FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Parikh, H Lyssenko, V Groop, LC AF Parikh, Hemang Lyssenko, Valeriya Groop, Leif C. TI Prioritizing genes for follow-up from genome wide association studies using information on gene expression in tissues relevant for type 2 diabetes mellitus SO BMC MEDICAL GENOMICS LA English DT Article ID PROBE LEVEL DATA; INSULIN SENSITIVITY; SUSCEPTIBILITY LOCI; RISK LOCI; DEFINITIONS; VARIANTS; METAANALYSIS; REPLICATION; SECRETION; SUMMARIES AB Background: Genome-wide association studies (GWAS) have emerged as a powerful approach for identifying susceptibility loci associated with polygenetic diseases such as type 2 diabetes mellitus (T2DM). However, it is still a daunting task to prioritize single nucleotide polymorphisms (SNPs) from GWAS for further replication in different population. Several recent studies have shown that genetic variation often affects gene-expression at proximal (cis) as well as distal (trans) genomic locations by different mechanisms such as altering rate of transcription or splicing or transcript stability. Methods: To prioritize SNPs from GWAS, we combined results from two GWAS related to T2DM, the Diabetes Genetics Initiative (DGI) and the Wellcome Trust Case Control Consortium (WTCCC), with genome-wide expression data from pancreas, adipose tissue, liver and skeletal muscle of individuals with or without T2DM or animal models thereof to identify T2DM susceptibility loci. Results: We identified 1,170 SNPs associated with T2DM with P < 0.05 in both GWAS and 243 genes that were located in the vicinity of these SNPs. Out of these 243 genes, we identified 115 differentially expressed in publicly available gene expression profiling data. Notably five of them, IGF2BP2, KCNJ11, NOTCH2, TCF7L2 and TSPAN8, have subsequently been shown to be associated with T2DM in different populations. To provide further validation of our approach, we reversed the approach and started with 26 known SNPs associated with T2DM and related traits. We could show that 12 (57%) (HHEX, HNF1B, IGF2BP2, IRS1, KCNJ11, KCNQ1, NOTCH2, PPARG, TCF7L2, THADA, TSPAN8 and WFS1) out of 21 genes located in vicinity of these SNPs were showing aberrant expression in T2DM from the gene expression profiling studies. Conclusions: Utilizing of gene expression profiling data from different tissues of individuals with or without T2DM or animal models thereof is a powerful tool for prioritizing SNPs from WGAS for further replication studies. C1 [Parikh, Hemang; Lyssenko, Valeriya; Groop, Leif C.] Lund Univ, Dept Clin Sci Diabet & Endocrinol, Malmo Univ Hosp, Malmo, Sweden. [Parikh, Hemang] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Groop, Leif C.] Univ Helsinki, Dept Med, Helsinki, Finland. RP Parikh, H (reprint author), Lund Univ, Dept Clin Sci Diabet & Endocrinol, Malmo Univ Hosp, Malmo, Sweden. EM parikhhm@mail.nih.gov; Valeri.Lyssenko@med.lu.se; Leif.Groop@med.lu.se FU Swedish Knowledge Foundation at the Karolinska Institute; The Diabetes Programme at Lund University; Diabetesforeningen in Malmo; The Medical Faculty at Lund University; Swedish Research Council; EC; Knut and Alice Wallenberg Foundation FX This work was supported by grants from the Swedish Knowledge Foundation through the Industrial PhD program in Medical Bioinformatics at the Center for Medical Innovations (CMI) at the Karolinska Institute (HP), The Diabetes Programme at Lund University (HP), Diabetesforeningen in Malmo (HP), The Medical Faculty at Lund University (HP), a Linne grant from the Swedish Research Council (LG), an EC grant (EXGENESIS) (LG) and a grant from the Knut and Alice Wallenberg Foundation (LG). NR 36 TC 16 Z9 18 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD DEC 31 PY 2009 VL 2 AR 72 DI 10.1186/1755-8794-2-72 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 552OM UT WOS:000274302300001 PM 20043853 ER PT J AU Williams, AJK Somerville, M Rokni, S Bonifacio, E Yu, LP Eisenbarth, G Akolkar, B Steffes, M Bingley, PJ AF Williams, Alistair J. K. Somerville, Michelle Rokni, Saba Bonifacio, Ezio Yu, Liping Eisenbarth, George Akolkar, Beena Steffes, Michael Bingley, Polly J. TI Azide and Tween-20 reduce binding to autoantibody epitopes of islet antigen-2; implications for assay performance and reproducibility SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE Islet autoantibody assay; Epitope; Protein tyrosine phosphatase; Tween-20; Azide; Type 1 diabetes ID RELATIVES; INSULIN; RISK; IA-2 AB Autoantibodies to islet antigen 2 (IA-2A) are important markers for predicting diabetes in children and young adults. Harmonization of IA-2A assay measurement is essential if results from different laboratories are to be compared. We investigated whether sodium azide, a bacteriostatic agent added to some assays, could affect IA-2A binding and thereby contribute to differences in IA-2A measurement between laboratories. Addition of 0.1% azide to assay buffer was found to reduce median IA-2A binding of 18 selected sera from IA-2A positive patients with type 1 diabetes and their relatives by 41% (range, 78 to -33%, p<0.001). The effect on binding was epitope specific; median IA-2A binding by 14 sera with antibodies to the protein tyrosine phosphatase region of IA-2 was reduced by 48% (range, 11 to 78%, p<0.001), while binding by 4 sera with antibodies specific to only the juxtamembrame region of IA-2 showed no change (median increase 16% range 6 to 33%, p=0.125). When the Tween-20 concentration was reduced from 1% to 0.15% the median reduction in IA-2A binding with azide by the 18 sera was only 10% (range, -12 to 41%, p<0.001). Tween-20 also exerted an independent effect, since median IA-2A binding increased by 23% (range 3% to 86%, p<0.001) when Tween-20 concentration was reduced from 1% to 0.15% in the absence of azide. We conclude that common assay reagents such as azide and Tween-20 can strongly influence IA-2A binding in an epitope-related manner, and their use may explain some of the differences between laboratories in IA-2A measurement. (C) 2009 Elsevier B.V. All rights reserved. C1 [Williams, Alistair J. K.] Southmead Hosp, Clin Sci N Bristol, Bristol BS10 5NB, Avon, England. [Bonifacio, Ezio] DFG Ctr Regenerat Therapies, Dresden, Germany. [Yu, Liping; Eisenbarth, George] Univ Colorado Hlth Sci, Barbara Davis Ctr Childhood Diabet, Denver, CO USA. [Akolkar, Beena] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Bethesda, MD USA. [Steffes, Michael] Univ Minnesota, Sch Med, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA. RP Williams, AJK (reprint author), Southmead Hosp, Clin Sci N Bristol, Bristol BS10 5NB, Avon, England. EM AJ.K.Williams@bristol.ac.uk RI Williams, Alistair/E-7647-2013; Bonifacio, Ezio/E-7700-2010; OI Bonifacio, Ezio/0000-0002-8704-4713; Williams, Alistair/0000-0002-3615-3899 FU NIDDK NIH HHS [U01 DK063790, U01 DK063790-02, U01 DK063790-03, U01 DK063790-04, U01 DK063790-05, U01 DK063790-01] NR 10 TC 4 Z9 4 U1 1 U2 6 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 31 PY 2009 VL 351 IS 1-2 BP 75 EP 79 DI 10.1016/j.jim.2009.10.004 PG 5 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 533VI UT WOS:000272853100011 PM 19837075 ER PT J AU Kim, YC Furchtgott, LA Hummer, G AF Kim, Young C. Furchtgott, Leon