstrate that at low pH, where the fusion process is triggered, the native peptide transiently visits activated states that are very similar to those sampled by a G8A mutant. This mutant retains a small fraction of helical hairpin conformation, in rapid equilibrium with at least two open structures. The exchange rate between the closed and open conformations of the wild-type fusion peptide is similar to 40 kHz, with a total open-state population of similar to 20%. Transitions to these activated states are likely to play a crucial role in formation of the fusion pore, an essential structure required in the final stage of membrane fusion. C1 [Lorieau, Justin L.; Louis, John M.; Bax, Adriaan] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Schwieters, Charles D.] NIH, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM bax@nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) mass spectrometry facility; National Institutes of Health (NIH) Intramural Research Programs of the NIDDK; Center for Information Technology; Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH FX We thank Annie Aniana for help with protein expression and purification, and acknowledge support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) mass spectrometry facility. This work was funded by the National Institutes of Health (NIH) Intramural Research Programs of the NIDDK and the Center for Information Technology, and by the Intramural AIDS-Targeted Antiviral Program of the Office of the Director, NIH. NR 36 TC 43 Z9 44 U1 0 U2 45 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 DEC 4 PY 2012 VL 109 IS 49 BP 19994 EP 19999 DI 10.1073/pnas.1213801109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054MF UT WOS:000312347200034 PM 23169643 ER PT J AU Wang, HS Shin, DM Abbasi, S Jain, S Kovalchuk, AL Beaty, N Chen, S Gonzalez-Garcia, I Morse, HC AF Wang, Hongsheng Shin, Dong-Mi Abbasi, Sadia Jain, Shweta Kovalchuk, Alexander L. Beaty, Natalie Chen, Sophia Gonzalez-Garcia, Ines Morse, Herbert C., III TI Expression of plasma cell alloantigen 1 defines layered development of B-1a B-cell subsets with distinct innate-like functions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE B-1 cells; natural antibody; innate immunity; B regulatory cells ID MARGINAL-ZONE; BONE-MARROW; AUTOANTIBODY PRODUCTION; POSITIVE SELECTION; NATURAL IMMUNITY; CHILDREN YOUNGER; B-2 CELLS; B10 CELLS; PERITONEAL; MICE AB Innate-like B-1a cells contribute significantly to circulating natural antibodies and mucosal immunity as well as to immunoregulation. Here we show that these classic functions of B-1a cells segregate between two unique subsets defined by expression of plasma cell alloantigen 1 (PC1), also known as ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1). These subsets, designated B-1a.PC1(lo) and B-1a.PC1(hi), differ significantly in IgH chain utilization. Adoptively transferred PC1(lo) cells secreted significantly more circulating natural IgM and intestinal IgA than PC1(hi) cells. In contrast, PC1(hi) cells produced more IL-10 than PC1(lo) cells when stimulated with LPS and phorbol 12-myristate 13-acetate (PMA). PC1(hi) cells were also more efficient than PC1(lo) cells in regulating Th1 cell differentiation, even though both B-1a subsets were comparably active in stimulating T-cell proliferation. Furthermore, PC1(lo) cells generated antigen-specific IgM responses to pneumococcal polysaccharide antigens, whereas PC1(hi) cells do not. We found that PC1(lo) cells develop from an early wave of B-1a progenitors in fetal life, whereas PC1(hi) cells are generated from a later wave after birth. We conclude that identification of B-1a.PC1(lo) and B-1a. PC1(hi) cells extends the concept of a layered immune system with important implications for developing effective vaccines and promoting the generation of immunoregulatory B cells. C1 [Wang, Hongsheng; Shin, Dong-Mi; Abbasi, Sadia; Jain, Shweta; Kovalchuk, Alexander L.; Beaty, Natalie; Chen, Sophia; Gonzalez-Garcia, Ines; Morse, Herbert C., III] NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Wang, HS (reprint author), NIAID, Virol & Cellular Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. EM wanghongs@niaid.nih.gov; hmorse@niaid.nih.gov OI Morse, Herbert/0000-0002-9331-3705 FU NIH, NIAID FX We thank Dr. Fumio Takei (University of British Columbia) for providing us with the anti-PC1 monoclonal antibody, Larry Lantz (NIAID Research Technologies Branch) for antibody purification and labeling, Mehrnoosh Abshari for cell sorting, and Alfonso Macias for technical assistance. We thank Dr. Stephen H. Clarke (University of North Carolina) for providing us VH12 Tg mice and FITC-liposomes, and Drs. Kyoko Hayakawa and Richard R. Hardy (Fox Chase Cancer Center) for valuable advice and analysis of VH11 cells. We also thank Drs. Leonore A. Herzenberg, Yang Yang, and Eliver Eid Bou Ghosn (Stanford University) for valuable technical input. This study was supported by the Intramural Research Program of the NIH, NIAID. NR 64 TC 11 Z9 12 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 4 PY 2012 VL 109 IS 49 BP 20077 EP 20082 DI 10.1073/pnas.1212428109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054MF UT WOS:000312347200048 PM 23169635 ER PT J AU Arinaminpathy, N Lavine, JS Grenfell, BT AF Arinaminpathy, Nimalan Lavine, Jennie S. Grenfell, Bryan T. TI Self-boosting vaccines and their implications for herd immunity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE herpesvirus; waning immunity ID HUMAN CYTOMEGALOVIRUS; PLASMODIUM-FALCIPARUM; SEVERE MALARIA; T-CELLS; PERTUSSIS; HERPES; VIRUS; TRANSMISSION; REACTIVATION; INFECTIONS AB Advances in vaccine technology over the past two centuries have facilitated far-reaching impact in the control of many infections, and today's emerging vaccines could likewise open new opportunities in the control of several diseases. Here we consider the potential, population-level effects of a particular class of emerging vaccines that use specific viral vectors to establish long-term, intermittent antigen presentation within a vaccinated host: in essence, "self-boosting" vaccines. In particular, we use mathematical models to explore the potential role of such vaccines in situations where current immunization raises only relatively short-lived protection. Vaccination programs in such cases are generally limited in their ability to raise lasting herd immunity. Moreover, in certain cases mass vaccination can have the counterproductive effect of allowing an increase in severe disease, through reducing opportunities for immunity to be boosted through natural exposure to infection. Such dynamics have been proposed, for example, in relation to pertussis and varicella-zoster virus. In this context we show how self-boosting vaccines could open qualitatively new opportunities, for example by broadening the effective duration of herd immunity that can be achieved with currently used immunogens. At intermediate rates of self-boosting, these vaccines also alleviate the potential counterproductive effects of mass vaccination, through compensating for losses in natural boosting. Importantly, however, we also show how sufficiently high boosting rates may introduce a new regime of unintended consequences, wherein the unvaccinated bear an increased disease burden. Finally, we discuss important caveats and data needs arising from this work. C1 [Arinaminpathy, Nimalan; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Lavine, Jennie S.] Univ Michigan, Dept Ecol & Evolutionary Biol, Ann Arbor, MI 48109 USA. [Lavine, Jennie S.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Arinaminpathy, N (reprint author), Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. EM nimpathy@princeton.edu FU National Institutes of Health (NIH) [R01 GM083983-01]; Bill and Melinda Gates Foundation; Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, NIH FX This research was supported by National Institutes of Health (NIH) Grant R01 GM083983-01 and the Bill and Melinda Gates Foundation. B. T. G. and J.S.L. were also supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, NIH. NR 53 TC 7 Z9 7 U1 1 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 DEC 4 PY 2012 VL 109 IS 49 BP 20154 EP 20159 DI 10.1073/pnas.1209683109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054MF UT WOS:000312347200061 PM 23169630 ER PT J AU Papaleo, F Erickson, L Liu, GP Chen, JS Weinberger, DR AF Papaleo, Francesco Erickson, Lucy Liu, Guangping Chen, Jingshan Weinberger, Daniel R. TI Effects of sex and COMT genotype on environmentally modulated cognitive control in mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gender; operant behavior; food ad libitum; psychiatric disorders ID CATECHOL-O-METHYLTRANSFERASE; DEFICIT HYPERACTIVITY DISORDER; RAT PREFRONTAL CORTEX; REACTION-TIME-TASK; DOPAMINE SYSTEM; SCHIZOPHRENIA; IMPULSIVITY; EXPRESSION; POLYMORPHISM; METAANALYSIS AB Cognitive functioning differs between males and females, likely in part related to genetic dimorphisms. An example of a common genetic variation reported to have sexually dimorphic effects on cognition and temperament in humans is the Val/Met polymorphism in catechol-O-methyltransferase (COMT). We tested male and female wild-type mice ((+/+)) and their COMT knockout littermates ((+/-) and (-/-)) in the five-choice serial reaction time task (5CSRTT) to investigate the effects of sex, COMT genotype, and their interactions with environmental manipulations of cognitive functions such as attention, impulsivity, compulsivity, motivation, and rule-reversal learning. No sex- or COMT-dependent differences were present in the basic acquisition of the five-choice serial reaction time task. In contrast, specific environmental manipulations revealed a variety of sex-and COMT-dependent effects. Following an experimental change to trigger impulsive responding, the sexes showed similar increases in impulsiveness, but males eventually habituated whereas females did not. Moreover, COMT knockout mice were more impulsive compared with wild-type littermates. Manipulations involving mild stress adversely affected cognitive performance in males, and particularly COMT knockout males, but not in females. In contrast, following amphetamine treatment, subtle sex by genotype and sex by treatment interactions emerged primarily limited to compulsive behavior. After repeated testing, female mice showed improved performance, working harder and eventually outperforming males. Finally, removing the food-restriction condition enhanced sex and COMT differences, revealing that overall, females outperform males and COMT knockout males outperform their wild-type littermates. These findings illuminate complex sex-and COMT-related effects and their interactions with environmental factors to influence specific executive cognitive domains. C1 [Papaleo, Francesco; Erickson, Lucy; Liu, Guangping; Chen, Jingshan; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program, Bethesda, MD 20892 USA. [Papaleo, Francesco] Ist Italiano Tecnol, Dept Neurosci & Brain Technol, I-16163 Genoa, Italy. [Papaleo, Francesco] Univ Padua, Dept Sci Farmaco, I-35131 Padua, Italy. [Weinberger, Daniel R.] Johns Hopkins Univ Med Campus, Lieber Inst Brain Dev, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. [Weinberger, Daniel R.] Johns Hopkins Sch Med, Inst Genet Med, Baltimore, MD 21205 USA. RP Papaleo, F (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, Intramural Res Program, Bethesda, MD 20892 USA. EM francesco.papaleo@iit.it OI Papaleo, Francesco/0000-0002-6326-0657 FU Intramural Program of the NIMH (DRW laboratory); NIMH Julius Axelrod Memorial Fellowship Training Award; Istituto Italiano di Tecnologia; Marie Curie Seventh Framework Programme Reintegration Grant [268247] FX We thank Dr. B. Lu for material support; Q. Tian and T. Telahun for technical assistance; and Drs. M. Karayiorgou and J. A. Gogos for donating the COMT-/- mice breeders. This research was supported by the Intramural Program of the NIMH (DRW laboratory). L.E.'s appointment and operant boxes were supported by an NIMH Julius Axelrod Memorial Fellowship Training Award (to F. P.). F. P. was also supported by the Istituto Italiano di Tecnologia and by the Marie Curie Seventh Framework Programme Reintegration Grant 268247. NR 50 TC 24 Z9 24 U1 1 U2 16 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 4 PY 2012 VL 109 IS 49 BP 20160 EP 20165 DI 10.1073/pnas.1214397109 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 054MF UT WOS:000312347200062 PM 23169629 ER PT J AU Rossouw, JE Manson, JE Kaunitz, AM Stefanick, ML AF Rossouw, Jacques E. Manson, JoAnn E. Kaunitz, Andrew M. Stefanick, Marcia L. TI HRT AND CARDIOVASCULAR EVENTS Study had insufficient power to investigate safety SO BRITISH MEDICAL JOURNAL LA English DT Letter ID THERAPY; WOMEN C1 [Rossouw, Jacques E.] NHLBI, Bethesda, MD 20892 USA. [Manson, JoAnn E.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Manson, JoAnn E.] Harvard Univ, Sch Med, Boston, MA USA. [Kaunitz, Andrew M.] Univ Florida, Coll Med, Jacksonville, FL USA. [Stefanick, Marcia L.] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Rossouw, JE (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM rossouwj@nih.gov NR 3 TC 3 Z9 3 U1 0 U2 1 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1756-1833 J9 BRIT MED J JI Br. Med. J. PD DEC 3 PY 2012 VL 345 AR e8146 DI 10.1136/bmj.e8146 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 052HO UT WOS:000312188700013 PM 23208257 ER PT J AU Wang, D Wong, HK Zhang, L McAlonan, GM Wang, XM Sze, SCW Feng, YB Zhang, ZJ AF Wang, Di Wong, Hei Kiu Zhang, Li McAlonan, Grainne M. Wang, Xiao-Min Sze, Stephen Cho Wing Feng, Yi-Bin Zhang, Zhang-Jin TI Not only dopamine D-2 receptors involved in Peony-Glycyrrhiza Decoction, an herbal preparation against antipsychotic-associated hyperprolactinemia SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Article DE Antipsychotics; Dopamine; D-2 receptors; Herbal medicine; Hyperprolactinemia; Peony-Glycyrrhiza Decoction (PGD) ID SHAKUYAKU-KANZO-TO; NEUROLEPTIC-INDUCED HYPERPROLACTINEMIA; GLYCYRRHETINIC ACID; PARKINSONS-DISEASE; SERUM TESTOSTERONE; PC12 CELLS; PAEONIFLORIN; MEDICINE; RISPERIDONE; EXPRESSION AB Clinical studies have demonstrated the effectiveness of an herbal preparation called Peony-Glycyrrhiza Decoction (PGD) in alleviating antipsychotic-induced hyperprolactinemia (hyperPRL). In the present study, we further examined the pharmacological action of PGD on prolactin (PRL) secretion using in vitro and in vivo models, with specific attention to the role of dopaminergic mediators and other sex hormones. Treatment with PGD at 1-5 mg/ml significantly suppressed PRL secretion and synthesis in MMQ cells, a model of hyperPRL derived from pituitary adenoma cells. The suppressive effects were completely abolished by pretreatment with 10 mu M haloperidol, a dopamine D-2 receptor antagonist Consistent with a D-2-action, PGD did not affect PRL in rat pituitary lactotropic tumor-derived GH3 cells that lack the D-2 receptor expression but significantly increased the expression of D-2 receptors and dopamine transporters (DAT) in PC12 cells. In a rat model of hyperPRL, produced by repeated injection of the dopamine blocker metoclopramide (MCP), chronic PGD (2.5-10 g/kg daily) significantly reduced elevated serum PRL The reduction in magnitude was similar to that elicited by bromocriptine (BMT), a dopamine D-2 receptor agonist currently used for treatment of hyperPRL Neither PGD nor BMT altered serum estradiol, but PGD reversed decreased serum progesterone to control level, whereas BMT did not These results indicate that the anti-hyperPRL effects of PGD are associated not only with D-2 receptor and DAT modulation, but also with a normalization of other sex hormone dysfunction. This experimental evidence supports clinical use of PGD as an effective treatment of antipsychotic-induced hyperPRL (C) 2012 Elsevier Inc. All rights reserved. C1 [Wang, Di; Wong, Hei Kiu; Sze, Stephen Cho Wing; Feng, Yi-Bin; Zhang, Zhang-Jin] Univ Hong Kong, Sch Chinese Med, LKS Fac Med, Pokfulam, Hong Kong, Peoples R China. [Zhang, Li] NIAAA, Lab Integrat Neurosci, NIH, Rockville, MD 20892 USA. [McAlonan, Grainne M.] Kings Coll London, Inst Psychiat, Dept Forens & Neurodev Sci, London WC2R 2LS, England. [Wang, Xiao-Min] NINR, NIH, Bethesda, MD 20892 USA. RP Zhang, ZJ (reprint author), Univ Hong Kong, Sch Chinese Med, LKS Fac Med, 10 Sassoon Rd, Pokfulam, Hong Kong, Peoples R China. EM zhangzj@hku.hk OI McAlonan, Grainne/0000-0002-4466-2343 FU Health and Health Service Research Fund (HHSRF) [09101141]; HKU intramural seed funds [201011159095, 201102160005] FX This study was supported by the Health and Health Service Research Fund (HHSRF) (09101141) and HKU intramural seed funds (201011159095, 201102160005). NR 48 TC 11 Z9 12 U1 2 U2 27 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 EI 1878-4216 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD DEC 3 PY 2012 VL 39 IS 2 BP 332 EP 338 DI 10.1016/j.pnpbp.2012.07.005 PG 7 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 035JU UT WOS:000310943500017 PM 22796279 ER PT J AU Britton, KA Pedley, A Massaro, JM Corsini, EM Murabito, JM Hoffmann, U Fox, CS AF Britton, Kathryn A. Pedley, Alison Massaro, Joseph M. Corsini, Erin M. Murabito, Joanne M. Hoffmann, Udo Fox, Caroline S. TI Prevalence, Distribution, and Risk Factor Correlates of High Thoracic Periaortic Fat in the Framingham Heart Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE body fat distribution; obesity; perivascular adipose tissue; risk factors; visceral adipose tissue ID PERIVASCULAR ADIPOSE-TISSUE; METABOLICALLY-OBESE; PHYSICAL-ACTIVITY; DISEASE; ASSOCIATION; NUTRITION; COHORT AB Background-Thoracic periaortic adipose tissue (TAT) is associated with atherosclerosis and cardiovascular disease (CVD) risk factors and may play a role in obesity-mediated vascular disease. We sought to determine the prevalence, distribution, and risk factor correlates of high TAT. Methods and Results-Participants from the Framingham Heart Study (n=3246, 48% women, mean age 51.1 years) underwent multidetector computed tomography; high TAT and visceral adipose tissue (VAT) were defined on the basis of sex-specific 90th percentiles in a healthy referent sample. The prevalence of high TAT was 38.1% in women and 35.7% in men. Among individuals without high VAT, 10.1% had high TAT. After adjustment for age and VAT, both women and men with high TAT in the absence of high VAT were older and had a higher prevalence of CVD (P<0.0001) compared with those without high TAT. In addition, men in this group were more likely to be smokers (P=0.02), whereas women were more likely to have low high-density lipoprotein cholesterol (P=0.005). Conclusions-Individuals in our community-based sample with high TAT in the absence of high VAT were characterized by an adverse cardiometabolic profile. This adipose tissue phenotype may identify a subset of individuals with distinct metabolic characteristics. C1 [Britton, Kathryn A.] Brigham & Womens Hosp, Div Cardiovasc Med, Boston, MA 02115 USA. [Britton, Kathryn A.; Hoffmann, Udo; Fox, Caroline S.] Harvard Univ, Sch Med, Boston, MA USA. [Britton, Kathryn A.; Pedley, Alison; Murabito, Joanne M.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Corsini, Erin M.; Hoffmann, Udo] Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Dept Med, Gen Internal Med Sect, Boston, MA 02118 USA. [Fox, Caroline S.] NHLBI, Div Intramural Res, Framingham, MA USA. [Fox, Caroline S.] NHLBI, Ctr Populat Studies, Framingham, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Metab & Hypertens, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBIs Framingham Heart Study, 75 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Murabito, Joanne/0000-0002-0192-7516; Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung, and Blood Institute's Framingham Heart Study [N01-HC-25195]; National Heart, Lung, and Blood Institute [K12 HL083786] FX This work was supported by the National Heart, Lung, and Blood Institute's Framingham Heart Study (contract N01-HC-25195). Dr. Britton was supported by a Research Career Development Award (K12 HL083786) from the National Heart, Lung, and Blood Institute. NR 26 TC 18 Z9 18 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD DEC PY 2012 VL 1 IS 6 AR UNSP e004200 DI 10.1161/JAHA.112.004200 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 243RY UT WOS:000326335900007 PM 23316328 ER PT J AU Thanassoulis, G Massaro, JM Corsini, E Rogers, I Schlett, CL Meigs, JB Hoffmann, U O'Donnell, CJ Fox, CS AF Thanassoulis, George Massaro, Joseph M. Corsini, Erin Rogers, Ian Schlett, Christopher L. Meigs, James B. Hoffmann, Udo O'Donnell, Christopher J. Fox, Caroline S. TI Periaortic Adipose Tissue and Aortic Dimensions in the Framingham Heart Study SO JOURNAL OF THE AMERICAN HEART ASSOCIATION LA English DT Article DE adipose tissue; aneurysm; aorta; peripheral vascular disease ID PERICARDIAL FAT; RISK-FACTORS; ANEURYSMS; DISEASE; HEALTH; COMMUNITY; DIAMETER; OBESITY; COHORT AB Background-Periaortic fat, because of its contiguity with the aorta, may promote vascular remodeling and aortic dilatation. However, the relations between perioartic fat depots and aortic dimensions have not been previously described. Methods and Results-A total of 3001 individuals (mean age 50 +/- 10 years, 49% women) from the Framingham Offspring and Third Generation cohorts underwent computed tomography for quantification of periaortic fat and aortic dimensions. We estimated the association between quantitative periaortic and visceral adipose tissue volumes (per standard deviation [SD] increment of volume) with aortic dimensions in both the thorax and abdomen. Thoracic periaortic fat was associated with higher thoracic aortic dimensions (beta coefficient per SD of fat volume 0.67 mm, 95% confidence interval 0.58 to 0.76 mm; P<0.001). The association persisted after adjustment for age, sex, and cardiovascular risk factors including body mass index and visceral adipose tissue volume. Results for the association of periaortic fat and abdominal aortic dimensions were similar. Further adjustment for adipokines (resistin and adiponectin) had no significant impact on these associations. Conclusions-Periaortic fat volume was associated with aortic dimensions in both the thorax and abdomen, supporting the notion that local fat depots may contribute to aortic remodeling. Further work to understand the mechanisms underlying this association is warranted. C1 [Thanassoulis, George; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, NIH, Framingham Heart Study, Framingham, MA USA. [Massaro, Joseph M.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Corsini, Erin; Rogers, Ian; Schlett, Christopher L.; Hoffmann, Udo] Massachusetts Gen Hosp, Cardiac MR PET CT Program, Boston, MA 02114 USA. [Meigs, James B.] Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. [O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, NIH, Intramural Res, Bethesda, MD 20892 USA. RP Fox, CS (reprint author), NHLBI, NIH, Framingham Heart Study, Framingham, MA USA. EM foxca@nhlbi.nih.gov OI Massaro, Joseph/0000-0002-2682-4812 FU National Heart, Lung and Blood Institute's Framingham Heart Study [N01-HC-25195]; Canadian Institute of Health Research; Fonds de Recherche en Sante du Quebec FX This work was supported by the National Heart, Lung and Blood Institute's Framingham Heart Study (contract N01-HC-25195). Dr Thanassoulis was supported by a Research Fellowship from the Canadian Institute of Health Research and the Fonds de Recherche en Sante du Quebec. NR 25 TC 18 Z9 18 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 2047-9980 J9 J AM HEART ASSOC JI J. Am. Heart Assoc. PD DEC PY 2012 VL 1 IS 6 AR UNSP e000885 DI 10.1161/JAHA.112.000885 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 243RY UT WOS:000326335900021 PM 23316310 ER PT J AU Revelli, DA Boylan, JA Gherardini, FC AF Revelli, David A. Boylan, Julie A. Gherardini, Frank C. TI A non-invasive intratracheal inoculation method for the study of pulmonary melioidosis SO FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY LA English DT Article DE pulmonary melioidosis; melioidosis; non-invasive inoculation method; intratracheal inoculation; Burkholderia pseudomallei ID BURKHOLDERIA-PSEUDOMALLEI; RESPIRATORY-TRACT; MICE; INSTILLATION; INFECTION; BALB/C; EPIDEMIOLOGY; INHALATION; PARTICLES; LUNGS AB Pulmonary melioidosis, a disease manifestation caused by the bacterium Burkholderia pseudomallei, has been studied using aerosols or intranasal (IN) inoculation in small animal models. Both have inherent disadvantages which may not accurately model primary pulmonary melioidosis in humans. Intratracheal inoculation (IT) by direct visualization of the tracheal opening offers an alternative technique for infection that overcomes the disadvantages of aerosol and IN challenge. In this study, we describe a method which requires relatively inexpensive equipment, little training, and is compliant with the operational constraints of a BSL3 laboratory. Results obtained using trypan blue demonstrated that an inoculum can be accurately delivered into the lungs of mice within a biosafety cabinet (BSC). Whole body imaging and histopathology confirmed that mice inoculated intratracheally with B. pseudomallei develop the primary focus of infection in the lungs, and not the nasal passages which can lead to invasion of the central nervous system and potential neurologic complications. Further, based on colony counts and bioluminescent imaging, dissemination to secondary organs occurred as expected. Taken together, this intratracheal method of inoculation fulfills four goals: (1) to accurately deliver B. pseudomallei into the lungs of the animal model, (2) to avoid potentially confounding complications due to primary infections at sites other than the lung, (3) to maintain normal organ dissemination, and (4) to be BSL3 compliant. C1 [Revelli, David A.; Boylan, Julie A.; Gherardini, Frank C.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Boylan, JA (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM jboylan@niaid.nih.gov FU NIH, NIAID FX We would like to thank Don Gardner and Dan Long for histology micrographs. We also thank the Rocky Mountain Veterinarian Branch of Rocky Mountain Laboratories, NIH, for their services, especially Doug Brining, Rachel LaCasse, and Brian Mosbrucker for their help and advice throughout the study. This work was supported by the Intramural Research Program of the NIH, NIAID NR 35 TC 13 Z9 13 U1 0 U2 0 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 2235-2988 J9 FRONT CELL INFECT MI JI Front. Cell. Infect. Microbiol. PD DEC PY 2012 VL 2 AR UNSP 164 DI 10.3389/fcimb.2012.00164 PG 8 WC Immunology; Microbiology SC Immunology; Microbiology GA 221EC UT WOS:000324639400013 PM 23267442 ER PT J AU Haraguchi, T Koujin, T Osakada, H Kojidani, T Kobayashi, S Kimura, H Nakano, M Masumoto, H Larionov, VL Earnshaw, WC Hiraoka, Y AF Haraguchi, Tokuko Koujin, Takako Osakada, Hiroko Kojidani, Tomoko Kobayashi, Shouhei Kimura, Hiroshi Nakano, Megumi Masumoto, Hiroshi Larionov, Vladimir L. Earnshaw, William C. Hiraoka, Yasushi TI Requirement of the nuclear envelope for genome maintenance: Incomplete nuclear envelope reformation causes disposal of the micronucleus formed by loss of centromere functions of human artificial chromosome SO GENES & GENETIC SYSTEMS LA English DT Meeting Abstract C1 [Haraguchi, Tokuko; Koujin, Takako; Osakada, Hiroko; Kojidani, Tomoko; Kobayashi, Shouhei; Hiraoka, Yasushi] Natl Inst Informat & Commun Tech, Adv ICT Res Inst Kobe, Tokyo, Japan. [Haraguchi, Tokuko; Kimura, Hiroshi; Hiraoka, Yasushi] Osaka Univ, Grad Sch Front BioSci, Suita, Osaka 565, Japan. [Larionov, Vladimir L.] NCI, Bethesda, MD 20892 USA. [Earnshaw, William C.] Univ Edinburgh, Edinburgh EH8 9YL, Midlothian, Scotland. NR 0 TC 0 Z9 0 U1 1 U2 3 PU GENETICS SOC JAPAN PI SHIZUOKA-KEN PA NATIONAL INST GENETICS YATA 1111, MISHIMA, SHIZUOKA-KEN, 411-8540, JAPAN SN 1341-7568 EI 1880-5779 J9 GENES GENET SYST JI Genes Genet. Syst. PD DEC PY 2012 VL 87 IS 6 BP 393 EP 393 PG 1 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 206PX UT WOS:000323535700084 ER PT J AU Masumoto, H Ohzeki, J Nakano, M Larionov, V Earnshaw, WC AF Masumoto, Hiroshi Ohzeki, Jun-ichirou Nakano, Megumi Larionov, Vladimir Earnshaw, William C. TI Fate of the DNA introduced into culture cells: How does artificial chromosome formation, chromosomal integration or exclusion from nuclei occur? SO GENES & GENETIC SYSTEMS LA English DT Meeting Abstract C1 [Larionov, Vladimir] NCI, NIH, Bethesda, MD 20892 USA. [Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH8 9YL, Midlothian, Scotland. NR 0 TC 0 Z9 0 U1 0 U2 0 PU GENETICS SOC JAPAN PI SHIZUOKA-KEN PA NATIONAL INST GENETICS YATA 1111, MISHIMA, SHIZUOKA-KEN, 411-8540, JAPAN SN 1341-7568 EI 1880-5779 J9 GENES GENET SYST JI Genes Genet. Syst. PD DEC PY 2012 VL 87 IS 6 BP 393 EP 393 PG 1 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 206PX UT WOS:000323535700083 ER PT J AU Pavletic, SZ Fowler, DH AF Pavletic, Steven Z. Fowler, Daniel H. TI Are we making progress in GVHD prophylaxis and treatment? SO HEMATOLOGY-AMERICAN SOCIETY HEMATOLOGY EDUCATION PROGRAM LA English DT Article ID VERSUS-HOST-DISEASE; STEM-CELL TRANSPLANTATION; CONSENSUS DEVELOPMENT PROJECT; BONE-MARROW-TRANSPLANTATION; WORKING GROUP-REPORT; CLINICAL-TRIALS NETWORK; UNRELATED DONOR TRANSPLANTATION; CHILDRENS ONCOLOGY GROUP; LOW-DOSE METHOTREXATE; TERM-FOLLOW-UP AB Allogeneic hematopoietic stem cell transplantation (allo-HCT) is an effective immunotherapy for human cancer. More than 20 000 allo-HCTs are performed each year worldwide, primarily for the treatment of hematologic malignancies. Several technical innovations implemented in allo-HCT over past 2 decades have reduced NRM by 50% and improved overall survival. The allo-HCT practice has changed with the introduction of peripheral blood, cord blood, and haploidentical transplantations and reduced-intensity conditioning, and the patient population is also different regarding age and diagnosis. However, both acute and chronic GVHD remain serious barriers to successful allo-HCT and it is not clear that a major improvement has occurred in our ability to prevent or treat GVHD. Nevertheless, there is an increasing knowledge of the biology and clinical manifestations and the field is getting better organized. These advances will almost certainly lead to major progress in the near future. As the long list of new potential targets and respective drugs are developed, systems need to be developed for rapid testing of them in clinical practice. The current reality is that no single agent has yet to be approved by the US Food and Drug Administration for GVHD prevention or therapy. Although a primary goal of these efforts is to develop better therapies for GVHD, the ultimate goal is to develop treatments that lead to effective prevention or preemption of life-threatening and disabling GVHD manifestations while harnessing the desirable graft-versus-tumor effects. C1 [Pavletic, Steven Z.; Fowler, Daniel H.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Pavletic, SZ (reprint author), NCI, Graft Versus Host & Autoimmun Unit, Expt Transplantat & Immunol Branch, Ctr Canc Res,NIH, Bldg 10,Rm CRC 3-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM pavletis@mail.nih.gov FU Center for Cancer Research, National Cancer Institute; National Institutes of Health FX This work is supported by the Center for Cancer Research, National Cancer Institute and National Institutes of Health. Statements included in this article do not represent the official position of the National Cancer Institute, the National Institutes of Health, or the US Government. NR 116 TC 22 Z9 22 U1 2 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 1520-4391 J9 HEMATOL-AM SOC HEMAT JI Hematol.-Am. Soc. Hematol. Educ. Program PD DEC PY 2012 BP 251 EP 264 DI 10.1182/asheducation-2012.1.251 PG 14 WC Education, Scientific Disciplines; Hematology SC Education & Educational Research; Hematology GA 209KT UT WOS:000323755900037 ER PT J AU Scheinberg, P AF Scheinberg, Phillip TI Aplastic anemia: therapeutic updates in immunosuppression and transplantation SO HEMATOLOGY-AMERICAN SOCIETY HEMATOLOGY EDUCATION PROGRAM LA English DT Article ID STEM-CELL TRANSPLANTATION; ANTI-THYMOCYTE GLOBULIN; RABBIT-ANTITHYMOCYTE GLOBULIN; UNRELATED DONOR TRANSPLANTATION; CORD BLOOD TRANSPLANTATION; COLONY-STIMULATING FACTOR; TOTAL-BODY IRRADIATION; ALEMTUZUMAB PLUS CYCLOSPORINE; BONE-MARROW-TRANSPLANTATION; MATCHED SIBLING DONORS AB Advances in hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy (IST) have improved survival in severe aplastic anemia (SAA) from 10%-20% in the 1960s to 80%-90% today. A matched sibling HSCT is the treatment of choice in younger patients, whereas IST is often used in older patients or in those who lack a histocompatible sibling. Graft rejection, GVHD, and poor immune reconstitution (with associated infectious complications) limit the success of HSCT, whereas lack of response, relapse, and clonal evolution limit the success of IST. The historically high rate of graft rejection in SAA is now less problematic in the matched setting, but with greater rates observed with unrelated and umbilical cord donors. The correlation of increasing age with the risk of GVHD and the significant morbidity and mortality of this transplantation complication continue to affect the decision to pursue HSCT versus IST as initial therapy in adults with SAA. Outcomes with matched unrelated donor HSCT have improved, likely due to better donor selection, supportive care, and improved transplantation protocols. Results with mismatched unrelated donor and umbilical HSCT are not as favorable, with higher rates of graft rejection, GVHD, and infectious complications. Investigation of several upfront alternative IST protocols has not improved outcomes beyond horse antithymocyte globulin and cyclosporine. More recently, the role of alemtuzumab in SAA has been better defined and an oral thrombomimetic, eltrombopag, is showing promising activity in refractory cases. The most recent advances in HSCT and IST in SAA are discussed in this review. C1 [Scheinberg, Phillip] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Scheinberg, P (reprint author), Hosp Sao Jose, Rua Martiniano Carvalho 951, BR-01321001 Sao Paulo, Brazil. EM scheinbp@mail.nih.gov OI Scheinberg, Phillip/0000-0002-9047-4538 NR 70 TC 32 Z9 33 U1 1 U2 7 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 1520-4391 J9 HEMATOL-AM SOC HEMAT JI Hematol.-Am. Soc. Hematol. Educ. Program PD DEC PY 2012 BP 292 EP 300 DI 10.1182/asheducation-2012.1.292 PG 9 WC Education, Scientific Disciplines; Hematology SC Education & Educational Research; Hematology GA 209KT UT WOS:000323755900043 ER PT J AU Kreitman, RJ AF Kreitman, Robert J. TI Immunoconjugates and new molecular targets in hairy cell leukemia SO HEMATOLOGY-AMERICAN SOCIETY HEMATOLOGY EDUCATION PROGRAM LA English DT Article ID IMMUNOTOXIN RFB4(DSFV)-PE38 BL22; MINIMAL RESIDUAL DISEASE; BRAF V600E MUTATION; PHASE-I TRIAL; HEMATOLOGIC MALIGNANCIES; MOXETUMOMAB PASUDOTOX; CYTOTOXIC ACTIVITY; FOLLOW-UP; CLADRIBINE; RITUXIMAB AB Hairy cell leukemia (HCL) is a B-cell malignancy that in its classic form is exquisitely sensitive to single-agent purine analog therapy, but that is associated in many patients with late relapse and eventual purine analog resistance. Minimal residual disease, which is present in most patients achieving complete remission with purine analogs, retains Ags that are ideal for targeted therapy. Rituximab, which targets CD20, is active as a single agent, particularly if combined with purine analogs. Recombinant immunotoxins targeting either CD25 or CD22 and containing truncated Pseudomonas exotoxin have achieved major responses in relapsed/refractory HCL. Moxetumomab pasudotox in phase 1 testing achieved responses in 86% of such patients (complete in 46%) without dose limiting toxicity and often without MRD. Soluble CD22 has been used for improved detection and monitoring of HCL, particularly the poor-prognosis variant that lacks CD25. Ig rearrangements unique for each HCL patient have been cloned, sequenced, and followed by real-time quantitative PCR using sequence-specific reagents. Analysis of these rearrangements has identified an unmutated IGVH4-34-expressing poor-prognosis variant with immunophenotypic characteristics of either classic or variant HCL. The BRAF V600E mutation, reported in 50% of melanomas, is present in > 85% of HCL cases that are both classic and express rearrangements other than IGVH4-34, making HCL a potential target for specific inhibitors of BRAF V600E. Additional targets are being defined in both classic and variant HCL, which should improve both detection and therapy. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), NCI, Mol Biol Lab, NIH, 37-5124B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov NR 40 TC 8 Z9 8 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 1520-4391 J9 HEMATOL-AM SOC HEMAT JI Hematol.-Am. Soc. Hematol. Educ. Program PD DEC PY 2012 BP 660 EP 666 DI 10.1182/asheducation-2012.1.660 PG 7 WC Education, Scientific Disciplines; Hematology SC Education & Educational Research; Hematology GA 209KT UT WOS:000323755900097 ER PT J AU Wiestner, A AF Wiestner, Adrian TI Emerging role of kinase-targeted strategies in chronic lymphocytic leukemia SO HEMATOLOGY-AMERICAN SOCIETY OF HEMATOLOGY EDUCATION PROGRAM LA English DT Article ID B-CELL-RECEPTOR; NON-HODGKIN-LYMPHOMA; TYROSINE KINASE; ANTIGEN RECEPTOR; FOSTAMATINIB DISODIUM; THERAPEUTIC TARGET; AUTOIMMUNE-DISEASE; SYK INHIBITOR; ACTIVATION; SURVIVAL AB Chronic lymphocytic leukemia (CLL) is a malignancy of mature B cells that depend on host factors in the tissue microenvironment for survival and proliferation. In vitro, CLL cells rapidly undergo apoptosis unless microenvironmental factors are provided that support their survival. Signaling pathways activated in the microenvironment in vivo include the B-cell receptor (BCR) and NF-kappa B pathways. Thus, CLL is a disease "addicted to the host" and is dependent on pathways that promote normal B-cell development, expansion, and survival; this is particularly true in the case of the BCR signaling cascade. Small-molecule inhibitors of kinases that are essential for BCR signal transduction abrogate the stimulating effects of the microenvironment on CLL cells. The orally administered tyrosine kinase inhibitors fostamatinib and ibrutinib and the phosphatidylinositol 3-kinase inhibitor GS-1101 have induced impressive responses in relapsed and refractory CLL patients, mostly with moderate side effects. Reductions in lymphadenopathy and splenomegaly are seen within weeks and are frequently accompanied by a transient rise in absolute lymphocyte count that is asymptomatic and probably the result of changes in CLL cell trafficking. This review discusses the biologic basis for kinase inhibitors as targeted therapy of CLL and summarizes the exciting early clinical experience with these agents. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Wiestner, A (reprint author), NHLBI, Hematol Branch, NIH, 10 Ctr Dr,Bldg 10,CRC 3-5140, Bethesda, MD 20892 USA. EM wiestnera@mail.nih.gov FU Heart, Lung, and Blood Institute, National Institutes of Health FX A.W. is supported by the intramural research program of the Heart, Lung, and Blood Institute, National Institutes of Health. NR 80 TC 17 Z9 17 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 1520-4391 EI 1520-4383 J9 HEMATOL-AM SOC HEMAT JI Hematol.-Am. Soc. Hematol. Educ. Program PD DEC PY 2012 BP 88 EP 96 DI 10.1182/asheducation-2012.1.88 PG 9 WC Education, Scientific Disciplines; Hematology SC Education & Educational Research; Hematology GA 209KT UT WOS:000323755900013 ER PT J AU Reynolds, SJ Laeyendecker, O Nakigozi, G Gallant, JE Huang, W Hudelson, SE Quinn, TC Newell, K Serwadda, D Gray, RH Wawer, MJ Eshleman, SH AF Reynolds, Steven J. Laeyendecker, Oliver Nakigozi, Gertrude Gallant, Joel E. Huang, Wei Hudelson, Sarah E. Quinn, Thomas C. Newell, Kevin Serwadda, David Gray, Ronald H. Wawer, Maria J. Eshleman, Susan H. TI Antiretroviral Drug Susceptibility Among HIV-Infected Adults Failing Antiretroviral Therapy in Rakai, Uganda SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID RESISTANCE MUTATIONS; TREATMENT FAILURE; SOUTH-AFRICA; RESOURCE; INDIVIDUALS; CRITERIA AB We analyzed antiretroviral drug susceptibility in HIV-infected adults failing first-and second-line antiretroviral treatment (ART) in Rakai, Uganda. Samples obtained from participants at baseline (pretreatment) and at the time of failure on first-line ART and second-line ART were analyzed using genotypic and phenotypic assays for antiretroviral drug resistance. Test results were obtained from 73 samples from 38 individuals (31 baseline samples, 36 first-line failure samples, and six second-line failure samples). Four (13%) of the 31 baseline samples had mutations associated with resistance to nucleoside or nonnucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively). Among the 36 first-line failure samples, 31 (86%) had NNRTI resistance mutations and 29 (81%) had lamivudine resistance mutations; only eight (22%) had other NRTI resistance mutations. None of the six individuals failing a second-line protease inhibitor (PI)-based regimen had PI resistance mutations. Six (16%) of the participants had discordant genotypic and phenotypic test results. Genotypic resistance to drugs included in first-line ART regimens was detected prior to treatment and among participants failing first-line ART. PI resistance was not detected in individuals failing second-line ART. Surveillance for transmitted and acquired drug resistance remains a priority for scale-up of ART. C1 [Reynolds, Steven J.; Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Reynolds, Steven J.; Laeyendecker, Oliver; Gallant, Joel E.; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. [Nakigozi, Gertrude] Rakai Hlth Sci Program, Kalisizo, Uganda. [Huang, Wei] Monogram Biosci, San Francisco, CA USA. [Hudelson, Sarah E.; Eshleman, Susan H.] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Newell, Kevin] NCI, Clin Monitoring Res Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Serwadda, David] Makerere Univ, Coll Hlth Sci, Kampala, Uganda. [Gray, Ronald H.; Wawer, Maria J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Reynolds, SJ (reprint author), US Embassy, NIAID NIH ICER Program, POB 7007, Kampala, Uganda. EM sjr@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases; Eunice B. Shriver National Institute of Child Health Development (NICHD) [R01 HD050180]; National Institutes of Health (NIMH); Division of Intramural Research; National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); National Cancer Institute, NIH [HHSN261200800001E]; HIV Prevention Trials Network [U01-AI068613, UM1-AI068613]; National Institute on Drug Abuse (NIDA); NIMH; Office of AIDS Research, NIH, through the Department of Health and Human Services (DHHS) FX Source of funding: (1) The Division of Intramural Research, National Institute of Allergy and Infectious Diseases, (2) R01 Grant R01 HD050180 from the Eunice B. Shriver National Institute of Child Health Development (NICHD), National Institutes of Health (NIMH) and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), (3) Contract HHSN261200800001E from the National Cancer Institute, NIH, (4) the HIV Prevention Trials Network (U01-AI068613 and UM1-AI068613) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the NIMH, and the Office of AIDS Research, NIH, through the Department of Health and Human Services (DHHS). NR 19 TC 3 Z9 3 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 DEC PY 2012 VL 28 IS 12 BP 1739 EP 1744 DI 10.1089/aid.2011.0352 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 047FW UT WOS:000311825000030 PM 22443282 ER PT J AU Nguyen, HT Bertoni, AG Nettleton, JA Bluemke, DA Levitan, EB Burke, GL AF Nguyen, Ha T. Bertoni, Alain G. Nettleton, Jennifer A. Bluemke, David A. Levitan, Emily B. Burke, Gregory L. TI DASH Eating Pattern Is Associated with Favorable Left Ventricular Function in the Multi-Ethnic Study of Atherosclerosis SO JOURNAL OF THE AMERICAN COLLEGE OF NUTRITION LA English DT Article DE DASH diet; LV function; preclinical heart failure ID CONGESTIVE-HEART-FAILURE; HIGH BLOOD-PRESSURE; LIFE-STYLE MODIFICATION; HEALTH-STUDY-I; RISK-FACTORS; FOLLOW-UP; CARDIOVASCULAR-DISEASE; DIFFERENT CULTURES; DIETARY PATTERNS; NUT CONSUMPTION AB Objective: Potential associations between consistency with the Dietary Approaches to Stop Hypertension (DASH) diet and preclinical stages of heart failure (HF) in a large multiethnic cohort have not been evaluated. This study sought to determine the cross-sectional relationship between the DASH eating pattern and left ventricular (LV) function in the Multi-Ethnic Study of Atherosclerosis (MESA).Design: A total of 4506 men and women from four ethnic groups (40% white, 24% African American, 22% Hispanic American, and 14% Chinese American) aged 45-84 years and free of clinical cardiovascular disease (CVD) were studied. Diet was assessed using a validated food-frequency questionnaire. LV functional parameters including end-diastolic volume, stroke volume, and LV ejection fraction were measured by magnetic resonance imaging. Multivariate analyses were conducted to examine the association between LV function and DASH eating pattern (including high consumption of fruits, vegetables, whole grains, poultry, fish, nuts, and low-fat dairy products and low consumption of red meat, sweets, and sugar-sweetened beverages).Results: A 1-unit increase in DASH eating pattern score was associated with a 0.26 ml increase in end-diastolic volume and increases of 0.10 ml/m(2) in stroke volume, adjusted for key confounders. A 1-unit increase in DASH eating pattern score was also associated with a 0.04% increase in ejection fraction, but the relationship was marginally significant (p = 0.08).Conclusions: In this population, greater DASH diet consistency is associated with favorable LV function. DASH dietary patterns could be protective against HF. C1 [Nguyen, Ha T.] Wake Forest Sch Med, Dept Family & Community Med, Winston Salem, NC 27157 USA. [Bertoni, Alain G.; Burke, Gregory L.] Wake Forest Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Nettleton, Jennifer A.] Univ Texas Hlth Sci Ctr Houston, Div Epidemiol Human Genet & Environm Sci, Houston, TX 77030 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, Bethesda, MD USA. [Levitan, Emily B.] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA. RP Nguyen, HT (reprint author), Wake Forest Sch Med, Dept Family & Community Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM hnguyen@wakehealth.edu OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159 through N01-HC-95169] FX This research was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. NR 42 TC 2 Z9 2 U1 0 U2 8 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0731-5724 EI 1541-1087 J9 J AM COLL NUTR JI J. Am. Coll. Nutr. PD DEC 1 PY 2012 VL 31 IS 6 BP 401 EP 407 DI 10.1080/07315724.2012.10720466 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 190SX UT WOS:000322361600004 PM 23756584 ER PT J AU Masse, LC Blanck, HM Valente, M Atienza, AA Agurs-Collins, T Weber, D Yaroch, AL AF Masse, Louise C. Blanck, Heidi M. Valente, Maria Atienza, Audie A. Agurs-Collins, Tanya Weber, Deanne Yaroch, Amy L. TI Association Between Self-Reported Household Practices and Body Mass Index of US Children and Adolescents, 2005 SO PREVENTING CHRONIC DISEASE LA English DT Article ID FAMILY-BASED TREATMENT; PHYSICAL-ACTIVITY; CHILDHOOD OBESITY; PARENTING PRACTICES; OVERWEIGHT STATUS; FOLLOW-UP; WEIGHT; MEALS; ENVIRONMENT; FOOD AB Introduction Parents can set household practices that influence children's behaviors. The objective of this study was to determine whether children (children and adolescents aged 9-18 y) who live in a household that has healthful practices related to behaviors associated with obesity have a lower body mass index (BMI). Methods We analyzed data from the 2005 Styles mail panel survey (N = 1,6 8 5 parents and children). We used multiple logistic regression to assess associations between 4 household practices and 3 children's behaviors: watching television, participating in vigorous physical activity, and purchasing sodas and snacks at school. Results Children watched more television if they had a television in their bedrooms, were less active as a family, and had no junk food restrictions at home. Children in less active families participated in about half as much VPA as children in more active families. Children purchased more sodas and snacks at school if they had a television in their bedrooms and their family consumed more meals at fast-food restaurants. Children whose families were less active were more likely to have a self-reported BMI at or above the 85th percentile. In addition, children who watched more television were more likely to have a self-reported BMI at or above the 85th percentile. Conclusion Household practices were associated with children's behaviors and self-reported BMI. A household profile that includes being active as a family may counteract the increase in childhood obesity. C1 [Blanck, Heidi M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Valente, Maria] Univ British Columbia, Vancouver, BC V6H 3V4, Canada. [Atienza, Audie A.; Agurs-Collins, Tanya] NCI, Bethesda, MD 20892 USA. [Weber, Deanne] Porter Novelli, Washington, DC USA. [Yaroch, Amy L.] Gretchen Swanson Ctr Nutr, Omaha, NE USA. RP Masse, LC (reprint author), Univ British Columbia, Dept Pediat, L408,4480 Oak St, Vancouver, BC V6H 3V4, Canada. EM lmasse@cfri.ubc.ca FU Michael Smith Foundation for Health Research; Child and the Family Research Institute; Sunny Hill Foundation FX Dr Louise C. Masse received salary support from the Michael Smith Foundation for Health Research (senior scholar award), the Child and the Family Research Institute (Level 2 investigator scientist award), and the Sunny Hill Foundation. In addition, Dr Masse received support from the National Cancer Institute at the National Institutes of Health to prepare this article. The findings and conclusions in this article are those of the authors and do not necessarily represent the official positions of the National Cancer Institute at the National Institutes of Health. NR 29 TC 2 Z9 2 U1 1 U2 8 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1545-1151 J9 PREV CHRONIC DIS JI Prev. Chronic Dis. PD DEC PY 2012 VL 9 AR UNSP 110149 DI 10.5888/pcd9.110149 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 173CB UT WOS:000321054600003 ER PT J AU Spande, TF AF Spande, Thomas F. TI BERNHARD WITKOP 9 MAY 1917 . 22 NOVEMBER 2010 SO PROCEEDINGS OF THE AMERICAN PHILOSOPHICAL SOCIETY LA English DT Biographical-Item C1 NIH, Chem Lab, Bethesda, MD 20892 USA. RP Spande, TF (reprint author), NIH, Chem Lab, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER PHILOSOPHICAL SOC PI PHILADELPHIA PA 104 SOUTH FIFTH ST, PHILADELPHIA, PA 19106-3387 USA SN 0003-049X J9 P AM PHILOS SOC JI Proc. Amer. Philos. Soc. PD DEC PY 2012 VL 156 IS 4 BP 463 EP 473 PG 11 WC Humanities, Multidisciplinary SC Arts & Humanities - Other Topics GA 145QZ UT WOS:000319033200011 ER PT J AU Metcalf, CJE Lessler, J Klepac, P Cutts, F Grenfell, BT AF Metcalf, C. J. E. Lessler, J. Klepac, P. Cutts, F. Grenfell, B. T. TI Impact of birth rate, seasonality and transmission rate on minimum levels of coverage needed for rubella vaccination SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE CRS; demography; extinction; rubella; seasonality; vaccine coverage ID DEVELOPING-COUNTRIES; INFECTIOUS-DISEASES; PREDICTED IMPACT; MEASLES; DYNAMICS; AGE; EPIDEMICS; MUMPS; MODEL; IMMUNIZATION AB Childhood rubella infection in early pregnancy can lead to fetal death or congenital rubella syndrome (CRS) with multiple disabilities. Reduction of transmission via universal vaccination can prevent CRS, but inadequate coverage may increase CRS numbers by increasing the average age at infection. Consequently, many countries do not vaccinate against rubella. The World Health Organization recommends that for safe rubella vaccination, at least 80% coverage of each birth cohort should be sustained. The nonlinear relationship between CRS burden and infection dynamics has been much studied; however, how the complex interaction between epidemic and demographic dynamics affects minimum safe levels of coverage has not been quantitatively evaluated across scales necessary for a global assessment. We modelled 30-year CRS burdens across epidemiological and demographic settings, including the effect of local interruption of transmission via stochastic fadeout. Necessary minimum vaccination coverage increases markedly with birth and transmission rates, independent of amplitude of seasonal fluctuations in transmission. Susceptible build-up in older age groups following local stochastic extinction of rubella increased CRS burden, indicating that spatial context is important. In low birth-rate settings, 80% routine coverage is a conservative guideline, particularly if supplemented with campaigns and vaccination of women of childbearing age. Where birth and transmission rates are high, immunization coverage must be well above 80% and campaigns may be needed. Policy-makers should be aware of the potential negative effect of local extinction of rubella, since heterogeneity in vaccination coverage will shape extinction patterns, potentially increasing CRS burdens. C1 [Metcalf, C. J. E.] Univ Oxford, Dept Zool, Oxford OX1 3PS, England. [Metcalf, C. J. E.; Klepac, P.; Grenfell, B. T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Lessler, J.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Cutts, F.] London Sch Hyg & Trop Med, Dept Infect Dis Epidemiol, London WC1, England. [Grenfell, B. T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Metcalf, CJE (reprint author), Univ Oxford, Dept Zool, S Parks Rd, Oxford OX1 3PS, England. EM charlotte.metcalf@zoo.ox.ac.uk OI Lessler, Justin/0000-0002-9741-8109 FU Royal Society; Bill and Melinda Gates Foundation; RAPIDD program of the Science & Technology Directorate of the Department of Homeland Security; Fogarty International Center National Institute of Health; NIH [NIH/GM R01-GM083983-01] FX S. Reef suggested analyses and provided feedback; W. J. Moss and S. A. Lowther contributed data for vaccination age profiles; E. Vynnycky gave detailed comments; the WHO Rubella Working Group provided helpful discussion. This work was funded by the Royal Society (C. J. E. M.), the Bill and Melinda Gates Foundation (C. J. E. M., B. G., J. L., P. K.), the RAPIDD program of the Science & Technology Directorate of the Department of Homeland Security, and the Fogarty International Center National Institute of Health (B. G.) and NIH grant NIH/GM R01-GM083983-01 (C. J. E. M., B. G.). NR 38 TC 31 Z9 33 U1 1 U2 28 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD DEC PY 2012 VL 140 IS 12 BP 2290 EP 2301 DI 10.1017/S0950268812000131 PG 12 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 031IC UT WOS:000310631700019 PM 22335852 ER PT J AU O'Toole, D Delle Fave, G Jensen, RT AF O'Toole, Dermot Delle Fave, Gianfranco Jensen, Robert T. TI Gastric and duodenal neuroendocrine tumours SO BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY LA English DT Article DE Neuroendocrine tumours; Gastrin; Stomach; Gastric neuroendocrine tumours; Duodenal neuroendocrine tumours ID ZOLLINGER-ELLISON-SYNDROME; ENDOCRINE NEOPLASIA TYPE-1; ENTEROCHROMAFFIN-LIKE CELLS; AMPULLARY CARCINOID-TUMORS; ATROPHIC BODY GASTRITIS; LYMPH-NODE METASTASIS; DUODX AFFECT RATE; CLINICAL CHARACTERISTICS; RECEPTOR ANTAGONIST; HORMONE CONTENT AB Gastric neuroendocrine neoplasms (NENs) are increasing in frequency and have a varied spectrum with regard to histology, clinicopathologic background, stage, and prognosis. They are usually discovered incidentally, are for the most part benign and are associated with hypergastrinaemia (secondary either to chronic atrophic gastritis or rarely Zollinger-Ellison syndrome; types 1 and 2, respectively) or more rarely sporadic type 3. Applications of recent staging and grading systems - namely using Ki-67 proliferative indices - (from ENETS and WHO 2010) can be particularly helpful in further categorising these tumours. The natural history of Type 1 gastric carcinoids is generally (>95%) favourable and simple surveillance is usually recommended for small (<1 cm) T1 tumours, with local (endoscopic or surgical) resection for larger lesions. Other potential therapies such as somatostatin analogues and gastrin receptor antagonists may offer newer therapeutic possibilities. Rarely, gastric NENs have a malignant course and this is usually confined to Type 2 and especially Type 3 tumours; the latter mimic the biological course of gastric adenocarcinoma and require radical oncological therapies. Most duodenal NENs, apart from gastrinomas (that are not dealt with here) are sporadic and non functional. They are also increasing in frequency probably due to incidental discovery at endoscopy or imaging for other reasons and this may account for their overall good prognosis. Peri-ampullary and ampullary NENs may have a more aggressive outcome and should be carefully appraised and treated (often with surgical resection). (c) 2013 Elsevier Ltd. All rights reserved. C1 [O'Toole, Dermot] St James Hosp, Dept Gastroenterol & Clin Med, Dublin, Ireland. [O'Toole, Dermot] Trinity Coll Dublin, Dublin, Ireland. [Delle Fave, Gianfranco] Osped St Andrea, Dept Digest & Liver Dis, Rome, Italy. [Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD USA. RP O'Toole, D (reprint author), St James Hosp, Dept Gastroenterol & Clin Med, Dublin, Ireland. EM dermot.otoole@tcd.ie NR 120 TC 15 Z9 15 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6918 J9 BEST PRACT RES CL GA JI Best Pract. Res. Clin. Gastroenterol. PD DEC PY 2012 VL 26 IS 6 BP 719 EP 735 DI 10.1016/j.bpg.2013.01.002 PG 17 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 137RJ UT WOS:000318454800004 PM 23582915 ER PT J AU Ito, T Igarashi, H Jensen, RT AF Ito, Tetsuhide Igarashi, Hisato Jensen, Robert T. TI Pancreatic neuroendocrine tumors: Clinical features, diagnosis and medical treatment: Advances SO BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY LA English DT Article DE Pancreatic neuroendocrine tumor (pNET); Neuroendocrine tumor (NET); Gastrinoma; Zollinger-Ellison syndrome (ZES); Insulinoma; VIPoma; Glucagonoma; Somatostatinoma; Growth hormone-releasing factor secreting tumor (GRPoma); Nonfunctional pancreatic endocrine tumor (NF-pNET); Pancreatic polypeptide secreting tumor (PPoma); Hypergastrinemia; hypoglycemia; Multiple endocrine neoplasia type 1(MEN1); Von Hippel Lindau disease (VHL); Von Recklinghausen's disease; Neurofibromatosis 1 (NF-1); Tuberous sclerosis ID ZOLLINGER-ELLISON-SYNDROME; ENDOCRINE NEOPLASIA TYPE-1; ENETS CONSENSUS GUIDELINES; HIPPEL-LINDAU-DISEASE; INSTITUTES-OF-HEALTH; ISLET CELL TUMORS; HYPERINSULINEMIC HYPOGLYCEMIA; SURGICAL-MANAGEMENT; INSULINOMA PATIENTS; ECTOPIC SECRETION AB Pancreatic neuroendocrine tumors (pNETs) comprise with gastrointestinal carcinoids, the main groups of gastrointestinal neuroendocrine tumors (GI-NETs). Although these two groups of GI-NETs share many features including histological aspects; over-/ectopic expression of somatostatin receptors; the ability to ectopically secrete hormones/peptides/amines which can result in distinct functional syndromes; similar approaches used for tumor localization and some aspects of treatment, it is now generally agreed they should be considered separate. They differ in their pathogenesis, hormonal syndromes produced, many aspects of biological behaviour and most important, in their response to certain anti-tumour treatment (chemotherapy, molecular targeted therapies). In this chapter the clinical features of the different types of pNETs will be considered as well as aspects of their diagnosis and medical treatment of the hormone-excess state. Emphasis will be on controversial areas or recent advances. The other aspects of the management of these tumors (surgery; treatment of advanced disease, tumor localization) are not dealt with here, because they are covered in other chapters in this volume. (C) 2013 Elsevier Ltd. All rights reserved. C1 [Ito, Tetsuhide; Igarashi, Hisato] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Higashi Ku, Fukuoka 8128582, Japan. [Ito, Tetsuhide; Igarashi, Hisato; Jensen, Robert T.] NIDDK, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. RP Jensen, RT (reprint author), NIH, Digest Dis Branch, Bldg 10,Room 9C-103, Bethesda, MD 20892 USA. EM robertj@bdg10.bdg10.niddk.nih.gov RI U-ID, Kyushu/C-5291-2016 FU NIDDK, National Institutes of Health FX This work was partially supported by intramural funds provided by NIDDK, National Institutes of Health. NR 109 TC 36 Z9 38 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1521-6918 J9 BEST PRACT RES CL GA JI Best Pract. Res. Clin. Gastroenterol. PD DEC PY 2012 VL 26 IS 6 BP 737 EP 753 DI 10.1016/j.bpg.2012.12.003 PG 17 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 137RJ UT WOS:000318454800005 PM 23582916 ER PT J AU Murray, DM Blitstein, JL Hannan, PJ Shadish, WR AF Murray, David M. Blitstein, Jonathan L. Hannan, Peter J. Shadish, William R. TI Increasing the Degrees of Freedom in Future Group Randomized Trials: The df(*) Method Revisited SO EVALUATION REVIEW LA English DT Article DE group-randomized trial; degrees of freedom; power; causal inference ID INTRACLUSTER CORRELATION-COEFFICIENT; INTERVENTION; PREVENTION; BEHAVIOR; PROGRAM; TOBACCO; DESIGN AB Background: This article revisits an article published in Evaluation Review in 2005 on sample size estimation and power analysis for group-randomized trials. With help from a careful reader, we learned of an important error in the spreadsheet used to perform the calculations and generate the results presented in that article. As we studied the spreadsheet, we discovered other minor errors. When we corrected the errors, we found that the results were substantially different and that the conclusions reported in the original article were not always appropriate. Objective: This article corrects the errors and reports the results as they should have been reported originally. Method: Using a random-effects meta-analytic model, estimates of intraclass correlation were combined from two studies to guide sample size calculations for a new study. Results: The df(*) method can result in improved power or smaller studies when used a priori to plan future group-randomized trials, though the improvements will be modest in larger studies and will likely be insufficient to provide adequate power to small studies. Conclusion: Smaller group-randomized trials are often desirable, for example, as pilot studies to help plan for a full-scale efficacy trial, as replication studies, or in situations in which resource constraints prohibit a larger trial. We discuss the circumstances under which the df(*) method will be most helpful and the risks associated with conducting smaller studies. C1 [Murray, David M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20892 USA. [Blitstein, Jonathan L.] RTI Int, Ctr Hlth Promot Res, Res Triangle Pk, NC USA. [Hannan, Peter J.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Shadish, William R.] Univ Calif, Sch Social Sci Humanities & Arts, Merced, CA USA. RP Murray, DM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,2B03, Rockville, MD 20892 USA. EM david.murray2@nih.gov OI Blitstein, Jonathan L./0000-0001-5202-4934 NR 25 TC 0 Z9 0 U1 0 U2 3 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0193-841X J9 EVALUATION REV JI Eval. Rev. PD DEC PY 2012 VL 36 IS 6 BP 430 EP 448 DI 10.1177/0193841X13480147 PG 19 WC Social Sciences, Interdisciplinary SC Social Sciences - Other Topics GA 136GT UT WOS:000318351100002 PM 23640051 ER PT J AU Treger, RS Cook, A Rai, G Maloney, DJ Simeonov, A Jadhav, A Thomas, CJ Williams, DL Cappello, M Vermeire, JJ AF Treger, Rebecca S. Cook, Aaron Rai, Ganesha Maloney, David J. Simeonov, Anton Jadhav, Ajit Thomas, Craig J. Williams, David L. Cappello, Michael Vermeire, Jon J. TI Oxadiazole 2-oxides are toxic to the human hookworm, Ancylostoma ceylanicum, however glutathione reductase is not the primary target SO INTERNATIONAL JOURNAL FOR PARASITOLOGY-DRUGS AND DRUG RESISTANCE LA English DT Article DE Hookworm; Antioxidant; Glutathione reductase; Oxadiazole 2-oxides; Furoxan ID MAMMALIAN THIOREDOXIN REDUCTASE; TRANSMITTED HELMINTH INFECTIONS; ANTHELMINTIC RESISTANCE; SCHISTOSOMA-MANSONI; ENZYME; DRUGS; PLATYHELMINTHS; FAILURE; SYSTEMS AB Hookworm disease, characterized by severe anemia and cognitive and growth delays, currently affects an estimated 740 million people worldwide. Despite the prevalence of this parasitic disease, few effective drug therapies are in use today, and the heavy reliance upon benzimidazoles highlights the need for the development of novel chemotherapies. Recent work with the trematode parasite Schistosoma mansoni has identified oxadiazole 2-oxides as effective antischistosomal compounds that function by targeting and inhibiting the antioxidant enzyme, thioredoxin glutathione reductase. In this study, a related enzyme, glutathione reductase, from the human hookworm Ancylostoma ceylanicum was identified and characterized, and its in vitro activity in the presence of the oxadiazole 2-oxides was analyzed. Ex vivo worm killing assays were also conducted to establish the relationship between a given compound's effect upon worm survival and inhibition of recombinant glutathione reductase (rAceGR). Finally, the in vivo anthelminthic efficacy of furoxan (Fx) was assessed in the hamster model of hookworm infection. The predicted amino acid sequence of AceGR contained a prototypical glutathione reductase active site sequence, but no thioredoxin reductase consensus sequences, suggesting that the glutathione and thioredoxin pathways of A. ceylanicum are distinct. Although 10 of the 42 oxadiazole 2-oxides tested inhibited rAceGR activity by at least 50%, and 15 compounds were toxic to parasites ex vivo, little overlap existed between these two results. We therefore suggest that AceGR is not the primary target of the oxadiazole 2-oxides in effecting parasite death. Lastly, oral treatment of A. ceylanicum infected hamsters with furoxan resulted in significantly improved weight gains and reduced intestinal worm burdens compared to vehicle treated controls, supporting continued development of this molecule as a novel anthelminthic. (C) 2012 Australian Society for Parasitology Published by Elsevier Ltd. All rights reserved. C1 [Treger, Rebecca S.; Cook, Aaron; Cappello, Michael; Vermeire, Jon J.] Yale Univ, Sch Med, Program Int Child Hlth, New Haven, CT USA. [Treger, Rebecca S.; Cook, Aaron; Cappello, Michael; Vermeire, Jon J.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Rai, Ganesha; Maloney, David J.; Simeonov, Anton; Jadhav, Ajit; Thomas, Craig J.] NIH, Chem Genom Ctr, Rockville, MD USA. [Williams, David L.] Rush Univ, Med Ctr, Dept Immunol Microbiol, Chicago, IL 60612 USA. RP Vermeire, JJ (reprint author), Yale Child Hlth Res Ctr, 464 Congress Ave, New Haven, CT 06511 USA. EM jon.vermeire@yale.edu FU NIH [K22 AI089969] FX This work was partially funded as a pilot program through the NIH Therapeutics and Rare Diseases (TRND) program and a Research Scholar Development Award to J.J.V. (K22 AI089969). The authors also thank Lorine D. Lantz and Lisa M. Harrison for expert technical assistant. NR 28 TC 8 Z9 8 U1 0 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 2211-3207 J9 INT J PARASITOL-DRUG JI Int. J. Parasitol.-Drugs Drug Resist. PD DEC PY 2012 VL 2 BP 171 EP 177 DI 10.1016/j.ijpddr.2012.05.001 PG 7 WC Parasitology; Pharmacology & Pharmacy SC Parasitology; Pharmacology & Pharmacy GA 123QH UT WOS:000317404800019 PM 22844653 ER PT J AU Wistow, G AF Wistow, Graeme TI The human crystallin gene families SO HUMAN GENOMICS LA English DT Review DE Crystallins; Lens; Cataract; Evolution; Pseudogene; Heat-shock; Enzymes ID AUTOSOMAL-DOMINANT CATARACT; BETA-GAMMA-CRYSTALLIN; HUMAN-MALIGNANT MELANOMA; COPPOCK-LIKE CATARACT; SEQUENCE TAG ANALYSIS; SPLICE-SITE MUTATION; CONGENITAL CATARACT; MISSENSE MUTATION; LENS CRYSTALLINS; CHINESE FAMILY AB Crystallins are the abundant, long-lived proteins of the eye lens. The major human crystallins belong to two different superfamilies: the small heat-shock proteins (alpha-crystallins) and the beta gamma-crystallins. During evolution, other proteins have sometimes been recruited as crystallins to modify the properties of the lens. In the developing human lens, the enzyme betaine-homocysteine methyltransferase serves such a role. Evolutionary modification has also resulted in loss of expression of some human crystallin genes or of specific splice forms. Crystallin organization is essential for lens transparency and mutations; even minor changes to surface residues can cause cataract and loss of vision. C1 NEI, Sect Mol Struct & Funct Genom, NIH, Bethesda, MD 20892 USA. RP Wistow, G (reprint author), NEI, Sect Mol Struct & Funct Genom, NIH, Bg 6,Rm 106, Bethesda, MD 20892 USA. EM graeme@helix.nih.gov NR 95 TC 19 Z9 21 U1 1 U2 15 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1473-9542 J9 HUM GENOMICS JI Hum. Genomics PD DEC 1 PY 2012 VL 6 AR 26 DI 10.1186/1479-7364-6-26 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 121EJ UT WOS:000317225400002 PM 23199295 ER PT J AU Pandiri, AR Sills, RC Ziglioli, V Ton, TVT Hong, HHL Lahousse, SA Gerrish, KE Auerbach, SS Shockley, KR Bushel, PR Peddada, SD Hoenerhoff, MJ AF Pandiri, Arun R. Sills, Robert C. Ziglioli, Vincent Ton, Thai-Vu T. Hong, Hue-Hua L. Lahousse, Stephanie A. Gerrish, Kevin E. Auerbach, Scott S. Shockley, Keith R. Bushel, Pierre R. Peddada, Shyamal D. Hoenerhoff, Mark J. TI Differential Transcriptomic Analysis of Spontaneous Lung Tumors in B6C3F1 Mice: Comparison to Human Non-Small Cell Lung Cancer SO TOXICOLOGIC PATHOLOGY LA English DT Article DE lung cancer; B6C3F1 mouse; microarray; gene expression analysis; comparative genomics ID HEPATOCYTE NUCLEAR FACTOR-4-ALPHA; ANTI-APOPTOSIS GENE; KINASE SIGNALING PATHWAYS; GENOME-WIDE ANALYSIS; SUPPRESSOR GENE; GROWTH-FACTOR; MOUSE MODELS; MITOCHONDRIAL DYSFUNCTION; RETINOBLASTOMA PROTEIN; TRANSLATION INITIATION AB Lung cancer is the leading cause of cancer-related death in people and is mainly due to environmental factors such as smoking and radon. The National Toxicology Program(NTP) tests various chemicals and mixtures for their carcinogenic hazard potential. In the NTP chronic bioassay using B6C3F1 mice, the incidence of lung tumors in treated and control animals is second only to the liver tumors. In order to study the molecular mechanisms of chemically induced lung tumors, an understanding of the genetic changes that occur in spontaneous lung (SL) tumors from untreated control animals is needed. The authors have evaluated the differential transcriptomic changes within SL tumors compared to normal lungs from untreated age-matched animals. Within SL tumors, several canonical pathways associated with cancer (eukaryotic initiation factor 2 signaling, RhoA signaling, PTEN signaling, and mammalian target of rapamycin signaling), metabolism (Inositol phosphate metabolism, mitochondrial dysfunction, and purine and pyramidine metabolism), and immune responses (Fc gamma R-mediated phagocytosis, clathrin-mediated endocytosis, interleukin 8 signaling, and CXCR4 signaling) were altered. Meta-analysis of murine SL tumors and human non-small cell lung cancer transcriptomic data sets revealed a high concordance. These data provide important information on the differential transcriptomic changes in murine SL tumors that will be critical to our understanding of chemically induced lung tumors and will aid in hazard analysis in the NTP 2-year carcinogenicity bioassays. C1 [Pandiri, Arun R.; Sills, Robert C.; Ton, Thai-Vu T.; Hong, Hue-Hua L.; Lahousse, Stephanie A.; Hoenerhoff, Mark J.] NIEHS, Cellular & Mol Pathol Branch, NTP, Res Triangle Pk, NC 27709 USA. [Pandiri, Arun R.] Expt Pathol Labs Inc, Durham, NC USA. [Ziglioli, Vincent] N Carolina State Univ, Coll Vet Med, Raleigh, NC USA. [Gerrish, Kevin E.] NIEHS, Lab Toxicol & Pharmacol, Res Triangle Pk, NC 27709 USA. [Auerbach, Scott S.] NIEHS, Host Susceptibil Branch, NTP, Res Triangle Pk, NC 27709 USA. [Shockley, Keith R.; Bushel, Pierre R.; Peddada, Shyamal D.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Pandiri, AR (reprint author), NIEHS, Cellular & Mol Pathol Branch, NTP, B358 Rall Bldg,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM pandiriak@niehs.nih.gov FU Division of the NTP at the NIEHS FX The authors would like to thank Grace Kissling of the Bioinformatics Branch, NIEHS, for assistance with statistical analysis; Danica Andrews, NIEHS for microarray assays; Tiwanda Masinde, and the NIEHS histology and immunohistochemistry groups for providing support for immunohistochemistry; Emily Singletary, Keith Connelly, Leslie Couch, and Beth Mahler at Experimental Pathology Laboratories, Inc., for providing support with acquisition of samples and images. This work was funded by the Division of the NTP at the NIEHS as well as by the intramural research program at NIEHS/DHHS. NR 133 TC 8 Z9 8 U1 0 U2 6 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 DEC PY 2012 VL 40 IS 8 BP 1141 EP 1159 DI 10.1177/0192623312447543 PG 19 WC Pathology; Toxicology SC Pathology; Toxicology GA 119EF UT WOS:000317079700005 PM 22688403 ER PT J AU Kadekar, S Peddada, S Silins, I French, JE Hogberg, J Stenius, U AF Kadekar, Sandeep Peddada, Shyamal Silins, Ilona French, John E. Hogberg, Johan Stenius, Ulla TI Gender Differences in Chemical Carcinogenesis in National Toxicology Program 2-Year Bioassays SO TOXICOLOGIC PATHOLOGY LA English DT Article DE NTP; gender; 2-year bioassay; tumor; carcinogens ID ANDROGEN-RECEPTOR GENE; PANCREATIC-CANCER; SEX-DIFFERENCES; LUNG-CANCER; BLADDER-CANCER; CAG REPEATS; TUMOR; RISK; CELL; RAT AB Differences in cancer incidences between men and women are often explained by either differences in environmental exposures or by influences of sex hormones. However, there are few studies on intrinsic gender differences in susceptibility to chemical carcinogens. We have analyzed the National Toxicology Program (NTP) database for sex differences in rat responses to chemical carcinogens. We found that the odds that male rat bioassays were assigned a higher level of evidence than female rat bioassays was 1.69 (p < .001). Of 278 carcinogenic chemicals in the database, 201 (72%) exhibited statistical gender differences (p <= .05) in at least one nonreproductive organ. One hundred thirty of these 201 chemicals induced gender-specific tumors in male rats and 59 in female rats. Sixty-eight chemicals induced tumors in males but no tumors in females. Less than one third (i.e., 19 chemicals) induced tumors in females but not males. Male-specific tumors included pancreatic and skin tumors, and female-specific tumors included lung tumors. For some tumor sites, these differences in gender susceptibility can be associated with literature data on sex hormone receptor expression. In conclusion, gender-specific tumors were common. The male dominance is in line with recent human data, and the male susceptibility to carcinogens should be further studied. C1 [Kadekar, Sandeep; Silins, Ilona; Hogberg, Johan; Stenius, Ulla] Karolinska Inst, Inst Environm Med, S-17177 Stockholm, Sweden. [Peddada, Shyamal; French, John E.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Stenius, U (reprint author), Karolinska Inst, Inst Environm Med, Box 210, S-17177 Stockholm, Sweden. EM ulla.stenius@ki.se FU Swedish Research Council for the Environment, Agricultural Sciences and Spatial Planning (FORMAS); Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences [ES045005-14] FX The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Swedish Research Council for the Environment, Agricultural Sciences and Spatial Planning (FORMAS) and by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, project ES045005-14. NR 55 TC 6 Z9 6 U1 0 U2 2 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 DEC PY 2012 VL 40 IS 8 BP 1160 EP 1168 DI 10.1177/0192623312446527 PG 9 WC Pathology; Toxicology SC Pathology; Toxicology GA 119EF UT WOS:000317079700006 PM 22585941 ER PT J AU Cheng, AW Wan, RQ Yang, JL Kamimura, N Son, TG Ouyang, X Luo, YQ Okun, E Mattson, MP AF Cheng, Aiwu Wan, Ruiqian Yang, Jenq-Lin Kamimura, Naomi Son, Tae Gen Ouyang, Xin Luo, Yongquan Okun, Eitan Mattson, Mark P. TI Involvement of PGC-1 alpha in the formation and maintenance of neuronal dendritic spines SO NATURE COMMUNICATIONS LA English DT Article ID COACTIVATOR 1-ALPHA PGC-1-ALPHA; MITOCHONDRIAL BIOGENESIS; NEUROTROPHIC FACTOR; SYNAPTIC PLASTICITY; SIGNAL-TRANSDUCTION; PHOSPHATIDYLINOSITOL 3-KINASE; GAMMA COACTIVATOR-1-ALPHA; INDUCIBLE COACTIVATOR; EXCITATORY SYNAPSES; BEHAVIORAL DEFICITS AB The formation, maintenance and reorganization of synapses are critical for brain development and the responses of neuronal circuits to environmental challenges. Here we describe a novel role for peroxisome proliferator-activated receptor gamma co-activator 1 alpha, a master regulator of mitochondrial biogenesis, in the formation and maintenance of dendritic spines in hippocampal neurons. In cultured hippocampal neurons, proliferator-activated receptor gamma coactivator 1 alpha overexpression increases dendritic spines and enhances the molecular differentiation of synapses, whereas knockdown of proliferator-activated receptor gamma coactivator 1 alpha inhibits spinogenesis and synaptogenesis. Proliferator-activated receptor gamma co-activator 1 alpha knockdown also reduces the density of dendritic spines in hippocampal dentate granule neurons in vivo. We further show that brain-derived neurotrophic factor stimulates proliferator-activated receptor gamma co-activator-1 alpha-dependent mitochondrial biogenesis by activating extracellular signal-regulated kinases and cyclic AMP response element-binding protein. Proliferator-activated receptor gamma co-activator-1 alpha knockdown inhibits brain-derived neurotrophic factor-induced dendritic spine formation without affecting expression and activation of the brain-derived neurotrophic factor receptor tyrosine receptor kinase B. Our findings suggest that proliferator-activated receptor gamma co-activator-1 alpha and mitochondrial biogenesis have important roles in the formation and maintenance of hippocampal dendritic spines and synapses. C1 [Cheng, Aiwu; Wan, Ruiqian; Yang, Jenq-Lin; Kamimura, Naomi; Son, Tae Gen; Ouyang, Xin; Luo, Yongquan; Okun, Eitan; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Yang, Jenq-Lin] NIA, Lab Mol Gerontol, Intramural Res Program, Baltimore, MD 21224 USA. [Kamimura, Naomi] Nippon Med Sch, Dept Biochem & Cell Biol, Inst Dev & Aging Sci, Grad Sch Med, Kawasaki, Kanagawa 2118533, Japan. [Mattson, Mark P.] Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Cheng, AW (reprint author), NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. EM chengai@mail.nih.gov RI okun, eitan/K-1314-2016 OI okun, eitan/0000-0001-8474-1487 FU National Institute on Aging FX This work was supported by the Intramural Research Programs of the National Institute on Aging. We thank Dr Heping Cheng (Peking University, China) for his critical reading and inputs. We thank Dr Marc Montminy (Salk Institute for Biological Studies) for the Ad-GFP-Si-PGC-1 alpha and Ad-GFP-Si-Con) plasmids and Dr Pere Puigserver (John Hopkins University) for Ad-GFP-PGC-1 alpha adenovirus. NR 63 TC 65 Z9 67 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD DEC PY 2012 VL 3 AR 1250 DI 10.1038/ncomms2238 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109HH UT WOS:000316356700018 PM 23212379 ER PT J AU Xie, J Cha, SK An, SW Kuro-o, M Birnbaumer, L Huang, CL AF Xie, Jian Cha, Seung-Kuy An, Sung-Wan Kuro-o, Makoto Birnbaumer, Lutz Huang, Chou-Long TI Cardioprotection by Klotho through downregulation of TRPC6 channels in the mouse heart SO NATURE COMMUNICATIONS LA English DT Article ID CHRONIC KIDNEY-DISEASE; RECEPTOR POTENTIAL CHANNELS; CARDIAC-HYPERTROPHY; CARDIOVASCULAR-DISEASE; TUMOR-SUPPRESSOR; TRPV5 CHANNEL; MUTANT MICE; CALCINEURIN; EXPRESSION; RELEASE AB Klotho is a membrane protein predominantly produced in the kidney that exerts some antiageing effects. Ageing is associated with an increased risk of heart failure; whether Klotho is cardioprotective is unknown. Here we show that Klotho-deficient mice have no baseline cardiac abnormalities but develop exaggerated pathological cardiac hypertrophy and remodelling in response to stress. Cardioprotection by Klotho in normal mice is mediated by downregulation of TRPC6 channels in the heart. We demonstrate that deletion of Trpc6 prevents stress-induced exaggerated cardiac remodelling in Klotho-deficient mice. Furthermore, mice with heart-specific overexpression of TRPC6 develop spontaneous cardiac hypertrophy and remodelling. Klotho overexpression ameliorates cardiac pathologies in these mice and improves their long-term survival. Soluble Klotho present in the systemic circulation inhibits TRPC6 currents in cardiomyocytes by blocking phosphoinositide-3-kinase-dependent exocytosis of TRPC6 channels. These results provide a new perspective on the pathogenesis of cardiomyopathies and open new avenues for treatment of the disease. C1 [Xie, Jian; Cha, Seung-Kuy; An, Sung-Wan; Huang, Chou-Long] UT Southwestern Med Ctr, Dept Med, Dallas, TX 75390 USA. [Kuro-o, Makoto] UT Southwestern Med Ctr, Dept Pathol, Dallas, TX 75390 USA. [Birnbaumer, Lutz] NIEHS, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. RP Huang, CL (reprint author), UT Southwestern Med Ctr, Dept Med, Dallas, TX 75390 USA. EM chou-long.huang@utsouthwestern.edu FU NIH [DK59530, DK85726, DK79328, DK91392]; Intramural Research Program of the NIH [ZO1-ES-101684]; GRIP grant from Genzyme, Inc. FX We thank Eric Olson for TRPC6-Tg mice, Jyothsna Gattineni for assistance with measurements of serum FGF23 and phosphate, Masaya Takahashi and Kim Kangasniemi for cardiac MRI, and Peter Igarashi, Orson Moe and Aylin Rodan for discussions and comments. This work was supported by NIH (DK59530, DK85726, DK79328, DK91392), the Intramural Research Program of the NIH (ZO1-ES-101684) and by a GRIP grant from Genzyme, Inc. C.