A. Hummer, Gerhard TI Biological Proton Pumping in an Oscillating Electric Field SO PHYSICAL REVIEW LETTERS LA English DT Article ID CYTOCHROME-C-OXIDASE; FREE-ENERGY TRANSDUCTION; STOCHASTIC RESONANCE; MOLECULAR MOTORS; NOISE; FLUCTUATIONS; ACTIVATION; DESCRIBES; DYNAMICS; SYSTEM AB Time-dependent external perturbations provide powerful probes of the function of molecular machines. Here we study biological proton pumping in an oscillating electric field. The protein cytochrome c oxidase is the main energy transducer in aerobic life, converting chemical energy into an electric potential by pumping protons across a membrane. With the help of master-equation descriptions that recover the key thermodynamic and kinetic properties of this biological "fuel cell," we show that the proton pumping efficiency and the electronic currents in steady state depend significantly on the frequency and amplitude of the applied field, allowing us to distinguish between different microscopic mechanisms of the machine. A spectral analysis reveals dominant reaction steps consistent with an electron-gated pumping mechanism. C1 [Kim, Young C.; Furchtgott, Leon A.; Hummer, Gerhard] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM Gerhard.Hummer@nih.gov RI Hummer, Gerhard/A-2546-2013; OI Hummer, Gerhard/0000-0001-7768-746X; Furchtgott, Leon/0000-0002-4258-0950 FU NIH, NIDDK FX We thank Professor Marten Wikstrom for many stimulating and helpful discussions. This work was supported by the Intramural Research Program of the NIH, NIDDK. NR 29 TC 5 Z9 5 U1 1 U2 8 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD DEC 31 PY 2009 VL 103 IS 26 AR 268102 DI 10.1103/PhysRevLett.103.268102 PG 4 WC Physics, Multidisciplinary SC Physics GA 539CY UT WOS:000273232200053 PM 20366348 ER PT J AU Nagao, K Zhu, JJ Heneghan, MB Hanson, JC Morasso, MI Tessarollo, L Mackem, S Udey, MC AF Nagao, Keisuke Zhu, Jianjian Heneghan, Mallorie B. Hanson, Jeffrey C. Morasso, Maria I. Tessarollo, Lino Mackem, Susan Udey, Mark C. TI Abnormal Placental Development and Early Embryonic Lethality in EpCAM-Null Mice SO PLOS ONE LA English DT Article ID CELL ADHESION MOLECULE; CD44 VARIANT ISOFORMS; EP-CAM; E-CADHERIN; HEPATOCELLULAR-CARCINOMA; EPITHELIAL GLYCOPROTEIN; INSERTIONAL MUTATIONS; DENDRITIC CELLS; MURINE HOMOLOG; STEM-CELLS AB Background: EpCAM (CD326) is encoded by the tacstd1 gene and expressed by a variety of normal and malignant epithelial cells and some leukocytes. Results of previous in vitro experiments suggested that EpCAM is an intercellular adhesion molecule. EpCAM has been extensively studied as a potential tumor marker and immunotherapy target, and more recent studies suggest that EpCAM expression may be characteristic of cancer stem cells. Methodology/Principal Findings: To gain insights into EpCAM function in vivo, we generated EpCAM -/- mice utilizing an embryonic stem cell line with a tacstd1 allele that had been disrupted. Gene trapping resulted in a protein comprised of the N-terminus of EpCAM encoded by 2 exons of the tacstd1 gene fused in frame to beta geo. EpCAM +/- mice were viable and fertile and exhibited no obvious abnormalities. Examination of EpCAM +/- embryos revealed that bgeo was expressed in several epithelial structures including developing ears (otocysts), eyes, branchial arches, gut, apical ectodermal ridges, lungs, pancreas, hair follicles and others. All EpCAM -/- mice died in utero by E12.5, and were small, developmentally delayed, and displayed prominent placental abnormalities. In developing placentas, EpCAM was expressed throughout the labyrinthine layer and by spongiotrophoblasts as well. Placentas of EpCAM -/- embryos were compact, with thin labyrinthine layers lacking prominent vascularity. Parietal trophoblast giant cells were also dramatically reduced in EpCAM -/- placentas. Conclusion: EpCAM was required for differentiation or survival of parietal trophoblast giant cells, normal development of the placental labyrinth and establishment of a competent maternal-fetal circulation. The findings in EpCAM-reporter mice suggest involvement of this molecule in development of vital organs including the gut, kidneys, pancreas, lungs, eyes, and limbs. C1 [Nagao, Keisuke; Heneghan, Mallorie B.; Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Nagao, Keisuke; Heneghan, Mallorie B.; Udey, Mark C.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Zhu, Jianjian; Hanson, Jeffrey C.; Mackem, Susan] NCI, Pathol Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Zhu, Jianjian; Hanson, Jeffrey C.; Mackem, Susan] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Morasso, Maria I.] NIAMSD, Dev Skin Biol Unit, NIH, Bethesda, MD 20892 USA. [Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Tessarollo, Lino] NCI, Mouse Canc Genet Program, Ctr Canc Res, NIH, Frederick, MD 21701 USA. [Zhu, Jianjian; Mackem, Susan] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zhu, Jianjian; Mackem, Susan] NCI, Canc & Dev Biol Lab, Ctr Canc Res, NIH, Frederick, MD 21701 USA. RP Nagao, K (reprint author), Keio Univ, Sch Med, Dept Dermatol, Tokyo, Japan. EM udeym@mail.nih.gov RI Nagao, Keisuke/J-5116-2013 OI Nagao, Keisuke/0000-0002-7005-3138 FU NIH; Center for Cancer Research of the NCI; NIAMS FX These studies were supported the Intramural Program of the NIH, specifically the Center for Cancer Research of the NCI and the Intramural Program of NIAMS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 42 TC 24 Z9 24 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 31 PY 2009 VL 4 IS 12 AR e8543 DI 10.1371/journal.pone.0008543 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 538JK UT WOS:000273180200020 PM 20046825 ER PT J AU Yang, JH Pospisil, R Ray, S Milton, J Mage, RG AF Yang, Jiahui Pospisil, Richard Ray, Satyajit Milton, Jacqueline Mage, Rose G. TI Investigations of a Rabbit (Oryctolagus cuniculus) Model of Systemic Lupus Erythematosus (SLE), BAFF and Its Receptors SO PLOS ONE LA English DT Article ID LYMPHOCYTE STIMULATOR BLYS; ANTI-DNA ANTIBODIES; B-CELL; EXPRESSION; TACI; AUTOIMMUNITY; SURVIVAL; DISEASE; TISSUES; CD5 AB B-cell activation factor belonging to the tumor necrosis factor family (BAFF) is a major contributor to survival of B lymphocytes during development and maturation. A relationship between circulating BAFF levels and disease activity has been reported in patients with the autoimmune disease Systemic Lupus Erythematosus (SLE). Clinical trials targeting BAFF or its receptors are currently in progress. In order to further characterize a rabbit (Oryctolagus cuniculus) model of SLE, we investigated the expression of BAFF and its receptors in non-inbred, pedigreed rabbits derived from breeding and selection based on autoantibody responses. We immunized rabbits related to previous groups that developed autoantibodies and inflammatory responses after immunizations with peptides synthesized on multiple antigen-branched polylysine backbones. Blood and sera collected before immunization and after boosts were used for health monitoring, analyses of serum autoantibody responses by ELISA and immunofluorescence. Peripheral blood mononuclear cells (PBMC) were studied by flow cytometry and were the source of mRNA for quantitative PCR analyses. We hypothesized that BAFF mRNA expression