-L. H. holds the Jacob Lemann Professorship in Calcium Transport of University of Texas Southwestern Medical Center. NR 55 TC 62 Z9 67 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2041-1723 J9 NAT COMMUN JI Nat. Commun. PD DEC PY 2012 VL 3 AR 1238 DI 10.1038/ncomms2240 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 109HH UT WOS:000316356700006 PM 23212367 ER PT J AU Nix, JW Turkbey, B Hoang, A Volkin, D Yerram, N Chua, C Linehan, WM Wood, B Choyke, P Pinto, PA AF Nix, Jeffrey W. Turkbey, Baris Hoang, Anthony Volkin, Dmitry Yerram, Nitin Chua, Celene Linehan, W. Marston Wood, Bradford Choyke, Peter Pinto, Peter A. TI Very distal apical prostate tumours: identification on multiparametric MRI at 3 Tesla SO BJU INTERNATIONAL LA English DT Article DE prostate cancer; MRI; distal apical region; biopsy ID LAPAROSCOPIC RADICAL PROSTATECTOMY; POSITIVE SURGICAL MARGINS; CANCER-DETECTION; BIOPSY; LOCATION; SPECIMENS; MEN AB OBJECTIVE To describe an undescribed 'very distal' apical prostate cancer on multiparametric MRI (mpMRI) since apical prostate cancer can be difficult to detect in transrectal ultrasound guided biopsy and might therefore be missed in treatment decisions such as high intensity focused ultrasound or surgical therapy. PATIENTS AND METHODS From January 2011 to December 2012 a total of 210 consecutive patients underwent 3 T mpMRI with endorectal coil followed by our previously described MRI/ultrasound image fused and directed TRUS biopsies. Patients also underwent 12-core TRUS sextant biopsies. The inclusion criteria required at least one distal apical prostate lesion visualized on mpMRI and targeted for biopsy. RESULTS A total of 38 men (median age 62 years, median PSA 7.68 ng/dL) were identified as having distal apical prostate cancer on mpMRI. Thirteen patients (34%) had a prior diagnosis of cancer and were on active surveillance protocols while 25 (66%) did not. Of those patients, 21 (55%) had undergone a median of two prior negative biopsies. Twenty-two patients (58%) were positive on biopsy for prostate cancer. On breakdown of patients who were positive, 17 (77%) were positive on TRUS random biopsies and 21 (95%) were positive on MRI targeted biopsies with the majority of patients having multifocal disease. At the distal apical lesions of interest, 80% were positive on MRI targeted biopsy. In addition 33% of these patients were upgraded based on MRI targeted biopsy at the distal lesion. CONCLUSIONS Very distal apical prostate cancer can be accurately detected and sampled with mpMRI and subsequent MRI/ultrasound fusion biopsy. This may aid clinicians and patients in decision making for therapeutic modalities. C1 [Nix, Jeffrey W.; Hoang, Anthony; Volkin, Dmitry; Yerram, Nitin; Chua, Celene; Linehan, W. Marston; Pinto, Peter A.] NCI, NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter] NCI, NIH, Mol Imaging Program, Bethesda, MD 20892 USA. [Wood, Bradford] NIH, Diagnost Radiol Div, Ctr Clin, Bethesda, MD 20892 USA. RP Nix, JW (reprint author), NCI, Urol Oncol Branch, 10 Ctr Dr,MSC 1107,CRC Room 1-5940W, Bethesda, MD 20892 USA. EM jeffrey.nix@nih.gov NR 22 TC 25 Z9 26 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 J9 BJU INT JI BJU Int. PD DEC PY 2012 VL 110 IS 11B BP E694 EP E700 DI 10.1111/j.1464-410X.2012.11503.x PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 091BQ UT WOS:000315024200049 PM 23035719 ER PT J AU Yerram, NK Volkin, D Turkbey, B Nix, J Hoang, AN Vourganti, S Gupta, GN Linehan, WM Choyke, PL Wood, BJ Pinto, PA AF Yerram, Nitin K. Volkin, Dmitry Turkbey, Baris Nix, Jeffrey Hoang, Anthony N. Vourganti, Srinivas Gupta, Gopal N. Linehan, W. Marston Choyke, Peter L. Wood, Bradford J. Pinto, Peter A. TI Low suspicion lesions on multiparametric magnetic resonance imaging predict for the absence of high-risk prostate cancer SO BJU INTERNATIONAL LA English DT Article DE active surveillance; low suspicion lesion; prostate MRI ID RADICAL PROSTATECTOMY; ACTIVE SURVEILLANCE; BIOPSY; RECURRENCE; SCORE; MRI; FEATURES; FUSION; TIME AB OBJECTIVE To determine whether multiparametric magnetic resonance imaging (mpMRI) has the potential to identify patients at low risk for cancer, thus obviating the need for biopsy. Prostate cancer is currently diagnosed by random biopsies, resulting in the discovery of multiple low-risk cancers that often lead to overtreatment. PATIENTS AND METHODS We reviewed 800 consecutive patients who underwent a 3 Tesla mpMRI of the prostate with an endorectal coil from M arch 2007 to November 2011. All suspicious lesions were independently reviewed by two radiologists using T2-weighted, diffusion-weighted, spectroscopic and dynamic contrast-enhanced MRI sequences. Patients with only low suspicion lesions (maximum of two positive parameters on mpMRI) who subsequently underwent transrectal ultrasonography (TRUS)/MRI fusion targeted biopsy were selected for analysis. RESULTS In total, 125 patients with only low suspicion prostatic lesions on mpMRI were identified. On TRUS /MRI fusion biopsy, 77 (62%) of these patients had no cancer detected, 38 patients had Gleason 6 disease and 10 patients had Gleason 7 (3 + 4) disease. There were 30 patients with cancer detected on biopsy who qualified for active surveillance using 2011 National Comprehensive Cancer Network guidelines. No cases of high-risk (>= Gleason 4 + 3) cancer were identified on biopsy and, of the fifteen patients who underwent radical prostatectomy at our institution, none were pathologically upgraded to high-risk cancer. Thus, for patients with only low suspicion lesions, 107 (88%) patients either had no cancer or clinically insignificant disease. CONCLUSIONS The results obtained in the present study show that low suspicion lesions on mpMRI are associated with either negative biopsies or low-grade tumours suitable for active surveillance. Such patients have a low risk of harbouring high-risk prostate cancers. C1 [Yerram, Nitin K.; Volkin, Dmitry; Turkbey, Baris; Nix, Jeffrey; Hoang, Anthony N.; Vourganti, Srinivas; Gupta, Gopal N.; Linehan, W. Marston; Pinto, Peter A.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. [Wood, Bradford J.; Pinto, Peter A.] NCI, Dept Radiol & Imaging Sci, Ctr Intervent Oncol, NIH, Bethesda, MD 20892 USA. [Turkbey, Baris; Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. RP Pinto, PA (reprint author), NCI, Urol Oncol Branch, 10 Ctr Dr MSC 1210,Bldg 10,CRC,Room 2W-5940, Bethesda, MD 20892 USA. EM pintop@mail.nih.gov FU National Cancer Institute, National Institutes of Health FX This research was supported (in part) by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 22 TC 46 Z9 47 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1464-4096 J9 BJU INT JI BJU Int. PD DEC PY 2012 VL 110 IS 11B BP E783 EP E788 DI 10.1111/j.1464-410X.2012.11646.x PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 091BQ UT WOS:000315024200067 PM 23130821 ER PT J AU Numao, S Sasai, H Nomata, Y Matsuo, T Eto, M Tsujimoto, T Tanaka, K AF Numao, Shigeharu Sasai, Hiroyuki Nomata, Yasuhiro Matsuo, Tomoaki Eto, Miki Tsujimoto, Takehiko Tanaka, Kiyoji TI Effects of Exercise Training on Circulating Retinol-Binding Protein 4 and Cardiovascular Disease Risk Factors in Obese Men SO OBESITY FACTS LA English DT Article DE Obesity; Triglycerides; High-density lipoprotein cholesterol ID TYPE-2 DIABETES-MELLITUS; INSULIN-RESISTANCE; WEIGHT-LOSS; SERUM RETINOL-BINDING-PROTEIN-4; METABOLIC SYNDROME; AEROBIC EXERCISE; LEPTIN LEVELS; ADIPONECTIN; PLASMA; SENSITIVITY AB Introduction: The purpose of this study was to investigate the effects of 12-week exercise training on circulating retinol-binding protein 4 (RBP4) concentration and cardiovascular disease (CVD) risk factors in obese men. Methods: 29 obese men (age 48 +/- 2 years; BMI 29.6 +/- 0.7 kg/m(2)) participated in a 12-week exercise program (50-70% maximal heart rates; 3 times/week) without calorie restriction. Anthropometric parameters, CVD risk factors (total cholesterol, high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol, triglycerides (TG), and quantitative insulin sensitivity check index), and circulating RBP4 and adipokine (adiponectin, leptin, and interleukin-6 (IL-6)) concentrations were measured. Results: Exercise training significantly improved in absolute peak oxygen consumption (p < 0.05), and CVD risk factors (p < 0.05), with the exception of HDLC. There was a significant decrease in circulating RBP4, leptin, and IL-6 concentrations (p < 0.05). Stepwise regression analysis revealed that changes in RBP4 concentration were independently related to the changes in TG concentration (beta = 0.46, p < 0.05). Conclusion: These results demonstrate that exercise training without calorie restriction improves several CVD risk factors and circulating RBP4 and adipokine concentrations. Moreover, the change in circulating RBP4 may be more associated with the improvements in TG concentration in obese men. Copyright (C) 2012 S. Karger GmbH, Freiburg C1 [Numao, Shigeharu] Kyoto Pharmaceut Univ, Dept Hlth & Sports Sci, Kyoto 607, Japan. [Numao, Shigeharu] Waseda Inst Sport Sci, Saitama, Japan. [Sasai, Hiroyuki] NIDDK, Diabet Endocrinol & Obes Branch, NIH, Bethesda, MD USA. [Sasai, Hiroyuki] Japan Soc Promot Sci, Tokyo, Japan. [Nomata, Yasuhiro; Eto, Miki] Univ Tsukuba, Grad Sch Comprehens Human Sci, Div Sports Med, Ibaraki, Japan. [Matsuo, Tomoaki] Japan Aerosp Explorat Agcy, Ibaraki, Japan. [Tsujimoto, Takehiko] Univ Tsukuba, Grad Sch Comprehens Human Sci, Doctoral Program Sports Med, Ibaraki, Japan. [Tanaka, Kiyoji] Univ Tsukuba, Fac Hlth & Sport Sci, Ibaraki, Japan. RP Numao, S (reprint author), 5 Nakauchi Cho,Yamashina Ku, Kyoto 6078414, Japan. EM numashige@mb.kyoto-phu.ac.jp OI Sasai, Hiroyuki/0000-0001-8120-6163 FU Japan Society for the Promotion of Science of Japan [19800047] FX This work was supported in part by a Grant-in-Aid for Young Scientists Start-up (19800047) awarded by the Japan Society for the Promotion of Science of Japan. NR 41 TC 4 Z9 4 U1 0 U2 3 PU KARGER PI BASEL PA ALLSCHWILERSTRASSE 10, CH-4009 BASEL, SWITZERLAND SN 1662-4025 J9 OBESITY FACTS JI Obes. Facts PD DEC PY 2012 VL 5 IS 6 BP 845 EP 855 DI 10.1159/000346205 PG 11 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 101JW UT WOS:000315772300005 PM 23258073 ER PT J AU Pelletier, M Lepow, TS Billingham, LK Murphy, MP Siegel, RM AF Pelletier, Martin Lepow, Talya S. Billingham, Leah K. Murphy, Michael P. Siegel, Richard M. TI New tricks from an old dog: Mitochondrial redox signaling in cellular inflammation SO SEMINARS IN IMMUNOLOGY LA English DT Review DE Reactive oxygen species; Mitochondria; Inflammation; Metabolism; Signaling ID HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; CHRONIC GRANULOMATOUS-DISEASE; TARGETED ANTIOXIDANT MITOQ; NF-KAPPA-B; REACTIVE OXYGEN; NADPH OXIDASE; SUPEROXIDE-PRODUCTION; GLUCOSE-METABOLISM; ENDOTHELIAL-CELLS; ENERGY-METABOLISM AB Reactive oxygen species (ROS) such as superoxide (O-2(-)) and hydrogen peroxide (H2O2) have long been implicated as pro-inflammatory, yet the sources of ROS and the molecular mechanisms by which they enhance inflammation have been less clear. Recent advances in the understanding of the molecular basis of inflammation mediated by the innate immune system have allowed these issues to be revisited. Although the Nox2 NADPH oxidases generate the bulk of ROS for antimicrobial host defense, recent studies have found that NADPH oxidase-dependent ROS production can actually dampen macrophage inflammatory responses to sterile pro-inflammatory stimuli. Instead, production of mitochondrial ROS has emerged as an important factor in both host defense and sterile inflammation. Excess mitochondrial ROS can be generated by either damage to the respiratory chain or by alterations of mitochondrial function such as those that increase membrane potential and reduce respiratory electron carriers. In autoinflammatory diseases, where key components of innate immune responses are activated by genetic mutations or environmental stimuli, inflammation has been found to be particularly sensitive to inhibition of mitochondrial ROS production. These findings have highlighted mitochondrial ROS as a novel generator of pro-inflammatory ROS and a potential therapeutic target in inflammatory diseases. Published by Elsevier Ltd. C1 [Pelletier, Martin; Lepow, Talya S.; Billingham, Leah K.; Siegel, Richard M.] Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. [Murphy, Michael P.] MRC Mitochondrial Biol Unit, Cambridge CB2 0XY, England. RP Siegel, RM (reprint author), Natl Inst Arthrit & Musculoskeletal & Skin Dis NI, Immunoregulat Sect, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. EM rsiegel@nih.gov RI Murphy, Michael/C-2120-2009 OI Murphy, Michael/0000-0003-1115-9618 FU Intramural NIH HHS [Z01 AR041175-01]; Medical Research Council [, MC_U105663142] NR 117 TC 31 Z9 32 U1 0 U2 10 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD DEC PY 2012 VL 24 IS 6 BP 384 EP 392 DI 10.1016/j.smim.2013.01.002 PG 9 WC Immunology SC Immunology GA 101AG UT WOS:000315746800002 PM 23391428 ER PT J AU Hedrick, A Lee, Y Wallace, GL Greenstein, D Clasen, L Giedd, JN Raznahan, A AF Hedrick, Alexis Lee, Yohan Wallace, Gregory L. Greenstein, Deanna Clasen, Liv Giedd, Jay N. Raznahan, Armin TI Autism Risk Gene MET Variation and Cortical Thickness in Typically Developing Children and Adolescents SO AUTISM RESEARCH LA English DT Article DE MET receptor tyrosine kinase; cortex; autism; development; MRI ID RECEPTOR TYROSINE KINASE; HUMAN CEREBRAL-CORTEX; SPECTRUM DISORDER; ASSOCIATION; TRAITS; VALIDATION; PHENOTYPES; ANATOMY AB MET receptor tyrosine kinase (MET) has been proposed as a candidate risk gene for autism spectrum disorder (ASD) based on associations between MET polymorphisms and ASD diagnosis, as well as evidence from animal studies that MET protein may regulate early development of cortical regions implicated in the neurobiology of ASD. The relevance of differences in MET signaling for human cortical development remains unexamined, however. We sought to address this issue by relating genotype at a functional single nucleotide polymorphism within the MET promoter (rs1858830, G -> C) to in vivo measures of cortical thickness (CT) development derived from 222 healthy children and adolescents with 514 longitudinally acquired structural magnetic resonance imaging brain scans between ages 9 and 22 years. We identified a statistically significant, developmentally fixed, and stepwise CT reduction with increasing C allele dose in superior and middle temporal gyri, ventral precentral and postcentral gyri, and anterior cingulate bilaterally, and in the right frontopolar cortex. We were also able to demonstrate that mean CT within these cortical regions showed a statistically significant reduction with increasing scores on a continuous measure of autistic traits (the Social Responsiveness Scale). The cortical regions highlighted by our analyses are not only established areas of MET expression during prenatal life but are also key components of the "social brain" that have frequently shown structural and functional abnormalities in autism. Our results suggest that genetic differences in the MET gene may influence the development of cortical systems implicated in the neurobiology of ASD. Autism Res 2012, 5: 434-439. (C) 2012 International Society for Autism Research, Wiley Periodicals, Inc. C1 [Hedrick, Alexis; Lee, Yohan; Greenstein, Deanna; Clasen, Liv; Giedd, Jay N.; Raznahan, Armin] NIMH, Child Psychiat Branch, Bethesda, MD 20814 USA. [Wallace, Gregory L.] NIMH, Lab Brain & Cognit, Bethesda, MD 20814 USA. RP Raznahan, A (reprint author), NIMH, NIH, 10 Ctr Dr Bldg 10,Room 4C108, Bethesda, MD 20814 USA. EM raznahana@mail.nih.gov RI Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Wallace, Gregory/0000-0003-0329-5054 FU National Institutes of Health, National Institute of Mental Health Intramural Research; UK MRC Clinical Research Training Grant [G0701370] FX This research was supported by the National Institutes of Health, National Institute of Mental Health Intramural Research, and a UK MRC Clinical Research Training Grant awarded to A.R. (G0701370). We thank the participants and families who took part in this study. NR 38 TC 17 Z9 17 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1939-3792 J9 AUTISM RES JI Autism Res. PD DEC PY 2012 VL 5 IS 6 BP 434 EP 439 DI 10.1002/aur.1256 PG 6 WC Behavioral Sciences; Psychology, Developmental SC Behavioral Sciences; Psychology GA 083KU UT WOS:000314463300006 PM 23097380 ER PT J AU Fick, LJ Fick, GH Li, ZC Cao, E Bao, B Heffelfinger, D Parker, HG Ostrander, EA Riabowol, K AF Fick, Laura J. Fick, Gordon H. Li, Zichen Cao, Eric Bao, Bo Heffelfinger, Doug Parker, Heidi G. Ostrander, Elaine A. Riabowol, Karl TI Telomere Length Correlates with Life Span of Dog Breeds SO CELL REPORTS LA English DT Article ID NORMAL HUMAN-CELLS; HUMAN FIBROBLASTS; REPLICATIVE SENESCENCE; DOMESTIC DOG; OLDEST-OLD; MORTALITY; AGE; ASSOCIATION; CANCER; LEUKOCYTES AB Telomeric DNA repeats are lost as normal somatic cells replicate. When telomeres reach a critically short length, a DNA damage signal is initiated, inducing cell senescence. Some studies have indicated that telomere length correlates with mortality, suggesting that telomere length contributes to human life span; however, other studies report no correlation, and thus the issue remains controversial. Domestic dogs show parallels in telomere biology to humans, with similar telomere length, telomere attrition, and absence of somatic cell telomerase activity. Using this model, we find that peripheral blood mononuclear cell (PBMC) telomere length is a strong predictor of average life span among 15 different breeds (p < 0.0001), consistent with telomeres playing a role in life span determination. Dogs lose telomeric DNA similar to 10-fold faster than humans, which is similar to the ratio of average life spans between these species. Breeds with shorter mean telomere lengths show an increased probability of death from cardiovascular disease, which was previously correlated with short telomere length in humans. C1 [Fick, Laura J.; Li, Zichen; Cao, Eric; Bao, Bo; Riabowol, Karl] Univ Calgary, Fac Med, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada. [Fick, Gordon H.] Univ Calgary, Fac Med, Dept Community Hlth Sci, Calgary, AB T2N 4N1, Canada. [Heffelfinger, Doug] Crestwood Vet Clin, Edmonton, AB T5P 1J9, Canada. [Parker, Heidi G.; Ostrander, Elaine A.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Riabowol, K (reprint author), Univ Calgary, Fac Med, Dept Biochem & Mol Biol, Calgary, AB T2N 4N1, Canada. EM karl@ucalgary.ca OI Ostrander, Elaine/0000-0001-6075-9738 FU Canadian Institutes of Health Research; Alberta Innovations-Heath Solutions (AI-HS); Alberta Cancer Foundation; Intramural Program of the National Human Genome Research Institute; AI-HS FX We thank G. Muench and M. Read for help with blood sample collection and animal health, A. Denson and M. Czub for advice and consultation, and the Royal Canadian Mounted Police, veterinarians, and many dog owners who provided us with dog blood samples. This work was funded by grants to K.R. from the Canadian Institutes of Health Research, Alberta Innovations-Heath Solutions (AI-HS), and the Alberta Cancer Foundation. H.G.P. and E.A.O. gratefully acknowledge support from the Intramural Program of the National Human Genome Research Institute. L.J.F. is supported by an AI-HS fellowship, and K.R. is a Scientist of the Alberta Heritage Foundation for Medical Research. NR 41 TC 15 Z9 15 U1 12 U2 40 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD DEC PY 2012 VL 2 IS 6 BP 1530 EP 1536 DI 10.1016/j.celrep.2012.11.021 PG 7 WC Cell Biology SC Cell Biology GA 083JJ UT WOS:000314459200009 PM 23260664 ER PT J AU Xu, Y Cai, ML Yang, YY Huang, L Ye, YH AF Xu, Yue Cai, Mengli Yang, Yingying Huang, Lan Ye, Yihong TI SGTA Recognizes a Noncanonical Ubiquitin-like Domain in the Bag6-Ubl4A-Trc35 Complex to Promote Endoplasmic Reticulum-Associated Degradation SO CELL REPORTS LA English DT Article ID ER-ASSOCIATED DEGRADATION; TAIL-ANCHORED PROTEINS; MISFOLDED GLYCOPROTEINS; LARGER PROTEINS; QUALITY-CONTROL; CUE DOMAIN; MEMBRANE; CHAPERONE; BINDING; ATPASE AB Elimination of aberrantly folded polypeptides from the endoplasmic reticulum (ER) by the ER-associated degradation (ERAD) system promotes cell survival under stress conditions. This quality control mechanism requires movement of misfolded proteins across the ER membrane for targeting to the cytosolic proteasome, a process facilitated by a "holdase" complex, consisting of Bag6 and the cofactors Ubl4A and Trc35. This multiprotein complex also participates in several other protein quality control processes. Here, we report SGTA as a component of the Bag6 system, which cooperates with Bag6 to channel dislocated ERAD substrates that are prone to aggregation. Using nuclear magnetic resonance spectroscopy and biochemical assays, we demonstrate that SGTA contains a noncanonical ubiquitin-like-binding domain that interacts specifically with an unconventional ubiquitin-like protein/domain in Ubl4A at least in part via electrostatics. This interaction helps recruit SGTA to Bag6, enhances substrate loading to Bag6, and thus prevents the formation of nondegradable protein aggregates in ERAD. C1 [Xu, Yue; Ye, Yihong] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Cai, Mengli] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Yang, Yingying; Huang, Lan] Univ Calif Irvine, Dept Biophys & Physiol, Irvine, CA 92612 USA. RP Ye, YH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov RI Huang, Lan/C-3618-2011; Xu, Yue/F-8188-2015 FU Intramural Research Program of the NIDDK; NIH Intramural AIDS Targeted Antiviral Program; National Institutes of Health [RO1GM74830-06A1] FX We thank R. Hegde (MRC, UK) for the SGTA antibody; J. W. Chartron and W. Clemons (Caltech) for sharing unpublished information and for building the human SGTA N-domain-Ubl4A UBL model; and Fred Dyda, Marius Clore, and Martin Gellert (NIDDK) for critical reading of the manuscript. The research is supported by the Intramural Research Program of the NIDDK, a grant from the NIH Intramural AIDS Targeted Antiviral Program to Y.Y., and National Institutes of Health grant RO1GM74830-06A1 to L.H. M.C. designed and conducted the NMR experiments. Y.Yang and L.H. performed the mass spectrometry analyses. Y.X. and Y.Ye contributed to the design of all other experiments. All authors contributed to the interpretation and conclusions of the experiments. NR 58 TC 35 Z9 35 U1 0 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD DEC PY 2012 VL 2 IS 6 BP 1633 EP 1644 DI 10.1016/j.celrep.2012.11.010 PG 12 WC Cell Biology SC Cell Biology GA 083JJ UT WOS:000314459200019 PM 23246001 ER PT J AU Li, DQ Nair, SS Ohshiro, K Kumar, A Nair, VS Pakala, SB Reddy, SDN Gajula, RP Eswaran, J Aravind, L Kumar, R AF Li, Da-Qiang Nair, Sujit S. Ohshiro, Kazufumi Kumar, Anupam Nair, Vasudha S. Pakala, Suresh B. Reddy, Sirigiri Divijendra Natha Gajula, Rajendra P. Eswaran, Jeyanthy Aravind, L. Kumar, Rakesh TI MORC2 Signaling Integrates Phosphorylation-Dependent, ATPase-Coupled Chromatin Remodeling during the DNA Damage Response SO CELL REPORTS LA English DT Article ID DOUBLE-STRAND BREAKS; HISTONE H2AX; IONIZING-RADIATION; NUCLEAR-MATRIX; PROTEIN-KINASE; ATM; REPAIR; TRANSCRIPTION; FAMILY; HETEROCHROMATIN AB Chromatin dynamics play a central role in maintaining genome integrity, but how this is achieved remains largely unknown. Here, we report that microrchidia CW-type zinc finger 2 (MORC2), an uncharacterized protein with a derived PHD finger domain and a conserved GHKL-type ATPase module, is a physiological substrate of p21-activated kinase 1 (PAK1), an important integrator of extracellular signals and nuclear processes. Following DNA damage, MORC2 is phosphorylated on serine 739 in a PAK1-dependent manner, and phosphorylated MORC2 regulates its DNA-dependent ATPase activity to facilitate chromatin remodeling. Moreover, MORC2 associates with chromatin and promotes gamma-H2AX induction in a PAK1 phosphorylation-dependent manner. Consequently, cells expressing MORC2-S739A mutation displayed a reduction in DNA repair efficiency and were hypersensitive to DNA-damaging agent. These findings suggest that the PAK1-MORC2 axis is critical for orchestrating the interplay between chromatin dynamics and the maintenance of genomic integrity through sequentially integrating multiple essential enzymatic processes. C1 [Li, Da-Qiang; Nair, Sujit S.; Ohshiro, Kazufumi; Kumar, Anupam; Nair, Vasudha S.; Pakala, Suresh B.; Reddy, Sirigiri Divijendra Natha; Gajula, Rajendra P.; Eswaran, Jeyanthy; Kumar, Rakesh] George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Washington, DC 20037 USA. [Nair, Sujit S.; Kumar, Rakesh] George Washington Univ, Sch Med & Hlth Sci, McCormick Genom & Prote Ctr, Washington, DC 20037 USA. [Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Kumar, Rakesh] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA. RP Li, DQ (reprint author), George Washington Univ, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Washington, DC 20037 USA. EM bcmdql@gwu.edu; bcmrxk@gwu.edu RI sirigiri, divijendra reddy/E-1031-2017 OI sirigiri, divijendra reddy/0000-0003-4657-2285 FU National Library of Medicine, National Institutes of Health (NIH); NIH [CA139573, CA90970]; McCormick Genomic and Proteomic Center FX We thank Ratna K. Vadlamudi, Feng Li, and Zhibo Yang for their technical assistance in the early phase of the MORC2 work in the laboratory; Xifeng Wu and Uma Raju (M. D. Anderson Cancer Center, Houston, TX, USA) for their help with the comet and clonogenic survival assays, respectively. We are grateful to Ronald C. Conaway (Stowers Institute for Medical Research, Kansas City, MO, USA), Yosef Shiloh (Tel Aviv University, Ramat Aviv, Israel), and Weidong Wang (National Institutes of Health, Baltimore, MD, USA) for providing essential expression vectors and cell lines. The MORC2 structural and proteomic work was supported by the McCormick Genomic and Proteomic Center. L. A. is supported by the intramural funds of the National Library of Medicine, National Institutes of Health (NIH). This study was supported in part by an NIH grant (CA139573 and CA90970 to R.K.). NR 38 TC 30 Z9 30 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 2211-1247 J9 CELL REP JI Cell Reports PD DEC PY 2012 VL 2 IS 6 BP 1657 EP 1669 DI 10.1016/j.celrep.2012.11.018 PG 13 WC Cell Biology SC Cell Biology GA 083JJ UT WOS:000314459200021 PM 23260667 ER PT J AU Blanco, N Reidy, M Arroyo, J Cabib, E AF Blanco, Noelia Reidy, Michael Arroyo, Javier Cabib, Enrico TI Crosslinks in the cell wall of budding yeast control morphogenesis at the mother-bud neck SO JOURNAL OF CELL SCIENCE LA English DT Article DE Morphogenesis; Yeast; Cell wall; Chitin; Glucan ID SACCHAROMYCES-CEREVISIAE; GTP-BINDING; CHITIN; CYTOKINESIS; GROWTH; MUTANTS; PROTEIN; SEPTUM; CYCLE; RING AB Previous work has shown that, in cla4 Delta cells of budding yeast, where septin ring organization is compromised, the chitin ring at the mother-daughter neck becomes essential for prevention of neck widening and for cytokinesis. Here, we show that it is not the chitin ring per se, but its linkage to beta(1-3) glucan that is required for control of neck growth. When in a cla4 Delta background, crh1 Delta crh2 Delta mutants, in which the chitin ring is not connected to beta(1-3) glucan, grew very slowly and showed wide and growing necks, elongated buds and swollen cells with large vacuoles. A similar behavior was elicited by inhibition of the Crh proteins. This aberrant morphology matched that of cla4 Delta chs3 Delta cells, which have no chitin at the neck. Thus, this is a clear case in which a specific chemical bond between two substances, chitin and glucan, is essential for the control of morphogenesis. This defines a new paradigm, in which chemistry regulates growth. C1 [Blanco, Noelia; Arroyo, Javier] Univ Complutense Madrid, Fac Farm, Dept Microbiol 2, E-28040 Madrid, Spain. [Reidy, Michael; Cabib, Enrico] NIDDK, Lab Biochem & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Arroyo, J (reprint author), Univ Complutense Madrid, Fac Farm, Dept Microbiol 2, E-28040 Madrid, Spain. EM jarroyo@farm.ucm.es; enricoc@bdg10.niddk.nih.gov RI Arroyo, Javier/E-9308-2016; OI Arroyo, Javier/0000-0002-1971-1721; Reidy, Michael/0000-0002-9290-7595 FU National Institutes of Health (Intramural Research Program, NIDDK); Ministerio de Educacion y Ciencia [BIO2010-22146]; Comunidad de Madrid [S2010/BDM 2414]; Programme for UCM Research Groups [920640] FX This study was supported by the National Institutes of Health (Intramural Research Program, NIDDK), the Ministerio de Educacion y Ciencia (BIO2010-22146), Comunidad de Madrid (S2010/BDM 2414) and the Programme for UCM Research Groups (920640). Deposited in PMC for release after 12 months. NR 37 TC 10 Z9 10 U1 1 U2 10 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 EI 1477-9137 J9 J CELL SCI JI J. Cell Sci. PD DEC 1 PY 2012 VL 125 IS 23 BP 5781 EP 5789 DI 10.1242/jcs.110460 PG 9 WC Cell Biology SC Cell Biology GA 093AN UT WOS:000315164200019 PM 23077181 ER PT J AU Lodish, MB Dagalakis, U Sinaii, N Bornstein, E Kim, A Lokie, KB Baldwin, AM Reynolds, JC Dombi, E Stratakis, CA Widemann, BC AF Lodish, Maya B. Dagalakis, Urania Sinaii, Ninet Bornstein, Ethan Kim, AeRang Lokie, Kelsey B. Baldwin, Andrea M. Reynolds, James C. Dombi, Eva Stratakis, Constantine A. Widemann, Brigitte C. TI Bone mineral density in children and young adults with neurofibromatosis type 1 SO ENDOCRINE-RELATED CANCER LA English DT Article ID PEDIATRIC OFFICIAL POSITIONS; X-RAY ABSORPTIOMETRY; ADOLESCENTS; FRACTURES; EPIDEMIOLOGY; POPULATION; CRITERIA AB Concern for impaired bone health in children with neurofibromatosis type 1 (NF-1) has led to increased interest in bone densitometry in this population. Our study assessed bone mineral apparent density (BMAD) and whole-body bone mineral content (BMC)/height in pediatric patients with NF-1 with a high plexiform neurofibroma burden. Sixty-nine patients with NF-1 (age range 5.2-24.8; mean 13.7 +/- 4.8 years) were studied. Hologic dual-energy X-ray absorptiometry scans (Hologic, Inc., Bedford, MA, USA) were performed on all patients. BMD was normalized to derive a reference volume by correcting for height through the use of the BMAD, as well as the BMC. BMAD of the lumbar spine (LS 2-4), femoral neck (FN), and total body BMC/height were measured and Z-scores were calculated. Impaired bone mineral density was defined as a Z-score <= - 2. Forty-seven percent of patients exhibited impaired bone mineral density at any bone site, with 36% at the LS, 18% at the FN, and 20% total BMC/height. BMAD Z-scores of the LS (-1.60 +/- 1.26) were more impaired compared with both the FN (-0.54 +/- 1.58; P = 0.0003) and the whole-body BMC/height Z-scores (-1.16 +/- 0.90; P = 0.036). Plexiform neurofibroma burden was negatively correlated with LS BMAD (r(s) = -0.36, P = 0.01). In pediatric and young adult patients with NF-1, LS BMAD was more severely affected than the FN BMAD or whole-body BMC/height. Endocrine-Related Cancer (2012) 19 817-825 C1 [Lodish, Maya B.; Dagalakis, Urania; Bornstein, Ethan; Lokie, Kelsey B.; Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Sinaii, Ninet] NIH, Biostat & Clin Epidemiol Serv, Ctr Clin, Bethesda, MD 20982 USA. [Kim, AeRang; Baldwin, Andrea M.; Dombi, Eva; Widemann, Brigitte C.] NCI, Pharmacol & Expt Therapeut Sect, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Reynolds, James C.] NIH, Div Nucl Med, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20892 USA. [Kim, AeRang] Childrens Natl Med Ctr, Dept Oncol, Washington, DC 20010 USA. RP Lodish, MB (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, NIH, Bldg 10 CRC,Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM lodishma@mail.nih.gov FU National Cancer Institute; Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health FX This work was supported by the Intramural programs of the National Cancer Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health. NR 37 TC 0 Z9 0 U1 1 U2 5 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD DEC PY 2012 VL 19 IS 6 BP 817 EP 825 DI 10.1530/ERC-12-0293 PG 9 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 090QT UT WOS:000314994800014 PM 23089139 ER PT J AU Xekouki, P Stratakis, CA AF Xekouki, Paraskevi Stratakis, Constantine A. TI Succinate dehydrogenase (SDHx) mutations in pituitary tumors: could this be a new role for mitochondrial complex II and/or Krebs cycle defects? SO ENDOCRINE-RELATED CANCER LA English DT Article ID MULTIPLE ENDOCRINE NEOPLASIA; GENE-MUTATIONS; PHEOCHROMOCYTOMA; PARAGANGLIOMA; PATIENT; ASSOCIATION; HYPERPARATHYROIDISM; PROLACTINOMA; ADENOMATOSIS; DYSFUNCTION AB Succinate dehydrogenase (SDH) or mitochondrial complex II is a multimeric enzyme that is bound to the inner membrane of mitochondria and has a dual role as it serves both as a critical step of the tricarboxylic acid or Krebs cycle and as a member of the respiratory chain that transfers electrons directly to the ubiquinone pool. Mutations in SDH subunits have been implicated in the formation of familial paragangliomas (PGLs) and/or pheochromocytomas (PHEOs) and in Carney-Stratakis syndrome. More recently, SDH defects were associated with predisposition to a Cowden disease phenotype, renal, and thyroid cancer. We recently described a kindred with the coexistence of familial PGLs and an aggressive GH-secreting pituitary adenoma, harboring an SDHD mutation. The pituitary tumor showed loss of heterozygosity at the SDHD locus, indicating the possibility that SDHD's loss was causatively linked to the development of the neoplasm. In total, 29 cases of pituitary adenomas presenting in association with PHEOs and/or extra-adrenal PGLs have been reported in the literature since 1952. Although a number of other genetic defects are possible in these cases, we speculate that the association of PHEOs and/or PGLs with pituitary tumors is a new syndromic association and a novel phenotype for SDH defects. Endocrine-Related Cancer (2012) 19 C33-C40 C1 [Xekouki, Paraskevi; Stratakis, Constantine A.] Kennedy Shriver Natl Inst Child Hlth & Human Dev, Sect Endocrinol & Genet SEGEN, Program Dev Endocrinol & Genet PDEGEN, Interinst Pediat Endocrinol Program,NIH,CRC, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), Kennedy Shriver Natl Inst Child Hlth & Human Dev, Sect Endocrinol & Genet SEGEN, Program Dev Endocrinol & Genet PDEGEN, Interinst Pediat Endocrinol Program,NIH,CRC, Bldg 10,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) FX This work was entirely supported by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). NR 49 TC 28 Z9 28 U1 0 U2 8 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD DEC PY 2012 VL 19 IS 6 BP C33 EP C40 DI 10.1530/ERC-12-0118 PG 8 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 090QT UT WOS:000314994800001 PM 22889736 ER PT J AU Dropulic, LK Cohen, JI AF Dropulic, Lesia K. Cohen, Jeffrey I. TI The challenge of developing a herpes simplex virus 2 vaccine SO EXPERT REVIEW OF VACCINES LA English DT Review DE animal models; genital herpes; herpes simplex virus; immune response; prophylactic vaccine; therapeutic vaccine ID RECURRENT GENITAL HERPES; PLACEBO-CONTROLLED TRIAL; CD8(+) T-CELLS; GLYCOPROTEIN-D; GUINEA-PIGS; RECOMBINANT GLYCOPROTEIN; DOUBLE-BLIND; PAPILLOMAVIRUS INFECTION; AOTUS-TRIVIRGATUS; DELETION MUTANT AB Expert Rev. Vaccines 11(12), 1429-1440 (2012) HSV infections are prevalent worldwide. A vaccine to prevent genital herpes would have a significant impact on this disease. Several vaccines have shown promise in animal models; however, so far these have not been successful in human clinical studies. Prophylactic HSV vaccines to prevent HSV infection or disease have focused primarily on eliciting antibody responses. Potent antibody responses are needed to result in sufficiently high levels of virus-specific antibody in the genital tract. Therapeutic vaccines that reduce recurrences need to induce potent T-cell responses at the site of infection. With the increasing incidence of HSV-1 genital herpes, an effective herpes vaccine should protect against both HSV-1 and HSV-2. Novel HSV vaccines, such as replication-defective or attenuated viruses, have elicited humoral and cellular immune responses in preclinical studies. These vaccines and others hold promise in future clinical studies. C1 [Dropulic, Lesia K.; Cohen, Jeffrey I.] NIAID, Med Virol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Dropulic, LK (reprint author), NIAID, Med Virol Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM dropulicl@niaid.nih.gov FU intramural research program of the National Institute of Allergy and Infectious Diseases at the NIH; Immune Design Corporation; Sanofi Pasteur FX This work was supported by the intramural research program of the National Institute of Allergy and Infectious Diseases at the NIH. One of the authors (JI Cohen) has a Cooperative Research and Development Agreement (CRADA) with Immune Design Corporation that provides funding to test a therapeutic HSV-2 vaccine in an animal model and both authors have a CRADA with Sanofi Pasteur which will provide funding to evaluate the HSV-2 dl5-29 vaccine in a clinical trial. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 89 TC 20 Z9 20 U1 2 U2 18 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1476-0584 J9 EXPERT REV VACCINES JI Expert Rev. Vaccines PD DEC PY 2012 VL 11 IS 12 BP 1429 EP 1440 DI 10.1586/ERV.12.129 PG 12 WC Immunology SC Immunology GA 086GG UT WOS:000314671500010 PM 23252387 ER PT J AU An, L Dani, KA Shen, J Warach, S AF An, Li Dani, Krishna A. Shen, Jun Warach, Steven CA Nat Hist Stroke Investigators TI Pilot results of in vivo brain glutathione measurements in stroke patients SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Article DE glutathione; magnetic resonance imaging; magnetic resonance spectroscopy; oxidative stress; stroke ID OXIDATIVE STRESS; METABOLISM; MICE AB Measurement of glutathione concentration for the study of redox status in subjects with neurological disease has been limited to peripheral markers. We recruited 19 subjects with large strokes. Using magnetic resonance spectroscopy we measured brain glutathione concentration in the stroke region and in healthy tissue to calculate a glutathione-ratio. Elevated glutathione-ratio was observed in subacute (<72 hours) subjects without hemorrhagic transformation (mean = 1.19, P = 0.03, n = 6). No trend was seen when all subjects were considered (n = 19, 3 to 754 hours, range = 0.45 to 1.41). This technique can detect glutathione changes because of disease, and may be valuable in clinical trials of stroke and other neurological diseases. Journal of Cerebral Blood Flow & Metabolism (2012) 32, 2118-2121; doi:10.1038/jcbfm.2012.127; published online 26 September 2012 C1 [An, Li; Dani, Krishna A.; Warach, Steven] NINDS, Sect Stroke Diagnost & Therapeut, NIH, Bethesda, MD 20892 USA. [Shen, Jun] NIMH, NIH, Bethesda, MD 20892 USA. RP Warach, S (reprint author), UT SW Med Ctr, Seton UT SW Clin Res Inst Austin Vice Chair Austi, Dept Neurol & Neurotherapeut, 1400N IH 35,Suite 2-240, Austin, TX 78701 USA. EM swarach@seton.org FU Division of Intramural Research of the NIH, NINDS; Patrick Berthoud Charitable Trust FX This research was performed on behalf of the Natural History of Stroke Investigators and was supported by the Division of Intramural Research of the NIH, NINDS. Krishna Dani was supported by the Patrick Berthoud Charitable Trust. NR 15 TC 1 Z9 1 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD DEC PY 2012 VL 32 IS 12 BP 2118 EP 2121 DI 10.1038/jcbfm.2012.127 PG 4 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 095QJ UT WOS:000315349200005 PM 23010948 ER PT J AU Haruoni, AA Hossain, J El Khouli, R Matsuda, KM Bluemke, DA Osman, NF Jacobs, MA AF Haruoni, Ahmed A. Hossain, Jakir El Khouli, Riham Matsuda, Kant M. Bluemke, David A. Osman, Nael F. Jacobs, Michael A. TI Strain-encoded breast MRI in phantom and ex vivo specimens with histological validation: Preliminary results SO MEDICAL PHYSICS LA English DT Article DE breast MRI; SENC; elastography; strain; cancer; diffusion ID MAGNETIC-RESONANCE-ELASTOGRAPHY; ELASTIC-MODULI; STIFF MASSES; CANCER; VISUALIZATION; COMPRESSION; PROSTATE; TISSUES AB Purpose: To evaluate the feasibility of using strain-encoded (SENC) breast magnetic resonance images (MRI) for breast cancer detection by examining the compression and relaxation response properties in phantoms and ex vivo breast samples. Methods: A tissue phantom was constructed to mimic different sizes of breast masses and tissue stiffness. In addition, five human ex vivo whole breast specimens with and without masses were studied. MR data was acquired on a 3T scanner consisting of T-1-weighted, fat suppressed spin echo T-2-weighted, and SENC breast images. Mechanical tissue characteristics (strain) of the phantoms and breast tissue samples were measured using SENC imaging in both compression and relaxation modes. The breast tissue specimens were sectioned and stained in the same plane as the MRI for histological evaluation. Results: For the phantom, SENC images showed soft masses with quantitative strain values between 35% and 50%, while harder masses had strain values between 0% and 20%. Combined compression (CMP) and relaxation (REX) breast SENC images separately categorized all masses into three different groups. For breast SENC, the signal intensities between ex vivo breast mass and breast glandular tissue were significantly different (-7.6 +/- 2.6 verses -20.6 +/- 5.4 for SENC-CMP, and 4.2 +/- 1.5 verses 22.6 +/- 5 for SENC-REX, p < 0.05). Conclusions: We have demonstrated that SENC breast MRI can be used to obtain mechanical tissue properties and give quantitative estimates of strain in tumors. This feasibility study provides the basis for future clinical studies. (C) 2012 American Association of Physicists in Medicine. [http://dx.doi.org/10.1118/1.4749963] C1 [Hossain, Jakir; El Khouli, Riham; Bluemke, David A.; Osman, Nael F.; Jacobs, Michael A.] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA. [Jacobs, Michael A.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. [Haruoni, Ahmed A.] Johns Hopkins Univ, Dept Elect & Comp Engn, Baltimore, MD 21218 USA. [El Khouli, Riham; Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH Clin Ctr, Bethesda, MD 20892 USA. [Matsuda, Kant M.] NYU, Dept Pathol, Div Neuropathol, New York, NY 10016 USA. RP Jacobs, MA (reprint author), Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21205 USA. EM mikej@mri.jhu.edu RI Jacobs, Michael/G-2901-2010; OI Bluemke, David/0000-0002-8323-8086 FU NIH [1R44CA162870, P50CA103175, 5P30CA06973, Breast SPORE P50CA88843, U01CA070095, U01CA140204] FX We thank the reviewers for their comments and Mary McAllister, MA for her assistance. This work was supported in part by the intramural NIH research program and NIH grants 1R44CA162870, P50CA103175, 5P30CA06973, Breast SPORE P50CA88843, U01CA070095, and U01CA140204. NR 24 TC 2 Z9 2 U1 0 U2 3 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD DEC PY 2012 VL 39 IS 12 BP 7710 EP 7718 DI 10.1118/1.4749963 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 049FJ UT WOS:000311967400051 PM 23231318 ER PT J AU Bada, HS Bann, CM Whitaker, TM Bauer, CR Shankaran, S LaGasse, L Lester, BM Hammond, J Higgins, R AF Bada, Henrietta S. Bann, Carla M. Whitaker, Toni M. Bauer, Charles R. Shankaran, Seetha LaGasse, Linda Lester, Barry M. Hammond, Jane Higgins, Rosemary TI Protective Factors Can Mitigate Behavior Problems After Prenatal Cocaine and Other Drug Exposures SO PEDIATRICS LA English DT Article DE behavior problems; cumulative risks; prenatal cocaine exposure; protective factors ID MATERNAL LIFE-STYLE; CHILD-BEHAVIOR; COMMUNITY VIOLENCE; AGGRESSIVE-BEHAVIOR; SUBSTANCE EXPOSURE; INHIBITORY CONTROL; EARLY ADOLESCENCE; PARENT REPORT; RISK; GENDER AB BACKGROUND: We determined the role of risk and protective factors on the trajectories of behavior problems associated with high prenatal cocaine exposure (PCE)/polydrug exposure. METHODS: The Maternal Lifestyle Study enrolled 1388 children with or without PCE, assessed through age 15 years. Because most women using cocaine during pregnancy also used other substances, we analyzed for the effects of 4 categories of prenatal drug exposure: high PCE/other drugs (OD), some PCE/OD, OD/no PCE, and no PCE/no OD. Risks and protective factors at individual, family, and community levels that may be associated with behavior outcomes were entered stepwise into latent growth curve models, then replaced by cumulative risk and protective indexes, and finally by a combination of levels of risk and protective indexes. Main outcome measures were the trajectories of externalizing, internalizing, total behavior, and attention problems scores from the Child Behavior Checklist (parent). RESULTS: A total of 1022 (73.6%) children had known outcomes. High PCE/OD significantly predicted externalizing, total, and attention problems when considering the balance between risk and protective indexes. Some PCE/OD predicted externalizing and attention problems. OD/no PCE also predicted behavior outcomes except for internalizing behavior. High level of protective factors was associated with declining trajectories of problem behavior scores over time, independent of drug exposure and risk index scores. CONCLUSIONS: High PCE/OD is a significant risk for behavior problems in adolescence; protective factors may attenuate its detrimental effects. Clinical practice and public health policies should consider enhancing protective factors while minimizing risks to improve outcomes of drug-exposed children. Pediatrics 2012;130:e1479-e1488 C1 [Bada, Henrietta S.] Univ Kentucky, Dept Pediat, Coll Med, Lexington, KY 40536 USA. [Bann, Carla M.; Hammond, Jane] RTI Int, Res Triangle Pk, NC USA. [Whitaker, Toni M.] Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA. [Bauer, Charles R.] Univ Miami, Sch Med, Dept Pediat, Miami, FL USA. [Shankaran, Seetha] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. [LaGasse, Linda; Lester, Barry M.] Brown Univ, Sch Med, Dept Pediat, Providence, RI 02912 USA. [Higgins, Rosemary] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Bada, HS (reprint author), Univ Kentucky, Dept Pediat, 800 Rose St,Room MN 470, Lexington, KY 40536 USA. EM hbada2@uky.edu FU National Institutes of Health through the National Institute on Drug Abuse; Eunice Kennedy Shriver National Institute of Child Health and Human Development [U10 HD42638, U10 DA024128, GCRC M01 RR16587, U10 HD21397, U10 HD21385, U10 HD27904, N01 HD23159, U10 HD36790]; National Institute of Mental Health; Administration on Children, Youth, and Families; Center for Substance Abuse and Treatment, US Department of Health and Human Services; National Institutes of Health (NIH); Brown University; Brown University Warren Alpert Medical School Women & Infants Hospital of Rhode Island [U10 HD27904, N01 HD23159]; Eunice Kennedy Shriver National Institute of Child Health and Human Development; National Institute on Drug Abuse; RTI International [U10 HD36790]; University of Miami Holtz Children's Hospital [GCRC M01 RR16587, U10 HD21397]; MSN; ARNP; MSW; University of Tennessee [U10 HD42638, U10 DA024128]; Wayne State University Hutzel Women's Hospital and Children's Hospital of Michigan [U10 HD21385] FX Support for the Maternal Lifestyle Study was provided by the National Institutes of Health through the National Institute on Drug Abuse and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U10 HD42638, U10 DA024128 to Dr Bada; GCRC M01 RR16587, U10 HD21397 to Dr Bauer; U10 HD21385 to Dr Shankaran; U10 HD27904, N01 HD23159 to Dr Lester; U10 HD36790 to Dr Hammond) with supplemental funding from the National Institute of Mental Health; the Administration on Children, Youth, and Families; and the Center for Substance Abuse and Treatment, US Department of Health and Human Services. Funded by the National Institutes of Health (NIH).; The following individuals, in addition to those listed as authors, and federal funding grants contributed to this study: Steering Committee Chair: Barry M. Lester, PhD, Brown University; Brown University Warren Alpert Medical School Women & Infants Hospital of Rhode Island (U10 HD27904, N01 HD23159), Cynthia Miller-Loncar, PhD, and Jean E. Twomey, PhD; Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rosemary D. Higgins, MD; National Institute on Drug Abuse: Nicolette Borek, PhD, and Vincent Smeriglio, PhD (for his involvement during Phases 1 to 4); RTI International (U10 HD36790), Abhik Das, PhD, Debra Fleischmann, BS, and Sylvia Tan, MS; University of Miami Holtz Children's Hospital (GCRC M01 RR16587, U10 HD21397), Ann L. Graziotti, MSN, ARNP, Rafael Guzman, MSW, and Carmel Azemar, MSW; University of Tennessee (U10 HD42638, U10 DA024128), Charlotte Bursi, MSSW, Kimberly A. Yolton, PhD, Deloris Lee, MSSW, Lillie Hughey, MSSW, Sara Jean Ivy, AA, Leanne Pollard, BS, Jonathan Rowland, BS, Pam Lenoue, RN, Chandra Ward, MSW, and Marilyn G. Williams, EdDLCSW; and Wayne State University Hutzel Women's Hospital and Children's Hospital of Michigan (U10 HD21385), Eunice Woldt, RN, MSN, Jay Ann Nelson, BSN, Catherine Bartholomay, BA, Lisa Sulkowski, BS, and Nicole Walker, BA. NR 67 TC 9 Z9 10 U1 0 U2 8 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 DEC PY 2012 VL 130 IS 6 BP E1479 EP E1488 DI 10.1542/peds.2011-3306 PG 10 WC Pediatrics SC Pediatrics GA 087YZ UT WOS:000314802000008 PM 23184114 ER PT J AU Roberts, JR Karr, CJ Paulson, JA Brock-Utne, AC Brumberg, HL Campbell, CC Lanphear, BP Osterhoudt, KC Sandel, MT Trasande, L Wright, RO Binns, HJ Forman, JA Seltzer, JM Mortensen, M Rogan, WJ Savage, S Spire, P AF Roberts, James R. Karr, Catherine J. Paulson, Jerome A. Brock-Utne, Alice C. Brumberg, Heather L. Campbell, Carla C. Lanphear, Bruce P. Osterhoudt, Kevin C. Sandel, Megan T. Trasande, Leonardo Wright, Robert O. Binns, Helen J. Forman, Joel A. Seltzer, James M. Mortensen, Mary Rogan, Walter J. Savage, Sharon Spire, Paul CA Council Environm Hlth TI Pesticide Exposure in Children SO PEDIATRICS LA English DT Article DE pesticides; toxicity; children; pest control; integrated pest management ID YOUNG-CHILDREN; ORGANOPHOSPHORUS PESTICIDES; ENVIRONMENTAL-HEALTH; SURFACES; RISKS; CHLORPYRIFOS; ACCUMULATION; PREVENTION; CARBAMATE; CENTERS AB This statement presents the position of the American Academy of Pediatrics on pesticides. Pesticides are a collective term for chemicals intended to kill unwanted insects, plants, molds, and rodents. Children encounter pesticides daily and have unique susceptibilities to their potential toxicity. Acute poisoning risks are clear, and understanding of chronic health implications from both acute and chronic exposure are emerging. Epidemiologic evidence demonstrates associations between early life exposure to pesticides and pediatric cancers, decreased cognitive function, and behavioral problems. Related animal toxicology studies provide supportive biological plausibility for these findings. Recognizing and reducing problematic exposures will require attention to current inadequacies in medical training, public health tracking, and regulatory action on pesticides. Ongoing research describing toxicologic vulnerabilities and exposure factors across the life span are needed to inform regulatory needs and appropriate interventions. Policies that promote integrated pest management, comprehensive pesticide labeling, and marketing practices that incorporate child health considerations will enhance safe use. Pediatrics 2012;130:e1757-e1763 C1 [Mortensen, Mary] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA 30333 USA. [Savage, Sharon] NCI, Bethesda, MD 20892 USA. RI Rogan, Walter/I-6034-2012 OI Rogan, Walter/0000-0002-9302-0160 NR 33 TC 9 Z9 9 U1 1 U2 25 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 DEC PY 2012 VL 130 IS 6 BP E1757 EP E1763 DI 10.1542/peds.2012-2757 PG 7 WC Pediatrics SC Pediatrics GA 087YZ UT WOS:000314802000044 ER PT J AU Pinto, AM Subak, LL Nakagawa, S Vittinghoff, E Wing, RR Kusek, JW Herman, WH West, DS Kuppermann, M AF Pinto, Angela Marinilli Subak, Leslee L. Nakagawa, Sanae Vittinghoff, Eric Wing, Rena R. Kusek, John W. Herman, William H. West, Delia Smith Kuppermann, Miriam TI The effect of weight loss on changes in health-related quality of life among overweight and obese women with urinary incontinence SO QUALITY OF LIFE RESEARCH LA English DT Article DE Quality of life; Weight loss; Urinary incontinence; HUI; eQWB; SF-6D ID PREFERENCE-BASED MEASURE; STYLE INTERVENTION; OVERACTIVE BLADDER; PHYSICAL-ACTIVITY; EQ-5D; TRIAL; INDEX; VALIDITY; OUTCOMES; UTILITY AB Objective To estimate the effect of change in weight and change in urinary incontinence (UI) frequency on changes in preference-based measures of health-related quality of life (HRQL) among overweight and obese women with UI participating in a weight loss trial. Methods We conducted a longitudinal cohort analysis of 338 overweight and obese women with UI enrolled in a randomized clinical trial comparing a behavioral weight loss intervention to an educational control condition. At baseline, 6, and 18 months, health utilities were estimated using the Health Utilities Index Mark 3 (HUI3), a transformation of the SF-36 to the preference-based SF-6D, and the estimated Quality of Well-Being (eQWB) score (a summary calculated from the SF-36 physical functioning, mental health, bodily pain, general health perceptions, and role limitations-physical subscale scores). Potential predictors of changes in these outcomes were examined using generalized estimating equations. Results In adjusted multivariable models, weight loss was associated with improvement in HUI3, SF-6D, and eQWB at 6 and 18 months (P < 0.05). Increases in physical activity also were independently associated with improvement in HUI3 (P = 0.01) and SF-6D (P = 0.006) scores at 18 months. In contrast, reduction in UI frequency did not predict improvements in HRQL at 6 or 18 months. Conclusion Weight loss and increased physical activity, but not reduction in UI frequency, were strongly associated with improvements in health utilities measured by the HUI3, SF-6D, and eQWB. These findings provide important information that can be used to inform cost-utility analyses of weight loss interventions. C1 [Pinto, Angela Marinilli] CUNY, Baruch Coll, Dept Psychol, New York, NY 10010 USA. [Subak, Leslee L.; Nakagawa, Sanae; Kuppermann, Miriam] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94143 USA. [Subak, Leslee L.; Vittinghoff, Eric; Kuppermann, Miriam] UCSF, Dept Epidemiol & Biostat, San Francisco, CA USA. [Subak, Leslee L.] UCSF, Dept Urol, San Francisco, CA USA. [Wing, Rena R.] Brown Univ, Warren Alpert Med Sch, Dept Psychiat & Human Behav, Providence, RI 02912 USA. [Kusek, John W.] NIDDK, Bethesda, MD USA. [Herman, William H.] Univ Michigan, Dept Internal Med & Epidemiol, Ann Arbor, MI 48109 USA. [West, Delia Smith] Univ Arkansas Med Sci, Dept Hlth Behav & Hlth Educ, Little Rock, AR 72205 USA. RP Pinto, AM (reprint author), CUNY, Baruch Coll, Dept Psychol, 55 Lexington Ave,B8-215, New York, NY 10010 USA. EM Angela.Pinto@baruch.cuny.edu FU NIDDK NIH HHS [U01 DK067861, #U01 DK067860, 5K23DK075645, K23 DK075645, K23 DK075645-04, K24 DK080775, U01 DK067860, U01 DK067862] NR 54 TC 6 Z9 6 U1 1 U2 9 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0962-9343 J9 QUAL LIFE RES JI Qual. Life Res. PD DEC PY 2012 VL 21 IS 10 BP 1685 EP 1694 DI 10.1007/s11136-011-0086-2 PG 10 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 089MT UT WOS:000314915400002 PM 22161726 ER PT J AU Masdeu, JC AF Masdeu, Joseph C. TI Searching for Novelty: Challenges with Open Access Data SO ANNALS OF NEUROLOGY LA English DT Letter C1 NIH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Masdeu, JC (reprint author), NIH, Sect Integrat Neuroimaging, Clin Brain Disorders Branch, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 2012 VL 72 IS 6 BP 983 EP 983 DI 10.1002/ana.23755 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 086CH UT WOS:000314660100021 PM 23280847 ER PT J AU Schendel, D Nelson, KB Blair, E AF Schendel, Diana Nelson, Karin B. Blair, Eve TI Neonatal Encephalopathy Or Hypoxic-Ischemic Encephalopathy? SO ANNALS OF NEUROLOGY LA English DT Letter C1 [Schendel, Diana] Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. [Nelson, Karin B.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Nelson, Karin B.] NINDS, Bethesda, MD 20892 USA. [Blair, Eve] Univ Western Australia, Telethon Inst Child Hlth, Perth, WA 6009, Australia. RP Schendel, D (reprint author), Ctr Dis Control & Prevent, Natl Ctr Birth Defects & Dev Disabil, Atlanta, GA 30333 USA. NR 5 TC 5 Z9 6 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 2012 VL 72 IS 6 BP 984 EP 984 DI 10.1002/ana.23753 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 086CH UT WOS:000314660100024 PM 23280849 ER PT J AU Stillman, MJ Chinnery, PF Kleindorfer, D Pittock, SJ Sahin, M Selcen, D Traynor, B Cash, SS Titulaer, M AF Stillman, Michael J. Chinnery, Patrick F. Kleindorfer, Dawn Pittock, Sean J. Sahin, Mustafa Selcen, Duygu Traynor, Brian Cash, Sydney S. Titulaer, Maarten TI What Do New ANA Members Think of the Future of Academic Neurology? SO ANNALS OF NEUROLOGY LA English DT Editorial Material C1 [Chinnery, Patrick F.] Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. [Kleindorfer, Dawn] Univ Cincinnati, Cincinnati, OH 45221 USA. [Pittock, Sean J.; Selcen, Duygu] Mayo Clin, Rochester, MN USA. [Sahin, Mustafa] Childrens Hosp Boston, Boston, MA USA. [Traynor, Brian] NIA, NIH, Bethesda, MD 20892 USA. [Cash, Sydney S.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Titulaer, Maarten] IDIBAPS Univ Barcelona, Barcelona, Spain. NR 0 TC 0 Z9 0 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD DEC PY 2012 VL 72 IS 6 BP A8 EP A9 DI 10.1002/ana.23826 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 086CH UT WOS:000314660100003 PM 23280853 ER PT J AU Mathay, C Yan, WS Chuaqui, R Skubitz, APN Jeon, JP Fall, N Betsou, F Barnes, M AF Mathay, Conny Yan, Wusheng Chuaqui, Rodrigo Skubitz, Amy P. N. Jeon, Jae-Pil Fall, Ndate Betsou, Fay Barnes, Michael CA ISBER Biospecimen Sci Working Grp TI Short-Term Stability Study of RNA at Room Temperature SO BIOPRESERVATION AND BIOBANKING LA English DT Article ID GENE-EXPRESSION; STORAGE; GENTEGRA(TM); QPCR; DNA AB The quality of RNA preserved in different stabilization matrices was investigated after 2 weeks of storage at room temperature. RNA samples in RNAstable (Biomatrica), GenTegra (IntegenX), and RNAshell (Imagene) were compared to RNA stored at -80 degrees C (the current gold standard for RNA preservation) and with liquid or dried RNA stored at room temperature without additives in this multi-center study. One center prepared all of the RNA samples, and five participating laboratories applied the samples to the matrices and stored them for 2 weeks at room temperature. Samples were shipped to three testing laboratories, where the 336 RNA samples were rehydrated and then analyzed for RNA recovery, purity, and integrity. Parallel RNA quality analyses and real-time PCR analyses were performed at each of the three testing laboratories. Each of the RNA matrices tested was shown to be fit-for-purpose for short-term room temperature storage in terms of total RNA recovery and rRNA integrity. All but one of the matrices was judged to be fit-for-purpose for mRNA integrity when assessed by real-time PCR analysis. In a follow-up study, RNase-contaminated samples were shown to provide accurate real-time PCR results when stored for up to 3.5 months in either RNAshell or RNAstable. C1 [Mathay, Conny; Betsou, Fay] Integrated Biobank Luxembourg, L-1210 Luxembourg, Luxembourg. [Yan, Wusheng] NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Chuaqui, Rodrigo] NCI, Canc Diag Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. [Skubitz, Amy P. N.] Univ Minnesota, Dept Lab Med & Pathol, BioNet Tissue Procurement Facil, Minneapolis, MN 55455 USA. [Jeon, Jae-Pil] Korea Natl Inst Hlth, Natl Biobank Korea, Chungbuk, South Korea. [Fall, Ndate; Barnes, Michael] Cincinnati Childrens Hosp Med Ctr, Cincinnati, OH USA. RP Mathay, C (reprint author), Integrated Biobank Luxembourg, 6 Rue Nicolas Ernest Barble, L-1210 Luxembourg, Luxembourg. EM conny.mathay@ibbl.lu NR 22 TC 10 Z9 10 U1 2 U2 17 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1947-5535 J9 BIOPRESERV BIOBANK JI Biopreserv. Biobank. PD DEC PY 2012 VL 10 IS 6 BP 532 EP 542 DI 10.1089/bio.2012.0030 PG 11 WC Cell Biology; Chemistry, Applied; Medical Laboratory Technology SC Cell Biology; Chemistry; Medical Laboratory Technology GA 083WT UT WOS:000314496800011 PM 24845140 ER PT J AU Takebe, N Hunsberger, S Yang, SX AF Takebe, Naoko Hunsberger, Sally Yang, Sherry X. TI Expression of Gli1 in the hedgehog signaling pathway and breast cancer recurrence SO CHINESE JOURNAL OF CANCER RESEARCH LA English DT Editorial Material ID INHIBITION C1 [Takebe, Naoko] NCI, Canc Therapy Evaluat Program, NIH, Rockville, MD 20852 USA. [Hunsberger, Sally] NCI, Bioinformat Res Branch, NIH, Rockville, MD 20852 USA. [Yang, Sherry X.] NCI, Natl Clin Target Validat Lab, Div Canc Treatment & Diag, NIH, Rockville, MD 20852 USA. RP Takebe, N (reprint author), Canc Therapy Evaluat Program, 6130 Execut Blvd,EPN7124, Rockville, MD 20852 USA. EM takeben@mail.nih.gov; Sherry.Yang@nih.gov NR 7 TC 3 Z9 4 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1000-9604 J9 CHINESE J CANCER RES JI Chin. J. Cancer Res. PD DEC PY 2012 VL 24 IS 4 BP 257 EP 258 DI 10.3978/j.issn.1000-9604.2012.09.07 PG 2 WC Oncology SC Oncology GA 087VT UT WOS:000314793100001 PM 23358885 ER PT J AU Burgess, RC Misteli, T Oberdoerffer, P AF Burgess, Rebecca C. Misteli, Tom Oberdoerffer, Philipp TI DNA damage, chromatin, and transcription: the trinity of aging SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID DOUBLE-STRAND BREAKS; REMODELING FACTOR CHD4; HOMOLOGOUS RECOMBINATION; GENE-EXPRESSION; GENOMIC INSTABILITY; HUMAN-CELLS; REPAIR; ATM; HETEROCHROMATIN; MAINTENANCE AB Aging brings about numerous cellular defects. Amongst the most prominent are elevated levels of persistent DNA damage, changes to chromatin structure and epigenetic modifications, and alterations of global transcription programs. These are not independent events and recent work begins to shed light on the intricate interplay between these aging-related defects. C1 [Burgess, Rebecca C.; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Oberdoerffer, Philipp] NCI, NIH, Frederick, MD 21701 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU Intramural NIH HHS [ZIA BC010309-12] NR 62 TC 24 Z9 26 U1 0 U2 12 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD DEC PY 2012 VL 24 IS 6 BP 724 EP 730 DI 10.1016/j.ceb.2012.07.005 PG 7 WC Cell Biology SC Cell Biology GA 087EC UT WOS:000314743100003 PM 22902297 ER PT J AU Cooper, JP Youle, RJ AF Cooper, Julia Promisel Youle, Richard J. TI Balancing cell growth and death SO CURRENT OPINION IN CELL BIOLOGY LA English DT Editorial Material C1 [Cooper, Julia Promisel] London Res Inst, Canc Res UK, Telomere Biol Lab, London WC2A 3LY, England. [Youle, Richard J.] NINDS, NIH, Biochem Sect, Bethesda, MD 20892 USA. RP Cooper, JP (reprint author), London Res Inst, Canc Res UK, Telomere Biol Lab, London WC2A 3LY, England. EM youler@ninds.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 0 TC 0 Z9 0 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD DEC PY 2012 VL 24 IS 6 BP 802 EP 803 DI 10.1016/j.ceb.2012.11.003 PG 2 WC Cell Biology SC Cell Biology GA 087EC UT WOS:000314743100012 PM 23246130 ER PT J AU Coleman, CN Hrdina, C Casagrande, R Cliffer, KD Mansoura, MK Nystrom, S Hatchett, R Caro, JJ Knebel, AR Wallace, KS Adams, SA AF Coleman, C. Norman Hrdina, Chad Casagrande, Rocco Cliffer, Kenneth D. Mansoura, Monique K. Nystrom, Scott Hatchett, Richard Caro, J. Jaime Knebel, Ann R. Wallace, Katherine S. Adams, Steven A. TI User-Managed Inventory: An Approach to Forward-Deployment of Urgently Needed Medical Countermeasures for Mass-Casualty and Terrorism Incidents SO DISASTER MEDICINE AND PUBLIC HEALTH PREPAREDNESS LA English DT Article DE medical countermeasures; user-managed inventory; nuclear ID NUCLEAR DETONATION; SCARCE RESOURCES; SURGE CAPACITY; HEALTH; ALLOCATION AB The user-managed inventory (UMI) is an emerging idea for enhancing the current distribution and maintenance system for emergency medical countermeasures (MCMs). It increases current capabilities for the dispensing and distribution of MCMs and enhances local/regional preparedness and resilience. In the UMI, critical MCMs, especially those in routine medical use ("dual utility") and those that must be administered soon after an incident before outside supplies can arrive, are stored at multiple medical facilities (including medical supply or distribution networks) across the United States. The medical facilities store a sufficient cache to meet part of the surge needs but not so much that the resources expire before they would be used in the normal course of business. In an emergency, these extra supplies can be used locally to treat casualties, including evacuees from incidents in other localities. This system, which is at the interface of local/regional and federal response, provides response capacity before the arrival of supplies from the Strategic National Stockpile (SNS) and thus enhances the local/regional medical responders' ability to provide life-saving MCMs that otherwise would be delayed. The UMI can be more cost-effective than stockpiling by avoiding costs due to drug expiration, disposal of expired stockpiled supplies, and repurchase for replacement. (Disaster Med Public Health Preparedness. 2012; 6:408-414) C1 [Coleman, C. Norman; Hrdina, Chad; Cliffer, Kenneth D.; Mansoura, Monique K.; Nystrom, Scott; Hatchett, Richard; Knebel, Ann R.] US Dept HHS, Off Assistant Secretary Preparedness & Response, Washington, DC 20201 USA. [Coleman, C. Norman] NCI, Radiat Res Program, NIH, Bethesda, MD 20892 USA. [Casagrande, Rocco] Gryphon Sci, Takoma Pk, MD USA. [Caro, J. Jaime] UnitedBiosource Corp, Lexington, MA USA. [Caro, J. Jaime] McGill Univ, Dept Epidemiol Biostat & Occupat Hlth, Montreal, PQ, Canada. [Caro, J. Jaime] McGill Univ, Div Gen Internal Med, Montreal, PQ, Canada. [Wallace, Katherine S.] US Dept Vet Affairs, Off Operat Secur & Preparedness, Washington, DC USA. [Adams, Steven A.] Ctr Dis Control & Prevent, Div Strateg Natl Stockpile, Off Publ Hlth Preparedness & Response, Atlanta, GA USA. RP Coleman, CN (reprint author), 6130 Execut Blvd, Rockville, MD 20852 USA. EM Norman.Coleman@nih.gov NR 16 TC 4 Z9 4 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 1935-7893 J9 DISASTER MED PUBLIC JI Dis. Med. Public Health Prep. PD DEC PY 2012 VL 6 IS 4 BP 408 EP 414 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 083WY UT WOS:000314497800015 PM 23241473 ER PT J AU Kristie, TM AF Kristie, Thomas M. TI The rise of epigenetic targets for the development of novel antivirals SO EXPERT REVIEW OF ANTI-INFECTIVE THERAPY LA English DT Editorial Material DE chromatin; chromatin inhibitors; demethylase inhibitors; herpesvirus; JMJD2; LSD1; MAOI ID CYTOMEGALOVIRUS GENE-EXPRESSION; CHROMATIN-STRUCTURE; INFECTION; LATENCY; REACTIVATION; INHIBITION; CANCER C1 NIAID, Mol Genet Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Kristie, TM (reprint author), NIAID, Mol Genet Sect, Viral Dis Lab, NIH, 33-3W20B7,33 N Dr, Bethesda, MD 20892 USA. EM thomas_kristie@nih.gov FU Intramural NIH HHS [Z01 AI000711-15] NR 20 TC 2 Z9 2 U1 0 U2 10 PU EXPERT REVIEWS PI LONDON PA UNITEC HOUSE, 3RD FL, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON N3 1QB, ENGLAND SN 1478-7210 J9 EXPERT REV ANTI-INFE JI Expert Rev. Anti-Infect. Ther. PD DEC PY 2012 VL 10 IS 12 BP 1359 EP 1361 DI 10.1586/ERI.12.143 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 080KW UT WOS:000314241900001 PM 23253311 ER PT J AU Zustiak, S Riley, J Boukari, H Gandjbakhche, A Nossal, R AF Zustiak, Silviya Riley, Jason Boukari, Hacene Gandjbakhche, Amir Nossal, Ralph TI Effects of multiple scattering on fluorescence correlation spectroscopy measurements of particles moving within optically dense media SO JOURNAL OF BIOMEDICAL OPTICS LA English DT Article DE multiple light scattering; fluorescence correlation spectroscopy; polystyrene; illuminated volume; diffusion; complex media; Monte-Carlo simulations ID PHOTON MIGRATION; POLARIZED-LIGHT; CELL-MEMBRANE; TURBID MEDIA; LIVING CELLS; DIFFUSION; COEFFICIENT; INCEPTION; PROBE AB Fluorescence correlation spectroscopy (FCS) is increasingly being used to assess the movement of particles diffusing in complex, optically dense surroundings, in which case measurement conditions may complicate data interpretation. It is considered how a single-photon FCS measurement can be affected if the sample properties result in scattering of the incident light. FCS autocorrelation functions of Atto 488 dye molecules diffusing in solutions of polystyrene beads are measured, which acted as scatterers. Data indicated that a scattering-linked increase in the illuminated volume, as much as two fold, resulted in minimal increase in diffusivity. To analyze the illuminated beam profile, Monte-Carlo simulations were employed, which indicated a larger broadening of the beam along the axial than the radial directions, and a reduction of the incident intensity at the focal point. The broadening of the volume in the axial direction has only negligible effect on the measured diffusion time, since intensity fluctuations due to diffusion events in the radial direction are dominant in FCS measurements. Collectively, results indicate that multiple scattering does not result in FCS measurement artifacts and thus, when sufficient signal intensity is attainable, single-photon FCS can be a useful technique for measuring probe diffusivity in optically dense media. (c) 2012 Society of Photo-Optical Instrumentation Engineers (SPIE). [DOI: 10.1117/1.JBO.17.12.125004] C1 [Zustiak, Silviya; Nossal, Ralph] Eunice Shriver Natl Inst Child Hlth & Human Dev, Programs Phys Biol, NIH, Bethesda, MD 20892 USA. [Riley, Jason; Gandjbakhche, Amir] Eunice Shriver Natl Inst Child Hlth & Human Dev, NIH, Bethesda, MD 20892 USA. [Boukari, Hacene] Delaware State Univ, Dept Phys & Preengn, Dover, DE USA. RP Zustiak, S (reprint author), Eunice Shriver Natl Inst Child Hlth & Human Dev, Programs Phys Biol, NIH, 9 Mem Dr,Room 1E122, Bethesda, MD 20892 USA. EM zustiaksp@mail.nih.gov FU Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; National Science Foundation (NSF Grant) [0630388]; National Aeronautics and Space Administration (NASA Grant) [NNX09AU90A] FX This work was supported by funds from the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. It was also supported by funding from the National Science Foundation (NSF Grant #0630388) and the National Aeronautics and Space Administration (NASA Grant #NNX09AU90A). NR 34 TC 1 Z9 1 U1 2 U2 10 PU SPIE-SOC PHOTO-OPTICAL INSTRUMENTATION ENGINEERS PI BELLINGHAM PA 1000 20TH ST, PO BOX 10, BELLINGHAM, WA 98225 USA SN 1083-3668 J9 J BIOMED OPT JI J. Biomed. Opt. PD DEC PY 2012 VL 17 IS 12 AR 125004 DI 10.1117/1.JBO.17.12.125004 PG 9 WC Biochemical Research Methods; Optics; Radiology, Nuclear Medicine & Medical Imaging SC Biochemistry & Molecular Biology; Optics; Radiology, Nuclear Medicine & Medical Imaging GA 083ZB UT WOS:000314504400006 PM 23208294 ER PT J AU Cremasco, V Decker, CE Stumpo, D Blackshear, PJ Nakayama, KI Nakayama, K Lupu, TS Graham, DB Novack, DV Faccio, R AF Cremasco, Viviana Decker, Corinne E. Stumpo, Deborah Blackshear, Perry J. Nakayama, Keiichi I. Nakayama, Keiko Lupu, Traian S. Graham, Daniel B. Novack, Deborah V. Faccio, Roberta TI Protein Kinase C-Delta Deficiency Perturbs Bone Homeostasis by Selective Uncoupling of Cathepsin K Secretion and Ruffled Border Formation in Osteoclasts SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Article DE OSTEOCLASTS; PKC delta; BONE RESORPTION; LYSOSOMAL SECRETION ID CORTICAL F-ACTIN; CHROMAFFIN CELLS; RESORBING OSTEOCLASTS; PLASMA-MEMBRANE; SUBSTRATE; MARCKS; EXOCYTOSIS; PHOSPHORYLATION; LOCALIZATION; ACTIVATION AB Bone homeostasis requires stringent regulation of osteoclasts, which secrete proteolytic enzymes to degrade the bone matrix. Despite recent progress in understanding how bone resorption occurs, the mechanisms regulating osteoclast secretion, and in particular the trafficking route of cathepsin K vesicles, remain elusive. Using a genetic approach, we describe the requirement for protein kinase C-delta (PKC delta) in regulating bone resorption by affecting cathepsin K exocytosis. Importantly, PKC delta deficiency does not perturb formation of the ruffled border or trafficking of lysosomal vesicles containing the vacuolar-ATPase (v-ATPase). Mechanistically, we find that cathepsin K exocytosis is controlled by PKC delta through modulation of the actin bundling protein myristoylated alanine-rich C-kinase substrate (MARCKS). The relevance of our finding is emphasized in vivo because PKC delta-/- mice exhibit increased bone mass and are protected from pathological bone loss in a model of experimental postmenopausal osteoporosis. Collectively, our data provide novel mechanistic insights into the pathways that selectively promote secretion of cathepsin K lysosomes independently of ruffled border formation, providing evidence of the presence of multiple mechanisms that regulate lysosomal exocytosis in osteoclasts. (C) 2012 American Society for Bone and Mineral Research. C1 [Cremasco, Viviana; Decker, Corinne E.; Lupu, Traian S.; Faccio, Roberta] Washington Univ, Sch Med, Dept Orthopaed, St Louis, MO USA. [Stumpo, Deborah; Blackshear, Perry J.] NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. [Nakayama, Keiichi I.] Kyushu Univ, Dept Mol & Cellular Biol, Med Inst Bioregulat, Fukuoka 812, Japan. [Nakayama, Keiko] Tohoku Univ, Dept Dev Genet, Ctr Translat & Adv Anim Res, Grad Sch Med,Aoba Ku, Sendai, Miyagi 980, Japan. [Graham, Daniel B.; Novack, Deborah V.] Washington Univ, Sch Med, Dept Pathol & Immunol, St Louis, MO USA. [Novack, Deborah V.] Washington Univ, Sch Med, Dept Med, Div Bone & Mineral Dis, St Louis, MO 63110 USA. RP Faccio, R (reprint author), Box 8233,660 S Euclid, St Louis, MO 63110 USA. EM faccior@wustl.edu OI Novack, Deborah/0000-0001-7101-5582 FU National Institute of Health [5R01 AR053628]; Shriners Hospital [85120]; Arthritis Foundation; American Heart Association [10PRE4030030]; NIH [AR052705, EB007568]; NIH; NIEHS; Center for Musculoskeletal Biology and Medicine at Washington University from the National Institute of Arthritis, Musculoskeletal and Skin Diseases [P30AR057235]; Genome Center at Washington University from Children's Discovery Institute [CDI-LI-2010-94] FX We gratefully thank Dr. Steven Teitelbaum (Department of Pathology and Immunology, Washington University) for helpful discussion, Dr. Wei Zou (Department of Pathology and Immunology, Washington University) for his help with the ovariectomy surgical procedure, and Dr. Wandy L. Beatty (Molecular Microbiology Imaging Facility, Washington University) for electron-microscopy. This work was supported by a National Institute of Health grant 5R01 AR053628 to RF, Shriners Hospital grant 85120 to RF, Arthritis Foundation grant to RF, American Heart Association Grant 10PRE4030030 to VC, and NIH grants AR052705 and EB007568 to DVN. The study was supported in part by the Intramural Research Program of the NIH, NIEHS (to PJB). The histological and mu CT analysis were supported by The Center for Musculoskeletal Biology and Medicine at Washington University, Award Number P30AR057235 from the National Institute of Arthritis, Musculoskeletal and Skin Diseases. The silencing constructs were provided by the Genome Center at Washington University, grant number CDI-LI-2010-94 from the Children's Discovery Institute to S. Stewart, E. Mardis, and D. Piwnica-Worms. NR 44 TC 21 Z9 22 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD DEC PY 2012 VL 27 IS 12 BP 2452 EP 2463 DI 10.1002/jbmr.1701 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 083GE UT WOS:000314450000006 PM 22806935 ER PT J AU Palys, KE Berger, VW AF Palys, Kaitlin E. Berger, Vance W. TI On the need for competent evaluation of trial quality SO RESPIRATORY MEDICINE LA English DT Letter ID RESPIRATORY-DISTRESS-SYNDROME C1 [Palys, Kaitlin E.] Virginia Polytech Inst & State Univ, Bethesda, MD 20892 USA. [Berger, Vance W.] NCI, Biometry Res Grp, Bethesda, MD 20892 USA. [Berger, Vance W.] UMBC, Bethesda, MD 20892 USA. RP Palys, KE (reprint author), Virginia Polytech Inst & State Univ, 6130 Execut Blvd, Bethesda, MD 20892 USA. EM palysk@vt.edu; vb78c@nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0954-6111 J9 RESP MED JI Respir. Med. PD DEC PY 2012 VL 106 IS 12 BP 1804 EP 1805 DI 10.1016/j.rmed.2012.07.015 PG 2 WC Cardiac & Cardiovascular Systems; Respiratory System SC Cardiovascular System & Cardiology; Respiratory System GA 088TM UT WOS:000314860000024 PM 22959912 ER PT J AU Li, Y Linnoila, RI AF Li, Yan Linnoila, R. Ilona TI Multidirectional Differentiation of Achaete-Scute Homologue-1-Defined Progenitors in Lung Development and Injury Repair SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE Ascl1; lung; neuroendocrine; mouse; progenitor ID NEUROENDOCRINE CELL HYPERPLASIA; BRONCHIOALVEOLAR STEM-CELLS; BRONCHOPULMONARY DYSPLASIA; SMOOTH-MUSCLE; MOUSE LUNG; INNERVATION; EXPRESSION; AIRWAY; EPITHELIUM; LINEAGE AB Multiple cells contribute to the function of lungs. Pulmonary neuroendocrine cells (PNECs) are important for the regulation of breathing and carcinogenesis, although they represent only a small population of the airway lining. Achaete-Scute homologue-1 (Ascl1), a proneural basic helix-loop-helix transcription factor, is critical for the development of PNECs. We postulated that Ascl1-defined cells (ASDCs) maybe progenitors, and traced their fate during development and injury repair. R26R-stop-lacZ (Rosa) reporter mice were crossed with Ascl1-Cre or Ascl1-CreERTM mice, in which the Ascl1 promoter drives the expression of Cre or inducible Cre recombinase, respectively. ASDCs and their descendants will be permanently labeled. The labeled cells were characterized by immunohistochemistry, using highly specific differentiation markers. Lineage studies revealed a population that proliferates before the pseudoglandular stage, and widely contributes to different compartments. When ASDCs were labeled on Embryonic Day 9.5, they gave rise to both airway and alveolar cells, but when labeled on Embryonic Day 11.5, they only gave rise to airway cells. In postnatal naphthalene injury, ASDCs contributed to regenerating Clara cells. In conclusion, Ascl1-defined cells in the lung represent a novel multipotent lineage, indicating a close relationship of neuroendocrine cells with other cell types. C1 [Li, Yan; Linnoila, R. Ilona] NCI, Expt Pathol Sect, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. RP Linnoila, RI (reprint author), NCI, Expt Pathol Sect, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. EM il17h@nih.gov FU Center for Cancer Research, National Cancer Institute, National Institutes of Health FX This research was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health (R.I.L.). NR 50 TC 13 Z9 13 U1 1 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD DEC PY 2012 VL 47 IS 6 BP 768 EP 775 DI 10.1165/rcmb.2012-0027OC PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 082QH UT WOS:000314406800006 PM 22878413 ER PT J AU Zhang, B Chen, Z Albert, PS AF Zhang, Bo Chen, Zhen Albert, Paul S. TI Estimating Diagnostic Accuracy of Raters Without a Gold Standard by Exploiting a Group of Experts SO BIOMETRICS LA English DT Article DE Diagnostic error; Imperfect tests; Model selection; Prevalence; Sensitivity; Specificity ID LATENT CLASS ANALYSIS; TESTS; ENDOMETRIOSIS; ERROR; SPECIFICITY; SENSITIVITY; MODELS AB In diagnostic medicine, estimating the diagnostic accuracy of a group of raters or medical tests relative to the gold standard is often the primary goal. When a gold standard is absent, latent class models where the unknown gold standard test is treated as a latent variable are often used. However, these models have been criticized in the literature from both a conceptual and a robustness perspective. As an alternative, we propose an approach where we exploit an imperfect reference standard with unknown diagnostic accuracy and conduct sensitivity analysis by varying this accuracy over scientifically reasonable ranges. In this article, a latent class model with crossed random effects is proposed for estimating the diagnostic accuracy of regional obstetrics and gynaecological (OB/GYN) physicians in diagnosing endometriosis. To avoid the pitfalls of models without a gold standard, we exploit the diagnostic results of a group of OB/GYN physicians with an international reputation for the diagnosis of endometriosis. We construct an ordinal reference standard based on the discordance among these international experts and propose a mechanism for conducting sensitivity analysis relative to the unknown diagnostic accuracy among them. A Monte Carlo EM algorithm is proposed for parameter estimation and a BIC-type model selection procedure is presented. Through simulations and data analysis we show that this new approach provides a useful alternative to traditional latent class modeling approaches used in this setting. C1 [Zhang, Bo] Oregon State Univ, Coll Publ Hlth & Human Sci, Sch Biol & Populat Hlth Sci, Biostat Core, Corvallis, OR 97331 USA. [Chen, Zhen; Albert, Paul S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Bethesda, MD 20892 USA. RP Zhang, B (reprint author), Oregon State Univ, Coll Publ Hlth & Human Sci, Sch Biol & Populat Hlth Sci, Biostat Core, Corvallis, OR 97331 USA. EM bo.zhang@oregonstate.edu FU Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development FX We thank Editor, Associate Editor, and the anonymous reviewer for their thoughtful and constructive comments, which have led to an improved article. This research was supported by the Intramural Research Program of the National Institutes of Health, Eunice Kennedy Shriver National Institute of Child Health and Human Development. We thank the Center for Information Technology, the National Institutes of Health, for providing access to the high performance computational capabilities of the Biowulf Linux cluster. NR 17 TC 8 Z9 8 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD DEC PY 2012 VL 68 IS 4 BP 1294 EP 1302 DI 10.1111/j.1541-0420.2012.01789.