and serum BAFF levels measured indirectly through BAFF receptor binding might increase in autoantibody-producing rabbits. Immunized rabbits developed elevated levels of leucocyte populations, anti-nuclear, anti-dsDNA and other autoantibodies. BR3 mRNA levels in total PBMC decreased and BAFF levels remained low and unchanged in most immunized rabbits. By flow cytometry, percentages of BAFF positive cells decreased. Percentages of transmembrane activator and CAML interactor (TACI) decreased in most rabbits from all the immunized groups. The rabbit is an important model for human autoimmune and infectious diseases, and a high quality draft rabbit genome assembly was recently completed. Human disease models developed in non-inbred pedigreed animals are better able to reflect the complexities of diseases such as SLE with familial patterns of inheritance. Although no consistent pattern of elevated expression of BAFF mRNA or protein was found in the rabbits studied, the data collected and reported here build upon previous data to refine understanding of a rabbit model of SLE. C1 [Yang, Jiahui; Pospisil, Richard; Ray, Satyajit; Milton, Jacqueline; Mage, Rose G.] NIAID, Immunol Lab, NIH, Baltimore, MD USA. RP Yang, JH (reprint author), NIAID, Immunol Lab, NIH, Baltimore, MD USA. EM rmage@niaid.nih.gov RI Pospisil, Richard/B-7467-2012 FU NIH; NIAID; Oak Ridge Associated Universities FX This research was supported by the intramural research program of the NIH, NIAID (http://www3.niaid.nih.gov/) and the Oak Ridge Associated Universities (http://www.orau.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 4 Z9 6 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 30 PY 2009 VL 4 IS 12 AR e8494 DI 10.1371/journal.pone.0008494 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 601NW UT WOS:000278068700009 PM 20041151 ER PT J AU Dean, C Elvevag, B Storms, G Diaz-Asper, C AF Dean, Claire Elvevag, Brita Storms, Gert Diaz-Asper, Catherine TI Perception of self and other in psychosis: A method for analyzing the structure of the phenomenology SO PSYCHIATRY RESEARCH LA English DT Article DE HICLAS; Clustering; Features ID DELUSIONS AB Although the phenomenology accompanying psychoses is fascinating, hitherto empirical examinations have been qualitative and thus limited in their clinical conclusions regarding the actual underlying cognitive mechanisms responsible for the formation and maintenance of the delusion. which is often distressing to the patient. We investigated the internal cognitive structure (i.e., connections) of some delusions pertaining to self and others in a patient with psychosis who was very fluent and thus able to provide a lucid account of his phenomenological experiences. To this end we employed a clustering method (HICLAS disjunctive model) in conjunction with standard neuropsychological tests. A well-fitting, but parsimonious solution revealed the absence of unique feature sets associated with certain persons, findings that provide a compelling case underlying the confusion in certain instances between real and delusional people. We illustrate the methodology in one patient and suggest that it is sensitive enough to explore the structure of delusions, which in conjunction with standard neuropsychological and clinical assessments promises to be useful in uncovering the mechanisms underlying delusions in psychosis. Published by Elsevier Ireland Ltd. C1 [Dean, Claire; Elvevag, Brita; Diaz-Asper, Catherine] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Storms, Gert] Univ Leuven, Dept Psychol, Louvain, Belgium. RP Elvevag, B (reprint author), NIMH, Clin Brain Disorders Branch, NIH, Bldg 10,Room 4 S235,MSC 1379, Bethesda, MD 20892 USA. EM brita@elvevaag.net FU Intramural Research Program of the National Institute of Mental Health FX The authors are grateful to the patient for allowing us to discuss these findings. This research was supported by the Intramural Research Program of the National Institute of Mental Health. NR 12 TC 0 Z9 0 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD DEC 30 PY 2009 VL 170 IS 2-3 BP 128 EP 131 DI 10.1016/j.psychres.2008.12.017 PG 4 WC Psychiatry SC Psychiatry GA 533WD UT WOS:000272855200007 PM 19900718 ER PT J AU Elia, J Arcos-Burgos, M Bolton, KL Ambrosini, PJ Berrettini, W Muenke, M AF Elia, Josephine Arcos-Burgos, Mauricio Bolton, Kelly L. Ambrosini, Paul J. Berrettini, Wade Muenke, Maximilian TI ADHD latent class clusters: DSM-IV subtypes and comorbidity SO PSYCHIATRY RESEARCH LA English DT Article DE Children; DSMAV; Oppositional defiant disorder ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT-HYPERACTIVITY-DISORDER; ADOLESCENT FEMALE TWINS; POPULATION-BASED SAMPLE; SCHOOL-AGE-CHILDREN; SYMPTOMS; CHILDHOOD; PREVALENCE; PSYCHOPATHOLOGY; STABILITY AB ADHD (Attention Deficit Hyperactivity Disorder) has a complex. heterogeneous phenotype only partially captured by Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. In this report, latent class analyses (LCA) are used to identify ADHD phenotypes using K-SADS-IVR (Schedule for Affective Disorders & Schizophrenia for School Age Children-IV-Revised) symptoms and symptom severity data from a clinical sample of 500 ADHD subjects, ages 6-18. participating in an ADHD genetic study. Results show that LCA identified six separate ADHD clusters, some corresponding to specific DSM-IV subtypes while others included several subtypes. DSM-IV comorbid anxiety and mood disorders were generally similar across all clusters, and subjects without comorbidity did not aggregate within any one cluster. Age and gender composition also varied. These results support findings from population-based LCA studies. The six clusters provide additional homogenous groups that can be used to define ADHD phenotypes in genetic association studies. The limited age ranges aggregating in the different clusters may prove to be a particular advantage in genetic studies where candidate gene expression may vary during developmental phases. DSM-IV comorbid mood and anxiety disorders also do not appear to increase cluster heterogeneity; however, longitudinal studies that cover period of risk are needed to support this finding. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Elia, Josephine] Childrens Hosp Philadelphia, Ctr Sci, Philadelphia, PA 19104 USA. [Elia, Josephine; Berrettini, Wade] Univ Penn, Philadelphia, PA 19104 USA. [Arcos-Burgos, Mauricio] Univ Miami, Miami, FL USA. [Bolton, Kelly L.; Muenke, Maximilian] NHGRI, NIH, Bethesda, MD 20892 USA. [Ambrosini, Paul J.] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. RP Elia, J (reprint author), Childrens Hosp Philadelphia, Ctr Sci, Suite 200,3440 Market St, Philadelphia, PA 19104 USA. EM elia@email.chop.edu FU NIMH [K23MH066275-01]; CTR [UL1-RR-024134]; NHGRI FX We want to thank all the families that have participated, the referring clinicians and Tamika Scott, research coordinator. This research is supported by NIMH (K23MH066275-01), CTR (UL1-RR-024134) and NHGRI. NR 42 TC 20 Z9 20 U1 0 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD DEC 30 PY 2009 VL 170 IS 2-3 BP 192 EP 198 DI 10.1016/j.psychres.2008.10.008 PG 7 WC Psychiatry SC Psychiatry GA 533WD UT WOS:000272855200017 PM 19900717 ER PT J AU Yang, SL Salmeron, BJ Ross, TJ Xi, ZX Stein, EA Yang, YH AF Yang, Shaolin Salmeron, Betty Jo Ross, Thomas J. Xi, Zheng-Xiong Stein, Elliot A. Yang, Yihong TI Lower glutamate levels in rostral anterior cingulate of chronic cocaine users - A H-1-MRS study using TE-averaged PRESS at 3 T with an optimized quantification strategy SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE Drug addiction; Neurotransmitter; Relaxation; J-coupling ID MAGNETIC-RESONANCE-SPECTROSCOPY; BRAIN IN-VIVO; RAT-BRAIN; ABSTINENT COCAINE; ADDICTION; DEPENDENCE; NMR; NEUROTRANSMISSION; METABOLITES; ALCOHOL AB Previous studies have shown significantly lower metabolism and functional activity in the anterior cingulate cortex (ACC) of human cocaine addicts. The present study examined whether this ACC hypoactivity is associated with altered glutamate (Glu), the primary excitatory neurotransmitter in the central nervous system (CNS), which has been recently implicated in drug addiction. Participants comprised 14 chronic cocaine addicts and 14 matched healthy volunteers who were examined using H-1 magnetic resonance spectroscopy at 3 T. A new quantification strategy for echo time (TE)-averaged point-resolved spectroscopy (PRESS) was applied to disentangle relaxation effects from J-evolution of coupled spin systems such as Glu. The concentrations of Glu as well as N-acetyl aspartate (NAA), total creatine (tCr), choline-containing compounds (tCho), and myo-inositol (ins) were estimated from both groups. Glu/tCr was significantly lower in chronic cocaine users compared to control subjects and was significantly correlated with years of cocaine use. Glu/tCr was also positively correlated with NAA/tCr. NAA/tCr significantly decreased with age but was not significantly different between the two groups. These findings suggest a metabolic/neurotransmitter dysregulation associated with cocaine addiction and support a possible therapeutic intervention strategy aimed at normalizing the Glu transmission and function in the treatment of cocaine addiction. Published by Elsevier Ireland Ltd. C1 [Yang, Shaolin; Salmeron, Betty Jo; Ross, Thomas J.; Stein, Elliot A.; Yang, Yihong] NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. [Xi, Zheng-Xiong] NIDA, Chem Biol Res Branch, NIH, Baltimore, MD 21224 USA. RP Yang, YH (reprint author), NIDA, Neuroimaging Res Branch, NIH, 251 Bayview Blvd,Suite 200,Room 07A709, Baltimore, MD 21224 USA. EM yihongyang@intra.nida.nih.gov RI Ross, Thomas/B-7469-2008; Salmeron, Betty Jo/M-1793-2016 OI Ross, Thomas/0000-0002-7745-3572; Salmeron, Betty Jo/0000-0003-1699-9333 FU National Institute on Drug Abuse (NIDA), National institutes of Health (NIH) FX The work was supported by the Intramural Research Program (IRP) of the National Institute on Drug Abuse (NIDA), National institutes of Health (NIH). NR 37 TC 28 Z9 29 U1 2 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD DEC 30 PY 2009 VL 174 IS 3 BP 171 EP 176 DI 10.1016/j.pscychresns.2009.05.004 PG 6 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 534OW UT WOS:000272908000002 PM 19906515 ER PT J AU Tsurupa, G Hantgan, RR Burton, RA Pechik, I Tjandra, N Medved, L AF Tsurupa, Galina Hantgan, Roy R. Burton, Robert A. Pechik, Igor Tjandra, Nico Medved, Leonid TI Structure, Stability, and Interaction of the Fibrin(ogen) alpha C-Domains SO BIOCHEMISTRY LA English DT Article ID NATIVE CHICKEN FIBRINOGEN; CRYSTAL-STRUCTURE; BOVINE FIBRINOGEN; ELECTRON-MICROSCOPY; CONFORMATION; FRAGMENTS; OLIGOMERIZATION; IDENTIFICATION; ORGANIZATION; RESOLUTION AB Our recent Study established the NMR Structure of the recombinant bA alpha 406-483 fragment corresponding to the NH(2)-terminal half of the bovine fibrinogen alpha C-domain and revealed that at Increasing concentrations this fragment forms oligomers (self-associates). The major goals Of the Study presented here were to determine the structure and self-association of the full-length human fibrinogen alpha C-domains. To accomplish these goals, we prepared a recombinant human fragment, hA alpha 425-503, homologous to bovine bA alpha 406-483, and demonstrated using NMR, CD, and size-exclusion chromatography that its overall fold and ability to form oligomers are similar to those of bA alpha 406-483. We also prepared recombinant hA alpha 392-610 and bA alpha 374-568 fragments corresponding to the full-length human and bovine alpha C-domains, respectively, and tested their structure, stability, and ability to self-associate. Size-exclusion chromatography revealed that both fragments form reversible oligomers in a concentration-dependent manner. Their oligomerization was confirmed in sedimentation equilibrium experiments, which also established the self-association affinities of these fragments and revealed that the addition of each monomer to assembling oligomers substantially increases the stabilizing free energy. In agreement, unfolding experiments monitored by CD established that self-association of both fragments results in a significant increase in their thermal stability. Analysis of CD spectra of both fragments revealed that alpha C self-association results in an increase in the level of regular structure, Implying that the COOH-terminal half of the alpha C-domain adopts an ordered conformation in alpha C-oligomers and that this domain contains two independently folded subdomains. Altogether, these data further clarify the Structure of the human and bovine alpha C-domains and the molecular mechanism of their self-association into alpha C-polymers in fibrin. C1 [Burton, Robert A.; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Tsurupa, Galina; Medved, Leonid] Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Baltimore, MD 21201 USA. [Tsurupa, Galina; Medved, Leonid] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Hantgan, Roy R.] Wake Forest Univ, Bowman Gray Sch Med, Dept Biochem, Winston Salem, NC 27157 USA. [Pechik, Igor] Univ Maryland, Inst Biotechnol, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, NIH, 50 Ctr Dr, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov; lmedved@som.umaryland.edu FU National Institutes of Health [HL-56051]; American Heart Association; Mid-Atlantic Affiliate [055527U]; National Heart, Lung, and Blood Institute FX This work was supported by National Institutes of Health Grant HL-56051 to L.M., by American Heart Association, Mid-Atlantic Affiliate, Grant-in-Aid 055527U to R.R.H., and by the Intramural Research Program of the National Heart, Lung, and Blood Institute to N.T. NR 37 TC 32 Z9 32 U1 0 U2 9 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 29 PY 2009 VL 48 IS 51 BP 12191 EP 12201 DI 10.1021/bi901640e PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 533UY UT WOS:000272852100014 PM 19928926 ER PT J AU Pickens, CL Adams-Deutsch, T Nair, SG Navarre, BM Heilig, M Shaham, Y AF Pickens, C. L. Adams-Deutsch, T. Nair, S. G. Navarre, B. M. Heilig, M. Shaham, Y. TI EFFECT OF PHARMACOLOGICAL MANIPULATIONS OF NEUROPEPTIDE Y AND CORTICOTROPIN-RELEASING FACTOR NEUROTRANSMISSION ON INCUBATION OF CONDITIONED FEAR SO NEUROSCIENCE LA English DT Article DE D-Phe CRF(12-41); fear conditioning; incubation; MTIP; neuropeptide Y; PTSD ID ELEVATED PLUS-MAZE; YY2 RECEPTOR ANTAGONIST; POTENTIATED STARTLE; EMOTIONAL RESPONSE; EXTINGUISHED