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 080IX UT WOS:000314236200031 PM 23006010 ER PT J AU Vinson, C Chatterjee, R AF Vinson, Charles Chatterjee, Raghunath TI CG methylation SO EPIGENOMICS LA English DT Review DE C/EBP; CG; CG dinucleotide; CGI; CpG; CpG island; cytosine; methylation; TFBS; tissue specific ID EMBRYONIC STEM-CELLS; ACTIVE DNA DEMETHYLATION; GENOME-WIDE ANALYSIS; GENE-EXPRESSION; CPG METHYLATION; METHYLOME ANALYSIS; PATERNAL GENOME; SELF-RENEWAL; TET PROTEINS; NUCLEAR-DNA AB A striking feature of mammalian genomes is the paucity of the CG dinucleotide. There are approximately 20,000 regions termed CpG islands where CGs cluster. This represents 5% of all CGs and 1% of the genome. CpG islands are typically unmethylated and are often promoters for housekeeping genes. The remaining 95% of CG dinucleotides are disposed throughout 99% of the genome and are typically methylated and found in half of all promoters. CG methylation facilitates binding of the C/EBP family of transcription factors, proteins critical for differentiation of many tissues. This allows these proteins to localize in the methylated CG poor regions of the genome where they may produce advantageous changes in gene expression at nearby or more distant regions of the genome. In this review, our growing understanding of the consequences of CG methylation will be surveyed. C1 [Vinson, Charles; Chatterjee, Raghunath] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), NCI, Lab Metab, NIH, Bldg 37,Room 3128, Bethesda, MD 20892 USA. EM vinsonc@mail.nih.gov FU National Cancer Institute, NIH, USA FX This work is supported by the intramural project of National Cancer Institute, NIH, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 80 TC 24 Z9 24 U1 2 U2 28 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1750-1911 J9 EPIGENOMICS-UK JI Epigenomics PD DEC PY 2012 VL 4 IS 6 BP 655 EP 663 DI 10.2217/EPI.12.55 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 082NR UT WOS:000314399200009 PM 23244310 ER PT J AU Li, TW Zhao, HT Hung, GC Han, J Tsai, S Li, BJ Zhang, J Puri, RK Lo, SC AF Li, Tianwei Zhao, Hongtao Hung, Guo-Chiuan Han, Jing Tsai, Shien Li, Bingjie Zhang, Jing Puri, Raj K. Lo, Shyh-Ching TI Differentially expressed genes and pathways induced by organophosphates in human neuroblastoma cells SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Article DE organophosphate; neuroblastoma; microarray; pathway analysis; gene regulation ID CHLORPYRIFOS; NEUROTOXICITY; PESTICIDES; MUTATIONS; EXPOSURES; STRESS; AGENTS; RAT AB Organophosphates (OPs) are toxic chemicals commonly used as pesticides and herbicides. Some OPs are highly toxic to humans and have been used in warfare and terrorist attacks. In order to elucidate the molecular mechanisms of injury caused by OPs, the differentially expressed genes were analyzed in human SK-N-SH neuroblastoma cells induced by three OPs. The SK-N-SH cells were treated with one of the three OPs, chlorpyrifos, dichlorvos or methamidophos at LC20 (high-dose), the concentration causing 20% cell death, as well as 1/20 of LC20 (low-dose), a sub-lethal concentration with no detectable cell death, for 24 h. The genome-wide gene changes were identified by Agilent Microarray System, and analyzed by microarray analysis tools. The analysis revealed neuroblastoma cells treated with the high doses of all three OPs markedly activated cell apoptosis and inhibited cell growth and proliferation genes, which would most likely lead to the process of cell death. Interestingly, the analysis also revealed significant decrease in expressions of many genes in a specific spliceosome pathway in cells treated with the low doses of all three different OPs. The change of spliceosome pathway may represent an important mechanism of injury in neuronal cells exposed to low doses of various OPs. In addition to unraveling a potentially different form of OP pathogenesis, this finding could provide a new diagnostic marker in assessing OP-associated injury in cells or tissues. In addition, these results could also contribute to the development of new prevention and/or therapeutic regimens against OP toxicity. C1 [Li, Tianwei; Zhao, Hongtao; Hung, Guo-Chiuan; Tsai, Shien; Li, Bingjie; Zhang, Jing; Lo, Shyh-Ching] US FDA, Tissue Safety Lab Program, Bethesda, MD 20892 USA. [Li, Tianwei; Zhao, Hongtao; Hung, Guo-Chiuan; Han, Jing; Tsai, Shien; Li, Bingjie; Zhang, Jing; Puri, Raj K.; Lo, Shyh-Ching] US FDA, Tumor Vaccines & Biotechnol Branch, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Lo, SC (reprint author), US FDA, Tissue Safety Lab Program, NIH Bldg 29B,29 Lincoln Dr, Bethesda, MD 20892 USA. EM shyhching.lo@fda.hhs.gov FU Defense Threat Reduction Agency (DTRA) [CBS.MEDCHEM.01.10.FDA.PP008] FX This research was supported by a grant from Defense Threat Reduction Agency (DTRA: #CBS.MEDCHEM.01.10.FDA.PP008). We thank Dr Amy Yang for her help on microarray experiments and data analysis, Dr Ephrem Tekle for his help on confocal microscope. NR 33 TC 2 Z9 2 U1 2 U2 14 PU ROYAL SOC MEDICINE PRESS LTD PI LONDON PA 1 WIMPOLE STREET, LONDON W1G 0AE, ENGLAND SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD DEC PY 2012 VL 237 IS 12 BP 1413 EP 1423 DI 10.1258/ebm.2012.012178 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 082GS UT WOS:000314380900006 PM 23354400 ER PT J AU Osinusi, A Heytens, L Lee, YJ Bon, D Shivakumar, B Nelson, A Meissner, EG Kohli, A Barrett, L Proschan, M Silk, R Kwan, R Herrmann, E Sneller, M Teferi, G Talwani, R Symonds, WT Polis, MA Masur, H McHutchison, JG Fauci, AS Kottilil, S AF Osinusi, Anu Heytens, Laura Lee, Yu-Jin Bon, Dimitra Shivakumar, Bhavana Nelson, Amy Meissner, Eric G. Kohli, Anita Barrett, Lisa Proschan, Mike Silk, Rachel Kwan, Richard Herrmann, Eva Sneller, Michael Teferi, Gebeyehu Talwani, Rohit Symonds, William T. Polis, Michael A. Masur, Henry McHutchison, John G. Fauci, Anthony S. Kottilil, Shyam TI High Efficacy Of GS-7977 In Combination With Low or Full dose Ribavirin for 24 weeks In Difficult To Treat HCV Infected Genotype 1 Patients : Interim Analysis From The SPARE Trial SO HEPATOLOGY LA English DT Meeting Abstract C1 [Osinusi, Anu; Lee, Yu-Jin; Shivakumar, Bhavana; Nelson, Amy; Meissner, Eric G.; Kohli, Anita; Barrett, Lisa; Proschan, Mike; Sneller, Michael; Polis, Michael A.; Fauci, Anthony S.; Kottilil, Shyam] NIAID, LIR, NIH, Bethesda, MD 20892 USA. [Osinusi, Anu; Kohli, Anita; Silk, Rachel] SAIC Frederick Inc, Frederick Natl Lab Canc Res, Clin Res Directorate CMRP, Frederick, MD USA. [Heytens, Laura; Kwan, Richard; Masur, Henry] NIH, CCMD, CC, Bethesda, MD 20892 USA. [Bon, Dimitra; Herrmann, Eva] Goethe Univ Frankfurt, Inst Biostat & Math Modeling, D-60054 Frankfurt, Germany. [Teferi, Gebeyehu] Unity Hlth Care Inc, Washington, DC USA. [Talwani, Rohit] Univ Maryland, Baltimore, MD 21201 USA. [Symonds, William T.; McHutchison, John G.] Gilead Sci Inc, Foster City, CA 94404 USA. NR 0 TC 4 Z9 4 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2012 VL 56 IS 6 MA LB4 BP 1518 EP 1518 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 081BD UT WOS:000314288900005 ER PT J AU O'Brien, TR Muchmore, B Tang, W Pfeiffer, R Park, H Dickensheets, H Buckett, D Porter-Gill, P Chen, S Astemborski, J Bonkovsky, HL Edlin, BR Howell, CD Morgan, T Thomas, DL Rehermann, B Donnelly, RP Prokunina-Olsson, L AF O'Brien, Thomas R. Muchmore, Brian Tang, Wei Pfeiffer, Ruth Park, Heiyoung Dickensheets, Harold Buckett, Dianna Porter-Gill, Patricia Chen, Sabrina Astemborski, Jacquie Bonkovsky, Herbert L. Edlin, Brian R. Howell, Charles D. Morgan, Timothy Thomas, David L. Rehermann, Barbara Donnelly, Raymond P. Prokunina-Olsson, Ludmila TI A Novel Frame-Shift Genetic Variant Located Near IL28B Creates an Interferon Analog (IFNAN) Protein and Explains Genetic Associations with Impaired HCV Clearance SO HEPATOLOGY LA English DT Meeting Abstract C1 [O'Brien, Thomas R.; Muchmore, Brian; Tang, Wei; Pfeiffer, Ruth; Buckett, Dianna; Porter-Gill, Patricia; Prokunina-Olsson, Ludmila] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Park, Heiyoung; Rehermann, Barbara] NIDDKD, Liver Dis Branch, Bethesda, MD 20892 USA. [Dickensheets, Harold; Donnelly, Raymond P.] US FDA, Div Therapeut Prot, Bethesda, MD 20014 USA. [Chen, Sabrina] Informat Management Serv Inc, Silver Spring, MD USA. [Astemborski, Jacquie; Thomas, David L.] Johns Hopkins Univ, Baltimore, MD USA. [Bonkovsky, Herbert L.] Carolinas Med Ctr, Charlotte, NC 28203 USA. [Edlin, Brian R.] SUNY Downstate Coll Med, Brooklyn, NY USA. [Howell, Charles D.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Morgan, Timothy] VA Long Beach Healthcare Syst, Long Beach, CA USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2012 VL 56 IS 6 MA LB7 BP 1520 EP 1521 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 081BD UT WOS:000314288900008 ER PT J AU Park, H Serti, E Eke, O Muchmore, B Prokunina-Olsson, L Capone, S Folgori, A Rehermann, B AF Park, Heiyoung Serti, Elisavet Eke, Onyinyechi Muchmore, Brian Prokunina-Olsson, Ludmila Capone, Stefania Folgori, Antonella Rehermann, Barbara TI IL-29 Is the Dominant Type III Interferon Produced by Hepatocytes During Acute Hepatitis C Virus Infection SO HEPATOLOGY LA English DT Article ID JAK-STAT PATHWAY; GENETIC-VARIATION; IFN-LAMBDA; ANTIVIRAL ACTIVITY; EXPRESSION; REPLICATION; IL28B; THERAPY; ALPHA; CELLS AB Early, vigorous intrahepatic induction of interferon (IFN)-stimulated gene (ISG) induction is a feature of hepatitis C virus (HCV) infection, even though HCV inhibits the induction of type I IFNs in vitro. To identify the cytokines and cells that drive ISG induction and mediate antiviral activity during acute HCV infection, type I and III IFN responses were studied in (1) serial liver biopsies and plasma samples obtained from 6 chimpanzees throughout acute HCV infection and (2) primary human hepatocyte (PHH) cultures upon HCV infection. Type I IFNs were minimally induced at the messenger RNA (mRNA) level in the liver and were undetectable at the protein level in plasma during acute HCV infection of chimpanzees. In contrast, type III IFNs, in particular, interleukin (IL)-29 m A and protein, were strongly induced and these levels correlated with ISG expression and viremia. However, there was no association between intrahepatic or peripheral type III IFN levels and the outcome of acute HCV infection. Infection of PHH with HCV recapitulated strong type III and weak type I IFN responses. Supernatants from HCV-infected PHH cultures mediated antiviral activity upon transfer to HCV-replicon containing cells. This effect was significantly reduced by neutralization of type III IFNs and less by neutralization of type I IFNs. Furthermore, IL-29 production by HCV-infected PHH occurred independently from type I IFN signaling and was not enhanced by the presence of plasmacytoid dendritic cells. Conclusion: Hepatocyte-derived type III IFNs contribute to ISG induction and antiviral activity, but are not the principal determinant of the outcome of HCV infection. (HEPATOLOGY 2012;56:2060-2070) C1 [Park, Heiyoung; Serti, Elisavet; Eke, Onyinyechi; Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, Bethesda, MD USA. [Muchmore, Brian; Prokunina-Olsson, Ludmila] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. [Capone, Stefania; Folgori, Antonella] Okairos, Rome, Italy. RP Rehermann, B (reprint author), Natl Inst Digest & Kidney Dis, Immunol Sect, Liver Dis Branch, NIH,US Dept HHS, 10 Ctr Dr,Bldg 10,Room 9B16, Bethesda, MD 20892 USA. EM BarbaraR@intra.niddk.nih.gov OI Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Capone, Stefania/0000-0002-2272-120X FU National Institute of Diabetes and Digestive and Kidney Diseases; National Cancer Institute of the National Institutes of Health FX This study was supported by the intramural research programs of the National Institute of Diabetes and Digestive and Kidney Diseases and National Cancer Institute of the National Institutes of Health. The authors thank Volker Lohmann for the Huh7-HCV-Luc cells. NR 32 TC 63 Z9 66 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2012 VL 56 IS 6 BP 2060 EP 2070 DI 10.1002/hep.25897 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 081BD UT WOS:000314288900039 PM 22706965 ER PT J AU Yu, JH Zhu, BM Riedlinger, G Kang, K Hennighausen, L AF Yu, Ji Hoon Zhu, Bing-Mei Riedlinger, Gregory Kang, Keunsoo Hennighausen, Lothar TI The Liver-Specific Tumor Suppressor STAT5 Controls Expression of the Reactive Oxygen Species-Generating Enzyme NOX4 and the Proapoptotic Proteins PUMA and BIM in Mice SO HEPATOLOGY LA English DT Article ID ADENINE-DINUCLEOTIDE PHOSPHATE; UP-REGULATION; HEPATOCELLULAR-CARCINOMA; CANCER DEVELOPMENT; ENDOTHELIAL-CELLS; SIGNAL TRANSDUCER; GROWTH-HORMONE; TGF-BETA; ACTIVATION; APOPTOSIS AB Loss of signal transducer and activator of transcription 5 (STAT5) from liver tissue results in steatosis and enhanced cell proliferation. This study demonstrates that liver-specific Stat5-null mice develop severe hepatic steatosis as well as hepatocellular carcinomas at 17 months of age, even in the absence of chemical insults. To understand STAT5's role as a tumor suppressor, we identified and investigated new STAT5 target genes. Expression of Nox4, the gene encoding the reactive oxygen species (ROS)-generating enzyme NOX4, was induced by growth hormone through STAT5. In addition, the genes encoding the proapoptotic proteins PUMA and BIM were induced by growth hormone through STAT5, which bound to GAS motifs in the promoter regions of all three genes. We further show that STAT5-induced activation of Puma and Bim was dependent on NOX4. Treatment of mice with transforming growth factor-beta, an inducer of apoptosis, resulted in cleaved caspase-3 in control but not in liver-specific Stat5-null mice. This study demonstrates for the first time that cytokines through STAT5 regulate the expression of the ROS-generating enzyme NOX4 and key proapoptotic proteins. Conclusion: STAT5 harnesses several distinct signaling pathways in the liver and thereby functions as a tumor suppressor. Besides suppressing the activation of STAT3, STAT5 induces the expression of proapoptotic genes and the production of ROS. (HEPATOLOGY 2012;56:2375-2386) C1 [Yu, Ji Hoon; Kang, Keunsoo; Hennighausen, Lothar] NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [Riedlinger, Gregory] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Zhu, Bing-Mei] Nanjing Univ Chinese Med, Key Lab Acupuncture & Med Res, Minist Educ, Nanjing, Peoples R China. [Hennighausen, Lothar] Dankook Univ, Dept Nanobiomed Sci, Cheonan, Chungnam, South Korea. [Hennighausen, Lothar] Dankook Univ, WCU Res Ctr Nanobiomed Sci, Cheonan, Chungnam, South Korea. RP Hennighausen, L (reprint author), NIDDKD, Lab Genet & Physiol, NIH, 8 Ctr Dr,Room 101, Bethesda, MD 20892 USA. EM lotharh@mail.nih.gov FU Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; World Class University Program, Ministry of Education, Science and Technology, through the National Research Foundation of Korea [R31-10069] FX Supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases and in part by the World Class University Program, Ministry of Education, Science and Technology, through the National Research Foundation of Korea (grant R31-10069). NR 34 TC 17 Z9 18 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD DEC PY 2012 VL 56 IS 6 BP 2375 EP 2386 DI 10.1002/hep.25900 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 081BD UT WOS:000314288900070 PM 22711600 ER PT J AU Battesti, A Bouveret, E AF Battesti, Aurelia Bouveret, Emmanuelle TI The bacterial two-hybrid system based on adenylate cyclase reconstitution in Escherichia coli SO METHODS LA English DT Article DE Protein-protein interaction; Two-hybrid; Escherichia coli; Adenylate cyclase; Calmodulin, beta-galactosidase assay ID TANDEM AFFINITY PURIFICATION; PROTEIN-PROTEIN INTERACTIONS; BORDETELLA-PERTUSSIS; CALMODULIN-BINDING; MYCOBACTERIUM-TUBERCULOSIS; INTERACTION NETWORK; SIGNALING CASCADE; VIRULENCE FACTOR; CELL-DIVISION; IDENTIFICATION AB The bacterial two-hybrid system based on the reconstitution of adenylate cyclase in Escherichia coli (BACTH) was described 14 years ago (Karimova, Pidoux, Ullmann, and Ladant, 1998, PNAS, 95:5752). For microbiologists, it is a practical and powerful alternative to the use of the widely spread yeast two-hybrid technology for testing protein-protein interactions. In this review, we aim at giving the reader clear and most importantly simple instructions that should break any reticence to try the technique. Yet, we also add recommendations in the use of the system, related to its specificities. Finally, we expose the advantages and disadvantages of the technique, and review its diverse applications in the literature, which should help in deciding if it is the appropriate method to choose for the case at hand. (C) 2012 Elsevier Inc. All rights reserved. C1 [Battesti, Aurelia] NCI, NIH, Bethesda, MD 20892 USA. [Bouveret, Emmanuelle] Aix Marseille Univ, CNRS, LISM, F-13009 Marseille, France. RP Bouveret, E (reprint author), Aix Marseille Univ, CNRS, LISM, 31 Chemin Joseph Aiguier, F-13009 Marseille, France. EM bouveret@imm.cnrs.fr FU CNRS; ANR; NIH FX First, we are deeply grateful to Daniel Ladant and Gouzel Karimova who invented and developed the BACTH system. We thank Laetitia My, Julie Via la, Rim Maouche, all past members of the Bouveret team, and Susan Gottesman and Olivier Genest for support and discussion. We would like to thank all the BACTH users in our laboratories, from whom we got back experience and discussion. Research in EB laboratory is funded by CNRS and ANR. AB is funded by the NIH. NR 58 TC 73 Z9 76 U1 4 U2 57 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-2023 EI 1095-9130 J9 METHODS JI Methods PD DEC PY 2012 VL 58 IS 4 BP 325 EP 334 DI 10.1016/j.ymeth.2012.07.018 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 082FS UT WOS:000314378300003 PM 22841567 ER PT J AU Tsai, YC Leichner, GS Pearce, MMP Wilson, GL Wojcikiewicz, RJH Roitelman, J Weissman, AM AF Tsai, Yien Che Leichner, Gil S. Pearce, Margaret M. P. Wilson, Gaye Lynn Wojcikiewicz, Richard J. H. Roitelman, Joseph Weissman, Allan M. TI Differential regulation of HMG-CoA reductase and Insig-1 by enzymes of the ubiquitin-proteasome system SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID RETICULUM-ASSOCIATED DEGRADATION; COENZYME-A REDUCTASE; LOW-DENSITY-LIPOPROTEIN; INOSITOL 1,4,5-TRISPHOSPHATE RECEPTORS; ER-ASSOCIATED DEGRADATION; ENDOPLASMIC-RETICULUM; 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE; ACCELERATES DEGRADATION; MEMBRANE-PROTEIN; GENE-EXPRESSION AB The endoplasmic reticulum (ER)-resident enzyme 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase catalyzes the rate-limiting step in sterol production and is the therapeutic target of statins. Understanding HMG-CoA reductase regulation has tremendous implications for atherosclerosis. HMG-CoA reductase levels are regulated in response to sterols both transcriptionally, through a complex regulatory loop involving the ER Insig proteins, and posttranslationally, by Insig-dependent protein degradation by the ubiquitin-proteasome system. The ubiquitin ligase (E3) gp78 has been implicated in the sterol-regulated degradation of HMG-CoA reductase and Insig-1 through ER-associated degradation (ERAD). More recently, a second ERAD E3, TRC8, has also been reported to play a role in the sterol-accelerated degradation of HMG-CoA reductase. We interrogated this network in gp78(-/-) mouse embryonic fibroblasts and also assessed two fibroblast cell lines using RNA interference. Although we consistently observe involvement of gp78 in Insig-1 degradation, we find no substantive evidence to support roles for either gp78 or TRC8 in the robust sterol-accelerated degradation of HMG-CoA reductase. We discuss factors that might lead to such discrepant findings. Our results suggest a need for additional studies before definitive mechanistic conclusions are drawn that might set the stage for development of drugs to manipulate gp78 function in metabolic disorders. C1 [Tsai, Yien Che; Wilson, Gaye Lynn; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Frederick, MD 20712 USA. [Leichner, Gil S.; Roitelman, Joseph] Chaim Sheba Med Ctr, Bert W Strassburger Lipid Ctr, IL-52621 Tel Hashomer, Israel. [Leichner, Gil S.; Roitelman, Joseph] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Biochem, IL-69978 Tel Aviv, Israel. [Pearce, Margaret M. P.; Wojcikiewicz, Richard J. H.] SUNY Upstate Med Univ, Dept Pharmacol, Syracuse, NY 13210 USA. RP Roitelman, J (reprint author), Chaim Sheba Med Ctr, Bert W Strassburger Lipid Ctr, IL-52621 Tel Hashomer, Israel. EM Joseph.Roitelman@sheba.health.gov.il; weissmaa@mail.nih.gov OI Tsai, Yien Che/0000-0001-9624-1092 FU National Cancer Institute, National Institutes of Health; Amalia Biron-Cegla Fund; Crown Family Foundation; National Institutes of Health [DK49194]; PhRMA Foundation FX We thank Lino Tessarollo and Shyam K. Sharan (National Cancer Institute) for invaluable advice and assistance in generating mice expressing a conditional gp78-knockout allele, Joseph Goldstein and Jin Ye (University of Texas Southwestern Medical Center) for gifts of invaluable reagents, Amy James (National Cancer Institute) for excellent animal technical service, Mei Yang (National Cancer Institute) for assistance with genotyping and MEF generation, and Acong Yang (National Cancer Institute) for assistance with quantitative PCR. We are also grateful to Shoshana Bar-Nun, Stanley Lipkowitz, Meredith Metzger, and Daniel Stringer for useful discussions and critical reading of the manuscript. This work was supported by the National Cancer Institute, National Institutes of Health Intramural Research Program (Y.C.T., G. L. W., A. M. W.), fellowships from the Amalia Biron-Cegla Fund and the Crown Family Foundation (G. S. L.), National Institutes of Health Grant DK49194 (R.J.H.W.), and a pre-doctoral fellowship from the PhRMA Foundation (M.M.P.). NR 57 TC 16 Z9 18 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD DEC 1 PY 2012 VL 23 IS 23 BP 4484 EP 4494 DI 10.1091/mbc.E12-08-0631 PG 11 WC Cell Biology SC Cell Biology GA 082PR UT WOS:000314404900002 PM 23087214 ER PT J AU Dyer, KD Garcia-Crespo, KE Glineur, S Domachowske, JB Rosenberg, HF AF Dyer, Kimberly D. Garcia-Crespo, Katia E. Glineur, Stephanie Domachowske, Joseph B. Rosenberg, Helene F. TI The Pneumonia Virus of Mice (PVM) Model of Acute Respiratory Infection SO VIRUSES-BASEL LA English DT Review DE PVM; inflammation; leukocytes; eosinophils; respiratory syncytial virus; RSV; TLR; IFN; heterologous immunity; MIP-1 alpha ID ACUTE PNEUMOVIRUS INFECTION; PLASMACYTOID DENDRITIC CELLS; SYNCYTIAL VIRUS; INFLAMMATORY RESPONSES; RSV INFECTION; PULMONARY EOSINOPHILIA; ALVEOLAR MACROPHAGES; IMMUNE-RESPONSE; VIRAL-INFECTION; NATURAL HOST AB Pneumonia Virus of Mice (PVM) is related to the human and bovine respiratory syncytial virus (RSV) pathogens, and has been used to study respiratory virus replication and the ensuing inflammatory response as a component of a natural host-pathogen relationship. As such, PVM infection in mice reproduces many of the clinical and pathologic features of the more severe forms of RSV infection in human infants. Here we review some of the most recent findings on the basic biology of PVM infection and its use as a model of disease, most notably for explorations of virus infection and allergic airways disease, for vaccine evaluation, and for the development of immunomodulatory strategies for acute respiratory virus infection. C1 [Dyer, Kimberly D.; Garcia-Crespo, Katia E.; Glineur, Stephanie; Rosenberg, Helene F.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Domachowske, Joseph B.] SUNY Upstate Med Univ, Dept Pediat, Syracuse, NY 13210 USA. RP Dyer, KD (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kdyer@niaid.nih.gov; garciacrespoke@niaid.nih.gov; stephanie.glineur@nih.gov; domachoj@upstate.edu; hrosenberg@niaid.nih.gov FU NIAID Division of Intramural Research [AI000943]; Children's Miracle Network of NY FX Funding for this work was provided by the NIAID Division of Intramural Research (AI000943 to HFR) and from the Children's Miracle Network of NY (to JBD). NR 102 TC 18 Z9 19 U1 1 U2 8 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD DEC PY 2012 VL 4 IS 12 BP 3494 EP 3510 DI 10.3390/v4123494 PG 17 WC Virology SC Virology GA 082OO UT WOS:000314401700012 PM 23342367 ER PT J AU Wahl-Jensen, V Bollinger, L Safronetz, D de Kok-Mercado, F Scott, DP Ebihara, H AF Wahl-Jensen, Victoria Bollinger, Laura Safronetz, David de Kok-Mercado, Fabian Scott, Dana P. Ebihara, Hideki TI Use of the Syrian Hamster as a New Model of Ebola Virus Disease and Other Viral Hemorrhagic Fevers SO VIRUSES-BASEL LA English DT Review DE Ebola; filovirus; hamster model; rodent model; pathogenesis ID HANTAVIRUS PULMONARY SYNDROME; PROTECT GUINEA-PIGS; GOLDEN-HAMSTER; NONHUMAN-PRIMATES; GENE-EXPRESSION; MESOCRICETUS-AURATUS; IMMUNE-RESPONSES; CLINICAL-OBSERVATIONS; FILOVIRUS INFECTIONS; PATHOLOGICAL-CHANGES AB Historically, mice and guinea pigs have been the rodent models of choice for therapeutic and prophylactic countermeasure testing against Ebola virus disease (EVD). Recently, hamsters have emerged as a novel animal model for the in vivo study of EVD. In this review, we discuss the history of the hamster as a research laboratory animal, as well as current benefits and challenges of this model. Availability of immunological reagents is addressed. Salient features of EVD in hamsters, including relevant pathology and coagulation parameters, are compared directly with the mouse, guinea pig and nonhuman primate models. C1 [Wahl-Jensen, Victoria; Bollinger, Laura] NIAID, Integrated Res Facil Ft Detrick, NIH, Frederick, MD 21702 USA. [Safronetz, David; de Kok-Mercado, Fabian; Scott, Dana P.; Ebihara, Hideki] NIAID, Integrated Res Facil, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. RP Wahl-Jensen, V (reprint author), NIAID, Integrated Res Facil Ft Detrick, NIH, Natl Interagency Biodef Campus,B-8200 Res Plaza, Frederick, MD 21702 USA. EM victoria.jensen@nih.gov; bollingerl@niaid.nih.gov; safronetzd@niaid.nih.gov; dekokmercadof@niaid.nih.gov; dana.scott@nih.gov; ebiharah@niaid.nih.gov FU NIAID [HHSN272200200016I] FX The authors are grateful to Deborah A. Baer for assistance with formatting and Donna Perry for helpful discussions. VWJ performed this work as an employee of Tunnell Consulting, Inc., a subcontractor to Battelle Memorial Institute under its prime contract with NIAID, under Contract No. HHSN272200200016I. FdKM and LB are contractors to Battelle Memorial Institute under Contract No. HHSN272200200016I. NR 109 TC 22 Z9 22 U1 1 U2 23 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD DEC PY 2012 VL 4 IS 12 BP 3754 EP 3784 DI 10.3390/v4123754 PG 31 WC Virology SC Virology GA 082OO UT WOS:000314401700025 PM 23242370 ER PT J AU Shurtleff, AC Garza, N Lackemeyer, M Carrion, R Griffiths, A Patterson, J Edwin, SS Bavari, S AF Shurtleff, Amy C. Garza, Nicole Lackemeyer, Matthew Carrion, Ricardo, Jr. Griffiths, Anthony Patterson, Jean Edwin, Samuel S. Bavari, Sina TI The Impact of Regulations, Safety Considerations and Physical Limitations on Research Progress at Maximum Biocontainment SO VIRUSES-BASEL LA English DT Review DE biocontainment; biosafety level 4 (BSL-4); biological select agents and toxins (BSAT); positive pressure suit; biodefense; biosecurity; ebola virus; highly pathogenic viruses; limitations; collaboration ID LABORATORY WORKERS; VIRUS; INACTIVATION; BIOSURETY; TISSUES AB We describe herein, limitations on research at biosafety level 4 (BSL-4) containment laboratories, with regard to biosecurity regulations, safety considerations, research space limitations, and physical constraints in executing experimental procedures. These limitations can severely impact the number of collaborations and size of research projects investigating microbial pathogens of biodefense concern. Acquisition, use, storage, and transfer of biological select agents and toxins (BSAT) are highly regulated due to their potential to pose a severe threat to public health and safety. All federal, state, city, and local regulations must be followed to obtain and maintain registration for the institution to conduct research involving BSAT. These include initial screening and continuous monitoring of personnel, controlled access to containment laboratories, accurate and current BSAT inventory records. Safety considerations are paramount in BSL-4 containment laboratories while considering the types of research tools, workflow and time required for conducting both in vivo and in vitro experiments in limited space. Required use of a positive-pressure encapsulating suit imposes tremendous physical limitations on the researcher. Successful mitigation of these constraints requires additional time, effort, good communication, and creative solutions. Test and evaluation of novel vaccines and therapeutics conducted under good laboratory practice (GLP) conditions for FDA approval are prioritized and frequently share the same physical space with important ongoing basic research studies. The possibilities and limitations of biomedical research involving microbial pathogens of biodefense concern in BSL-4 containment laboratories are explored in this review. C1 [Shurtleff, Amy C.; Garza, Nicole; Bavari, Sina] USA, Integrated Toxicol Div, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. [Lackemeyer, Matthew] Natl Inst Allergy & Immunol, Integrated Res Facil Frederick, Div Clin Res, NIH, Ft Detrick, MD 21702 USA. [Carrion, Ricardo, Jr.; Griffiths, Anthony; Patterson, Jean] Texas Biomed Res Inst, Dept Virol & Immunol, San Antonio, TX 78245 USA. [Edwin, Samuel S.] USA, Select Agent Management Div, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. RP Bavari, S (reprint author), USA, Integrated Toxicol Div, Med Res Inst Infect Dis, 1425 Porter St, Ft Detrick, MD 21702 USA. EM amy.c.shurtleff.ctr@us.army.mil; nicole.garza@us.army.mil; matthew.lackemeyer@nih.gov; carrion@txbiomed.org; agriffiths@txbiomed.org; jpatters@txbiomed.org; samuel.edwin@us.army.mil; sina.bavari@us.army.mil NR 17 TC 6 Z9 6 U1 1 U2 18 PU MDPI AG PI BASEL PA POSTFACH, CH-4005 BASEL, SWITZERLAND SN 1999-4915 J9 VIRUSES-BASEL JI Viruses-Basel PD DEC PY 2012 VL 4 IS 12 BP 3932 EP 3951 DI 10.3390/v4123932 PG 20 WC Virology SC Virology GA 082OO UT WOS:000314401700033 PM 23342380 ER PT J AU Ma, SG Zhang, YW Huang, J Huang, Y Lan, Q Rothman, N Zheng, TZ AF Ma, Shuangge Zhang, Yawei Huang, Jian Huang, Yuan Lan, Qing Rothman, Nathaniel Zheng, Tongzhang TI Integrative Analysis of Cancer Prognosis Data With Multiple Subtypes Using Regularized Gradient Descent SO GENETIC EPIDEMIOLOGY LA English DT Article DE integrative analysis; cancer prognosis; gradient descent; NHL; SNP ID NON-HODGKIN-LYMPHOMA; MICROARRAY DATA; GENE; IDENTIFICATION; RISK; POLYMORPHISMS; CONNECTICUT; EXPRESSION; SURVIVAL; PATHWAY AB In cancer research, high-throughput profiling studies have been extensively conducted, searching for genes/single nucleotide polymorphisms (SNPs) associated with prognosis. Despite seemingly significant differences, different subtypes of the same cancer (or different types of cancers) may share common susceptibility genes. In this study, we analyze prognosis data on multiple subtypes of the same cancer but note that the proposed approach is directly applicable to the analysis of data on multiple types of cancers. We describe the genetic basis of multiple subtypes using the heterogeneity model that allows overlapping but different sets of susceptibility genes/SNPs for different subtypes. An accelerated failure time (AFT) model is adopted to describe prognosis. We develop a regularized gradient descent approach that conducts gene-level analysis and identifies genes that contain important SNPs associated with prognosis. The proposed approach belongs to the family of gradient descent approaches, is intuitively reasonable, and has affordable computational cost. Simulation study shows that when prognosis-associated SNPs are clustered in a small number of genes, the proposed approach outperforms alternatives with significantly more true positives and fewer false positives. We analyze an NHL (non-Hodgkin lymphoma) prognosis study with SNP measurements and identify genes associated with the three major subtypes of NHL, namely, DLBCL, FL, and CLL/SLL. The proposed approach identifies genes different from using alternative approaches and has the best prediction performance. Genet. Epidemiol. 36:829-838,2012. (C) 2012 Wiley Periodicals, Inc. C1 [Ma, Shuangge; Zhang, Yawei; Zheng, Tongzhang] Yale Univ, Sch Publ Hlth, New Haven, CT USA. [Huang, Jian] Univ Iowa, Dept Stat & Actuarial Sci, Iowa City, IA 52242 USA. [Huang, Jian] Univ Iowa, Dept Biostat, Iowa City, IA USA. [Huang, Yuan] Penn State Univ, Dept Stat, University Pk, PA 16802 USA. [Lan, Qing; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Ma, SG (reprint author), 60 Coll ST,LEPH 209, New Haven, CT 06520 USA. EM shuangge.ma@yale.edu FU NIH [CA165923, CA62006, D43TW008323, HD70324, CA142774]; National Cancer Institute; NSF [DMS-0904181] FX We thank the editor and two referees for careful review and insightful comments. This research was supported by NIH grants CA165923, CA62006, D43TW008323, HD70324, and CA142774, and the Intramural Research Program of the National Cancer Institute, and NSF grant DMS-0904181. NR 28 TC 3 Z9 3 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2012 VL 36 IS 8 BP 829 EP 838 DI 10.1002/gepi.21669 PG 10 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 036TS UT WOS:000311055200005 PM 22851516 ER PT J AU Fan, RZ Zhang, YW Albert, PS Liu, AY Wang, YJ Xiong, MM AF Fan, Ruzong Zhang, Yiwei Albert, Paul S. Liu, Aiyi Wang, Yuanjia Xiong, Momiao TI Longitudinal Association Analysis of Quantitative Traits SO GENETIC EPIDEMIOLOGY LA English DT Article DE association mapping; quantitative trait loci; longitudinal analysis ID ANALYSIS WORKSHOP 13; GENETIC-ANALYSIS; BLOOD-PRESSURE; LINKAGE DISEQUILIBRIUM; VARIANCE-COMPONENTS; GAMETIC DISEQUILIBRIUM; CHARACTER PROCESS; TEMPORAL TRENDS; RISK-FACTORS; LOCI AB Longitudinal genetic studies provide a valuable resource for exploring key genetic and environmental factors that affect complex traits over time. Genetic analysis of longitudinal data that incorporate temporal variations is important for understanding genetic architecture and biological variations of common complex diseases. Although they are important, there is a paucity of statistical methods to analyze longitudinal human genetic data. In this article, longitudinal methods are developed for temporal association mapping to analyze population longitudinal data. Both parametric and nonparametric models are proposed. The models can be applied to multiple diallelic genetic markers such as single-nucleotide polymorphisms and multiallelic markers such as microsatellites. By analytical formulae, we show that the models take both the linkage disequilibrium and temporal trends into account simultaneously. Variance-covariance structure is constructed to model the single measurement variation and multiple measurement correlations of an individual based on the theory of stochastic processes. Novel penalized spline models are used to estimate the time-dependent mean functions and regression coefficients. The methods were applied to analyze Framingham Heart Study data of Genetic Analysis Workshop (GAW) 13 and GAW 16. The temporal trends and genetic effects of the systolic blood pressure are successfully detected by the proposed approaches. Simulation studies were performed to find out that the nonparametric penalized linear model is the best choice in fitting real data. The research sheds light on the important area of longitudinal genetic analysis, and it provides a basis for future methodological investigations and practical applications. Genet. Epidemiol. 36:856-869, 2012. (C) 2012 Wiley Periodicals, Inc. C1 [Fan, Ruzong; Albert, Paul S.; Liu, Aiyi] Eunice Kennedy Shrivel Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD 20852 USA. [Zhang, Yiwei] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Wang, Yuanjia] Columbia Univ, Dept Biostat, Mailman Sch Publ Hlth, New York, NY USA. [Xiong, Momiao] Univ Texas Houston, Ctr Human Genet, Houston, TX USA. RP Fan, RZ (reprint author), Eunice Kennedy Shrivel Natl Inst Child Hlth & Hum, Biostat & Bioinformat Branch, Div Epidemiol Stat & Prevent Res, NIH, 6100 Execut Blvd,Room 7B05,MSC 7510, Bethesda, MD 20852 USA. EM fanr@mail.nih.gov OI , Yuanjia/0000-0002-1510-3315; Liu, Aiyi/0000-0002-6618-5082 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Maryland FX This study was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Maryland. NR 42 TC 9 Z9 10 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD DEC PY 2012 VL 36 IS 8 BP 856 EP 869 DI 10.1002/gepi.21673 PG 14 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 036TS UT WOS:000311055200008 PM 22965819 ER PT J AU Sharma, N Goel, P Sherman, A AF Sharma, Neelima Goel, Pranay Sherman, Arthur TI Differential roles for ionic and metabolic glucosensing in a minimal model of VMH glucose-excited neurons SO INTERNATIONAL JOURNAL OF DEVELOPMENTAL NEUROSCIENCE LA English DT Meeting Abstract CT 19th Biennial Meeting of the International-Society-for-Developmental-Neuroscience (ISDN) CY JAN 11-14, 2012 CL Mumbai, INDIA SP Int Soc Dev Neurosci (ISDN) C1 [Sharma, Neelima] NCBS, Bangalore, Karnataka, India. [Goel, Pranay] IISER, Pune, Maharashtra, India. [Sherman, Arthur] NIDDK, NIH, LBM, Bethesda, MD USA. RI Goel, Pranay/D-1081-2013 NR 0 TC 0 Z9 0 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0736-5748 J9 INT J DEV NEUROSCI JI Int. J. Dev. Neurosci. PD DEC PY 2012 VL 30 IS 8 BP 651 EP 652 DI 10.1016/j.ijdevneu.2012.03.263 PG 2 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 077EE UT WOS:000314009900089 ER PT J AU Simons-Morton, BG Ouimet, MC Chen, RS Klauer, SG Lee, SE Wang, J Dingus, TA AF Simons-Morton, Bruce G. Ouimet, Marie Claude Chen, Rusan Klauer, Sheila G. Lee, Suzanne E. Wang, Jing Dingus, Thomas A. TI Peer influence predicts speeding prevalence among teenage drivers SO JOURNAL OF SAFETY RESEARCH LA English DT Article DE Adolescence; Risk taking; Motor vehicle crashes; Naturalistic; Social influence ID RISKY DRIVING BEHAVIOR; MOTOR-VEHICLE CRASHES; NOVICE DRIVERS; YOUNG DRIVERS; ADOLESCENTS; PRESSURE; SUSCEPTIBILITY; PERSONALITY; INTENTIONS; EXPERIENCE AB Impact on Industry: Preventing speed-related crashes could reduce costs and improve efficiency in the transportation industry. Objective: This research examined the psychosocial and personality predictors of observed speeding among young drivers. Method: Survey and driving data were collected from 42 newly-licensed teenage drivers during the first 18 months of licensure. Speeding (i.e., driving 10 mph over the speed limit; about 16 km/h) was assessed by comparing speed data collected with recording systems installed in participants' vehicles with posted speed limits. Results: Speeding was correlated with elevated g-force event rates (r = 0.335, pb0.05), increased over time, and predicted by day vs. night trips, higher sensation seeking, substance use, tolerance of deviance, susceptibility to peer pressure, and number of risky friends. Perceived risk was a significant mediator of the association between speeding and risky friends. Conclusion: The findings support the contention that social norms may influence teenage speeding behavior and this relationship may operate through perceived risk. (C) 2012 National Safety Council and Elsevier Ltd. All rights reserved. C1 [Simons-Morton, Bruce G.; Wang, Jing] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. [Ouimet, Marie Claude] Univ Sherbrooke, Fac Med & Hlth Sci, Longueuil, PQ, Canada. [Chen, Rusan] Georgetown Univ, Washington, DC USA. [Klauer, Sheila G.; Lee, Suzanne E.; Dingus, Thomas A.] Virginia Tech Univ, Blacksburg, VA USA. RP Simons-Morton, BG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. EM mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [ZIA HD001707-14]; NICHD NIH HHS [N01-HD-5-3405] NR 56 TC 20 Z9 20 U1 1 U2 23 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0022-4375 J9 J SAFETY RES JI J. Saf. Res. PD DEC PY 2012 VL 43 IS 5-6 BP 397 EP 403 DI 10.1016/j.jsr.2012.10.002 PG 7 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA 073VD UT WOS:000313770300010 PM 23206513 ER PT J AU Valm, AM Welch, JLM Borisy, GG AF Valm, Alex M. Welch, Jessica L. Mark Borisy, Gary G. TI CLASI-FISH: Principles of combinatorial labeling and spectral imaging SO SYSTEMATIC AND APPLIED MICROBIOLOGY LA English DT Article DE Spectral imaging; Combinatorial labeling; Fluorescence in situ hybridization; FISH; Microbial diversity ID IN-SITU HYBRIDIZATION; RIBOSOMAL-RNA; OLIGONUCLEOTIDE PROBES; IDENTIFICATION; MICROBIOLOGY; BACTERIA; BIOFILM; CELLS AB Although the number of phylotypes present in a microbial community may number in the hundreds or more, until recently, fluorescence in situ hybridization has been used to label, at most, only a handful of different phylotypes in a single sample. We recently developed a technique, CLASI-FISH for combinatorial labeling and spectral imaging - fluorescence in situ hybridization, to greatly expand the number of distinguishable taxa in a single FISH experiment. The CLASI technique involves labeling microbes of interest with combinations of probes coupled with spectral imaging to allow the use of fluorophores with highly overlapping excitation and emission spectra. Here, we present the basic principles and theory of CLASI-FISH along with some guidelines for performing CLASI-FISH experiments. We further include a protocol for creating fluorescence spectral reference standards, a vital component of successful CLASI-FISH. (c) 2012 Elsevier GmbH. All rights reserved. C1 [Valm, Alex M.; Welch, Jessica L. Mark; Borisy, Gary G.] Marine Biol Lab, Woods Hole, MA 02543 USA. [Valm, Alex M.; Borisy, Gary G.] Brown Univ, Providence, RI 02912 USA. RP Valm, AM (reprint author), NHGRI, NIH, Bethesda, MD 20814 USA. EM alex.valm@nih.gov OI Borisy, Gary/0000-0002-0266-8018 FU Alfred P. Sloan Foundation; NIH [F31DE019576]; National Institute for Dental and Craniofacial Research [RC1DE20630] FX We are grateful to Rudolf Oldenbourg for help revising this manuscript. This work was supported in part by a grant from the Alfred P. Sloan Foundation to G.G.B., and NIH Grants F31DE019576 to A.M.V. and RC1DE20630 to G.G.B. from the National Institute for Dental and Craniofacial Research. NR 18 TC 11 Z9 11 U1 1 U2 26 PU ELSEVIER GMBH, URBAN & FISCHER VERLAG PI JENA PA OFFICE JENA, P O BOX 100537, 07705 JENA, GERMANY SN 0723-2020 J9 SYST APPL MICROBIOL JI Syst. Appl. Microbiol. PD DEC PY 2012 VL 35 IS 8 SI SI BP 496 EP 502 DI 10.1016/j.syapm.2012.03.004 PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 077GD UT WOS:000314015000003 PM 22521573 ER PT J AU Meissner, HI Klabunde, CN Breen, N Zapka, JM AF Meissner, Helen I. Klabunde, Carrie N. Breen, Nancy Zapka, Jane M. TI Breast and Colorectal Cancer Screening U.S. Primary Care Physicians' Reports of Barriers SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID FORCE RECOMMENDATION STATEMENT; UNITED-STATES AB Background: Primary care physicians (PCPs) play a key role in performing and referring patients for cancer screening. Understanding barriers to test use is critical to developing strategies that promote adherence to clinical guidelines, but current literature does not distinguish the extent to which barriers may be similar or unique across screening modalities. Purpose: To describe PCPs' self-reported perceptions of barriers to screening for breast and colorectal cancer (CRC) and compare the top three barriers associated with these screening modalities. Methods: Cross-sectional data analyzed in 2011 from a nationally representative survey of 2478 PCPs in the U.S. in 2006-2007. Results: PCPs reported greater barriers for CRC screening than for mammography. Lack of patient follow-through to complete recommended screening and the inability to pay for tests were the main barriers perceived by PCPs for both types of screening. Another major barrier cited was that patients do not perceive CRC as a threat. This was a lesser concern for the well-diffused message about the need for mammography. Conclusions: This is the first national study to provide a comparison of physician-perceived barriers to breast and CRC screening. Study results suggest that efforts to improve use of cancer screening, and CRC screening in particular, will require interventions at physician, practice, and health-system levels. (Am J Prev Med 2012;43(6):584-589) Published by Elsevier Inc. on behalf of American Journal of Preventive Medicine C1 [Meissner, Helen I.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Klabunde, Carrie N.; Breen, Nancy] NCI, Div Canc Control & Populat Sci, Rockville, MD USA. [Zapka, Jane M.] Med Univ S Carolina, Div Biostat & Epidemiol, Charleston, SC 29425 USA. RP Meissner, HI (reprint author), NIH, Off Behav & Social Sci Res, 31 Ctr Dr,Bldg 31,Room B1C19, Bethesda, MD 20892 USA. EM meissneh@od.nih.gov FU National Cancer Institute [N02-PC-51308]; Agency for Healthcare Research and Quality [Y3-PC-5019-01, Y3-PC-5019-02]; CDC [Y3-PC-6017-01] FX The authors thank Ms. Gigi Yuan of Information Management Services, Inc. (Silver Spring MD), for programming support. Funding support for the National Survey of Primary Care Physicians' Recommendations and Practices for Breast, Cervical, Colorectal, and Lung Cancer Screening was provided by the National Cancer Institute (contract number N02-PC-51308), the Agency for Healthcare Research and Quality (inter-agency agreement numbers Y3-PC-5019-01 and Y3-PC-5019-02), and the CDC (inter agency agreement number Y3-PC-6017-01). NR 19 TC 20 Z9 20 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD DEC PY 2012 VL 43 IS 6 BP 584 EP 589 DI 10.1016/j.amepre.2012.08.016 PG 6 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 071FR UT WOS:000313574800003 PM 23159253 ER PT J AU Schuz, J Grell, K Kinsey, S Linet, MS Link, MP Mezei, G Pollock, BH Roman, E Zhang, Y McBride, ML Johansen, C Spix, C Hagihara, J Saito, AM Simpson, J Robison, LL Dockerty, JD Feychting, M Kheifets, L Frederiksen, K AF Schuz, J. Grell, K. Kinsey, S. Linet, M. S. Link, M. P. Mezei, G. Pollock, B. H. Roman, E. Zhang, Y. McBride, M. L. Johansen, C. Spix, C. Hagihara, J. Saito, A. M. Simpson, J. Robison, L. L. Dockerty, J. D. Feychting, M. Kheifets, L. Frederiksen, K. TI Extremely low-frequency magnetic fields and survival from childhood acute lymphoblastic leukemia: an international follow-up study SO BLOOD CANCER JOURNAL LA English DT Article DE leukemia; children; survival; electromagnetic fields; adverse effects; pooled analyses ID POOLED ANALYSIS; ELECTROMAGNETIC-FIELDS; RISK; EXPOSURE; CHILDREN; CANCER; IMMUNOGLOBULIN; REARRANGEMENTS AB A previous US study reported poorer survival in children with acute lymphoblastic leukemia (ALL) exposed to extremely low-frequency magnetic fields (ELF-MF) above 0.3 mu T, but based on small numbers. Data from 3073 cases of childhood ALL were pooled from prospective studies conducted in Canada, Denmark, Germany, Japan, UK and US to determine death or relapse up to 10 years from diagnosis. Adjusting for known prognostic factors, we calculated hazard ratios (HRs) and 95% confidence intervals (CI) for overall survival and event-free survival for ELF-MF exposure categories and by 0.1 mu T increases. The HRs by 0.1 mu T increases were 1.00 (CI, 0.93-1.07) for event-free survival analysis and 1.04 (CI, 0.97-1.11) for overall survival. ALL cases exposed to >0.3 mu T did not have a poorer event-free survival (HR = 0.76; CI, 0.44-1.33) or overall survival (HR = 0.96; CI, 0.49-1.89). HRs varied little by subtype of ALL. In conclusion, ELF-MF exposure has no impact on the survival probability or risk of relapse in children with ALL. Blood Cancer Journal (2012) 2, e98; doi: 10.1038/bcj.2012.43; published online 21 December 2012 C1 [Schuz, J.] Int Agcy Res Canc, Sect Environm & Radiat, F-69372 Lyon, France. [Schuz, J.; Grell, K.; Johansen, C.; Frederiksen, K.] Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. [Kinsey, S.] Univ Leeds, Leeds Gen Infirm, Leeds LS2 9JT, W Yorkshire, England. [Kinsey, S.] Univ Leeds, Leeds Inst Mol Med, Leeds LS2 9JT, W Yorkshire, England. [Linet, M. S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Link, M. P.] Stanford Univ, Sch Med, Dept Pediat, Palo Alto, CA 94304 USA. [Mezei, G.] Elect Power Res Inst, Palo Alto, CA USA. [Pollock, B. H.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Pollock, B. H.] Univ Texas Hlth Sci Ctr San Antonio, Canc Therapy & Res Ctr, San Antonio, TX 78229 USA. [Roman, E.; Simpson, J.] Univ York, Dept Hlth Serv, York YO10 5DD, N Yorkshire, England. [Roman, E.; Simpson, J.] Univ York, HYMS, York YO10 5DD, N Yorkshire, England. [Zhang, Y.; McBride, M. L.] Univ British Columbia, Sch Populat & Publ Hlth, Vancouver, BC V5Z 1M9, Canada. [Zhang, Y.; McBride, M. L.] British Columbia Canc Agcy, Canc Control Res, Vancouver, BC V5Z 4E6, Canada. [Spix, C.] Johannes Gutenberg Univ Mainz, German Childhood Canc Registry, Inst Med Biostat Epidemiol & Informat, Univ Med Ctr, D-55122 Mainz, Germany. [Hagihara, J.] Miyagi Univ, Sch Nursing, Sendai, Miyagi, Japan. [Saito, A. M.] Natl Hosp Org Nagoya Med Ctr Clin Res Ctr, Lab Clin Epidemiol & Hlth Serv Res, Nagoya, Aichi, Japan. [Robison, L. L.] St Jude Childrens Res Hosp, Dept Epidemiol & Canc Control, Memphis, TN 38105 USA. [Dockerty, J. D.] Univ Otago, Dunedin Sch Med, Dunedin, New Zealand. [Feychting, M.] Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. [Kheifets, L.] UCLA Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA USA. RP Schuz, J (reprint author), Int Agcy Res Canc, Sect Environm & Radiat, 150 Cours Albert Thomas, F-69372 Lyon, France. EM schuzj@iarc.fr FU Energy Denmark via a firewall; Electric Power Research Institute (EPRI) FX GM is employed at the Electric Power Research Institute. CJ received funding from the Danish utility companies for other studies than the present one; all funds from Energy Denmark was provided via a firewall and CJ certify that his freedom to design, conduct, interpret, and publish research was not compromised by this or any other sponsor.; This project was supported by a research contract from the Electric Power Research Institute (EPRI) to the Institute of Cancer Epidemiology, The Danish Cancer Society. The research agreement between EPRI and the Institute of Cancer Epidemiology guaranteed the complete freedom of the investigators to decide on study design, data collection methods, analysis plan, interpretation of the data, and the decision to submit the paper for publication. Dr Nick Douglas collected the survival data in New Zealand and Professor G Peter Herbison assisted with NZ data preparation. We thank Drs Masahiro Tsuchida (TCCSG), Masahito Tsurusawa (CCLSG), Keizo Horibe (JACLS), Jun Okamura (KYCCSG), and Tomohiro Saito (Funabashi Central Hospital) for their assistance to collect Japanese data. NR 26 TC 4 Z9 4 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 2044-5385 J9 BLOOD CANCER J JI Blood Cancer J. PD DEC PY 2012 VL 2 AR UNSP e98 DI 10.1038/bcj.2012.43 PG 5 WC Oncology SC Oncology GA 068LM UT WOS:000313368200002 PM 23262804 ER PT J AU Spitz, MR Caporaso, NE Sellers, TA AF Spitz, Margaret R. Caporaso, Neil E. Sellers, Thomas A. TI Integrative Cancer Epidemiology-The Next Generation SO CANCER DISCOVERY LA English DT Editorial Material ID WIDE ASSOCIATION; RARE VARIANTS; OPPORTUNITIES; DISEASES; SUCCESS; SCIENCE; DESIGNS; DRUG AB We outline an integrative approach to extend the boundaries of molecular cancer epidemiology by integrating modern and rapidly evolving "omics" technologies into state-of-the-art molecular epidemiology. In this way, one can comprehensively explore the mechanistic underpinnings of epidemiologic observations in cancer risk and outcome. We highlight the exciting opportunities to collaborate across large observational studies and to forge new interdisciplinary collaborative ventures. Cancer Discov; 2(12); 1087-90. (C) 2012 AACR. C1 [Spitz, Margaret R.] Baylor Coll Med, Dan L Duncan Canc Ctr, Houston, TX 77030 USA. [Caporaso, Neil E.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Sellers, Thomas A.] Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. RP Spitz, MR (reprint author), Baylor Coll Med, Dan L Duncan Canc Ctr, 1 Baylor Plaza,Cullen Bldg,Suite 450-A8,Mail Stop, Houston, TX 77030 USA. EM spitz@bcm.edu FU NCI NIH HHS [CA55769, R01 CA055769, R01 CA127219, CA127219] NR 29 TC 19 Z9 19 U1 0 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 2159-8274 J9 CANCER DISCOV JI Cancer Discov. PD DEC PY 2012 VL 2 IS 12 BP 1087 EP 1090 DI 10.1158/2159-8290.CD-12-0424 PG 4 WC Oncology SC Oncology GA 072AZ UT WOS:000313641700020 PM 23230187 ER PT J AU Sasaki, T Miller, CF Hansford, R Yang, JM Caffo, BS Zviman, MM Henrikson, CA Marine, JE Spragg, D Cheng, A Tandri, H Sinha, S Kolandaivelu, A Zimmerman, SL Bluemke, DA Tomaselli, GF Berger, RD Calkins, H Halperin, HR Nazarian, S AF Sasaki, Takeshi Miller, Christopher F. Hansford, Rozann Yang, Juemin Caffo, Brian S. Zviman, Menekhem M. Henrikson, Charles A. Marine, Joseph E. Spragg, David Cheng, Alan Tandri, Harikrishna Sinha, Sunil Kolandaivelu, Aravindan Zimmerman, Stefan L. Bluemke, David A. Tomaselli, Gordon F. Berger, Ronald D. Calkins, Hugh Halperin, Henry R. Nazarian, Saman TI Myocardial Structural Associations With Local Electrograms A Study of Postinfarct Ventricular Tachycardia Pathophysiology and Magnetic Resonance-Based Noninvasive Mapping SO CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY LA English DT Article DE ischemic heart disease; magnetic resonance imaging; mapping; ventricular tachycardia; late gadolinium enhancement ID NONISCHEMIC CARDIOMYOPATHY; QUANTITATIVE ASSESSMENT; TISSUE HETEROGENEITY; ABLATION LESIONS; INFARCT SCARS; SINUS RHYTHM; ENHANCEMENT; INTEGRATION; SUBSTRATE; IDENTIFICATION AB Background-The association of scar on late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) with local electrograms on electroanatomic mapping has been investigated. We aimed to quantify these associations to gain insights regarding LGE-CMR image characteristics of tissues and critical sites that support postinfarct ventricular tachycardia (VT). Methods and Results-LGE-CMR was performed in 23 patients with ischemic cardiomyopathy before VT ablation. Left ventricular wall thickness and postinfarct scar thickness were measured in each of 20 sectors per LGE-CMR short-axis plane. Electroanatomic mapping points were retrospectively registered to the corresponding LGE-CMR images. Multivariable regression analysis, clustered by patient, revealed significant associations among left ventricular wall thickness, postinfarct scar thickness, and intramural scar location on LGE-CMR, and local endocardial electrogram bipolar/unipolar voltage, duration, and deflections on electroanatomic mapping. Anteroposterior and septal/lateral scar localization was also associated with bipolar and unipolar voltage. Antiarrhythmic drug use was associated with electrogram duration. Critical sites of postinfarct VT were associated with >25% scar transmurality, and slow conduction sites with >40 ms stimulus-QRS time were associated with >75% scar transmurality. Conclusions-Critical sites for maintenance of postinfarct VT are confined to areas with >25% scar transmurality. Our data provide insights into the structural substrates for delayed conduction and VT and may reduce procedural time devoted to substrate mapping, overcome limitations of invasive mapping because of sampling density, and enhance magnetic resonance-based ablation by feature extraction from complex images. (Circ Arrhythm Electrophysiol. 2012;5:1081-1090.) C1 [Sasaki, Takeshi] Johns Hopkins Univ, Div Cardiol, Sch Med, Dept Med Cardiol, Baltimore, MD 21287 USA. [Halperin, Henry R.] Johns Hopkins Univ, Sch Med, Dept Med Radiol & Biomed Engn, Baltimore, MD 21287 USA. [Yang, Juemin; Caffo, Brian S.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Henrikson, Charles A.] Oregon Hlth & Sci Univ, Dept Med Cardiol, Portland, OR 97201 USA. [Zimmerman, Stefan L.] Johns Hopkins Univ, Dept Med Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Bluemke, David A.] Natl Inst Biomed Imaging & Bioengn, NIH, Ctr Clin, Bethesda, MD USA. RP Sasaki, T (reprint author), Johns Hopkins Univ, Div Cardiol, Sch Med, Dept Med Cardiol, Carnegie 592C,600 N Wolfe St, Baltimore, MD 21287 USA. EM tsasaki1@jhu.edu OI Bluemke, David/0000-0002-8323-8086 FU Francis Chiaramonte MD Private Foundation [K23HL089333]; National Institutes of Health [R01-HL094610]; Zoll Circulation Inc; St. Jude Medical Inc; Medtronic Inc; Boston Scientific Corp; Cameron Health Inc. FX Dr Sasaki is funded by the Francis Chiaramonte MD Private Foundation. Dr Nazarian is supported by grant K23HL089333 and Dr Halperin by grant R01-HL094610 from the National Institutes of Health.; Dr Nazarian has received honoraria for lectures from St. Jude Medical Inc, Boston Scientific Inc, and Biotronic Inc. Dr Nazarian is on the MRI advisory board to Medtronic Inc and is a scientific advisor to Biosense-Webster Inc. Dr Halperin has received research grant and consultant fees from Zoll Circulation Inc and has ownership interests in IMRICOR Medical Systems Inc. Dr Calkins has received honoraria from Biosense- Webster Inc and Medtronic Inc. Dr Berger has received research grants from St. Jude Medical Inc and Medtronic Inc and consultant fees from Boston Scientific Corp and Cameron Health Inc. The Johns Hopkins University Conflict of Interest Committee manages all commercial arrangements. The other authors have no conflicts to report. NR 26 TC 23 Z9 24 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1941-3149 J9 CIRC-ARRHYTHMIA ELEC JI Circ.-Arrhythmia Electrophysiol. PD DEC PY 2012 VL 5 IS 6 BP 1081 EP 1090 DI 10.1161/CIRCEP.112.970699 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 071IW UT WOS:000313586900015 PM 23149263 ER PT J AU Gopinath, A Xu, GL Ress, D Oktem, O Subramaniam, S Bajaj, C AF Gopinath, Ajay Xu, Guoliang Ress, David Oktem, Ozan Subramaniam, Sriram Bajaj, Chandrajit TI Shape-Based Regularization of Electron Tomographic Reconstruction SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Article DE Bayesian methods; electron microscopy; reconstruction; shape-based regularization; tomography ID LEVEL SET METHOD; ANATOMICAL INFORMATION; IMAGE-RECONSTRUCTION; ALGORITHM; PRIORS; GP120 AB We introduce a tomographic reconstruction method implemented using a shape-based regularization technique. Spatial models of known features in the structure being reconstructed are integrated into the reconstruction process as regularizers. Our regularization scheme is driven locally through shape information obtained from segmentation and compared with a known spatial model. We demonstrated our method on tomography data from digital phantoms, simulated data, and experimental electron tomography (ET) data of virus complexes. Our reconstruction showed reduced blurring and an improvement in the resolution of the reconstructed volume was also measured. This method also produced improved demarcation of spike boundaries in viral membranes when compared with popular techniques like weighted back projection and the algebraic reconstruction technique. Improved ET reconstructions will provide better structure elucidation and improved feature visualization, which can aid in solving key biological issues. Our method can also be generalized to other tomographic modalities. C1 [Gopinath, Ajay] Univ Texas Austin, Dept Elect & Comp Engn, Austin, TX 78712 USA. [Xu, Guoliang] Chinese Acad Sci, Acad Math & Syst Sci, Beijing 100190, Peoples R China. [Ress, David] Univ Texas Austin, Neurobiol & Imaging Res Ctr, Austin, TX 78712 USA. [Oktem, Ozan] KTH Royal Inst Technol, Ctr Ind & Appl Math, Dept Math, SE-10044 Stockholm, Sweden. [Subramaniam, Sriram] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Bajaj, Chandrajit] Univ Texas Austin, Dept Comp Sci, Austin, TX 78712 USA. [Bajaj, Chandrajit] Univ Texas Austin, Inst Computat Engn & Sci, Austin, TX 78712 USA. RP Gopinath, A (reprint author), Univ Texas Austin, Dept Elect & Comp Engn, Austin, TX 78712 USA. EM ajay.gopinath@utexas.edu RI Gopinath, Ajay/F-2061-2014 FU National Institutes of Health (NIH) [R01-EB00487, R01-GM074258]; UT-Portugal CoLab project FX The work of A. Gopinath and C. Bajaj was supported in part by the National Institutes of Health (NIH) under Contract R01-EB00487 and Contract R01-GM074258, and in part by a grant from the UT-Portugal CoLab project. NR 33 TC 6 Z9 6 U1 1 U2 10 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD DEC PY 2012 VL 31 IS 12 BP 2241 EP 2252 DI 10.1109/TMI.2012.2214229 PG 12 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 072RT UT WOS:000313690600007 PM 22922711 ER PT J AU Li, XL Chen, XJ Yao, JH Zhang, X Yang, F Tian, J AF Li, Xiuli Chen, Xinjian Yao, Jianhua Zhang, Xing Yang, Fei Tian, Jie TI Automatic Renal Cortex Segmentation Using Implicit Shape Registration and Novel Multiple Surfaces Graph Search (vol 31, pg 1849, 2012) SO IEEE TRANSACTIONS ON MEDICAL IMAGING LA English DT Correction C1 [Li, Xiuli; Zhang, Xing; Yang, Fei; Tian, Jie] Chinese Acad Sci, Intelligent Med Res Ctr, Inst Automat, Beijing 100190, Peoples R China. [Chen, Xinjian; Yao, Jianhua] NIH, Radiol & Imaging Sci Dept, Ctr Clin, Bethesda, MD 20814 USA. RP Tian, J (reprint author), Chinese Acad Sci, Intelligent Med Res Ctr, Inst Automat, Beijing 100190, Peoples R China. EM tian@ieee.org NR 1 TC 0 Z9 0 U1 0 U2 7 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 0278-0062 J9 IEEE T MED IMAGING JI IEEE Trans. Med. Imaging PD DEC PY 2012 VL 31 IS 12 BP 2366 EP 2366 DI 10.1109/TMI.2012.2229852 PG 1 WC Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Engineering, Electrical & Electronic; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging SC Computer Science; Engineering; Imaging Science & Photographic Technology; Radiology, Nuclear Medicine & Medical Imaging GA 072RT UT WOS:000313690600017 ER PT J AU Selmi, C Lu, QJ Humble, MC AF Selmi, Carlo Lu, Qianjin Humble, Michael C. TI Heritability versus the role of the environment in autoimmunity SO JOURNAL OF AUTOIMMUNITY LA English DT Review DE Tolerance breakdown; Monozygotic twins; Familiarity; Environment; Exposure ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; DNA METHYLATION CHANGES; RHEUMATOID-ARTHRITIS; TRAFFIC PARTICLES; SJOGREN SYNDROME; DIZYGOTIC TWINS; DISEASE; AUTOANTIBODIES; CONCORDANCE; SUSCEPTIBILITY AB The higher concordant occurrence of autoimmune diseases in monozygotic twins compared to dizygotic or sibling pairs supports the role for genetic susceptibility. For most conditions, however, concordance rates are considerably below 100% and lead to the estimate of the weight of genetics coined "heritability". In the group of autoimmune diseases heritability ranges between 0.008 and 1 with median values of approximately 0.60. A complementary term coined "environmentability" represents the environmental influence on individual phenotype, and can include dietary habits, chemicals, or hygienic conditions. Genorne-wide association data in complex diseases confirmed a role for the environment in disease etiology as significantly associated polymorphisms were found only in subgroups of patients and controls. Environmental links to autoimmunity range from anecdotal associations or case series to largely investigated experimental and epidemiological studies. A bibliographic analysis reveals that the number of publications dedicated to environmental factors in autoimmunity has grown on average by 7% every year since 1997. The National Institute of Environmental Health Sciences (NIEHS) convened an expert panel workshop to review the body of literature examining the role of the environment in the development of autoimmune disease and to identify conclusions, confidences, and critical knowledge gaps in this area. The results of the workshop discussion are summarized in the articles found in this issue of the Journal of Autoimmunity. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Selmi, Carlo] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. [Selmi, Carlo] Humanitas Clin & Res Ctr, I-20089 Rozzano, MI, Italy. [Lu, Qianjin] Cent S Univ, Dept Dermatol, Xiangya Hosp 2, Hunan Key Lab Med Epigen, Changsha 410011, Hunan, Peoples R China. [Humble, Michael C.] NIEHS, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. RP Selmi, C (reprint author), Humanitas Clin & Res Ctr, Via A Manzoni 56, I-20089 Rozzano, MI, Italy. EM carlo.selmi@unimi.it; qianlu5860@gmail.com; humble@niehs.nih.gov NR 47 TC 68 Z9 70 U1 0 U2 18 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD DEC PY 2012 VL 39 IS 4 BP 249 EP 252 DI 10.1016/j.jaut.2012.07.011 PG 4 WC Immunology SC Immunology GA 069VS UT WOS:000313465800001 PM 22980030 ER PT J AU Miller, FW Pollard, KM Parks, CG Germolec, DR Leung, PSC Selmi, C Humble, MC Rose, NR AF Miller, Frederick W. Pollard, K. Michael Parks, Christine G. Germolec, Dori R. Leung, Patrick S. C. Selmi, Carlo Humble, Michael C. Rose, Noel R. TI Criteria for environmentally associated autoimmune diseases SO JOURNAL OF AUTOIMMUNITY LA English DT Review DE Autoimmune disease; Environmental risk factors; Criteria ID EOSINOPHILIA-MYALGIA-SYNDROME; SYSTEMIC-LUPUS-ERYTHEMATOSUS; DRUG-INDUCED LUPUS; PROTEIN MICROARRAYS; AUTOANTIBODIES; BIOMARKERS; DISORDERS; ONSET; RISK AB Increasing evidence supports a role for the environment in the development of autoimmune diseases, as reviewed in the accompanying three papers from the National Institute of Environmental Health Sciences Expert Panel Workshop. An important unresolved issue, however, is the development of criteria for identifying autoimmune disease phenotypes for which the environment plays a causative role, herein referred to as environmentally associated autoimmune diseases. There are several different areas in which such criteria need to be developed, including: 1) identifying the necessary and sufficient data to define environmental risk factors for autoimmune diseases meeting current classification criteria; 2) establishing the existence of and criteria for new environmentally associated autoimmune disorders that do not meet current disease classification criteria; and 3) identifying in clinical practice specific environmental agents that induce autoimmune disease in individual patients. Here we discuss approaches that could be useful for developing criteria in these three areas, as well as factors that should be considered in evaluating the evidence for criteria that can distinguish individuals with such disorders from individuals without such disorders with high sensitivity and specificity. Current studies suggest that multiple lines of complementary evidence will be important and that in many cases there will be clinical, serologic, genetic, epigenetic, and/or other laboratory features that could be incorporated as criteria for environmentally associated autoimmune diseases to improve diagnosis and treatment and possibly allow for preventative strategies in the future. Published by Elsevier Ltd. C1 [Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. [Pollard, K. Michael] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Parks, Christine G.] NIEHS, Epidemiol Branch, Bethesda, MD 20892 USA. [Germolec, Dori R.] NIEHS, Natl Toxicol Program, Morrisville, NC USA. [Leung, Patrick S. C.; Selmi, Carlo] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. [Selmi, Carlo] IRCCS Ist Clin Humanitas, Autoimmun & Metab Unit, Milan, Italy. [Humble, Michael C.] NIEHS, Div Extramural Res & Training, Bethesda, MD 20892 USA. [Rose, Noel R.] Bloomberg Sch Publ Hlth, John Hopkins Ctr Autoimmune Dis Res, Baltimore, MD USA. RP Miller, FW (reprint author), NIEHS, Environm Autoimmun Grp, NIH, Clin Res Ctr, NIH 10,Room 4-2352,10 Ctr Dr,MSC 1301, Bethesda, MD 20892 USA. EM millerf@mail.nih.gov OI Miller, Frederick/0000-0003-2831-9593; Parks, Christine/0000-0002-5734-3456 FU intramural and extramural programs of the National Institute of Environmental Health Sciences, NIH FX Support was provided in part by the intramural and extramural programs of the National Institute of Environmental Health Sciences, NIH. NR 44 TC 53 Z9 54 U1 0 U2 11 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD DEC PY 2012 VL 39 IS 4 BP 253 EP 258 DI 10.1016/j.jaut.2012.05.001 PG 6 WC Immunology SC Immunology GA 069VS UT WOS:000313465800002 PM 22771005 ER PT J AU Miller, FW Alfredsson, L Costenbader, KH Kamen, DL Nelson, LM Norris, JM De Roos, AJ AF Miller, Frederick W. Alfredsson, Lars Costenbader, Karen H. Kamen, Diane L. Nelson, Lorene M. Norris, Jill M. De Roos, Anneclaire J. TI Epidemiology of environmental exposures and human autoimmune diseases: Findings from a National Institute of Environmental Health Sciences Expert Panel Workshop SO JOURNAL OF AUTOIMMUNITY LA English DT Review DE Autoimmune disease; Environmental risk factors; Biologic agents; Chemical agents; Physical factors; Research priorities ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; INFLAMMATORY-BOWEL-DISEASE; EPSTEIN-BARR-VIRUS; OCCUPATIONAL RISK-FACTORS; BETA-CELL AUTOIMMUNITY; ULTRAVIOLET-RADIATION INTENSITY; MULTIPLE-SCLEROSIS PREVALENCE; PRIMARY BILIARY-CIRRHOSIS; RHEUMATOID-ARTHRITIS; SILICA EXPOSURE AB Autoimmune diseases (AID) are a collection of many complex disorders of unknown etiology resulting in immune responses to self-antigens and are thought to result from interactions between genetic and environmental factors. Here we review the epidemiologic evidence for the role of environmental factors in the development of human AID, the conclusions that can be drawn from the existing data, critical knowledge gaps, and research needed to fill these gaps and to resolve uncertainties. We specifically summarize the state of knowledge and our levels of confidence in the role of specific agents in the development of autoimmune diseases, and we define the areas of greatest impact for future investigations. Among our consensus findings we are confident that: 1) crystalline silica exposure can contribute to the development of several AID; 2) solvent exposure can contribute to the development of systemic sclerosis; 3) smoking can contribute to the development of seropositive rheumatoid arthritis; and 4) an inverse association exists between ultraviolet radiation exposure and the risk of development of multiple sclerosis. We suggest that more studies of phenotypes, genotypes, and multiple exposures are needed. Additional knowledge gaps needing investigation include: defining important windows in the timing of exposures and latencies relating to age, developmental state, and hormonal changes; understanding dose response relationships; and elucidating mechanisms for disease development. Addressing these essential issues will require more resources to support research, particularly of rare AID, but knowledge of the risks conferred by environmental. factors in specific genetic contexts could pave the way for prevention of AID in the future. (C) 2012 Published by Elsevier Ltd. C1 [Miller, Frederick W.] NIEHS, Environm Autoimmun Grp, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. [Alfredsson, Lars] Karolinska Inst, Inst Environm Med, SE-17177 Stockholm, Sweden. [Costenbader, Karen H.] Harvard Univ, Brigham & Womens Hosp, Div Rheumatol Immunol & Allergy, Med Sch PBB B3, Boston, MA 02115 USA. [Kamen, Diane L.] Med Univ S Carolina, Div Rheumatol & Immunol, Charleston, SC 29425 USA. [Nelson, Lorene M.] Stanford Univ, Div Epidemiol, Dept Hlth Res & Policy, Sch Med, Stanford, CA 94305 USA. [Norris, Jill M.] Univ Colorado, Dept Epidemiol, Colorado Sch Publ Hlth, Aurora, CO 80045 USA. [De Roos, Anneclaire J.] Univ Washington, Dept Epidemiol, Seattle, WA 98109 USA. [De Roos, Anneclaire J.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. RP Miller, FW (reprint author), NIEHS, Environm Autoimmun Grp, NIH, Clin Res Ctr, NIH 10,Room 4-2352,10 Ctr Dr,MSC 1301, Bethesda, MD 20892 USA. EM millerf@mail.nih.gov OI Alfredsson, Lars/0000-0003-1688-6697; Miller, Frederick/0000-0003-2831-9593 FU intramural and extramural programs of the National Institute of Environmental Health Sciences, NIH FX Support was provided in part by the intramural and extramural programs of the National Institute of Environmental Health Sciences, NIH. NR 185 TC 85 Z9 85 U1 2 U2 36 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD DEC PY 2012 VL 39 IS 4 BP 259 EP 271 DI 10.1016/j.jaut.2012.05.002 PG 13 WC Immunology SC Immunology GA 069VS UT WOS:000313465800003 PM 22739348 ER PT J AU Selmi, C Leung, PSC Sherr, DH Diaz, M Nyland, JF Monestier, M Rose, NR Gershwin, ME AF Selmi, Carlo Leung, Patrick S. C. Sherr, David H. Diaz, Marilyn Nyland, Jennifer F. Monestier, Marc Rose, Noel R. Gershwin, M. Eric. TI Mechanisms of environmental influence on human autoimmunity: A national institute of environmental health sciences expert panel workshop SO JOURNAL OF AUTOIMMUNITY LA English DT Review DE Tolerance breakdown; Adjuvant; Antigen modification; Epigenetics ID ARYL-HYDROCARBON RECEPTOR; REGULATORY T-CELLS; PRIMARY BILIARY-CIRRHOSIS; GENOME-WIDE ASSOCIATION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; IMMUNE-MEDIATED DISEASES; CHINESE HAN POPULATION; DNA METHYLATION; RHEUMATOID-ARTHRITIS; B-CELLS AB The mechanisms leading to autoimmune diseases remain largely unknown despite numerous lines of experimental inquiry and epidemiological evidence. The growing number of genome-wide association studies and the largely incomplete concordance for autoimmune diseases in monozygotic twins support the role of the environment (including infectious agents and chemicals) in the breakdown of tolerance leading to autoimmunity via numerous mechanisms. The present article reviews the major theories on the mechanisms of the environmental influence on autoimmunity by addressing the different degrees of confidence that characterize our knowledge. The theories discussed herein include (i) the role of innate immunity mediated by toll-like receptors in triggering the autoimmune adaptive response characterizing the observed pathology; (ii) changes in spleen marginal zone B cells in autoantibody production with particular focus on the B10 subpopulation; (iii) Th17 cell differentiation and T regulatory cells in the aryl hydrocarbon receptor model; (iv) self antigen changes induced by chemical and infectious agents which could break tolerance by post-translational modifications and molecular mimicry; and finally (v) epigenetic changes, particularly DNA methylation, that are induced by environmental stimuli and may contribute to autoimmunity initiation. We are convinced that these working hypotheses, in most cases supported by solid evidence, should be viewed in parallel with animal models and epidemiological observations to provide a comprehensive picture of the environmental causes of autoimmune diseases. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Selmi, Carlo; Leung, Patrick S. C.; Gershwin, M. Eric.] Univ Calif Davis, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. [Selmi, Carlo] Humanitas Clin & Res Ctr, Dept Med, I-20089 Milan, Italy. [Sherr, David H.] Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02215 USA. [Diaz, Marilyn] NIEHS, NIH, Bethesda, MD USA. [Nyland, Jennifer F.] Univ S Carolina, Dept Pathol Microbiol & Immunol, Columbia, SC 29208 USA. [Monestier, Marc] Temple Univ, Dept Microbiol & Immunol, Sch Med, Philadelphia, PA 19122 USA. [Rose, Noel R.] Bloomberg Sch Publ Hlth, John Hopkins Ctr Autoimmune Dis Res, Baltimore, MD USA. RP Selmi, C (reprint author), Humanitas Clin & Res Ctr, Dept Med, Via A Manzoni 56, I-20089 Milan, Italy. EM carlo.selmi@unimi.it OI Sherr, David/0000-0003-3353-0553 NR 139 TC 74 Z9 76 U1 3 U2 35 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD DEC PY 2012 VL 39 IS 4 BP 272 EP 284 DI 10.1016/j.jaut.2012.05.007 PG 13 WC Immunology SC Immunology GA 069VS UT WOS:000313465800004 PM 22749494 ER PT J AU Germolec, D Kono, DH Pfau, JC Pollard, KM AF Germolec, Dori Kono, Dwight H. Pfau, Jean C. Pollard, K. Michael TI Animal models used to examine the role of the environment in the development of autoimmune disease: Findings from an NIEHS Expert Panel Workshop SO JOURNAL OF AUTOIMMUNITY LA English DT Review DE Autoimmunity; Animal model; Environmental factors; Chemicals; Biological ID EOSINOPHILIA-MYALGIA-SYNDROME; TOXIC OIL SYNDROME; INDUCED DEMYELINATING DISEASE; GENETICALLY SUSCEPTIBLE MICE; PRISTANE-INDUCED ARTHRITIS; GOLD-INDUCED AUTOIMMUNITY; IMMUNE-COMPLEX DEPOSITS; CHAGAS HEART-DISEASE; ZEALAND MIXED MICE; DRUG-INDUCED LUPUS AB Autoimmunity is thought to result from a combination of genetics, environmental triggers, and stochastic events. Environmental factors, such as chemicals, drugs or infectious agents, have been implicated in the expression of autoimmune disease, yet human studies are extremely limited in their ability to test isolated exposures to demonstrate causation or to assess pathogenic mechanisms. In this review we examine the research literature on the ability of chemical, physical and biological agents to induce and/or exacerbate autoimmunity in a variety of animal models. There is no single animal model capable of mimicking the features of human autoimmune disease, particularly as related to environmental exposures. An objective, therefore, was to assess the types of information that can be gleaned from the use of animal models, and how well that information can be used to translate back to human health. Our review notes the importance of genetic background to the types and severity of the autoimmune response following exposure to environmental factors, and emphasizes literature where animal model studies have led to increased confidence about environmental factors that affect expression of autoimmunity. A high level of confidence was reached if there were multiple studies from different laboratories confirming the same findings. Examples include mercury, pristane, and infection with Streptococcus or Coxsackie B virus. A second level of consensus identified those exposures likely to influence autoimmunity but requiring further confirmation. To fit into this category, there needed to be significant supporting data, perhaps by multiple studies from a single laboratory, or repetition of some but not all findings in multiple laboratories. Examples include silica, gold, TCE, TCDD, UV radiation, and Theiler's murine encephalomyelitis virus. With the caveat that researchers must keep in mind the limitations and appropriate applications of the various approaches, animal models are shown to be extremely valuable tools for studying the induction or exacerbation of autoimmunity by environmental conditions and exposures. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Germolec, Dori] NIEHS, Natl Toxicol Program, Morrisville, NC 27560 USA. [Kono, Dwight H.] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA. [Pfau, Jean C.] Idaho State Univ, Dept Biol Sci, Pocatello, ID 83209 USA. [Pollard, K. Michael] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. RP Pfau, JC (reprint author), Idaho State Univ, Dept Biol Sci, 921 S 8th Ave, Pocatello, ID 83209 USA. EM pfaujean@isu.edu FU NIEHS; American Autoimmune Related Diseases Association, East Detroit, Michigan, USA FX This review is a condensed version of a white paper prepared following the National Institute of Environmental Health Sciences (NIEHS) Expert Panel Workshop to Examine the Role of the Environment in the Development of Autoimmune Disease held in Durham, North Carolina, USA on September 7-8, 2010. The more detailed and wider ranging workshop white paper, including agents that suppress autoimmunity, is available from the corresponding author. The Authors gratefully acknowledge the contributions of the following individuals in compiling the literature review: Ryan Marcum (Idaho State University), Sarah Briwa (Siena College), Sang-Hyun Kim PhD (NIEHS), David A. Lawrence PhD (Wadsworth Center), and Michael McCabe Jr., PhD (Robson Forensic, Inc). Support was provided by the NIEHS, and the American Autoimmune Related Diseases Association, East Detroit, Michigan, USA. NR 121 TC 46 Z9 46 U1 2 U2 19 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD DEC PY 2012 VL 39 IS 4 BP 285 EP 293 DI 10.1016/j.jaut.2012.05.020 PG 9 WC Immunology SC Immunology GA 069VS UT WOS:000313465800005 PM 22748431 ER PT J AU Moutsopoulos, NM Kling, HM Angelov, N Jin, WW Palmer, RJ Nares, S Osorio, M Wahl, SM AF Moutsopoulos, Niki M. Kling, Heather M. Angelov, Nikola Jin, Wenwen Palmer, Robert J. Nares, Salvador Osorio, Manuel Wahl, Sharon M. TI Porphyromonas gingivalis promotes Th17 inducing pathways in chronic periodontitis SO JOURNAL OF AUTOIMMUNITY LA English DT Article DE Periodontitis; Th17; P. gingivalis; Host-pathogen interactions; Oral; Mucosal inflammation; Immune-mediated bone loss ID HELPER T-CELLS; OSTEOPROTEGERIN LIGAND; ARTHRITIS PATIENTS; BONE DESTRUCTION; IMMUNE-SYSTEM; RESPONSES; DISEASE; INTERLEUKIN-17; PATHOGENESIS; ACTIVATION AB In periodontitis, a common chronic inflammatory condition, gram-negative-rich bacterial biofilms trigger, in susceptible individuals, perpetuating inflammation that results in extensive tissue damage of tooth supporting structures. To delineate immune cell-dependent menchanisms whereby bacterial challenge drives persistent destructive inflammation in periodontitis and other inflammatory diseases, we studied involved tissues ex vivo and investigated host cell responses to the periodontal pathogen Porphyromonas gingivalis, in vitro. Diseased lesions were populated by abundant Th17 cells, linked to infection, chronic inflammation/autoimmunity and tissue pathology. In vitro, P. gingivalis, particularly the more virulent strain W83, stimulated myeloid antigen presenting cells (APC) to drive Th17 polarization. Supernatants from myeloid APC exposed to P. gingivalis were capable of enhancing Th17 but not Th1 polarization. P. gingivalis.favored the generation of Th17 responses by stimulating the production of Th17 related cytokines IL-1 beta, IL-6 and IL-23, but not Th1 related IL-12. By inducing NF kappa B activation, P. gingivalis promoted IL-1 beta, IL-6 and IL-12p40 production, but not IRF3 phosphorylation, connected to generation of the IL-12p35 chain, ultimately restricting formation of the intact IL-12 molecule. Promotion of Th17 lineage responses was also aided by P. gingivalis proteases, which appeared to differentially degrade pivotal cytokines. In this regard, IL-12 was largely degraded by P. gingivalis, whereas IL-1 beta was more resistant to proteolysis. Our data unveil multiple pathways by which P. gingivalis may orchestrate chronic inflammation, providing insights into interventional strategies. Published by Elsevier Ltd. C1 [Moutsopoulos, Niki M.; Kling, Heather M.; Jin, Wenwen; Palmer, Robert J.; Nares, Salvador; Wahl, Sharon M.] NIDCR, NIH, Bethesda, MD 20892 USA. [Angelov, Nikola] Loma Linda Univ, Sch Dent, Dept Periodont, Loma Linda, CA 92350 USA. [Osorio, Manuel] US FDA, Div Bacterial Parasit & Allergen Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Moutsopoulos, NM (reprint author), NIDCR, NIH, Bldg 30,Room 327,30 Convent Dr,MSC4352, Bethesda, MD 20892 USA. EM nmoutsopoulos@dir.nidr.nih.gov FU NIH, National Institute of Dental and Craniofacial Research FX The authors are grateful to Calley Grace for editorial assistance and Teresa Wild and Sarala Sarah for technical assistance. This research was supported in part by the Intramural Research Program of the NIH, National Institute of Dental and Craniofacial Research. NR 45 TC 46 Z9 51 U1 1 U2 12 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0896-8411 J9 J AUTOIMMUN JI J. Autoimmun. PD DEC PY 2012 VL 39 IS 4 BP 294 EP 303 DI 10.1016/j.jaut.2012.03.003 PG 10 WC Immunology SC Immunology GA 069VS UT WOS:000313465800006 PM 22560973 ER PT J AU Hall, RM Sun, T Ferrari, M AF Hall, Rebecca M. Sun, Tong Ferrari, Mauro TI A Portrait of Nanomedicine and Its Bioethical Implications SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID MESOPOROUS SILICON PARTICLES; DELIVERY-SYSTEM; DRUG-DELIVERY; CANCER; NANOTECHNOLOGY; NANOPARTICLES; NANOMATERIALS; CHALLENGES; THERAPY; PROTEIN AB This review addresses the current and future potential of nanomedicine, and its ethical considerations within the comprehensive framework of the four dimensions of medical ethics: Beneficence, Non-Maleficence, Respect, and Justice. From this perspective, the ethical considerations for nanomedicine are not novel, but have been addressed by precedents throughout the history of medicine. While these ethical challenges are not unique to nanomedicine, some require additional consideration, given the envisioned pervasive impact of nanomedicine on society. C1 [Hall, Rebecca M.; Sun, Tong; Ferrari, Mauro] Methodist Hosp, Res Inst, Houston, TX USA. [Hall, Rebecca M.] Baylor Coll Med, Houston, TX 77030 USA. [Sun, Tong] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Sun, Tong] Univ Texas Hlth Sci Ctr, Dept Nanomed & Biomed Engn, Houston, TX USA. [Ferrari, Mauro] Alliance NanoHlth, Houston, TX USA. [Ferrari, Mauro] NCI, Bethesda, MD 20892 USA. RP Hall, RM (reprint author), Methodist Hosp, Res Inst, Houston, TX USA. OI Hall, Rebecca/0000-0002-5460-0090 FU Methodist Hospital Research Institute (Ferrari, Hall, Sun); Earnest Cockrell Jr. Distinguished Endowed Chair (Ferrari); National Institutes of Health (NIH), National Human Genome Research Institute (NHGRI) American Recovery & Reinvestment Act (ARRA) Challenge [1-RC1-HG005338-01] FX Work on this paper was supported by The Methodist Hospital Research Institute (Ferrari, Hall, Sun) and the Earnest Cockrell Jr. Distinguished Endowed Chair (Ferrari), and partially funded by the National Institutes of Health (NIH), National Human Genome Research Institute (NHGRI) American Recovery & Reinvestment Act (ARRA) Challenge grant # 1-RC1-HG005338-01 on "Nanodiagnostics and Nanotherapeutics: Building Research Ethics and Oversight" (Wolf, PI; McCullough, Hall, Kahn, Co-Is). The views expressed are those of the authors and do not necessarily reflect the views of The Methodist Hospital System, NIH, or NHGRI. NR 81 TC 4 Z9 4 U1 2 U2 32 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1073-1105 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD WIN PY 2012 VL 40 IS 4 SI SI BP 763 EP 779 DI 10.1111/j.1748-720X.2012.00705.x PG 17 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 065AW UT WOS:000313120000004 PM 23289679 ER PT J AU Resnik, DB AF Resnik, David B. TI Responsible Conduct in Nanomedicine Research: Environmental Concerns Beyond the Common Rule SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article AB Nanomedicine research raises ethical concerns beyond those covered by the Common Rule. Investigators and research institutions should comply with environmental and occupational health laws protect research staff and the environment. Though the IRB should concentrate on risks to human research participants, it should also consider risks to identifiable third parties. Investigators should also address risks to identifiable third parties. Professional and governmental organizations should deal with the long-term social, ethical, and environmental consequences of nanomedicine. C1 NIEHS, NIH, Bethesda, MD 20892 USA. RP Resnik, DB (reprint author), NIEHS, NIH, Bethesda, MD 20892 USA. FU National Institute of Health (NIH), National Human Genome Research Institute (NHGRI) American Recovery & Reinvestment Act (AARA) Challenge grant [1-RC1-HG005338-01] FX This article is the work product of an employee or group of employees of the National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH). However, the statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions, or conclusions of NIEHS, NIH, or the United States government. Preparation of this article was supported by National Institute of Health (NIH), National Human Genome Research Institute (NHGRI) American Recovery & Reinvestment Act (AARA) Challenge grant # 1-RC1-HG005338-01 on "Nanodiagnostics and Nanotherapeutics: Building Research Ethics and Oversight" (S. M. Wolf, PI; J. McCullough, R. Hall, J. P. Kahn, Co-Is). The contents of this article are solely the responsibility of the author and do not necessarily represent the views of NIH or NHGRI. I am grateful to Bruce Androphy for helpful comments. NR 26 TC 2 Z9 2 U1 0 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1073-1105 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD WIN PY 2012 VL 40 IS 4 SI SI BP 848 EP 855 DI 10.1111/j.1748-720X.2012.00713.x PG 8 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 065AW UT WOS:000313120000012 PM 23289687 ER PT J AU Dresser, R AF Dresser, Rebecca TI Alive and Well: The Research Imperative SO JOURNAL OF LAW MEDICINE & ETHICS LA English DT Article ID STEM-CELL RESEARCH; OBLIGATION; DATABASE; ETHICS; TRIALS AB Many features of the existing biomedical research enterprise rest on questionable judgments about the value of research. Policymakers and research ethicists make assumptions about research value that aren't necessarily warranted. A more balanced view of research value could contribute to more defensible decisions about research policy and practice. C1 [Dresser, Rebecca] Washington Univ, St Louis, MO 63130 USA. RP Dresser, R (reprint author), Natl Inst Hlth, Recombinant DNA Advisory Comm, Bethesda, MD 20892 USA. NR 31 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1073-1105 J9 J LAW MED ETHICS JI J. Law Med. Ethics PD WIN PY 2012 VL 40 IS 4 SI SI BP 915 EP 921 DI 10.1111/j.1748-720X.2012.00720.x PG 7 WC Ethics; Law; Medical Ethics; Medicine, Legal SC Social Sciences - Other Topics; Government & Law; Medical Ethics; Legal Medicine GA 065AW UT WOS:000313120000019 PM 23289694 ER PT J AU Eto, M Ohkawara, K Sasai, H Tsujimoto, T So, R Matsuo, T Ohkubo, H Tanaka, K AF Eto, Miki Ohkawara, Kazunori Sasai, Hiroyuki Tsujimoto, Takehiko So, Rina Matsuo, Tomoaki Ohkubo, Hiroyuki Tanaka, Kiyoji TI Efficiency of a Free-Living Physical Activity Promotion Program Following Diet Modification for Fat Loss in Japanese Obese Men SO JOURNAL OF NUTRITIONAL SCIENCE AND VITAMINOLOGY LA English DT Article DE physical activity; fat loss; obesity; energy compensation ID INDUCED WEIGHT-LOSS; ENERGY-EXPENDITURE; BODY-COMPOSITION; EXERCISE; TRIAL; WOMEN; COMPENSATION; INTERVENTION; RESTRICTION; MAINTENANCE AB The aim of the current study was to examine the efficiency of a free-living physical activity promotion (PAP) program following a diet modification program for fat loss. Fifty obese men, aged 51.4 +/- 7.0 y, received a 6-mo regimen consisting of 2 phases. Weekly 90-min free-living PAP sessions were provided for 3 mo immediately after a 3-mo diet modification phase. Fat mass (FM) was measured at baseline and at months 3 and 6 using dual energy X-ray absorptiometry. The time spent in moderate-vigorous physical activity (MVPA) was monitored by a validated single-axis accelerometer. The total energy intake of all participants was assessed at baseline and during weeks 9 and 10 of both the diet modification and PAP programs. The change (Delta) in FM was -1.4 +/- 1.9 kg (p<0.05) during the PAP program after the diet modification program (-4.3 +/- 2.9 kg, p<0.01). Although there was no significant relationship between Delta FM and Delta MVPA during the PAP phase (p=0.11), MVPA was significantly increased during the PAP phase (+76.0 +/- 146.5 min/wk, p<0.01). However, a significant correlation was observed between energy intake/weight and MVPA during the PAP program (r=0.39). Our results suggest that the magnitude of expected FM loss induced by an increase in PA may be suppressed as a result of increased energy intake, even during a PAP program after a diet modification program. C1 [Eto, Miki; Tsujimoto, Takehiko; So, Rina; Ohkubo, Hiroyuki] Univ Tsukuba, Grad Sch Comprehens Human Sci, Doctoral Program Sports Med, Tsukuba, Ibaraki 3058574, Japan. [Ohkawara, Kazunori] Univ Electrocommun, Fac Informat & Engn, Chofu, Tokyo 1828585, Japan. [Ohkawara, Kazunori] Natl Inst Hlth & Nutr, Dept Nutr Sci, Shinjuku Ku, Tokyo 1628636, Japan. [Sasai, Hiroyuki] NIH, Bethesda, MD 20892 USA. [Sasai, Hiroyuki] NIH, JSPS Res Fellow Biomed & Behav Res, Chiyoda Ku, Tokyo 1020082, Japan. [Matsuo, Tomoaki] Japan Aerosp Explorat Agcy, Tsukuba, Ibaraki 3058505, Japan. [Tanaka, Kiyoji] Univ Tsukuba, Fac Hlth & Sport Sci, Tsukuba, Ibaraki 3058574, Japan. RP Eto, M (reprint author), Univ Tsukuba, Grad Sch Comprehens Human Sci, Doctoral Program Sports Med, 1-1-1 Tennodai, Tsukuba, Ibaraki 3058574, Japan. EM eto@stat.taiiku.tsukuba.ac.jp RI Biguzzi, Felipe/E-4724-2015 FU Japan Dairy Association; Japan Society for the Promotion of Science [19200047] FX This work was supported in part by the Japan Dairy Association (2009-2010), and the Japan Society for the Promotion of Science (Grant-in-aid for Scientific Research [A] #19200047). NR 38 TC 3 Z9 3 U1 1 U2 3 PU CENTER ACADEMIC PUBL JAPAN PI TOKYO PA 2-4-16 YAYOI, BUNKYO-KU, TOKYO, 113-0032, JAPAN SN 0301-4800 J9 J NUTR SCI VITAMINOL JI J. Nutr. Sci. Vitaminol. PD DEC PY 2012 VL 58 IS 6 BP 384 EP 392 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 069XG UT WOS:000313469800002 PM 23419396 ER PT J AU Danaher, MR Roy, A Chen, Z Mumford, SL Schisterman, EF AF Danaher, Michelle R. Roy, Anindya Chen, Zhen Mumford, Sunni L. Schisterman, Enrique F. TI Minkowski-Weyl Priors for Models With Parameter Constraints: An Analysis of the BioCycle Study SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Bayesian inference; Extreme directions; Extreme points; Parameter restriction; Polyhedral region ID EARLY MENOPAUSAL TRANSITION; LINEAR MIXED MODELS; BAYESIAN-ANALYSIS; MENSTRUAL-CYCLE; REPRODUCTIVE HORMONES; WOMENS HEALTH; BODY-SIZE; SELECTION; INFERENCE; ETHNICITY AB We propose a general framework for performing full Bayesian analysis under linear inequality parameter constraints. The proposal is motivated by the BioCycle Study, a large cohort study of hormone levels of healthy women where certain well-established linear inequality constraints on the log-hormone levels should be accounted for in the statistical inferential procedure. Based on the Minkowski-Weyl decomposition of polyhedral regions, we propose a class of priors that are fully supported on the parameter space with linear inequality constraints, and we fit a Bayesian linear mixed model to the BioCycle data using such a prior. We-observe positive associations between estrogen and progesterone levels and F-2-isoprostanes, a marker for oxidative stress. These findings are of particular interest to reproductive epidemiologists. C1 [Danaher, Michelle R.; Chen, Zhen; Mumford, Sunni L.; Schisterman, Enrique F.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD 20852 USA. [Roy, Anindya] Univ Maryland Baltimore Cty, Dept Math & Stat, Baltimore, MD 21250 USA. RP Danaher, MR (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD 20852 USA. EM danahermr@mail.nih.gov; anindya@umbc.edu; chenzhe@mail.nih.gov; mumfords@mail.nih.gov; schistee@mail.nih.gov OI Schisterman, Enrique/0000-0003-3757-641X FU Long-Range Research Initiative of the American Chemistry Council; Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health FX Michelle R. Danaher is a Predoctoral Fellow, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD 20852 (E-mail: danahermr@mail.nih.gov). Anindya Roy is a Professor, Department of Mathematics and Statistics, University of Maryland Baltimore County, Baltimore, MD 21250 (E-mail: anindya@umbc.edu). Zhen Chen is an Investigator (E-mail: chenzhe@mail.nih.gov), Sunni L. Mumford is a Research Fellow (E-mail: mumfords@mail.nih.gov), and Enrique F. Schisterman is a Chief and Senior Investigator, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD 20852 (E-mail: schistee@mail.nih.gov). This research was partially supported by the Long-Range Research Initiative of the American Chemistry Council and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. NR 41 TC 1 Z9 1 U1 0 U2 5 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD DEC PY 2012 VL 107 IS 500 BP 1395 EP 1409 DI 10.1080/01621459.2012.712414 PG 15 WC Statistics & Probability SC Mathematics GA 068VP UT WOS:000313394600011 PM 27099406 ER PT J AU Han, SS Rosenberg, PS Chatterjee, N AF Han, Summer S. Rosenberg, Philip S. Chatterjee, Nilanjan TI Testing for Gene-Environment and Gene-Gene Interactions Under Monotonicity Constraints SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Gene-environment interaction; Gene-gene interaction; Isotonic regression; Constrained likelihood ratio test; Order restrictions; Genome-wide association study (GWAS) ID GENOME-WIDE ASSOCIATION; LUNG-CANCER; INDEPENDENT VARIABLES; ORDERED ALTERNATIVES; SUSCEPTIBILITY LOCUS; BLADDER-CANCER; MODELS; HOMOGENEITY; REGRESSION; ALGORITHM AB Recent genome-wide association studies (GWASs) designed to detect the main effects of genetic markers have had considerable success with many findings validated by replication studies. However, relatively few findings of gene-gene or gene-environment interactions have been successfully reproduced. Besides the main issues associated with insufficient sample size in current studies, a complication is that interactions that rank high based on p-values often correspond to extreme forms of joint effects that are biologically less plausible. To reduce false positives and to increase power, we develop various gene-environment/gene-gene tests based on biologically more plausible constraints using bivariate isotonic regressions for case-control data. We extend our method to exploit gene-environment or gene-gene independence information, integrating the approach proposed by Chatterjee and Carroll. We propose appropriate nonparametric and parametric permutation procedures for evaluating the significance of the tests. Simulation's show that our method gains power over traditional unconstrained methods by reducing the sizes of alternative parameter spaces. We apply our method to several real-data examples, including an analysis of bladder cancer data to detect interactions between the NAT2 gene and smoking. We also show that the-proposed method is computationally feasible for large-scale problems by applying it to the National Cancer Institute (NCI) lung cancer GWAS data. C1 [Han, Summer S.; Rosenberg, Philip S.; Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Han, SS (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. EM summerhan@nih.gov; rosenbep@exchange.nih.gov; chattern@mail.nih.gov FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX Summer S. Han is a Research Fellow (E-mail: summer.han@nih.gov) and Philip S. Rosenberg (E-mail: rosenbep@exchange.nih.gov), and Nilanjan Chatterjee (E-mail: chattern@mail.nih.gov) are Senior Investigators, Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20852. This research was supported-by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. The findings in this article reflect the viewpoints of the authors and do not necessarily reflect the views of the Department of Health and Human Services. NR 33 TC 4 Z9 4 U1 0 U2 19 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD DEC PY 2012 VL 107 IS 500 BP 1441 EP 1452 DI 10.1080/01621459.2012.726892 PG 12 WC Statistics & Probability SC Mathematics GA 068VP UT WOS:000313394600014 ER PT J AU Oner, P Oner, O Cop, E Munir, KM AF Oner, Pinar Oner, Ozgur Cop, Esra Munir, Kerim M. TI Effect of Ferritin on Short-Term Treatment Response in Attention Deficit Hyperactivity Disorder SO KLINIK PSIKOFARMAKOLOJI BULTENI-BULLETIN OF CLINICAL PSYCHOPHARMACOLOGY LA English DT Article DE Attention deficit hyperactivity disorder; ferritin; pharmacologic therapy; methylphenidate ID DEFICIT/HYPERACTIVITY DISORDER; IRON-DEFICIENCY; MULTIMODAL-TREATMENT; CHILDREN; BRAIN; ADHD; MODERATORS; SUBTYPES; SCHOOL AB Effect of ferritin on short-term treatment response in attention deficit hyperactivity disorder Objectives: Several studies have shown that iron deficiency and ferritin levels are associated with parent and teacher Attention Deficit Hyperactivity Disorder (ADHD) ratings. Although there are conflicting results, it has also been reported that iron supplementation may help to decrease ADHD symptoms. When all these previous studies are taken into account, it is clear that a large study investigating the effects of iron deficiency and ferritin levels on routine pharmacological treatment of ADHD with stimulants would be helpful to elucidate this treatment from a clinical point of view. Methods: A total of 345 subjects with combined or predominantly hyperactive-impulsive (PHI) subtypes of ADHD were included. All diagnoses were based on the DSM-IV criteria and ascertained by direct interviews conducted by the authors, who are experienced child psychiatrists certified in the use of the Schedule for Affective Disorders and Schizophrenia for School-Age Children - Present and Lifetime Version (K-SADS-PL) semi-structured interview. The two treatment response criteria were: 1) 25% or more decrease in pre-treatment Conners Parent Rating Scale (CPRS) and Conners Teacher Rating Scale (CTRS) Hyperactivity (HA) and Total Problems scores; 2) CPRS and CTRS HA scores lower than the cut-off point ("very improved"). Results: A total of 255 (73.9%) patients were on OROS-methylphenidate (OROS-MPH) and 90 (26.1%) were on immediate release methylphenidate (IR-MPH). The mean +/- sd of OROS-MPH and IR-MPH doses were 28.8 +/- 8.1 and 20.9 +/- 7.1 mg, respectively. More than half (52.5%) of the subjects were previously drug-naive at treatment inception. Two hundred and seventy eight (80.6%) subjects had combined subtype ADHD and the remainder had predominantly hyperactive-impulsive subtype. Only 60 (17.4%) of the subjects had no comorbid disorders, while 38.3% had one comorbid disorder, 32.8% had two comorbid disorders, and 11.6% had three or more comorbid disorders. The most frequent comorbidity was Oppositional Defiant Disorder/Conduct Disorder (ODD/CD, 51.6%), followed by Learning Disabilities (LD, 35.4%) and Anxiety Disorders (AD, 15.9%). Logistic regression analysis showed that subjects with comorbid ODD/CD and LD were less likely to respond to treatment. Ferritin levels and iron deficiency were not associated significantly with outcomes. Conclusions: In a large sample of subjects with combined or predominantly hyperactive-impulsive subtypes of ADHD, after controlling for several factors, we found that neither iron deficiency (ferritin <12 ng/ml) nor ferritin levels were associated with less favorable short-term treatment outcomes with stimulants. Subjects with comorbid ODD/CD and LD were less likely to have a 25% or more decrease in CTRS Total score. The presence of ODD/CD was also a negative predictor of treatment response in terms of CPRS Total and HA scores. The lack of a negative treatment response in ADHD subjects with iron deficiency and lack of a negative association with ferritin levels suggest that the relationship between iron metabolism and ADHD, a highly heterogeneous disorder, may be more complicated than previously believed. C1 [Oner, Pinar; Oner, Ozgur; Cop, Esra] Dr Sami Ulus Childrens Hosp, Dept Child & Adolescent Psychiat, Ankara, Turkey. [Oner, Pinar; Oner, Ozgur; Munir, Kerim M.] Childrens Hosp, Fogarty Int Ctr, Mental Hlth & Dev Disabil Program, Boston, MA 02115 USA. [Munir, Kerim M.] Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Oner, P (reprint author), Yenimahalle Devlet Hastanesi, Child Psychiat Dept, Dr Sami Ulus Childrens Hosp, Ankara, Turkey. EM pinaryoner@yahoo.com RI Munir, Kerim/D-6910-2015 OI Munir, Kerim/0000-0002-2404-1806 NR 29 TC 0 Z9 0 U1 1 U2 11 PU KURE ILETISIM GRUBU A S PI ISTANBUL PA SIRACEVIZLER CAD 43/3 SISLI, ISTANBUL, 34381, TURKEY SN 1017-7833 J9 KLIN PSIKOFARMAKOL B JI Klin. Psikofarmakol. Bul. PD DEC PY 2012 VL 22 IS 4 BP 325 EP 331 DI 10.5455/bcp.20120403015900 PG 7 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 069TU UT WOS:000313460800006 ER PT J AU Kim, TY Wang, D Kim, AK Lau, E Lin, AJ Liem, DA Zhang, J Zong, NC Lam, MPY Ping, PP AF Kim, Tae-Young Wang, Ding Kim, Allen K. Lau, Edward Lin, Amanda J. Liem, David A. Zhang, Jun Zong, Nobel C. Lam, Maggie P. Y. Ping, Peipei TI Metabolic Labeling Reveals Proteome Dynamics of Mouse Mitochondria SO MOLECULAR & CELLULAR PROTEOMICS LA English DT Article ID IN-VIVO; HEAVY-WATER; CARDIAC MITOCHONDRIA; MASS-SPECTROMETRY; SKELETAL-MUSCLE; AMINO-ACIDS; TURNOVER; (H2O)-H-2; PROTEINS; STABILITY AB Mitochondrial dysfunction is associated with many human diseases. Mitochondrial damage is exacerbated by inadequate protein quality control and often further contributes to pathogenesis. The maintenance of mitochondrial functions requires a delicate balance of continuous protein synthesis and degradation, i.e. protein turnover. To understand mitochondrial protein dynamics in vivo, we designed a metabolic heavy water ((H2O)-H-2) labeling strategy customized to examine individual protein turnover in the mitochondria in a systematic fashion. Mice were fed with (H2O)-H-2 at a minimal level (<5% body water) without physiological impacts. Mitochondrial proteins were analyzed from 9 mice at each of the 13 time points between 0 and 90 days (d) of labeling. A novel multiparameter fitting approach computationally determined the normalized peak areas of peptide mass isotopomers at initial and steady-state time points and permitted the protein half-life to be determined without plateau-level 2H incorporation. We characterized the turnover rates of 458 proteins in mouse cardiac and hepatic mitochondria and found median turnover rates of 0.0402 d(-1) and 0.163 d(-1), respectively, corresponding to median half-lives of 17.2 d and 4.26 d. Mitochondria in the heart and those in the liver exhibited distinct turnover kinetics, with limited synchronization within functional clusters. We observed considerable interprotein differences in turnover rates in both organs, with half-lives spanning from hours to months (similar to 60 d). Our proteomics platform demonstrates the first large-scale analysis of mitochondrial protein turnover rates in vivo, with potential applications in translational research. Molecular & Cellular Proteomics 11: 10.1074/mcp.M012.021162, 1586-1594, 2012. C1 [Kim, Tae-Young; Wang, Ding; Kim, Allen K.; Lau, Edward; Lin, Amanda J.; Liem, David A.; Zhang, Jun; Zong, Nobel C.; Lam, Maggie P. Y.; Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, Dept Physiol, Los Angeles, CA 90095 USA. [Kim, Tae-Young; Wang, Ding; Kim, Allen K.; Lau, Edward; Lin, Amanda J.; Liem, David A.; Zhang, Jun; Zong, Nobel C.; Lam, Maggie P. Y.; Ping, Peipei] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Los Angeles, CA 90095 USA. RP Ping, PP (reprint author), Univ Calif Los Angeles, Sch Med, NHLBI Prote Ctr, Dept Physiol, Los Angeles, CA 90095 USA. EM pping@mednet.ucla.edu OI Wang, Ding/0000-0001-8236-8551; Ping, Peipei/0000-0003-3583-3881 FU National Institutes of Health [NIH-R37-63901, NHLBI-HHSN-268201000035C]; AHA predoctoral fellowship award [12PRE11610024] FX This study was supported in part by National Institutes of Health awards (NIH-R37-63901 and NHLBI-HHSN-268201000035C) to Dr. Peipei Ping and by the AHA predoctoral fellowship award (12PRE11610024) to Edward Lau. NR 29 TC 65 Z9 66 U1 0 U2 13 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 1535-9476 J9 MOL CELL PROTEOMICS JI Mol. Cell. Proteomics PD DEC PY 2012 VL 11 IS 12 SI SI BP 1586 EP 1594 DI 10.1074/mcp.M112.021162 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 071AH UT WOS:000313557000007 PM 22915825 ER PT J AU Yoon, GA Yeum, KJ Cho, YS Chen, CYO Tang, GW Blumberg, JB Russell, RM Yoon, S Lee-Kim, YC AF Yoon, Gun-Ae Yeum, Kyung-Jin Cho, Yoon-Suk Chen, C-Y. Oliver Tang, Guangwen Blumberg, Jeffrey B. Russell, Robert M. Yoon, Sun Lee-Kim, Yang Cha TI Carotenoids and total phenolic contents in plant foods commonly consumed in Korea SO NUTRITION RESEARCH AND PRACTICE LA English DT Review DE Phytochemicals; carotenoids; total phenolics; plant foods in Korea ID ANTI PROLIFERATIVE ACTIVITIES; CORONARY-HEART-DISEASE; RANDOMIZED CONTROLLED-TRIALS; RETINOL EFFICACY TRIAL; GREEN TEA CONSUMPTION; BETA-CAROTENE; CARDIOVASCULAR-DISEASE; ANTIOXIDANT ACTIVITY; LUNG-CANCER; VITAMIN-E AB Phytochemicals are reported to provide various biological functions leading to the promotion of health as well as the reduced risk of chronic diseases. Fat-soluble plant pigments, carotenoids, are extensively studied micronutrient phytochemicals for their potential health benefits. It is noteworthy that specific carotenoids may be responsible for different protective effects against certain diseases. In addition, each carotenoid can be obtained from different types of plant foods. Considering the fact that the phytochemical content in foods can vary according to, but not limited to, the varieties and culture conditions, it is important to establish a database of phytochemicals in locally produced plant foods. Currently, information on individual carotenoid content in plant foods commonly consumed in Korea is lacking. As the first step to support the production and consumption of sustainable local plant foods, carotenoids and total phenolic contents of plant foods commonly consumed in Korea are presented and their potential biological functions are discussed in this review. C1 [Yoon, Gun-Ae] Dong Eui Univ, Dept Food & Nutr, Coll Human Ecol, Pusan 614714, South Korea. [Yeum, Kyung-Jin; Chen, C-Y. Oliver; Tang, Guangwen; Blumberg, Jeffrey B.] Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Cho, Yoon-Suk] Florida Coastal Sch Law, Jacksonville, FL USA. [Russell, Robert M.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Yoon, Sun; Lee-Kim, Yang Cha] Yonsei Univ, Dept Food & Nutr, Brain Korea Project 21, Coll Human Ecol, Seoul 120749, South Korea. RP Yeum, KJ (reprint author), Tufts Univ, Jean Mayer USDA Human Nutr Res Ctr Aging, Boston, MA 02111 USA. EM kyungjin.yeum@tufts.edu FU Rural Development Administration, Republic of Korea [PJ008755]; U.S. Department of Agriculture [58-1950-7-707] FX This research has been supported in part by Cooperative Research Program for Agriculture Science & Technology Development (Project No. PJ008755) Rural Development Administration, Republic of Korea and U.S. Department of Agriculture, under Agreement 58-1950-7-707. The contents of this publication do not necessarily reflect the views or policies of the U.S. Department of Agriculture, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 102 TC 3 Z9 5 U1 3 U2 17 PU KOREAN NUTRITION SOC PI SEOUL PA 804 KST CTR, 635-4 YEOGSAM-SONG KANGNAM-KU, SEOUL, 135-703, SOUTH KOREA SN 1976-1457 J9 NUTR RES PRACT JI Nutr. Res. Pract. PD DEC PY 2012 VL 6 IS 6 BP 481 EP 490 DI 10.4162/nrp.2012.6.6.481 PG 10 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 069ZF UT WOS:000313474900001 PM 23346297 ER PT J AU Wallen, GR Middleton, KR Miller-Davis, C Tataw-Ayuketah, G Todaro, A Rivera-Goba, M Mittleman, BB AF Wallen, Gwenyth R. Middleton, Kimberly R. Miller-Davis, Claiborne Tataw-Ayuketah, Gladys Todaro, Alyssa Rivera-Goba, Migdalia Mittleman, Barbara B. TI Rheumatic Disease Patients, Community Leaders, and Health Behavior Researchers: Partners in Research SO PROGRESS IN COMMUNITY HEALTH PARTNERSHIPS-RESEARCH EDUCATION AND ACTION LA English DT Letter C1 [Wallen, Gwenyth R.; Middleton, Kimberly R.; Miller-Davis, Claiborne; Tataw-Ayuketah, Gladys; Todaro, Alyssa; Rivera-Goba, Migdalia; Mittleman, Barbara B.] NIH, Bethesda, MD 20892 USA. RP Wallen, GR (reprint author), NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1557-0541 J9 PROG COMM HLTH PARTN JI Prog. Community Health Partnersh. PD WIN PY 2012 VL 6 IS 4 BP 403 EP 404 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 068ND UT WOS:000313372500002 ER PT J AU Wallen, GR Middleton, KR Miller-Davis, C Tataw-Ayuketah, G Todaro, A Rivera-Goba, M Mittleman, BB AF Wallen, Gwenyth R. Middleton, Kimberly R. Miller-Davis, Claiborne Tataw-Ayuketah, Gladys Todaro, Alyssa Rivera-Goba, Migdalia Mittleman, Barbara B. TI Patients' and Community Leaders' Perceptions Regarding Conducting Health Behavior Research in a Diverse, Urban Clinic Specializing in Rheumatic Diseases SO PROGRESS IN COMMUNITY HEALTH PARTNERSHIPS-RESEARCH EDUCATION AND ACTION LA English DT Article DE Community health partnerships; community-based participatory research; community health research; health disparities; rheumatic diseases; musculoskeletal diseases; urban population ID UNITED-STATES; PARTICIPATORY RESEARCH; ARTHRITIS; PREVALENCE; IMPACT; PHYSICIANS; QUALITY; ASTHMA AB Background: Disparities in the incidence, prevalence, severity, care, and outcomes for rheumatic diseases exist among racial and ethnic groups compared with White Americans. Objective: This paper describes a community-based participatory research (CBPR) approach engaging researchers, community leaders, and patients in purposeful dialogues related to the implementation of health behavior research in an urban rheumatic disease clinic. Methods: Seven focused discussions were led in either English or Spanish. Discussions were audiotaped and transcribed verbatim. Results: Six community leaders and nine patients participated in the seven scheduled focused discussions. Transcripts uncovered five major themes that assisted with study design: trust, patient provider relationship, study implementation suggestions, decreased functional capacity, and access to healthcare. Conclusions: Engaging community partners and patients in informal and formal discussions from early phases of research design through implementation, followed by systematic application of these insights, may serve to accelerate the potential for translation from findings into improved clinical practice and optimal outcomes. C1 [Wallen, Gwenyth R.; Middleton, Kimberly R.; Miller-Davis, Claiborne; Tataw-Ayuketah, Gladys; Todaro, Alyssa; Rivera-Goba, Migdalia; Mittleman, Barbara B.] NIH, Bethesda, MD 20892 USA. RP Wallen, GR (reprint author), NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA CL001141-09] NR 27 TC 1 Z9 1 U1 1 U2 4 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1557-0541 J9 PROG COMM HLTH PARTN JI Prog. Community Health Partnersh. PD WIN PY 2012 VL 6 IS 4 BP 405 EP 415 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 068ND UT WOS:000313372500003 PM 23221285 ER PT J AU Du, XG Zhao, B Li, JY Cao, XH Diao, MK Feng, HB Chen, XB Chen, ZY Zeng, XY AF Du, Xiaogang Zhao, Bing Li, Jinyao Cao, Xiaohan Diao, Mingkun Feng, Haibo Chen, Xiaobing Chen, Zhiyu Zeng, Xianyin TI Astragalus polysaccharides enhance immune responses of HBV DNA vaccination via promoting the dendritic cell maturation and suppressing Treg frequency in mice SO INTERNATIONAL IMMUNOPHARMACOLOGY LA English DT Article DE APS; Adjuvant; HBV; DNA vaccine; Dendritic cell; Regulatory T cell ID REGULATORY T-CELLS; TRANSGENIC MOUSE MODEL; CHRONIC HEPATITIS-B; ECHINACEA-PURPUREA; GLYCYRRHIZA-GLABRA; MEMBRANACEUS; EXPRESSION; VACCINES; IMMUNIZATION; ACTIVATION AB Astragalus polysaccharides (APS), an extract from a kind of Chinese traditional herb Astragalus membranaceus, was proved to have strong immunoregulatoiy properties. In this study, APS was employed as an adjuvant of Hepatitis B virus (HBV) DNA vaccine (pcDS2) and its' effects on immune system of mice were investigated. Our data demonstrated that APS as an adjuvant could increase the HBsAg-specific antibody level as well as the proliferating activity of T cells. APS also could induce CD4(+) T cells to produce IL-4, IL-2 and IFN-gamma and enhance IFN-gamma expression of CD8(+) T cells. Moreover, APS could induce the robust activity of the cytotoxic lymphocytes (CTL). Additionally, APS could stimulate the dendritic cells (DC) maturation which is characterized by up-regulation of MHC I/II, CD40, CD80 and CD86, and decreased the frequency of the regulatory T cells (nTreg). Collectively, these findings suggest that APS is a potent adjuvant for the hepatitis B DNA vaccine and can enhance the immune responses of HBV DNA vaccine via promoting DC maturation and inhibit the Treg frequency. (C) 2012 Elsevier B.V. All rights reserved. C1 [Du, Xiaogang; Zhao, Bing; Cao, Xiaohan; Diao, Mingkun; Feng, Haibo; Chen, Xiaobing; Chen, Zhiyu; Zeng, Xianyin] Sichuan Agr Univ, Appl Biophys & Immune Engn Lab, Coll Life Sci, Yaan 625014, Sichuan, Peoples R China. [Li, Jinyao] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. RP Zeng, XY (reprint author), Sichuan Agr Univ, Appl Biophys & Immune Engn Lab, Coll Life Sci, Yaan 625014, Sichuan, Peoples R China. EM xyzeng@sicau.edu.cn FU Two Sides Supporting Plan in Sichuan Agriculture University [00770103]; Changing Scholars and Innovative Research Team in University [IRT0848]; Sichuan Education Commission [09ZA072] FX This work was supported in part by Two Sides Supporting Plan in Sichuan Agriculture University (00770103), Changing Scholars and Innovative Research Team in University (IRT0848) and the Sichuan Education Commission (Project No. 09ZA072). NR 27 TC 27 Z9 35 U1 7 U2 38 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-5769 J9 INT IMMUNOPHARMACOL JI Int. Immunopharmacol. PD DEC PY 2012 VL 14 IS 4 BP 463 EP 470 DI 10.1016/j.intimp.2012.09.006 PG 8 WC Immunology; Pharmacology & Pharmacy SC Immunology; Pharmacology & Pharmacy GA 065MP UT WOS:000313152900016 PM 23006659 ER PT J AU Murphy, AJ de Caestecker, C Pierce, J Boyle, SC Ayers, GD Zhao, ZG Libes, JM Correa, H Walter, T Huppert, SS Perantoni, AO de Caestecker, MP Lovvorn, HN AF Murphy, Andrew J. de Caestecker, Christian Pierce, Janene Boyle, Scott C. Ayers, Gregory D. Zhao, Zhiguo Libes, Jaime M. Correa, Hernan Walter, Teagan Huppert, Stacey S. Perantoni, Alan O. de Caestecker, Mark P. Lovvorn, Harold N., III TI CITED1 Expression in Liver Development and Hepatoblastoma SO NEOPLASIA LA English DT Article ID WILMS-TUMORS; GENE-EXPRESSION; BETA-CATENIN; KIDNEY; CELLS; OVEREXPRESSION; TUMORIGENESIS; ESTABLISHMENT; COACTIVATOR; MUTATIONS AB Hepatoblastoma, the most common pediatric liver cancer, consists of epithelial mixed embryonal/fetal (EMEF) and pure fetal histologic subtypes, with the latter exhibiting a more favorable prognosis. Few embryonal histology markers that yield insight into the biologic basis for this prognostic discrepancy exist. CBP/P-300 interacting transactivator 1 (CITED1), a transcriptional co-activator, is expressed in the self-renewing nephron progenitor population of the developing kidney and broadly in its malignant analog, Wilms tumor (WT). In this current study, CITED1 expression is detected in mouse embryonic liver initially on post-coitum day 10.5 (e10.5), begins to taper by e14.5, and is undetectable in e18.5 and adult livers. CITED1 expression is detected in regenerating murine hepatocytes following liver injury by partial hepatectomy and 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Importantly, while CITED1 is undetectable in normal human adult livers, 36 of 41 (87.8%) hepatoblastoma specimens express CITED1, where it is enriched in EMEF specimens compared to specimens of pure fetal histology. CITED1 overexpression in Hep293TT human hepatoblastoma cells induces cellular proliferation and upregulates the Wnt inhibitors Kringle containing transmembrane protein 1 (KREMEN1) and CXXC finger protein 4 (CXXC4). CITED1 mRNA expression correlates with expression of CXXC4 and KREMEN1 in clinical hepatoblastoma specimens. These data show that CITED1 is expressed during a defined time course of liver development and is no longer expressed in the adult liver but is upregulated in regenerating hepatocytes following liver injury. Moreover, as in WT, this embryonic marker is re-expressed in hepatoblastoma and correlates with embryonal histology. These findings identify CITED1 as a novel marker of hepatic progenitor cells that is re-expressed following liver injury and in embryonic liver tumors. Neoplasia (2012) 14, 1153-1163 C1 [Murphy, Andrew J.; de Caestecker, Christian; Pierce, Janene; Libes, Jaime M.; Lovvorn, Harold N., III] Vanderbilt Univ, Dept Pediat Surg, Med Ctr, Nashville, TN USA. [Boyle, Scott C.] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO USA. [Ayers, Gregory D.; Zhao, Zhiguo] Vanderbilt Univ, Med Ctr, Ctr Quantitat Sci, Nashville, TN USA. [Correa, Hernan] Vanderbilt Univ, Med Ctr, Dept Pediat Pathol, Nashville, TN USA. [Walter, Teagan; Huppert, Stacey S.; de Caestecker, Mark P.] Vanderbilt Univ, Med Ctr, Dept Cell & Dev Biol, Nashville, TN USA. [Perantoni, Alan O.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, Frederick, MD 21701 USA. [de Caestecker, Mark P.] Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN USA. RP Murphy, AJ (reprint author), Vanderbilt Childrens Hosp, 2200 Childrens Way,Suite 7102,Doctors Off Tower, Nashville, TN 37232 USA. EM andrew.j.murphy@vanderbilt.edu RI Huppert, Stacey/A-4103-2010 OI Huppert, Stacey/0000-0003-3977-8728 FU Section of Surgical Sciences; Ingram Cancer Center of the Vanderbilt Medical Center; National Cancer Institute (NCI) [5T32CA106183-06A1, 4R00CA135695-03, P30 CA68485] FX This work was supported by the Section of Surgical Sciences and the Ingram Cancer Center of the Vanderbilt Medical Center, by the National Cancer Institute (NCI) grant 5T32CA106183-06A1 (A.J.M.), and by NCI grant 4R00CA135695-03 (H.N.L.). The authors have no conflicts of interest to disclose.; We acknowledge the excellent services of the COG Biopathology Center, which were instrumental in specimen acquisition and data analysis, and also the NCI-funded Human Tissue Acquisition and Pathology Shared Resource at Vanderbilt (grant P30 CA68485). We also acknowledge Julia Kutaka and Jennifer Westrup Slone for their contributions to the experiments described herein. We were graciously provided the Hep293TT human hepatoblastoma cell line from the laboratory of Tina Chen and Gail Tomlinson and experimental murine hepatoblastoma specimens from the laboratory of Lucy Anderson. NR 34 TC 8 Z9 8 U1 0 U2 2 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD DEC PY 2012 VL 14 IS 12 BP 1153 EP + DI 10.1593/neo.12958 PG 20 WC Oncology SC Oncology GA 068EA UT WOS:000313346200007 PM 23308048 ER PT J AU Wang, H Jurado, KA Wu, XL Shun, MC Li, X Ferris, AL Smith, SJ Patel, PA Fuchs, JR Cherepanov, P Kvaratskhelia, M Hughes, SH Engelman, A AF Wang, Hao Jurado, Kellie A. Wu, Xiaolin Shun, Ming-Chieh Li, Xiang Ferris, Andrea L. Smith, Steven J. Patel, Pratiq A. Fuchs, James R. Cherepanov, Peter Kvaratskhelia, Mamuka Hughes, Stephen H. Engelman, Alan TI HRP2 determines the efficiency and specificity of HIV-1 integration in LEDGF/p75 knockout cells but does not contribute to the antiviral activity of a potent LEDGF/p75-binding site integrase inhibitor SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; PREINTEGRATION COMPLEX-FORMATION; RETROVIRAL DNA INTEGRATION; SMALL-MOLECULE INHIBITORS; TYPE-1 REPLICATION; CHROMATIN-BINDING; COACTIVATOR P75; HUMAN GENOME; IN-VITRO; DOMAIN AB The binding of integrase (IN) to lens epithelium-derived growth factor (LEDGF)/p75 in large part determines the efficiency and specificity of HIV-1 integration. However, a significant residual preference for integration into active genes persists in Psip1 (the gene that encodes for LEDGF/p75) knockout (KO) cells. One other cellular protein, HRP2, harbors both the PWWP and IN-binding domains that are important for LEDGF/p75 co-factor function. To assess the role of HRP2 in HIV-1 integration, cells generated from Hdgfrp2 (the gene that encodes for HRP2) and Psip1/Hdgfrp2 KO mice were infected alongside matched control cells. HRP2 depleted cells supported normal infection, while disruption of Hdgfrp2 in Psip1 KO cells yielded additional defects in the efficiency and specificity of integration. These deficits were largely restored by ectopic expression of either LEDGF/p75 or HRP2. The double-KO cells nevertheless supported residual integration into genes, indicating that IN and/or other host factors contribute to integration specificity in the absence of LEDGF/p75 and HRP2. Psip1 KO significantly increased the potency of an allosteric inhibitor that binds the LEDGF/p75 binding site on IN, a result that was not significantly altered by Hdgfrp2 disruption. These findings help to rule out the host factor-IN interactions as the primary antiviral targets of LEDGF/p75-binding site IN inhibitors. C1 [Wang, Hao; Jurado, Kellie A.; Shun, Ming-Chieh; Li, Xiang; Engelman, Alan] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. [Wang, Hao; Jurado, Kellie A.; Shun, Ming-Chieh; Li, Xiang; Engelman, Alan] Harvard Univ, Sch Med, Dept Med, Boston, MA 02215 USA. [Wu, Xiaolin] SAIC Frederick Inc, Lab Mol Technol, Frederick, MD 21702 USA. [Ferris, Andrea L.; Smith, Steven J.; Hughes, Stephen H.] Frederick Natl Lab Canc Res, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Patel, Pratiq A.; Fuchs, James R.] Ohio State Univ, Coll Pharm, Div Med Chem & Pharmacognosy, Columbus, OH 43210 USA. [Cherepanov, Peter] Canc Res UK, London Res Inst, Clare Hall Labs, S Mimms EN6 3LD, Herts, England. [Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Ctr Retrovirus Res, Columbus, OH 43210 USA. [Kvaratskhelia, Mamuka] Ohio State Univ, Coll Pharm, Ctr Comprehens Canc, Columbus, OH 43210 USA. RP Engelman, A (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02215 USA. EM alan_engelman@dfci.harvard.edu RI wang, hao/O-6217-2014; Cherepanov, Peter/F-6859-2010 OI Cherepanov, Peter/0000-0002-0634-538X FU US National Institutes of Health (NIH) [AI039394, AI081581, AI097044]; National Cancer Institute's Intramural Center for Cancer Research; UK Medical Research Council [G1000917] FX US National Institutes of Health (NIH) [AI039394 to A. E., AI081581 to M. K., AI097044 to J.R.F.]; National Cancer Institute's Intramural Center for Cancer Research, which supports the HIV Drug Resistance Program [to S. H. H.]; UK Medical Research Council [G1000917 to P. C.]. Funding for open access charge: US NIH [AI039394]. NR 70 TC 34 Z9 34 U1 1 U2 6 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 DEC PY 2012 VL 40 IS 22 BP 11518 EP 11530 DI 10.1093/nar/gks913 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 069DG UT WOS:000313414800036 PM 23042676 ER PT J AU Abdelmohsen, K Tominaga-Yamanaka, K Srikantan, S Yoon, JH Kang, MJ Gorospe, M AF Abdelmohsen, Kotb Tominaga-Yamanaka, Kumiko Srikantan, Subramanya Yoon, Je-Hyun Kang, Min-Ju Gorospe, Myriam TI RNA-binding protein AUF1 represses Dicer expression SO NUCLEIC ACIDS RESEARCH LA English DT Article ID TARGET MESSENGER-RNAS; RICH ELEMENT; DOWN-REGULATION; MICRORNA MACHINERY; GENE-REGULATION; OVARIAN-CANCER; IDENTIFICATION; TRANSLATION; TURNOVER; HUR AB MicroRNA (miRNA) biogenesis is tightly regulated by numerous proteins. Among them, Dicer is required for the processing of the precursor (pre-)miRNAs into the mature miRNA. Despite its critical function, the mechanisms that regulate Dicer expression are not well understood. Here we report that the RNA-binding protein (RBP) AUF1 (AU-binding factor 1) associates with the endogenous DICER1 mRNA and can interact with several segments of DICER1 mRNA within the coding region (CR) and the 3'-untranslated region (UTR). Through these interactions, AUF1 lowered DICER1 mRNA stability, since silencing AUF1 lengthened DICER1 mRNA half-life and increased Dicer expression, while overexpressing AUF1 lowered DICER1 mRNA and Dicer protein levels. Given that Dicer is necessary for the synthesis of mature miRNAs, the lowering of Dicer levels by AUF1 diminished the levels of miRNAs tested, but not the levels of the corresponding pre-miRNAs. In summary, AUF1 suppresses miRNA production by reducing Dicer production. C1 [Abdelmohsen, Kotb; Tominaga-Yamanaka, Kumiko; Srikantan, Subramanya; Yoon, Je-Hyun; Kang, Min-Ju; Gorospe, Myriam] NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Gorospe, M (reprint author), NIA, Lab Mol Biol & Immunol, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM abdelmohsenk@mail.nih.gov; myriam-gorospe@nih.gov OI srikantan, subramanya/0000-0003-1810-6519; abdelmohsen, Kotb/0000-0001-6240-5810 FU National Institutes of Health FX National Institute on Aging-Intramural Research Program of the National Institutes of Health. Funding for open access charge: National Institute on Aging-Intramural Research Program, National Institutes of Health. NR 61 TC 26 Z9 27 U1 0 U2 13 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 DEC PY 2012 VL 40 IS 22 BP 11531 EP 11544 DI 10.1093/nar/gks930 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 069DG UT WOS:000313414800037 PM 23066106 ER PT J AU Prasad, R Williams, JG Hou, EW Wilson, SH AF Prasad, Rajendra Williams, Jason G. Hou, Esther W. Wilson, Samuel H. TI Pol beta associated complex and base excision repair factors in mouse fibroblasts SO NUCLEIC ACIDS RESEARCH LA English DT Article ID DNA-POLYMERASE-BETA; STRAND BREAK REPAIR; CELL NUCLEAR ANTIGEN; REPLICATION PROTEIN-A; END-JOINING PATHWAY; LONG-PATCH; MAMMALIAN-CELLS; POLY(ADP-RIBOSE) POLYMERASE; APURINIC/APYRIMIDINIC ENDONUCLEASE-1; INDUCED CYTOTOXICITY AB During mammalian base excision repair (BER) of lesion-containing DNA, it is proposed that toxic strand-break intermediates generated throughout the pathway are sequestered and passed from one step to the next until repair is complete. This stepwise process is termed substrate channeling. A working model evaluated here is that a complex of BER factors may facilitate the BER process. FLAG-tagged DNA polymerase (pol) beta was expressed in mouse fibroblasts carrying a deletion in the endogenous pol beta gene, and the cell extract was subjected to an 'affinity-capture' procedure using anti-FLAG antibody. The pol beta affinity-capture fraction (ACF) was found to contain several BER factors including polymerase-1, X-ray cross-complementing factor1-DNA ligase III and enzymes involved in processing 3'-blocked ends of BER intermediates, e. g. polynucleotide kinase and tyrosyl-DNA phosphodiesterase 1. In contrast, DNA glycosylases, apurinic/aprymidinic endonuclease 1 and flap endonuclease 1 and several other factors involved in BER were not present. Some of the BER factors in the pol beta ACF were in a multi-protein complex as observed by sucrose gradient centrifugation. The pol beta ACF was capable of substrate channeling for steps in vitro BER and was proficient in in vitro repair of substrates mimicking a 3'-blocked topoisomerase I covalent intermediate or an oxidative stress-induced 3'-blocked intermediate. C1 [Prasad, Rajendra; Williams, Jason G.; Hou, Esther W.; Wilson, Samuel H.] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr, 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 [Z01ES050158, Z01ES50159]; Laboratory of Structural Biology, NIEHS FX Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, project numbers [Z01ES050158 and Z01ES50159]. Funding for open access charge: Laboratory of Structural Biology, NIEHS. NR 82 TC 24 Z9 25 U1 0 U2 13 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 DEC PY 2012 VL 40 IS 22 BP 11571 EP 11582 DI 10.1093/nar/gks898 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 069DG UT WOS:000313414800041 PM 23042675 ER PT J AU Houzet, L Klase, Z Yeung, ML Wu, AN Le, SY Quinones, M Jeang, KT AF Houzet, Laurent Klase, Zachary Yeung, Man Lung Wu, Annie Le, Shu-Yun Quinones, Mariam Jeang, Kuan-Teh TI The extent of sequence complementarity correlates with the potency of cellular miRNA-mediated restriction of HIV-1 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INFLUENZA-A VIRUS; VIRAL REPLICATION; HUMAN MICRORNAS; BINDING-SITES; HUMAN GENES; HUMAN-CELLS; SMALL RNAS; EXPRESSION; TYPE-1 AB MicroRNAs (miRNAs) are 22-nt non-coding RNAs involved in the regulation of cellular gene expression and potential cellular defense against viral infection. Using in silico analyses, we predicted target sites for 22 human miRNAs in the HIV genome. Transfection experiments using synthetic miRNAs showed that five of these miRNAs capably decreased HIV replication. Using one of these five miRNAs, human miR-326 as an example, we demonstrated that the degree of complementarity between the predicted viral sequence and cellular miR-326 correlates, in a Dicer-dependent manner, with the potency of miRNA-mediated restriction of viral replication. Antagomirs to miR-326 that knocked down this cell endogenous miRNA increased HIV-1 replication in cells, suggesting that miR-26 is physiologically functional in moderating HIV-1 replication in human cells. C1 [Houzet, Laurent; Klase, Zachary; Wu, Annie; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Yeung, Man Lung] Univ Hong Kong, Dept Microbiol, Pokfulam 070, Peoples R China. [Le, Shu-Yun] NCI, Ctr Canc Res Nanobiol Program, NCI Ctr Canc Res, Frederick, MD 21702 USA. [Quinones, Mariam] NIAID, Bioinformat & Computat Biosci Branch, NIH, 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 kjeang@nih.gov FU Intramural NIAID funds; Intramural AIDS Targeted Antiviral Program (IATAP) from the Office of the Director, NIH; Office of AIDS Research; NIH (NIAID intramural fund) FX Intramural NIAID funds and by the Intramural AIDS Targeted Antiviral Program (IATAP) from the Office of the Director, NIH [grants for laboratory research to K.T.J.]; fellowship from the Office of AIDS Research [to Z.K.]. Funding for open access charge: NIH (NIAID intramural fund). NR 65 TC 21 Z9 21 U1 0 U2 6 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 DEC PY 2012 VL 40 IS 22 BP 11684 EP 11696 DI 10.1093/nar/gks912 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 069DG UT WOS:000313414800051 PM 23042677 ER PT J AU Cho, DY Kim, YA Przytycka, TM AF Cho, Dong-Yeon Kim, Yoo-Ah Przytycka, Teresa M. TI Chapter 5: Network Biology Approach to Complex Diseases SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID PROTEIN-INTERACTION NETWORKS; GENE REGULATORY NETWORKS; COPY-NUMBER VARIATION; RARE DE-NOVO; FUNCTIONAL MODULES; MOLECULAR NETWORKS; SPECTRUM DISORDERS; CLUSTER-ANALYSIS; MICROARRAY DATA; CELL BIOLOGY AB Complex diseases are caused by a combination of genetic and environmental factors. Uncovering the molecular pathways through which genetic factors affect a phenotype is always difficult, but in the case of complex diseases this is further complicated since genetic factors in affected individuals might be different. In recent years, systems biology approaches and, more specifically, network based approaches emerged as powerful tools for studying complex diseases. These approaches are often built on the knowledge of physical or functional interactions between molecules which are usually represented as an interaction network. An interaction network not only reports the binary relationships between individual nodes but also encodes hidden higher level organization of cellular communication. Computational biologists were challenged with the task of uncovering this organization and utilizing it for the understanding of disease complexity, which prompted rich and diverse algorithmic approaches to be proposed. We start this chapter with a description of the general characteristics of complex diseases followed by a brief introduction to physical and functional networks. Next we will show how these networks are used to leverage genotype, gene expression, and other types of data to identify dysregulated pathways, infer the relationships between genotype and phenotype, and explain disease heterogeneity. We group the methods by common underlying principles and first provide a high level description of the principles followed by more specific examples. We hope that this chapter will give readers an appreciation for the wealth of algorithmic techniques that have been developed for the purpose of studying complex diseases as well as insight into their strengths and limitations. C1 [Cho, Dong-Yeon; Kim, Yoo-Ah; Przytycka, Teresa M.] NLM, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD USA. RP Przytycka, TM (reprint author), NLM, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD USA. EM przytyck@ncbi.nlm.nih.gov FU intramural program of National Library of Medicine, NIH FX This work is supported by the intramural program of National Library of Medicine, NIH. The funders had no role in the preparation of the manuscript. NR 98 TC 61 Z9 64 U1 0 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD DEC PY 2012 VL 8 IS 12 AR e1002820 DI 10.1371/journal.pcbi.1002820 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 062EI UT WOS:000312901500026 PM 23300411 ER PT J AU Gonzalez, MW Kann, MG AF Gonzalez, Mileidy W. Kann, Maricel G. TI Chapter 4: Protein Interactions and Disease SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID DOMAIN-DOMAIN INTERACTIONS; CO-EVOLUTIONARY ANALYSIS; INTERACTION NETWORK; HUNTINGTONS-DISEASE; TOPOLOGICAL FEATURES; PHYLOGENETIC TREES; REVEALS INSIGHTS; INTERACTION MAPS; COMPLEX DISEASE; GENE AB Proteins do not function in isolation; it is their interactions with one another and also with other molecules (e.g. DNA, RNA) that mediate metabolic and signaling pathways, cellular processes, and organismal systems. Due to their central role in biological function, protein interactions also control the mechanisms leading to healthy and diseased states in organisms. Diseases are often caused by mutations affecting the binding interface or leading to biochemically dysfunctional allosteric changes in proteins. Therefore, protein interaction networks can elucidate the molecular basis of disease, which in turn can inform methods for prevention, diagnosis, and treatment. In this chapter, we will describe the computational approaches to predict and map networks of protein interactions and briefly review the experimental methods to detect protein interactions. We will describe the application of protein interaction networks as a translational approach to the study of human disease and evaluate the challenges faced by these approaches. C1 [Gonzalez, Mileidy W.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. [Kann, Maricel G.] Univ Maryland, Baltimore, MD 21201 USA. RP Gonzalez, MW (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM mkann@umbc.edu FU National Institutes of Health (NIH) [1K22CA143148]; ACS-IRG grant; Intramural Research Program of the NIH, National Library of Medicine; [R01LM009722] FX This research was funded by the National Institutes of Health (NIH) 1K22CA143148 to MGK (PI); ACS-IRG grant to MGK (PI), and R01LM009722 to MGK (co-investigator). MWG's research was supported in part by the Intramural Research Program of the NIH, National Library of Medicine. The funders had no role in the preparation of the manuscript. NR 88 TC 32 Z9 34 U1 1 U2 9 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD DEC PY 2012 VL 8 IS 12 AR e1002819 DI 10.1371/journal.pcbi.1002819 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 062EI UT WOS:000312901500025 PM 23300410 ER PT J AU Ratmann, O Donker, G Meijer, A Fraser, C Koelle, K AF Ratmann, Oliver Donker, Ge Meijer, Adam Fraser, Christophe Koelle, Katia TI Phylodynamic Inference and Model Assessment with Approximate Bayesian Computation: Influenza as a Case Study SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID EVOLUTIONARY DYNAMICS; A H3N2; POPULATION-DYNAMICS; INFECTIOUS-DISEASE; EPOCHAL EVOLUTION; IMPACT; VIRUS; EPIDEMIOLOGY; DETERMINANTS; TRANSMISSION AB A key priority in infectious disease research is to understand the ecological and evolutionary drivers of viral diseases from data on disease incidence as well as viral genetic and antigenic variation. We propose using a simulation-based, Bayesian method known as Approximate Bayesian Computation (ABC) to fit and assess phylodynamic models that simulate pathogen evolution and ecology against summaries of these data. We illustrate the versatility of the method by analyzing two spatial models describing the phylodynamics of interpandemic human influenza virus subtype A(H3N2). The first model captures antigenic drift phenomenologically with continuously waning immunity, and the second epochal evolution model describes the replacement of major, relatively long-lived antigenic clusters. Combining features of long-term surveillance data from the Netherlands with features of influenza A (H3N2) hemagglutinin gene sequences sampled in northern Europe, key phylodynamic parameters can be estimated with ABC. Goodness-of-fit analyses reveal that the irregularity in interannual incidence and H3N2's ladder-like hemagglutinin phylogeny are quantitatively only reproduced under the epochal evolution model within a spatial context. However, the concomitant incidence dynamics result in a very large reproductive number and are not consistent with empirical estimates of H3N2's population level attack rate. These results demonstrate that the interactions between the evolutionary and ecological processes impose multiple quantitative constraints on the phylodynamic trajectories of influenza A(H3N2), so that sequence and surveillance data can be used synergistically. ABC, one of several data synthesis approaches, can easily interface a broad class of phylodynamic models with various types of data but requires careful calibration of the summaries and tolerance parameters. C1 [Ratmann, Oliver; Koelle, Katia] Duke Univ, Dept Biol, Durham, NC 27706 USA. [Ratmann, Oliver; Fraser, Christophe] Univ London Imperial Coll Sci Technol & Med, Dept Infect Dis Epidemiol, London, England. [Donker, Ge] Netherlands Inst Hlth Serv Res, NIVEL, Utrecht, Netherlands. [Meijer, Adam] Natl Inst Publ Hlth & Environm, RIVM, Ctr Infect Dis Control, NL-3720 BA Bilthoven, Netherlands. [Koelle, Katia] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Ratmann, O (reprint author), Duke Univ, Dept Biol, Durham, NC 27706 USA. EM oliver.ratmann@imperial.ac.uk RI Fraser, Christophe/A-8109-2008; OI Fraser, Christophe/0000-0003-2399-9657; Donker, Ge/0000-0001-6314-9249; Ratmann, Oliver/0000-0001-8667-4118 FU Wellcome Trust [WR092311MF]; National Science Foundation [NSF-EF-08-27416]; Science and Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health FX We gratefully accept financial support from the Wellcome Trust (http://www.wellcome.ac.uk), grant WR092311MF, the National Science Foundation (http://www.nsf.gov), grant NSF-EF-08-27416, and through the RAPIDD program of the Science and Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (http://www.fic.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 11 Z9 11 U1 2 U2 22 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD DEC PY 2012 VL 8 IS 12 AR e1002835 DI 10.1371/journal.pcbi.1002835 PG 14 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 062EI UT WOS:000312901500037 PM 23300420 ER PT J AU Hamlin, KL Moss, DM Priest, JW Roberts, J Kubofcik, J Gass, K Streit, TG Nutman, TB Eberhard, ML Lammie, PJ AF Hamlin, Katy L. Moss, Delynn M. Priest, Jeffrey W. Roberts, Jacquelin Kubofcik, Joseph Gass, Katherine Streit, Thomas G. Nutman, Thomas B. Eberhard, Mark L. Lammie, Patrick J. TI Longitudinal Monitoring of the Development of Antifilarial Antibodies and Acquisition of Wuchereria bancrofti in a Highly Endemic Area of Haiti SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID ELIMINATE LYMPHATIC FILARIASIS; BRUGIA-MALAYI INFECTION; DIROFILARIA-IMMITIS; INHIBITOR HOMOLOG; DIAGNOSTIC-TOOLS; GLOBAL PROGRAM; CHILDREN; DRUG; ALBENDAZOLE; ANTIGENS AB Antifilarial antibody testing has been established as a sensitive and specific method of diagnosing lymphatic filariasis. However, the development of serological responses to specific filarial antigens and their relationship to acquisition of infection is poorly understood. In order to evaluate whether the development of antigen specific antifilarial antibodies precedes microfilaremia and antigenemia, we compared the antibody responses of serum samples collected between 1990 and 1999 from a cohort of 142 Haitian children followed longitudinally. Antigen status was determined using the Og4C3 ELISA and the presence of microfilaremia was detected using microscopy. Antibody responses to Wb123, a Wuchereria bancrofti L3 antigen, were measured using a Luciferase Immunoprecipitation System (LIPS) assay. Antibody responses to Bm14 and Bm33, Brugia malayi antigens and to a major surface protein (WSP) from Wolbachia were analyzed using a multiplex bead assay. Over follow-up, 80 (56%) of the children became antigen-positive and 30 (21%) developed microfilaremia. Detectable antibody responses to Bm14, Bm33, Wb123, and WSP developed in 95%, 100%, 92%, and 29% of children, respectively. With the exception of WSP, the development of antibody responses generally preceded detection of filarial antigen. Our results show that antifilarial antibody responses can serve as an important epidemiological indicator in a sentinel population of young children and thus, may be valuable as tool for surveillance in the context of lymphatic filariasis elimination programs. C1 [Hamlin, Katy L.; Moss, Delynn M.; Priest, Jeffrey W.; Roberts, Jacquelin; Eberhard, Mark L.; Lammie, Patrick J.] Ctr Dis Control & Prevent, Atlanta, GA 30329 USA. [Kubofcik, Joseph; Nutman, Thomas B.] NIH, Bethesda, MD 20892 USA. [Gass, Katherine] Task Force Global Hlth, LF Support Ctr, Decatur, GA USA. [Streit, Thomas G.] Univ Notre Dame, Notre Dame Haiti Program, Notre Dame, IN 46556 USA. RP Hamlin, KL (reprint author), Ctr Dis Control & Prevent, Atlanta, GA 30329 USA. EM Plammie@cdc.gov FU Centers for Disease Control; National Institutes of Health; United Nations Development Programme/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases [920528, 940441]; CDC/APHL Emerging Infectious Disease Fellowship FX Financial support was provided by Centers for Disease Control, the National Institutes of Health and the United Nations Development Programme/World Bank/World Health Organization Special Program for Research and Training in Tropical Diseases (grants #920528 and #940441). KLH was supported by a CDC/APHL Emerging Infectious Disease Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 19 Z9 19 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2012 VL 6 IS 12 AR e1941 DI 10.1371/journal.pntd.0001941 PG 11 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 062HN UT WOS:000312910200014 PM 23236534 ER PT J AU Kubofcik, J Fink, DL Nutman, TB AF Kubofcik, Joseph Fink, Doran L. Nutman, Thomas B. TI Identification of Wb123 as an Early and Specific Marker of Wuchereria bancrofti Infection SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID LOA-LOA INFECTION; PAPUA-NEW-GUINEA; LYMPHATIC FILARIASIS; ONCHOCERCA-VOLVULUS; MULTICENTER EVALUATION; ANTIBODY-RESPONSES; DIAGNOSTIC-TOOLS; DRUG; TRANSMISSION; ALBENDAZOLE AB Background: The current antibody tests used for monitoring in lymphatic filariasis (LF) elimination programs suffer from poor specificity because of the considerable geographical overlap with other filarial infections such as Loa loa (Ll), Onchocerca volvulus (Ov), and Mansonella perstans (Mp). Methods: Using bioinformatics to assemble into contigs 2048 expressed sequence tags (ESTs) from the L3 infective larvae of W. bancrofti (Wb), these were next assessed for homology to known proteins and nucleotides and to similar assemblies of L3 larval ESTs of B. malayi (Bm - n = 5068), Ov (n = 4166), and Ll (n = 3315). Nineteen potential L3- and Wb- and/or Bm-specific antigens were identified. Sixteen of the 19 antigens could be expressed as fusion proteins with Renilla luciferase (Ruc); these were used in a rapid Luciferase Immunopreciptation System (LIPS) assay. Results: One of the 16 expressed antigens (Wb123) was both highly immunogenic and specific for Wb. Using Wb123-based IgG and IgG4 LIPS assays on well-defined sera from normal North Americans and those infected exclusively with intestinal helminths, we could detect all of the Wb- infected individuals (from diverse geographic regions) with 100% sensitivity and 100% specificity. Using sera from exclusively Ll-infected, Ov-infected Mp-infected or Bm-infected subjects as the negative comparator, the sensitivities were between 98-100% and the specificities ranged between 84-100% (for IgG anti-Wb 123) and between 98-100% (for IgG4 anti-Wb 123). Blinded assessments using panels of sera from various Wb-, Bm- or non-Wb helminth-infected subjects demonstrated equally high degrees of sensitivity and specificity. Significance: We have identified a Wb- encoded antigen that can be used both as a rapid, high throughput tool to diagnose individual Wb infections and as a sensitive method for early detection of recrudescent infections in areas of control and for mapping new areas of Wb transmission. C1 [Kubofcik, Joseph; Fink, Doran L.; Nutman, Thomas B.] NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Kubofcik, J (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM tnutman@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID) FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 33 TC 11 Z9 11 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2012 VL 6 IS 12 AR e1930 DI 10.1371/journal.pntd.0001930 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 062HN UT WOS:000312910200007 PM 23236529 ER PT J AU Marzi, A Reinheckel, T Feldmann, H AF Marzi, Andrea Reinheckel, Thomas Feldmann, Heinz TI Cathepsin B & L Are Not Required for Ebola Virus Replication SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID NIEMANN-PICK C1; CORONAVIRUS SPIKE PROTEIN; CYSTEINE CATHEPSINS; ENTRY; GLYCOPROTEIN; ACTIVATION; CELLS; INHIBITORS; INFECTION; MICE AB Ebola virus (EBOV), family Filoviridae, emerged in 1976 on the African continent. Since then it caused several outbreaks of viral hemorrhagic fever in humans with case fatality rates up to 90% and remains a serious Public Health concern and biothreat pathogen. The most pathogenic and best-studied species is Zaire ebolavirus (ZEBOV). EBOV encodes one viral surface glycoprotein (GP), which is essential for replication, a determinant of pathogenicity and an important immunogen. GP mediates viral entry through interaction with cellular surface molecules, which results in the uptake of virus particles via macropinocytosis. Later in this pathway endosomal acidification activates the cysteine proteases Cathepsin B and L (CatB, CatL), which have been shown to cleave ZEBOV-GP leading to subsequent exposure of the putative receptor-binding and fusion domain and productive infection. We studied the effect of CatB and CatL on in vitro and in vivo replication of EBOV. Similar to previous findings, our results show an effect of CatB, but not CatL, on ZEBOV entry into cultured cells. Interestingly, cell entry by other EBOV species (Bundibugyo, Cote d'Ivoire, Reston and Sudan ebolavirus) was independent of CatB or CatL as was EBOV replication in general. To investigate whether CatB and CatL have a role in vivo during infection, we utilized the mouse model for ZEBOV. Wild-type (control), catB(-/-) and catL(-/-) mice were equally susceptible to lethal challenge with mouse-adapted ZEBOV with no difference in virus replication and time to death. In conclusion, our results show that CatB and CatL activity is not required for EBOV replication. Furthermore, EBOV glycoprotein cleavage seems to be mediated by an array of proteases making targeted therapeutic approaches difficult. C1 [Marzi, Andrea; Feldmann, Heinz] NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. [Marzi, Andrea; Feldmann, Heinz] Publ Hlth Agcy Canada, Special Pathogens Program, Natl Microbiol Lab, Winnipeg, MB, Canada. [Reinheckel, Thomas] Univ Freiburg, Inst Mol Med & Cell Res, D-79106 Freiburg, Germany. [Reinheckel, Thomas] Univ Freiburg, BIOSS Ctr Biol Signaling Studies, D-79106 Freiburg, Germany. [Feldmann, Heinz] Univ Manitoba, Dept Med Microbiol, Winnipeg, MB, Canada. RP Marzi, A (reprint author), NIAID, Virol Lab, Div Intramural Res, NIH, Hamilton, MT USA. EM feldmannh@niaid.nih.gov FU Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID); National Institutes of Health (NIH); Public Health Agency of Canada (PHAC); Natural Science and Engineering Council of Canada (NSERC) FX This research was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) and the Public Health Agency of Canada (PHAC). A.M. was in part funded by the Natural Science and Engineering Council of Canada (NSERC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 50 TC 19 Z9 21 U1 0 U2 12 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2012 VL 6 IS 12 AR e1923 DI 10.1371/journal.pntd.0001923 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 062HN UT WOS:000312910200005 PM 23236527 ER PT J AU Steel, C Kubofcik, J Ottesen, EA Nutman, TB AF Steel, Cathy Kubofcik, Joseph Ottesen, Eric A. Nutman, Thomas B. TI Antibody to the Filarial Antigen Wb123 Reflects Reduced Transmission and Decreased Exposure in Children Born following Single Mass Drug Administration (MDA) SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID ELIMINATE LYMPHATIC FILARIASIS; WUCHERERIA-BANCROFTI INFECTION; PAPUA-NEW-GUINEA; ENDEMIC FILARIASIS; GLOBAL PROGRAM; PACIFIC ISLAND; ALBENDAZOLE; DIETHYLCARBAMAZINE; IMPACT; RESPONSIVENESS AB Background: Antibody (Ab) to the Wuchereria bancrofti (Wb) infective larval (L3) antigen Wb123, using a Luciferase Immunoprecipitation System (LIPS) assay, has been shown to be a species-specific, early marker of infection developed for potential use as a surveillance tool following transmission interruption post mass drug administration. To examine its usefulness in a single filarial-endemic island assessed at two time points with markedly different levels of transmission, Ab to Wb123 was measured in sera collected from subjects from Mauke, Cook Islands in 1975 (no previous treatment) and 1992 (5 years after a one time island-wide treatment with diethylcarbamazine [DEC]). Findings: Between 1975 and 1992, Wb transmission decreased dramatically as evidenced by reduced prevalences of microfilariae (31% vs. 5%) and circulating Ag (CAg, 49% vs. 16%). Age specific prevalence analysis showed a dramatic reduction in Wb123 Ab positivity from 54% (25/46) in 1975 to 8% (3/38) in 1992 in children 1-5 years (p<0.0001), reflecting the effects of single-dose treatment five years earlier. By 1992, Wb123 Ab prevalence in children 6-10 years had fallen from 75% (42/56) in 1975 to 42% (33/79) consistent with a lower cumulative transmission potential. In the whole population, Wb123 seropositivity decreased from 86% to 60% between 1975 and 1992. In CAg+ subjects the levels of Wb123 Ab were indistinguishable between the 2 time points but differed in those who were CAg- (p, 0.0001). In paired sample analysis, individuals who were CAg+ in 1975 but became CAg- in 1992 had significantly lower Ab levels in 1992 (p<0.0001), with 9/40 (23%) becoming seronegative for Wb123. Conclusions: The relationship between reduction in Wb123 Ab prevalence and the reduction of transmission, seen most clearly in young children, strongly advocates for the continuing assessment and rapid development of Wb123 as a surveillance tool to detect potential transmission of bancroftian filariasis in treated endemic areas. C1 [Steel, Cathy; Kubofcik, Joseph; Nutman, Thomas B.] NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. [Ottesen, Eric A.] Task Force Global Hlth, Lymphat Filariasis Support Ctr, Decatur, GA USA. RP Steel, C (reprint author), NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. EM csteel@niaid.nih.gov FU Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 9 Z9 9 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD DEC PY 2012 VL 6 IS 12 AR e1940 DI 10.1371/journal.pntd.0001940 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 062HN UT WOS:000312910200013 PM 23236533 ER PT J AU Stephan, Y Demulier, V Terracciano, A AF Stephan, Yannick Demulier, Virginie Terracciano, Antonio TI Personality, Self-Rated Health, and Subjective Age in a Life-Span Sample: The Moderating Role of Chronological Age SO PSYCHOLOGY AND AGING LA English DT Article DE subjective age; personality; self-rated health; life span ID NEO-PI-R; OLDER-ADULTS; UNITED-STATES; SOCIOECONOMIC-STATUS; 5-FACTOR MODEL; SATISFACTION; PREDICTORS; MORTALITY; IDENTITY; YOUNGER AB The present study tested whether chronological age moderates the association between subjective age and self-rated health and personality in a community-dwelling life-span sample (N = 1,016; age range: 18-91 years). Self-rated health, extraversion, and openness to experience were associated with a younger subjective age at older ages. Conscientious individuals felt more mature early in life. Conscientiousness, neuroticism, and agreeableness were not related to subjective age at older ages. These findings suggest that with aging self-rated health and personality traits are increasingly important for subjective age. C1 [Stephan, Yannick] Univ Grenoble 1, EA Sport & Environm Social 3742, F-38041 Grenoble 9, France. [Demulier, Virginie] Univ Paris 11, UR CIAMS, Paris, France. [Terracciano, Antonio] NIA, NIH, Baltimore, MD 21224 USA. RP Stephan, Y (reprint author), Univ Grenoble 1, EA Sport & Environm Social 3742, BP 53, F-38041 Grenoble 9, France. EM yannick.stephan@ujf-grenoble.fr RI terracciano, antonio/B-1884-2008 FU Intramural NIH HHS [Z99 AG999999, ZIA AG000180-25, ZIA AG000180-26, ZIA AG000183-22, ZIA AG000183-23] NR 44 TC 19 Z9 19 U1 1 U2 20 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD DEC PY 2012 VL 27 IS 4 BP 875 EP 880 DI 10.1037/a0028301 PG 6 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 067PB UT WOS:000313306500011 PM 22582885 ER PT J AU Gamaldo, AA Allaire, JC Whitfield, KE AF Gamaldo, Alyssa A. Allaire, Jason C. Whitfield, Keith E. TI Intraindividual Variability in Psychometrically Defined Mild Cognitive Impairment Status in Older African Americans SO PSYCHOLOGY AND AGING LA English DT Article DE mild cognitive impairment; intraindividual variability; sleep; blood pressure ID BLOOD-PRESSURE; NEUROPSYCHIATRIC SYMPTOMS; SLEEP DURATION; MEMORY; POPULATION; PERFORMANCE; PREVALENCE; COMMUNITY; ENTITY; HEALTH AB This study examines day-to-day variability in psychometrically defined mild cognitive impairment (MCI) status and potential predictors of changes in MCI status in an independent-living sample of urban dwelling older adults in Baltimore, Maryland. The participant sample consisted of 50 older adults, ranging in age from 50 to 80 years. Participants completed health and cognitive measures (i.e., executive function, language, memory, and global cognition) over 8 occasions within a 2-3-week period. After each testing occasion, a post hoc classification of MCI status was determined using psychometrically defined criteria based on cognitive performance. Participants who classified as MCI after one assessment often did not meet MCI criteria at subsequent occasions. Daily fluctuations in sleep duration were associated with an increased risk for MCI classification. These results demonstrate that changes in sleep may explain changes in MCI status, particularly for African Americans. C1 [Gamaldo, Alyssa A.] NIA, Lab Behav Neurosci, Biomed Res Ctr, NIH, Baltimore, MD 21224 USA. [Allaire, Jason C.] N Carolina State Univ, Dept Psychol, Raleigh, NC 27695 USA. [Whitfield, Keith E.] Duke Univ, Durham, NC 27706 USA. RP Gamaldo, AA (reprint author), NIA, Lab Behav Neurosci, Biomed Res Ctr, NIH, 251 Bayview Blvd,Suite 100,Room 04B316, Baltimore, MD 21224 USA. EM Alyssa.Gamaldo@nih.gov; jason_allaire@ncsu.edu FU Intramural NIH HHS [Z99 AG999999]; NIA NIH HHS [AG024108-02S1, R01 AG024108, R01 AG24108] NR 43 TC 6 Z9 6 U1 1 U2 7 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD DEC PY 2012 VL 27 IS 4 BP 989 EP 997 DI 10.1037/a0028557 PG 9 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 067PB UT WOS:000313306500024 PM 22708537 ER PT J AU Kouprina, N Samoshkin, A Erliandri, I Nakano, M Lee, HS Fu, HG Iida, Y Aladjem, M Oshimura, M Masumoto, H Earnshaw, WC Larionov, V AF Kouprina, Natalay Samoshkin, Alexander Erliandri, Indri Nakano, Megumi Lee, Hee-Sheung Fu, Haiging Iida, Yuichi Aladjem, Mirit Oshimura, Mitsuo Masumoto, Hiroshi Earnshaw, William C. Larionov, Vladimir TI Organization of Synthetic Alphoid DNA Array in Human Artificial Chromosome (HAC) with a Conditional Centromere SO ACS SYNTHETIC BIOLOGY LA English DT Article DE human artificial chromosome; HAC; gene delivery; TAR cloning ID TRANSFORMATION-ASSOCIATED RECOMBINATION; GENE-EXPRESSION; MAMMALIAN-CELLS; ENGINEERED CHROMOSOMES; STRAND BREAKS; GENOMIC LOCI; MURINE CELLS; STEM-CELLS; INPUT DNA; VECTORS AB Human artificial chromosomes (HACs) represent a novel promising episomal system for functional genomics, gene therapy, and synthetic biology. HACs are engineered from natural and synthetic alphoid DNA arrays upon transfection into human cells. The use of HACs for gene expression studies requires the knowledge of their structural organization. However, none of the de novo HACs constructed so far has been physically mapped in detail. Recently we constructed a synthetic alphoid(tetO)-HAC that was successfully used for expression of full-length genes to correct genetic deficiencies in human cells. The HAC can be easily eliminated from cell populations by inactivation of its conditional kinetochore. This unique feature provides a control for phenotypic changes attributed to expression of HAC-encoded genes. This work describes organization of a megabase-size synthetic alphoid DNA array in the alphoid(tetO)-HAC that has been formed from a similar to 50 kb synthetic alphoid(tetO)-construct. Our analysis showed that this array represents a 1.1 Mb continuous sequence assembled from multiple copies of input DNA, a significant part of which was rearranged before assembling. The tandem and inverted alphoid DNA repeats in the HAC range in size from 25 to 150 kb. In addition, we demonstrated that the structure and functional domains of the HAC remains unchanged after several rounds of its transfer into different host cells. The knowledge of the alphoidt(tetO)-HAC structure provides a tool to control HAC integrity during different manipulations. Our results also shed light on a mechanism for de novo MAC formation in human cells. C1 [Kouprina, Natalay; Samoshkin, Alexander; Erliandri, Indri; Lee, Hee-Sheung; Fu, Haiging; Aladjem, Mirit; Larionov, Vladimir] NCI, Labs Mol Pharmacol, Bethesda, MD 20892 USA. [Nakano, Megumi; Masumoto, Hiroshi] Kazusa DNA Res Inst, Dept Human Genome Res, Lab Cell Engn, Kisarazu, Chiba 2920818, Japan. [Iida, Yuichi; Oshimura, Mitsuo] Tottori Univ, Grad Sch Med Sci, Inst Regenerat Med & Biofunct, Dept Biomed Sci, Yonago, Tottori, Japan. [Earnshaw, William C.] Univ Edinburgh, Wellcome Trust Ctr Cell Biol, Edinburgh EH9 3JR, Midlothian, Scotland. RP Larionov, V (reprint author), NCI, Labs Mol Pharmacol, Bethesda, MD 20892 USA. EM larionov@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; Wellcome Trust; The Darwin Trust of Edinburgh; Ministry of Education, Culture, Sports, Science and Technology of Japan; Kazusa DNA Research Institute Foundation FX This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, USA (V.L.), the Wellcome Trust and The Darwin Trust of Edinburgh (W.C.E.), 21st Century COE program from the Ministry of Education, Culture, Sports, Science and Technology of Japan (M.O.), the Grand-in-Aid for Scientific Research from Ministry of Education, Culture, Sports, Science and Technology of Japan (M.O. and H.M.), and the Kazusa DNA Research Institute Foundation (H.M.). NR 56 TC 12 Z9 12 U1 2 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 2161-5063 J9 ACS SYNTH BIOL JI ACS Synth. Biol. PD DEC PY 2012 VL 1 IS 12 BP 590 EP 601 DI 10.1021/sb3000436 PG 12 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 059BQ UT WOS:000312679800004 PM 23411994 ER PT J AU Zhang, Y Catalan, MA Melvin, JE AF Zhang, Yan Catalan, Marcelo A. Melvin, James E. TI TRPV4 activation in mouse submandibular gland modulates Ca2+ influx and salivation SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE transient receptor potential vanilloid subtype 4; submandibular gland; calcium; salivation ID INSULIN-SECRETION; ENDOTHELIAL-CELLS; ACINAR-CELLS; ATP RELEASE; AIRWAY EPITHELIA; CALCIUM-ENTRY; CHANNELS; MICE; COTRANSPORTER; HYPOTONICITY AB Zhang Y, Catalan MA, Melvin JE. TRPV4 activation in mouse submandibular gland modulates Ca2+ influx and salivation. Am J Physiol Gastrointest Liver Physiol 303: G1365-G1372, 2012. First published October 18, 2012; doi: 10.1152/ajpgi.00366.2012.