FEAR; FEEDING-BEHAVIOR; INDUCED RELAPSE; PEPTIDE YY3-36; FACTOR CRF; BIBO 3304 AB We recently developed a procedure to study fear incubation in which rats given 100 tone-shock pairings over 10 days show low fear 2 days after conditioned fear training and high fear after 30 or 60 days. Here, we studied the role of the stress-related peptides, neuropeptide Y (NPY) and corticotropin-releasing factor (CRF), in fear incubation. We gave rats either 10 or 100 30-s tone-0.5-s footshock pairings over 1 day (short training) or 10 days (long training) and then assessed tone-cue-induced conditioned suppression of lever responding 2 days after short training or 2 days and 1 month after long training. Prior to testing, we injected NPY (5-10 mu g, i.c.v.), the NPY Y1 receptor antagonist BIBO3304 (20-40 mu g, i.c.v.), the NPY Y2 receptor antagonist BIIE0246 (2.5-5 mg/kg s.c.), the non-selective CRF receptor antagonist D-Phe CRF(12-41) (10 mu g, i.c.v.), or the CRF1 receptor antagonist MTIP (10-20 mg/kg s.c.). Conditioned suppression after long training was higher after 1 month than after 2 days (fear incubation); conditioned suppression was robustly expressed 2 days after short training (non-incubated fear). Both incubated and non-incubated fear responses were attenuated by NPY. In contrast, D-Phe CRF(12-41), MTIP, BIBO3304, or BIIE0246 had no effect on conditioned fear at the different time points. Results confirm previous work on the potent effect of exogenous NPY administration on conditioned fear, but the negative results with BIBO3304 and BIIE0246 question whether endogenous NPY contributes to incubated (or non-incubated) fear. Results also suggest that CRF receptors are not involved in cue-induced fear in the conditioned suppression procedure. Published by Elsevier Ltd on behalf of IBRO. C1 [Pickens, C. L.; Adams-Deutsch, T.; Nair, S. G.; Navarre, B. M.; Shaham, Y.] NIDA, Behav Neurosci Branch, IRP, NIH,Dept Hlth & Human Serv, Baltimore, MD 21218 USA. [Heilig, M.] NIAAA, Lab Clin & Translat Studies, Intramural Res Program, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH,Dept Hlth & Human Serv, 251 Bayview Blvd, Baltimore, MD 21218 USA. EM yshaham@intra.nida.nih.gov RI Pickens, Charles/E-8984-2010; shaham, yavin/G-1306-2014 FU NIDA; NIAAA, NIH FX Research was supported by the Intramural Research Programs of the NIDA and NIAAA, NIH. We thank Evan Goldart for technical assistance. NR 65 TC 16 Z9 16 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD DEC 29 PY 2009 VL 164 IS 4 BP 1398 EP 1406 DI 10.1016/j.neuroscience.2009.09.079 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 526WQ UT WOS:000272327000002 PM 19800945 ER PT J AU Hutchinson, MR Ramos, KM Loram, LC Wieseler, J Sholar, PW Kearney, JJ Lewis, MT Crysdale, NY Zhang, Y Harrison, JA Maier, SF Rice, KC Watkins, LR AF Hutchinson, M. R. Ramos, K. M. Loram, L. C. Wieseler, J. Sholar, P. W. Kearney, J. J. Lewis, M. T. Crysdale, N. Y. Zhang, Y. Harrison, J. A. Maier, S. F. Rice, K. C. Watkins, L. R. TI EVIDENCE FOR A ROLE OF HEAT SHOCK PROTEIN-90 IN TOLL LIKE RECEPTOR 4 MEDIATED PAIN ENHANCEMENT IN RATS SO NEUROSCIENCE LA English DT Article DE HEK293-TLR4; lipopolysaccharide; chronic constriction injury; morphine; mechanical allodynia; analgesia ID HIV-1 ENVELOPE GLYCOPROTEIN; PERIPHERAL-NERVE INJURY; SPINAL-CORD; BACTERIAL LIPOPOLYSACCHARIDE; MECHANICAL ALLODYNIA; NEUROPATHIC PAIN; PROINFLAMMATORY CYTOKINES; THERMAL HYPERALGESIA; DIMETHYL-SULFOXIDE; IMMUNE ACTIVATION AB Spinal cord microglial toll-like receptor 4 (TLR4) has been implicated in enhancing neuropathic pain and opposing morphine analgesia. The present study was initiated to explore TLR4-mediated pain modulation by intrathecal lipopolysaccharide, a classic TLR4 agonist. However, our initial study revealed that intrathecal lipopolysaccharide failed to induce low-threshold mechanical allodynia in naive rats, suggestive that TLR4 agonism may be insufficient to enhance pain. These studies explore the possibility that a second signal is required; namely, heat shock protein-90 (HSP90). This candidate was chosen for study given its known importance as a regulator of TLR4 signaling. A combination of in vitro TLR4 cell signaling and in vivo behavioral studies of pain modulation suggest that TLR4-enhancement of neuropathic pain and TLR4-suppression of morphine analgesia each likely require HSP90 as a cofactor for the effects observed. In vitro studies revealed that dimethyl sulfoxide (DMSO) enhances HSP90 release, suggestive that this may be a means by which DMSO enhances TLR4 signaling. While 2 and 100 mu g lipopolysaccharide intrathecally did not induce mechanical allodynia across the time course tested, co-administration of 1 mu g lipopolysaccharide with a drug that enhances HSP90-mediated TLR4 signaling now induced robust allodynia. In support of this allodynia being mediated via a TLR4/HSP90 pathway, it was prevented or reversed by intrathecal co-administration of a HSP90 inhibitor, a TLR4 inhibitor, a microglia/monocyte activation inhibitor (as monocyte-derived cells are the predominant cell type expressing TLR4), and interleukin-1 receptor antagonist (as this proinflammatory cytokine is a downstream consequence of TLR4 activation). Together, these results suggest for the first time that TLR4 activation is necessary but not sufficient to induce spinally mediated pain enhancement. Rather, the data suggest that TLR4-dependent pain phenomena may require contributions by multiple components of the TLR4 receptor complex. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Hutchinson, M. R.; Ramos, K. M.; Loram, L. C.; Wieseler, J.; Sholar, P. W.; Kearney, J. J.; Lewis, M. T.; Crysdale, N. Y.; Zhang, Y.; Harrison, J. A.; Maier, S. F.; Watkins, L. R.] Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. [Hutchinson, M. R.; Ramos, K. M.; Loram, L. C.; Wieseler, J.; Sholar, P. W.; Kearney, J. J.; Lewis, M. T.; Crysdale, N. Y.; Zhang, Y.; Harrison, J. A.; Maier, S. F.; Watkins, L. R.] Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA. [Hutchinson, M. R.] Univ Adelaide, Discipline Pharmacol, Sch Med Sci, Adelaide, SA, Australia. [Rice, K. C.] NIDA, Chem Biol Res Branch, Rockville, MD USA. [Rice, K. C.] NIAAA, NIH, Rockville, MD 20852 USA. RP Watkins, LR (reprint author), Univ Colorado, Dept Psychol, Campus Box 345, Boulder, CO 80309 USA. EM linda.watkins@colorado.edu RI Hutchinson, Mark/G-4147-2014 OI Hutchinson, Mark/0000-0003-2154-5950 FU American Australian Association Merck & Company Foundation Fellowship; National Health and Medical Research Council CJ Martin Fellowship [ID 465423]; NIH [DA015642, DA017670, DA024044, DE017782]; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX These studies were supported by an International Association for the Study of Pain International Collaborative grant, American Australian Association Merck & Company Foundation Fellowship, National Health and Medical Research Council CJ Martin Fellowship (ID 465423) and NIH Grants DA015642, DA01 7670, DA024044 and DE017782. A portion of this work was supported by the NIH Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. We thank Amgen for the gift of IL- I RA and its vehicle and A vigen for the gift of HEK-TLR4 cells NR 64 TC 29 Z9 31 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD DEC 29 PY 2009 VL 164 IS 4 BP 1821 EP 1832 DI 10.1016/j.neuroscience.2009.09.046 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 526WQ UT WOS:000272327000043 PM 19788917 ER PT J AU Baboolal, TG Sakamoto, T Forgacs, E White, HD Jackson, SM Takagi, Y Farrow, RE Molloy, JE Knight, PJ Sellers, JR Peckham, M AF Baboolal, Thomas G. Sakamoto, Takeshi Forgacs, Eva White, Howard D. Jackson, Scott M. Takagi, Yasuharu Farrow, Rachel E. Molloy, Justin E. Knight, Peter J. Sellers, James R. Peckham, Michelle TI The SAH domain extends the functional length of the myosin lever SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ATPase; electron microscopy; optical trap; single alpha helix ID MOLECULE MECHANICS; KINETIC MECHANISM; OPTICAL TWEEZERS; NECK LENGTH; HEAD; PROCESSIVITY; MOVEMENT; RABBIT; MODEL; MOTOR AB Stable, single alpha-helix (SAH) domains are widely distributed in the proteome, including in myosins, but their functions are unknown. To test whether SAH domains can act as levers, we replaced four of the six calmodulin-binding IQ motifs in the levers of mouse myosin 5a (Myo5) with the putative SAH domain of Dictyostelium myosin MyoM of similar length. The SAH domain was inserted between the IQ motifs and the coiled coil in a Myo5 HMM construct in which the levers were truncated from six to two IQ motifs (Myo5-2IQ). Electron microscopy of this chimera (Myo5 2IQ-SAH) showed the SAH domain was straight and 17 nm long as predicted, restoring the truncated lever to the length of wild-type (Myo5-6IQ). The powerstroke (of 21.5 nm) measured in the optical trap was slightly less than that for Myo5-6IQ but much greater than for Myo5-2IQ. Myo5-2IQ-SAH moved processively along actin at physiological ATP concentrations with similar stride and run lengths to Myo5-6IQ in in-vitro single molecule assays. In comparison, Myo5-2IQ is not processive under these conditions. Solution biochemical experiments indicated that the rear head did not mechanically gate the rate of ADP release from the lead head, unlike Myo5-6IQ. These data show that the SAH domain can form part of a functional lever in myosins, although its mechanical stiffness might be lower. More generally, we conclude that SAH domains can act as stiff structural extensions in aqueous solution and this structural role may be important in other proteins. C1 [Baboolal, Thomas G.; Jackson, Scott M.; Knight, Peter J.; Peckham, Michelle] Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England. [Baboolal, Thomas G.; Jackson, Scott M.; Knight, Peter J.; Peckham, Michelle] Univ Leeds, Inst Mol & Cellular Biol, Leeds LS2 9JT, W Yorkshire, England. [Sakamoto, Takeshi; Takagi, Yasuharu; Sellers, James R.] NHLBI, Lab Mol Physiol, Bethesda, MD 20892 USA. [Forgacs, Eva; White, Howard D.] Eastern Virginia Med Sch, Dept Physiol Sci, Norfolk, VA 23507 USA. [Farrow, Rachel E.; Molloy, Justin E.] Natl Inst Med Res, Div Phys Biochem, Med Res Council, London NW7 1AA, England. RP Peckham, M (reprint author), Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England. EM m.peckham@leeds.ac.uk RI Baboolal, Thomas/L-4590-2013 OI Baboolal, Thomas/0000-0003-4444-0318 FU Biotechnology and Biological Sciences Research Council [BB/C004906/1]; Underwood fund; Wellcome Trust [VS/07/LEE/A4]; National Institutes of Health [EB00209]; National Institutes of Health/National Institute on Deafness and Other Communication Disorders [5R03DC009335]; National Heart, Lung, and Blood Institute FX We thank Dr. Thierry Soldati (University of Geneva) for the MyoM cDNA used to generate the chimera, Dr. Martin Webb (National Institute for Medical Research) for supplying deac-aminoATP, and Dr. Stan Burgess (University of Leeds) for help with image analysis. This work was supported by Biotechnology and Biological Sciences Research Council BB/C004906/1 (to M.P. and P.J.K.), an Underwood fund grant (to M.P., P.J.K., and J.R.S.), a Wellcome Trust vacation studentship VS/07/LEE/A4 (to P.J.K. and S.M.J.), National Institutes of Health Grant EB00209 (to H.D.W.) and National Institutes of Health/National Institute on Deafness and Other Communication Disorders Grant 5R03DC009335 (to E.F.). J.R.S. was supported by intramural funds from National Heart, Lung, and Blood Institute. NR 30 TC 40 Z9 40 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 29 PY 2009 VL 106 IS 52 BP 22193 EP 22198 DI 10.1073/pnas.0909851106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 538IV UT WOS:000273178700030 PM 20018767 ER PT J AU Hoskins, JR Doyle, SM Wickner, S AF Hoskins, Joel R. Doyle, Shannon M. Wickner, Sue TI Coupling ATP utilization to protein remodeling by ClpB, a hexameric AAA plus protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DnaJ; DnaK; GrpE; protein disaggregation ID HEAT-SHOCK-PROTEIN; CHAPERONE CLPB; AGGREGATED PROTEINS; ESCHERICHIA-COLI; CENTRAL PORE; DNA-BINDING; HSP104; DISAGGREGATION; HYDROLYSIS; MECHANISM AB ClpB and Hsp104 are members of the AAA+ (ATPases associated with various cellular activities) family of proteins and are molecular machines involved in thermotolerance. They are hexameric proteins containing 12 ATP binding sites with two sites per protomer. ClpB and Hsp104 possess some innate protein remodeling activities; however, they require the collaboration of the DnaK/Hsp70 chaperone system to disaggregate and reactivate insoluble aggregated proteins. We investigated the mechanism by which ClpB couples ATP utilization to protein remodeling with and without the DnaK system. When wild-type ClpB, which is unable to remodel proteins alone in the presence of ATP, was mixed with a ClpB mutant that is unable to hydrolyze ATP, the heterohexamers surprisingly gained protein remodeling activity. Optimal protein remodeling by the heterohexamers in the absence of the DnaK system required approximately three active and three inactive protomers. In addition, the location of the active and inactive ATP binding sites in the hexamer was not important. The results suggest that in the absence of the DnaK system, ClpB acts by a probabilistic mechanism. However, when we measured protein disaggregation by ClpB heterohexamers in conjunction with the DnaK system, incorporation of a single inactive ClpB subunit blocked activity, supporting a sequential mechanism of ATP utilization. Taken together, the results suggest that the mechanism of ATP utilization by ClpB is adaptable and can vary depending on the specific substrate and the presence of the DnaK system. C1 [Hoskins, Joel R.; Doyle, Shannon M.; Wickner, Sue] NCI, Mol Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), NCI, Mol Biol Lab, Natl Inst Hlth, Bldg 37, Bethesda, MD 20892 USA. EM wickners@mail.nih.gov FU National Institutes of Health (NIH) National Cancer Institute Center for Cancer Research FX We thank Danielle Johnston, Jodi Camberg, Marika Miot, and Olivier Genest for critical reading of the manuscript and helpful discussions. We thank Michal Zolkiewski (Kansas State University) for the plasmid pET20b-K611T and BK Lee (National Cancer Institute) for generating mathematical models. This work was supported by the Intramural Research Program of the National Institutes of Health (NIH) National Cancer Institute Center for Cancer Research. NR 39 TC 29 Z9 29 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 29 PY 2009 VL 106 IS 52 BP 22233 EP 22238 DI 10.1073/pnas.0911937106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 538IV UT WOS:000273178700037 PM 19940245 ER PT J AU Tsai, SY Hayashi, T Harvey, BK Wang, Y Wu, WW Shen, RF Zhang, YQ Becker, KG Hoffer, BJ Su, TP AF Tsai, Shang-Yi Hayashi, Teruo Harvey, Brandon K. Wang, Yun Wu, Wells W. Shen, Rong-Fong Zhang, Yongqing Becker, Kevin G. Hoffer, Barry J. Su, Tsung-Ping TI Sigma-1 receptors regulate hippocampal dendritic spine formation via a free radical-sensitive mechanism involving Rac1.GTP pathway SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mitochondria; ROS; N-acetyl cyteine; learning and memory; caspase-3 ID N-ACETYL CYSTEINE; PERMEABILITY TRANSITION; ENDOPLASMIC-RETICULUM; STEROID-BINDING; APOPTOSIS; NEURONS; PLASTICITY; CALCIUM; DRUGS; MORPHOGENESIS AB Sigma-1 receptors (Sig-1Rs) are endoplasmic reticulum (ER)-resident proteins known to be involved in learning and memory. Dendritic spines in hippocampal neurons play important roles in neuroplasticity and learning and memory. This study tested the hypothesis that Sig-1Rs might regulate denritic spine formation in hippocampal neurons and examined potential mechanisms therein. In rat hippocampal primary neurons, the knockdown of Sig-1Rs by siRNAs causes a deficit in the formation of dendritic spines that is unrelated to ER Ca(2+) signaling or apoptosis, but correlates with the mitochondrial permeability transition and cytochrome c release, followed by caspase-3 activation, Tiam1 cleavage, and a reduction in Rac1.GTP. Sig-1R-knockdown neurons contain higher levels of free radicals when compared to control neurons. The activation of superoxide dismutase or the application of the hydroxyl-free radical scavenger N-acetyl cysteine (NAC) to the Sig-1R-knockdown neurons rescues dendritic spines and mitochondria from the deficits caused by Sig-1R siRNA. Further, the caspase-3-resistant TIAM1 construct C1199DN, a stable guanine exchange factor able to constitutively activate Rac1 in the form of Rac1.GTP, also reverses the siRNA-induced dendritic spine deficits. In addition, constitutively active Rac1.GTP reverses this deficit. These results implicate Sig-1Rs as endogenous regulators of hippopcampal dendritic spine formation and suggest a free radical-sensitive ER-mitochondrion-Rac1.GTP pathway in the regulation of dendritic spine formation in the hippocampus. C1 [Tsai, Shang-Yi; Hayashi, Teruo; Su, Tsung-Ping] NIDA, Cellular Pathobiol Sect, Cellular Neurobiol Res Branch, Baltimore, MD 21224 USA. [Harvey, Brandon K.; Wang, Yun] NIDA, Neural Protect & Regenerat Sect, Mol Neuropsychiat Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Wu, Wells W.; Shen, Rong-Fong] NIA, Prote & Analyt Biochem Unit, Biomed Res Ctr, NIH,US Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Zhang, Yongqing; Becker, Kevin G.] NIA, Gene Express & Genom Unit, Res Resources Branch, Intramural Res Program,Biomed Res Ctr,NIH,US Dept, Baltimore, MD 21224 USA. [Hoffer, Barry J.] NIDA, Cellular Neurophysiol Sect, Cellular Neurobiol Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. RP Su, TP (reprint author), NIDA, Cellular Pathobiol Sect, Cellular Neurobiol Res Branch, 333 Cassell Dr, Baltimore, MD 21224 USA. EM tsu@intra.nida.nih.gov RI Harvey, Brandon/A-5559-2010 FU National Institute on Drug Abuse; National Institute on Aging, National Institutes of Health, Department of Health and Human Services FX The kindness and generosity of Dr. Margaret Chou in supplying various plasmids of the TIAM1 mutants is greatly appreciated. We thank Mr. Doug Howard for his technical assistance with the AAV vectors. This study is supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Aging, National Institutes of Health, Department of Health and Human Services. NR 46 TC 59 Z9 60 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 29 PY 2009 VL 106 IS 52 BP 22468 EP 22473 DI 10.1073/pnas.0909089106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 538IV UT WOS:000273178700077 PM 20018732 ER PT J AU Krueger, F Barbey, AK McCabe, K Strenziok, M Zamboni, G Solomon, J Raymont, V Grafman, J AF Krueger, Frank Barbey, Aron K. McCabe, Kevin Strenziok, Maren Zamboni, Giovanna Solomon, Jeffrey Raymont, Vanessa Grafman, Jordan TI The neural bases of key competencies of emotional intelligence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE emotion; neuroeconomics; prefrontal cortex; social cognition; head injury ID ECONOMIC DECISION-MAKING; PENETRATING HEAD-INJURY; PREFRONTAL CORTEX; FRONTAL-LOBE; RHESUS-MONKEY; COGNITIVE NEUROSCIENCE; ULTIMATUM GAME; BRAIN; PROJECTIONS; LESIONS AB Emotional intelligence (EI) refers to a set of competencies that are essential features of human social life. Although the neural substrates of EI are virtually unknown, it is well established that the prefrontal cortex (PFC) plays a crucial role in human social-emotional behavior. We studied a unique sample of combat veterans from the Vietnam Head Injury Study, which is a prospective, long-term follow-up study of veterans with focal penetrating head injuries. We administered the Mayer-Salovey-Caruso Emotional Intelligence Test as a valid standardized psychometric measure of EI behavior to examine two key competencies of EI: (i) Strategic EI as the competency to understand emotional information and to apply it for the management of the self and of others and (ii) Experiential EI as the competency to perceive emotional information and to apply it for the integration into thinking. The results revealed that key competencies underlying EI depend on distinct neural PFC substrates. First, ventromedial PFC damage diminishes Strategic EI, and therefore, hinders the understanding and managing of emotional information. Second, dorsolateral PFC damage diminishes Experiential EI, and therefore, hinders the perception and integration of emotional information. In conclusion, EI should be viewed as complementary to cognitive intelligence and, when considered together, provide a more complete understanding of human intelligence. C1 [Solomon, Jeffrey] Med Numer, Germantown, MD 20876 USA. [Krueger, Frank] George Mason Univ, Krasnow Inst Adv Study, Fairfax, VA 22030 USA. [Krueger, Frank; Barbey, Aron K.; Strenziok, Maren; Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Barbey, Aron K.] Georgetown Univ, Dept Psychol, Washington, DC 20057 USA. [McCabe, Kevin] George Mason Univ, Ctr Study Neuroecon, Fairfax, VA 22030 USA. [Zamboni, Giovanna] Univ Oxford, Div Expt Med, NDM, Oxford OX3 9DU, England. [Raymont, Vanessa] Johns Hopkins Univ, Dept Radiol, Baltimore, MD 21287 USA. RP Solomon, J (reprint author), Med Numer, Germantown, MD 20876 USA. EM grafmanj@ninds.nih.gov RI Barbey, Aron/L-7312-2015; Zamboni, Giovanna/F-3583-2017; OI Barbey, Aron/0000-0002-6092-0912; Zamboni, Giovanna/0000-0002-6133-3373; Grafman, Jordan H./0000-0001-8645-4457; McCabe, Kevin/0000-0003-0544-157X FU United States National Institute of Neurological Disorders and Stroke intramural research program; Henry M. Jackson Foundation [DAMD17-01-1-0675] FX We thank 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 the testing of participants and organization of this study. The work was supported by the United States National Institute of