-Transient receptor potential vanilloid subtype 4 (TRPV4) is a ligand-gated nonselective cation channel that participates in the transduction of mechanical and osmotic stimuli in different tissues. TRPV4 is activated by endogenous arachidonic acid metabolites, 4 alpha-phorbol-12,13 didecanoate, GSK1016790A, moderate heat, and mechanical stress. TRPV4 is expressed in the salivary glands, but its expression pattern and function are poorly understood. The aim of this study was to evaluate the functional role of TRPV4 channels in the mouse submandibular gland. Using RT-PCR and Western blot analysis, we detected expression of TRPV4 message and protein, respectively, in the submandibular gland. Immunolocalization studies showed that TRPV4 targeted to the basolateral membrane of mouse submandibular gland acinar cells. Pharmacological TRPV4 activation using the selective agonist GSK1016790A caused Ca2+ influx in isolated acinar cells in a basal-to-apical wave. Consistent with these observations, GSK1016790A elicited salivation in the perfused submandibular gland that was dependent on extracellular Ca2+. In summary, we report that activation of TRPV4 channels induced Ca2+ influx and salivation and, thus, may contribute a novel nonadrenergic, noncholinergic secretion pathway in the mouse submandibular gland. C1 [Zhang, Yan; Catalan, Marcelo A.; Melvin, James E.] Natl Inst Dent & Craniofacial Res, Secretory Mech & Dysfunct Sect, NIH, Bethesda, MD 20892 USA. RP Melvin, JE (reprint author), Natl Inst Dent & Craniofacial Res, Secretory Mech & Dysfunct Sect, NIH, 10 Ctr Dr,Bldg 10,Rm 5-2531, Bethesda, MD 20892 USA. EM james.melvin@nih.gov OI Catalan, Marcelo/0000-0003-3544-2821 FU National Institute of Dental and Craniofacial Research FX This study was supported by intramural grants from the National Institute of Dental and Craniofacial Research to J. E. Melvin. NR 40 TC 4 Z9 4 U1 1 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 DEC PY 2012 VL 303 IS 12 BP G1365 EP G1372 DI 10.1152/ajpgi.00366.2012 PG 8 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 056PH UT WOS:000312502600008 PM 23086916 ER PT J AU Satoh, M Nagasu, H Morita, Y Yamaguchi, TP Kanwar, YS Kashihara, N AF Satoh, Minoru Nagasu, Hajime Morita, Yoshitaka Yamaguchi, Terry P. Kanwar, Yashpal S. Kashihara, Naoki TI Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE cell cycle; G(2)/M; unilateral ureteral obstruction; fibrogenic cytokine ID UNILATERAL URETERAL OBSTRUCTION; ISCHEMIA-REPERFUSION INJURY; BETA-CATENIN; CELL-CYCLE; INTERSTITIAL FIBROSIS; OXIDATIVE STRESS; EPITHELIAL-CELLS; BREAST-CANCER; ALPHA-KLOTHO; G2/M ARREST AB Satoh M, Nagasu H, Morita Y, Yamaguchi TP, Kanwar YS, Kashihara N. Klotho protects against mouse renal fibrosis by inhibiting Wnt signaling. Am J Physiol Renal Physiol 303: F1641-F1651, 2012. First published October 3, 2012; doi:10.1152/ajprenal.00460.2012.-Augmented Wnt signaling has been implicated in many fibrotic diseases including obstructive nephropathy. Soluble form Klotho has been reported to function as a secreted Wnt antagonist. In this study, we tested whether Klotho protein could reduce renal fibrosis by inhibition of Wnt signaling. Transgenic mice that overexpressed Klotho, wild-type mice, and Klotho hetero mutant mice underwent unilateral ureteral obstruction (UUO). In some Klotho hetero mutant mice, Klotho-encoding plasmid was transferred into the skeletal muscle by electroporation. UUO induced activation of Wnt signaling in wild-type but less in Klotho transgenic mice. Enhanced tubulointerstitial fibrosis in wild-type mice was also attenuated in Klotho transgenic mice. In contrast, Wnt signaling and concomitant tubulointerstitial fibrosis were further augmented in Klotho hetero mutant mice after UUO compared with wild-type mice. In Klotho-encoding plasmid-transfected Klotho hetero mutant mice, however, Wnt signaling was markedly reduced accompanied by a decrease in extracellular matrix deposition after UUO. In vitro studies showed that stimulation of Wnt3a induced prolonged cell cycle arrest at G(2)/M phase, with a resultant increase in production of fibrogenic cytokines. Cotreatment with Klotho bypassed the G(2)/M arrest and reduced fibrogenic cytokine production. In conclusion, Klotho is a critical negative regulator of Wnt signaling and a suppressor of renal fibrosis in the obstructed kidney model. C1 [Satoh, Minoru; Nagasu, Hajime; Kashihara, Naoki] Kawasaki Med Univ, Dept Hypertens & Nephrol, Kurashiki, Okayama 7010192, Japan. [Morita, Yoshitaka] Kawasaki Med Univ, Dept Rheumatol, Kurashiki, Okayama 7010192, Japan. [Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, Ctr Canc Res, Frederick, MD 21701 USA. [Kanwar, Yashpal S.] Northwestern Univ, Dept Pathol & Med, Chicago, IL 60611 USA. RP Satoh, M (reprint author), Kawasaki Med Univ, Dept Hypertens & Nephrol, 577 Matsushima, Kurashiki, Okayama 7010192, Japan. EM msatoh@med.kawasaki-m.ac.jp FU Japan Society for the Promotion of Science [21591046]; Research Project Grant from Kawasaki Medical School [21-208, 22-A73]; National Institute of Diabetes and Digestive and Kidney Diseases [DK-60635] FX This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science No. 21591046 and the Research Project Grant from Kawasaki Medical School No. 21-208 and No. 22-A73 (to M. Satoh) and National Institute of Diabetes and Digestive and Kidney Diseases DK-60635 (to Y. S. Kanwar). NR 36 TC 37 Z9 43 U1 0 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 DEC PY 2012 VL 303 IS 12 BP F1641 EP F1651 DI 10.1152/ajprenal.00460.2012 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 056PC UT WOS:000312502100010 PM 23034937 ER PT J AU Holbrook, MR AF Holbrook, Michael R. TI Kyasanur forest disease SO ANTIVIRAL RESEARCH LA English DT Review DE Kyasanur forest disease; Alkhurma virus; Tick-borne encephalitis; Flavivirus ID ALKHURMA HEMORRHAGIC-FEVER; ENCEPHALITIS-VIRUS VACCINE; SAUDI-ARABIA; SHIMOGA DISTRICT; MYSORE STATE; EXPERIMENTAL TRANSMISSION; PATHOLOGICAL OBSERVATIONS; HAEMAPHYSALIS SPINIGERA; SEROLOGICAL RESPONSE; IXODES PETAURISTAE AB In the spring of 1957, an outbreak of severe disease was documented in people living near the Kyasanur forest in Karnataka state, India, which also affected wild nonhuman primates. Collection of samples from dead animals and the use of classical virological techniques led to the isolation of a previously unrecognized virus, named Kyasanur forest disease virus (KFDV), which was found to be related to the Russian spring-summer encephalitis (RSSE) complex of tick-borne viruses. Further evaluation found that KFD, which frequently took the form of a hemorrhagic syndrome, differed from most other RSSE virus infections, which were characterized by neurologic disease. Its association with illness in wild primates was also unique. Hemaphysalis spinigera was identified as the probable tick vector. Despite an estimated annual incidence in India of 400-500 cases, KFD is historically understudied. Most of what is known about the disease comes from studies in the late 1950s and early 1960s by the Virus Research Center in Pune, India and their collaborators at the Rockefeller Foundation. A report in ProMED in early 2012 indicated that the number of cases of KFD this year is possibly the largest since 2005, reminding us that there are significant gaps in our knowledge of the disease, including many aspects of its pathogenesis, the host response to infection and potential therapeutic options. A vaccine is currently in use in India, but efforts could be made to improve its long-term efficacy. (C) 2012 Elsevier B.V. All rights reserved. C1 NIAID, Integrated Res Facil, Frederick, MD 21702 USA. RP Holbrook, MR (reprint author), NIAID, Integrated Res Facil, 8200 Res Plaza, Frederick, MD 21702 USA. EM michael.holbrook@nih.gov FU NIAID [HHSN272200200016I] FX MRH is an employee of the Battelle Memorial Institute under its prime contract with NIAID No. HHSN272200200016I. The information presented here is the responsibility of the author and does not necessarily represent views or policies of the US Department of Health and Human Services or the Battelle Memorial Institute. NR 65 TC 19 Z9 19 U1 2 U2 13 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD DEC PY 2012 VL 96 IS 3 BP 353 EP 362 DI 10.1016/j.antiviral.2012.10.005 PG 10 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 056UY UT WOS:000312518100011 PM 23110991 ER PT J AU Zhou, YX Wu, SL Wang, HC Hayakawa, Y Bird, GS Shears, SB AF Zhou, Yixing Wu, Shilan Wang, Huanchen Hayakawa, Yoichi Bird, Gary S. Shears, Stephen B. TI Activation of PLC by an endogenous cytokine (GBP) in Drosophila S3 cells and its application as a model for studying inositol phosphate signalling through ITPK1 SO BIOCHEMICAL JOURNAL LA English DT Article DE calcium; Drosophila; inositol phosphate; insect physiology; phospholipase C (PLC) ID SACCHAROMYCES-CEREVISIAE; POLYPHOSPHATE KINASES; PHOSPHOLIPASE-C; G-PROTEIN; RECEPTOR; 1,4,5-TRISPHOSPHATE; MELANOGASTER; HEXAKISPHOSPHATE; ROLES; PENTAKISPHOSPHATES AB Using immortalized [H-3]inositol-labelled S3 cells, we demonstrated in the present study that various elements of the inositol phosphate signalling cascade are recruited by a Drosophila homologue from a cytokine family of so-called GBPs (growth-blocking peptides). HPLC analysis revealed that dGBP (Drosophila GBP) elevated Ins(1,4,5)P-3 levels 9-fold. By using fluorescent Ca2+ probes, we determined that dGBP initially mobilized Ca2+ from intracellular pools; the ensuing depletion of intracellular Ca2+ stores by dGBP subsequently activated a Ca2+ entry pathway. The addition of dsRNA (double-stranded RNA) to knock down expression of the Drosophila Ins(1,4,5)P-3 receptor almost completely eliminated mobilization of intracellular Ca2+ stores by dGBP. Taken together, the results of the present study describe a classical activation of PLC (phospholipase C) by dGBP. The peptide also promoted increases in the levels of other inositol phosphates with signalling credentials: Ins(1,3,4,5)P-4, Ins(1,4,5,6)P-4 and Ins(1,3,4,5,6)P-5. These results greatly expand the regulatory repertoire of the dGBP family, and also characterize S3 cells as a model for studying the regulation of inositol phosphate metabolism and signalling by endogenous cell-surface receptors. We therefore created a cell-line (S3(ITPK1)) in which heterologous expression of human ITPK (inositol tetrakisphosphate kinase) was controlled by an inducible metallothionein promoter. We found that dGBP-stimulated S3(ITPK1) cells did not synthesize Ins(3,4,5,6)P-4, contradicting a hypothesis that the PLC-coupled phosphotransferase activity of ITPK1 [Ins(1,3,4,5,6)P-5 + Ins(1,3,4)P-3 -> Ins(3,4,5,6)P-4 + Ins(1,3,4,6)P-4] is driven solely by the laws of mass action [Chamberlain, Qian, Stiles, Cho, Jones, Lesley, Grabau, Shears and Spraggon (2007) J. Biol. Chem. 282, 28117-28125]. This conclusion represents a fundamental breach in our understanding of ITPK1 signalling. C1 [Zhou, Yixing; Wang, Huanchen; Shears, Stephen B.] NIEHS, Inositol Signaling Sect, Lab Signal Transduct, NIH,US Dept HHS, Res Triangle Pk, NC 27709 USA. [Wu, Shilan; Bird, Gary S.] NIEHS, Calcium Regulat Sect, Lab Signal Transduct, NIH,US Dept HHS, Res Triangle Pk, NC 27709 USA. [Hayakawa, Yoichi] Saga Univ, Dept Appl Biol Sci, Saga 8408502, Japan. RP Shears, SB (reprint author), NIEHS, Inositol Signaling Sect, Lab Signal Transduct, NIH,US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov OI Bird, Geoffrey/0000-0002-2310-0202 FU Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Sciences FX This work was supported by the Intramural Research Program of the National Institutes of Health/National Institute of Environmental Health Sciences. NR 50 TC 2 Z9 3 U1 0 U2 7 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD DEC 1 PY 2012 VL 448 BP 273 EP 283 DI 10.1042/BJ20120730 PN 2 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 047YU UT WOS:000311878200010 PM 22928859 ER PT J AU Mariani, ME Villarreal, MA Cheung, F Leiva, EPM Madoery, RR Fidelio, GD AF Elisa Mariani, Maria Ariel Villarreal, Marcos Cheung, Foo Marcos Leiva, Ezequiel Pedro Roman Madoery, Ricardo Daniel Fidelio, Gerardo TI In silico and in vitro characterization of phospholipase A(2) isoforms from soybean (Glycine max) SO BIOCHIMIE LA English DT Article DE Glycine max phospholipase A(2); PLA(2) phylogenetic tree; Molecular dynamics simulations; i-face; Soybean PLA(2); Plant secreted phospholipase ID MOLECULAR-DYNAMICS SIMULATIONS; PARTICLE MESH EWALD; N-TERMINAL REGION; RICE ORYZA-SATIVA; ACTIVE-SITE; ARABIDOPSIS-THALIANA; ENZYMATIC-PROPERTIES; STRUCTURE PREDICTION; COBRA VENOM; PROTEIN AB At the present, no secreted phospholipase A(2) (sPLA(2)) from soybean (Glycine max) was investigated in detail. In this work we identified five sequences of putative secreted sPLA(2) from soybean after a BLAST search in G. max database. Sequence analysis showed a conserved PA2c domain bearing the Ca2+ binding loop and the active site motif. All the five mature proteins contain 12 cysteine residues, which are commonly conserved in plant sPLA(2)s. We propose a phylogenetic tree based on sequence alignment of reported plant sPLA(2)s including the novel enzymes from G. max. According to PLA(2) superfamily, two of G. max sPLA(2)s are grouped as XIA and the rest of sequences as XIB, on the basis of differences found in their molecular weights and deviating sequences especially in the N- and C-terminal regions of the isoenzymes. Furthermore, we report the cloning, expression and purification of one of the putative isoenzyme denoted as GmsPLA(2)-XIA-1. We demonstrate that this mature sPLA(2) of 114 residues had PLA(2) activity on Triton:phospholipid mixed micelles and determine the kinetic parameters for this system. We generate a model based on the known crystal structure of sPLA(2) from rice (isoform II), giving first insights into the three-dimensional structure of folded GmsPLA2-XIA-1. Besides describing the spatial arrangement of highly conserved pair HIS-49/ASP-50 and the Ca+2 loop domains, we propose the putative amino acids involved in the interfacial recognition surface. Additionally, molecular dynamics simulations indicate that calcium ion, besides its key function in the catalytic cycle, plays an important role in the overall stability of GmsPLA(2)-XIA-1 structure. (C) 2012 Elsevier Masson SAS. All rights reserved. C1 [Elisa Mariani, Maria; Daniel Fidelio, Gerardo] Univ Nacl Cordoba, Ctr Invest Quim Biol Cordoba, Dept Quim Biol, Fac Cs Quim,CIQUIBIC,UNIC CONICET, RA-5000 Cordoba, Argentina. [Ariel Villarreal, Marcos; Marcos Leiva, Ezequiel Pedro] Univ Nacl Cordoba, Fac Ciencias Quim, Dept Matemat & Fis, RA-5000 Cordoba, Argentina. [Cheung, Foo] NIH, Ctr Human Immunol Autoimmun & Inflammat, Bethesda, MD 20892 USA. [Elisa Mariani, Maria; Roman Madoery, Ricardo] Univ Nacl Cordoba, Fac Ciencias Agr, Dept Fundamentac Biol, RA-5000 Cordoba, Argentina. RP Fidelio, GD (reprint author), Univ Nacl Cordoba, Ctr Invest Quim Biol Cordoba, Dept Quim Biol, Fac Cs Quim,CIQUIBIC,UNIC CONICET, Ciudad Univ,X5000HUA, RA-5000 Cordoba, Argentina. EM gfidelio@dqb.fcq.unc.edu.ar FU MinCyT Cordoba (ex-Agencia Cordoba Ciencia); CONICET; FONCYT; SeCyT-UNC; USDA [2006-35300-17144] FX This work was supported, in part, by grants from MinCyT Cordoba (ex-Agencia Cordoba Ciencia), CONICET, FONCYT and SeCyT-UNC. M.E.M. is a fellow from MinCyT Cordoba-CONICET under special agreement. M.A.V., E.P.M.L. and G.D.F. are members of the Scientific Research Career (CIC) from CONICET. We thank to Ann-Maree Catanzariti for the PHUE vector system. The clone was generated under funding from the USDA (Grant Number 2006-35300-17144) to the J. Craig Venter Institute (P.I. Christopher D. Town). We also thank Rodrigo Quiroga for useful comments in bioinformatic analysis. NR 78 TC 7 Z9 7 U1 0 U2 8 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0300-9084 J9 BIOCHIMIE JI Biochimie PD DEC PY 2012 VL 94 IS 12 BP 2608 EP 2619 DI 10.1016/j.biochi.2012.07.021 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 056UV UT WOS:000312517800018 PM 23281487 ER PT J AU Butler, AM Yin, XY Evans, DS Nalls, MA Smith, EN Tanaka, T Li, G Buxbaum, SG Whitsel, EA Alonso, A Arking, DE Benjamin, EJ Berenson, GS Bis, JC Chen, W Deo, R Ellinor, PT Heckbert, SR Heiss, G Hsueh, WC Keating, BJ Kerr, KF Li, Y Limacher, MC Liu, YM Lubitz, SA Marciante, KD Mehra, R Meng, YA Newman, AB Newton-Cheh, C North, KE Palmer, CD Psaty, BM Quibrera, PM Redline, S Reiner, AP Rotter, JI Schnabel, RB Schork, NJ Singleton, AB Smith, JG Soliman, EZ Srinivasan, SR Zhang, ZM Zonderman, AB Ferrucci, L Murray, SS Evans, MK Sotoodehnia, N Magnani, JW Avery, CL AF Butler, Anne M. Yin, Xiaoyan Evans, Daniel S. Nalls, Michael A. Smith, Erin N. Tanaka, Toshiko Li, Guo Buxbaum, Sarah G. Whitsel, Eric A. Alonso, Alvaro Arking, Dan E. Benjamin, Emelia J. Berenson, Gerald S. Bis, Josh C. Chen, Wei Deo, Rajat Ellinor, Patrick T. Heckbert, Susan R. Heiss, Gerardo Hsueh, Wen-Chi Keating, Brendan J. Kerr, Kathleen F. Li, Yun Limacher, Marian C. Liu, Yongmei Lubitz, Steven A. Marciante, Kristin D. Mehra, Reena Meng, Yan A. Newman, Anne B. Newton-Cheh, Christopher North, Kari E. Palmer, Cameron D. Psaty, Bruce M. Quibrera, P. Miguel Redline, Susan Reiner, Alex P. Rotter, Jerome I. Schnabel, Renate B. Schork, Nicholas J. Singleton, Andrew B. Smith, J. Gustav Soliman, Elsayed Z. Srinivasan, Sathanur R. Zhang, Zhu-ming Zonderman, Alan B. Ferrucci, Luigi Murray, Sarah S. Evans, Michele K. Sotoodehnia, Nona Magnani, Jared W. Avery, Christy L. TI Novel Loci Associated With PR Interval in a Genome-Wide Association Study of 10 African American Cohorts SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE electrocardiography; epidemiology; genome-wide association study; PR interval; single-nucleotide polymorphism genetics ID ATRIAL-FIBRILLATION; COMMON VARIANTS; CARDIAC CONDUCTION; QRS DURATION; HEART-RATE; POPULATION; METAANALYSIS; RISK; INDIVIDUALS; PREDICTORS AB Background-The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans. Methods and Results-We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and approximate to 2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (lambda range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (lambda: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0x10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0x10-8). Conclusions-This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent. (Circ Cardiovasc Genet. 2012;5:639-646.) C1 [Butler, Anne M.; Whitsel, Eric A.; Heiss, Gerardo; North, Kari E.; Quibrera, P. Miguel; Avery, Christy L.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Whitsel, Eric A.] Univ N Carolina, Sch Med, Dept Pediat, Chapel Hill, NC 27514 USA. [Liu, Yongmei] Univ N Carolina, Dept Genet, Chapel Hill, NC 27514 USA. [Liu, Yongmei] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27514 USA. [North, Kari E.] Univ N Carolina, Carolina Ctr Genome Sci, Chapel Hill, NC 27514 USA. [Yin, Xiaoyan; Benjamin, Emelia J.; Magnani, Jared W.] NHLBI, Framingham, MA USA. [Yin, Xiaoyan; Benjamin, Emelia J.; Magnani, Jared W.] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Evans, Daniel S.] Calif Pacific Med Ctr Res Inst, San Francisco, CA USA. [Butler, Anne M.; Evans, Michele K.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Tanaka, Toshiko; Ferrucci, Luigi; Evans, Michele K.] NIA, Clin Res Branch, Bethesda, MD 20892 USA. [Smith, Erin N.] Univ Calif San Diego, Sch Med, Dept Pediat, La Jolla, CA 92093 USA. [Smith, Erin N.] Univ Calif San Diego, Sch Med, Rady Childrens Hosp, La Jolla, CA 92093 USA. [Li, Guo; Bis, Josh C.; Heckbert, Susan R.; Marciante, Kristin D.; Psaty, Bruce M.; Schork, Nicholas J.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. [Keating, Brendan J.; Redline, Susan] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Kerr, Kathleen F.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Buxbaum, Sarah G.] Jackson State Univ, Jackson Heart Study, Jackson, MS USA. [Buxbaum, Sarah G.] Jackson State Univ, Sch Hlth Sci, Jackson, MS USA. [Alonso, Alvaro] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. [Magnani, Jared W.] Boston Univ, Sch Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Benjamin, Emelia J.] Boston Univ, Dept Epidemiol, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sect Prevent Med, Boston, MA 02215 USA. [Berenson, Gerald S.; Chen, Wei; Srinivasan, Sathanur R.] Tulane Univ, Dept Epidemiol, New Orleans, LA 70118 USA. [Deo, Rajat] Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Ellinor, Patrick T.; Lubitz, Steven A.; Newton-Cheh, Christopher] MGH, Cardiovasc Res Ctr, Charlestown, MA USA. [Ellinor, Patrick T.; Lubitz, Steven A.; Newton-Cheh, Christopher] Harvard Univ, Sch Med, Charlestown, MA USA. [Ellinor, Patrick T.] MGH, Ctr Human Genet Res, Cardiac Arrhythmia Serv, Boston, MA USA. [Newton-Cheh, Christopher] Harvard Univ, Sch Med, Boston, MA USA. [Hsueh, Wen-Chi] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Keating, Brendan J.] Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA. [Limacher, Marian C.] Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL USA. [Liu, Yongmei; Soliman, Elsayed Z.; Zhang, Zhu-ming] Wake Forest Univ, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Mehra, Reena] Case Western Sch Med, Dept Med, Cleveland, OH USA. [Meng, Yan A.; Newton-Cheh, Christopher; Palmer, Cameron D.] Broad Inst Harvard & MIT, Program Med & Populat Genet, Cambridge, MA USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Redline, Susan] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Sleep Med, Boston, MA 02115 USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Schnabel, Renate B.] Univ Med Ctr Hamburg, Clin Gen & Intervent Cardiol, Hamburg, Germany. [Schork, Nicholas J.; Murray, Sarah S.] Scripps Translat Sci Inst, La Jolla, CA USA. [Schork, Nicholas J.] Scripps Res Inst, La Jolla, CA 92037 USA. [Smith, J. Gustav] Lund Univ, Dept Cardiol, Fac Med, Lund, Sweden. [Singleton, Andrew B.] NIA, Lab Personal & Cognit, Bethesda, MD 20892 USA. [Murray, Sarah S.] Scripps Hlth, La Jolla, CA USA. RP Butler, AM (reprint author), Univ N Carolina, Dept Epidemiol, 137 E Franklin St,Suite 306, Chapel Hill, NC 27514 USA. EM anne.butler@unc.edu RI Singleton, Andrew/C-3010-2009; Alonso, Alvaro/A-4917-2010; Schnabel, Renate/F-6527-2014; Newman, Anne/C-6408-2013; Kerr, Kathleen/A-2893-2013; Buxbaum, Sarah/E-1970-2013; OI Zonderman, Alan B/0000-0002-6523-4778; Alonso, Alvaro/0000-0002-2225-8323; Newman, Anne/0000-0002-0106-1150; Buxbaum, Sarah/0000-0002-4886-3564; Mehra, Reena/0000-0002-6222-2675; Benjamin, Emelia/0000-0003-4076-2336 FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; National Human Genome Research Institute [U01HG004402]; National institute of Health (NIH) [HHSN268200625226C, HL 46380, M01RR00080, HHSN268200782096C, N01-HC-95170, N01-HC-95171, N01-HC-95172]; NIH Roadmap for Medical Research [UL1RR025005]; NIH/National Institute on Aging (NIA); MedStar Research Institute; National Institute of Child Health and Human Development [HD-061437, HD-062783]; National Institute on Aging [AG-16592, AG-023629, AG-15928, AG-20098, AG-027058, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; NIH/National Center for Research Resources (NCRR) [UL1 RR025774]; Scripps Genomic Medicine; Case Western Reserve University; National Institute of Neurological Disorders and Stroke (NINDS); National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; NIH, NIA; National Center on Minority Health and Health Disparities [Z01-AG000513, 2009-149]; University of Washington [N01-HC-95159]; Regents of the University of California [N01-HC-95160]; Columbia University [N01-HC-95161]; Johns Hopkins University [N01-HC-95162, N01-HC-95168]; University of Minnesota [N01-HC-95163]; Northwestern University [N01-HC-95164]; Wake Forest University [N01-HC-95165]; University of Vermont [N01-HC-95166]; New England Medical Center [N01-HC-95167]; Harbor-UCLA Research and Education Institute [N01-HC-95169]; Cedars-Sinai Medical Center [R01-HL-071205]; University of Virginia [R01-HL-071205]; National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118, 32119, 32122, 42107-26, 42129-32, 44221]; National Institute of Environmental Health Sciences [ES017794]; NHLBI [N01-HC-85239, N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01-HC-55222, N01-HC-75150, N01-HC-45133, HL080295, HL075366, HL087652, HL085251, HL105756, N02-HL-64278]; [R01HL087641]; [R01HL59367]; [R01HL086694]; [HL098458]; [CA009330]; [HL092577]; [DA027021]; [HL104156]; [HL105780]; [HG006292]; [HG006703] FX The ARIC study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National institute of Health (NIH) contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the NIH Roadmap for Medical Research.; The BLSA was supported in part by the Intramural Research Program of the NIH/National Institute on Aging (NIA). A portion of that support was through a contract with MedStar Research Institute.; The BHS was supported by grants HD-061437 and HD-062783 from the National Institute of Child Health and Human Development and AG-16592 from the National Institute on Aging. ENS, SSM, and NJS were supported in part by NIH/National Center for Research Resources (NCRR) Grant Number UL1 RR025774 and Scripps Genomic Medicine.; The CFS was supported by NIH (HL 46380, M01RR00080) and Case Western Reserve University.; CHS was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086; N01-HC-35129, N01 HC-15103, N01-HC-55222, N01-HC-75150, and N01-HC-45133; and NHLBI grants HL080295, HL075366, HL087652, HL085251, and HL105756, with additional contribution from National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chs-nhlbi.org/pi.htm. DNA handling and genotyping was supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center.; The HABC study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The GWA study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research, which is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, NIA.; The HANDLS study was supported by the Intramural Research Program of the NIH, NIA, and the National Center on Minority Health and Health Disparities (contract #Z01-AG000513 and human subjects protocol #2009-149). Data analyses for the Healthy Aging in Neighborhoods of Diversity across the Life Span Study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH (http://biowulf.nih.gov).; The JHS was supported by NIH contracts N01-HC-95170, N01-HC-95171, and N01-HC-95172 provided by the NHLBI and the National Center for Minority Health and Health Disparities.; The MESA study was supported by University of Washington (N01-HC-95159), Regents of the University of California (N01-HC-95160), Columbia University (N01-HC-95161), Johns Hopkins University (N01-HC-95162, N01-HC-95168), University of Minnesota (N01-HC-95163), Northwestern University (N01-HC-95164), Wake Forest University (N01-HC-95165), University of Vermont (N01-HC-95166), New England Medical Center (N01-HC-95167), Harbor-UCLA Research and Education Institute (N01-HC-95169), Cedars-Sinai Medical Center (R01-HL-071205), and University of Virginia (subcontract to R01-HL-071205).; The WHI was funded by the National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118 to 32119, 32122, 42107-26, 42129-32, and 44221. Funding for the WHI SHARE genotyping was provided by NHLBI contract N02-HL-64278.; Dr Avery was supported by HL098458 and A. M. Butler acknowledges support from CA009330. Dr Ellinor was supported by grants HL092577, DA027021, HL104156, and HL105780. Dr Liu was supported by grants HG006292 and HG006703. Additional support was provided by the National Institute of Environmental Health Sciences (ES017794). NR 43 TC 18 Z9 19 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2012 VL 5 IS 6 BP 639 EP 646 DI 10.1161/CIRCGENETICS.112.963991 PG 8 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 060JY UT WOS:000312774800012 PM 23139255 ER PT J AU Smith, JG Avery, CL Evans, DS Nalls, MA Meng, YA Smith, EN Palmer, C Tanaka, T Mehra, R Butler, AM Young, T Buxbaum, SG Kerr, KF Berenson, GS Schnabel, RB Li, G Ellinor, PT Magnani, JW Chen, W Bis, JC Curb, JD Hsueh, WC Rotter, JI Liu, YM Newman, AB Limacher, MC North, KE Reiner, AP Quibrera, PM Schork, NJ Singleton, AB Psaty, BM Soliman, EZ Solomon, AJ Srinivasan, SR Alonso, A Wallace, R Redline, S Zhang, ZM Post, WS Zonderman, AB Taylor, HA Murray, SS Ferrucci, L Arking, DE Evans, MK Fox, ER Sotoodehnia, N Heckbert, SR Whitsel, EA Newton-Cheh, C AF Smith, J. Gustav Avery, Christy L. Evans, Daniel S. Nalls, Michael A. Meng, Yan A. Smith, Erin N. Palmer, Cameron Tanaka, Toshiko Mehra, Reena Butler, Anne M. Young, Taylor Buxbaum, Sarah G. Kerr, Kathleen F. Berenson, Gerald S. Schnabel, Renate B. Li, Guo Ellinor, Patrick T. Magnani, Jared W. Chen, Wei Bis, Joshua C. Curb, J. David Hsueh, Wen-Chi Rotter, Jerome I. Liu, Yongmei Newman, Anne B. Limacher, Marian C. North, Kari E. Reiner, Alexander P. Quibrera, P. Miguel Schork, Nicholas J. Singleton, Andrew B. Psaty, Bruce M. Soliman, Elsayed Z. Solomon, Allen J. Srinivasan, Sathanur R. Alonso, Alvaro Wallace, Robert Redline, Susan Zhang, Zhu-Ming Post, Wendy S. Zonderman, Alan B. Taylor, Herman A. Murray, Sarah S. Ferrucci, Luigi Arking, Dan E. Evans, Michele K. Fox, Ervin R. Sotoodehnia, Nona Heckbert, Susan R. Whitsel, Eric A. Newton-Cheh, Christopher CA CARe & COGENT Consortia TI Impact of Ancestry and Common Genetic Variants on QT Interval in African Americans SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE electrocardiography; electrophysiology; genome-wide association studies; ion channels; repolarization ID SUDDEN CARDIAC DEATH; ATRIAL-FIBRILLATION; HEART; DESIGN; RISK; ASSOCIATION; POPULATION; HEALTH; GENOME; REPOLARIZATION AB Background-Ethnic differences in cardiac arrhythmia incidence have been reported, with a particularly high incidence of sudden cardiac death and low incidence of atrial fibrillation in individuals of African ancestry. We tested the hypotheses that African ancestry and common genetic variants are associated with prolonged duration of cardiac repolarization, a central pathophysiological determinant of arrhythmia, as measured by the electrocardiographic QT interval. Methods and Results-First, individual estimates of African and European ancestry were inferred from genome-wide single-nucleotide polymorphism (SNP) data in 7 population-based cohorts of African Americans (n=12 097) and regressed on measured QT interval from ECGs. Second, imputation was performed for 2.8 million SNPs, and a genome-wide association study of QT interval was performed in 10 cohorts (n=13 105). There was no evidence of association between genetic ancestry and QT interval (P=0.94). Genome-wide significant associations (P<2.5x10(-8)) were identified with SNPs at 2 loci, upstream of the genes NOS1AP (rs12143842, P=2x10(-15)) and ATP1B1 (rs1320976, P=2x10(-10)). The most significant SNP in NOS1AP was the same as the strongest SNP previously associated with QT interval in individuals of European ancestry. Low probability values (P<10(-5)) were observed for SNPs at several other loci previously identified in genome-wide association studies in individuals of European ancestry, including KCNQ1, KCNH2, LITAF, and PLN. Conclusions-We observed no difference in duration of cardiac repolarization with global genetic indices of African American ancestry. In addition, our genome-wide association study extends the association of polymorphisms at several loci associated with repolarization in individuals of European ancestry to include individuals of Afr. (Circ Cardiovasc Genet. 2013;5:647-655.) C1 [Li, Guo; Bis, Joshua C.; Schork, Nicholas J.; Psaty, Bruce M.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Sotoodehnia, Nona] Univ Washington, Div Cardiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Psaty, Bruce M.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Magnani, Jared W.] Boston Univ, Sch Med, Sect Cardiovasc Med, Boston, MA 02118 USA. [Magnani, Jared W.] NHLBIs Framingham Heart Study, Framingham, MA USA. [Curb, J. David] Univ Hawaii, John A Burns Sch Med, Dept Med, Div Clin Epidemiol, Honolulu, HI 96822 USA. [Hsueh, Wen-Chi] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Liu, Yongmei] Wake Forest Univ, Dept Epidemiol & Prevent, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Limacher, Marian C.] Univ Florida, Div Cardiovasc Med, Gainesville, FL USA. [Reiner, Alexander P.; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Sch Publ Hlth, Seattle, WA 98195 USA. [Reiner, Alexander P.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Schork, Nicholas J.; Murray, Sarah S.] Scripps Translat Sci Inst, La Jolla, CA USA. [Schork, Nicholas J.; Murray, Sarah S.] Scripps Res Inst, La Jolla, CA 92037 USA. [Psaty, Bruce M.] Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA USA. [Soliman, Elsayed Z.; Zhang, Zhu-Ming] Wake Forest Univ, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Butler, Anne M.] George Washington Univ, Dept Cardiol, Washington, DC USA. [Alonso, Alvaro] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Wallace, Robert] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Redline, Susan] Harvard Univ, Sch Med, Dept Med, Div Sleep Med, Boston, MA USA. [Redline, Susan] Harvard Univ, Sch Med, Dept Med, Div Pulm Med, Boston, MA USA. [Post, Wendy S.] Johns Hopkins Univ, Dept Med, Bethesda, MD USA. [Singleton, Andrew B.] NIA, Lab Personal & Cognit, NIH, Bethesda, MD 20892 USA. [Taylor, Herman A.; Fox, Ervin R.] Univ Mississippi, Div Cardiovasc Dis, Dept Med, Jackson, MS USA. [Ferrucci, Luigi; Evans, Michele K.] NIA, Clin Res Branch, NIH, Bethesda, MD 20892 USA. [Arking, Dan E.] Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. RP Smith, JG (reprint author), Lund Univ, Skane Univ Hosp, Dept Cardiol, S-22185 Lund, Sweden. EM gustav.smith@med.lu.se RI Singleton, Andrew/C-3010-2009; Alonso, Alvaro/A-4917-2010; Schnabel, Renate/F-6527-2014; Newman, Anne/C-6408-2013; Kerr, Kathleen/A-2893-2013; Buxbaum, Sarah/E-1970-2013; OI Alonso, Alvaro/0000-0002-2225-8323; Newman, Anne/0000-0002-0106-1150; Buxbaum, Sarah/0000-0002-4886-3564; Mehra, Reena/0000-0002-6222-2675; Zonderman, Alan B/0000-0002-6523-4778 FU National Heart, Lung, and Blood Institute (NHLBI) [HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C]; Cleveland Family Study: Case Western Reserve University (National Institutes of Health [NIH]) [HL 46380, M01RR00080]; Jackson Heart Study: Jackson State University [N01-HC-95170]; University of Mississippi [N01-HC-95171]; Tougaloo College by the NHLBI [N01-HC-95172]; National Center for Minority Health and Health Disparities; Multi-Ethnic Study of Atherosclerosis: University of Washington [N01-HC-95159]; Regents of the University of California [N01-HC-95160]; Columbia University [N01-HC-95161]; Johns Hopkins University [N01-HC-95162, N01-HC-95168]; University of Minnesota [N01-HC-95163]; Northwestern University [N01-HC-95164]; Wake Forest University [N01-HC-95165]; University of Vermont [N01-HC-95166]; New England Medical Center [N01-HC-95167]; Harbor-UCLA Research and Education Institute [N01-HC-95169]; Cedars-Sinai Medical Center [R01-HL-071205]; NIH, National Institute on Aging (NIA); NIA [AG-023629, AG-15928, AG-20098, AG-027058, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1]; National Center for Research Resources [M01-RR00425]; National Institute of Diabetes and Digestive and Kidney Diseases [DK063491]; NIH [HHSN268200782096C, R01-HL-111089, R01-HL-088456, 1R01HL098283]; NIH, NIA; National Center for Minority Health and Health Disparities, NIH; National Center on Minority Health and Health Disparities [Z01-AG000513]; NHLBI, NIH, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221]; NHLBI [N02-HL-64278, R00-HL-098458]; Swedish Heart Lung Foundation; NIH/National Institute of Environmental Health Sciences [1-R01-ES017794]; NIH/ National Cancer Institute [N01-WH-2-2110]; Doris Duke Charitable Foundation; Burroughs Wellcome Fund Career Award for Medical Scientists FX The following 4 parent studies contributed parent study data, ancillary study data, and DNA samples through the Massachusetts Institute of Technology-Broad Institute (N01-HC-65226) to create the Candidate Gene Association Resource genotype/phenotype database for wide dissemination to the biomedical research community. The Atherosclerosis Risk in Communities study is carried out as a collaborative study supported by National Heart, Lung, and Blood Institute (NHLBI) contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C); Cleveland Family Study: Case Western Reserve University (National Institutes of Health [NIH] HL 46380, M01RR00080); Jackson Heart Study: Jackson State University (N01-HC-95170); University of Mississippi (N01-HC-95171); Tougaloo College (N01-HC-95172) provided by the NHLBI and the National Center for Minority Health and Health Disparities; Multi-Ethnic Study of Atherosclerosis: University of Washington (N01-HC-95159); Regents of the University of California (N01-HC-95160); Columbia University (N01-HC-95161); Johns Hopkins University (N01-HC-95162, N01-HC-95168); University of Minnesota (N01-HC-95163); Northwestern University (N01-HC-95164); Wake Forest University (N01-HC-95165); University of Vermont (N01-HC-95166); New England Medical Center (N01-HC-95167); Harbor-UCLA Research and Education Institute (N01-HC-95169); Cedars-Sinai Medical Center (R01-HL-071205); and University of Virginia (subcontract to R01-HL-071205). The Baltimore Longitudinal Study of Aging was supported in part by the Intramural Research Program of the NIH, National Institute on Aging (NIA). A portion of that support was through an R&D contract with MedStar Research Institute. Bogalusa Heart Study investigators Drs Smith, Murray, and Schork were supported in part by NIH/National Center for Research Resources Grant Number UL1 RR025774 and Scripps Genomic Medicine. The Bogalusa Heart Study was supported by grants HD-061437 and HD-062783 from the National Institute of Child Health and Human Development and AG-16592 from the NIA. The Cardiovascular Health Study was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, and N01-HC-45133, and NHLBI grants HL080295, HL075366, HL087652, HL085251, and HL105756, with additional contributions from the National Institute of Neurological Disorders and Stroke. Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the NIA. See also http://www.chsnhlbi.org/pi.htm. DNA handling and genotyping were supported in part by National Center for Research Resources grant M01-RR00425 to the Cedars-Sinai General Clinical Research Center Genotyping core and National Institute of Diabetes and Digestive and Kidney Diseases grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Health, Aging, and Body Composition Study was supported by NIA contracts N01AG62101, N01AG62103, and N01AG62106. The GWA study was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research, which is fully funded through a federal contract from the NIH to The Johns Hopkins University, contract number HHSN268200782096C. This research was supported in part by the Intramural Research Program of the NIH, NIA.; The HANDLS study was in part supported by the intramural research program of the NIA and the National Center for Minority Health and Health Disparities, NIH. This research was supported by the Intramural Research Program of the NIH, NIA, and the National Center on Minority Health and Health Disparities (project Z01-AG000513 and human subjects protocol 2009-149). Data analyses for the HANDLS study used the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD. (http://biowulf.nih.gov). The WHI is funded by the NHLBI, NIH, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. This article was prepared in collaboration with investigators of the WHI and has been reviewed and approved by the WHI. WHI investigators are listed at http:// www.whiscience.org/publications/WHI_investigators_shortlist.pdf. Funding for WHI SHARE genotyping was provided by NHLBI contract N02-HL-64278. Dr Smith was supported by the Swedish Heart Lung Foundation. Dr Avery was supported by NHLBI grant R00-HL-098458. A. Butler was supported by National Cancer Institute grant 5T32CA009330-30. This work was funded in part by grants from the NIH/National Institute of Environmental Health Sciences (1-R01-ES017794, Dr Whitsel) and the NIH/ National Cancer Institute (N01-WH-2-2110, Dr North). Dr Sotoodehnia was supported by NIH grants R01-HL-111089 and R01-HL-088456. Dr Newton-Cheh was supported by NIH grant 1R01HL098283, Doris Duke Charitable Foundation Clinical Scientist Development Award, and Burroughs Wellcome Fund Career Award for Medical Scientists. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article. NR 45 TC 19 Z9 19 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2012 VL 5 IS 6 BP 647 EP 655 DI 10.1161/CIRCGENETICS.112.962787 PG 9 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 060JY UT WOS:000312774800013 PM 23166209 ER PT J AU Gertow, K Sennblad, B Strawbridge, RJ Ohrvik, J Zabaneh, D Shah, S Veglia, F Fava, C Kavousi, M McLachlan, S Kivimaki, M Bolton, JL Folkersen, L Gigante, B Leander, K Vikstrom, M Larsson, M Silveira, A Deanfield, J Voight, BF Fontanillas, P Sabater-Lleal, M Colombo, GI Kumari, M Langenberg, C Wareham, NJ Uitterlinden, AG Gabrielsen, A Hedin, U Franco-Cereceda, A Nyyssonen, K Rauramaa, R Tuomainen, TP Savonen, K Smit, AJ Giral, P Mannarino, E Robertson, CM Talmud, PJ Hedblad, B Hofman, A Erdmann, J Reilly, MP O'Donnell, CJ Farrall, M Clarke, R Franzosi, MG Seedorf, U Syvanen, AC Hansson, GK Eriksson, P Samani, NJ Watkins, H Price, JF Hingorani, AD Melander, O Witteman, JCM Baldassarre, D Tremoli, E de Faire, U Humphries, SE Hamsten, A AF Gertow, Karl Sennblad, Bengt Strawbridge, Rona J. Oehrvik, John Zabaneh, Delilah Shah, Sonia Veglia, Fabrizio Fava, Cristiano Kavousi, Maryam McLachlan, Stela Kivimaeki, Mika Bolton, Jennifer L. Folkersen, Lasse Gigante, Bruna Leander, Karin Vikstrom, Max Larsson, Malin Silveira, Angela Deanfield, John Voight, Benjamin F. Fontanillas, Pierre Sabater-Lleal, Maria Colombo, Gualtiero I. Kumari, Meena Langenberg, Claudia Wareham, Nick J. Uitterlinden, Andre G. Gabrielsen, Anders Hedin, Ulf Franco-Cereceda, Anders Nyyssonen, Kristiina Rauramaa, Rainer Tuomainen, Tomi-Pekka Savonen, Kai Smit, Andries J. Giral, Philippe Mannarino, Elmo Robertson, Christine M. Talmud, Philippa J. Hedblad, Bo Hofman, Albert Erdmann, Jeanette Reilly, Muredach P. O'Donnell, Christopher J. Farrall, Martin Clarke, Robert Franzosi, Maria Grazia Seedorf, Udo Syvanen, Ann-Christine Hansson, Goran K. Eriksson, Per Samani, Nilesh J. Watkins, Hugh Price, Jacqueline F. Hingorani, Aroon D. Melander, Olle Witteman, Jacqueline C. M. Baldassarre, Damiano Tremoli, Elena de Faire, Ulf Humphries, Steve E. Hamsten, Anders TI Identification of the BCAR1-CFDP1-TMEM170A Locus as a Determinant of Carotid Intima-Media Thickness and Coronary Artery Disease Risk SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE atherosclerosis; carotid intima-media thickness; coronary artery disease; genetics ID GENOME-WIDE ASSOCIATION; VASCULAR SMOOTH-MUSCLE; CARDIOVASCULAR RISK; MYOCARDIAL-INFARCTION; WHITEHALL-II; ATHEROSCLEROSIS; SUSCEPTIBILITY; METAANALYSIS; ROTTERDAM; CALCIFICATION AB Background-Carotid intima-media thickness (cIMT) is a widely accepted marker of subclinical atherosclerosis. To date, large-scale investigations of genetic determinants of cIMT are sparse. Methods and Results-To identify cIMT-associated genes and genetic variants, a discovery analysis using the Illumina 200K CardioMetabochip was conducted in 3430 subjects with detailed ultrasonographic determinations of cIMT from the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a High Risk European Population) study. Segment-specific IMT measurements of common carotid, bifurcation, and internal carotid arteries, and composite IMT variables considering the whole carotid tree (IMTmean, IMTmax, and IMTmean-max), were analyzed. A replication stage investigating 42 single-nucleotide polymorphisms for association with common carotid IMT was undertaken in 5 independent European cohorts (total n=11 590). A locus on chromosome 16 (lead single-nucleotide polymorphism rs4888378, intronic in CFDP1) was associated with cIMT at significance levels passing multiple testing correction at both stages (array-wide significant discovery P=6.75x10(-7) for IMTmax; replication P=7.24x10(-6) for common cIMT; adjustments for sex, age, and population substructure where applicable; minor allele frequency 0.43 and 0.41, respectively). The protective minor allele was associated with lower carotid plaque score in a replication cohort (P=0.04, n=2120) and lower coronary artery disease risk in 2 case-control studies of subjects with European ancestry (odds ratio [95% confidence interval] 0.83 [0.77-0.90], P=6.53x10(-6), n=13 591; and 0.95 [0.92-0.98], P=1.83x10(-4), n= 82 297, respectively). Queries of human biobank data sets revealed associations of rs4888378 with nearby gene expression in vascular tissues (n=126-138). Conclusions-This study identified rs4888378 in the BCAR1-CFDP1-TMEM170A locus as a novel genetic determinant of cIMT and coronary artery disease risk in individuals of European descent. (Circ Cardiovasc Genet. 2012;5:656-665.) C1 [Gertow, Karl; Sennblad, Bengt; Strawbridge, Rona J.; Oehrvik, John; Folkersen, Lasse; Larsson, Malin; Silveira, Angela; Sabater-Lleal, Maria; Eriksson, Per; Hamsten, Anders] Karolinska Univ Hosp Solna, Ctr Mol Med, Atherosclerosis Res Unit, Dept Med,Karolinska Inst, S-17176 Stockholm, Sweden. [Folkersen, Lasse; Uitterlinden, Andre G.; Hansson, Goran K.] Karolinska Univ Hosp Solna, Ctr Mol Med, Expt Cardiovasc Res Unit, Dept Med,Karolinska Inst, S-17176 Stockholm, Sweden. [Zabaneh, Delilah; Shah, Sonia] UCL, Genet Inst, London, England. [Kivimaeki, Mika; Kumari, Meena; Langenberg, Claudia; Hingorani, Aroon D.] UCL, Genet Epidemiol Grp, Dept Epidemiol & Publ Hlth, London, England. [Talmud, Philippa J.; Humphries, Steve E.] UCL, BHF Labs, Dept Med, Ctr Clin Pharmacol, London, England. [Veglia, Fabrizio; Colombo, Gualtiero I.; Baldassarre, Damiano; Tremoli, Elena] IRCCS, Ctr Cardiol Monzino, Milan, Italy. [Fava, Cristiano; Hedblad, Bo; Melander, Olle] Lund Univ, Skane Univ Hosp, Dept Clin Sci, Clin Res Ctr, Lund, Sweden. [Fava, Cristiano] Univ Verona, Hosp Policlin GB Rossi, Dept Med, Div Internal Med C, Verona, Italy. [Kavousi, Maryam; Uitterlinden, Andre G.; Hofman, Albert; Witteman, Jacqueline C. M.] Erasmus Univ, Med Ctr, Dept Epidemiol, Rotterdam, Netherlands. [Uitterlinden, Andre G.] Erasmus Univ, Med Ctr, Dept Internal Med, Rotterdam, Netherlands. [Kavousi, Maryam; Uitterlinden, Andre G.; Hofman, Albert; Witteman, Jacqueline C. M.] Sponsored Netherlands Consortium Healthy Ageing, Netherlands Genom Initiat, Rotterdam, Netherlands. [McLachlan, Stela; Bolton, Jennifer L.; Robertson, Christine M.; Price, Jacqueline F.] Univ Edinburgh, Ctr Populat Hlth Sci, Edinburgh, Midlothian, Scotland. [Gigante, Bruna; Leander, Karin; Vikstrom, Max; de Faire, Ulf] Karolinska Inst, Div Cardiovasc Epidemiol, Inst Environm Med, Stockholm, Sweden. [Hedin, Ulf; Franco-Cereceda, Anders] Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden. [Deanfield, John] Great Ormond St Hosp Sick Children, Cardiothorac Unit, London, England. [Voight, Benjamin F.; Fontanillas, Pierre] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Voight, Benjamin F.; Fontanillas, Pierre] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Voight, Benjamin F.; Fontanillas, Pierre] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA. [Langenberg, Claudia; Wareham, Nick J.] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, MRC Epidemiol Unit, Cambridge CB2 2QQ, England. [Nyyssonen, Kristiina; Tuomainen, Tomi-Pekka] Univ Eastern Finland, Inst Publ Hlth & Clin Nutr, Kuopio, Finland. [Rauramaa, Rainer; Savonen, Kai] Fdn Res Hlth Exercise & Nutr, Kuopio Res Inst Exercise Med, Kuopio, Finland. [Rauramaa, Rainer; Savonen, Kai] Kuopio Univ Hosp, Dept Clin Physiol & Nucl Med, SF-70210 Kuopio, Finland. [Smit, Andries J.] Univ Groningen, Univ Med Ctr Groningen, Dept Med, NL-9713 AV Groningen, Netherlands. [Giral, Philippe] Grp Hop Pitie Salpetriere, AP HP, Serv Endocrinol Metab, Unites Prevent Cardiovasc, Paris, France. [Mannarino, Elmo] Univ Perugia, Dept Clin & Expt Med, I-06100 Perugia, Italy. [Erdmann, Jeanette] Med Univ Lubeck, Med Klin 2, D-23538 Lubeck, Germany. [Reilly, Muredach P.] Univ Penn, Inst Translat Med & Therapeut, Philadelphia, PA 19104 USA. [Reilly, Muredach P.] Univ Penn, Cardiovasc Inst, Perelman Sch Med, Philadelphia, PA 19104 USA. [O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [O'Donnell, Christopher J.] NHLBI, Div Intramural Res, Bethesda, MD 20892 USA. [O'Donnell, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Cardiol Div,Dept Med, Boston, MA USA. [Farrall, Martin; Watkins, Hugh] Univ Oxford, Wellcome Trust Ctr Human Genet, Dept Cardiovasc Med, Oxford, England. [Clarke, Robert] Univ Oxford, Clin Trial Serv Unit, Oxford, England. [Farrall, Martin; Watkins, Hugh] Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX3 9DU, England. [Franzosi, Maria Grazia] Inst Mario Negri, Dept Cardiovasc Res, Milan, Italy. [Seedorf, Udo] Univ Munster, LIFA, Gesell Arterioskleroseforsch eV, Munster, Germany. [Syvanen, Ann-Christine] Uppsala Univ, Dept Med Sci, Mol Med & Sci Life Lab, Uppsala, Sweden. [Samani, Nilesh J.] Univ Leicester, Dept Cardiovasc Sci, Leicester, Leics, England. [Samani, Nilesh J.] Glenfield Hosp, Leicester NIHR Biomed Res Unit Cardiovasc Dis, Leicester, Leics, England. [Baldassarre, Damiano; Tremoli, Elena] Univ Milan, Dipartimento Sci Farmacol & Biomol, Milan, Italy. RP Gertow, K (reprint author), Karolinska Univ Hosp Solna, Ctr Mol Med, Atherosclerosis Res Unit, Dept Med,Karolinska Inst, Bldg L8 03, S-17176 Stockholm, Sweden. EM karl.gertow@ki.se RI Sabater-Lleal, Maria/I-5832-2013; Shah, Sonia/N-7547-2013; Colombo, Gualtiero/B-4737-2010; Strawbridge, Rona/H-5422-2012; Veglia, Fabrizio/K-1958-2016; Leander, Karin/C-7261-2017; Baldassarre, Damiano/J-3295-2016; Erdmann, Jeanette/P-7513-2014; OI Shah, Sonia/0000-0001-5860-4526; Colombo, Gualtiero/0000-0002-7348-1939; Strawbridge, Rona/0000-0001-8506-3585; Veglia, Fabrizio/0000-0002-9378-8874; Leander, Karin/0000-0002-1404-9222; TREMOLI, ELENA/0000-0002-0929-6106; Baldassarre, Damiano/0000-0002-2766-8882; mannarino, elmo/0000-0002-9771-8056; Kivimaki, Mika/0000-0002-4699-5627; Talmud, Philippa/0000-0002-5560-1933; Seedorf, Udo/0000-0003-4652-5358; Erdmann, Jeanette/0000-0002-4486-6231; Gigante, Bruna/0000-0003-4508-7990; Folkersen, Lasse/0000-0003-0708-9530; Humphries, Stephen E/0000-0002-8221-6547; Kumari, Meena/0000-0001-9716-1035; Watkins, Hugh/0000-0002-5287-9016; Hedin, Ulf/0000-0001-9212-3945; Sabater Lleal, Maria/0000-0002-0128-379X FU Medical Research Council-GlaxoSmithKline pilot program grant [ID 85374]; European Commission [QLG1-CT-2002-00896, Health F2 2008 200647, FP7-HEALTH- 2007-A-201668]; Swedish Heart-Lung Foundation [20090541]; Swedish Research Council [8691, 0593, 12660]; Knut and Alice Wallenberg Foundation; Torsten and Ragnar Sderberg Foundation; Swedish Foundation for Strategic Research; Stockholm County Council [562183]; Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet; Stockholm County Council, Academy of Finland [110413]; Ministry of Education and Culture of Finland; City of Kuopio; British Heart Foundation (BHF) [RG2008/014, RG2008/08, RG005/014, PG1041133124260, RG1081008]; Italian Ministry of Health (Ricerca Corrente); University College London Genetics Institute; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly [014-93-015; RIDE2]; Ministry of Education, Culture and Science; Ministry for Health, Welfare and Sports; European Commission (DG XII); Municipality of Rotterdam; Netherlands Organization of Scientific Research (De Nederlandse Organisatie voor Wetenschappelijk Onderzoek) [175.010.2005.011, 911-03-012]; Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging [050-060-810]; Netherlands Organization of Scientific Research [918-76-619]; Medical Research Council; National Institutes of Health [R01HL36310, AG13196]; European Research Council [ERC-StG-282255]; Chief Scientist Office of the Scottish Executive Health Department; AFA Insurance Foundation; European Community Sixth Framework Program [LSHM-CT-2007-037273]; AstraZeneca; Wellcome Trust [090532/Z/09/Z]; Strategic Cardiovascular Program of Karolinska Institutet; Foundation for Strategic Research; BHF Center of Research Excellence; Marie Curie Intra European Fellowship within the seventh Framework Program of the European Union [PIEF-GA-2009-252361]; National Heart, Lung and Blood Institute [R01HL36310]; Medical Research Foundation; National Heart, Blood and Lung Institute [HL36310]; Academy of Finland [110413]; French Health Ministry; European Commission 6th Framework Program; European Commission Seventh Framework Program on Diabetes FX The authors fully acknowledge the thousands of study participants who volunteered their time to help advance science and the scores of research staff and scientists who have made this research possible. The Edinburgh Artery Study would particularly like to acknowledge all staff and participants. The authors representing the Rotterdam Study are grateful to the participants and staff, the participating general practitioners, and the pharmacists. Whitehall-II genotyping was, in part, supported by a Medical Research Council-GlaxoSmithKline pilot program grant (ID 85374). David Altshuler, Sekar Kathiresan, and " The Pfizer Broad-Massachusetts General Hospital-Broad Genetics Collaboration" are acknowledged for supporting the genotyping in the MDC study. Members, sources of funding, and disclosures of the CARDIOGRAM consortium are listed in onlineonly Data Supplement Section S7. Members of the PROCARDIS consortium are listed in online-only Data Supplement Section S8. Members of the writing group and affiliations by participating study are listed in online-only Data Supplement Section S9.; The IMPROVE study was supported by the European Commission (Contract No. QLG1-CT-2002-00896), the Swedish Heart-Lung Foundation, the Swedish Research Council (projects 8691 and 0593), the Knut and Alice Wallenberg Foundation, the Torsten and Ragnar Sderberg Foundation, the Swedish Foundation for Strategic Research, the Stockholm County Council (project 562183), the Strategic Cardiovascular and Diabetes Programmes of Karolinska Institutet and Stockholm County Council, Academy of Finland (Grant 110413), the Ministry of Education and Culture of Finland, the City of Kuopio, the British Heart Foundation (BHF) (RG2008/014), and the Italian Ministry of Health (Ricerca Corrente). The University College London Genetics Institute supported Dr Zabaneh and S. Shah, and Dr Humphries was supported by the BHF (RG2008/08). The Rotterdam Study was funded by the Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The Rotterdam Genome-Wide Association study was funded by the Netherlands Organization of Scientific Research (De Nederlandse Organisatie voor Wetenschappelijk Onderzoek) Investments (number 175.010.2005.011, 911-03-012), the Research Institute for Diseases in the Elderly (014-93-015; RIDE2) and the Netherlands Genomics Initiative/Netherlands Consortium for Healthy Aging (project 050-060-810). The present work was further supported by a Netherlands Organization of Scientific Research grant (vici, 918-76-619). The Whitehall-II study was supported by the Medical Research Council, the BHF, and the National Institutes of Health (R01HL36310). Drs Humphries and Talmud were supported by BHF RG005/014. The Malm Diet and Cancer Study was supported by the Swedish Research Council, the Swedish Heart-Lung Foundation, and the European Research Council (ERC-StG-282255). The Edinburgh Artery Study was financed by the BHF and the Chief Scientist Office of the Scottish Executive Health Department. The Advanced Study of Aortic Pathology Study was supported by the Swedish Research Council (12660), the Swedish Heart-Lung Foundation (20090541), the European Commission (FAD, Health F2 2008 200647), and a donation from Fredrik Lundberg. The Biobank of Karolinska Endarterectomies Study was funded by the Swedish Heart-Lung Foundation, the Swedish Research Council, the European Commission (AtheroRemo; FP7-HEALTH- 2007-A-201668), the AFA Insurance Foundation, and the Torsten and Ragnar Sderberg Foundation. PROCARDIS was supported by the European Community Sixth Framework Program (LSHM-CT-2007-037273), AstraZeneca, the BHF, the Wellcome Trust (Contract No. 090532/Z/09/Z), the Swedish Research Council, the Knut and Alice Wallenberg Foundation, the Swedish Heart-Lung Foundation, the Torsten and Ragnar Sderberg Foundation, the Strategic Cardiovascular Program of Karolinska Institutet and Stockholm County Council, the Foundation for Strategic Research and the Stockholm County Council. M. Farall and H. Watkins are supported by the BHF Center of Research Excellence. Dr SabaterLleal is a recipient of a Marie Curie Intra European Fellowship within the seventh Framework Program of the European Union (PIEF-GA-2009-252361).; Dr McLachlan reports stock ownership interest in Pfizer. Dr Kivim ki reports receiving research grant support from the National Heart, Lung and Blood Institute (R01HL36310; principal investigator). Dr Deanfield reports receiving research grant support from the BHF and Medical Research Foundation and honoraria payment and payment for speakers' bureau appointments (Novartis, Roche, Merck, Danone, Pfizer). Dr Voight reports receiving research grant support from the National Institutes of Health (A Genome-Wide Association Study for Early Onset MI; postdoc) and an industry grant (Toward Therapeutical Markers for MI in a T2D Background; postdoc). Dr Kumari reports receiving research grant support from the BHF (PG1041133124260, RG1081008), the National Institutes of Health (AG13196), the Medical Research Council, and the National Heart, Blood and Lung Institute (HL36310). Dr Gabrielsen was employed by Bayer after completion of the study. Dr Hedin reports consultant relationship with Cardoz AB. Dr Nyyssnen reports receiving research grant support from the Academy of Finland for the IMPROVE study (Grant 110413). Dr Giral reports receiving Hospital Clinical Research Program research grant support, awarded by the French Health Ministry. Dr Clarke reports receiving research grant support from the BHF. Dr Franzosi reports receiving research grant support from the European Commission 6th Framework Program as collaborator in the PROCARDIS project. Dr Hingorani reports receiving research grant support from the BHF. Dr Baldassarre reports receiving research grant support from the European Commission (Contract No. QLG1-CT-2002-00896) for the IMPROVE study. Dr Tremoli reports receiving research grant support from the European Commission (Contract No. QLG1-CT-2002-00896) for the IMPROVE study. Dr Humphries reports receiving research grant support from the BHF (RG2008/08, program and project grants on cardiovascular genetics) and the European Commission Seventh Framework Program on Diabetes, and discloses speakers' bureau appointment payment (Genzyme meeting on FH, Amsterdam, November 2011) and 1 consultant/advisory board relationship (Store Gene, a Coronary Heart Disease risk genetic testing University College London spin-off company). NR 33 TC 13 Z9 13 U1 0 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2012 VL 5 IS 6 BP 656 EP 665 DI 10.1161/CIRCGENETICS.112.963660 PG 10 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 060JY UT WOS:000312774800014 PM 23152477 ER PT J AU Chu, AY Guilianini, F Grallert, H Dupuis, J Ballantyne, CM Barratt, BJ Nyberg, F Chasman, DI Ridker, PM AF Chu, Audrey Y. Guilianini, Franco Grallert, Harald Dupuis, Josee Ballantyne, Christie M. Barratt, Bryan J. Nyberg, Fredrik Chasman, Daniel I. Ridker, Paul M. TI Genome-Wide Association Study Evaluating Lipoprotein-Associated Phospholipase A(2) Mass and Activity at Baseline and After Rosuvastatin Therapy SO CIRCULATION-CARDIOVASCULAR GENETICS LA English DT Article DE epidemiology; genome-wide association study; lipoprotein-associated phospholipase A(2); genetics; meta-analysis; statin therapy ID ACTIVATING-FACTOR-ACETYLHYDROLASE; LOW-DENSITY-LIPOPROTEIN; HEART-DISEASE RISK; CARDIOVASCULAR-DISEASE; GENE; METAANALYSIS; ATHEROSCLEROSIS; DETERMINANTS; EXPRESSION; HAPLOTYPES AB Background-Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a proinflammatory enzyme bound to low-density lipoprotein cholesterol and other circulating lipoproteins. Two measures of Lp-PLA(2), mass and activity, are associated with increased cardiovascular risk. Data are sparse regarding genetic determinants of Lp-PLA(2) mass and activity, and no prior data are available addressing genetic determinants of statin-induced changes for this proinflammatory biomarker. Methods and Results-We performed a genome-wide association study of Lp-PLA(2) mass and activity at baseline and after 12 months of rosuvastatin therapy (20 mg/d) among 6851 participants of European ancestry from the Justification for Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) and performed replication in a meta-analysis of 13 664 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Novel associations were identified and replicated at MS4A4E and TMEM49 for baseline Lp-PLA(2) activity with genome-wide significant joint P values (P=2.0x10(-11) and P=2.9x10(-9), respectively). In addition, genome-wide associations (P<5x10(-8)) were identified and replicated for baseline Lp-PLA(2) mass at CETP and for Lp-PLA(2) activity at the APOC1-APOE and PLA2G7 loci. Among 2673 statin-allocated participants, both Lp-PLA(2) mass and activity were reduced by >30% and low-density lipoprotein cholesterol by 50% after 12 months of statin therapy (P<0.001 for both). Variants in ABCG2 and LPA were associated with change in statin-induced Lp-PLA(2) activity at genome-wide significance but were substantially attenuated after adjustment for statin-induced changes in lipid levels. Conclusions-Genome-wide significant associations at MS4A4E and TMEM49 may reflect novel influences on circulating levels of Lp-PLA(2) activity. In addition, genome-wide significant associations with rosuvastatin-induced change in Lp-PLA(2) activity were observed in ABCG2 and LPA, likely because of their impact on statin-induced low-density lipoprotein cholesterol lowering. (Circ Cardiovasc Genet. 2012;5:676-685.) C1 [Chu, Audrey Y.; Guilianini, Franco; Chasman, Daniel I.; Ridker, Paul M.] Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Div Prevent Med, Boston, MA 02215 USA. [Chasman, Daniel I.] Brigham & Womens Hosp, Div Genet, Boston, MA 02215 USA. [Ridker, Paul M.] Brigham & Womens Hosp, Div Cardiol, Boston, MA 02215 USA. [Grallert, Harald] German Res Ctr Environm Hlth, Helmholtz ZentrumMunchen, Res Unit Mol Epidemiol, Neuherberg, Germany. [Dupuis, Josee] NHLBI, Framingham, MA USA. [Dupuis, Josee] Boston Univ, Framingham Heart Study, Framingham, MA USA. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Ballantyne, Christie M.] Baylor Coll Med, Dept Med, Methodist DeBaakey Heart & Vasc Ctr, Div Atherosclerosis & Vasc Med, Houston, TX 77030 USA. [Nyberg, Fredrik] AstraZeneca Res & Dev, Global Epidemiol, Molndal, Sweden. [Nyberg, Fredrik] Univ Gothenburg, Sahlgrenska Acad, Unit Occupat & Environm Med, Gothenburg, Sweden. [Chasman, Daniel I.; Ridker, Paul M.] Harvard Univ, Sch Med, Boston, MA USA. RP Chu, AY (reprint author), Brigham & Womens Hosp, Ctr Cardiovasc Dis Prevent, Div Prevent Med, 900 Commonwealth Ave E, Boston, MA 02215 USA. EM aychu@partners.org RI Grallert, Harald/B-3424-2013; OI Barratt, Bryan/0000-0002-5598-2422; Dupuis, Josee/0000-0003-2871-3603 FU AstraZeneca; National Heart, Lung, and Blood Institute; National Cancer Institute; Sanofi-Aventis; Novartis FX Drs Barratt and Nyberg are employees of AstraZeneca. Dr Ridker reports being listed as a coinventor on patents related to the use of inflammatory biomarkers in cardiovascular disease, which are held by the Brigham and Women's Hospital and have been licensed by Siemens and AstraZeneca. Dr Ridker receives funding from the National Heart, Lung, and Blood Institute, the National Cancer Institute, AstraZeneca, Sanofi-Aventis, and Novartis. The other authors report no conflicts. NR 32 TC 16 Z9 16 U1 0 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1942-325X J9 CIRC-CARDIOVASC GENE JI Circ.-Cardiovasc. Genet. PD DEC PY 2012 VL 5 IS 6 BP 676 EP 685 DI 10.1161/CIRCGENETICS.112.963314 PG 10 WC Cardiac & Cardiovascular Systems; Genetics & Heredity SC Cardiovascular System & Cardiology; Genetics & Heredity GA 060JY UT WOS:000312774800016 PM 23118302 ER PT J AU Raju, TNK Singhal, N AF Raju, Tonse N. K. Singhal, Nalini TI Optimal Timing for Clamping the Umbilical Cord After Birth SO CLINICS IN PERINATOLOGY LA English DT Article DE Early cord clamping; Delayed cord clamping; Umbilical cord milking ID RANDOMIZED CONTROLLED-TRIAL; 29 WEEKS GESTATION; INFANTS BORN; TERM INFANTS; PULMONARY HEMODYNAMICS; PLACENTAL TRANSFUSION; CEREBRAL OXYGENATION; IRON-DEFICIENCY; PRETERM INFANTS; BLOOD-FLOW AB This article provides a brief overview of pros and cons of clamping the cord too early (within seconds) after birth. It also highlights evolving data that suggest that delaying cord clamping for 30 to 60 seconds after birth is beneficial to the baby, with no measurable negative effects either the baby or the mother. C1 [Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Singhal, Nalini] Univ Calgary, Calgary, AB T3B 6C8, Canada. RP Raju, TNK (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, 6100 Execut Blvd,4B03, Bethesda, MD 20892 USA. EM rajut@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999] NR 52 TC 16 Z9 16 U1 2 U2 26 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0095-5108 J9 CLIN PERINATOL JI Clin. Perinatol. PD DEC PY 2012 VL 39 IS 4 BP 889 EP 900 DI 10.1016/j.clp.2012.09.006 PG 12 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 058HE UT WOS:000312623900012 PM 23164185 ER PT J AU Driscoll, DM Dal Monte, O Solomon, J Krueger, F Grafman, J AF Driscoll, David M. Dal Monte, Olga Solomon, Jeffrey Krueger, Frank Grafman, Jordan TI Empathic Deficits in Combat Veterans with Traumatic Brain Injury: A Voxel-Based Lesion-Symptom Mapping Study SO COGNITIVE AND BEHAVIORAL NEUROLOGY LA English DT Article DE empathy; emotion; prefrontal cortex; traumatic brain injury; voxel-based lesion-symptom mapping ID GENDER-DIFFERENCES; SOCIAL-BEHAVIOR; EMOTION; SYSTEMS; MECHANISMS; RESONANCE; COGNITION; CORTEX; MIND; INTELLIGENCE AB Objective: To understand better which brain regions support emotional empathy. Background: Emotional empathy, the ability to interpret and share the affective states of others, is a key component in human social interaction. Previous research has suggested that emotional empathy relies on several distinct brain regions, although further evidence from human lesion studies is needed to determine which regions are critical. Methods: We studied 192 male Vietnam combat veterans who had sustained focal penetrating traumatic brain injuries, and 54 non-brain-injured veterans. We used voxel-based lesion-symptom mapping on computed tomographic scans to elucidate the neural bases of self-reported emotional empathy as measured by the Balanced Emotional Empathy Scale. Results: Damage in several brain regions, particularly the ventrolateral prefrontal cortex, left and right posterior temporal lobes, and insula, was associated with diminished emotional empathy. Conclusions: These findings provide further insight into the neural substrates of emotional empathy, and are consistent with the notion that emotional empathy is supported by a distributed network of brain regions. Additional work may advance our understanding of the empathic deficits commonly observed in patients with neurologic and psychiatric disorders. C1 [Driscoll, David M.; Dal Monte, Olga] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Driscoll, David M.; Dal Monte, Olga] Uniformed Serv Univ Hlth Sci, Ctr Neurosci & Regenerat Med, Bethesda, MD 20814 USA. [Dal Monte, Olga] Univ Turin, Dept Neuropsychol, Turin, Italy. [Solomon, Jeffrey] Expert Image Anal LLC, Potomac, MD USA. [Krueger, Frank] George Mason Univ, Mol Neurosci Dept, Fairfax, VA 22030 USA. [Krueger, Frank] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Grafman, Jordan] Kessler Fdn Res Ctr, Traumat Brain Injury Res Lab, W Orange, NJ USA. RP Driscoll, DM (reprint author), Nebraska Western Iowa Hlth Care Syst, Dept Vet Affairs, 600 S 70th St, Lincoln, NE 68510 USA. EM david.driscoll@va.gov OI Grafman, Jordan H./0000-0001-8645-4457; dal monte, olga/0000-0002-7823-4769 FU US National Institute of Neurological Disorders and Stroke Intramural Research Program; US Army Medical Research and Material Command; Center for Neuroscience and Regenerative Medicine via the Henry M. Jackson Foundation; National Naval Medical Center FX Supported in part by the US National Institute of Neurological Disorders and Stroke Intramural Research Program and a project grant from the US Army Medical Research and Material Command administered by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: a 30-year post-injury follow-up study). D.M.D. and O.D.M. were supported with funding from the Center for Neuroscience and Regenerative Medicine via the Henry M. Jackson Foundation.; The authors thank all of the Vietnam veterans who participated in this study for their long-term commitment to improving the health care of veterans; the National Naval Medical Center for their support and provision of their facilities; and S. Bonifant, B. Cheon, C. Ngo, A. Greathouse, K. Reding, and G. Tasick for their invaluable help with organizing the study and testing the participants. NR 55 TC 9 Z9 9 U1 4 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1543-3633 J9 COGN BEHAV NEUROL JI Cogn. Behav. Neurol. PD DEC PY 2012 VL 25 IS 4 BP 160 EP 166 DI 10.1097/WNN.0b013e318280cf4e PG 7 WC Behavioral Sciences; Clinical Neurology SC Behavioral Sciences; Neurosciences & Neurology GA 062TB UT WOS:000312944200002 PM 23277137 ER PT J AU Yessis, JL Kost, RG Lee, LM Coller, BS Henderson, DK AF Yessis, Jennifer L. Kost, Rhonda G. Lee, Laura M. Coller, Barry S. Henderson, David K. TI Development of a Research Participants' Perception Survey to Improve Clinical Research SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE research participants; validated survey; participant perceptions; research ethics; human subjects protection; informed consent ID INFORMED-CONSENT; EXPERIENCES; TRIALS AB Introduction: Clinical research participants perceptions regarding their experiences during research protocols provide outcome-based insights into the effectiveness of efforts to protect rights and safety, and opportunities to enhance participants clinical research experiences. Use of validated surveys measuring patient-centered outcomes is standard in hospitals, yet no instruments exist to assess outcomes of clinical research processes. Methods: We derived survey questions from data obtained from focus groups comprised of research participants and professionals. We assessed the survey for face/content validity, and privacy/confidentiality protections and fielded it to research participants at 15 centers. We conducted analyses of response rates, sample characteristics, and psychometrics, including survey and item completion and analysis, internal consistency, item internal consistency, criterion-related validity, and item usefulness. Responses were tested for fit into existing patient-centered dimensions of care and new clinical research dimensions using Cronbach's alpha coefficient. Results: Surveys were mailed to 18,890 individuals; 4,961 were returned (29%). Survey completion was 89% overall; completion rates exceeded 90% for 88 of 93 evaluable items. Questions fit into three dimensions of patient-centered care and two novel clinical research dimensions (Cronbach's alpha for dimensions: 0.690.85). Conclusions: The validated survey offers a new method for assessing and improving outcomes of clinical research processes. Clin Trans Sci 2012; Volume 5: 452460 C1 [Yessis, Jennifer L.] Univ Waterloo, Propel Ctr Populat Hlth Impact, Waterloo, ON N2L 3G1, Canada. [Kost, Rhonda G.; Coller, Barry S.] Rockefeller Univ, New York, NY 10021 USA. [Lee, Laura M.; Henderson, David K.] NIH, Off Deputy Director Clin Care, Ctr Clin, Bethesda, MD 20892 USA. RP Yessis, JL (reprint author), Univ Waterloo, Propel Ctr Populat Hlth Impact, Waterloo, ON N2L 3G1, Canada. EM jyessis@uwaterloo.ca FU National Center for Research Resources [8 UL1 TR000043]; National Center for Advancing Sciences (NCATS), National Institutes of Health FX Supported in part by grant 8 UL1 TR000043, and by an Administrative Supplement, from the National Center for Research Resources and the National Center for Advancing Sciences (NCATS), National Institutes of Health. NR 20 TC 6 Z9 6 U1 1 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD DEC PY 2012 VL 5 IS 6 BP 452 EP 460 DI 10.1111/j.1752-8062.2012.00443.x PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 057ER UT WOS:000312545900008 PM 23253666 ER PT J AU Segal, JB Kapoor, W Carey, T Mitchell, PH Murray, MD Saag, KG Schumock, G Jonas, D Steinman, M Filart, R Weinberger, M Selker, H AF Segal, Jodi B. Kapoor, Wishwa Carey, Timothy Mitchell, Pamela H. Murray, Michael D. Saag, Kenneth G. Schumock, Glen Jonas, Daniel Steinman, Michael Filart, Rosemarie Weinberger, Morris Selker, Harry TI Preliminary Competencies for Comparative Effectiveness Research SO CTS-CLINICAL AND TRANSLATIONAL SCIENCE LA English DT Article DE comparative effectiveness research; competencies; work force ID EFFECTIVENESS RESEARCH WORKFORCE; HEALTH-CARE; CLINICAL-RESEARCH; DECISION-MAKING; TRIALS AB The Clinical and Translational Science Award (CTSA) Workgroup for Comparative Effectiveness Research (CER) Education, Training, and Workforce Development identified a need to delineate the competencies that practitioners and users of CER for patient-centered outcomes research, should acquire. With input from CTSA representatives and collaborators, we began by describing the workforce. We recognize the workforce that conducts CER and the end users who use CER to improve the health of individuals and communities. We generated a preliminary set of competencies and solicited feedback from the CER representatives at each member site of the CTSA consortium. We distinguished applied competencies (i.e., skills needed by individuals who conduct CER) from foundational competencies that are needed by the entire CER workforce, including end users of CER. Key competency categories of relevance to both practitioners and users of CER were: (1) asking relevant research questions; (2) recognizing or designing ideal CER studies; (3) executing or using CER studies; (4) using appropriate statistical analyses for CER; and (5) communicating and disseminating CER study results to improve health. Although CER is particularly broad concept, we anticipate that these preliminary, relatively generic competencies will be used in tailoring curricula to individual learners from a variety of programmatic perspectives. Clin Trans Sci 2012; Volume 5: 476479 C1 [Segal, Jodi B.] Johns Hopkins Univ, Dept Med, Baltimore, MD 21218 USA. [Kapoor, Wishwa] Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. [Carey, Timothy] Univ N Carolina, Cecil G Sheps Ctr Hlth Serv Res, Chapel Hill, NC USA. [Mitchell, Pamela H.] Univ Washington, Inst Translat Hlth Sci, Seattle, WA 98195 USA. [Murray, Michael D.] Regenstrief Inst Hlth Care, Indianapolis, IN 46202 USA. [Saag, Kenneth G.] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA. [Schumock, Glen] Univ Illinois, Dept Pharm, Chicago, IL USA. [Jonas, Daniel] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Steinman, Michael] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Filart, Rosemarie] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. [Weinberger, Morris] Durham VAMC Ctr Hlth Serv Res, Durham, NC USA. [Selker, Harry] Tufts Univ, Dept Med, Boston, MA 02111 USA. RP Segal, JB (reprint author), Johns Hopkins Univ, Dept Med, Baltimore, MD 21218 USA. EM jsegal@jhmi.edu RI Segal, Jodi/A-2863-2009 OI Segal, Jodi/0000-0003-3978-9662 FU National Center for Research Resources; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), part of the Roadmap Initiative, and Re-Engineering the Clinical Research Enterprise; Department of Veterans Affairs HSR&D Service Career Scientist Program [RCS 91-408]; [UL1RR025747]; [UL1RR024153]; [UL1RR025761]; [UL1RR025014]; [UL1RR025005]; [UL1RR029879]; [UL1 RR025752]; [UL1RR024131]; [UL1RR025777] FX This project has been funded in whole or in part with Federal funds from the National Center for Research Resources and National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH), through the Clinical and Translational Science Awards Program (CTSA), part of the Roadmap Initiative, and Re-Engineering the Clinical Research Enterprise. The relevant contracts are UL1RR025747 (T. C., D.J., M. W.), UL1RR024153 (W. K.), UL1RR025761 (M. M), UL1RR025014 (P. M.), UL1RR025005 (J.S.), UL1RR029879 (G. S.), UL1 RR025752 (H. S.), UL1RR024131 (M. S.), and UL1RR025777 (K. S.). Other support comes from the Department of Veterans Affairs HSR&D Service Career Scientist Program [RCS 91-408] (M. W). The manuscript was approved by the CTSA Consortium Publications Committee. NR 17 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1752-8054 J9 CTS-CLIN TRANSL SCI JI CTS-Clin. Transl. Sci. PD DEC PY 2012 VL 5 IS 6 BP 476 EP 479 DI 10.1111/j.1752-8062.2012.00420.x PG 4 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 057ER UT WOS:000312545900012 PM 23253670 ER PT J AU Koh, K Quon, M AF Koh, K. Quon, M. TI Effects of fenofibrate therapy on circulating adipocytokines in patients with primary hypertriglyceridemia SO DIABETES-METABOLISM RESEARCH AND REVIEWS LA English DT Meeting Abstract CT 1st Asia Pacific Congress on Controversies to Consensus in Diabetes, Obesity and Hypertension (CODHy) CY JUN 02-05, 2011 CL Shanghai, PEOPLES R CHINA C1 [Quon, M.] NIH, Diabet Unit, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1520-7552 J9 DIABETES-METAB RES JI Diabetes-Metab. Res. Rev. PD DEC PY 2012 VL 28 SU 2 SI SI BP 108 EP 108 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 062TC UT WOS:000312944300073 ER PT J AU Birnbaum, LS Bucher, JR Collman, GW Zeldin, DC Johnson, AF Schug, TT Heindel, JJ AF Birnbaum, Linda S. Bucher, John R. Collman, Gwen W. Zeldin, Darryl C. Johnson, Anne F. Schug, Thaddeus T. Heindel, Jerrold J. TI Consortium-Based Science: The NIEHS's Multipronged, Collaborative Approach to Assessing the Health Effects of Bisphenol A SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE bisphenol A; consortium-based research; endocrine disruptor; low dose; NIEHS ID HUMAN EXPOSURE; REPRODUCTIVE TOXICITY; WIDESPREAD EXPOSURE; URINARY; MECHANISMS; CHEMICALS; PROFILES; MICE AB BACKGROUND: Bisphenol A (BPA) is a high production volume chemical used to make polycarbonate plastic and is found in many consumer products. Some studies using animal models have suggested that BPA exposures may have adverse health effects. However, research gaps have precluded a full understanding of the effects of BPA in humans and engendered controversies surrounding the chemical's potential toxicity. OBJECTIVES: The National Institute of Environmental Health Sciences (NIEHS) and National Toxicology Program (NTP) have developed an integrated, multipronged, consortium-based approach to optimize BPA-focused research investments to more effectively address data gaps and inform decision making. DISCUSSION: NIEHS/NTP BPA research investments made over the past 4 years include extramural research grants, establishment of a BPA Grantee Consortium, intramural research activities on BPA's mechanisms of action, the launch of two clinical studies and an occupational study, development of a round-robin experiment to validate BPA measurements in human serum, and, in collaboration with the Food and Drug Administration (FDA), formation of a consortium to design and execute a chronic toxicity study of BPA in rats. The NIEHS's new consortium-based approach has led to more integrated, collaborative efforts and should improve our ability to resolve controversies over the potential human health effects of exposures to low levels of endocrine-active agents. C1 [Birnbaum, Linda S.] Natl Inst Environm Hlth Sci NIEHS, Natl Inst Hlth NIH, Dept Hlth & Human Serv DHHS, Res Triangle Pk, NC USA. [Birnbaum, Linda S.; Bucher, John R.] NIEHS, Div Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Zeldin, Darryl C.] NIEHS, Div Extramural Res, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Johnson, Anne F.] MDB Inc, Res Triangle Pk, NC USA. [Schug, Thaddeus T.; Heindel, Jerrold J.] NIEHS, Div Extramural Res, Cellular Organs & Syst Pathobiol Branch, NIH,DHHS, Res Triangle Pk, NC 27709 USA. RP Birnbaum, LS (reprint author), NIEHS, Div Natl Toxicol Program, POB 112233,Mail Drop B2-01, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov NR 30 TC 32 Z9 33 U1 2 U2 34 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD DEC PY 2012 VL 120 IS 12 BP 1640 EP 1644 DI 10.1289/ehp.1205330 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 056QB UT WOS:000312504900022 PM 23052487 ER PT J AU Maull, EA Ahsan, H Edwards, J Longnecker, MP Navas-Acien, A Pi, JB Silbergeld, EK Styblo, M Tseng, CH Thayer, KA Loomis, D AF Maull, Elizabeth A. Ahsan, Habibul Edwards, Joshua Longnecker, Matthew P. Navas-Acien, Ana Pi, Jingbo Silbergeld, Ellen K. Styblo, Miroslay Tseng, Chin-Hsiao Thayer, Kristina A. Loomis, Dana TI Evaluation of the Association between Arsenic and Diabetes: A National Toxicology Program Workshop Review SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE animal; arsenic toxicity; cell line; chemically induced/epidemiology; cultured cell; diabetes; environmental epidemiology; glucose; insulin; metabolism; obesity ID PANCREATIC BETA-CELLS; IMPAIRED GLUCOSE-TOLERANCE; DRINKING-WATER; INSULIN-SECRETION; US POPULATION; MDCK CELLS; IN-VITRO; EPIDEMIOLOGIC EVIDENCE; OXIDATIVE DAMAGE; EPITHELIAL-CELLS AB BACKGROUND: Diabetes affects an estimated 346 million persons globally, and total deaths from diabetes are projected to increase > 50% in the next decade. Understanding the role of environmental chemicals in the development or progression of diabetes is an emerging issue in environmental health. In 2011, the National Toxicology Program (NTP) organized a workshop to assess the literature for evidence of associations between certain chemicals, including inorganic arsenic, and diabetes and/or obesity to help develop a focused research agenda. This review is derived from discussions at that workshop. OBJECTIVES: Our objectives were to assess the consistency, strength/weaknesses, and biological plausibility of findings in the scientific literature regarding arsenic and diabetes and to identify data gaps and areas for future evaluation or research. The extent of the existing literature was insufficient to consider obesity as an outcome. DATA SOURCES, EXTRACTION, AND SYNTHESIS: Studies related to arsenic and diabetes or obesity were identified through PubMed and supplemented with relevant studies identified by reviewing the reference lists in the primary literature or review articles. CONCLUSIONS: Existing human data provide limited to sufficient support for an association between arsenic and diabetes in populations with relatively high exposure levels (>= 150 mu g arsenic/L in drinking water). The evidence is insufficient to conclude that arsenic is associated with diabetes in lower exposure (< 150 mu g arsenic/L drinking water), although recent studies with better measures of outcome and exposure support an association. The animal literature as a whole was inconclusive; however, studies using better measures of diabetes-relevant end points support a link between arsenic and diabetes. C1 [Loomis, Dana] Univ Nebraska Med Ctr, Nebraska Med Ctr 984395, Dept Epidemiol, Coll Publ Hlth, Omaha, NE 68198 USA. [Maull, Elizabeth A.] Natl Inst Environm Sci NIEHS, Biomol Screening Branch, Div Natl Toxicol Program, Natl Inst Hlth NIH,Dept Hlth & Human Serv DHHS, Res Triangle Pk, NC USA. [Ahsan, Habibul] Univ Chicago, Canc Res Ctr, Dept Hlth Studies, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Canc Res Ctr, Dept Med, Chicago, IL 60637 USA. [Ahsan, Habibul] Univ Chicago, Canc Res Ctr, Dept Human Genet, Chicago, IL 60637 USA. [Edwards, Joshua] Midwestern Univ, Dept Pharmacol, Downers Grove, IL 60515 USA. [Longnecker, Matthew P.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Navas-Acien, Ana; Silbergeld, Ellen K.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Navas-Acien, Ana] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Pi, Jingbo] Hamner Inst Hlth Sci, Inst Chem Safety Sci, Res Triangle Pk, NC USA. [Styblo, Miroslay] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Tseng, Chin-Hsiao] Natl Taiwan Univ, Coll Med, Taipei 10764, Taiwan. [Tseng, Chin-Hsiao] Natl Taiwan Univ Hosp, Dept Internal Med, Taipei, Taiwan. [Thayer, Kristina A.] NIEHS, Off Hlth Assessment & Translat, Div Natl Toxicol Program, NIEHS,NIH,DHHS, Res Triangle Pk, NC 27709 USA. RP Loomis, D (reprint author), Univ Nebraska Med Ctr, Nebraska Med Ctr 984395, Dept Epidemiol, Coll Publ Hlth, Omaha, NE 68198 USA. EM dana.loomis@unmc.edu OI TSENG, CHIN-HSIAO/0000-0001-9545-7123; Longnecker, Matthew/0000-0001-6073-5322 FU National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP); U.S. Environmental Protection Agency (EPA); Food and Drug Administration National Center for Toxicological Research (FDA/NCTR); Intramural Research Program of the National Institutes of Health (NIH), NIEHS; American Chemistry Council FX This review is based on deliberations that occurred at an 11-13 January 2011 Workshop [Role of Environmental Chemicals in the Development of Diabetes and Obesity (http://ntp.niehs.nih.gov/go/36433)] sponsored by the National Institute of Environmental Health Sciences/National Toxicology Program (NIEHS/NTP), U.S. Environmental Protection Agency (EPA), and the Food and Drug Administration National Center for Toxicological Research (FDA/NCTR). D. Loomis served as chair and E. Maull served as rapporteur for the arsenic breakout group. Other members of the arsenic breakout group included H. Ahsan, G. Cooper, J. Edwards; M.P. Longnecker, A. Navas-Acien, J. Pi, E. Silbergeld, M. Styblo, and C.-H. Tseng. K Thayer was the primary author of the background literature review document prepared prior to the workshop.; This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), NIEHS.; J.P. is an employee of The Hamner Institutes for Health Sciences; the Hamner is a 501(c)3 not-for-profit organization that has a diverse research portfolio that includes funding from the American Chemistry Council, a trade association that represents chemical manufacturers. The authors declare they have no actual or potential competing financial interests. NR 138 TC 95 Z9 96 U1 3 U2 106 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD DEC PY 2012 VL 120 IS 12 BP 1658 EP 1670 DI 10.1289/ehp.1104579 PG 13 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 056QB UT WOS:000312504900025 PM 22889723 ER PT J AU Little, MP Bazyka, D Bouffler, SD Harrison, JD Cardis, E Cucinotta, FA Kreuzer, M Laurent, O Tapio, S Wakeford, R Zablotska, L Lipshulrz, SE AF Little, Mark P. Bazyka, Dimitry Bouffler, Simon D. Harrison, John D. Cardis, Elisabeth Cucinotta, Francis A. Kreuzer, Michaela Laurent, Olivier Tapio, Soile Wakeford, Richard Zablotska, Lydia Lipshulrz, Steven E. TI Estimating Risk of Circulatory Disease: Little et al. Respond SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Letter ID ATOMIC-BOMB SURVIVORS; IONIZING-RADIATION; MORTALITY; EXPOSURE C1 [Little, Mark P.] NCI, Radiat Epidemiol Branch, Rockville, MD USA. [Bazyka, Dimitry] Res Ctr Radiat Med, Kiev, Ukraine. [Bouffler, Simon D.; Harrison, John D.] Hlth Protect Agcy, Chilton, England. [Cardis, Elisabeth] CREAL Ctr Res Environm Epidemiol, Barcelona, Spain. [Cucinotta, Francis A.] NASA, Lyndon B Johnson Space Ctr, Radiat Hlth Off, Houston, TX 77058 USA. [Kreuzer, Michaela] Fed Off Radiat Protect, Dept Radiat Protect & Hlth, Oberschleissheim, Germany. [Laurent, Olivier] Inst Radioprotect & Surete Nucl, Lab Epidemiol, Fontenay Aux Roses, France. [Tapio, Soile] Helmholtz Zentrum Munchen, Inst Radiat Biol, Oberschleissheim, Germany. [Wakeford, Richard] Univ Manchester, Dalton Nucl Inst, Manchester, Lancs, England. [Zablotska, Lydia] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Lipshulrz, Steven E.] Univ Miami, Dept Pediat, Leonard M Miller Sch Med, Miami, FL 33152 USA. RP Little, MP (reprint author), NCI, Radiat Epidemiol Branch, Rockville, MD USA. EM mark.little@nih.gov RI Tapio, Soile/M-7358-2014; Cardis, Elisabeth/C-3904-2017; OI Tapio, Soile/0000-0001-9860-3683; Wakeford, Richard/0000-0002-2934-0987 NR 9 TC 2 Z9 2 U1 1 U2 4 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD DEC PY 2012 VL 120 IS 12 BP A453 EP A454 DI 10.1289/ehp.1206046R PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 056QB UT WOS:000312504900006 ER PT J AU Tilson, HA AF Tilson, Hugh A. TI EHP Paper of the Year, 2012 SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material ID PRENATAL EXPOSURE; CLASSIC PAPER C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Tilson, HA (reprint author), NIEHS, NIH, Mail Drop K3-01,POB 12233, Res Triangle Pk, NC 27709 USA. EM tilsonha@niehs.nih.gov NR 7 TC 0 Z9 0 U1 0 U2 3 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD DEC PY 2012 VL 120 IS 12 BP A451 EP A451 DI 10.1289/ehp.1206266 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 056QB UT WOS:000312504900002 ER PT J AU Li, FY Deck, JA Dersch, CM Rothman, RB Deschamps, JR Jacobson, AE Rice, KC AF Li, Fuying Deck, Jason A. Dersch, Christina M. Rothman, Richard B. Deschamps, Jeffrey R. Jacobson, Arthur E. Rice, Kenner C. TI Probes for narcotic receptor mediated phenomena. 46. N-substituted-2,3,4,9,10,10a-hexahydro-1H-1,4a-(epiminoethano)phenanthre n-6-and 8-ols - Carbocyclic relatives of f-oxide-bridged phenylmorphans SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE Synthesis; Opioid receptor binding and efficacy; N-substituted-2,3,4,9,10,10a-hexahydro-1H-1,4a-(epiminoethano)phenanthre n-6-and 8-ols; f-Oxide-bridged phenylmorphans; Opioid antagonist ID N-PHENETHYL ANALOGS; MU-OPIOID RECEPTOR; BIOLOGICAL EVALUATION; BINDING-AFFINITY; ORTHO-C; ANTAGONIST; ISOMERS; 5-(META-HYDROXYPHENYL)MORPHAN; 5-PHENYLMORPHANS; MORPHINE AB Oxide-bridged phenylmorphans were conceptualized as topologically distinct, structurally rigid ligands with 3-dimensional shapes that could not be appreciably modified on interaction with opioid receptors. An enantiomer of the N-phenethyl-substituted ortho-f isomer was found to have high affinity for the mu-receptor (K-i = 7 nM) and was about four times more potent than naloxone as an antagonist. In order to examine the effect of introduction of a small amount of flexibility into these molecules, we have replaced the rigid 5-membered oxide ring with a more flexible 6-membered carbon ring. Synthesis of the new N-phenethyl-substituted tricyclic N-substituted-2,3,4,9,10,10a-hexahydro-1H-1,4a-(epiminoethano)phenanthren-6- and 8-ols resulted in a two carbon-bridged relative of the f-isomers, the dihydrofuran ring was replaced by a cyclohexene ring. The carbocyclic compounds had much higher affinity and greater selectivity for the mu-receptor than the f-oxide-bridged phenylmorphans. They were also much more potent mu-antagonists, with activities comparable to naltrexone in the [S-35]GTP-gamma-S assay. Published by Elsevier Masson SAS. C1 [Li, Fuying; Deck, Jason A.; Jacobson, Arthur E.; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Li, Fuying; Deck, Jason A.; Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Dersch, Christina M.; Rothman, Richard B.] NIDA, Clin Psychopharmacol Sect, Chem Biol Res Branch, Addict Res Ctr,NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Deschamps, Jeffrey R.] USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. RP Rice, KC (reprint author), NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, 5625 Fishers Lane,Room 4N03, Bethesda, MD 20892 USA. EM kr21f@nih.gov OI Deschamps, Jeffrey/0000-0001-5845-0010 FU NIH Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases; NIH Intramural Research Program of the National Institute on Drug Abuse; NIH Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism, NIH, DHHS; NIDA [Y1-DA1101]; Naval Research Laboratory (NRL) FX This research was supported by the NIH Intramural Research Programs of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Drug Abuse, and the National Institute of Alcohol Abuse and Alcoholism, NIH, DHHS. The X-ray crystallographic work was supported by NIDA through an Interagency Agreement #Y1-DA1101 with the Naval Research Laboratory (NRL). We thank Noel Whittaker and Dr. John Lloyd (Mass Spectrometry Facility, NIDDK) for the mass spectral data, and Drs. Klaus Gawrisch and Walter Teague (Laboratory of Membrane Biochemistry and Biophysics, NIAAA) for NMR spectroscopic data. NR 34 TC 5 Z9 5 U1 0 U2 5 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD DEC PY 2012 VL 58 BP 557 EP 567 DI 10.1016/j.ejmech.2012.10.041 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 059ZT UT WOS:000312745100058 PM 23168379 ER PT J AU Liu, C Cao, YF Fang, ZZ Zhang, YY Hu, CM Sun, XY Huang, T Zeng, J Fan, XR Hong, M AF Liu, Cong Cao, Yun-Feng Fang, Zhong-Ze Zhang, Yan-Yan Hu, Cui-Min Sun, Xiao-Yu Huang, Ting Zeng, Jia Fan, Xu-Ran Hong, Mo TI Strong inhibition of deoxyschizandrin and schisantherin A toward UDP-glucuronosyltransferase (UGT) 1A3 indicating UGT inhibition-based herb-drug interaction SO FITOTERAPIA LA English DT Article DE Deoxyschizandrin; UDP-glucuronosyltransferases (UGTs); Herb-drug interaction ID LIVER CYTOCHROME-P450 ENZYMES; METABOLISM; EXTRACT; IDENTIFICATION; BIOACTIVATION; SCHIZANDRIN; CYP3A4 AB Deoxyschizandrin and schisantherin A are major bioactive lignans isolated from Fructus schisandrae which has been widely used as a tonic in traditional Chinese medicine for many years. Inhibition of UDP-glucuronosyltransferases (UGTs) by herbal components might be an important reason for clinical herb-drug interaction. The aim of the present study is to investigate the inhibitory effect of deoxyschizandrin and schisantherin A on major UGT isoforms. Recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate 4-methylumbelliferone (4-MU) was utilized as substrate. The results showed that 100 mu M of deoxyschizandrin and schisantherin A exhibited strong inhibition on UGT1A3, and negligible inhibition on other tested UGT isoforms. Furthermore, deoxyschizandrin and schisantherin A were demonstrated to inhibit UGT1A3 in a concentration-dependent manner, with IC50 value of 10.8 +/- 0.4 mu M and 12.5 +/- 0.5 mu M, respectively. Dixon and Lineweaver-Burk plots showed that inhibition of UGT1A3 by deoxyschizandrin was best fit to competitive inhibition type, and inhibition kinetic parameter (KO was calculated to be 0.48 mu M. Inhibition of UGT1A3 by schisantherin A gave the best fit for types of noncompetitive inhibition, and the results showed K-i to be 11.3 mu M. All these experimental data suggested that herb-drug interaction might occur when deoxyschizandrin or schisantherin A containing herbs were co-administered with drugs which mainly undergo UGT1A3-mediated metabolism. However, given that many in vivo factors could influence the in vitro-in vivo extrapolation (IVIVE), these in vitro inhibitory parameters should be considered with caution. (C) 2012 Elsevier B.V. All rights reserved. C1 [Liu, Cong] China Med Univ, Shengjing Hosp, Dept Endocrinol, Shenyang 110004, Peoples R China. [Cao, Yun-Feng; Huang, Ting; Zeng, Jia] Shanghai Inst Planned Parenthood Res, Natl Populat & Family Planning Key Lab Contracept, Shanghai 200032, Peoples R China. [Cao, Yun-Feng; Fang, Zhong-Ze; Zhang, Yan-Yan; Sun, Xiao-Yu; Fan, Xu-Ran; Hong, Mo] Chinese Acad Sci, Dalian Inst Chem Phys, Joint Ctr Translat Med, Dalian 116023, Peoples R China. [Cao, Yun-Feng; Fang, Zhong-Ze; Zhang, Yan-Yan; Sun, Xiao-Yu; Fan, Xu-Ran; Hong, Mo] Liaoning Med Univ, Affiliated Hosp 1, Dalian 116023, Peoples R China. [Fang, Zhong-Ze; Hu, Cui-Min] NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Liu, C (reprint author), China Med Univ, Shengjing Hosp, Dept Endocrinol, Shenyang 110004, Peoples R China. EM liucongjp@yahoo.com FU National Natural Science Foundation of China [81102507, 81202586] FX This work was supported by the National Natural Science Foundation of China (nos. 81102507 and 81202586). NR 22 TC 14 Z9 17 U1 2 U2 26 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0367-326X J9 FITOTERAPIA JI Fitoterapia PD DEC PY 2012 VL 83 IS 8 SI SI BP 1415 EP 1419 DI 10.1016/j.fitote.2012.08.004 PG 5 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 062JP UT WOS:000312916400017 PM 23339253 ER PT J AU Hoyo, C Cook, MB Kamangar, F Freedman, ND Whiteman, DC Bernstein, L Brown, LM Risch, HA Ye, WM Sharp, L Wu, AH Ward, MH Casson, AG Murray, LJ Corley, DA Nyren, O Pandeya, N Vaughan, TL Chow, WH Gammon, MD AF Hoyo, Cathrine Cook, Michael B. Kamangar, Farin Freedman, Neal D. Whiteman, David C. Bernstein, Leslie Brown, Linda M. Risch, Harvey A. Ye, Weimin Sharp, Linda Wu, Anna H. Ward, Mary H. Casson, Alan G. Murray, Liam J. Corley, Douglas A. Nyren, Olof Pandeya, Nirmala Vaughan, Thomas L. Chow, Wong-Ho Gammon, Marilie D. TI Body mass index in relation to oesophageal and oesophagogastric junction adenocarcinomas: a pooled analysis from the International BEACON Consortium SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Oesophageal neoplasms; aetiology; risk factors; gastro-oesophageal reflux; obesity; oesophagogastric junction ID GASTROESOPHAGEAL-REFLUX DISEASE; GASTRIC CARDIA; BARRETTS-ESOPHAGUS; RISK-FACTORS; ABDOMINAL OBESITY; UNITED-STATES; SOCIOECONOMIC-FACTORS; PROSPECTIVE COHORT; DISTAL STOMACH; CANCER AB Background Previous studies suggest an association between obesity and oesophageal (OA) and oesophagogastric junction adenocarcinomas (OGJA). However, these studies have been limited in their ability to assess whether the effects of obesity vary by gender or by the presence of gastro-oesophageal reflux (GERD) symptoms. Methods Individual participant data from 12 epidemiological studies (8 North American, 3 European and 1 Australian) comprising 1997 OA cases, 1900 OGJA cases and 11 159 control subjects were pooled. Logistic regression was used to estimate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between body mass index (BMI, kg/m(2)) and the risk of OA and OGJA. Random-effects meta-analysis was used to combine these ORs. We also investigated effect modification and synergistic interaction of BMI with GERD symptoms and gender. Results The association of OA and OGJA increased directly with increasing BMI (P for trend < 0.001). Compared with individuals with a BMI < 25, BMI epsilon 40 was associated with both OA (OR 4.76, 95% CI 2.96-7.66) and OGJA (OR 3.07, 95% CI 1.89-4.99). These associations were similar when stratified by gender and GERD symptoms. There was evidence for synergistic interaction between BMI and GERD symptoms in relation to OA/OGJA risk. Conclusions These data indicate that BMI is directly associated with OA and OGJA risk in both men and women and in those with and without GERD symptoms. Disentangling the relationship between BMI and GERD will be important for understanding preventive efforts for OA and OGJA. C1 [Hoyo, Cathrine] Duke Univ, Sch Med, Dept Obstet & Gynecol, Div Clin Epidemiol, Durham, NC 27710 USA. [Cook, Michael B.; Kamangar, Farin; Freedman, Neal D.; Ward, Mary H.; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Kamangar, Farin] Morgan State Univ, Sch Community Hlth & Policy, Dept Publ Hlth Anal, Baltimore, MD 21239 USA. [Whiteman, David C.; Pandeya, Nirmala] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Whiteman, David C.; Pandeya, Nirmala] Univ Queensland, Sch Populat Hlth, Brisbane, Qld, Australia. [Bernstein, Leslie] City Hope Natl Med Ctr, Dept Populat Sci, Div Canc Etiol, Duarte, CA USA. [Brown, Linda M.] RTI Int, Rockville, MD USA. [Risch, Harvey A.] Yale Univ, Sch Publ Hlth, Dept Epidemiol & Publ Hlth, New Haven, CT USA. [Ye, Weimin; Nyren, Olof] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Sharp, Linda] Natl Canc Registry Ireland, Cork, Ireland. [Wu, Anna H.] Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. [Casson, Alan G.] Univ Saskatchewan, Coll Med, Dept Surg, Saskatoon, SK S7N 0W0, Canada. [Casson, Alan G.] Univ Saskatchewan, Coll Med, Genom Med & Pathobiol Grp, Saskatoon, SK S7N 0W0, Canada. [Murray, Liam J.] Queens Univ Belfast, Ctr Publ Hlth, Belfast, Antrim, North Ireland. [Corley, Douglas A.] Kaiser Permanente, Div Res, Oakland, CA USA. [Corley, Douglas A.] Kaiser Permanente, Oakland Med Ctr, Oakland, CA USA. [Vaughan, Thomas L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Gammon, Marilie D.] Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. RP Hoyo, C (reprint author), Duke Univ, Sch Med, Dept Obstet & Gynecol, Div Clin Epidemiol, POB 104006, Durham, NC 27710 USA. EM cathrine.hoyo@duke.edu RI Cook, Michael/A-5641-2009; Freedman, Neal/B-9741-2015; Whiteman, David/P-2728-2014; Pandeya, Nirmala/F-8054-2010 OI Cook, Michael/0000-0002-0533-7302; Freedman, Neal/0000-0003-0074-1098; Whiteman, David/0000-0003-2563-9559; Pandeya, Nirmala/0000-0003-1462-4968 FU National Institute of Health [K01CA104517, U01CA057983, P30ES10126, U01CA057923]; National Cancer Institute of Canada; Canadian Cancer Society [14676]; National Cancer Institute of Canada [U01CA57949, K05CA124911, R01CA59636, U54CA 116848, K05CA136967]; Canadian Cancer Society; Intramural Program of the National Institutes of Health; Australian Research Council FX This work was supported in part by extramural grants from the National Institute of Health for C. H. (K01CA104517), M. D. G. (U01CA057983 and P30ES10126), H. A. R. (U01CA057923), National Cancer Institute of Canada with funds from the Canadian Cancer Society for A. G. C. (14676), T. L. V. (U01CA57949 and K05CA124911), L. B. (R01CA59636, U54CA 116848 and K05CA136967), by the National Cancer Institute of Canada with funds from the Canadian Cancer Society for A. G. C. (14676), and by the Intramural Program of the National Institutes of Health. D. C. W. is supported in part by the Australian Research Council. NR 74 TC 63 Z9 63 U1 0 U2 13 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD DEC PY 2012 VL 41 IS 6 BP 1706 EP 1718 DI 10.1093/ije/dys176 PG 13 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 065DL UT WOS:000313128000025 PM 23148106 ER PT J AU Peluso, M Bollati, V Munnia, A Srivatanakul, P Jedpiyawongse, A Sangrajrang, S Piro, S Ceppi, M Bertazzi, PA Boffetta, P Baccarelli, AA AF Peluso, Marco Bollati, Valentina Munnia, Armelle Srivatanakul, Petcharin Jedpiyawongse, Adisorn Sangrajrang, Suleeporn Piro, Sara Ceppi, Marcello Bertazzi, Pier Alberto Boffetta, Paolo Baccarelli, Andrea A. TI DNA methylation differences in exposed workers and nearby residents of the Ma Ta Phut industrial estate, Rayong, Thailand SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE Air pollution; Ma Ta Phut; blood leucocytes; DNA methylation; DNA damage ID POLYCYCLIC AROMATIC-HYDROCARBONS; LUNG-CANCER; PROMOTER METHYLATION; BLOOD DNA; EPIGENETICS; POPULATION; PATTERNS AB Background Adverse biological effects from airborne pollutants are a primary environmental concern in highly industrialized areas. Recent studies linked air pollution exposures with altered blood Deoxyribonucleic acid (DNA) methylation, but effects from industrial sources and underlying biological mechanisms are still largely unexplored. Methods The Ma Ta Phut industrial estate (MIE) in Rayong, Thailand hosts one of the largest steel, oil refinery and petrochemical complexes in south-eastern Asia. We measured a panel of blood DNA methylation markers previously associated with air pollution exposures, including repeated elements [long interspersed nuclear element-1 (LINE-1) and Alu] and genes [p53, hypermethylated-in-cancer-1 (HIC1), p16 and interleukin-6 (IL-6)], in 67 MIE workers, 65 Ma Ta Phut residents and 45 rural controls. To evaluate the role of DNA damage and oxidation, we correlated DNA methylation measures with bulky DNA and 3-(2-deoxy-beta-D-erythro-pentafuranosyl)pyrimido[1,2-alpha]purin-10(3H)-one deoxyguanosine (M(1)dG) adducts. Results In covariate-adjusted models, MIE workers, compared with rural residents, showed lower LINE-1 (74.8% vs 78.0%; P < 0.001), p53 (8.0% vs 15.7%; P < 0.001) and IL-6 methylation (39.2% vs 45.0%; P = 0.027) and higher HIC1 methylation (22.2% vs 15.3%, P < 0.001). For all four markers, Ma Ta Phut residents exhibited methylation levels intermediate between MIE workers and rural controls (LINE-1, 75.7%, P < 0.001; p53, 9.0%, P < 0.001; IL-6, 39.8%, P = 0.041; HIC1, 17.8%, P = 0.05; all P-values vs rural controls). Bulky DNA adducts showed negative correlation with p53 methylation (P = 0.01). M(1)dG showed negative correlations with LINE-1 (P = 0.003) and IL-6 methylation (P = 0.05). Conclusions Our findings indicate that industrial exposures may induce alterations of DNA methylation patterns detectable in blood leucocyte DNA. Correlation of DNA adducts with DNA hypomethylation suggests potential mediation by DNA damage. C1 [Baccarelli, Andrea A.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Lab Environm Epigenet,Landmark Ctr, Boston, MA 02115 USA. [Peluso, Marco; Munnia, Armelle; Piro, Sara] Canc Prevent & Res Inst, Canc Risk Factor Branch, Florence, Italy. [Bollati, Valentina; Bertazzi, Pier Alberto] Univ Milan, Dept Occupat & Environm Hlth, Milan, Italy. [Bollati, Valentina; Bertazzi, Pier Alberto] Ca Granda Maggiore Policlin Hosp, Ist Ricovero & Cura Carattere Sci, Milan, Italy. [Srivatanakul, Petcharin; Jedpiyawongse, Adisorn; Sangrajrang, Suleeporn] Natl Canc Inst, Div Res, Mol Epidemiol Unit, Bangkok, Thailand. [Ceppi, Marcello] Natl Canc Inst, Mol Epidemiol Unit, Genoa, Italy. [Boffetta, Paolo] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, Paolo] Mt Sinai Sch Med, Inst Translat Epidemiol, New York, NY USA. [Boffetta, Paolo] Int Prevent Res Inst, Lyon, France. RP Baccarelli, AA (reprint author), Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Lab Environm Epigenet,Landmark Ctr, Room 415E W,POB 15677,401 Pk Dr, Boston, MA 02115 USA. EM abaccare@hsph.harvard.edu RI bertazzi, pietro alberto/D-5039-2017; OI bertazzi, pietro alberto/0000-0003-3475-2449; Baccarelli, Andrea/0000-0002-3436-0640; PIRO, SARA/0000-0003-4198-7035; Bollati, Valentina/0000-0002-0370-9598 FU 'Associazione Italiana per la Ricerca sul Cancro', Milan, Italy; National Cancer Institute, Bangkok, Thailand; U.S. National Institute of Environmental Health Sciences [ES000002, ES019773, ES020268, ES020010] FX The study was partially funded by the 'Associazione Italiana per la Ricerca sul Cancro', Milan, Italy; the National Cancer Institute, Bangkok, Thailand and the U.S. National Institute of Environmental Health Sciences (ES000002, ES019773, ES020268 and ES020010). NR 36 TC 25 Z9 25 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD DEC PY 2012 VL 41 IS 6 BP 1753 EP 1760 DI 10.1093/ije/dys129 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 065DL UT WOS:000313128000031 PM 23064502 ER PT J AU Glenn, CR Lieberman, L Hajcak, G AF Glenn, Catherine R. Lieberman, Lynne Hajcak, Greg TI Comparing electric shock and a fearful screaming face as unconditioned stimuli for fear learning SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE Fear learning; Fear conditioning; Fear-potentiated startle; Startle reflex; Unconditioned stimuli ID ANXIETY DISORDERS; POTENTIATED STARTLE; ANXIOUS RESPONSES; AVERSIVE STIMULI; CHILDREN; ADOLESCENTS; PREPAREDNESS; THREAT; EXTINCTION; PHOBIAS AB The potency of an unconditioned stimulus (UCS) can impact the degree of fear learning. One of the most common and effective UCSs is an electric shock, which is inappropriate for certain populations (e.g., children). To address this need, a novel fear learning paradigm was recently developed that uses a fearful female face and scream as the UCS. The present study directly compared the efficacy of the screaming female UCS and a traditional shock UCS in two fear learning paradigms. Thirty-six young adults completed two fear learning tasks and a measure of trait anxiety; fear learning was indexed with fear-potentiated startle (FPS) and self-reported fear ratings. Results indicated comparable FPS across the two tasks. However, larger overall startle responses were exhibited in the shock task, and participants rated the shock UCS and overall task as more aversive than the screaming female. In addition, trait anxiety was only related to FPS in the fear learning task that employed a shock as the UCS. Taken together, results indicate that, although both UCS paradigms can be used for fear conditioning (i.e., to produce differences between CS+ and CS-). the shock UCS paradigm is more aversive and potentially more sensitive to individual differences in anxiety. (C) 2012 Elsevier B.V. All rights reserved. C1 [Glenn, Catherine R.] Harvard Univ, Dept Psychol, Cambridge, MA 02138 USA. [Lieberman, Lynne] NIMH, Sect Neurobiol Fear & Anxiety, Bethesda, MD 20892 USA. [Hajcak, Greg] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. RP Glenn, CR (reprint author), Harvard Univ, Dept Psychol, William James Hall 1280,33 Kirkland St, Cambridge, MA 02138 USA. EM catherineglenn@fas.harvard.edu; lnlieberman@gmail.com; greg.hajcak@stonybrook.edu FU NIMH NIH HHS [F31 MH086197] NR 32 TC 11 Z9 11 U1 1 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD DEC PY 2012 VL 86 IS 3 BP 214 EP 219 DI 10.1016/j.ijpsycho.2012.09.006 PG 6 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 056WI UT WOS:000312521700003 PM 23007035 ER PT J AU Branham, K Othman, M Brumm, M Karoukis, AJ Atmaca-Sonmez, P Yashar, BM Schwartz, SB Stover, NB Trzupek, K Wheaton, D Jennings, B Ciccarelli, ML Jayasundera, KT Lewis, RA Birch, D Bennett, J Sieving, PA Andreasson, S Duncan, JL Fishman, GA Iannaccone, A Weleber, RG Jacobson, SG Heckenlively, JR Swaroop, A AF Branham, Kari Othman, Mohammad Brumm, Matthew Karoukis, Athanasios J. Atmaca-Sonmez, Pelin Yashar, Beverly M. Schwartz, Sharon B. Stover, Niamh B. Trzupek, Karmen Wheaton, Dianna Jennings, Barbara Ciccarelli, Maria Laura Jayasundera, K. Thiran Lewis, Richard A. Birch, David Bennett, Jean Sieving, Paul A. Andreasson, Sten Duncan, Jacque L. Fishman, Gerald A. Iannaccone, Alessandro Weleber, Richard G. Jacobson, Samuel G. Heckenlively, John R. Swaroop, Anand TI Mutations in RPGR and RP2 Account for 15% of Males with Simplex Retinal Degenerative Disease SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID LINKED RETINITIS-PIGMENTOSA; MULTIPOINT LINKAGE ANALYSIS; SYNDROME TYPE-II; HOMOGENEITY TESTS; SPANISH FAMILIES; GENE-THERAPY; USH2A GENE; IDENTIFICATION; PHENOTYPE; DYSTROPHY AB PURPOSE. To determine the proportion of male patients presenting simplex retinal degenerative disease (RD: retinitis pigmentosa [RP] or cone/cone-rod dystrophy [COD/CORD]) with mutations in the X-linked retinal degeneration genes RPGR and RP2. METHODS. Simplex males were defined as patients with no known affected family members. Patients were excluded if they had a family history of parental consanguinity. Blood samples from a total of 214 simplex males with a diagnosis of retinal degeneration were collected for genetic analysis. The patients were screened for mutations in RPGR and RP2 by direct sequencing of PCR-amplified genomic DNA. RESULTS. We identified pathogenic mutations in 32 of the 214 patients screened (15%). Of the 29 patients with a diagnosis of COD/CORD, four mutations were identified in the ORF15 mutational hotspot of the RPGR gene. Of the 185 RP patients, three patients had mutations in RP2 and 25 had RPGR mutations (including 12 in the ORF15 region). CONCLUSIONS. This study represents mutation screening of RPGR and RP2 in the largest cohort, to date, of simplex males affected with RP or COD/CORD. Our results demonstrate a substantial contribution of RPGR mutations to retinal degenerations, and in particular, to simplex RP. Based on our findings, we suggest that RPGR should be considered as a first tier gene for screening isolated males with retinal degeneration. (Invest Ophthalmol Vis Sci. 2012;53:8232-8237) DOI:10.1167/iovs.12-11025 C1 [Swaroop, Anand] NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bethesda, MD 20892 USA. [Branham, Kari; Othman, Mohammad; Brumm, Matthew; Karoukis, Athanasios J.; Atmaca-Sonmez, Pelin; Jayasundera, K. Thiran; Sieving, Paul A.; Heckenlively, John R.; Swaroop, Anand] Univ Michigan, Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. [Yashar, Beverly M.; Swaroop, Anand] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48105 USA. [Schwartz, Sharon B.; Jacobson, Samuel G.] Univ Penn, Scheie Eye Inst, Philadelphia, PA 19104 USA. [Stover, Niamh B.; Trzupek, Karmen; Weleber, Richard G.] Oregon Hlth & Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. [Wheaton, Dianna; Birch, David] Retina Fdn SW, Dallas, TX USA. [Jennings, Barbara; Iannaccone, Alessandro] Univ Tennessee, Ctr Hlth Sci, Hamilton Eye Inst, Memphis, TN 38163 USA. [Ciccarelli, Maria Laura] Israelit Hosp, Div Ophthalmol, Rome, Italy. [Lewis, Richard A.] Baylor Coll Med, Cullen Eye Inst, Dept Ophthalmol, Houston, TX 77030 USA. [Bennett, Jean] Univ Penn, Sch Med, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Andreasson, Sten] Lund Univ, Dept Ophthalmol, Sch Med, Lund, Sweden. [Duncan, Jacque L.] Univ Calif San Francisco, Dept Ophthalmol, San Francisco, CA USA. [Fishman, Gerald A.] Univ Illinois, Dept Ophthalmol, Chicago, IL 60680 USA. RP Swaroop, A (reprint author), NEI, Neurobiol Neurodegenerat & Repair Lab, NIH, Bldg 6-338,6 Ctr Dr,MSC 0610, Bethesda, MD 20892 USA. EM jrheck@umich.edu; swaroopa@nei.nih.gov OI Birch, David/0000-0002-6594-2897; Swaroop, Anand/0000-0002-1975-1141 FU intramural research program of the National Eye Institute [ZO1 EY000473, NIH-EY007961]; Foundation Fighting Blindness; Harold F. Falls Collegiate Professorship; Research to Prevent Blindness, New York, New York; Kellogg Eye Center; UCSF Department of Ophthalmology; Cullen Eye Institute; Hamilton Eye Institute FX Supported by intramural research program of the National Eye Institute ZO1 EY000473 (AS), NIH-EY007961 (AS), The Foundation Fighting Blindness (AS, DB, GAF, JB, JLD, JRH, SGJ, RGW), Harold F. Falls Collegiate Professorship (AS), unrestricted grants from Research to Prevent Blindness, New York, New York to the W. K. Kellogg Eye Center, UCSF Department of Ophthalmology, Cullen Eye Institute, and Hamilton Eye Institute. RAL is a Senior Scientific Investigator of RPB. NR 49 TC 39 Z9 39 U1 0 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD DEC PY 2012 VL 53 IS 13 BP 8232 EP 8237 DI 10.1167/iovs.12-11025 PG 6 WC Ophthalmology SC Ophthalmology GA 064EX UT WOS:000313056000043 PM 23150612 ER PT J AU Slomski, C Julian, TB AF Slomski, Carol Julian, Thomas B. TI Does Predicting Positive Nonsentinel Nodes Answer the Question of Axillary Dissection and Provide a Benefit?. SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID INVASIVE BREAST-CANCER; METASTASIS; WOMEN C1 [Julian, Thomas B.] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. [Slomski, Carol; Julian, Thomas B.] Allegheny Gen Hosp, Allegheny Canc Ctr, Pittsburgh, PA 15212 USA. RP Julian, TB (reprint author), Natl Surg Adjuvant Breast & Bowel Project, 320 E North Ave, Pittsburgh, PA 15212 USA. EM tjulian@nasbp.org NR 7 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD DEC PY 2012 VL 104 IS 24 BP 1858 EP 1859 DI 10.1093/jnci/djs489 PG 2 WC Oncology SC Oncology GA 062AJ UT WOS:000312891200005 PM 23221924 ER PT J AU Chase, JM Holland, SM Greenberg, DE Marshall-Batty, K Zelazny, AM Church, JA AF Chase, John M. Holland, Steven M. Greenberg, David E. Marshall-Batty, Kimberly Zelazny, Adrian M. Church, Joseph A. TI Acidomonas Methanolica-Associated Necrotizing Lymphadenitis in a Patient with Chronic Granulomatous Disease SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Chronic granulomatous disease; Acidomonas methanolica ID GRANULIBACTER-BETHESDENSIS; ACETOBACTER-METHANOLICUS; BACTERIUM; NOV AB Adenitis for which no causative organism can be isolated is a common occurrence in patients with chronic granulomatous disease (CGD). Here we identify Acidomonas methanolica as a pathogen associated with adenitis in a patient with CGD. The causative pathogen was obtained after prolonged incubation of an excised lymph node in thioglycolate broth. Identification was carried out by sequencing the 16s rRNA. Immunoblots were prepared utilizing protein extracts from the case patient's A. methanolica isolate, an ATCC type strain of A. methanolica and G. bethesdensis. Fastidious gram-negative rods grew after prolonged incubation of an excised lymph node in thioglycolate broth. Sequencing of the 16s rRNA identified the organism as A. methanolica. Immunoblot confirmed the pathogen's role in the patient's adenitis by showing the patient's specific immune response to the organism. A. methanolica is the second member of the family, Acetobacteaceae to be associated with adenitis in patients with CGD. C1 [Chase, John M.] Childrens Hosp Los Angeles, Div Gen Pediat, Los Angeles, CA 90027 USA. [Chase, John M.; Church, Joseph A.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90027 USA. [Holland, Steven M.; Greenberg, David E.; Marshall-Batty, Kimberly; Zelazny, Adrian M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. [Church, Joseph A.] Childrens Hosp Los Angeles, Div Clin Immunol & Allergy, Los Angeles, CA 90027 USA. RP Chase, JM (reprint author), Childrens Hosp Los Angeles, Div Gen Pediat, MS 75,4650 Sunset Blvd, Los Angeles, CA 90027 USA. EM chasejm@gmail.com; jchurch@chla.usc.edu FU Department of Laboratory Medicine, National Institutes of Health FX Funding: Department of Laboratory Medicine, National Institutes of Health NR 11 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD DEC PY 2012 VL 32 IS 6 BP 1193 EP 1196 DI 10.1007/s10875-012-9728-6 PG 4 WC Immunology SC Immunology GA 059XL UT WOS:000312738800006 PM 22752310 ER PT J AU Bassim, CW Ambatipudi, KS Mays, JW Edwards, DA Swatkoski, S Fassil, H Baird, K Gucek, M Melvin, JE Pavletic, SZ AF Bassim, Carol W. Ambatipudi, Kiran S. Mays, Jacqueline W. Edwards, Dean A. Swatkoski, Stephan Fassil, Helen Baird, Kristin Gucek, Marjan Melvin, James E. Pavletic, Steven Z. TI Quantitative Salivary Proteomic Differences in Oral Chronic Graft-versus-Host Disease SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Saliva; oral; GVHD; biomarker; proteomics; label-free quantitation; transplant; graft versus host ID CONSENSUS DEVELOPMENT PROJECT; BONE-MARROW-TRANSPLANTATION; WORKING GROUP-REPORT; MASS-SPECTROMETRY; CLINICAL-TRIALS; CYSTATIN-D; PROTEIN; LACTOFERRIN; PLASMA; REPRODUCIBILITY AB Chronic graft-versus-host disease (cGVHD) is a severe immunological complication that occurs after allogeneic hematopoietic stem cell transplantation (HSCT). Although oral cGVHD occurs in > 25 % of cGVHD patients and leads to decreased quality of life, its etiology is poorly understood. The present retrospective cross-sectional analysis of oral cGVHD patients sought to (1) test the feasibility of liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify protein biomarkers of oral cGVHD and (2) to gain a clearer understanding of salivary proteins impacted by oral cGVHD. Using unstimulated whole saliva, we compared pooled saliva from five patients with a diagnosis of moderate or severe oral cGVHD, with a gender-and age- matched pool of five cGVHD patients with no oral mucosal findings. LC-MS/MS was used to identify salivary proteins, followed by Ingenuity Pathway Analysis (IPA). Selected mass spectrometric findings, including lactotransferrin, lactoperoxidase, and albumin, were confirmed by targeted label-free quantification. LC-MS/MS led to confident identification of 180 proteins. Of these proteins, 102 changed in abundance at least 2 fold, including 12 proteins identified only in the No oral cGVHD group. Downregulation of similar to 0.4 fold was confirmed for both lactotransferrin and lactoperoxidase in Oral cGVHD saliva using targeted label-free quantification. IPA analysis implicated pathways involved in cellular metabolism and immunoregulation. Reduction of salivary lactoperoxidase, lactotransferrin, and several cysteine proteinase inhibitor family proteins suggests impaired oral antimicrobial host immunity in cGVHD patients. This shotgun proteomic analysis of oral cGVHD saliva using targeted label-free quantification of select proteins supports the use of mass spectrometry for future validation in a large patient population as noninvasive tests for screening, early detection, and monitoring of cGVHD. C1 [Bassim, Carol W.; Ambatipudi, Kiran S.; Mays, Jacqueline W.; Edwards, Dean A.; Melvin, James E.] Natl Inst Dent & Craniofacial Res, Bethesda, MD 20892 USA. [Fassil, Helen; Baird, Kristin; Pavletic, Steven Z.] NCI, Bethesda, MD 20892 USA. [Swatkoski, Stephan; Gucek, Marjan] Natl Inst Heart, Prote Core Facil, Lung & Blood Inst, NIH, Bethesda, MD 20892 USA. RP Melvin, JE (reprint author), Natl Inst Dent & Craniofacial Res, 10 Ctr Dr,Room 5-2531,MSC 1470, Bethesda, MD 20892 USA. EM melvinje@mail.nih.gov FU NIDCR, NIH; NCI, NIH FX We gratefully acknowledge Dr. Frances Hakim for thoughtful discussions during the course of this study, and sincerely thank the patients who were willing to participate in this research. This work was supported by the Intramural Research Programs of the NIDCR, NIH and the NCI, NIH. The authors declare no conflict of interest. NR 41 TC 15 Z9 15 U1 2 U2 13 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD DEC PY 2012 VL 32 IS 6 BP 1390 EP 1399 DI 10.1007/s10875-012-9738-4 PG 10 WC Immunology SC Immunology GA 059XL UT WOS:000312738800028 PM 22806177 ER PT J AU Falcone, EL Zelazny, AM Holland, SM AF Falcone, E. Liana Zelazny, Adrian M. Holland, Steven M. TI Rothia aeria Neck Abscess in A Patient with Chronic Granulomatous Disease: Case Report and Brief Review of the Literature SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Chronic granulomatous disease; Rothia aeria; neck abscess; lymphadenitis ID DENTOCARIOSA; MUCILAGINOSA; PERITONITIS; BACTEREMIA; SEPSIS AB Rothia aeria caused a necrotic lymphadenitis and neck abscess in a patient with CGD. This infection was aggressive, crossed tissue planes, required two surgeries, as well as prolonged antibiotics for complete resolution. Rothia aeria is a rare pathogen that can be added to the spectrum of agents causing disease in CGD, a finding that further reinforces the importance of microbiologic identification of infections in this patient population. C1 [Falcone, E. Liana; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Zelazny, Adrian M.] NIH, Microbiol Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Falcone, EL (reprint author), NIAID, Lab Clin Infect Dis, NIH, 10 Ctr Dr,CRC,Rm B3 4141,MSC 1684, Bethesda, MD 20892 USA. EM emilia.falcone@nih.gov; sholland@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892. The views expressed in this article are those of the authors and do not reflect the official policy of the U.S. Government. NR 22 TC 6 Z9 6 U1 0 U2 5 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD DEC PY 2012 VL 32 IS 6 BP 1400 EP 1403 DI 10.1007/s10875-012-9726-8 PG 4 WC Immunology SC Immunology GA 059XL UT WOS:000312738800029 PM 22730055 ER PT J AU Jain, S Marotta, F Catanzaro, R Yadav, H AF Jain, Shalini Marotta, Francesco Catanzaro, Roberto Yadav, Hariom TI Immune System and Gut Flora Interactions Are Important Episodes in Metabolic Diseases SO JOURNAL OF GASTROINTESTINAL AND LIVER DISEASES LA English DT Editorial Material ID INSULIN-RESISTANCE; OBESITY; BARRIER C1 [Jain, Shalini; Yadav, Hariom] NIDDKD, NIH, Bethesda, MD 20892 USA. [Marotta, Francesco] ReGenera Res Grp Aging Intervent, Milan, Italy. [Catanzaro, Roberto] Univ Catania, Dept Gastroenterol, Catania, Italy. RP Yadav, H (reprint author), NIDDKD, NIH, Bethesda, MD 20892 USA. EM yadavhariom@gmail.com NR 17 TC 0 Z9 0 U1 1 U2 5 PU MEDICAL UNIV PRESS PI CLUJ-NAPOCA PA 3RD MEDICAL CLINIC, STR CROITORILOR NO 19-21, CLUJ-NAPOCA, 400162, ROMANIA SN 1841-8724 J9 J GASTROINTEST LIVER JI J. Gastrointest. Liver Dis. PD DEC PY 2012 VL 21 IS 4 BP 347 EP 348 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 059AZ UT WOS:000312678100005 PM 23256115 ER PT J AU Pepin, KM VanDalen, KK Mooers, NL Ellis, JW Sullivan, HJ Root, JJ Webb, CT Franklin, AB Shriner, SA AF Pepin, K. M. VanDalen, K. K. Mooers, N. L. Ellis, J. W. Sullivan, H. J. Root, J. J. Webb, C. T. Franklin, A. B. Shriner, S. A. TI Quantification of heterosubtypic immunity between avian influenza subtypes H3N8 and H4N6 in multiple avian host species SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID MALLARDS ANAS-PLATYRHYNCHOS; WILD BIRDS; A VIRUSES; INDIVIDUAL VARIATION; INFECTION; PROTECTION; CHALLENGE; EVOLUTION; CHICKENS; ECOLOGY AB Low-pathogenicity avian influenza virus (LPAIV) can lead to epizootics that cause economic losses in poultry or the emergence of human-infectious strains. LPAIVs experience a complex immunity landscape as they are endemic in numerous host species, and many antigenically distinct strains co-circulate. Prevention and control of emergence of detrimental strains requires an understanding of infection/transmission characteristics of the various subtypes in different hosts, including interactions between subtypes. In order to develop analytical frameworks for examining control efficacy, quantification of heterosubtypic immunity interactions is fundamental. However, these data are scarce, especially for wild avian subtypes in natural hosts. Consequently, in this study, three host species (mallards, quail and pheasants) were infected with two LPAIV subtypes isolated from wild birds: H3N8 and H4N6. The recovered hosts were also reinfected with the alternate subtype to measure the effects of heterosubtypic immunity. Oropharyngeal and cloacal swabs were collected and viral RNA load was quantified by real-time RT-PCR. For secondary infections in recovered hosts, peak viral load was up to four orders of magnitude lower and shedding length was up to 4 days shorter. However, both the magnitude and presence of heterosubtypic immunity varied across specific host species/subtype combinations. Using a mathematical model of virus replication, the variation in virus replication dynamics due to host individuals was quantified. It was found that accounting for individual heterogeneity is important for drawing accurate conclusions about treatment effects. These results are relevant for developing epidemiological models to inform control practices and for analysing virus replication data. C1 [VanDalen, K. K.; Mooers, N. L.; Ellis, J. W.; Sullivan, H. J.; Root, J. J.; Franklin, A. B.; Shriner, S. A.] US Fish & Wildlife Serv, Natl Wildlife Res Ctr, USDA, Ft Collins, CO USA. [Pepin, K. M.] Fogarty Int Ctr, Bethesda, MD USA. [Pepin, K. M.; Webb, C. T.] Colorado State Univ, Ft Collins, CO 80523 USA. RP Shriner, SA (reprint author), US Fish & Wildlife Serv, Natl Wildlife Res Ctr, USDA, Ft Collins, CO USA. EM susan.a.shriner@aphis.usda.gov OI Shriner, Susan/0000-0003-0349-7182; Ellis, Jeremy/0000-0003-4512-0906 FU RAPIDD program of the Science and Technology Directorate; US Department of Homeland Security; Fogarty International Center, NIH FX Thanks to Helen Sofaer for helpful discussion and sharing the code for the non-linear mixed modelling methods in R. Thanks also to Nick Thomas, Darcy Orahood and Alexis Freifeld for laboratory assistance, Daniel N. Gossett and the National Wildlife Research Center Animal Care Staff for animal husbandry, and Dr Gordon R. Gathright for veterinary support. K. M. P and C. T. W were supported by the RAPIDD program of the Science and Technology Directorate, US Department of Homeland Security, and the Fogarty International Center, NIH. NR 33 TC 12 Z9 14 U1 0 U2 7 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD DEC PY 2012 VL 93 BP 2575 EP 2583 DI 10.1099/vir.0.045427-0 PN 12 PG 9 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 063UM UT WOS:000313027500005 PM 22956733 ER PT J AU Nelson, MI Detmer, SE Wentworth, DE Tan, Y Schwartzbard, A Halpin, RA Stockwell, TB Lin, XD Vincent, AL Gramer, MR Holmes, EC AF Nelson, Martha I. Detmer, Susan E. Wentworth, David E. Tan, Yi Schwartzbard, Aaron Halpin, Rebecca A. Stockwell, Timothy B. Lin, Xudong Vincent, Amy L. Gramer, Marie R. Holmes, Edward C. TI Genomic reassortment of influenza A virus in North American swine, 1998-2011 SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID UNITED-STATES; NEURAMINIDASE ACTIVITIES; H1N1; TRANSMISSION; PIGS; HEMAGGLUTININ; MODEL AB Revealing the frequency and determinants of reassortment among RNA genome segments is fundamental to understanding basic aspects of the biology and evolution of the influenza virus. To estimate the extent of genomic reassortment in influenza viruses circulating in North American swine, we performed a phylogenetic analysis of 139 whole-genome viral sequences sampled during 1998-2011 and representing seven antigenically distinct viral lineages. The highest amounts of reassortment were detected between the H3 and the internal gene segments (PB2, PB1, PA, NP, M and NS), while the lowest reassortment frequencies were observed among the H1 gamma, H1pdm and neuraminidase segments, particularly N1. Less reassortment was observed among specific haemagglutinin neuraminidase combinations that were more prevalent in swine, suggesting that some genome constellations may be evolutionarily more stable. C1 [Nelson, Martha I.; Tan, Yi; Schwartzbard, Aaron; Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Detmer, Susan E.] Univ Saskatchewan, Western Coll Vet Med, Saskatoon, SK S7N 0W0, Canada. [Wentworth, David E.; Halpin, Rebecca A.; Stockwell, Timothy B.; Lin, Xudong] J Craig Venter Inst, Rockville, MD 20850 USA. [Vincent, Amy L.] USDA ARS, Virus & Prion Res Unit, Natl Anim Ctr, Ames, IA 50010 USA. [Gramer, Marie R.] Univ Minnesota, Vet Diagnost Lab, St Paul, MN 55108 USA. [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. RP Nelson, MI (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM nelsonma@mail.nih.gov OI Wentworth, David/0000-0002-5190-980X; Holmes, Edward/0000-0001-9596-3552 FU Office of Global Affairs at the Department of Health and Human Services (DHHS); National Institute of Allergy and Infectious Disease; National Institutes of Health; Department of Health and Human Services [HHSN272200900007C, HHSN266200700007C] FX We are grateful to the pork producers and swine practitioners for participating in the USDA Swine Influenza Surveillance System through the National Animal Health Laboratory Network (NAHLN). We thank Dan Weinberger and Cecile Viboud of the Fogarty International Center for technical input. This research was conducted within the context of the Multinational Influenza Seasonal Mortality Study (MISMS), an on-going international collaborative effort to understand influenza epidemiology and evolution, led by the Fogarty International Center, NTH, with funding from the Office of Global Affairs at the Department of Health and Human Services (DHHS) (A. S., E. C. H., M. I. N. and Y. T.). This work was supported in part by funds from the National Institute of Allergy and Infectious Disease, the National Institutes of Health and the Department of Health and Human Services under contract no. HHSN272200900007C (D. E. W., R. A. H., T. B. S. and X. L.) and HHSN266200700007C (S. E. D. and M. R. G.). NR 29 TC 15 Z9 15 U1 0 U2 18 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD DEC PY 2012 VL 93 BP 2584 EP 2589 DI 10.1099/vir.0.045930-0 PN 12 PG 6 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 063UM UT WOS:000313027500006 PM 22993190 ER PT J AU Li, L Xiao, XS Yi, CX Jiao, XD Guo, XM Hejtmancik, JF Zhang, QJ AF Li, Lin Xiao, Xueshan Yi, Changxian Jiao, Xiaodong Guo, Xiangming Hejtmancik, James Fielding Zhang, Qingjiong TI Confirmation and refinement of an autosomal dominant congenital motor nystagmus locus in chromosome 1q31.3-q32.1 SO JOURNAL OF HUMAN GENETICS LA English DT Article DE autosomal dominant; congenital motor nystagmus; linkage; locus ID FAMILY; MUTATIONS; 6P12; GENE; MAPS AB Congenital motor nystagmus (CMN) is characterized by early-onset bilateral ocular oscillations. To identify the disease locus for autosomal dominant CMN in a Chinese family 86001, clinical data, including slit lamp and funduscopic examination and blood samples were collected from family. Genomic DNA was prepared from leukocytes, and a genome-wide linkage scan was performed using 382 polymorphic microsatellite markers and two-point linkage analysis using the logarithm of odds (LOD) score method as implemented in the LINKAGE program package. Maximum two-point scores were calculated using ILINK, and LINKMAP was used for multipoint analysis. All nine affected individuals in the family showed typical phenotypes for CMN. Maximum two-point LOD scores (3.61 at h 0) were obtained with D1S2619, D1S2877 and D1S2622. The 24.6 cM (28.07 Mb) linked region is flanked by markers D1S218 and D1S2655, placing the disease locus on chromosome 1q25.2-1q32.1. Multipoint analysis confirmed linkage to the region of D1S218 and D1S2655 with Maximum two-point scores of 3.61. The linkage interval overlaps with that of a newly reported CMN locus on 1q31-q32.2 and narrows down the linked region to 5.90 cM (5.92 Mb). This study confirms and refines a novel locus for autosomal dominant CMN to chromosome 1q31.3-q32.1 (5.90 cM) and demonstrates its presence in the Chinese population. Journal of Human Genetics (2012) 57, 756-759; doi:10.1038/jhg.2012.103; published online 23 August 2012 C1 [Li, Lin; Jiao, Xiaodong; Hejtmancik, James Fielding] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Rockville, MD 20852 USA. [Li, Lin; Xiao, Xueshan; Yi, Changxian; Guo, Xiangming; Zhang, Qingjiong] Sun Yat Sen Univ, State Key Lab Ophthalmol, Zhongshan Ophthalm Ctr, Guangzhou 510060, Guangdong, Peoples R China. RP Hejtmancik, JF (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, 5635 Fishers Lane RM1120, Rockville, MD 20852 USA. EM hejtmancikj@nei.nih.gov; zhangqji@mail.sysu.edu.cn FU National Natural Science Foundation of China [30800615]; National Science Fund for Distinguished Young Scholars [30725044]; Fundamental Research Funds of State Key Laboratory of Ophthalmology FX We thank all patients and controls for their participation. This study was supported by the National Natural Science Foundation of China (30800615), the National Science Fund for Distinguished Young Scholars (30725044) and the Fundamental Research Funds of State Key Laboratory of Ophthalmology. NR 14 TC 2 Z9 3 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1434-5161 J9 J HUM GENET JI J. Hum. Genet. PD DEC PY 2012 VL 57 IS 12 BP 756 EP 759 DI 10.1038/jhg.2012.103 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 060SW UT WOS:000312799400003 PM 22914672 ER PT J AU Joo, JS Song, JY Baik, SC Lee, WK Cho, MJ Lee, KH Youn, HS Seo, JH Rhee, KH Kang, HL AF Joo, Jung-Soo Song, Jae-Young Baik, Seung-Chul Lee, Woo-Kon Cho, Myung-Je Lee, Kon-Ho Youn, Hee-Shang Seo, Ji-Hyun Rhee, Kwang-Ho Kang, Hyung-Lyun TI Genetic organization and conjugal plasmid DNA transfer of pHP69, a plasmid from a Korean isolate of Helicobacter pylori SO JOURNAL OF MICROBIOLOGY LA English DT Article DE Helicobacter pylori; pHP69; relaxase; conjugation ID SMALL CRYPTIC PLASMID; GASTRIC-CARCINOMA; IV SECRETION; REPLICATION; RELAXASE; PROTEINS; SEQUENCE; CELLS AB We isolated pHP69, a 9,153 bp plasmid from Helicobacter pylori with a 33.98% (G+C) content. We identified 11 open reading frames (ORFs), including replication initiation protein A (repA), fic (cAMP-induced filamentation protein), mccC, mccB, mobA, mobD, mobB, and mobC, as well as four 22 bp tandem repeat sequences. The nucleic acid and predicted amino acid sequences of these ORFs exhibited significant homology to those of other H. pylori plasmids. pHP69 repA encodes a replication initiation protein and its amino acid sequence is similar to those of replicase proteins from theta-type plasmids. pHP69 contains two types of repeat sequences (R1 and R2), a MOBHEN family mobilization region comprising mobC, mobA, mobB, and mobD, and genes encoding microcin B and C. Among the 36 H. pylori strains containing plasmids, mobA or mccBC are present in 12 or 6, respectively and 3 contain both genes. To examine intrinsic capability of H. pylori for conjugative plasmid transfer, a shuttle vector pBHP69KH containing pHP69 and replication origin of pBR322 was constructed. It was shown that this vector could stably replicate and be mobilized among clinical H. pylori strains and demonstrated to gene transfer by natural plasmid. C1 [Song, Jae-Young; Baik, Seung-Chul; Lee, Woo-Kon; Cho, Myung-Je; Lee, Kon-Ho; Rhee, Kwang-Ho; Kang, Hyung-Lyun] Gyeongsang Natl Univ, Sch Med, Dept Microbiol, Jinju 660751, South Korea. [Youn, Hee-Shang; Seo, Ji-Hyun] Gyeongsang Natl Univ, Sch Med, Dept Pediat, Jinju 660751, South Korea. [Song, Jae-Young; Baik, Seung-Chul; Lee, Woo-Kon; Cho, Myung-Je; Lee, Kon-Ho; Rhee, Kwang-Ho; Kang, Hyung-Lyun] Gyeongsang Natl Univ, Life Sci Res Inst, Jinju 660701, South Korea. [Joo, Jung-Soo] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Kang, HL (reprint author), Gyeongsang Natl Univ, Sch Med, Dept Microbiol, Jinju 660751, South Korea. EM kangssi@gnu.kr OI Youn, Hee-Shang/0000-0002-5498-838X FU National Research Foundation of Korea (NRF); Ministry of Education, Science and Technology [2011-0027200] FX This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2011-0027200). NR 30 TC 1 Z9 2 U1 0 U2 5 PU MICROBIOLOGICAL SOCIETY KOREA PI SEOUL PA KOREA SCIENCE & TECHNOLOGY CENTER 803, 635-4 YEOGSAM-DONG, KANGNAM-KU, SEOUL 135-703, SOUTH KOREA SN 1225-8873 J9 J MICROBIOL JI J. Microbiol. PD DEC PY 2012 VL 50 IS 6 BP 955 EP 961 DI 10.1007/s12275-012-2580-9 PG 7 WC Microbiology SC Microbiology GA 061VW UT WOS:000312879300009 PM 23274982 ER PT J AU Nomura, T Matsumoto, S Kitamura, S Ishiwata, A Ishii, C Nemoto, R Kawanami, O AF Nomura, Toshiaki Matsumoto, Satoko Kitamura, Shin Ishiwata, Akiko Ishii, Chika Nemoto, Rumi Kawanami, Oichi TI Roles of Consultation Organizations in the Early Detection of Dementia: From the Practices of the Community Consultation Center for Citizens with Mild Cognitive Impairment and Dementia, Nippon Medical School SO JOURNAL OF NIPPON MEDICAL SCHOOL LA English DT Article DE community coordination; consultation organization; dementia; early detection; memory loss check system AB Background: As society ages, early detection of dementia is becoming increasingly important. Many hospitals have opened memory-loss clinics, and various new approaches for early examination and appropriate diagnosis are being tried. However, these memory-loss clinics are ultimately part of the hospital establishment, implying that, in addition to the burdens of time and effort to undergo examinations and consultations, patients might have a certain psychological resistance. With a grant from the Ministry of Education, Culture, Sports, Science and Technology, the Institute of Development and Aging Science at Nippon Medical School has opened a center called the Community Consultation Center for Citizens with Mild Cognitive Impairment and Dementia, which is a dementia-related center outside the regular hospital. This center has been developing a system that makes consultations easier. We performed a retrospective follow-up study that aimed to determine how much this approach contributes to the early detection of dementia compared with outpatient visits to university hospitals. Methods: Persons who were found to have organic brain syndrome (defined as organic diseases related to dementia, including mild cognitive impairment) after visiting the Consultation Center during the survey period were referred to as the Consultation Center group, and persons who were found to have organic brain syndrome after an initial visit to the Department of Neurology at Nippon Medical School Musashi Kosugi Hospital were referred to as the Hospital group. We compared the groups in terms of sex, age, Mini-Mental State Examination (MMSE) score, and subclassification by means of the t-test and chi(2) test. Results: Both the mean MMSE score (p<0.001) and percentage of subjects with an MMSE score of 24 points of higher (p=0.007) were significantly higher in the Consultation Center group than in the Hospital group. Conclusions: Consultations can be made more casually at the Consultation Center than at hospitals. Our results suggest that more casual consultations contribute to the early detection of dementia. (J Nippon Med Sch 2012; 79: 438-443) C1 [Nomura, Toshiaki] Nippon Med Sch, Inst Dev & Aging Sci, Community Consultat Ctr Citizens Mild Cognit Impa, Nakahara Ku, Kawasaki, Kanagawa 2118533, Japan. [Nomura, Toshiaki] Nippon Med Sch, Dept Psychol, Kawasaki, Kanagawa 2118533, Japan. [Matsumoto, Satoko] NIMH, Natl Ctr Neurol & Psychiat, Rockville, MD USA. [Kitamura, Shin] Musashi Kosugi Hosp, Nippon Med Sch, Tokyo, Japan. [Ishiwata, Akiko] Nippon Med Sch, Dept Neurol & Internal Med, Kawasaki, Kanagawa 2118533, Japan. RP Nomura, T (reprint author), Nippon Med Sch, Inst Dev & Aging Sci, Community Consultat Ctr Citizens Mild Cognit Impa, Nakahara Ku, 1-396 Kosugi Cho, Kawasaki, Kanagawa 2118533, Japan. EM t-nomura@nms.ac.jp FU Ministry of Education, Culture, Sports, Science and Technology FX This study was performed with a grant for strategic basic research for social initiatives from the Ministry of Education, Culture, Sports, Science and Technology. In addition, considerable support was obtained from the Institute of Development and Aging Science in Kawasaki City and from other organizations associated with the activities of the Consultation Center. In particular, Mr. Takao Abe, Mayor of Kawasaki City, and Dr. Akira Kurokawa, Director of Nippon Medical School Musashi Kosugi Hospital, provided tremendous support and understanding in advancing this project. NR 19 TC 1 Z9 1 U1 1 U2 7 PU MEDICAL ASSOC NIPPON MEDICAL SCH PI TOKYO PA 1-1-5, SENDAGI, TOKYO, 113-8602, JAPAN SN 1345-4676 J9 J NIPPON MED SCH JI J. Nippon Med. Sch. PD DEC PY 2012 VL 79 IS 6 BP 438 EP 443 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 062LP UT WOS:000312921600008 PM 23291842 ER PT J AU Gupta, S Hunsberger, S Boerner, SA Rubinstein, L Royds, R Ivy, P LoRusso, P AF Gupta, Sachin Hunsberger, Sally Boerner, Scott A. Rubinstein, Larry Royds, Robert Ivy, Percy LoRusso, Patricia TI Meta-analysis of the Relationship Between Dose and Benefit in Phase I Targeted Agent Trials SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Review ID GASTROINTESTINAL STROMAL TUMORS; NONCYTOTOXIC AGENTS; END-POINTS; ALWAYS GO; SELECTION; IMATINIB; THERAPY; DESIGNS AB To date, the primary objective of phase I trials has been to safely select the maximum tolerated dose (MTD) of a drug or drug combination for utilization in subsequent trials. Although conventional cytotoxic chemotherapy is generally more effective at the MTD than molecularly targeted agents (MTAs), recent single-institution data suggest that molecularly targeted agent may not require an MTD for efficacy. We analyzed patient outcome results in MTA phase I trials at multiple institutions throughout North America sponsored by the National Cancer Institute's Cancer Therapy Evaluation Program. We retrospectively collected and analyzed data on patients treated on monotherapy phase I trials investigating novel MTAs with a defined MTD from 2000 to 2009. Logistic regression analysis was used to test whether there was an increase in the probability of a response as dose increased. A Cox proportional hazards model was used to determine if overall survival increased with increasing dose. All statistical tests were two-sided. We analyzed 1908 patients treated on 55 eligible clinical trials. The probability of both overall response (complete response plus partial response) and overall survival increased with increasing dose (odds ratio for increased response 1.56, P .10; hazard ratio for death 0.37, P .008) when controlling for study as a covariate. Patients treated in the context of phase I trials with MTAs continue to derive reasonable clinical benefit. Contrary to other single institution data, our data suggest clinical benefit in terms of increasing response and overall survival with increasing dose. J Natl Cancer Inst 2012:104;1860-1866 C1 [Gupta, Sachin; Boerner, Scott A.; LoRusso, Patricia] Wayne State Univ, Karmanos Canc Inst, Dept Oncol, Detroit, MI 48201 USA. [Hunsberger, Sally; Rubinstein, Larry] NCI, Biometr Res Branch, NIH, Rockville, MD USA. [Ivy, Percy] NCI, Canc Therapy Evaluat Program, NIH, Rockville, MD USA. [Royds, Robert] Theradex, Princeton, NJ USA. RP LoRusso, P (reprint author), Wayne State Univ, Karmanos Canc Inst, Dept Oncol, 4100 John R St, Detroit, MI 48201 USA. EM lorussop@karmanos.org NR 22 TC 15 Z9 15 U1 0 U2 4 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 DEC PY 2012 VL 104 IS 24 BP 1860 EP 1866 DI 10.1093/jnci/djs439 PG 7 WC Oncology SC Oncology GA 062AJ UT WOS:000312891200006 PM 23169991 ER PT J AU Amaral, AFS Mendez-Pertuz, M Munoz, A Silverman, DT Allory, Y Kogevinas, M Lloreta, J Rothman, N Carrato, A del Fresno, MR Real, FX Malats, N AF Amaral, Andre F. S. Mendez-Pertuz, Marinela Munoz, Alberto Silverman, Debra T. Allory, Yves Kogevinas, Manolis Lloreta, Josep Rothman, Nathaniel Carrato, Alfredo Rivas del Fresno, Manuel Real, Francisco X. Malats, Nuria CA Spanish Bladder Canc EPICURO Study TI Plasma 25-Hydroxyvitamin D-3 and Bladder Cancer Risk According to Tumor Stage and FGFR3 Status: A Mechanism-Based Epidemiological Study SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SERUM VITAMIN-D; TRANSITIONAL-CELL CARCINOMA; RECEPTOR EXPRESSION; PROGNOSTIC-FACTOR; SCREENING TRIAL; PROSTATE-CANCER; COLON-CANCER; D DEFICIENCY; METAANALYSES; POPULATION AB Previous evidence suggests that 25-hydroxyvitamin D-3 [25(OH)D-3] protects against several cancers. However, little is known regarding urothelial bladder cancer (UBC). We analyzed the association between plasma 25(OH)D-3 and overall risk of UBC, as well as according to stage and FGFR3 molecular subphenotypes. Plasma concentrations of 25(OH)D-3 in 1125 cases with UBC and 1028 control subjects were determined by a chemiluminescence immunoassay. FGFR3 mutational status and expression in tumor tissue were assessed. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression adjusting for potential confounders. Analyses were further stratified by tumor invasiveness and grade, FGFR3 expression, and smoking status. Cell proliferation was measured in human UBC cell lines cultured with 1,25-dihydroxyvitamin D-3. A statistically significantly increased risk of UBC was observed among subjects presenting the lowest concentrations of 25(OH)D-3 (ORadj 1.83; 95% CI 1.19 to 2.82; P .006), showing a doseresponse effect (P-trend .004). The association was stronger for patients with muscle-invasive tumors, especially among low-FGFR3 expressers (ORadj 5.94; 95% CI 1.72 to 20.45; P .005). The biological plausibility of these associations is supported by the fact that, in vitro, 1,25-dihydroxyvitamin D-3 upregulates FGFR3 expression in UBC cell lines with low levels of wild-type FGFR3. These findings support a role of vitamin D in the pathogenesis of UBC and show that 25(OH)D-3 levels are associated with FGFR3 expression in the tumor. Because FGFR3 mutation and overexpression are markers of better outcome, our findings suggest that individuals with low levels of plasma 25(OH)D-3 may be at high risk of more aggressive forms of UBC. J Natl Cancer Inst 2012;104:1897-1904 C1 [Malats, Nuria] Spanish Natl Canc Res Ctr, Human Canc Genet Program, Genet & Mol Epidemiol Grp, Madrid 28029, Spain. [Mendez-Pertuz, Marinela; Real, Francisco X.] Spanish Natl Canc Res Ctr, Epithelial Carcinogenesis Grp, Madrid 28029, Spain. [Munoz, Alberto] Univ Autonoma Madrid, CSIC, Inst Invest Biomed Alberto Sols, Madrid, Spain. [Silverman, Debra T.; Rothman, Nathaniel] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Allory, Yves] Inst Mondor Rech Biomed, INSERM, U955, Creteil, France. [Kogevinas, Manolis] Ctr Res Environm Epidemiol, Barcelona, Spain. [Kogevinas, Manolis] Hosp del Mar, Res Inst, Barcelona, Spain. [Kogevinas, Manolis] CIBER Epidemiol & Salud Publ, Barcelona, Spain. [Kogevinas, Manolis] Natl Sch Publ Hlth, Athens, Greece. [Lloreta, Josep] Hosp del Mar, Dept Patol, Barcelona, Spain. [Lloreta, Josep; Real, Francisco X.] Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona, Spain. [Carrato, Alfredo] Hosp Gen Univ Elche, Elche, Spain. [Carrato, Alfredo] Hosp Ramon & Cajal, E-28034 Madrid, Spain. [Rivas del Fresno, Manuel] Hosp Cabuenes, Gijon, Spain. RP Malats, N (reprint author), Spanish Natl Canc Res Ctr, Human Canc Genet Program, Genet & Mol Epidemiol Grp, Melchor Fernandez Almagro 3, Madrid 28029, Spain. EM nuria@cnio.es RI Lloreta, J/I-2112-2014; Munoz, Alberto/O-6393-2014; Malats, Nuria/H-7041-2015; Real Arribas, Francisco/H-5275-2015; Kogevinas, Manolis/C-3918-2017; Amaral, Andre/A-7662-2008 OI Lloreta, J/0000-0003-1644-9470; Munoz, Alberto/0000-0003-3890-4251; Malats, Nuria/0000-0003-2538-3784; Real Arribas, Francisco/0000-0001-9501-498X; Amaral, Andre/0000-0002-0369-9449 FU World Cancer Research Fund [2010/250]; Fondo de Investigacion Sanitaria, Spain [00/0745, PI051436, PI061614, G03/174]; Red Tematica de Investigacion Cooperativa en Cancer, Spain; Fundacion Cientifica de la AECC, Spain; Consolider ONCOBIO; Comunidad de Madrid, Spain [S2011/BMD-02344, Colomics2]; Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health FX This work was supported by the World Cancer Research Fund (2010/250); Fondo de Investigacion Sanitaria, Spain (00/0745, PI051436, PI061614, and G03/174); Red Tematica de Investigacion Cooperativa en Cancer, Spain; Fundacion Cientifica de la AECC, Spain; Consolider ONCOBIO; Comunidad de Madrid, Spain (S2011/BMD-02344, Colomics2); and the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 40 TC 20 Z9 20 U1 0 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 DEC PY 2012 VL 104 IS 24 BP 1897 EP 1904 DI 10.1093/jnci/djs444 PG 8 WC Oncology SC Oncology GA 062AJ UT WOS:000312891200010 PM 23108201 ER PT J AU Eliassen, AH Hendrickson, SJ Brinton, LA Buring, JE Campos, H Dai, Q Dorgan, JF Franke, AA Gao, YT Goodman, MT Hallmans, G Helzlsouer, KJ Hoffman-Bolton, J Hulteen, K Sesso, HD Sowell, AL Tamimi, RM Toniolo, P Wilkens, LR Winkvist, A Zeleniuch-Jacquotte, A Zheng, W Hankinson, SE AF Eliassen, A. Heather Hendrickson, Sara J. Brinton, Louise A. Buring, Julie E. Campos, Hannia Dai, Qi Dorgan, Joanne F. Franke, Adrian A. Gao, Yu-tang Goodman, Marc T. Hallmans, Goeran Helzlsouer, Kathy J. Hoffman-Bolton, Judy Hulten, Kerstin Sesso, Howard D. Sowell, Anne L. Tamimi, Rulla M. Toniolo, Paolo Wilkens, Lynne R. Winkvist, Anna Zeleniuch-Jacquotte, Anne Zheng, Wei Hankinson, Susan E. TI Circulating Carotenoids and Risk of Breast Cancer: Pooled Analysis of Eight Prospective Studies SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID PROGESTERONE-RECEPTOR STATUS; BLACK WOMENS HEALTH; VITAMIN-E LEVELS; ADIPOSE-TISSUE; BETA-CAROTENE; POSTMENOPAUSAL WOMEN; PLASMA CAROTENOIDS; PROSPECTIVE COHORT; ESTROGEN-RECEPTOR; SERUM CAROTENOIDS AB Carotenoids, micronutrients in fruits and vegetables, may reduce breast cancer risk. Most, but not all, past studies of circulating carotenoids and breast cancer have found an inverse association with at least one carotenoid, although the specific carotenoid has varied across studies. We conducted a pooled analysis of eight cohort studies comprising more than 80% of the world's published prospective data on plasma or serum carotenoids and breast cancer, including 3055 case subjects and 3956 matched control subjects. To account for laboratory differences and examine population differences across studies, we recalibrated participant carotenoid levels to a common standard by reassaying 20 plasma or serum samples from each cohort together at the same laboratory. Using conditional logistic regression, adjusting for several breast cancer risk factors, we calculated relative risks (RRs) and 95% confidence intervals (CIs) using quintiles defined among the control subjects from all studies. All P values are two-sided. Statistically significant inverse associations with breast cancer were observed for -carotene (top vs bottom quintile RR 0.87, 95% CI 0.71 to 1.05, Ptrend .04), -carotene (RR 0.83, 95% CI 0.70 to 0.98, Ptrend .02), luteinzeaxanthin (RR 0.84, 95% CI 0.70 to 1.01, Ptrend .05), lycopene (RR 0.78, 95% CI 0.62 to 0.99, Ptrend .02), and total carotenoids (RR 0.81, 95% CI 0.68 to 0.96, Ptrend .01). -Cryptoxanthin was not statistically significantly associated with risk. Tests for heterogeneity across studies were not statistically significant. For several carotenoids, associations appeared stronger for estrogen receptor negative (ER) than for ER tumors (eg, -carotene: ER: top vs bottom quintile RR 0.52, 95% CI 0.36 to 0.77, Ptrend .001; ER: RR 0.83, 95% CI 0.66 to 1.04, Ptrend .06; Pheterogeneity .01). This comprehensive prospective analysis suggests women with higher circulating levels of -carotene, -carotene, luteinzeaxanthin, lycopene, and total carotenoids may be at reduced risk of breast cancer. J Natl Cancer Inst 2012;104:1905-1916 C1 [Eliassen, A. Heather; Tamimi, Rulla M.; Hankinson, Susan E.] Brigham & Womens Hosp, Dept Med, Channing Div Network Med, Boston, MA 02115 USA. [Buring, Julie E.; Sesso, Howard D.] Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. [Eliassen, A. Heather] Harvard Univ, Sch Med, Boston, MA USA. [Eliassen, A. Heather; Hendrickson, Sara J.; Tamimi, Rulla M.; Hankinson, Susan E.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Hendrickson, Sara J.; Campos, Hannia] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Dai, Qi; Zheng, Wei] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Dorgan, Joanne F.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Franke, Adrian A.; Goodman, Marc T.; Wilkens, Lynne R.] Univ Hawaii, Ctr Canc, Honolulu, HI 96822 USA. [Gao, Yu-tang] Shanghai Canc Inst, Shanghai, Peoples R China. [Hallmans, Goeran; Hulten, Kerstin] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. [Helzlsouer, Kathy J.; Hoffman-Bolton, Judy] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, George W Comstock Ctr Publ Hlth Res & Prevent, Baltimore, MD USA. [Helzlsouer, Kathy J.] Mercy Med Ctr, Prevent & Res Ctr, Baltimore, MD USA. [Sowell, Anne L.] Ctr Dis Control & Prevent, Div Hlth Studies, Agcy Tox Subst & Dis Registry, Atlanta, GA USA. [Toniolo, Paolo] NYU, Sch Med, Inst Canc, Dept Obstet & Gynecol, New York, NY USA. [Zeleniuch-Jacquotte, Anne] NYU, Sch Med, Inst Canc, Dept Environm Med, New York, NY USA. [Winkvist, Anna] Univ Gothenburg, Dept Clin Nutr, Gothenburg, Sweden. [Hankinson, Susan E.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Div Biostat & Epidemiol, Amherst, MA 01003 USA. RP Eliassen, AH (reprint author), Brigham & Womens Hosp, Dept Med, Channing Div Network Med, 181 Longwood Ave, Boston, MA 02115 USA. EM heather.eliassen@channing.harvard.edu RI Brinton, Louise/G-7486-2015; OI Brinton, Louise/0000-0003-3853-8562; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU National Cancer Institute at the National Institutes of Health [R03 CA128073]; National Cancer Institute [R01 CA131218, P01 CA87969, R01 CA49449, R01 CA098661, P30 CA016087, P01 CA33619, R37 CA54281, CA-047988, R01 CA106591, R37 CA70867]; National Institute of Environmental Health Sciences Center [ES000260]; National Heart Lung and Blood Institute [HL043851, HL080467, HL099355]; National Institutes of Health [N01 PC35137, N01 PC35139, N02 CP1101066, 5 T32 CA09001-35]; Swedish Cancer Society; Swedish Scientific Council; Swedish Research Council; Regional Government of Vasterbotten, Sweden; DSM Nutritional Products, Inc. FX This work was supported primarily by the National Cancer Institute at the National Institutes of Health (R03 CA128073 to AHE). Funding to individual cohorts included grants from the National Cancer Institute (R01 CA131218, P01 CA87969, R01 CA49449, R01 CA098661, P30 CA016087, P01 CA33619, R37 CA54281, CA-047988, R01 CA106591, R37 CA70867); the National Institute of Environmental Health Sciences Center (ES000260); the National Heart Lung and Blood Institute (HL043851, HL080467, HL099355); contracts from the National Institutes of Health (N01 PC35137, N01 PC35139, N02 CP1101066); the Intramural Research Program of the National Institutes of Health; the Swedish Cancer Society; Swedish Scientific Council; Swedish Research Council; Regional Government of Vasterbotten, Sweden; and a grant from DSM Nutritional Products, Inc. (formerly Roche Vitamins). SJH was supported in part by a training grant (5 T32 CA09001-35) from the National Institutes of Health. NR 69 TC 57 Z9 60 U1 3 U2 26 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 DEC PY 2012 VL 104 IS 24 BP 1905 EP 1916 DI 10.1093/jnci/djs461 PG 12 WC Oncology SC Oncology GA 062AJ UT WOS:000312891200011 PM 23221879 ER PT J AU Sun, HM Veith, H Xia, MH Austin, CP Tice, RR Huang, RL AF Sun, Hongmao Veith, Henrike Xia, Menghang Austin, Christopher P. Tice, Raymond R. Huang, Ruili TI Prediction of Cytochrome P450 Profiles of Environmental Chemicals with QSAR Models Built from Drug-Like Molecules SO MOLECULAR INFORMATICS LA English DT Article DE Human CYPs; QSAR models; Predictive capacity; SVM; Predictive toxicology ID APPLICABILITY DOMAIN; VARIABLE SELECTION; CRYSTAL-STRUCTURE; TRAINING SET; HUMAN HEALTH; METABOLISM; TOXICITY; P450; CIMETIDINE; LIBRARIES AB The human cytochrome P450 (CYP) enzyme family is involved in the biotransformation of many xenobiotics. As part of the U.S. Tox21 Phase I effort, we profiled the CYP activity of approximately three thousand compounds, primarily those of environmental concern, against human CYP1A2, CYP2C19, CYP2C9, CYP2D6, and CYP3A4 isoforms in a quantitative high throughput screening (qHTS) format. In order to evaluate the extent to which computational models built from a drug-like library screened in these five CYP assays under the same conditions can accurately predict the outcome of an environmental compound library, five support vector machine (SVM) models built from over 17,000 drug-like compounds were challenged to predict the CYP activities of the Tox21 compound collection. Although a large fraction of the test compounds fall outside of the applicability domain (AD) of the models, as measured by k-nearest neighbor (k-NN) similarities, the predictions were largely accurate for CYP1A2, CYP2C9, and CYP3A4 ioszymes with area under the receiver operator characteristic curves (AUC-ROC) ranging between 0.82 and 0.84. The lower predictive power of the CYP2C19 model (AUC-ROC=0.76) is caused by experimental errors and that of the CYP2D6 model (AUC-ROC=0.76) can be rescued by rebalancing the training data. Our results demonstrate that decomposing molecules into atom types enhanced the coverage of the AD and that computational models built from drug-like molecules can be used to predict the ability of non-drug like compounds to interact with these CYPs. C1 [Sun, Hongmao; Veith, Henrike; Xia, Menghang; Austin, Christopher P.; Huang, Ruili] NIH, Natl Ctr Adv Translat Sci, Bethesda, MD 20892 USA. [Tice, Raymond R.] NIEHS, Div Natl Toxicol Program, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Huang, RL (reprint author), NIH, Natl Ctr Adv Translat Sci, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM huangru@mail.nih.gov FU National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS) [Y2-ES-7020-01]; National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) FX This work was supported by the Intramural Research Programs (Interagency Agreement #Y2-ES-7020-01) of the National Toxicology Program, National Institute of Environmental Health Sciences (NIEHS), and the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH). The statements, opinions, or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NCATS, NIH, or the United States government. NR 49 TC 8 Z9 9 U1 0 U2 32 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1868-1743 J9 MOL INFORM JI Mol. Inf. PD DEC PY 2012 VL 31 IS 11-12 BP 783 EP 792 DI 10.1002/minf.201200065 PG 10 WC Chemistry, Medicinal; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology SC Pharmacology & Pharmacy; Computer Science; Mathematical & Computational Biology GA 059GV UT WOS:000312693300003 PM 23459712 ER PT J AU Park, KS Kim, KK Piao, ZH Kim, MK Lee, HJ Kim, YC Lee, KS Lee, JH Kim, KE AF Park, Key Sun Kim, Kee Kwang Piao, Zheng-Hao Kim, Mi Kyung Lee, Hyun Jean Kim, Yong Chan Lee, Ki Sung Lee, Jeung-Hoon Kim, Kyoon Eon TI Olfactomedin 4 suppresses tumor growth and metastasis of mouse melanoma cells through downregulation of integrin and MMP genes SO MOLECULES AND CELLS LA English DT Article DE B16F10 cells; cancer; metastasis; OLFM4; tumor growth ID CANCER CELLS; MATRIX METALLOPROTEINASES; PROGRESSION; PROTEIN; HGC-1; PROMOTES; MARKER; COLON; DIFFERENTIATION; EXPRESSION AB Olfactomedin 4 (OLFM4) is highly expressed in gastrointestinal cancers and has an anti-apoptotic function. The roles of OLFM4 in tumor growth and metastasis and how it functions in these processes remain elusive. We investigated the function of OLFM4 in tumor growth and metastasis using B16F10 mouse melanoma cells as an experimental system. Our results showed that OLFM4 had no positive effect on cell viability or cell cycle progression in B16F10 cells. However, it significantly suppressed the tumorigenicity of B16F10 cells, i.e., intradermal primary tumor growth and lung metastasis. OLFM4 also suppressed the migration and invasion of B16F10 cells in vitro. For further insight into the mechanisms underlying OLFM4-mediated suppression of tumor progression, we examined the effect of OLFM4 on the expression of integrin and matrix metalloproteinase (MMP), both of which are involved in tumor progression. Overexpression of OLFM4 clearly reduced the expression levels of integrin alpha 1, integrin alpha 4, integrin alpha 5, integrin alpha 6, and MMP9. Moreover, forced expression of MMP9 attenuated the inhibitory activity of OLFM4 on migration and invasiveness. Our findings provide the experimental evidence that OLFM4 may function as a tumor suppressor and an anti-metastatic gene during tumor progression. C1 [Park, Key Sun; Kim, Kee Kwang; Piao, Zheng-Hao; Kim, Mi Kyung; Lee, Hyun Jean; Kim, Yong Chan; Kim, Kyoon Eon] Chungnam Natl Univ, Dept Biochem, Taejon 305764, South Korea. [Kim, Kee Kwang] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. [Piao, Zheng-Hao] Hangzhou Normal Univ, Sch Med, Dept Basic Med Sci, Hangzhou, Zhejiang, Peoples R China. [Kim, Yong Chan] Dept Med MED, Bethesda, MD 20814 USA. [Lee, Ki Sung] Pai Chai Univ, Coll Sci & Technol, Dept Biol & Med Sci, Taejon 302735, South Korea. [Lee, Jeung-Hoon] Chungnam Natl Univ, Coll Med, Dept Dermatol, Taejon 301747, South Korea. RP Kim, KE (reprint author), Chungnam Natl Univ, Dept Biochem, Taejon 305764, South Korea. EM kyoonkim@cnu.ac.kr RI Kim, Kee/F-8784-2011 FU National Research Foundation of Korea (NRF); Korea government (Ministry of Education, Science and Technology) [2012-004115] FX We gratefully acknowledge Jae Hwan Song of Office of the Scientific Director, NHLBI, NIH, for their helpful discussion and critical reading of the manuscript. This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Education, Science and Technology) (No. 2012-004115). NR 28 TC 10 Z9 10 U1 0 U2 7 PU KOREAN SOC MOLECULAR & CELLULAR BIOLOGY PI SEOUL PA 635-4, YUCKSAM-DONG, GANGNAM-GU, SEOUL 135-703, SOUTH KOREA SN 1016-8478 J9 MOL CELLS JI Mol. Cells PD DEC PY 2012 VL 34 IS 6 BP 555 EP 561 DI 10.1007/s10059-012-0251-7 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 059SD UT WOS:000312724600008 PM 23161172 ER PT J AU Nakahara, H Hikosaka, O AF Nakahara, Hiroyuki Hikosaka, Okihide TI Learning to represent reward structure: A key to adapting to complex environments SO NEUROSCIENCE RESEARCH LA English DT Article DE Reward; Dopamine; Reinforcement learning; Decision; Value; Salience; Structure ID DOPAMINE NEURONS ENCODE; PREDICTION ERROR; BASAL GANGLIA; DECISION-MAKING; MODEL-FREE; ORBITOFRONTAL CORTEX; BEHAVIORAL-CONTROL; LATERAL HABENULA; UNCERTAINTY; SIGNAL AB Predicting outcomes is a critical ability of humans and animals. The dopamine reward prediction error hypothesis, the driving force behind the recent progress in neural "value-based" decision making, states that dopamine activity encodes the signals for learning in order to predict a reward, that is, the difference between the actual and predicted reward, called the reward prediction error. However, this hypothesis and its underlying assumptions limit the prediction and its error as reactively triggered by momentary environmental events. Reviewing the assumptions and some of the latest findings, we suggest that the internal state representation is learned to reflect the environmental reward structure, and we propose a new hypothesis - the dopamine reward structural learning hypothesis - in which dopamine activity encodes multiplex signals for learning in order to represent reward structure in the internal state, leading to better reward prediction. (C) 2012 Elsevier Ireland Ltd and the Japan Neuroscience Society. All rights reserved. C1 [Nakahara, Hiroyuki] RIKEN, Brain Sci Inst, Lab Integrated Theoret Neurosci, Wako, Saitama 3510198, Japan. [Hikosaka, Okihide] NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. RP Nakahara, H (reprint author), RIKEN, Brain Sci Inst, Lab Integrated Theoret Neurosci, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. EM hiro@brain.riken.jp; oh@lsr.nei.nih.gov RI Nakahara, Hiroyuki/N-5411-2015 OI Nakahara, Hiroyuki/0000-0001-6891-1175 FU KAKENHI [21300129, 24120522] FX This work is partly supported by KAKENHI grants 21300129 and 24120522 (H.N.). NR 78 TC 9 Z9 10 U1 1 U2 31 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0168-0102 J9 NEUROSCI RES JI Neurosci. Res. PD DEC PY 2012 VL 74 IS 3-4 BP 177 EP 183 DI 10.1016/j.neures.2012.09.007 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 063EP UT WOS:000312979300002 PM 23069349 ER PT J AU Jett, DA AF Jett, David A. TI Chemical toxins that cause seizures SO NEUROTOXICOLOGY LA English DT Article DE Chemical toxins; Seizures; Mechanisms ID TOXICITY; CHANNEL; NEUROPATHOLOGY; BREVETOXINS; SODIUM AB Seizurogenic chemicals include a variety of toxic agents, including chemical warfare agents, toxic industrial chemicals, and natural toxins. Chemical weapons such as satin and VX, and pesticides such as parathion and carbaryl cause hyperstimulation of cholinergic receptors and an increase in excitatory neurotransmission. Glutamatergic hyperstimulation can occur after exposure to excitatory amino acid toxins such as the marine toxin domoic acid. Other pesticides such as lindane and strychnine do not affect excitatory neurotransmission directly, but rather, they block the inhibitory regulation of neurotransmission by antagonism of inhibitory GABA and glycine synapses. In this paper, chemicals that cause seizures by a variety of molecular mechanisms and pathways are discussed. Published by Elsevier Inc. C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Jett, DA (reprint author), NINDS, NIH, 6001 Execut Blvd NSC,Room 2177,MSC 9527, Bethesda, MD 20892 USA. EM jettd@ninds.nih.gov NR 21 TC 10 Z9 10 U1 3 U2 130 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD DEC PY 2012 VL 33 IS 6 SI SI BP 1473 EP 1475 DI 10.1016/j.neuro.2012.10.005 PG 3 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 063UI UT WOS:000313027100010 PM 23085523 ER PT J AU Rider, CV Janardhan, KS Rao, D Morrison, JP McPherson, CA Harry, GJ AF Rider, C. V. Janardhan, K. S. Rao, D. Morrison, J. P. McPherson, C. A. Harry, G. J. TI Evaluation of N-butylbenzenesulfonamide (NBBS) neurotoxicity in Sprague-Dawley male rats following 27-day oral exposure SO NEUROTOXICOLOGY LA English DT Article DE Peripheral nerve toxicity; Gliosis; NBBS; Neuropathology ID MUNICIPAL LANDFILL LEACHATES; BUTYL BENZENESULFONAMIDE; ORGANIC CONTAMINANTS; WATER; BUTYLBENZENESULPHONAMIDE; IDENTIFICATION; SURVEILLANCE; GROUNDWATER; RIVER AB N-Butylbenzenesulfonamide (NBBS) is widely used as a plasticizer in polyacetals, polyamides, and polycarbonates and has been found in ground water and effluent from wastewater treatment sites. The compound is lipophilic and distributes rapidly to the brain but also clears rapidly and shows little evidence of accumulation. Limited studies in the literature report neurotoxicity of NBBS in rabbits and rats. Adult Sprague-Dawley male rats (Harlan) received corn oil vehicle or NBBS (100, 200, or 400 mg/kg/d) via oral gavage (5 ml/kg bwt) daily/5 d/week for 27 d. Deaths were observed in the 400 mg/kg/d dose group in the first 5 d and dosing was decreased to 300 mg/kg/d. No alterations were observed in gait, locomotor activity, and rearing behavior. No histological lesions were observed in the testis, seminal vesicles, coagulating gland, epididymis, and prostate. In the liver, minimal centrilobular hypertrophy was evident in all rats of the high dose group. Contrary to previous reports, there was no evidence of peripheral nerve lesions or gliosis in the hippocampus or cerebellum. mRNA levels for glial fibrillary acidic acid protein, interferon gamma, CXCR-3, intracellular adhesion molecule-1, and CD11b were not altered in the hippocampus while lba-1 levels were decreased. These data do not support previous reports of neurotoxicity for NBBS within a 4-week exposure regimen; however, neuropathological injury occurring over an extended period of exposure cannot be ruled out and given the potential for human exposure requires further examination. Published by Elsevier Inc. C1 [McPherson, C. A.; Harry, G. J.] NIEHS, NTP Lab, Res Triangle Pk, NC 27709 USA. [Rider, C. V.] NIEHS, Toxicol Branch, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Janardhan, K. S.; Rao, D.] Integrated Lab Syst Inc, Res Triangle Pk, NC USA. [Morrison, J. P.] Charles River Pathol Associates, Durham, NC 27703 USA. RP Harry, GJ (reprint author), NIEHS, NTP Lab, POB 12233, Res Triangle Pk, NC 27709 USA. EM harry@niehs.nih.gov FU Division of Intramural Research; National Toxicology Program Laboratory FX The authors would like to acknowledge Dr. Mamta Behl, Natashia Clayton, Norris Flagler, and the Pathology Core Laboratory of NIEHS for their assistance in tissue collection, histology, and imaging analysis. This study was funded by the Division of Intramural Research and the National Toxicology Program Laboratory. Dr. Janardhan was responsible for the organ pathology review and Drs. Rao and Morrison conducted the sciatic nerve review. This article is the work product of an employee or group of employees of the National institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), however, the statements, opinions or conclusions contained therein do not necessarily represent the statements, opinions or conclusions of NIEHS, NIH or the United States government. NR 27 TC 2 Z9 2 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD DEC PY 2012 VL 33 IS 6 SI SI BP 1528 EP 1535 DI 10.1016/j.neuro.2012.07.002 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 063UI UT WOS:000313027100016 PM 22824510 ER PT J AU Guo, XC Segars, JH AF Guo, Xiaoxiao Catherine Segars, James H. TI The Impact and Management of Fibroids for Fertility An Evidence-Based Approach SO OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Leiomyoma; Infertility; Assisted reproductive technology (ART); Myomectomy; Hysteroscopy; Minimally invasive gynecologic surgeries; Magnetic resonance-guided focused ultrasound (MRgFUS); Uterine artery embolization (UAE) ID UTERINE ARTERY EMBOLIZATION; PROGESTERONE-RECEPTOR MODULATOR; RANDOMIZED CONTROLLED-TRIAL; FOCUSED ULTRASOUND SURGERY; ULIPRISTAL ACETATE; OBSTETRIC OUTCOMES; WHITE WOMEN; LEIOMYOMATA; PREGNANCY; MYOMAS AB Fibroids affect 35% to 77% of reproductive-age women. When selecting a treatment plan for symptomatic fibroids, the fibroid location, size, and number must be considered. Myomectomy remains the preferred method for women with fibroid-related infertility who wish to have children or maintain fertility. Currently available medical therapies reduce symptoms in the short term but may involve side effects when used long term. Initial fertility studies are encouraging but trials are needed. Recent medical advances have led to minimally invasive approaches for women with fibroid disease, but there is a strong demand for additional treatment options. C1 [Guo, Xiaoxiao Catherine; Segars, James H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Segars, JH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, NIH, 10 Ctr Dr,Bldg 10 CRC 1-3140,MSC 1109, Bethesda, MD 20892 USA. EM segarsj@mail.nih.gov FU Intramural Research Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health; National Institutes of Health; NICHD; PRAE; IRTA program FX This research was supported, in part, by the Intramural Research Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. The authors would like to thank Alan DeCherney, MD, for his mentorship and guidance and the National Institutes of Health, NICHD, PRAE, and IRTA program for their support. NR 60 TC 13 Z9 15 U1 0 U2 13 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8545 J9 OBSTET GYN CLIN N AM JI Obstet. Gynecol. Clin. N. Am. PD DEC PY 2012 VL 39 IS 4 BP 521 EP + DI 10.1016/j.ogc.2012.09.005 PG 14 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 065GV UT WOS:000313137600008 PM 23182558 ER PT J AU Rafique, S Sterling, EW Nelson, LM AF Rafique, Saima Sterling, Evelina W. Nelson, Lawrence M. TI A New Approach to Primary Ovarian Insufficiency SO OBSTETRICS AND GYNECOLOGY CLINICS OF NORTH AMERICA LA English DT Article DE Primary ovarian insufficiency; Premature ovarian failure; Premature menopause; Infertility; Integrated care ID RANDOMIZED-CONTROLLED-TRIAL; VITRO FERTILIZATION PREGNANCIES; BONE-MINERAL DENSITY; POSTMENOPAUSAL WOMEN; YOUNG-WOMEN; PREMATURE MENOPAUSE; NATURAL MENOPAUSE; VENOUS THROMBOEMBOLISM; REPLACEMENT THERAPY; COLLABORATIVE CARE AB There is a need for a new approach to managing women with primary ovarian insufficiency. This condition is a serious chronic disease that may have far reaching effects on physical and emotional health. An integrative and collaborative approach to management works best. To maintain wellness, most women with primary ovarian insufficiency need to reassess their primary source of meaning and purpose in life and how this diagnosis may have threatened that part of who they are. They also need assessment with regard to bone health, thyroid and adrenal function, determination of FMR1 premutation and karyotype status, and ongoing estradiol-progestin hormone replacement. C1 [Sterling, Evelina W.] Rachels Well, Project Vital Sign, Mclean, VA 22101 USA. [Nelson, Lawrence M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, US PHS, Intramural Res Program Reprod & Adult Endocrinol, NIH,CRC, Bethesda, MD 20892 USA. RP Nelson, LM (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, US PHS, Intramural Res Program Reprod & Adult Endocrinol, NIH,CRC, 10 Ctr Dr,Bldg 10,Room 1-3140, Bethesda, MD 20892 USA. EM Lawrence_Nelson@nih.gov FU Rachel's Well, Inc; National Institutes of Health FX The authors thank Peter and Cindy Catches of Oceti Wakan (http://www.ocetiwakan.org/) for valuable discussions regarding the spiritual care of women with primary ovarian insufficiency. This work was supported in part by Rachel's Well, Inc (http://www.rachelswell.org/) and the Intramural Research Program of the National Institutes of Health (http://irp.nih.gov/). NR 121 TC 19 Z9 21 U1 2 U2 15 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8545 J9 OBSTET GYN CLIN N AM JI Obstet. Gynecol. Clin. N. Am. PD DEC PY 2012 VL 39 IS 4 BP 567 EP + DI 10.1016/j.ogc.2012.09.007 PG 21 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 065GV UT WOS:000313137600011 PM 23182561 ER PT J AU Chan, K Sterling, JF Roberts, SA Bhagwat, AS Resnick, MA Gordenin, DA AF Chan, Kin Sterling, Joan F. Roberts, Steven A. Bhagwat, Ashok S. Resnick, Michael A. Gordenin, Dmitry A. TI Base Damage within Single-Strand DNA Underlies In Vivo Hypermutability Induced by a Ubiquitous Environmental Agent SO PLOS GENETICS LA English DT Article ID BONE-MARROW-CELLS; 21 BREAST CANCERS; SODIUM BISULFITE; SACCHAROMYCES-CEREVISIAE; SULFUR-DIOXIDE; POTASSIUM METABISULFITE; SALMONELLA-TYPHIMURIUM; HUMAN-LYMPHOCYTES; ESCHERICHIA-COLI; GENE DISRUPTION AB Chromosomal DNA must be in single-strand form for important transactions such as replication, transcription, and recombination to occur. The single-strand DNA (ssDNA) is more prone to damage than double-strand DNA (dsDNA), due to greater exposure of chemically reactive moieties in the nitrogenous bases. Thus, there can be agents that damage regions of ssDNA in vivo while being inert toward dsDNA. To assess the potential hazard posed by such agents, we devised an ssDNA-specific mutagenesis reporter system in budding yeast. The reporter strains bear the cdc13-1 temperature-sensitive mutation, such that shifting to 37 degrees C results in telomere uncapping and ensuing 5' to 3' enzymatic resection. This exposes the reporter region, containing three closely-spaced reporter genes, as a long 3' ssDNA overhang. We validated the ability of the system to detect mutagenic damage within ssDNA by expressing a modified human single-strand specific cytosine deaminase, APOBEC3G. APOBEC3G induced a high density of substitutions at cytosines in the ssDNA overhang strand, resulting in frequent, simultaneous inactivation of two reporter genes. We then examined the mutagenicity of sulfites, a class of reactive sulfur oxides to which humans are exposed frequently via respiration and food intake. Sulfites, at a concentration similar to that found in some foods, induced a high density of mutations, almost always as substitutions at cytosines in the ssDNA overhang strand, resulting in simultaneous inactivation of at least two reporter genes. Furthermore, sulfites formed a long-lived adducted 2'-deoxyuracil intermediate in DNA that was resistant to excision by uracil- DNA N-glycosylase. This intermediate was bypassed by error-prone translesion DNA synthesis, frequently involving Pol zeta, during repair synthesis. Our results suggest that sulfite-induced lesions in DNA can be particularly deleterious, since cells might not possess the means to repair or bypass such lesions accurately. C1 [Chan, Kin; Sterling, Joan F.; Roberts, Steven A.; Resnick, Michael A.; Gordenin, Dmitry A.] NIEHS, Chromosome Stabil Sect, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. [Bhagwat, Ashok S.] Wayne State Univ, Dept Chem, Detroit, MI 48202 USA. RP Chan, K (reprint author), NIEHS, Chromosome Stabil Sect, Mol Genet Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM gordenin@niehs.nih.gov OI Gordenin, Dmitry/0000-0002-8399-1836 FU Intramural Research Program of the NIEHS (NIH) [ES065073]; Intramural Research Program of the NIEHS (DHHS) [ES065073] FX This work was supported by the Intramural Research Program of the NIEHS (NIH, DHHS) project ES065073 to MAR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 55 TC 23 Z9 23 U1 1 U2 16 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 DEC PY 2012 VL 8 IS 12 AR e1003149 DI 10.1371/journal.pgen.1003149 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 062FV UT WOS:000312905600047 PM 23271983 ER PT J AU Hancock, DB Artigas, MS Gharib, SA Henry, A Manichaikul, A Ramasamy, A Loth, DW Imboden, M Koch, B McArdle, WL Smith, AV Smolonska, J Sood, A Tang, WB Wilk, JB Zhai, GJ Zhao, JH Aschard, H Burkart, KM Curjuric, I Eijgelsheim, M Elliott, P Gu, XJ Harris, TB Janson, C Homuth, G Hysi, PG Liu, JZ Loehr, LR Lohman, K Loos, RJF Manning, AK Marciante, KD Obeidat, M Postma, DS Aldrich, MC Brusselle, GG Chen, TH Eiriksdottir, G Franceschini, N Heinrich, J Rotter, JI Wijmenga, C Williams, OD Bentley, AR Hofman, A Laurie, CC Lumley, T Morrison, AC Joubert, BR Rivadeneira, F Couper, DJ Kritchevsky, SB Liu, YM Wjst, M Wain, LV Vonk, JM Uitterlinden, AG Rochat, T Rich, SS Psaty, BM O'Connor, GT North, KE Mirel, DB Meibohm, B Launer, LJ Khaw, KT Hartikainen, AL Hammond, CJ Glaser, S Marchini, J Kraft, P Wareham, NJ Volzke, H Stricker, BHC Spector, TD Probst-Hensch, NM Jarvis, D Jarvelin, MR Heckbert, SR Gudnason, V Boezen, M Barr, RG Cassano, PA Strachan, DP Fornage, M Hall, IP Dupuis, J Tobin, MD London, SJ AF Hancock, Dana B. Artigas, Maria Soler Gharib, Sina A. Henry, Amanda Manichaikul, Ani Ramasamy, Adaikalavan Loth, Daan W. Imboden, Medea Koch, Beate McArdle, Wendy L. Smith, Albert V. Smolonska, Joanna Sood, Akshay Tang, Wenbo Wilk, Jemma B. Zhai, Guangju Zhao, Jing Hua Aschard, Hugues Burkart, Kristin M. Curjuric, Ivan Eijgelsheim, Mark Elliott, Paul Gu, Xiangjun Harris, Tamara B. Janson, Christer Homuth, Georg Hysi, Pirro G. Liu, Jason Z. Loehr, Laura R. Lohman, Kurt Loos, Ruth J. F. Manning, Alisa K. Marciante, Kristin D. Obeidat, Ma'en Postma, Dirkje S. Aldrich, Melinda C. Brusselle, Guy G. Chen, Ting-hsu Eiriksdottir, Gudny Franceschini, Nora Heinrich, Joachim Rotter, Jerome I. Wijmenga, Cisca Williams, O. Dale Bentley, Amy R. Hofman, Albert Laurie, Cathy C. Lumley, Thomas Morrison, Alanna C. Joubert, Bonnie R. Rivadeneira, Fernando Couper, David J. Kritchevsky, Stephen B. Liu, Yongmei Wjst, Matthias Wain, Louise V. Vonk, Judith M. Uitterlinden, Andre G. Rochat, Thierry Rich, Stephen S. Psaty, Bruce M. O'Connor, George T. North, Kari E. Mirel, Daniel B. Meibohm, Bernd Launer, Lenore J. Khaw, Kay-Tee Hartikainen, Anna-Liisa Hammond, Christopher J. Glaeser, Sven Marchini, Jonathan Kraft, Peter Wareham, Nicholas J. Voelzke, Henry Stricker, Bruno H. C. Spector, Timothy D. Probst-Hensch, Nicole M. Jarvis, Deborah Jarvelin, Marjo-Riitta Heckbert, Susan R. Gudnason, Vilmundur Boezen, Marike Barr, R. Graham Cassano, Patricia A. Strachan, David P. Fornage, Myriam Hall, Ian P. Dupuis, Josee Tobin, Martin D. London, Stephanie J. TI Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function SO PLOS GENETICS LA English DT Article ID GENE-ENVIRONMENT INTERACTION; AIR-FLOW OBSTRUCTION; SMOOTH-MUSCLE-CELLS; CLASS-II ANTIGENS; BODY-MASS INDEX; LUNG-FUNCTION; FOLLOW-UP; RHEUMATOID-ARTHRITIS; SIGNALING CONTROLS; COMMON VARIANTS AB Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P-JMA = 5.00 x 10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P-JMA = 4.35 x 10(-9)), and KCNJ2 and SOX9 (smallest P-JMA = 1.28 x 10(-8)) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects. C1 [Hancock, Dana B.] Res Triangle Inst Int, Behav Hlth Epidemiol Program, Res Triangle Pk, NC USA. [Hancock, Dana B.; Joubert, Bonnie R.; London, Stephanie J.] NIEHS, Epidemiol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Artigas, Maria Soler; Wain, Louise V.; Tobin, Martin D.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Artigas, Maria Soler; Wain, Louise V.; Tobin, Martin D.] Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. [Gharib, Sina A.] Univ Washington, Ctr Lung Biol, Seattle, WA 98195 USA. [Gharib, Sina A.; Marciante, Kristin D.; Psaty, Bruce M.] Univ Washington, Dept Med, Seattle, WA USA. [Henry, Amanda; Obeidat, Ma'en; Hall, Ian P.] Univ Nottingham, Queens Med Ctr, Div Therapeut & Mol Med, Nottingham NG7 2RD, England. [Manichaikul, Ani; Rich, Stephen S.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA USA. [Manichaikul, Ani] Univ Virginia, Dept Publ Hlth Sci, Div Biostat & Epidemiol, Charlottesville, VA USA. [Ramasamy, Adaikalavan; Elliott, Paul; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, Sch Publ Hlth, Dept Epidemiol & Biostat, London, England. [Ramasamy, Adaikalavan] Kings Coll London, Guys Hosp, Dept Med & Mol Genet, London WC2R 2LS, England. [Loth, Daan W.; Eijgelsheim, Mark; Hofman, Albert; Rivadeneira, Fernando; Uitterlinden, Andre G.; Stricker, Bruno H. C.] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands. [Loth, Daan W.; Stricker, Bruno H. C.] Inspectorate Healthcare, The Hague, Netherlands. [Imboden, Medea; Curjuric, Ivan; Probst-Hensch, Nicole M.] Swiss Trop & Publ Hlth Inst, Dept Epidemiol & Publ Hlth, Basel, Switzerland. [Imboden, Medea; Curjuric, Ivan; Probst-Hensch, Nicole M.] Univ Basel, Basel, Switzerland. [Koch, Beate; Glaeser, Sven] Univ Hosp Greifswald, Dept Internal Med B, Greifswald, Germany. [McArdle, Wendy L.] Univ Bristol, Sch Social & Community Med, ALSPAC, Bristol, Avon, England. [Smith, Albert V.; Eiriksdottir, Gudny; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Smith, Albert V.; Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. [Smolonska, Joanna; Wijmenga, Cisca] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands. [Sood, Akshay] Univ New Mexico, Dept Med, Albuquerque, NM 87131 USA. [Tang, Wenbo; Cassano, Patricia A.] Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. [Wilk, Jemma B.] Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. [Wilk, Jemma B.; O'Connor, George T.; Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Zhai, Guangju; Hysi, Pirro G.; Hammond, Christopher J.; Spector, Timothy D.] Kings Coll London, Dept Twin Res & Genet Epidemiol, London WC2R 2LS, England. [Zhai, Guangju] Mem Univ Newfoundland, Fac Med, Discipline Genet, St John, NF, Canada. [Zhao, Jing Hua; Loos, Ruth J. F.; Wareham, Nicholas J.] Inst Metab Sci, MRC Epidemiol Unit, Cambridge, England. [Aschard, Hugues] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Burkart, Kristin M.; Barr, R. Graham] Columbia Univ, Coll Phys & Surg, Dept Med, New York, NY USA. [Elliott, Paul; Jarvis, Deborah; Jarvelin, Marjo-Riitta] Univ London Imperial Coll Sci Technol & Med, MRC HPA Ctr Environm & Hlth, London, England. [Gu, Xiangjun; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Brown Fdn, Brown Fdn Inst Mol Med, Houston, TX USA. [Harris, Tamara B.; Launer, Lenore J.] NIA, NIH, Bethesda, MD 20892 USA. [Janson, Christer] Uppsala Univ, Dept Med Sci, Uppsala, Sweden. [Homuth, Georg] Ernst Moritz Arndt Univ Greifswald, Dept Funct Genom, Interfac Inst Genet & Funct Genom, Greifswald, Germany. [Liu, Jason Z.; Marchini, Jonathan] Univ Oxford, Dept Stat, Oxford OX1 2JD, England. [Loehr, Laura R.; Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Gillings Sch Global Publ Hlth, Chapel Hill, NC USA. [Lohman, Kurt] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Biostat Sci, Winston Salem, NC USA. [Manning, Alisa K.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Manning, Alisa K.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Manning, Alisa K.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. [Postma, Dirkje S.] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, Groningen, Netherlands. [Postma, Dirkje S.; Vonk, Judith M.; Boezen, Marike] Univ Groningen, Univ Med Ctr Groningen, GRIAC Res Inst, NL-9713 AV Groningen, Netherlands. [Aldrich, Melinda C.] Vanderbilt Univ, Med Ctr, Dept Thorac Surg, Nashville, TN USA. [Aldrich, Melinda C.] Vanderbilt Univ, Med Ctr, Div Epidemiol, Nashville, TN USA. [Brusselle, Guy G.] Ghent Univ Hosp, Dept Resp Med, Ghent, Belgium. [Chen, Ting-hsu] Vet Adm Boston Healthcare Syst, Dept Med, Pulm & Crit Care Med Sect, Boston, MA USA. [Chen, Ting-hsu; O'Connor, George T.] Boston Univ, Sch Med, Dept Med, Ctr Pulm, Boston, MA 02118 USA. [Heinrich, Joachim] Helmholtz Zentrum Munchen, Inst Epidemiol 1, Munich, Germany. [Rotter, Jerome I.] Cedars Sinai Med Ctr, Inst Med Genet, Los Angeles, CA 90048 USA. [Williams, O. Dale] Florida Int Univ, Dept Biostat, Robert Stempel Coll Publ Hlth & Social Work, Miami, FL 33199 USA. [Bentley, Amy R.] NHGRI, Ctr Res Genom, NIH, Bethesda, MD 20892 USA. [Laurie, Cathy C.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Lumley, Thomas] Univ Auckland, Dept Stat, Auckland 1, New Zealand. [Morrison, Alanna C.; Fornage, Myriam] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX USA. [Rivadeneira, Fernando; Uitterlinden, Andre G.; Stricker, Bruno H. C.] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands. [Morrison, Alanna C.; Fornage, Myriam] NGI, Leiden, Netherlands. [Couper, David J.] Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. [Kritchevsky, Stephen B.] Wake Forest Sch Med, Sticht Ctr Aging, Winston Salem, NC USA. [Liu, Yongmei] Wake Forest Sch Med, Div Publ Hlth Sci, Dept Epidemiol & Prevent, Winston Salem, NC USA. [Wjst, Matthias] Helmholtz Zentrum Munchen, Comprehens Pneumol Ctr, Inst Lung Biol & Dis, Neuherberg, Germany. [Wjst, Matthias] Tech Univ Munich, IMSE, Munich, Germany. [Vonk, Judith M.; Boezen, Marike] Univ Groningen, Univ Med Ctr Groningen, Dept Epidemiol, Groningen, Netherlands. [Vonk, Judith M.; Boezen, Marike] LifeLines Cohort Study, Groningen, Netherlands. [Rochat, Thierry] Univ Hosp Geneva, Div Pulm Med, Geneva, Switzerland. [Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Psaty, Bruce M.] Univ Washington, Dept Hlth Serv, Seattle, WA 98195 USA. [Psaty, Bruce M.; Heckbert, Susan R.] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Inst, Seattle, WA 98121 USA. [Mirel, Daniel B.] Broad Inst MIT & Harvard, Cambridge, MA USA. [Meibohm, Bernd] Univ Tennessee, Ctr Hlth Sci, Coll Pharm, Memphis, TN 38163 USA. [Khaw, Kay-Tee] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. [Hartikainen, Anna-Liisa] Univ Oulu, Dept Obstet & Gynecol, Inst Clin Med, SF-90220 Oulu, Finland. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Voelzke, Henry] Ernst Moritz Arndt Univ Greifswald, Inst Community Med, Study Hlth Pomerania SHIP Clin Epidemiol Res, Greifswald, Germany. [Stricker, Bruno H. C.] Erasmus MC, Dept Med Informat, Rotterdam, Netherlands. [Jarvelin, Marjo-Riitta] Natl Inst Hlth & Welf, Dept Children Young People & Families, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Inst Hlth Sci, Oulu, Finland. [Jarvelin, Marjo-Riitta] Univ Oulu, Bioctr Oulu, Oulu, Finland. [Barr, R. Graham] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. [Cassano, Patricia A.] Weill Cornell Med Coll, Dept Publ Hlth, New York, NY USA. [Strachan, David P.] St Georges Univ London, Div Populat Hlth Sci & Educ, London, England. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [London, Stephanie J.] NIEHS, Lab Resp Biol, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Hancock, DB (reprint author), Res Triangle Inst Int, Behav Hlth Epidemiol Program, Res Triangle Pk, NC USA. EM mt47@leicester.ac.uk; london2@niehs.nih.gov RI Wijmenga, Cisca/D-2173-2009; Ramasamy, Adaikalavan/G-2632-2010; Gudnason, Vilmundur/K-6885-2015; Soler Artigas, Maria/L-6529-2013; Smith, Albert/K-5150-2015; OI Manichaikul, Ani/0000-0002-5998-795X; Hancock, Dana/0000-0003-2240-3604; Dupuis, Josee/0000-0003-2871-3603; Ramasamy, Adaikalavan/0000-0002-7598-2892; Gudnason, Vilmundur/0000-0001-5696-0084; Soler Artigas, Maria/0000-0002-3213-1107; Smith, Albert/0000-0003-1942-5845; O'Connor, George/0000-0002-6476-3926; Kritchevsky, Stephen/0000-0003-3336-6781; Wijmenga, Cisca/0000-0002-5635-1614; Hall, Ian/0000-0001-9933-3216; Rivadeneira, Fernando/0000-0001-9435-9441; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Hammond, Christopher/0000-0002-3227-2620; London, Stephanie/0000-0003-4911-5290; Wain, Louise/0000-0003-4951-1867 FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Environmental Health Sciences (NIEHS) [Z01ES043012]; National Heart, Lung, and Blood Institute (NHLBI) [HL105756]; UK MRC Senior Clinical Fellowship [G0902313]; MRC [G1000861]; NIH [N01-AG-12100, HHSN268200625226C, HHSN268200782096C]; Hjartavernd (the Icelandic Heart Association); Althingi (the Icelandic Parliament); NHLBI [HL105756, HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, HHSN268201100012C, R01HL087641, R01HL59367, R01HL086694, N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, N01-HC-45204, N01-HC-85239, N01-HC-85079, N01-HC-85080, N01-HC-85081, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, HHSN268201200036C, HL080295, HL075366, HL087652, N01-HC-25195, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, R01-HL077612, RC1-HL100543, N02-HL-6-4278]; National Human Genome Research Institute (NHGRI) [U01HG004402]; a component of the NIH and NIH Roadmap for Medical Research [UL1RR025005]; Medical Research Council [G0000934]; Wellcome Trust [068545/Z/02, 076113/B/04/Z]; National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); National Institute of Allergy and Infectious Diseases; NHGRI; National Institute of Child Health and Human Development; Juvenile Diabetes Research Foundation International; National Institute for Health Research Cambridge Biomedical Research Centre; Wellcome Trust Strategic Award [079895]; NHGRI [U01-HG-004729, U01-HG-004446, U01-HG-004424]; M Fornage Cardiovascular Health Study (CHS) [U01-HG-004729, R01-HL-084099]; National Institute on Aging (NIA) [AG-023629, AG-15928, AG-20098, AG-027058]; Cedars-Sinai Board of Governors' Chair in Medical Genetics; National Center for Research Resources CTSI [UL 1RR033176]; NIDDK grant [DK063491]; European Union (GABRIEL) [018996]; European Union (ECRHS II Coordination) [QLK4-CT-1999-01237]; Cancer Research UK; Medical Research Council; Affymetrix [N02-HL-6-4278]; Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center; Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (FAMRI); NIA [N01AG62101, N01AG2103, N01AG62106, 1R01AG032098-01A1]; Intramural Research Program of NIA; Intramural Research Programs of the NHGRI; Netherlands Organization of Scientific Research NWO [175.010.2007.006]; Economic Structure Enhancing Fund (FES) of the Dutch government; Ministry of Economic Affairs; Ministry of Education, Culture, and Science; Ministry for Health, Welfare, and Sports; Northern Netherlands Collaboration of Provinces (SNN); Province of Groningen; University Medical Center Groningen; University of Groningen; Dutch Kidney Foundation; Dutch Diabetes Research Foundation; Academy of Finland (Center of Excellence in Complex Disease Genetics and SALVE) [104781, 120315, 129269, 1114194]; University Hospital Oulu; Biocenter; University of Oulu, Finland [75617]; NHLBI grant through the STAMPEED program [5R01HL087679-02, 1RL1MH083268-01]; NIH/National Institute of Mental Health [5R01MH63706:02]; ENGAGE project [HEALTH-F4-2007-201413]; Medical Research Council, UK (PrevMetSyn/SALVE); NIHR Comprehensive Biomedical Research Centre; Imperial College Healthcare NHS Trust; Netherlands Organisation for Scientific Research (NWO) Investments [175.010.2005.011, 911-03-012]; Research Institute for Diseases in the Elderly (RIDE2) [014-93-015]; Netherlands Genomics Initiative (NGI)/NWO [050-060-810]; Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); Research Institute for Diseases in the Elderly (RIDE); European Commission (DG XII); Municipality of Rotterdam; Swiss National Science Foundation [3347CO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 32-65896.01, 32-59302.99, 32-52720.97, 32-4253.94, 4026-28099, PDFMP3-123171]; Federal Office for Forest, Environment, and Landscape; Federal Office of Public Health; Federal Office of Roads and Transport; canton's government of Aargau; canton's government of Basel-Stadt; canton's government of Basel-Land; canton's government of Geneva; canton's government of Luzern; canton's government of Ticino; canton's government of Zurich; Swiss Lung League; canton's Lung League of Basel Stadt/Basel Landschaft; canton's Lung League of Geneva; canton's Lung League of Ticino; canton's Lung League of Zurich; Federal Ministry of Education and Research [01ZZ9603, 01ZZ0103, 01ZZ0403, 03ZIK012]; German Asthma and COPD Network (COSYCONET); German Asthma and COPD Network (BMBP) [01GI0883]; Ministry of Cultural Affairs; Social Ministry of the Federal State of Mecklenburg-West Pomerania; Siemens Healthcare (Erlangen, Germany); Federal State of Mecklenburg-West Pomerania; European Community's FP7 [HEALTH-F2-2008-201865-GEFOS]; European Network of Genetic and Genomic Epidemiology (ENGAGE) [HEALTH-F4-2007-201413]; FP-5 GenomEUtwin Project [QLG2-CT-2002-01254]; NIH/National Eye Institute [1RO1EY018246]; [R21DK084529]; [U01 DK062418]; [RC1AG035835]; [RR-024156] FX This work was supported, in part, by the Intramural Research Program of the National Institutes of Health (NIH), the National Institute of Environmental Health Sciences (NIEHS, Z01ES043012). The CHARGE Pulmonary Working Group acknowledges funding from the National Heart, Lung, and Blood Institute (NHLBI) (HL105756) and organizational support from the CHARGE Consortium. From SpiroMeta, MD Tobin was supported by UK MRC Senior Clinical Fellowship G0902313; IP Hall and the laboratory work on expression profiling were supported by MRC (G1000861). P Kraft and H Aschard were supported by R21DK084529. The Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study is funded by NIH contract number N01-AG-12100, Hjartavernd (the Icelandic Heart Association), and the Althingi (the Icelandic Parliament). The Atherosclerosis Risk in Communities (ARIC) Study is carried out as a collaborative study supported by NHLBI contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute (NHGRI) contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. The British 1958 Cohort (B58C) DNA collection was funded by the Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. Genotyping for the Wellcome Trust Case Control Consortium of B58C was funded by the Wellcome Trust grant 076113/B/04/Z. The Type 1 Diabetes Genetics Consortium of B58C was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases, NHGRI, National Institute of Child Health and Human Development, and Juvenile Diabetes Research Foundation International and supported by U01 DK062418. Genome-wide data was deposited by the Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research (CIMR), University of Cambridge, which is funded by Juvenile Diabetes Research Foundation International, the Wellcome Trust, and the National Institute for Health Research Cambridge Biomedical Research Centre and is in receipt of a Wellcome Trust Strategic Award (079895). The Coronary Artery Risk Development in Young Adults (CARDIA) study was funded by contracts N01-HC-95095, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-45134, N01-HC-05187, N01-HC-45205, and N01-HC-45204 from NHLBI to the CARDIA investigators. Genotyping of the CARDIA participants was supported by grants U01-HG-004729, U01-HG-004446, and U01-HG-004424 from the NHGRI. Statistical analyses were supported by grants U01-HG-004729 and R01-HL-084099 to M Fornage Cardiovascular Health Study (CHS) was supported by NHLBI contracts N01-HC-85239, N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, and HHSN268201200036C and by NHLBI grants HL080295, HL075366, HL087652, and HL105756 with additional contribution from National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through AG-023629, AG-15928, AG-20098, and AG-027058 from the National Institute on Aging (NIA) and the Cedars-Sinai Board of Governors' Chair in Medical Genetics (JI Rotter).; DNA handling and genotyping was supported in part by National Center for Research Resources CTSI grant UL 1RR033176 and NIDDK grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The European Community Respiratory Health Survey (ECRHS) acknowledges funding from the European Union (GABRIEL GRANT Number: 018996, ECRHS II Coordination Number: QLK4-CT-1999-01237). The European Prospective Investigation of Cancer (EPIC)-Norfolk Study is funded by Cancer Research UK and the Medical Research Council. Framingham Heart Study (FHS) research was conducted in part using data and resources of the NHLBI and Boston University School of Medicine. The analyses reflect intellectual input and resource development from the FHS investigators participating in the SNP Health Association Resource (SHARe) project. This work was partially supported by NHLBI (contract no. N01-HC-25195) and its contract with Affymetrix for genotyping services (contract no. N02-HL-6-4278). A portion of this research utilized the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. JB Wilk was supported by a Young Clinical Scientist Award from the Flight Attendant Medical Research Institute (FAMRI). Health, Aging, and Body Composition (Health ABC) was supported by NIA contracts N01AG62101, N01AG2103, and N01AG62106, and in part by the Intramural Research Program of NIA. This work was also supported, in part, by Intramural Research Programs of the NHGRI. The genome-wide association study (GWAS) in Health ABC was funded by NIA grant 1R01AG032098-01A1 to Wake Forest University Health Sciences, and genotyping services were provided by the Center for Inherited Disease Research, which is fully funded through an NIH contract to The Johns Hopkins University (HHSN268200782096C). This research was further supported by RC1AG035835. The LifeLines Cohort Study, and generation and management of GWAS genotype data for the LifeLines Cohort Study, is supported by the Netherlands Organization of Scientific Research NWO (grant 175.010.2007.006); the Economic Structure Enhancing Fund (FES) of the Dutch government; the Ministry of Economic Affairs; the Ministry of Education, Culture, and Science; the Ministry for Health, Welfare, and Sports; the Northern Netherlands Collaboration of Provinces (SNN); the Province of Groningen; University Medical Center Groningen; the University of Groningen; Dutch Kidney Foundation; and Dutch Diabetes Research Foundation. We thank Behrooz Alizadeh, Annemieke Boesjes, Marcel Bruinenberg, Noortje Festen, Ilja Nolte, Lude Franke, Mitra Valimohammadi for their help in creating the GWAS database, and Rob Bieringa, Joost Keers, Rene Oostergo, and Rosalie Visser for their work related to data-collection and validation. The Multi-Ethnic Study of Atherosclerosis (MESA) study was supported by contracts N01-HC-95159 through N01-HC-95169 from the NHLBI and RR-024156. The MESA Lung study was supported by grants R01-HL077612 and RC1-HL100543 from the NHLBI. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-6-4278.; The Northern Finland Birth Cohort of 1966 (NFBC1966) (to M-R Jarvelin) received financial support from the Academy of Finland (project grants 104781, 120315, 129269, 1114194, Center of Excellence in Complex Disease Genetics and SALVE), University Hospital Oulu, Biocenter, University of Oulu, Finland (75617), NHLBI grant 5R01HL087679-02 through the STAMPEED program (1RL1MH083268-01), NIH/National Institute of Mental Health (5R01MH63706:02), ENGAGE project and grant agreement HEALTHF4-2007-201413, and the Medical Research Council, UK (PrevMetSyn/SALVE). P Elliott is a National Institute of Health Research (NIHR) Senior Investigator and acknowledges support from the NIHR Comprehensive Biomedical Research Centre, Imperial College Healthcare NHS Trust. The Rotterdam Study (RS) was supported from grants from the Netherlands Organisation for Scientific Research (NWO) Investments (175.010.2005.011, 911-03-012); the Research Institute for Diseases in the Elderly (014-93-015; RIDE2); the Netherlands Genomics Initiative (NGI)/NWO (050-060-810); Erasmus Medical Center; Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture, and Science; the Ministry for Health, Welfare, and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. SAPALDIA was supported by Swiss National Science Foundation grants (no. 3347CO-108796, 3247BO-104283, 3247BO-104288, 3247BO-104284, 32-65896.01, 32-59302.99, 32-52720.97, 32-4253.94, 4026-28099, PDFMP3-123171). Swiss Study on Air Pollution and Lung Diseases in Adults (SAPALDIA) is also supported by the Federal Office for Forest, Environment, and Landscape; the Federal Office of Public Health; the Federal Office of Roads and Transport; the canton's government of Aargau, Basel-Stadt, Basel-Land, Geneva, Luzern, Ticino, and Zurich; the Swiss Lung League; and the canton's Lung League of Basel Stadt/Basel Landschaft, Geneva, Ticino, and Zurich. Study of Health in Pomerania (SHIP) is part of the Community Medicine Research net of the University of Greifswald, which is funded by the Federal Ministry of Education and Research (grants no. 01ZZ9603, 01ZZ0103, and 01ZZ0403), the German Asthma and COPD Network (COSYCONET; BMBP grant 01GI0883), the Ministry of Cultural Affairs, as well as the Social Ministry of the Federal State of Mecklenburg-West Pomerania. Genome-wide data were supported by the Federal Ministry of Education and Research (grant no. 03ZIK012) and a joint grant from Siemens Healthcare (Erlangen, Germany) and the Federal State of Mecklenburg-West Pomerania. The University of Greifswald is a member of the "Center of Knowledge Interchange'' program of the Siemens AG. The TwinsUK study authors acknowledge funding from the Wellcome Trust, the European Community's FP7 (HEALTH-F2-2008-201865-GEFOS), European Network of Genetic and Genomic Epidemiology (ENGAGE) (HEALTH-F4-2007-201413), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254), and NIH/National Eye Institute grant 1RO1EY018246. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 86 TC 54 Z9 54 U1 1 U2 22 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 DEC PY 2012 VL 8 IS 12 AR e1003098 DI 10.1371/journal.pgen.1003098 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 062FV UT WOS:000312905600013 PM 23284291 ER PT J AU Mercader, JM Puiggros, M Segre, AV Planet, E Sorianello, E Sebastian, D Rodriguez-Cuenca, S Ribas, V Bonas-Guarch, S Draghici, S Yang, CJ Mora, S Vidal-Puig, A Dupuis, J Florez, JC Zorzano, A Torrents, D AF Mercader, Josep M. Puiggros, Montserrat Segre, Ayellet V. Planet, Evarist Sorianello, Eleonora Sebastian, David Rodriguez-Cuenca, Sergio Ribas, Vicent Bonas-Guarch, Silvia Draghici, Sorin Yang, Chenjing Mora, Silvia Vidal-Puig, Antoni Dupuis, Josee Florez, Jose C. Zorzano, Antonio Torrents, David CA DIAGRAM Consortium MITIN Consortium TI Identification of Novel Type 2 Diabetes Candidate Genes Involved in the Crosstalk between the Mitochondrial and the Insulin Signaling Systems SO PLOS GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; OXIDATIVE-PHOSPHORYLATION; SUSCEPTIBILITY LOCI; COMMON VARIANTS; RECEPTOR; GLUCOSE; ACTIVATION; EXPRESSION; COMPLEX; RISK AB Type 2 Diabetes (T2D) is a highly prevalent chronic metabolic disease with strong co-morbidity with obesity and cardiovascular diseases. There is growing evidence supporting the notion that a crosstalk between mitochondria and the insulin signaling cascade could be involved in the etiology of T2D and insulin resistance. In this study we investigated the molecular basis of this crosstalk by using systems biology approaches. We combined, filtered, and interrogated different types of functional interaction data, such as direct protein-protein interactions, co-expression analyses, and metabolic and signaling dependencies. As a result, we constructed the mitochondria-insulin (MITIN) network, which highlights 286 genes as candidate functional linkers between these two systems. The results of internal gene expression analysis of three independent experimental models of mitochondria and insulin signaling perturbations further support the connecting roles of these genes. In addition, we further assessed whether these genes are involved in the etiology of T2D using the genome-wide association study meta-analysis from the DIAGRAM consortium, involving 8,130 T2D cases and 38,987 controls. We found modest enrichment of genes associated with T2D amongst our linker genes (p = 0.0549), including three already validated T2D SNPs and 15 additional SNPs, which, when combined, were collectively associated to increased fasting glucose levels according to MAGIC genome wide meta-analysis (p = 8.12 x 10(-5)). This study highlights the potential of combining systems biology, experimental, and genome-wide association data mining for identifying novel genes and related variants that increase vulnerability to complex diseases. C1 [Mercader, Josep M.; Puiggros, Montserrat; Bonas-Guarch, Silvia; Torrents, David] Barcelona Supercomp Ctr, Joint IRB BSC Program Computat Biol, Barcelona, Catalonia, Spain. [Puiggros, Montserrat] Natl Inst Bioinformat, Madrid, Spain. [Segre, Ayellet V.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Segre, Ayellet V.] Massachusetts Gen Hosp, Dept Mol Biol, Boston, MA 02114 USA. [Segre, Ayellet V.; Florez, Jose C.] Broad Inst, Program Med & Populat Genet, Cambridge, MA USA. [Planet, Evarist] Inst Res Biomed, Biostat & Bioinformat Unit, Barcelona, Spain. [Sorianello, Eleonora; Sebastian, David; Ribas, Vicent; Zorzano, Antonio] Univ Barcelona, Inst Res Biomed, Barcelona, Spain. [Sorianello, Eleonora; Sebastian, David; Ribas, Vicent; Zorzano, Antonio] CIBERDEM, Barcelona, Spain. [Rodriguez-Cuenca, Sergio; Vidal-Puig, Antoni] Univ Cambridge, Addenbrookes Hosp, Metab Res Labs, Inst Metab Sci, Cambridge CB2 2QQ, England. [Draghici, Sorin] Wayne State Univ, Dept Comp Sci, Dept Clin & Translat Sci, Dept Obstet & Gynecol, Detroit, MI 48202 USA. [Draghici, Sorin] Wayne State Univ, Intelligent Syst & Bioinformat Lab, Detroit, MI USA. [Yang, Chenjing; Mora, Silvia] Inst Translat Med Cellular & Mol Physiol, Liverpool, Merseyside, England. [Dupuis, Josee] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Dupuis, Josee] NHLBI, Framingham Heart Study, Framingham, MA USA. [Florez, Jose C.] Massachusetts Gen Hosp, Ctr Human Genet Res, Diabet Unit, Boston, MA 02114 USA. [Florez, Jose C.] Massachusetts Gen Hosp, Diabet Res Ctr, Boston, MA 02114 USA. [Florez, Jose C.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Mercader, JM (reprint author), Barcelona Supercomp Ctr, Joint IRB BSC Program Computat Biol, Barcelona, Catalonia, Spain. EM david.torrents@bsc.es RI Draghici, Sorin/B-3074-2013; Ribas, Vicent/K-1390-2014; Torrents, David/G-5785-2015; OI Dupuis, Josee/0000-0003-2871-3603; Puiggros, Montserrat/0000-0001-5034-7924; Draghici, Sorin/0000-0002-0786-8377; Ribas, Vicent/0000-0003-3380-2256; Torrents, David/0000-0002-6086-9037; Mercader, Josep M/0000-0001-8494-3660 FU European Commission [HEALTH-F4-2008-223450]; NIDDK [RO1 RDK089167]; NIGMS [STTR R42GM087013]; NSF [DBI-0965741]; Sara Borrell Fellowship from the Instituto Carlos III; National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) [R01 DK078616]; MRC CORD; MRC programme grant FX This work has been conducted as part of MITIN project and partially funded by the European Commission (Grant Agreement no: HEALTH-F4-2008-223450). SD is supported by NIDDK RO1 RDK089167, NIGMS STTR R42GM087013, and NSF DBI-0965741. JMM was supported by Sara Borrell Fellowship from the Instituto Carlos III. SD and JCF are supported by National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK) R01 DK078616 to Dr. James Meigs, JD, and JCF. AV-P is supported by the MRC CORD and MRC programme grant. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the authors and do not necessarily reflect the views of any of the funding agencies. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 6 Z9 6 U1 0 U2 9 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 DEC PY 2012 VL 8 IS 12 AR e1003046 DI 10.1371/journal.pgen.1003046 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 062FV UT WOS:000312905600001 PM 23236286 ER PT J AU Tovin, A Alon, S Ben-Moshe, Z Mracek, P Vatine, G Foulkes, NS Jacob-Hirsch, J Rechavi, G Toyama, R Coon, SL Klein, DC Eisenberg, E Gothilf, Y AF Tovin, Adi Alon, Shahar Ben-Moshe, Zohar Mracek, Philipp Vatine, Gad Foulkes, Nicholas S. Jacob-Hirsch, Jasmine Rechavi, Gideon Toyama, Reiko Coon, Steven L. Klein, David C. Eisenberg, Eli Gothilf, Yoav TI Systematic Identification of Rhythmic Genes Reveals camk1gb as a New Element in the Circadian Clockwork SO PLOS GENETICS LA English DT Article ID ZEBRAFISH PINEAL-GLAND; ARYLALKYLAMINE N-ACETYLTRANSFERASE; REV-ERB-ALPHA; PROTEIN-KINASE; RNA-SEQ; DEPENDENT TRANSCRIPTION; EXPRESSION PATTERNS; MOLECULAR ANALYSIS; LARVAL ZEBRAFISH; COMPLEX AB A wide variety of biochemical, physiological, and molecular processes are known to have daily rhythms driven by an endogenous circadian clock. While extensive research has greatly improved our understanding of the molecular mechanisms that constitute the circadian clock, the links between this clock and dependent processes have remained elusive. To address this gap in our knowledge, we have used RNA sequencing (RNA-seq) and DNA microarrays to systematically identify clock-controlled genes in the zebrafish pineal gland. In addition to a comprehensive view of the expression pattern of known clock components within this master clock tissue, this approach has revealed novel potential elements of the circadian timing system. We have implicated one rhythmically expressed gene, camk1gb, in connecting the clock with downstream physiology of the pineal gland. Remarkably, knockdown of camk1gb disrupts locomotor activity in the whole larva, even though it is predominantly expressed within the pineal gland. Therefore, it appears that camk1gb plays a role in linking the pineal master clock with the periphery. C1 [Tovin, Adi; Alon, Shahar; Ben-Moshe, Zohar; Vatine, Gad; Gothilf, Yoav] Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiol, IL-69978 Tel Aviv, Israel. [Alon, Shahar; Eisenberg, Eli; Gothilf, Yoav] Tel Aviv Univ, Sagol Sch Neurosci, IL-69978 Tel Aviv, Israel. [Mracek, Philipp; Foulkes, Nicholas S.] Karlsruhe Inst Technol, Inst Toxicol & Genet, Eggenstein, Germany. [Jacob-Hirsch, Jasmine; Rechavi, Gideon] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Jacob-Hirsch, Jasmine; Rechavi, Gideon] Chaim Sheba Med Ctr, Canc Res Ctr, IL-52621 Tel Hashomer, Israel. [Toyama, Reiko] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Mol Genet Lab, NIH, Bethesda, MD USA. [Coon, Steven L.; Klein, David C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Endocrinol & Genet, NIH, Bethesda, MD USA. [Eisenberg, Eli] Tel Aviv Univ, Raymond & Beverly Sackler Sch Phys & Astron, IL-69978 Tel Aviv, Israel. RP Tovin, A (reprint author), Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiol, IL-69978 Tel Aviv, Israel. EM elieis@post.tau.ac.il; yoavg@tauex.tau.ac.il RI Foulkes, Nicholas/K-7003-2013; Eisenberg, Eli/D-2587-2009 OI Eisenberg, Eli/0000-0001-8681-3202 FU United States Israel Binational Science Foundation, Jerusalem, Israel [2009/290]; Clore Israel Foundation FX This work was supported by a grant from the United States Israel Binational Science Foundation (grant number 2009/290), Jerusalem, Israel. SA was supported by a scholarship from the Clore Israel Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 72 TC 15 Z9 16 U1 2 U2 13 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 DEC PY 2012 VL 8 IS 12 AR e1003116 DI 10.1371/journal.pgen.1003116 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 062FV UT WOS:000312905600024 PM 23284293 ER PT J AU Bogich, TL Chunara, R Scales, D Chan, E Pinheiro, LC Chmura, AA Carroll, D Daszak, P Brownstein, JS AF Bogich, Tiffany L. Chunara, Rumi Scales, David Chan, Emily Pinheiro, Laura C. Chmura, Aleksei A. Carroll, Dennis Daszak, Peter Brownstein, John S. TI Preventing Pandemics Via International Development: A Systems Approach SO PLOS MEDICINE LA English DT Editorial Material ID EMERGING INFECTIOUS-DISEASES; PATHOGENIC AVIAN INFLUENZA; ONE HEALTH; CHINA; CHALLENGE; EMERGENCE; ASIA C1 [Bogich, Tiffany L.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bogich, Tiffany L.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Bogich, Tiffany L.; Chmura, Aleksei A.; Daszak, Peter] EcoHlth Alliance, New York, NY USA. [Chunara, Rumi; Scales, David; Chan, Emily; Pinheiro, Laura C.; Brownstein, John S.] Childrens Hosp Boston, Div Emergency Med, Childrens Hosp Informat Program, Boston, MA USA. [Chunara, Rumi; Scales, David; Chan, Emily; Pinheiro, Laura C.; Brownstein, John S.] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. [Carroll, Dennis] USAID, Global Hlth Program, Washington, DC USA. RP Bogich, TL (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM tbogich@princeton.edu; John.Brownstein@childrens.harvard.edu OI Bogich, Tiffany/0000-0002-8143-5289 FU NIGMS NIH HHS [R01 GM100471]; NLM NIH HHS [R01 LM010812, 5G08LM009776, 5R01LM010812] NR 26 TC 11 Z9 11 U1 0 U2 13 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 DEC PY 2012 VL 9 IS 12 AR e1001354 DI 10.1371/journal.pmed.1001354 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 062QE UT WOS:000312934200004 PM 23239944 ER PT J AU Hughes, J Allen, RC Baguelin, M Hampson, K Baillie, GJ Elton, D Newton, JR Kellam, P Wood, JLN Holmes, EC Murcia, PR AF Hughes, Joseph Allen, Richard C. Baguelin, Marc Hampson, Katie Baillie, Gregory J. Elton, Debra Newton, J. Richard Kellam, Paul Wood, James L. N. Holmes, Edward C. Murcia, Pablo R. TI Transmission of Equine Influenza Virus during an Outbreak Is Characterized by Frequent Mixed Infections and Loose Transmission Bottlenecks SO PLOS PATHOGENS LA English DT Article ID EVOLUTIONARY DYNAMICS; A VIRUSES; EPIDEMIOLOGIC DATA; SOCIAL NETWORKS; DISEASE; HORSES; TREES; H3N8; PHYLOGENIES; NEWMARKET AB The ability of influenza A viruses (IAVs) to cross species barriers and evade host immunity is a major public health concern. Studies on the phylodynamics of IAVs across different scales - from the individual to the population - are essential for devising effective measures to predict, prevent or contain influenza emergence. Understanding how IAVs spread and evolve during outbreaks is critical for the management of epidemics. Reconstructing the transmission network during a single outbreak by sampling viral genetic data in time and space can generate insights about these processes. Here, we obtained intra-host viral sequence data from horses infected with equine influenza virus (EIV) to reconstruct the spread of EIV during a large outbreak. To this end, we analyzed within-host viral populations from sequences covering 90% of the infected yards. By combining gene sequence analyses with epidemiological data, we inferred a plausible transmission network, in turn enabling the comparison of transmission patterns during the course of the outbreak and revealing important epidemiological features that were not apparent using either approach alone. The EIV populations displayed high levels of genetic diversity, and in many cases we observed distinct viral populations containing a dominant variant and a number of related minor variants that were transmitted between infectious horses. In addition, we found evidence of frequent mixed infections and loose transmission bottlenecks in these naturally occurring populations. These frequent mixed infections likely influence the size of epidemics. C1 [Hughes, Joseph; Murcia, Pablo R.] Univ Glasgow, Coll Med Vet & Life Sci, MRC, Ctr Virus Res,Inst Infect Inflammat & Immun, Glasgow, Lanark, Scotland. [Allen, Richard C.; Wood, James L. N.; Murcia, Pablo R.] Univ Cambridge, Dept Vet Med, Dis Dynam Unit, Cambridge, England. [Baguelin, Marc] Hlth Protect Agcy, Immunisat Hepatitis & Blood Safety Dept, London, England. [Baguelin, Marc] London Sch Hyg & Trop Med, Ctr Math Modelling Infect Dis, London WC1, England. [Hampson, Katie] Univ Glasgow, Inst Biodivers Anim Hlth & Comparat Med, Boyd Orr Ctr Populat & Ecosyst Hlth, Glasgow, Lanark, Scotland. [Baillie, Gregory J.; Kellam, Paul] Wellcome Trust Sanger Inst, Cambridge, England. [Elton, Debra; Newton, J. Richard] Anim Hlth Trust, Ctr Prevent Med, Newmarket, Suffolk, England. [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. RP Hughes, J (reprint author), Univ Glasgow, Coll Med Vet & Life Sci, MRC, Ctr Virus Res,Inst Infect Inflammat & Immun, Glasgow, Lanark, Scotland. EM Pablo.Murcia@Glasgow.ac.uk RI Wood, James/A-1626-2008; Baillie, Gregory/F-9478-2013; Hughes, Joseph/B-7711-2009; OI Wood, James/0000-0002-0258-3188; Baillie, Gregory/0000-0002-6130-250X; Hughes, Joseph/0000-0003-2556-2563; Hampson, Katie/0000-0001-5392-6884; Holmes, Edward/0000-0001-9596-3552 FU Wellcome Trust; Medical Research Council of the United Kingdom; Veterinary Postdoctoral Fellowship from the Wellcome Trust; Alborada Trust; RAPIDD program of the Science & Technology Directorate, Department of Homeland Security; Fogarty International Center, National Institutes of Health; National Institutes of Health [2 R01 GM080533-06] FX This work was supported by the Wellcome Trust and the Medical Research Council of the United Kingdom. PRM was supported by a Veterinary Postdoctoral Fellowship from the Wellcome Trust. JLNW is supported by the Alborada Trust and by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health. ECH was supported by grant 2 R01 GM080533-06 from the 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 60 TC 21 Z9 21 U1 0 U2 30 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 DEC PY 2012 VL 8 IS 12 AR e1003081 DI 10.1371/journal.ppat.1003081 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 062GJ UT WOS:000312907100033 PM 23308065 ER PT J AU Ohm, RA Feau, N Henrissat, B Schoch, CL Horwitz, BA Barry, KW Condon, BJ Copeland, AC Dhillon, B Glaser, F Hesse, CN Kosti, I LaButti, K Lindquist, EA Lucas, S Salamov, AA Bradshaw, RE Ciuffetti, L Hamelin, RC Kema, GHJ Lawrence, C Scott, JA Spatafora, JW Turgeon, BG de Wit, PJGM Zhong, SB Goodwin, SB Grigoriev, IV AF Ohm, Robin A. Feau, Nicolas Henrissat, Bernard Schoch, Conrad L. Horwitz, Benjamin A. Barry, Kerrie W. Condon, Bradford J. Copeland, Alex C. Dhillon, Braham Glaser, Fabian Hesse, Cedar N. Kosti, Idit LaButti, Kurt Lindquist, Erika A. Lucas, Susan Salamov, Asaf A. Bradshaw, Rosie E. Ciuffetti, Lynda Hamelin, Richard C. Kema, Gert H. J. Lawrence, Christopher Scott, James A. Spatafora, Joseph W. Turgeon, B. Gillian de Wit, Pierre J. G. M. Zhong, Shaobin Goodwin, Stephen B. Grigoriev, Igor V. TI Diverse Lifestyles and Strategies of Plant Pathogenesis Encoded in the Genomes of Eighteen Dothideomycetes Fungi SO PLOS PATHOGENS LA English DT Article ID ASCOMYCETE LEPTOSPHAERIA-MACULANS; NONRIBOSOMAL PEPTIDE SYNTHETASES; INDUCED POINT MUTATIONS; POLYKETIDE SYNTHASE; COCHLIOBOLUS-HETEROSTROPHUS; COLLETOTRICHUM-GRAMINICOLA; FUSARIUM-GRAMINEARUM; STAGONOSPORA-NODORUM; PHYLOGENETIC TREES; NEUROSPORA-CRASSA AB The class Dothideomycetes is one of the largest groups of fungi with a high level of ecological diversity including many plant pathogens infecting a broad range of hosts. Here, we compare genome features of 18 members of this class, including 6 necrotrophs, 9 (hemi)biotrophs and 3 saprotrophs, to analyze genome structure, evolution, and the diverse strategies of pathogenesis. The Dothideomycetes most likely evolved from a common ancestor more than 280 million years ago. The 18 genome sequences differ dramatically in size due to variation in repetitive content, but show much less variation in number of (core) genes. Gene order appears to have been rearranged mostly within chromosomal boundaries by multiple inversions, in extant genomes frequently demarcated by adjacent simple repeats. Several Dothideomycetes contain one or more gene-poor, transposable element (TE)-rich putatively dispensable chromosomes of unknown function. The 18 Dothideomycetes offer an extensive catalogue of genes involved in cellulose degradation, proteolysis, secondary metabolism, and cysteine-rich small secreted proteins. Ancestors of the two major orders of plant pathogens in the Dothideomycetes, the Capnodiales and Pleosporales, may have had different modes of pathogenesis, with the former having fewer of these genes than the latter. Many of these genes are enriched in proximity to transposable elements, suggesting faster evolution because of the effects of repeat induced point (RIP) mutations. A syntenic block of genes, including oxidoreductases, is conserved in most Dothideomycetes and upregulated during infection in L. maculans, suggesting a possible function in response to oxidative stress. C1 [Ohm, Robin A.; Barry, Kerrie W.; Copeland, Alex C.; LaButti, Kurt; Lindquist, Erika A.; Lucas, Susan; Salamov, Asaf A.; Grigoriev, Igor V.] US DOE, JGI, Walnut Creek, CA 94598 USA. [Feau, Nicolas; Dhillon, Braham; Hamelin, Richard C.] Univ British Columbia, Fac Forestry, Forest Sci Ctr, Vancouver, BC V6T 1W5, Canada. [Henrissat, Bernard] Aix Marseille Univ, CNRS, Marseille, France. [Schoch, Conrad L.] NIH NLM NCBI, Bethesda, MD USA. [Horwitz, Benjamin A.; Kosti, Idit] Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. [Condon, Bradford J.; Turgeon, B. Gillian] Cornell Univ, Dept Plant Pathol & Plant Microbe Biol, Ithaca, NY USA. [Glaser, Fabian] Technion Israel Inst Technol, Bioinformat Knowledge Unit, Haifa, Israel. [Hesse, Cedar N.; Ciuffetti, Lynda; Spatafora, Joseph W.] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. [Bradshaw, Rosie E.] Massey Univ, Inst Mol BioSci, Palmerston North, New Zealand. [Hamelin, Richard C.] Nat Resources Canada, Ste Foy, PQ, Canada. [Kema, Gert H. J.] Plant Res Int, Wageningen, Netherlands. [Lawrence, Christopher] Virginia Bioinformat Inst, Blacksburg, VA USA. [Lawrence, Christopher] Dept Biol Sci, Blacksburg, VA USA. [Scott, James A.] Univ Toronto, Dalla Lana Sch Publ Hlth, Div Occupat & Environm Hlth, Toronto, ON, Canada. [de Wit, Pierre J. G. M.] Wageningen Univ, Phytopathol Lab, Wageningen, Netherlands. [Zhong, Shaobin] N Dakota State Univ, Dept Plant Pathol, Fargo, ND 58105 USA. [Goodwin, Stephen B.] Purdue Univ, USDA, ARS, W Lafayette, IN 47907 USA. RP Ohm, RA (reprint author), US DOE, JGI, Walnut Creek, CA 94598 USA. EM raohm@lbl.gov; ivgrigoriev@lbl.gov RI Scott, James/A-8598-2011; de Wit, Pierre/A-1998-2013; Bradshaw, Rosie/C-7846-2011; Ohm, Robin/I-6689-2016; OI Scott, James/0000-0002-5073-0832; de Wit, Pierre/0000-0002-4208-288X; Bradshaw, Rosie/0000-0001-5228-2685; Goodwin, Stephen/0000-0001-5708-9729 FU Office of Science of the U.S. Department of Energy [DE-AC02-05CH11231]; USDA-ARS CRIS project [3602-22000-015-00D]; Intramural Research Program of the NIH, National Library of Medicine FX The work done by U.S. Department of Energy Joint Genome Institute is supported by the Office of Science of the U.S. Department of Energy under contract number DE-AC02-05CH11231. This work was supported in part by USDA-ARS CRIS project 3602-22000-015-00D. CLS acknowledges support from the Intramural Research Program of the NIH, National Library of Medicine. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 135 TC 139 Z9 153 U1 6 U2 114 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 DEC PY 2012 VL 8 IS 12 AR e1003037 DI 10.1371/journal.ppat.1003037 PG 26 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 062GJ UT WOS:000312907100009 PM 23236275 ER PT J AU Berrigan, D AF Berrigan, David TI Better measurement for healthier places SO PREVENTIVE MEDICINE LA English DT Editorial Material DE Environment; Diet; Physical activity; Chronic disease; Urban form; Measurement C1 NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Berrigan, D (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, Room 4010,6130 Executive Blvd N, Bethesda, MD 20892 USA. EM berrigad@mail.nih.gov NR 9 TC 1 Z9 1 U1 2 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD DEC PY 2012 VL 55 IS 6 BP 567 EP 568 DI 10.1016/j.ypmed.2012.08.018 PG 2 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 063CT UT WOS:000312974400017 PM 22960161 ER PT J AU Li, R Xu, XZ Chen, C Yu, XF Edin, ML Degraff, LM Lee, CR Zeldin, DC Wang, DW AF Li, Rui Xu, Xizhen Chen, Chen Yu, Xuefeng Edin, Matthew L. Degraff, Laura Miller Lee, Craig R. Zeldin, Darryl C. Wang, Dao Wen TI Cytochrome P450 2J2 is protective against global cerebral ischemia in transgenic mice SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article DE Arachidonic acid; Cytochrome P450 epoxygenase; Global cerebral ischemia; Neuroprotection; Stroke ID NEURONAL CELL-DEATH; COPPER/ZINC SUPEROXIDE-DISMUTASE; FREE-RADICAL GENERATION; BLOOD-FLOW; ISCHEMIA/REPERFUSION INJURY; ARTERY OCCLUSION; EPOXYEICOSATRIENOIC ACIDS; SIGNALING PATHWAYS; FOREBRAIN ISCHEMIA; TEMPORAL PROFILE AB Cytochrome P450 epoxygenase metabolites of arachidonic acid, EETs, have multiple cardiovascular effects, including reduction of blood pressure, protection against myocardial ischemia-reperfusion injury, and attenuation of endothelial apoptosis. This study investigated the hypothesis that transgenic mice with endothelial overexpression of CYP2J2 (Tie2-CYP2J2-Tr) would be protected against global cerebral ischemia induced by bilateral common carotid artery occlusion (BCCAO) and action mechanisms of EETs on cerebral ischemia in cultures of astrocytes exposed to oxygen-glucose deprivation (OGD). Tie2-CYP2J2-Tr mice had significantly increased CYP2J2 expression, increased 14,15-EET production, increases regional cerebral blood flow (rCBF) and microvascular density, decreased ROS production, decreased brain infarct size and apoptosis after ischemia compared to wild type mice, these were associated with increased activation of the PI3K/AKT and apoptosis-related protein in ischemic brain. Addition of exogenous EETs or CYP2J2 transfection attenuated OGD-induced apoptosis in astrocytes via activation of PI3K/AKT and anti-apoptosis pathways. However, these effects were reduced by pretreatments with inhibitor of the PI3K (LY294002) and 14,15-EET (14,15-EEZE), respectively. These results indicate that CYP2J2 overexpression exerts marked neuroprotective effects against ischemic injury by a mechanism linked to increased level of circulating EETs and increases CBF and reduction of apoptosis. (c) 2012 Elsevier Inc. All rights reserved. C1 [Li, Rui; Xu, Xizhen; Chen, Chen; Yu, Xuefeng; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, Wuhan 430030, Peoples R China. [Li, Rui; Xu, Xizhen; Chen, Chen; Yu, Xuefeng; Wang, Dao Wen] Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Gene Therapy Ctr, Wuhan 430030, Peoples R China. [Edin, Matthew L.; Degraff, Laura Miller; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Lee, Craig R.] Univ N Carolina, Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC 27599 USA. RP Wang, DW (reprint author), Huazhong Univ Sci & Technol, Tongji Med Coll, Tongji Hosp, Dept Internal Med, 1095 Jiefang Ave, Wuhan 430030, Peoples R China. EM dwwang@tjh.tjmu.edu.cn OI Edin, Matthew/0000-0002-7042-500X; Lee, Craig/0000-0003-3595-5301 FU National Nature Science Foundation Committee of China [30770882, 30800458, 30930039]; "973" projects [2012CB518004]; Intramural Research Program of the NIH, National Institute of Environmental Health Sciences [Z01 ES025043, R01 GM088199]; Key Project of Health Ministry of China FX This work was supported by grants from National Nature Science Foundation Committee of China (no. 30770882, 30800458, 30930039), "973" projects (no. 2012CB518004), the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES025043, R01 GM088199) and Key Project of Health Ministry of China. NR 61 TC 11 Z9 11 U1 1 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD DEC PY 2012 VL 99 IS 3-4 BP 68 EP 78 DI 10.1016/j.prostaglandins.2012.09.004 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 056SN UT WOS:000312511800002 PM 23041291 ER PT J AU Radin, MJ Yu, MJ Stoedkilde, L Miller, RL Hoffert, JD Frokiaer, J Pisitkun, T Knepper, MA AF Radin, M. Judith Yu, Ming-Jiun Stoedkilde, Lene Miller, R. Lance Hoffert, Jason D. Frokiaer, Jorgen Pisitkun, Trairak Knepper, Mark A. TI Aquaporin-2 regulation in health and disease SO VETERINARY CLINICAL PATHOLOGY LA English DT Review DE Exosomes; polyuria; syndrome of inappropriate antidiuretic hormone excess; transcription; vasopressin ID CENTRAL DIABETES-INSIPIDUS; POLYCYSTIC KIDNEY-DISEASE; MEDULLARY COLLECTING DUCT; VASOPRESSIN-INDUCED ANTIDIURESIS; WATER CHANNEL EXPRESSION; INDUCED DOWN-REGULATION; UNILATERAL URETERAL OBSTRUCTION; ENHANCER-BINDING PROTEIN; ANTI-DIURETIC HORMONE; B-CELL LYMPHOMA AB Aquaporin-2 (AQP2), the vasopressin-regulated water channel of the renal collecting duct, is dysregulated in numerous disorders of water balance in people and animals, including those associated with polyuria (urinary tract obstruction, hypokalemia, inflammation, and lithium toxicity) and with dilutional hyponatremia (syndrome of inappropriate antidiuresis, congestive heart failure, cirrhosis). Normal regulation of AQP2 by vasopressin involves 2 independent regulatory mechanisms: (1) short-term regulation of AQP2 trafficking to and from the apical plasma membrane, and (2) long-term regulation of the total abundance of the AQP2 protein in the cells. Most disorders of water balance are the result of dysregulation of processes that regulate the total abundance of AQP2 in collecting duct cells. In general, the level of AQP2 in a collecting duct cell is determined by a balance between production via translation of AQP2 mRNA and removal via degradation or secretion into the urine in exosomes. AQP2 abundance increases in response to vasopressin chiefly due to increased translation subsequent to increases in AQP2 mRNA. Vasopressin-mediated regulation of AQP2 gene transcription is poorly understood, although several transcription factor-binding elements in the 5' flanking region of the AQP2 gene have been identified, and candidate transcription factors corresponding to these elements have been discovered in proteomics studies. Here, we review progress in this area and discuss elements of vasopressin signaling in the collecting duct that may impinge on regulation of AQP2 in health and in the context of examples of polyuric diseases. C1 [Yu, Ming-Jiun; Stoedkilde, Lene; Miller, R. Lance; Hoffert, Jason D.; Pisitkun, Trairak; Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. [Radin, M. Judith] Ohio State Univ, Coll Vet Med, Dept Vet Biosci, Columbus, OH 43210 USA. [Yu, Ming-Jiun] Natl Taiwan Univ, Coll Med, Inst Biochem & Mol Biol, Taipei, Taiwan. [Stoedkilde, Lene; Frokiaer, Jorgen] Univ Aarhus, Water & Salt Res Ctr, Aarhus, Denmark. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, 10 Ctr Dr, Bldg 10,Room 6N260, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271; YU, MING-JIUN/0000-0003-0393-4696 FU Intramural NIH HHS [ZIA HL001285-24, Z01 HL001285-21, Z01 HL001285-22, ZIA HL001285-23, ZIA HL001285-26, ZIA HL006128-02, ZIA HL006129-02] NR 173 TC 20 Z9 21 U1 3 U2 33 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0275-6382 J9 VET CLIN PATH JI Vet. Clin. Pathol. PD DEC PY 2012 VL 41 IS 4 BP 455 EP 470 DI 10.1111/j.1939-165x.2012.00488.x PG 16 WC Veterinary Sciences SC Veterinary Sciences GA 057HZ UT WOS:000312555200003 PM 23130944 ER PT J AU Liu, DB Wang, SJ Swierczewska, M Huang, XL Bhirde, AA Sun, JS Wang, Z Yang, M Jiang, XY Chen, XY AF Liu, Dingbin Wang, Shouju Swierczewska, Magdalena Huang, Xinglu Bhirde, Ashwinkumar A. Sun, Jiashu Wang, Zhuo Yang, Min Jiang, Xingyu Chen, Xiaoyuan TI Highly Robust, Recyclable Displacement Assay for Mercuric Ions in Aqueous Solutions and Living Cells SO ACS NANO LA English DT Article DE gold nanoparticles sensitivity; selectivity; recyclable detection; Rhodamine B isothiocyanate ID SURFACE-ENERGY TRANSFER; GOLD NANOPARTICLES; MULTIPLEXED DETECTION; MERCURY(II); PROTEIN; SENSOR; WATER; FLUORESCENCE; SPECIATION; BIOMARKERS AB We designed a recyclable Hg2+ probe based on Rhodamine B isothiocyanate (RBITC)-poly(ethylene glycol) (PEG)-comodified gold nanoparticles (AuNPs) with excellent robustness, selectivity, and sensitivity. On the basis of a rational design, only Hg2+ can displace RBITC from the AuNP surfaces, resulting in a remarkable enhancement of RBITC fluorescence initially quenched by AuNPs. To maintain stability and monodispersity of AuNPs in real samples, thiol-terminated PEG was employed to bind with the remaining active sites of AuNPs. Besides, this displacement assay can be regenerated by resupplying free RBITC into the AuNPs solutions that were already used for detecting Hg2+. Importantly, the detection limit of this assay for Hg2+ (2.3 nM) was lower than the maximum limits guided by the United States Environmental Protection Agency as well as that permitted by the World Health Organization. The efficiency of this probe was demonstrated in monitoring Hg2+ in complex samples such as river water and living cells. C1 [Liu, Dingbin; Yang, Min] Jiangsu Inst Nucl Med, Jiangsu Key Lab Mol Nucl Med, Minist Hlth, Key Lab Nucl Med, Wuxi 214063, Jiangsu, Peoples R China. [Liu, Dingbin; Wang, Shouju; Swierczewska, Magdalena; Huang, Xinglu; Bhirde, Ashwinkumar A.; Chen, Xiaoyuan] NIBIB, Lab Mol Imaging & Nanomed LOMIN, NIH, Bethesda, MD 20892 USA. [Sun, Jiashu; Wang, Zhuo; Jiang, Xingyu] Natl Ctr NanoSci & Technol, CAS Key Lab Biol Effects Nanomat & Nanosafety, Beijing 100190, Peoples R China. [Liu, Dingbin; Huang, Xinglu] Xiamen Univ, Sch Publ Hlth, Ctr Mol Imaging & Translat Med, Xiamen 361005, Peoples R China. RP Yang, M (reprint author), Jiangsu Inst Nucl Med, Jiangsu Key Lab Mol Nucl Med, Minist Hlth, Key Lab Nucl Med, Wuxi 214063, Jiangsu, Peoples R China. EM yangmin@jsinm.org; xingyujiang@nanoctr.cn; shawn.chen@nih.gov FU National Basic Research Program of China (973 program) [2013CB733802, 2013CB733800]; National Science Foundation of China (NSFC) [81101101, 51273165, 51173117, 50830107, 81171399, 81101077]; National Significant New Drugs Creation Program [2012ZX09505-001-001]; Jiangsu Province Social Development Program [BE2012622, BL2012031]; Outstanding Professional Fund of Health Ministry in Jiangsu Province [RC2011095]; Chinese Academy of Sciences [2011T2J06]; Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH) FX This work was supported in part, by the National Basic Research Program of China (973 program) (973 Program No. 2013CB733802, 2013CB733800), the National Science Foundation of China (NSFC) (81101101, 51273165, 51173117, 50830107, 81171399, and 81101077), the National Significant New Drugs Creation Program (2012ZX09505-001-001), the Jiangsu Province Social Development Program (BE2012622 and BL2012031), the Outstanding Professional Fund of Health Ministry in Jiangsu Province (RC2011095), the Chinese Academy of Sciences professorship for Senior International Scientists (2011T2J06), and the Intramural Research Program (IRP) of the National Institute of Biomedical Imaging and Bioengineering (NIBIB), National Institutes of Health (NIH). NR 43 TC 36 Z9 36 U1 3 U2 132 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 DEC PY 2012 VL 6 IS 12 BP 10999 EP 11008 DI 10.1021/nn3046192 PG 10 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 057LA UT WOS:000312563600064 PM 23121626 ER PT J AU Kaku, M Komatsu, Y Mochida, Y Yamauchi, M Mishina, Y Ko, CC AF Kaku, Masaru Komatsu, Yoshihiro Mochida, Yoshiyuki Yamauchi, Mitsuo Mishina, Yuji Ko, Ching-Chang TI Identification and characterization of neural crest-derived cells in adult periodontal ligament of mice SO ARCHIVES OF ORAL BIOLOGY LA English DT Article DE Neural crest cells; Neural crest marker; Periodontal ligament ID MESENCHYMAL STEM-CELLS; DENTAL-PULP; PRECURSOR CELLS; TRANSGENIC MICE; SELF-RENEWAL; IN-VIVO; MOUSE; EXPRESSION; MORPHOGENESIS; RECOMBINASE AB Objective: Cells derived from the neural crest (NC) contribute to the development of several adult tissues, including tooth and periodontal tissue. Here, two transgenic lines, Wnt1-Cre/ZEG and PO-Cre/ZEG, were analysed to determine the fate and distribution of neural crest cells (NCCs) in adult mouse periodontal ligament (PDL). Design: Paraffin-embedded and decalcified histology samples were prepared from Wnt1-Cre/ZEG and PO-Cre/ZEG mice that were 4-, 8-, or 12-weeks old. Expression of GFP (NC-derived cells), NC-markers (Slug, AP-2 alpha, HNK-1, p75NTR and Nestin), and mesenchymal stem cell markers (CD29 and STRO-1) were examined using immunohistochemistry. Results: In four-week-old Wnt1-Cre/ZEG mice, GFP((+)) NC-derived cells were specifically detected in the mid-zone of PDL. The GFP((+)) cells constituted 1.4% of all cells in PDL, and this percentage decreased as the mice aged. The distribution and prevalence of GFP((+)) cells were comparable between Wnt1-Cre/ZEG and PO-Cre/ZEG mice. NC-marker ((+)) cells were expressed only in GFP((+)) cells while MSC markers were detected only in GFP((-)) cells. Conclusion: The prevalence and specific distribution of NC-derived cells in adult PDL of Wnt1-Cre/ZEG and PO-Cre/ZEG mouse were examined. Interestingly, various NC markers, including markers for undifferentiated NCCs, were still expressed at high levels in GFP((+)) cells. These observations may indicate that labelled cells in the Wnt1-Cre/ZEG and PO-Cre/ZEG mice did not constituted all NC-derived cells, but rather an interesting subset of NC-derived cells. These findings may be useful in understanding the homeostatic character of the PDL and contribute to establishing successful periodontal tissue maintenance. (C) 2012 Elsevier Ltd. All rights reserved. C1 [Kaku, Masaru] Niigata Univ, Grad Sch Med & Dent Sci, Div Bioprosthodont, Chuo Ku, Niigata 9518514, Japan. [Kaku, Masaru; Mochida, Yoshiyuki; Yamauchi, Mitsuo; Ko, Ching-Chang] Univ N Carolina, Dent Res Ctr, Chapel Hill, NC 27599 USA. [Kaku, Masaru] Niigata Univ, Med & Dent Hosp, Niigata, Japan. [Komatsu, Yoshihiro; Mishina, Yuji] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Komatsu, Yoshihiro; Mishina, Yuji] NIH, Mol Dev Biol Grp, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC USA. [Mochida, Yoshiyuki] Boston Univ, Dept Periodontol & Oral Biol, Goldman Sch Dent Med, Boston, MA 02215 USA. [Ko, Ching-Chang] Univ N Carolina, Dept Orthodont, Chapel Hill, NC USA. RP Kaku, M (reprint author), Niigata Univ, Grad Sch Med & Dent Sci, Div Bioprosthodont, Chuo Ku, 2-5274 Gakkouchou Douri, Niigata 9518514, Japan. EM kakum@dent.niigata-u.ac.jp OI Mochida, Yoshiyuki/0000-0002-2115-4303; Kaku, Masaru/0000-0002-7988-6435 FU Japan Society for the Promotion of Science; NIDCR [K99DE021054, R01DE020843, DE019527, K08DE018695]; Intramural Research Program of the NIEHS/NIH [ES071003-11]; [21890081] FX This study was supported by the Japan Society for the Promotion of Science, Grant-in-Aid for Young Scientists 21890081 (M.K.), NIDCR Grant K99DE021054 (Y.K.), Intramural Research Program of the NIEHS/NIH Grant ES071003-11 (Y.M.), NIDCR Grant R01DE020843 (Y. Mishina), NIDCR Grant DE019527 (Y. Mochida) and NIDCR Grant K08DE018695 (C.-C.K.). NR 42 TC 9 Z9 10 U1 0 U2 16 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD DEC PY 2012 VL 57 IS 12 BP 1668 EP 1675 DI 10.1016/j.archoralbio.2012.04.022 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 056TO UT WOS:000312514500013 PM 22704955 ER PT J AU Kilicoglu, H Shin, D Fiszman, M Rosemblat, G Rindflesch, TC AF Kilicoglu, Halil Shin, Dongwook Fiszman, Marcelo Rosemblat, Graciela Rindflesch, Thomas C. TI SemMedDB: a PubMed-scale repository of biomedical semantic predications SO BIOINFORMATICS LA English DT Article AB Effective access to the vast biomedical knowledge present in the scientific literature is challenging. Semantic relations are increasingly used in knowledge management applications supporting biomedical research to help address this challenge. We describe SemMedDB, a repository of semantic predications (subject-predicate-object triples) extracted from the entire set of PubMed citations. We propose the repository as a knowledge resource that can assist in hypothesis generation and literature-based discovery in biomedicine as well as in clinical decision-making support. C1 [Kilicoglu, Halil; Shin, Dongwook; Fiszman, Marcelo; Rosemblat, Graciela; Rindflesch, Thomas C.] Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. RP Kilicoglu, H (reprint author), Natl Lib Med, Lister Hill Natl Ctr Biomed Commun, Bethesda, MD 20894 USA. EM kilicogluh@mail.nih.gov FU Intramural Research Program of the National Institutes of Health, National Library of Medicine FX This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 21 TC 35 Z9 35 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD DEC 1 PY 2012 VL 28 IS 23 BP 3158 EP 3160 DI 10.1093/bioinformatics/bts591 PG 3 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 048HT UT WOS:000311902700026 PM 23044550 ER PT J AU Hwang, SY Foley, J Numaga-Tomita, T Petranka, JG Bird, GS Putney, JW AF Hwang, Sung-Yong Foley, Julie Numaga-Tomita, Takuro Petranka, John G. Bird, Gary S. Putney, James W., Jr. TI Deletion of Orai1 alters expression of multiple genes during osteoclast and osteoblast maturation SO CELL CALCIUM LA English DT Article DE Store-operated channels; Orai1; Knock-out mouse; Gene regulation; Bone development ID TRANSCRIPTION FACTOR NFATC1; CELLS IN-VITRO; BONE-FORMATION; CALCIUM-CHANNELS; MICE LACKING; CRAC CHANNEL; TERMINAL DIFFERENTIATION; SKELETAL DEVELOPMENT; STROMAL CELLS; PORE SUBUNIT AB Store-operated Ca2+ entry (SOCE) is a major Ca2+ influx pathway in most non-excitable cell types and Orai1 was recently identified as an essential pore-subunit of SOCE channels. Here we investigate the physiological role of Orai1 in bone homeostasis using Orai1-deficient mice (Orai1(-/-)). Orail(-1-) mice developed osteopenia with decreased bone mineral density and trabecular bone volume. To identify the nature and origin of the bone defect, bone-resorbing osteoclasts and bone-forming osteoblasts from Orai1(-/-) mice were examined. Orai1-mediated SOCE was completely abolished in Orai1(-/-) osteoclast precursor cells and osteoclastogenesis in vitro from Orai1(-/-) mice was impaired due to a defect in cell fusion of pre-osteoclasts. Also, resorption activity in vitro was comparable but the size of pits formed by Orai1(-/-) osteoclasts was smaller. We next assessed the role of Orai1 in osteoblast differentiation and function by using a pre-osteoblast cell line, as well as primary osteoblasts from wild-type and Orai1(-/-) mice. SOCE in MC3T3-E1 pre-osteoblastic cells was inactivated by lentiviral overexpression of a pore-dead Orai1 mutant. Lack of SOCE in MC3T3-E1 had no effect on alkaline phosphatase staining and expression but substantially inhibited mineralized nodule formation. Consistent with this finding, Orai1-mediated SOCE was markedly reduced in Orai1(-/-) osteoblast precursor cells and osteoblastogenesis in vitro from Orail(-/-) stromal cells showed impaired mineral deposition but no change in differentiation. This indicates that Orail is involved in the function but not in the differentiation of osteoblasts. Together, these results suggest that Orai1 plays a critical role in bone homeostasis by regulating both osteoblasts and osteoclasts. Published by Elsevier Ltd. C1 [Hwang, Sung-Yong; Foley, Julie; Numaga-Tomita, Takuro; Petranka, John G.; Bird, Gary S.; Putney, James W., Jr.] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Putney, JW (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM putney@niehs.nih.gov FU 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. We thank Jeff Tucker, Drs. Agnes Janoshazi, and Shilan Wu for technical assistance. We thank Drs. Charles Romeo and Negin Martin (Viral Vector Core, NIEHS) for technical assistance in lentivirus preparations. We also thank Drs. Xiaoling Li and Robert Oakley for helpful comments. NR 67 TC 8 Z9 8 U1 1 U2 10 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD DEC PY 2012 VL 52 IS 6 BP 488 EP 500 DI 10.1016/j.ceca.2012.10.001 PG 13 WC Cell Biology SC Cell Biology GA 056FA UT WOS:000312472600008 PM 23122304 ER PT J AU Coffey, CS Levin, B Clark, C Timmerman, C Wittes, J Gilbert, P Harris, S AF Coffey, Christopher S. Levin, Bruce Clark, Christina Timmerman, Cate Wittes, Janet Gilbert, Peter Harris, Sara TI Overview, hurdles, and future work in adaptive designs: perspectives from a National Institutes of Health-funded workshop SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT University-of-Pennsylvania Annual Conference on Statistical Issues in Clinical Trials CY APR 13-13, 2011 CL Philadelphia, PA ID PHARMACEUTICAL PRODUCT DEVELOPMENT; CLINICAL DRUG DEVELOPMENT; SAMPLE-SIZE REESTIMATION; ACUTE ISCHEMIC-STROKE; TRIALS; ENRICHMENT; OPPORTUNITIES; CHALLENGES; ALS AB Background The clinical trials community has a never-ending search for dependable and reliable ways to improve clinical research. This exploration has led to considerable interest in adaptive clinical trial designs, which provide the flexibility to adjust trial characteristics on the basis of data reviewed at interim stages. Statisticians and clinical investigators have proposed or implemented a wide variety of adaptations in clinical trials, but specific approaches have met with differing levels of support. Within industry, investigators are actively exploring the benefits and pitfalls associated with adaptive designs (ADs). For example, a Drug Information Association (DIA) working group on ADs has engaged regulatory agencies in discussions. Many researchers working on publicly funded clinical trials, however, are not yet fully engaged in this discussion. We organized the Scientific Advances in Adaptive Clinical Trial Designs Workshop to begin a conversation about using ADs in publicly funded research. Held in November of 2009, the 1 1/2-day workshop brought together representatives from the National Institutes of Health (NIH), the Food and Drug Administration (FDA), the European Medicines Agency (EMA), the pharmaceutical industry, nonprofit foundations, the patient advocacy community, and academia. The workshop offered a forum for participants to address issues of ADs that arise at the planning, designing, and execution stages of clinical trials, and to hear the perspectives of influential members of the clinical trials community. The participants also set forth recommendations for guiding action to promote the appropriate use of ADs. These recommendations have since been presented, discussed, and vetted in a number of venues including the University of Pennsylvania Conference on Statistical Issues in Clinical Trials and the Society for Clinical Trials annual meeting. Purpose To provide a brief overview of ADs, describe the rationale behind conducting the workshop, and summarize the main recommendations that were produced as a result of this workshop. Conclusions There is a growing interest in the use of adaptive clinical trial designs. However, a number of logistical barriers need to be addressed in order to obtain the potential advantages of an AD. Currently, the pharmaceutical industry is well ahead of academic trialists with respect to addressing these barriers. Academic trialists will need to address important issues such as education, infrastructure, modifications to existing funding models, and the impact on Data and Safety Monitoring Boards (DSMB) in order to achieve the possible benefits of adaptive clinical trial designs. Clinical Trials 2012; 9: 671-680. http://ctj.sagepub.com C1 [Coffey, Christopher S.] Univ Iowa, Clin Trials Stat & Data Management Ctr, Dept Biostat, Iowa City, IA 52240 USA. [Levin, Bruce] Columbia Univ, Dept Biostat, New York, NY USA. [Clark, Christina] Fdn Interdisciplinary Motor Neuron Med, Metamora, MI USA. [Timmerman, Cate; Harris, Sara] Palladian Partners Inc, Silver Spring, MD USA. [Wittes, Janet] Stat Collaborat Inc, Washington, DC USA. [Gilbert, Peter] NINDS, Bethesda, MD 20892 USA. RP Coffey, CS (reprint author), Univ Iowa, Clin Trials Stat & Data Management Ctr, Dept Biostat, 2400 Univ Capitol Ctr, Iowa City, IA 52240 USA. EM christopher-coffey@uiowa.edu FU National Institute of Neurological Disorders and Stroke [R13NS065622]; NIH Office of Rare Diseases Research; National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Alpha-1 Foundation; American Parkinson Disease Association; CHDI Foundation; Hope for ALS; Juvenile Diabetes Research Foundation International; Michael J. Fox Foundation for Parkinson's Research; National Neurovision Research Institute/Foundation Fighting Blindness; National Organization for Rare Disorders; Parkinson's Action Network; Parkinson Alliance; Parkinson's Disease Foundation FX The Scientific Advances in Adaptive Clinical Trial Designs Workshop was supported by the National Institute of Neurological Disorders and Stroke (award number R13NS065622) with contributing support from the NIH Office of Rare Diseases Research; the National Institute of Allergy and Infectious Diseases; and the National Heart, Lung, and Blood Institute. In addition, the Foundation for Interdisciplinary Motor Neuron Medicine provided seed money for planning the workshop. The following nonprofit organizations generously contributed support to implement the workshop and produce this summary: Alpha-1 Foundation, American Parkinson Disease Association, CHDI Foundation, Hope for ALS, Juvenile Diabetes Research Foundation International, The Michael J. Fox Foundation for Parkinson's Research, National Neurovision Research Institute/Foundation Fighting Blindness, National Organization for Rare Disorders, Parkinson's Action Network, The Parkinson Alliance, and Parkinson's Disease Foundation. NR 38 TC 20 Z9 20 U1 0 U2 11 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2012 VL 9 IS 6 BP 671 EP 680 DI 10.1177/1740774512461859 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 055XZ UT WOS:000312452600002 PM 23250942 ER PT J AU Shepherd, BE Shaw, PA Dodd, LE AF Shepherd, Bryan E. Shaw, Pamela A. Dodd, Lori E. TI Using audit information to adjust parameter estimates for data errors in clinical trials SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT University-of-Pennsylvania Annual Conference on Statistical Issues in Clinical Trials CY APR 13-13, 2011 CL Philadelphia, PA ID COVARIATE ADJUSTMENT; MULTIPLE-IMPUTATION; SUBGROUP ANALYSIS AB Background Audits are often performed to assess the quality of clinical trial data, but beyond detecting fraud or sloppiness, the audit data are generally ignored. In an earlier study, using data from a nonrandomized study, Shepherd and Yu developed statistical methods to incorporate audit results into study estimates and demonstrated that audit data could be used to eliminate bias. Purpose In this article, we examine the usefulness of audit-based error-correction methods in clinical trial settings where a continuous outcome is of primary interest. Methods We demonstrate the bias of multiple linear regression estimates in general settings with an outcome that may have errors and a set of covariates for which some may have errors and others, including treatment assignment, are recorded correctly for all subjects. We study this bias under different assumptions, including independence between treatment assignment, covariates, and data errors (conceivable in a double-blinded randomized trial) and independence between treatment assignment and covariates but not data errors (possible in an unblinded randomized trial). We review moment-based estimators to incorporate the audit data and propose new multiple imputation estimators. The performance of estimators is studied in simulations. Results When treatment is randomized and unrelated to data errors, estimates of the treatment effect using the original error-prone data (i.e., ignoring the audit results) are unbiased. In this setting, both moment and multiple imputation estimators incorporating audit data are more variable than standard analyses using the original data. In contrast, in settings where treatment is randomized but correlated with data errors and in settings where treatment is not randomized, standard treatment-effect estimates will be biased. And in all settings, parameter estimates for the original, error-prone covariates will be biased. The treatment and covariate effect estimates can be corrected by incorporating audit data using either the multiple imputation or moment-based approaches. Bias, precision, and coverage of confidence intervals improve as the audit size increases. Limitations The extent of bias and the performance of methods depend on the extent and nature of the error as well as the size of the audit. This study only considers methods for the linear model. Settings much different than those considered here need further study. Conclusions In randomized trials with continuous outcomes and treatment assignment independent of data errors, standard analyses of treatment effects will be unbiased and are recommended. However, if treatment assignment is correlated with data errors or other covariates, naive analyses may be biased. In these settings, and when covariate effects are of interest, approaches for incorporating audit results should be considered. Clinical Trials 2012; 9 : 721-729. http://ctj.sagepub.com C1 [Shepherd, Bryan E.] Vanderbilt Univ, Dept Biostat, Sch Med, Nashville, TN 37232 USA. [Shaw, Pamela A.; Dodd, Lori E.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Shepherd, BE (reprint author), Vanderbilt Univ, Dept Biostat, Sch Med, 1161 21st Ave S,S2323 MCN, Nashville, TN 37232 USA. EM bryan.shepherd@vanderbilt.edu FU National Institutes of Health [1R01 AI093234-01, 2U01 AI069923-06] FX This study was supported in part by the National Institutes of Health (grant numbers 1R01 AI093234-01 and 2U01 AI069923-06). NR 13 TC 2 Z9 2 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2012 VL 9 IS 6 BP 721 EP 729 DI 10.1177/1740774512450100 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 055XZ UT WOS:000312452600008 PM 22848072 ER PT J AU Wang, MH Dignam, JJ Zhang, QE DeGroot, JF Mehta, MP Hunsberger, S AF Wang, Meihua Dignam, James J. Zhang, Qiang E. DeGroot, John F. Mehta, Minesh P. Hunsberger, Sally TI Integrated phase II/III clinical trials in oncology: A case study SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT University-of-Pennsylvania Annual Conference on Statistical Issues in Clinical Trials CY APR 13-13, 2011 CL Philadelphia, PA ID HYPOTHESES SELECTION; MALIGNANT GLIOMAS; II TRIALS; DESIGNS; RECURRENT; SURVIVAL; INTERIM; BEVACIZUMAB; TOXICITY; CANCER AB Background Integrated phase II/III trial designs implement the phase II and phase III aspects of oncology studies into a single trial. Despite a body of literature discussing the merits of integrated phase II/III clinical trial designs within the past two decades, implementation of this design has been limited in oncology studies. Purpose We provide a brief discussion of the potential advantages and disadvantages of integrated phase II/III clinical trial designs in oncology and provide an example of the operating characteristics of a Radiation Therapy Oncology Group (RTOG) trial. Methods We review the differences among proposed integrated phase II/III designs. Then, we illustrate the use of the design in a brain tumor trial to be conducted by the RTOG and examine the impact of association between endpoints on design performance in terms of type I error, power, study duration, and expected sample size. Results Although integrated phase II/III designs should not be used in all situations, under appropriate conditions, significant gains can be achieved when using integrated phase II/III designs, including smaller sample size, time and resources savings, and shorter study duration. Limitations Data submission without delay and sufficient evaluation of intermediate endpoints are assumed. Conclusions Although there are potential benefits in using phase II/III designs, there also may be disadvantages. We recommend running design simulations incorporating theoretical and practical issues before implementing an integrated phase II/III design. Clinical Trials 2012; 9: 741-747. http://ctj.sagepub.com C1 [Wang, Meihua; Dignam, James J.; Zhang, Qiang E.] Amer Coll Radiol, Radiat Therapy Oncol Grp, Dept Stat, Philadelphia, PA 19103 USA. [Dignam, James J.] Univ Chicago, Dept Hlth Studies, Chicago, IL 60637 USA. [DeGroot, John F.] Univ Texas MD Anderson Canc Ctr, Div Canc Med, Dept Neurooncol, Houston, TX 77030 USA. [Mehta, Minesh P.] Northwestern Univ, Feinberg Sch Med, Dept Radiat Oncol, Chicago, IL 60611 USA. [Hunsberger, Sally] NCI, Div Canc Treatment & Diag, Biometr Res Branch, Bethesda, MD 20892 USA. RP Wang, MH (reprint author), Amer Coll Radiol, Radiat Therapy Oncol Grp, Dept Stat, 1818 Market St,16th Floor, Philadelphia, PA 19103 USA. EM sumswang@yahoo.com OI mehta, minesh/0000-0002-4812-5713 FU RTOG grant from the National Cancer Institute (NCI) [U10 CA21661]; CCOP grant from the National Cancer Institute (NCI) [U10 CA37422]; Pennsylvania Department of Health [4100050889]; DEMOS Publishers FX This project was supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and by Pennsylvania Department of Health 2009 Formula Grant 4100050889.; Conflict of Interest Notification: Minesh Mehta has or has had the following roles in the last 2 years (2010-2011): Consultant: Adnexus, Bayer, Bristol-Meyers-Squibb, Elekta (non-reimbursed), Merck, Novartis, Quark, and Tomotherapy; Stock Options: Accuray, Colby, Pharmacyclics, Procertus, and Stemina; Data Safety Monitoring Boards: Apogenix; Board of Directors: Pharmacyclics; Medical Advisory Boards: Colby, Stemina, and Procertus; Speaker: GRACE Foundation, MCM, Merck, priME Oncology, Strategic Edge, and WebMD; Patents: WARF/Procertus; Royalties: DEMOS Publishers. This publication's contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute nor the Pennsylvania Department of Health. NR 32 TC 0 Z9 0 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2012 VL 9 IS 6 BP 741 EP 747 DI 10.1177/1740774512464724 PG 7 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 055XZ UT WOS:000312452600011 PM 23180870 ER PT J AU Wendler, D AF Wendler, David TI Taking the measure of the therapeutic misconception SO CLINICAL TRIALS LA English DT Article; Proceedings Paper CT University-of-Pennsylvania Annual Conference on Statistical Issues in Clinical Trials CY APR 13-13, 2011 CL Philadelphia, PA ID INFORMED-CONSENT C1 NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Wendler, D (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov NR 5 TC 0 Z9 0 U1 1 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1740-7745 EI 1740-7753 J9 CLIN TRIALS JI Clin. Trials PD DEC PY 2012 VL 9 IS 6 BP 762 EP 764 DI 10.1177/1740774512456778 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 055XZ UT WOS:000312452600013 PM 23250945 ER PT J AU Chang, T Kowalski, R Caserta, F Nyquist, P Carhuapoma, J Tamargo, R Naval, N AF Chang, Tiffany Kowalski, Robert Caserta, Filissa Nyquist, Paul Carhuapoma, Juan Tamargo, Rafael Naval, Neeraj TI WITHDRAWAL OF TECHNOLOGICAL SUPPORT FOLLOWING SUBARACHNOID HEMORRHAGE SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Chang, Tiffany; Kowalski, Robert; Tamargo, Rafael; Naval, Neeraj] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Nyquist, Paul] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Carhuapoma, Juan] Johns Hopkins Univ Hosp, Baltimore, MD 21287 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 875 BP U239 EP U239 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045701144 ER PT J AU Kadri, S Hoffman, M Dye, C Carter, C Quast, T AF Kadri, Sameer Hoffman, Marshall Dye, Cicely Carter, Corey Quast, Timothy TI A HARD PILL TO SWALLOW: INTRAMURAL ESOPHAGEAL HEMATOMA (IEH) IN A PATIENT ON SUNITINIB AND DALTEPARIN SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Kadri, Sameer] NIH, Bethesda, MD USA. [Hoffman, Marshall; Dye, Cicely; Carter, Corey; Quast, Timothy] Walter Reed Natl Mil Med Ctr, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 1138 BP U307 EP U307 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045701404 ER PT J AU Lloveras, JL Remy, K AF Lloveras, Jose Lucar Remy, Kenneth TI AN HIV-POSITIVE MAN WITH BACTERIAL MENINGITIS, OTI-TIS MEDIA AGUDA, AND CEREBRAL SINUS THROMBOSIS SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Lloveras, Jose Lucar] Washington Hosp Ctr, Washington, DC USA. [Remy, Kenneth] Natl Inst Hlth Clin Ctr, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 1198 BP U324 EP U325 PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045701464 ER PT J AU Meert, K Eggly, S AF Meert, Kathleen Eggly, Susan TI FEASIBILITY STUDY OF PHYSICIAN-PARENT FOLLOW-UP MEETINGS AFTER A CHILD'S DEATH IN THE PEDIATRIC INTENSIVE CARE UNIT (PICU) SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Meert, Kathleen] Childrens Hosp Michigan, Detroit, MI 48201 USA. [Eggly, Susan] NICHD, Karmanos Canc Inst, Collaborat Pediat Crit Care Res Network, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 871 BP U238 EP U238 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045701140 ER PT J AU Naval, N Kowalski, R Chang, T Caserta, F Nyquist, P Carhuapoma, J Tamargo, R AF Naval, Neeraj Kowalski, Robert Chang, Tiffany Caserta, Filissa Nyquist, Paul Carhuapoma, Juan Tamargo, Rafael TI SAH SCORE IMPROVES ACCURACY OF HOSPITAL MORTALITY PREDICTION SO CRITICAL CARE MEDICINE LA English DT Meeting Abstract CT 42nd Critical Care Congress of the Society-of-Critical-Care-Medicine CY JAN 19-23, 2013 CL San Juan, PR SP Soc Crit Care Medi C1 [Naval, Neeraj; Kowalski, Robert; Chang, Tiffany; Tamargo, Rafael] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Nyquist, Paul] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Carhuapoma, Juan] Johns Hopkins Univ Hosp, Baltimore, MD 21287 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 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD DEC PY 2012 VL 40 IS 12 SU S MA 647 BP U178 EP U178 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 050HZ UT WOS:000312045700608 ER PT J AU Stratakis, CA AF Stratakis, Constantine A. TI Cushing Syndrome in Pediatrics SO ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA LA English DT Article DE Cushing syndrome; Pituitary tumors; Cortisol; Adrenal cortex; Carney complex; Adrenocortical hyperplasia; Adrenal cancer ID CORTICOTROPIN-RELEASING HORMONE; NODULAR ADRENOCORTICAL DISEASE; DIFFERENTIAL-DIAGNOSIS; ADRENAL-HYPERPLASIA; PITUITARY-ADENOMAS; SYNDROME SECONDARY; CHILDREN; ADOLESCENTS; MUTATIONS; DEXAMETHASONE AB Cushing syndrome is characterized by truncal obesity, growth deceleration, skin changes, muscle weakness, and hypertension. Cushing syndrome in childhood usually results from the exogenous administration of glucocorticoids. This article presents the causes and discusses the treatment of endogenous Cushing syndrome. It also discusses the clinical and molecular genetics of inherited forms of this syndrome. Cushing syndrome needs to be diagnosed and treated properly when first recognized; improper treatment can turn this otherwise completely curable disorder into a chronic ailment. Barriers to optimal care of a pediatric patient with Cushing syndrome are discussed. C1 [Stratakis, Constantine A.] NICHHD, Pediat Endocrinol Training Program, NIH, CRC, Bethesda, MD 20892 USA. [Stratakis, Constantine A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHHD, Pediat Endocrinol Training Program, NIH, CRC, Bldg 10,Room 1-3330 E Labs,10 Ctr Dr, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD FX This work was completed with support by the Intramural Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1862. NR 29 TC 31 Z9 33 U1 2 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8529 J9 ENDOCRIN METAB CLIN JI Endocrinol. Metabol. Clin. North Amer. PD DEC PY 2012 VL 41 IS 4 BP 793 EP + DI 10.1016/j.ecl.2012.08.002 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 058FC UT WOS:000312618500011 PM 23099271 ER PT J AU Leitner, WW Denis, AS Wali, T AF Leitner, Wolfgang W. Costero-Saint Denis, Adriana Wali, Tonu TI Role of immune cell subsets in the establishment of vector-borne infections SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Arthropod saliva; immune modulation; skin immunity; vector-borne pathogen ID LANGERHANS CELLS; DENDRITIC CELLS; SALIVA; EXPRESSION; TRANSMISSION; MICE AB Many of the pathogens responsible for diseases that result in both economic and global health burdens are transmitted by arthropod vectors in the course of a blood meal. In the past, these vectors were viewed mainly as simple delivery vehicles but the appreciation of the role that factors in the saliva of vectors play during pathogen transmission is increasing. Vector saliva proteins alter numerous physiological events in the skin; in addition, potent immunomodulatory properties are attributed to arthropod saliva. The description of specific factors responsible for these activities and their mechanisms of action have thus far remained mostly anecdotal. The National Institute of Allergy and Infectious Diseases (NIAID) sponsored a workshop in May 2012 to explore novel approaches aimed at identifying how vector saliva components affect the function of various immune cell subsets and the subsequent impact on the transmission of vector-borne pathogens. Such knowledge could guide the development of novel drugs, vaccines and other strategies to block the transmission of vector-borne pathogens. This meeting report summarizes the discussions of the gaps/challenges which represent attractive research opportunities with significant translational potential. C1 [Leitner, Wolfgang W.] NIAID, Div Allergy Immunol & Transplantat, NIH, Bethesda, MD 20892 USA. [Costero-Saint Denis, Adriana; Wali, Tonu] NIAID, Div Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. RP Leitner, WW (reprint author), 6610 Rockledge Dr,Rm 6224, Bethesda, MD 20892 USA. EM wleitner@niaid.nih.gov RI Leitner, Wolfgang/F-5741-2011 OI Leitner, Wolfgang/0000-0003-3125-5922 NR 26 TC 3 Z9 3 U1 0 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2012 VL 42 IS 12 BP 3110 EP 3115 DI 10.1002/eji.201270102 PG 6 WC Immunology SC Immunology GA 057FJ UT WOS:000312547800006 PM 23255007 ER PT J AU Shatynski, KE Chen, HY Kwon, J Williams, MS AF Shatynski, Kristen E. Chen, Haiyan Kwon, Jaeyul Williams, Mark S. TI Decreased STAT5 phosphorylation and GATA-3 expression in NOX2-deficient T cells: Role in T helper development SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Chronic granulomatous disease; NADPH oxidase; Reactive oxygen species; STAT5 ID CHRONIC GRANULOMATOUS-DISEASE; NADPH OXIDASE; REACTIVE OXYGEN; RECEPTOR STIMULATION; TH2 DIFFERENTIATION; LINEAGE COMMITMENT; T-BET/GATA-3 RATIO; GENE-EXPRESSION; ANGIOTENSIN-II; ARTHRITIS AB Absence of phagocyte NADPH oxidase (NOX2) activity causes chronic granulomatous disease (CGD), a primary immunodeficiency characterized by recurrent bacterial infections. In contrast to this innate immune deficit, CGD patients and animal models display a predisposition toward autoimmune disease and enhanced response to Helicobacter pylori and influenza virus infection. These data imply an altered, perhaps augmented, adaptive immune response in CGD. As previous data demonstrated functional NOX2 expression in T cells, our goal here was to determine if NOX2-deficient T cells are inherently altered in their responses. Activation of purified naive CD4+ T cells from NOX2-deficient mice led to augmented IFN-? and diminished IL-4 production and an increased ratio of expression of the TH1-specific transcription factor T-bet versus the TH2-specfic transcription factor GATA-3, consistent with a TH1 skewing of naive T cells. Selective inhibition of TCR-induced STAT5 phosphorylation was identified as a potential mechanism for skewed T helper differentiation. Exposure to antioxidants inhibited, while pro-oxidants augmented TH2 cytokine secretion and STAT5 phosphorylation, supporting the redox dependence of these signaling changes. These data suggest that TCR-induced ROS generation from NOX2 activation can regulate the adaptive immune response in a T-cell-inherent fashion, and propose a possible role for redox signaling in T helper differentiation. C1 [Shatynski, Kristen E.; Chen, Haiyan; Williams, Mark S.] Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Kwon, Jaeyul] NIAID, Lab Host Def, NIH, Rockville, MD USA. RP Williams, MS (reprint author), Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Dept Microbiol & Immunol, UMB BioPark 1,Room 315,800 W Baltimore St, Baltimore, MD 21201 USA. EM marwilliams@som.umaryland.edu FU National Institutes of Health [R01-AI070823, T32-HL007698] FX The authors wish to thank the members of Dr. Jonathan Bromberg's lab for their generous sharing of resources. This work was supported by National Institutes of Health Grant R01-AI070823 (to M.S.W.) and National Institutes of Health Grant T32-HL007698 (to K.E.S.). K.E.S. is a PhD candidate at the University of Maryland School of Medicine Graduate Program in Life Sciences (GPILS) and this work is submitted in partial fulfillment of the requirement for her PhD. NR 51 TC 16 Z9 16 U1 0 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2012 VL 42 IS 12 BP 3202 EP 3211 DI 10.1002/eji.201242659 PG 10 WC Immunology SC Immunology GA 057FJ UT WOS:000312547800017 PM 22930452 ER PT J AU Rinchai, D Khaenam, P Kewcharoenwong, C Buddhisa, S Pankla, R Chaussabel, D Bancroft, GJ Lertmemongkolchai, G AF Rinchai, Darawan Khaenam, Prasong Kewcharoenwong, Chidchamai Buddhisa, Surachat Pankla, Rungnapa Chaussabel, Damien Bancroft, Gregory J. Lertmemongkolchai, Ganjana TI Production of interleukin-27 by human neutrophils regulates their function during bacterial infection SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Burkholderia pseudomallei; IL-27; melioidosis; Neutrophil; Sepsis ID HUMAN DENDRITIC CELLS; TOLL-LIKE RECEPTORS; BURKHOLDERIA-PSEUDOMALLEI; T-CELLS; MOLECULAR-MECHANISMS; GENE-EXPRESSION; B-LYMPHOCYTES; SEPSIS; IL-27; MELIOIDOSIS AB Septicemia is the most severe form of melioidosis caused by the Gram-negative bacterium, Burkholderia pseudomallei. Here, we show that levels of IL-27p28 transcript and protein were both significantly elevated in patients with sepsis, particularly melioidosis and in patients with unfavorable disease outcome. Moreover, human monocytes/macrophages and neutrophils were the major source of IL-27 during infection. The addition of exogenous IL-27 in vitro resulted in significantly increased bacterial survival, reduced B. pseudomallei-induced oxidative burst, and enhanced IL-1 beta and TNF-a production by purified neutrophils from healthy subjects. Finally, blockade of endogenous IL-27 in neutrophils using soluble IL-27 receptor antagonist prior to infection led to significantly reduced survival of bacteria and decreased IL-1 beta, but not TNF-a production. These results indicate a potential role for IL-27 in the suppression of anti-bacterial defense mechanisms that might contribute to disease severity in sepsis. The targeting of this cytokine may be beneficial in the management of human sepsis. C1 [Lertmemongkolchai, Ganjana] Khon Kaen Univ, Ctr Res & Dev, Med Diagnost Labs CMDL, Cellular & Mol Immunol Unit,Fac Associated Med Sc, Khon Kaen 40002, Thailand. [Khaenam, Prasong; Chaussabel, Damien] Benaroya Res Inst, Seattle, WA USA. [Chaussabel, Damien] Baylor NIAID Cooperat Ctr Translat Res Human Immu, BIIR, Dallas, TX USA. [Bancroft, Gregory J.] London Sch Hyg & Trop Med, Dept Immunol & Infect, London WC1, England. RP Lertmemongkolchai, G (reprint author), Khon Kaen Univ, Ctr Res & Dev, Med Diagnost Labs CMDL, Cellular & Mol Immunol Unit,Fac Associated Med Sc, Khon Kaen 40002, Thailand. EM ganja_le@kku.ac.th OI Chaussabel, Damien/0000-0002-6131-7242; Rinchai, Darawan/0000-0001-8851-7730; Lertmemongkolchai, Ganjana/0000-0001-6972-585X FU National Institutes of Health: NIAID Cooperative Center for Translational Research on Human Immunology and Biodefense [U01 AI0 82110]; Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program [PHD/0215/2550, PHD/0026/2552] FX We thank Dr. Manabu Ato and Professor Mark P. Stevens for their critical comments and review of the manuscript, the staff of Khon Kaen Regional Hospital and Sakornakorn Hospital, Thailand for patient recruitment, Dr. Kusumawadee Utispan, Duangchan Suwannasaen, and Donporn Riyapa for their technical assistance. This work was supported in part by the National Institutes of Health: NIAID Cooperative Center for Translational Research on Human Immunology and Biodefense (U01 AI0 82110 to D.C.) and The Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program (Grant No. PHD/0215/2550 to D.R. and G.L., PHD/0026/2552 to C.K. and G.L.) NR 41 TC 10 Z9 10 U1 0 U2 8 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2012 VL 42 IS 12 BP 3280 EP 3290 DI 10.1002/eji.201242526 PG 11 WC Immunology SC Immunology GA 057FJ UT WOS:000312547800024 PM 22965735 ER PT J AU Liu, XQ Stacey, KJ Horne-Debets, JM Cridland, JA Fischer, K Narum, D Mackay, F Pierce, SK Wykes, MN AF Liu, Xue Q. Stacey, Katryn J. Horne-Debets, Joshua M. Cridland, Jasmyn A. Fischer, Katja Narum, David Mackay, Fabienne Pierce, Susan K. Wykes, Michelle N. TI Malaria infection alters the expression of B-cell activating factor resulting in diminished memory antibody responses and survival SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE BAFF; DCs; Memory B cells; Malaria ID DENDRITIC CELLS; PLASMODIUM-FALCIPARUM; T-CELLS; BAFF; ANTIGEN; IMMUNITY; SIGNALS; VACCINE; DIFFERENTIATION; PLASMABLASTS AB Malaria is a major cause of morbidity worldwide with reports of over 200500 million infected individuals and nearly 1 million deaths each year. Antibodies have been shown to play a critical role in controlling the blood stage of this disease; however, in malaria-endemic areas antibody immunity is slow to develop despite years of exposure to Plasmodium spp. the causative parasite. Using rodent Plasmodium yoelii YM, we provide evidence that malarial infections result in a decrease in the proportion of DCs that express the B-cell survival factor, BAFF, resulting in a decreased ability of these DCs to support memory B-cell differentiation into antibody secreting cells (ASCs) and/or the survival of ASCs. Further, compared with infected WT mice, ASC numbers were significantly increased in malaria-infected transgenic mice that either overexpressed BAFF or mice with BAFF-independent B-cell survival (B-cell-restricted TRAF3 deletion). Remarkably, BAFF-overexpressing mice were protected from lethal malaria infections, indicating the significance of the role BAFF plays in determining the outcome of malaria infections. These findings describe a previously unappreciated mechanism by which Plasmodium spp. can depress the generation of protective antibody responses. C1 [Liu, Xue Q.; Horne-Debets, Joshua M.; Fischer, Katja; Wykes, Michelle N.] Queensland Inst Med Res, Bancroft Ctr, Brisbane, Qld 4029, Australia. [Stacey, Katryn J.; Cridland, Jasmyn A.] Univ Queensland, Sch Chem & Mol Biosci, Brisbane, Qld 4072, Australia. [Narum, David] NIAID, Lab Malaria Immunol & Vaccinol, NIH, Rockville, MD USA. [Mackay, Fabienne] Monash Univ, Alfred Hosp, Dept Immunol, Fac Med Nursing & Hlth Sci,Cent Clin Sch, Melbourne, Vic 3181, Australia. [Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Wykes, MN (reprint author), Queensland Inst Med Res, Bancroft Ctr, 300 Herston Rd,PO Royal Brisbane Hosp, Brisbane, Qld 4029, Australia. EM Michelle.Wykes@qimr.edu.au RI Mackay, Fabienne/B-7440-2008; Wykes, Michelle/G-6272-2013 OI Mackay, Fabienne/0000-0002-6074-2693; Wykes, Michelle/0000-0002-7956-0144 FU National Health and Medical Research Council (Australia); NIAID; NIH; Queensland Smart State Fellowship; Australian Research Council FX We sincerely thank Dr. Susan Kalled for kindly providing the BAFF transgenic mice and Dr. Robert Brink for providing TRAF3-knockout mice. We also thank Drs. Michael Good, Danielle Stanisic, Robin Anders, Christian Engwerda, Denise Doolan, Sharon Johnatty, Geoffrey Hill, and Kenneth Shortman for their critical reading and suggestions for the manuscript. We especially thank Ms. Grace Chojnowski and Paula Hall for their excellent cell sorting skills. This work was supported by National Health and Medical Research Council (Australia) grant to M.W. and S.P., in part by the Intramural Research Program of NIAID, NIH, and Queensland Smart State Fellowship to M.W. and an Australian Research Council Future Fellowship to K.S. NR 40 TC 13 Z9 13 U1 0 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD DEC PY 2012 VL 42 IS 12 BP 3291 EP 3301 DI 10.1002/eji.201242689 PG 11 WC Immunology SC Immunology GA 057FJ UT WOS:000312547800025 PM 22936176 ER PT J AU Chen, WZ Prabakaran, P Zhu, ZY Feng, Y Streaker, ED Dimitrov, DS AF Chen, Weizao Prabakaran, Ponraj Zhu, Zhongyu Feng, Yang Streaker, Emily D. Dimitrov, Dimiter S. TI Characterization of human IgG repertoires in an acute HIV-1 infection SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE HIV-1; Human monoclonal antibody; IgG; gp140; Envelope glycoprotein; Immunogen; High-throughput sequencing; Vaccine ID MONOCLONAL-ANTIBODIES; GENE REPERTOIRE; DIVERSITY; ANTIGENS; EPITOPE; DESIGN; CELLS AB All known broadly neutralizing antibodies (bnAbs) are highly somatically mutated and therefore significantly differ from their germline predecessors. Thus although the mature bnAbs bind to conserved epitopes of the HIV-1 envelope glycoprotein (Env) with high affinity their germline predecessors do not or weakly bind Envs failing to initiate an effective immune response. The identification of less somatically mutated bnAbs and/or antibody maturation intermediates that are clonally related to bnAbs may be useful to circumvent the major problem of initiating immune responses leading to elicitation of bnAbs. Here, we describe the identification of IgG antibodies from an acutely HIV-1-infected patient using a combination of phage display and high-throughput sequencing. We found two antibodies with only a single point mutation in the V region of their heavy chain variable domains compared to their putative germline predecessors which bound with high affinity to several Envs. They targeted the Env gp41 and did not neutralize HIV-1. Using high-throughput sequencing, we identified several highly abundant CDR3s, germline-like as well as somatically mutated V genes in the VH/VL repertoires of the patient which may provide antibody intermediates corresponding to known bnAbs as templates for design of novel HIV-1 vaccine immunogens. Published by Elsevier Inc. C1 [Chen, Weizao; Prabakaran, Ponraj; Zhu, Zhongyu; Feng, Yang; Streaker, Emily D.; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, NIH, Frederick, MD 21702 USA. [Prabakaran, Ponraj; Streaker, Emily D.] Sci Applicat Int Corp Frederick Inc, Basic Res Program, Frederick Natl Lab, Frederick, MD 21702 USA. RP Chen, WZ (reprint author), NCI, Prot Interact Grp, NIH, Bldg 469, Rm 150B, Frederick, MD 21702 USA. EM chenw3@mail.nih.gov; prabakaran.ponraj@nih.gov FU NIH, National Cancer Institute, Center for Cancer Research; Gates Foundation; NIH, National Cancer Institute [NO1-CO-12400] FX We thank Drs. B. Haynes, H. Liao, C. Broder, and T. Fouts for reagents. We thank the Laboratory of Molecular Technology and Advanced Biomedical Computing Center of SAIC-Frederick Inc. for sequencing service. We thank Ms. Maria G. Singarayan for constructing the PostgreSQL database and developing JAVA applications. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and the Gates Foundation to DSD, and by Federal funds from the NIH, National Cancer Institute, under Contract No. 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 the mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 22 TC 10 Z9 11 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4800 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD DEC PY 2012 VL 93 IS 3 SI SI BP 399 EP 407 DI 10.1016/j.yexmp.2012.09.022 PG 9 WC Pathology SC Pathology GA 056CN UT WOS:000312466100019 PM 23036472 ER PT J AU Wang, LL Li, QZ Li, ZH Zheng, G AF Wang, Linglu Li, Qizhai Li, Zhaohai Zheng, Gang TI Bayes Factor Based on a Maximum Statistic for Case-Control Genetic Association Studies SO JOURNAL OF AGRICULTURAL BIOLOGICAL AND ENVIRONMENTAL STATISTICS LA English DT Article DE Asymptotic distributions; Bayes factors; Bayesian model averaging; Genetic model; MAX3; Prior; Robustness ID GENOME-WIDE ASSOCIATION; TREND TESTS; SAMPLE-SIZE AB We study a Bayes factor based on a robust test statistic, MAX3, for case-control genetic association studies. MAX3 is the maximum of three trend tests derived under the recessive, additive and dominant genetic models, respectively. The proposed Bayes factor, denoted as BFM, models the asymptotic distributions of MAX3 under the null and alternative hypotheses. It is compared to an existing Bayes factor based on Bayesian model averaging (BMA). Through simulation studies, we show that both BFM and BMA are robust under genetic model uncertainty. They both depend on specifying the prior distribution for the genetic model, and have similar performance when common objective priors are used. When the prior places a large probability on the true (wrong) genetic model, BMA (BFM) is more powerful. Applications to real data from a genome-wide association study are presented to illustrate their use and show their sensitivity under genetic model uncertainty. C1 [Zheng, Gang] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Wang, Linglu] KPMG LLP, Econ & Valuat Serv, Mclean, VA 22102 USA. [Li, Qizhai] Chinese Acad Sci, Acad Math & Syst Sci, Beijing, Peoples R China. [Wang, Linglu; Li, Zhaohai] George Washington Univ, Dept Stat, Washington, DC 20052 USA. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM linglu.vicky.wang@gmail.com; liqz@amss.ac.cn; zli@gwu.edu; zhengg@nhlbi.nih.gov FU National Science Foundation of China [10901155, 61134013] FX The work of Qizhai Li was partially supported by the National Science Foundation of China (Grant Nos. 10901155, 61134013). The authors would like to thank two reviewers and the associate editor for their helpful suggestions that improved the presentation of this paper. NR 17 TC 1 Z9 1 U1 3 U2 9 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1085-7117 EI 1537-2693 J9 J AGR BIOL ENVIR ST JI J. Agric. Biol. Environ. Stat. PD DEC PY 2012 VL 17 IS 4 BP 568 EP 582 DI 10.1007/s13253-012-0092-z PG 15 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 058PH UT WOS:000312645500003 ER PT J AU Kim, H Stotts, NA Froelicher, ES Engler, MM Porter, C AF Kim, Hyunjung Stotts, Nancy A. Froelicher, Erika S. Engler, Marguerite M. Porter, Carol TI Why patients in critical care do not receive adequate enteral nutrition? A review of the literature SO JOURNAL OF CRITICAL CARE LA English DT Review DE Energy intake; Enteral nutrition; Intensive care unit; Nutritional adequacy; Protein intake ID MECHANICALLY VENTILATED PATIENTS; RANDOMIZED CLINICAL-TRIAL; ILL PATIENTS; UNIT PATIENTS; ICU PATIENTS; ENERGY-BALANCE; CALORIC-INTAKE; DELIVERY; OUTCOMES; SUPPORT AB Enteral nutrition is frequently used to provide nutrients for critically ill patients. However, only about half of critically ill enterally fed patients receive their energy requirements. Underfeeding is associated with detrimental clinical outcomes including infection, pressure ulcers, impaired wound healing, prolonged hospital stays, and increased morbidity and mortality. This literature review was conducted to identify major barriers to adequate enteral nutrition intake in critically ill adults and to identify gaps in the research literature. Studies (n = 30) reviewed addressed adult patients in critical care, published since 1999, and written in English. Findings showed that factors that explain inadequate enteral nutritional intake include delayed initiation of enteral nutrition and slow advancement of infusion rate, underprescription, incomplete delivery of prescribed nutrition, and frequent interruption of enteral nutrition. Frequent interruption was caused by diagnostic tests, surgical procedures, gastrointestinal intolerance, feeding tube problems, and routine nursing procedures. There are no standardized protocols that address these barriers to receiving adequate enteral intake. Such protocols must be developed, implemented, and tested to address undernutrition and mitigate the negative consequences of inadequate enteral intake. (C) 2012 Elsevier Inc. All rights reserved. C1 [Stotts, Nancy A.; Froelicher, Erika S.; Porter, Carol] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kim, Hyunjung] Hallym Univ, Chunchon, South Korea. [Engler, Marguerite M.] Natl Inst Hlth, Nat Inst Nursing Res, Bethesda, MD USA. RP Stotts, NA (reprint author), Univ Calif San Francisco, San Francisco, CA 94143 USA. EM nancy.stotts@nursing.ucsf.edu NR 41 TC 18 Z9 20 U1 1 U2 29 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0883-9441 J9 J CRIT CARE JI J. Crit. Care PD DEC PY 2012 VL 27 IS 6 BP 702 EP 713 DI 10.1016/j.jcrc.2012.07.019 PG 12 WC Critical Care Medicine SC General & Internal Medicine GA 057YF UT WOS:000312599800024 PM 23084129 ER PT J AU Acker, MA Pagani, FD Stough, WG Mann, DL Jessup, M Kormos, R Slaughter, MS Baldwin, T Stevenson, L Aaronson, KD Miller, L Naftel, D Yancy, C Rogers, J Teuteberg, J Starling, RC Griffith, B Boyce, S Westaby, S Blume, E Wearden, P Higgins, R Mack, M AF Acker, Michael A. Pagani, Francis D. Stough, Wendy Gattis Mann, Douglas L. Jessup, Mariell Kormos, Robert Slaughter, Mark S. Baldwin, Timothy Stevenson, Lynne Aaronson, Keith D. Miller, Leslie Naftel, David Yancy, Clyde Rogers, Joseph Teuteberg, Jeffrey Starling, Randall C. Griffith, Bartley Boyce, Steven Westaby, Stephen Blume, Elizabeth Wearden, Peter Higgins, Robert Mack, Michael TI Statement regarding the pre and post market assessment of durable, implantable ventricular assist devices in the United States SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Article ID ADVANCED HEART-FAILURE; INTERMACS ANNUAL-REPORT; CLINICAL-TRIAL DESIGN; CONTINUOUS-FLOW; CARDIOVASCULAR DEVICES; MEDICAL DEVICES; CARDIAC-RESYNCHRONIZATION; DESTINATION THERAPY; SUPPORT; OUTCOMES AB The incorporation of complex medical device technologies into clinical practice is governed by critical oversight of the United States Food and Drug Administration. This regulatory process requires a judicious balance between assuring safety and efficacy, while providing efficient review to facilitate access to innovative therapies. Recent contrasting views of the regulator), process have emphasized the difficulties in obtaining an optimal balance. Mechanical circulator), support has evolved to become an important therapy for patients who have advanced heart failure with the advent of more durable, implantable ventricular assist devices. The regulatory oversight of these new technologies has been difficult owing to the complexities of these devices, associated adverse event profile, and severity of illness of the intended patient population. Maintaining a regulatory environment to foster efficient introduction of safe and effective technologies is critical to the success of ventricular assist device therapy and the health of patients with advanced heart failure. Physicians representing key surgical and cardiology societies, and representatives from the Food and Drug Administration, National Heart Lung, and Blood Institute, Centers for Medicare and Medicaid Services, Inter-agency Registry of Mechanically Assisted Circulatory Support, and industry partners gathered to discuss relevant issues regarding the current regulatory environment assessing ventricular assist devices. The goal of the meeting was to explore innovative ways to foster the introduction of technologically advanced, safe, and effective ventricular assist devices. The following summary reflects opinions and conclusions endorsed by The Society of Thoracic Surgeons, American Association for Thoracic Surgery, American Heart Association, Heart Failure Society of America, International Society for Heart and Lung Transplantation, and Interagency Registry of Mechanically Assisted Circulatory Support. J Heart Lung Transplant 2012; 31: 1241-52 (C) 2012 International Society for Heart and Lung Transplantation. All rights reserved. C1 [Acker, Michael A.] Univ Penn, Div Cardiothorac Surg, Philadelphia, PA 19104 USA. [Pagani, Francis D.] Univ Michigan, Dept Cardiac Surg, Ann Arbor, MI 48109 USA. [Stough, Wendy Gattis] Campbell Univ, Coll Pharm & Hlth Sci, Buies Creek, NC 27506 USA. [Mann, Douglas L.] Washington Univ, Div Cardiovasc, St Louis, MO USA. [Jessup, Mariell] Univ Penn, Div Cardiovasc Med, Philadelphia, PA 19104 USA. [Kormos, Robert] Univ Pittsburgh, Dept Cardiothorac Surg, Pittsburgh, PA USA. [Slaughter, Mark S.] Univ Louisville, Div Cardiothorac Surg, Louisville, KY 40292 USA. [Baldwin, Timothy] NHLBI, Bethesda, MD 20892 USA. [Stevenson, Lynne] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Aaronson, Keith D.] Univ Michigan, Div Cardiovasc Med, Ann Arbor, MI 48109 USA. [Miller, Leslie] Univ S Florida, Dept Cardiovasc Sci, Tampa, FL USA. [Naftel, David] Univ Alabama Birmingham, Dept Cardiothorac Surg, Birmingham, AL USA. [Yancy, Clyde] Northwestern Univ, Div Cardiol, Chicago, IL 60611 USA. [Rogers, Joseph] Duke Univ, Div Cardiol, Durham, NC USA. [Teuteberg, Jeffrey] Univ Pittsburgh, Med Ctr, Inst Heart & Vasc, Pittsburgh, PA USA. [Starling, Randall C.] Cleveland Clin, Cleveland, OH 44106 USA. [Griffith, Bartley] Univ Maryland, Div Cardiac Surg, Baltimore, MD 21201 USA. [Boyce, Steven] Washington Hosp Ctr, MedStar Heart Inst, Dept Cardiac Surg, Washington, DC 20010 USA. [Westaby, Stephen] John Radcliffe Hosp, Oxford Heart Ctr, Oxford OX3 9DU, England. [Blume, Elizabeth] Bostons Childrens Hosp, Dept Cardiol, Boston, MA USA. [Wearden, Peter] Childrens Hosp Pittsburgh, Dept Cardiothorac Surg, Pittsburgh, PA 15213 USA. [Higgins, Robert] Ohio State Univ, Div Cardiac Surg, Columbus, OH 43210 USA. [Mack, Michael] Med City Dallas Hosp, Dallas, TX USA. RP Acker, MA (reprint author), Hosp Univ Penn, 3400 Spruce St, 6 Silverstein Pavilion, Philadelphia, PA 19104 USA. EM michael.acker@uphs.upenn.edu RI Stough, Wendy/R-4287-2016; OI Stough, Wendy/0000-0001-8290-1205; Mann, Douglas /0000-0002-2516-0145 FU Heart Ware International, Inc; Thoratec Corporation FX The authors report the following disclosures: Keith D. Aaronson, MD, research support and speaker fees from Heart Ware International, Inc; Michael A. Acker, MD, consultant for Thoratec Corporation; Timothy Baldwin, PhD, no disclosures; Steven Boyce, MD, educational grants from and stock ownership in Thoratec Corporation and Heart Ware International, Inc; Elizabeth Blume, MD, no disclosures; Bartley Griffith, MD, no disclosures; Robert Higgins, MD, no disclosures; Mariell Jessup, MD, research on investigational mechanical circulatory support devices within the past 5 years (uncompensated); Robert Kormos, MD, no disclosures; Michael Mack, MD, no disclosures; Douglas L. Mann, MD, no disclosures; Leslie Miller, MD, no disclosures; David Naftel, PhD, Berlin Heart, Inc and Heart Ware International, Inc; Francis D. Pagani, MD, PhD, national principal investigator, Heart-Ware Endurance trial, and national coprincipal investigator, NHLBI REVIVE-IT trial; Joseph Rogers, MD, consultant for Thoratec Corporation and national principal investigator, Heart-Ware Endurance trial; Mark S. Slaughter, :VID, training and educational grant support from Thoratec Corporation and Heart-Ware International, Inc; Randall C. Starling, M:D, MPH, member ROADMAP Steering Committee, and travel reimbursement (<$5,000 per annum) from Thoratec Corporation; Lynne Stevenson, MD, no disclosures; Wendy Gattis Stough, PharrnD, no disclosures; Jeffrey Teuteberg, MD, no disclosures; Peter Wearden, MD, PhD, no disclosures; Stephen Westaby, MD, PhD, Medical Director, Calon Cardiotechnology Corporation (uncompensated); and Clyde Yancy, MD, no disclosuros. NR 37 TC 4 Z9 4 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD DEC PY 2012 VL 31 IS 12 BP 1241 EP 1252 DI 10.1016/j.healun.2012.10.012 PG 12 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 055KE UT WOS:000312414100001 PM 23206981 ER PT J AU Yengo, CM Takagi, Y Sellers, JR AF Yengo, Christopher M. Takagi, Yasuharu Sellers, James R. TI Temperature dependent measurements reveal similarities between muscle and non-muscle myosin motility SO JOURNAL OF MUSCLE RESEARCH AND CELL MOTILITY LA English DT Article DE Myosin; Muscle contraction; Enzymatic activity; Motility ID SKELETAL-MUSCLE; ADP DISSOCIATION; ATPASE ACTIVITY; POWER STROKE; STEP-SIZE; SHORTENING VELOCITY; ACTOMYOSIN ATPASE; HEAVY-MEROMYOSIN; ACTIN ACTIVATION; SURFACE LOOPS AB We examined the temperature dependence of muscle and non-muscle myosin (heavy meromyosin, HMM) with in vitro motility and actin-activated ATPase assays. Our results indicate that myosin V (MV) has a temperature dependence that is similar in both ATPase and motility assays. We demonstrate that skeletal muscle myosin (SK), smooth muscle myosin (SM), and non-muscle myosin IIA (NM) have different temperature dependence in ATPase compared to in vitro motility assays. In the class II myosins we examined (SK, SM, and NM) the rate-limiting step in ATPase assays is thought to be attachment to actin or phosphate release, while for in vitro motility assays it is controversial. In MV the rate-limiting step for both in vitro motility and ATPase assays is known to be ADP release. Consequently, in MV the temperature dependence of the ADP release rate constant is similar to the temperature dependence of in vitro motility. Interestingly, the temperature dependence of the ADP release rate constant of SM and NM was shifted toward the in vitro motility temperature dependence. Our results suggest that the rate-limiting step in SK, SM, and NM may shift from attachment-limited in solution to detachment limited in the in vitro motility assay. Internal strain within the myosin molecule or by neighboring myosin motors may slow ADP release which becomes rate-limiting in the in vitro motility assay. Within this small subset of myosins examined, the in vitro sliding velocity correlates reasonably well with actin-activated ATPase activity, which was suggested by the original study by Barany (J Gen Physiol 50:197-218, 1967). C1 [Yengo, Christopher M.] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. [Takagi, Yasuharu; Sellers, James R.] NHLBI, Lab Mol Physiol, Bethesda, MD 20892 USA. RP Yengo, CM (reprint author), Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, 500 Univ Dr, Hershey, PA 17033 USA. EM cmy11@psu.edu FU NIH [EYE018141, HL093531]; NHLBI FX We thank Attila Nagy for assistance with expression and purification of the NM. We thank William Unrath, Darshan Trivedi, Anja Swenson, Pallavi Penumetcha, and Omar Quintero for assistance with collecting and analyzing the ATPase and motility results. We thank Ned Debold for help in generating Scheme 1. We thank Sean Stocker for allowing us to borrow the thermocouple for measuring the temperature in motility experiments. This work was supported by grants from NIH (EYE018141 and HL093531) to CMY, and NHLBI internal funds to JRS. NR 67 TC 13 Z9 13 U1 0 U2 23 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0142-4319 EI 1573-2657 J9 J MUSCLE RES CELL M JI J. Muscle Res. Cell Motil. PD DEC PY 2012 VL 33 IS 6 SI SI BP 385 EP 394 DI 10.1007/s10974-012-9316-7 PG 10 WC Cell Biology SC Cell Biology GA 056ON UT WOS:000312500300004 PM 22930330 ER PT J AU Goldstein, DS Sullivan, P Cooney, A Jinsmaa, Y Sullivan, R Gross, DJ Holmes, C Kopin, IJ Sharabi, Y AF Goldstein, David S. Sullivan, Patti Cooney, Adele Jinsmaa, Yunden Sullivan, Rachel Gross, Daniel J. Holmes, Courtney Kopin, Irwin J. Sharabi, Yehonatan TI Vesicular uptake blockade generates the toxic dopamine metabolite 3,4-dihydroxyphenylacetaldehyde in PC12 cells: relevance to the pathogenesis of Parkinson's disease SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE aldehyde dehydrogenase; dihydroxyphenylacetaldehyde; DOPAL; monoamine oxidase; Parkinson's disease; reserpine ID ALPHA-SYNUCLEIN OLIGOMERS; GENOME-WIDE ASSOCIATION; MONOAMINE TRANSPORTER-2; OXIDATIVE STRESS; SH-SY5Y CELLS; CATECHOLAMINE METABOLISM; CYTOSOLIC DOPAMINE; RISK-FACTORS; NEURODEGENERATION; NEURONS AB Parkinson's disease entails profound loss of nigrostriatal dopaminergic terminals, decreased vesicular uptake of intraneuronal catecholamines, and relatively increased putamen tissue concentrations of the toxic dopamine metabolite, 3,4-dihydroxyphenylacetaldehyde (DOPAL). The objective of this study was to test whether vesicular uptake blockade augments endogenous DOPAL production. We also examined whether intracellular DOPAL contributes to apoptosis and, as a-synuclein oligomers may be pathogenetic in Parkinson's disease, oligomerizes a-synuclein. Catechols were assayed in PC12 cells after reserpine to block vesicular uptake, with or without inhibition of enzymes metabolizing DOPALdaidzein for aldehyde dehydrogenase and AL1576 for aldehyde reductase. Vesicular uptake was quantified by a method based on 6F- or 13C-dopamine incubation; DOPAL toxicity by apoptosis responses to exogenous dopamine, with or without daidzein+AL1576; and DOPAL-induced synuclein oligomerization by synuclein dimer production during DOPA incubation, with or without inhibition of L-aromatic-amino-acid decarboxylase or monoamine oxidase. Reserpine inhibited vesicular uptake by 9597% and rapidly increased cell DOPAL content (p = 0.0008). Daidzein+AL1576 augmented DOPAL responses to reserpine (p = 0.004). Intracellular DOPAL contributed to dopamine-evoked apoptosis and DOPA-evoked synuclein dimerization. The findings fit with the catecholaldehyde hypothesis, according to which decreased vesicular sequestration of cytosolic catecholamines and impaired catecholaldehyde detoxification contribute to the catecholaminergic denervation that characterizes Parkinson's disease. C1 [Goldstein, David S.; Sullivan, Patti; Cooney, Adele; Jinsmaa, Yunden; Sullivan, Rachel; Gross, Daniel J.; Holmes, Courtney; Kopin, Irwin J.; Sharabi, Yehonatan] NINDS, Clin Neurocardiol Sect, CNP, DIR,NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), NINDS, Clin Neurocardiol Sect, CNP, DIR,NIH, 9000 Rockville Pike,Bldg 10,Rm 5N220, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU Intramural Research Program of the National Institute of Neurological Disorders and Stroke FX The research reported here was supported by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. The authors thank Gilberto Carmona, Nelson Cole, Richard Imrich, and Roshanak Mansouri for preliminary work that enabled us to carry out the current experiments. The authors have no conflicts of interest to disclose. NR 46 TC 26 Z9 26 U1 1 U2 10 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 EI 1471-4159 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2012 VL 123 IS 6 BP 932 EP 943 DI 10.1111/j.1471-4159.2012.07924.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 051WK UT WOS:000312158500005 PM 22906103 ER PT J AU Durk, MR Chan, GNY Campos, CR Peart, JC Chow, ECY Lee, E Cannon, RE Bendayan, R Miller, DS Pang, KS AF Durk, Matthew R. Chan, Gary N. Y. Campos, Christopher R. Peart, John C. Chow, Edwin C. Y. Lee, Eason Cannon, Ronald E. Bendayan, Reina Miller, David S. Pang, K. Sandy TI 1a,25-Dihydroxyvitamin D3-liganded vitamin D receptor increases expression and transport activity of P-glycoprotein in isolated rat brain capillaries and human and rat brain microvessel endothelial cells SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE 1a; 25-dihydroxyvitamin D3 and vitamin D receptor; amyloid beta; blood brain barrier; P-glycoprotein ID CENTRAL-NERVOUS-SYSTEM; AMYLOID BETA-PEPTIDE; ALZHEIMERS-DISEASE; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; UP-REGULATION; MOUSE MODEL; X-RECEPTOR; IN-VIVO; PROTEASE INHIBITORS; NUCLEAR RECEPTORS AB Induction of the multidrug resistance protein 1 (MDR1)/P-glycoprotein (P-gp) by the vitamin D receptor (VDR) was investigated in isolated rat brain capillaries and rat (RBE4) and human (hCMEC/D3) brain microvessel endothelial cell lines. Incubation of isolated rat brain capillaries with 10 nM of the VDR ligand, 1a,25-dihydroxyvitamin D3 [1,25(OH)2D3] for 4 h increased P-gp protein expression fourfold. Incubation with 1,25(OH)2D3 for 4 or 24 h increased P-gp transport activity (specific luminal accumulation of NBD-CSA, the fluorescent P-gp substrate) by 2530%. In RBE4 cells, Mdr1b mRNA was induced in a concentration-dependent manner by exposure to 1,25(OH)2D3. Concomitantly, P-gp protein expression increased 2.5-fold and was accompanied by a 2035% reduction in cellular accumulation of the P-gp substrates, rhodamine 6G (R6G), and HiLyte Fluor 488-labeled human amyloid beta 1-42 (hA beta 42). In hCMEC/D3 cells, a 3 day exposure to 100 nM 1,25(OH)2D3 increased MDR1 mRNA expression (40%) and P-gp protein (threefold); cellular accumulation of R6G and hA beta 42 was reduced by 30%. Thus, VDR activation up-regulates Mdr1/MDR1 and P-gp protein in isolated rat brain capillaries and rodent and human brain microvascular endothelia, implicating a role for VDR in increasing the brain clearance of P-gp substrates, including hA beta 42, a plaque-forming precursor in Alzheimer's disease. C1 [Durk, Matthew R.; Chan, Gary N. Y.; Chow, Edwin C. Y.; Bendayan, Reina; Pang, K. Sandy] Univ Toronto, Leslie Dan Fac Pharm, Dept Pharmaceut Sci, Toronto, ON M5S 3M2, Canada. [Campos, Christopher R.; Peart, John C.; Lee, Eason; Cannon, Ronald E.; Miller, David S.] NIEHS, Lab Toxicol & Pharmacol, NIH, Res Triangle Pk, NC 27709 USA. RP Pang, KS (reprint author), Univ Toronto, Leslie Dan Fac Pharm, Dept Pharmaceut Sci, 144 Coll St, Toronto, ON M5S 3M2, Canada. EM ks.pang@utoronto.ca FU Canadian Institutes of Health Research (CIHR); Intramural Research Program of the National Institute of Environmental Health Sciences, NIH; CIHR Strategic Training Grant in Biological Therapeutics (CIHR) FX The authors have no conflict of interest to declare. This work was supported by the Canadian Institutes of Health Research (CIHR) and by the Intramural Research Program of the National Institute of Environmental Health Sciences, NIH. Matthew R. Durk is a recipient of a CIHR Strategic Training Grant in Biological Therapeutics (CIHR). NR 55 TC 23 Z9 24 U1 0 U2 14 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD DEC PY 2012 VL 123 IS 6 BP 944 EP 953 DI 10.1111/jnc.12041 PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 051WK UT WOS:000312158500006 PM 23035695 ER PT J AU Kingman, A Hyman, J Masten, SA Jayaram, B Smith, C Eichmiller, F Arnold, MC Wong, PA Schaeffer, JM Solanki, S Dunn, WJ AF Kingman, Albert Hyman, Jeffrey Masten, Scott A. Jayaram, Beby Smith, Cynthia Eichmiller, Frederick Arnold, Michael C. Wong, Paul A. Schaeffer, James M. Solanki, Sheetal Dunn, William J. TI Bisphenol A and other compounds in human saliva and urine associated with the placement of composite restorations SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article DE Bisphenol A; dental composites; liquid chromatography/mass spectrometry; urine; saliva ID RESIN; DIMETHACRYLATE; 4-NONYLPHENOL; POPULATION; DENTISTRY; SEALANTS; EXPOSURE; ADULTS AB Background. Bisphenol A (BPA) and other related chemical compounds may be components used in the manufacturing process of resin-based composite dental restorative material. The purpose of the authors' study was to assess salivary and urinary concentrations of BPA and other compounds before and after placement of resin-based composite dental restorations. Methods. The authors collected saliva and urine from 172 participants receiving composite restorations before and as long as 30 hours after placement of composite restorations. The authors analyzed saliva specimens from 151 participants and urine specimens from 171 participants for concentrations of BPA and five related compounds by using liquid chromatography/mass spectrometry (LC/MS). Results. Salivary concentrations of BPA and some related compounds increased immediately (within one hour) after composite placement. Salivary concentrations of BPA and most study compounds returned to prerestoration levels within eight hours after composite placement. With the exception of a 43 percent increase in BPA, concentrations of the study compounds in urine returned to prerestoration levels nine to 30 hours after restoration placement. Concentrations in saliva were lower when a rubber dam was used; however, rubber dam use appeared to have no effect on urinary concentrations of the measured compounds during the study period. The authors observed similar changes in study compound levels in both saliva and urine between participants who received anterior restorations and those who received posterior restorations. Conclusions. Placement of resin-based composite restorations was associated with detectable increases in saliva of BPA and other study compounds within one hour after restoration placement and an increased concentration of BPA in urine nine to 30 hours after restoration placement. Rubber dam use did not reduce the absorption of BPA (measured as BPA level in urine) during the study. Clinical Implications. Additional studies are needed to address how long BPA levels in urine associated with composite placement remain elevated to aid in better understanding of the clearance rates of BPA and other study compounds. C1 [Kingman, Albert] Natl Inst Dent & Craniofacial Res, Clin Res Ctr, NIH, Bethesda, MD 20892 USA. [Smith, Cynthia] NIEHS, Program Operat Branch, Natl Toxicol Program Div, NIH, Res Triangle Pk, NC 27709 USA. [Eichmiller, Frederick] Delta Dent Wisconsin, Stevens Point, WI USA. [Eichmiller, Frederick] Amer Dent Assoc Fdn, Paffenbarger Res Ctr, Gaithersburg, MD USA. [Arnold, Michael C.] US PHS, Med Affairs Branch, Silver Spring, MD USA. [Arnold, Michael C.; Wong, Paul A.; Schaeffer, James M.; Solanki, Sheetal] NIH, Commissioned Officers Dent Clin, Rockville, MD USA. [Wong, Paul A.] Off Special Populat Hlth Hlth Resources & Serv Ad, Rockville, MD USA. [Schaeffer, James M.] Indian Hlth Serv, Div Oral Hlth, Rockville, MD USA. [Dunn, William J.] USAF, Sch Aerosp Med, Ft Sam Houston, TX USA. [Dunn, William J.] Dent Evaluat & Consultat Serv, Ft Sam Houston, TX USA. [Dunn, William J.] Kessler Med Ctr, Dent Residency Program, Keesler AFB, MS USA. RP Kingman, A (reprint author), Natl Inst Dent & Craniofacial Res, Clin Res Ctr, NIH, 6701 Democracy Blvd, Bethesda, MD 20892 USA. EM KingmanA@de45.nidr.nih.gov RI masten, scott/R-1403-2016 OI masten, scott/0000-0002-7847-181X FU National Institute of Environmental Health Sciences [HHSN-291-2005-55552]; Midwest Research Institute (Kansas City, Mo.) FX Analytical chemistry support for the study described in this article was provided by the National Institute of Environmental Health Sciences under contract HHSN-291-2005-55552 with Midwest Research Institute (Kansas City, Mo.). NR 27 TC 22 Z9 23 U1 0 U2 27 PU AMER DENTAL ASSOC PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD DEC PY 2012 VL 143 IS 12 BP 1292 EP 1302 PG 11 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 053NH UT WOS:000312279200011 PM 23204083 ER PT J AU Adams, K Bayliss, E Blumenthal, D Boyd, C Guralnik, J Krist, AH LaCroix, A Naylor, MD Patrick, DL Reuben, D Tinetti, M Wallace, RB Ware, JE Wolff, JL Hadley, E Salive, ME AF Adams, Karen Bayliss, Elizabeth Blumenthal, David Boyd, Cynthia Guralnik, Jack Krist, Alexander H. LaCroix, Andrea Naylor, Mary D. Patrick, Donald L. Reuben, David Tinetti, Mary Wallace, Robert B. Ware, John E., Jr. Wolff, Jennifer L. Hadley, Evan Salive, Marcel E. CA Working Grp Hlth Outcomes Older Pe TI Universal Health Outcome Measures for Older Persons with Multiple Chronic Conditions SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE geriatrics; chronic disease; comorbidity; outcome assessment; quality measurement ID QUALITY-OF-LIFE; GENERALIZED ANXIETY DISORDER; INFORMATION-SYSTEM PROMIS; PHYSICAL FUNCTION; FAMILY CAREGIVERS; INSTRUMENTS; PERFORMANCE; ADULTS; ACCURACY; VALIDITY AB Older adults with multiple chronic conditions (MCCs) require considerable health services and complex care. Because the persistence and progression of diseases and courses of treatments affect health status in multiple dimensions, well-validated universal outcome measures across diseases are needed for research, clinical care, and administrative purposes. An expert panel meeting held by the National Institute on Aging in September 2011 recommends that older persons with MCCs complete a brief initial composite measure that includes general health; pain; fatigue; and physical health, mental health, and social role function, along with gait speed measurement. Suitable composite measures include the Medical Outcomes Study 8 (SF-8) and 36 (SF-36) -item Short-Form Survey and the Patient Reported Outcomes Measurement Information System 29-item Health Profile. Based on responses to items in the initial measure, short follow-on measures should be selectively targeted to symptom burden, depression, anxiety, and daily activities. Persons unable to walk a short distance to assess gait speed should be assessed using a physical function scale. Remaining gaps to be considered for measure development include disease burden, cognitive function, and caregiver burden. Routine outcome assessment of individuals with MCCs could facilitate system-based care improvement and clinical effectiveness research. J Am Geriatr Soc 60: 2333-2341, 2012. C1 [Salive, Marcel E.] NIA, Geriatr Branch, Div Geriatr & Clin Gerontol, NIH, Bethesda, MD 20892 USA. [Bayliss, Elizabeth] Kaiser Permanente, Inst Hlth Res, Oakland, CA USA. [Blumenthal, David] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Wolff, Jennifer L.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Guralnik, Jack] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Krist, Alexander H.] Virginia Commonwealth Univ, Med Ctr, Richmond, VA 23284 USA. [LaCroix, Andrea] Fred Hutchinson Canc Res Ctr, Seattle, WA USA. [Naylor, Mary D.] Univ Penn, Sch Nursing, Philadelphia, PA 19104 USA. [Patrick, Donald L.] Univ Washington, Seattle, WA 98195 USA. [Reuben, David] UCLA Sch Med, Los Angeles, CA USA. [Tinetti, Mary] Yale Univ, Sch Med, New Haven, CT 06520 USA. [Wallace, Robert B.] Univ Iowa, Coll Publ Hlth, Iowa City, IA 52242 USA. [Ware, John E., Jr.] Univ Massachusetts, Sch Med, Amherst, MA 01003 USA. RP Salive, ME (reprint author), NIA, Geriatr Branch, Div Geriatr & Clin Gerontol, NIH, 7201 Wisconsin Ave,Suite 3C307, Bethesda, MD 20892 USA. EM saliveme@nia.nih.gov FU National Institute of Mental Health [K01MH082885]; NIH; NIA; Agency for Healthcare Research and Quality FX Jennifer Wolff was supported by National Institute of Mental Health Grant K01MH082885.; John E. Ware, Jr., PhD, is Chief Science Officer and Founder, John Ware Research Group (JWRG), Inc., a for-profit business funded by NIH SBIR grants and unrestricted gifts or industry grants to develop and integrate generic and disease-specific patient-reported outcome measures for use in research and improving healthcare outcomes. He has received grants from NIH, NIA, and the Agency for Healthcare Research and Quality and various honoraria from academic institutions (<$5,000 annually). He is a consultant to the medical products industry on measurement issues and clinical trial results and interpretations (< 10,000 annually), is the principal shareholder of JWRG, Inc., and has provided expert testimony in Food and Drug Administration review panel hearings (3 in past 5 years). He is the primary or co-inventor for numerous patents, all sold with the sale of Quality Metric, Inc. in March 2010. NR 46 TC 28 Z9 28 U1 8 U2 36 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0002-8614 EI 1532-5415 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD DEC PY 2012 VL 60 IS 12 BP 2333 EP 2341 DI 10.1111/j.1532-5415.2012.04240.x PG 9 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 056AY UT WOS:000312460500020 ER PT J AU Zhang, L Lan, Q Ji, Z Li, G Shen, M Vermeulen, R Guo, W Hubbard, AE McHale, CM Rappaport, SM Hayes, RB Linet, MS Yin, S Smith, MT Rothman, N AF Zhang, L. Lan, Q. Ji, Z. Li, G. Shen, M. Vermeulen, R. Guo, W. Hubbard, A. E. McHale, C. M. Rappaport, S. M. Hayes, R. B. Linet, M. S. Yin, S. Smith, M. T. Rothman, N. TI Leukemia-related chromosomal loss detected in hematopoietic progenitor cells of benzene-exposed workers SO LEUKEMIA LA English DT Article DE benzene; monosomy; hematopoietic progenitor ID IN-SITU HYBRIDIZATION; LONG ARM DELETION; CAUSES ANEUPLOIDY; HYDROQUINONE; METABOLITE; LYMPHOCYTES; ANEUSOMY; HEMATOTOXICITY; CYTOGENETICS; ABERRATIONS AB Benzene exposure causes acute myeloid leukemia and hematotoxicity, shown as suppression of mature blood and myeloid progenitor cell numbers. As the leukemia-related aneuploidies monosomy 7 and trisomy 8 previously had been detected in the mature peripheral blood cells of exposed workers, we hypothesized that benzene could cause leukemia through the induction of these aneuploidies in hematopoietic stem and progenitor cells. We measured loss and gain of chromosomes 7 and 8 by fluorescence in situ hybridization in interphase colony-forming unit-granulocyte-macrophage (CFU-GM) cells cultured from otherwise healthy benzene-exposed (n = 28) and unexposed (n = 14) workers. CFU-GM monosomy 7 and 8 levels (but not trisomy) were significantly increased in subjects exposed to benzene overall, compared with levels in the control subjects (P = 0.0055 and P = 0.0034, respectively). Levels of monosomy 7 and 8 were significantly increased in subjects exposed to < 10 p.p.m. (20%, P = 0.0419 and 28%, P = 0.0056, respectively) and >= 10 p.p.m. (48%, P = 0.0045 and 32%, 0.0354) benzene, compared with controls, and significant exposure-response trends were detected (P-trend = 0.0033 and 0.0057). These data show that monosomies 7 and 8 are produced in a dose-dependent manner in the blood progenitor cells of workers exposed to benzene, and may be mechanistically relevant biomarkers of early effect for benzene and other leukemogens. Leukemia (2012) 26, 2494-2498; doi:10.1038/leu.2012.143 C1 [Zhang, L.; Ji, Z.; Guo, W.; Hubbard, A. E.; McHale, C. M.; Rappaport, S. M.; Smith, M. T.] Univ Calif Berkeley, Div Environm Hlth Sci, Sch Publ Hlth, Berkeley, CA 94720 USA. [Lan, Q.; Shen, M.; Linet, M. S.; Rothman, N.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Li, G.; Yin, S.] Chinese Ctr Dis Control & Prevent, Inst Occupat Med, Beijing, Peoples R China. [Vermeulen, R.] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Hayes, R. B.] NYU, Dept Environm Med, Div Epidemiol, Sch Med, New York, NY 10016 USA. RP Smith, MT (reprint author), Univ Calif Berkeley, Div Environm Hlth Sci, Sch Publ Hlth, 237 Hildebrand Hall, Berkeley, CA 94720 USA. EM martynts@berkeley.edu; rothmann@mail.nih.gov RI Vermeulen, Roel/F-8037-2011; OI Vermeulen, Roel/0000-0003-4082-8163; Hayes, Richard/0000-0002-0918-661X FU American Petroleum Institute; NIH [RO1ES06721, P42ES04705, P30ES01896, P42ES05948, P30ES10126, N01-CO-12400]; SAIC-Frederick, Inc. FX MTS and SMR have received consulting and expert testimony fees from law firms representing both plaintiffs and defendants in cases involving exposure to benzene. GL has received funds from the American Petroleum Institute for consulting on benzene-related health research. The remaining authors declare no conflict of interest.; We thank the participants for taking part in this study. This study was supported by NIH grants RO1ES06721, P42ES04705 and P30ES01896 (MTS), P42ES05948 and P30ES10126 (SMR), and NIH contract N01-CO-12400 with SAIC-Frederick, Inc. NR 31 TC 12 Z9 12 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 EI 1476-5551 J9 LEUKEMIA JI Leukemia PD DEC PY 2012 VL 26 IS 12 BP 2494 EP 2498 DI 10.1038/leu.2012.143 PG 5 WC Oncology; Hematology SC Oncology; Hematology GA 052GP UT WOS:000312186000007 PM 22643707 ER PT J AU Miller, AC Hassan, R AF Miller, Andrew C. Hassan, Raffit TI Clinical and Pathological Features Are Still the Best Determinants of Prognosis in Mesothelioma SO ONCOLOGY-NEW YORK LA English DT Editorial Material ID MALIGNANT PLEURAL MESOTHELIOMA; SURVIVAL; EXPERIENCE; EXPRESSION; DIAGNOSIS; SUBTYPE; BIOPSY C1 [Miller, Andrew C.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Hassan, Raffit] NCI, Lab Mol Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Miller, AC (reprint author), NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. NR 15 TC 1 Z9 1 U1 0 U2 2 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 DEC PY 2012 VL 26 IS 12 BP 1176 EP 1180 PG 3 WC Oncology SC Oncology GA 058AA UT WOS:000312605000009 PM 23413598 ER PT J AU Haydon, AA Herring, AH Halpern, CT AF Haydon, Abigail A. Herring, Amy H. Halpern, Carolyn Tucker TI Associations Between Patterns of Emerging Sexual Behavior and Young Adult Reproductive Health SO PERSPECTIVES ON SEXUAL AND REPRODUCTIVE HEALTH LA English DT Article ID HETEROSEXUAL ANAL INTERCOURSE; AMERICAN FEMALE ADOLESCENTS; TRANSMITTED-DISEASES; UNITED-STATES; ORAL SEX; ROMANTIC RELATIONSHIPS; RISK; PREVALENCE; HIV; AGE AB CONTEXT: Identifying young adult outcomes associated with adolescent sexual behavior, including patterns of first oral, vaginal and anal sex, is critical to promoting healthy sexual development. METHODS: Associations between patterns of emerging sexual behavior, defined using latent class analysis, and young adult sexual and reproductive health were examined among 9,441 respondents to Waves 1 (1994-1995), 3 (2001-2002) and 4 (2008) of the National Longitudinal Study of Adolescent Health. Logistic regression analyses examined associations between class membership and young adult outcomes, and tested for interactions by race and ethnicity. RESULTS: Compared with respondents who initiated vaginal sex first and reported other sexual behaviors within two years, those who initiated oral and vaginal sex during the same year had similar odds of having had an STD diagnosis ever or in the last year, of having had concurrent sexual partnerships in the last year and of having exchanged sex for money. However, respondents who postponed sexual activity had reduced odds of each outcome (odds ratios, 0.2-0.4); those who initiated vaginal sex and reported only one type of sexual behavior had reduced odds of reporting STD diagnoses and concurrent partnerships (0.4-0.6). Respondents who reported early initiation of sexual activity combined with anal sex experience during adolescence had elevated odds of having had concurrent partnerships (1.6). The data suggest racial and ethnic disparities even when patterns of emerging sexual behavior were the same. CONCLUSIONS: Patterns of early sexual behavior considered high-risk may not predict poor sexual and reproductive health in young adulthood. Perspectives on Sexual and Reproductive Health, 2012, 44(4): 218-227, doi: 10.1363/4421812 C1 [Haydon, Abigail A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Halpern, Carolyn Tucker] Univ N Carolina, Dept Maternal & Child Hlth, Carolina Populat Ctr, Chapel Hill, NC USA. [Herring, Amy H.] Univ N Carolina, Dept Biostat, Carolina Populat Ctr, Chapel Hill, NC USA. RP Haydon, AA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. EM aahaydon@gmail.com FU NICHD NIH HHS [P01 HD031921, 5 R24 HD050924, P01-HD31921, R01 HD057046, R01HD57046, R24 HD050924, T32 HD007168] NR 54 TC 13 Z9 13 U1 2 U2 29 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1538-6341 J9 PERSPECT SEX REPRO H JI Perspect. Sex Reprod. Health PD DEC PY 2012 VL 44 IS 4 BP 218 EP 227 DI 10.1363/4421812 PG 10 WC Demography; Family Studies SC Demography; Family Studies GA 056IH UT WOS:000312481100001 PM 23231329 ER PT J AU Tercyak, KP O'Neill, SC Roter, DL McBride, CM AF Tercyak, Kenneth P. O'Neill, Suzanne C. Roter, Debra L. McBride, Colleen M. TI Bridging the Communication Divide: A Role for Health Psychology in the Genomic Era SO PROFESSIONAL PSYCHOLOGY-RESEARCH AND PRACTICE LA English DT Article DE genetics; genomics; communication; health; behavior ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; SOCIAL-SCIENCES RESEARCH; RANDOMIZED-TRIAL; PHYSICIAN COMMUNICATION; POPULATION HEALTH; BRCA2 MUTATIONS; DECISION AID; CANCER; RISK; FUTURE AB The application of genomics to population health has the potential to revolutionize the practice of medicine. Indeed, discoveries into the genomic basis of cancer and other common chronic diseases have resulted in new and improved predictive tests for identifying individuals at increased risk for these conditions and long before their onset occurs. When used properly, information gained from predictive genomic tests can be combined with other leading indicators (e.g., environmental and behavioral risk factors) to inform medical management decisions, preventive health practices, and risk-reducing strategies. However, genomics remains an emerging science and the translation of genomic discoveries into improved population health management remains elusive. There are divides in the translational science continuum at several junctures, and many of these divides could be narrowed or closed with additional data. For example, we know relatively little about how to effectively communicate with the public about the complex interplay among genomics, behavior, and health. Moreover, there is a need to develop better methods of counseling and educating the public in light of newly emerging knowledge about the genomic basis of health and disease. We assert that the discipline of psychology, and health psychology in particular, is well-poised to continue to make significant contributions to this growing area of science and practice. Through a focus on health-related social and behavioral research, psychology can lead the way in overcoming divides in communication, understanding, and action about genomics for the betterment of both individual and public health practices. C1 [Tercyak, Kenneth P.] Georgetown Univ, Med Ctr, Dept Oncol, Div Hlth Outcomes & Hlth Behav,Sch Med, Washington, DC 20007 USA. [Roter, Debra L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, Baltimore, MD USA. [McBride, Colleen M.] NHGRI, Bethesda, MD 20892 USA. RP Tercyak, KP (reprint author), Georgetown Univ, Med Ctr, Dept Oncol, Div Hlth Outcomes & Hlth Behav,Sch Med, 3300 Whitehaven St,NW,Suite 4100, Washington, DC 20007 USA. EM tercyakk@georgetown.edu RI Roter, Debra/N-8830-2014 FU NHGRI NIH HHS [K18 HG006754] NR 75 TC 4 Z9 4 U1 7 U2 15 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 DEC PY 2012 VL 43 IS 6 BP 568 EP 575 DI 10.1037/a0028971 PG 8 WC Psychology, Multidisciplinary SC Psychology GA 055NX UT WOS:000312424800005 PM 23503693 ER PT J AU Fischbeck, KH AF Fischbeck, Kenneth H. TI Developing treatment for spinal and bulbar muscular atrophy SO PROGRESS IN NEUROBIOLOGY LA English DT Review DE Spinal and bulbar muscular atrophy; Kennedy's disease; Motor neuron disease; Androgen receptor; Polyglutamine disease; IGF-1 ID TRANSGENIC MOUSE MODEL; POLYGLUTAMINE ANDROGEN RECEPTOR; EXPANDED POLYGLUTAMINE; PHENOTYPIC-EXPRESSION; TOXICITY; DISEASE; NEURODEGENERATION; LEUPRORELIN; DROSOPHILA; AUTOPHAGY AB Spinal and bulbar muscular atrophy is unique among the polyglutamine diseases in that the toxicity of the mutant protein, the androgen receptor, is ligand-dependent. In cell culture and animal models the mutant androgen receptor causes protein aggregation and alterations in transcriptional regulation, axonal transport, and mitochondrial function. Various therapeutic approaches have shown efficacy in mouse models, including androgen reduction and agents that alter the processing and degradation of the mutant androgen receptor protein, such as HSP90 inhibitors, IGF-1, and ASC-J9. Clinical trials of androgen-reducing agents have shown indications of efficacy but not proof of clinically meaningful benefit to date. This trial experience has set the stage for future clinical studies of other agents that have been found to be beneficial in transgenic animal models. Published by Elsevier Ltd. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Fischbeck, KH (reprint author), NINDS, Neurogenet Branch, NIH, 35-2A1000,35 Convent Dr, Bethesda, MD 20892 USA. EM kf@ninds.nih.gov FU National Institute of Neurological Disorders and Stroke, National Institutes of Health FX Supported in part by intramural research funds from the National Institute of Neurological Disorders and Stroke, National Institutes of Health. NR 34 TC 9 Z9 9 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD DEC PY 2012 VL 99 IS 3 SI SI BP 257 EP 261 DI 10.1016/j.pneurobio.2012.05.012 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 052BJ UT WOS:000312172400006 PM 22668795 ER PT J AU Davis, VL Newbold, RR Couse, JF Rea, SL Gallagher, KM Hamilton, KJ Goulding, EH Jefferson, W Eddy, EM Bullock, BC Korach, KS AF Davis, Vicki L. Newbold, Retha R. Couse, John F. Rea, Sheri L. Gallagher, Katie M. Hamilton, Katherine J. Goulding, Eugenia H. Jefferson, Wendy Eddy, E. M. Bullock, Bill C. Korach, Kenneth S. TI Expression of a dominant negative estrogen receptor alpha variant in transgenic mice accelerates uterine cancer induced by the potent estrogen diethylstilbestrol SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE Diethylstilbestrol; Dominant negative receptor; ER alpha variants; ER Delta 3; Lactoferrin; Non-classical ER signaling; Progesterone receptor; Uterine cancer ID HUMAN PROGESTERONE-RECEPTOR; MESSENGER-RIBONUCLEIC-ACID; EPIDERMAL-GROWTH-FACTOR; BREAST-CANCER; WILD-TYPE; ENDOMETRIAL CANCER; ER-ALPHA; HORMONAL CARCINOGENESIS; ACTIVATOR PROTEIN-1; TISSUE DISTRIBUTION AB ER Delta 3 transgenic mice expressing a dominant negative estrogen receptor alpha (ER alpha) variant lacking the second zinc finger in the DNA binding domain were developed to examine its potential to inhibit estrogen action in vivo. To investigate if ER Delta 3 expression influences uterine carcinogenesis, ER Delta 3 transgenic mice were exposed to diethylstilbestrol (DES) on post-natal days 1-5. Neonatal DES treatment induced uterine adenocarcinomas in 81% of 8-month-old ER Delta 3 mice compared to 49% of wild-type females (p <0.016). ER Delta 3 did not inhibit the expression of the estrogen-responsive progesterone receptor and lactoferrin genes in the presence of ER alpha or modify their expression in ER alpha knockout (alpha ERKO) mice. Higher circulating 17 beta-estradiol levels and non-classical signaling by ER Delta 3 may be related to the earlier incidence of uterine cancer. These findings indicate that expression of this ER alpha variant can influence determining events in uterine cancer development and its natural occurrence in the human uterus would unlikely be protective. Published by Elsevier Inc. C1 [Davis, Vicki L.; Couse, John F.; Hamilton, Katherine J.; Korach, Kenneth S.] NIEHS, Receptor Biol Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Davis, Vicki L.; Rea, Sheri L.; Gallagher, Katie M.] Duquesne Univ, Grad Sch Pharmaceut Sci, Pittsburgh, PA 15282 USA. [Newbold, Retha R.; Jefferson, Wendy] NIEHS, Dev Endocrinol & Pharmacol Sect, Reprod Toxicol Grp, Lab Toxicol,Environm Toxicol Program,NIH, Res Triangle Pk, NC 27709 USA. [Goulding, Eugenia H.; Eddy, E. M.] NIEHS, Gamete Biol Grp, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. [Bullock, Bill C.] Wake Forest Univ Sch Med, Comparat Med Sect, Dept Pathol, Winston Salem, NC 27157 USA. RP Davis, VL (reprint author), Clarion Univ Pennsylvania, Ctr Appl Res & Intellectual Property Dev, 840 Wood St, Clarion, PA 16214 USA. EM dr.vicki.davis@gmail.com OI Korach, Kenneth/0000-0002-7765-418X FU Division of Intramural Research of the NIEHS/NIH [Z01ES70065] FX We would like to thank William Tally and Mariana Molina for their skillful assistance with the mice and in processing the tissues for the histopathology. Support for the tumor study was provided through Z01ES70065 to KSK by the Division of Intramural Research of the NIEHS/NIH. NR 69 TC 3 Z9 3 U1 0 U2 2 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 DEC PY 2012 VL 34 IS 4 BP 512 EP 521 DI 10.1016/j.reprotox.2012.08.005 PG 10 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 055OZ UT WOS:000312427600004 PM 22989549 ER PT J AU Kerrin, A Weldon, S Chang, A Craig, T Simpson, AJ O'Kane, C McAuley, DF Taggart, C AF Kerrin, A. Weldon, S. Chang, A. Craig, T. Simpson, A. J. O'Kane, C. McAuley, D. F. Taggart, C. TI PROTEOLYTIC CLEAVAGE OF ELAFIN BY 20S PROTEASOME MAY CONTRIBUTE TO INFLAMMATION IN ACUTE LUNG INJURY SO THORAX LA English DT Meeting Abstract CT Winter Meeting of the British-Thoracic-Society 2012 CY DEC 05-07, 2012 CL London, ENGLAND SP British Thorac Soc C1 [Kerrin, A.; Weldon, S.; Craig, T.; O'Kane, C.; McAuley, D. F.; Taggart, C.] Queens Univ Belfast, Belfast, Antrim, North Ireland. [Chang, A.] NIH, Bethesda, MD 20892 USA. [Simpson, A. J.] Univ Newcastle, Newcastle Upon Tyne, Tyne & Wear, England. RI Taggart, Clifford/G-4492-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0040-6376 J9 THORAX JI Thorax PD DEC PY 2012 VL 67 SU 2 BP A38 EP A38 DI 10.1136/thoraxjnl-2012-202678.082 PG 1 WC Respiratory System SC Respiratory System GA 056PK UT WOS:000312503000083 ER EF