Neurological Disorders and Stroke intramural research program and a project grant from the United States Army Medical Research and Material Command administrated by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: a 30-year postinjury follow-up study, Grant DAMD17-01-1-0675). Note that the views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, the Department of Defense, nor the United States Government. NR 71 TC 27 Z9 27 U1 4 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 29 PY 2009 VL 106 IS 52 BP 22486 EP 22491 DI 10.1073/pnas.0912568106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 538IV UT WOS:000273178700080 PM 20080795 ER PT J AU Vergarajauregui, S Martina, JA Puertollano, R AF Vergarajauregui, Silvia Martina, Jose A. Puertollano, Rosa TI Identification of the Penta-EF-hand Protein ALG-2 as a Ca2+-dependent Interactor of Mucolipin-1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR POTENTIAL CHANNEL; CALCIUM-BINDING PROTEIN; APOPTOSIS-LINKED GENE-2; GROWTH-FACTOR RECEPTOR; RETICULUM EXIT SITES; CATION CHANNEL; CA2+-BINDING PROTEINS; MEMBRANE TRAFFICKING; LYSOSOMAL PATHWAY; EPITHELIAL-CELLS AB Loss of function mutations in mucolipin-1 (MCOLN1) have been linked to mucolipidosis type IV (MLIV), a recessive lysosomal storage disease characterized by severe neurological and ophthalmological abnormalities. MCOLN1 is an ion channel that regulates membrane transport along the endolysosomal pathway. It has been suggested that MCOLN1 participates in several Ca2+-dependent processes, including fusion of lysosomes with the plasma membrane, fusion of late endosomes and autophagosomes with lysosomes, and lysosomal biogenesis. Here, we searched for proteins that interact with MCOLN1 in a Ca2+-dependent manner. We found that the penta-EF-hand protein ALG-2 binds to the NH-terminal cytosolic tail of MCOLN1. The interaction is direct, strictly dependent on Ca2+, and mediated by a patch of charged and hydrophobic residues located between MCOLN1 residues 37 and 49. We further show that MCOLN1 and ALG-2 co-localize to enlarged endosomes induced by overexpression of an ATPase-defective dominant-negative form of Vps4B (Vps4B(E235Q)). In agreement with the proposed role of MCOLN1 in the regulation of fusion/fission events, we found that overexpression of MCOLN1 caused accumulation of enlarged, aberrant endosomes that contain both early and late endosome markers. Interestingly, aggregation of abnormal endosomes was greatly reduced when the ALG-2-binding domain in MCOLN1 was mutated, suggesting that ALG-2 regulates MCOLN1 function. Overall, our data provide new insight into the molecular mechanisms that regulate MCOLN1 activity. We propose that ALG-2 acts as a Ca2+ sensor that modulates the function of MCOLN1 along the late endosomal-lysosomal pathway. C1 [Vergarajauregui, Silvia; Martina, Jose A.; Puertollano, Rosa] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Puertollano, R (reprint author), NHLBI, Cell Biol Lab, NIH, 9000 Rockville Pike,Bldg 50-3537, Bethesda, MD 20892 USA. EM puertolr@mail.nih.gov FU NHLBI Intramural Research FX This work was supported, in whole or in part, by a National Institutes of Health grant from NHLBI Intramural Research. NR 80 TC 33 Z9 34 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 25 PY 2009 VL 284 IS 52 BP 36357 EP 36366 DI 10.1074/jbc.M109.047241 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 535LT UT WOS:000272970500037 PM 19864416 ER PT J AU Anthis, NJ Haling, JR Oxley, CL Memo, M Wegener, KL Lim, CJ Ginsberg, MH Campbell, ID AF Anthis, Nicholas J. Haling, Jacob R. Oxley, Camilla L. Memo, Massimiliano Wegener, Kate L. Lim, Chinten J. Ginsberg, Mark H. Campbell, Iain D. TI beta Integrin Tyrosine Phosphorylation Is a Conserved Mechanism for Regulating Talin-induced Integrin Activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SRC-FAMILY KINASES; CYTOPLASMIC DOMAIN; SIGNAL-TRANSDUCTION; ALPHA-V-BETA-3 INTEGRIN; ADHESION KINASE; INSIDE-OUT; BINDING; PATHWAYS; CELLS; TAIL AB Integrins are large membrane-spanning receptors fundamental to cell adhesion and migration. Integrin adhesiveness for the extracellular matrix is activated by the cytoskeletal protein talin via direct binding of its phosphotyrosine-binding-like F3 domain to the cytoplasmic tail of the beta integrin subunit. The phosphotyrosine-binding domain of the signaling protein Dok1, on the other hand, has an inactivating effect on integrins, a phenomenon that is modulated by integrin tyrosine phosphorylation. Using full-length tyrosine-phosphorylated (15)N-labeled beta 3, beta 1A, and beta 7 integrin tails and an NMR-based protein-protein interaction assay, we show that talin1 binds to the NPXY motif and the membrane-proximal portion of beta 3, beta 1A, and beta 7 tails, and that the affinity of this interaction is decreased by integrin tyrosine phosphorylation. Dok1 only interacts weakly with unphosphorylated tails, but its affinity is greatly increased by integrin tyrosine phosphorylation. The Dok1 interaction remains restricted to the integrin NPXY region, thus phosphorylation inhibits integrin activation by increasing the affinity of beta integrin tails for a talin competitor that does not form activating membrane-proximal interactions with the integrin. Key residues governing these specificities were identified by detailed structural analysis, and talin1 was engineered to bind preferentially to phosphorylated integrins by introducing the mutation D372R. As predicted, this mutation affects talin1 localization in live cells in an integrin phosphorylation-specific manner. Together, these results indicate that tyrosine phosphorylation is a common mechanism for regulating integrin activation, despite subtle differences in how these integrins interact with their binding proteins. C1 [Anthis, Nicholas J.; Oxley, Camilla L.; Memo, Massimiliano; Wegener, Kate L.; Campbell, Iain D.] Univ Oxford, Dept Biochem, Oxford OX1 3DR, England. [Haling, Jacob R.; Lim, Chinten J.; Ginsberg, Mark H.] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. RP Anthis, NJ (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM nick.anthis@gmail.com; iain.campbell@bioch.ox.ac.uk RI Wegener, Kate/E-5077-2010; Lim, Chinten James/G-3777-2013 OI Wegener, Kate/0000-0002-1562-6060; Lim, Chinten James/0000-0001-6381-7585 FU National Institutes of Health; Wellcome Trust; Rhodes Trust FX This work was supported, in whole or in part, by a National Institutes of Health grant (to M. H. G., I. D. C., and K. L. W.). This work was also supported by grants from the Wellcome Trust (to I. D. C. and C. L. O.) and the Rhodes Trust (to N. J. A.). NR 61 TC 62 Z9 62 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 25 PY 2009 VL 284 IS 52 BP 36700 EP 36710 DI 10.1074/jbc.M109.061275 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 535LT UT WOS:000272970500070 PM 19843520 ER PT J AU Wang, F Yang, W AF Wang, Feng Yang, Wei TI Structural Insight into Translesion Synthesis by DNA Pol II SO CELL LA English DT Article ID ESCHERICHIA-COLI; POLYMERASE-II; SPONTANEOUS MUTAGENESIS; FAMILY POLYMERASES; DAMAGE TOLERANCE; GENOME STABILITY; ABASIC LESION; Y-FAMILY; B-FAMILY; IN-VIVO AB E. coli DNA Pol II and eukaryotic Rev3 are B-family polymerases that can extend primers past a damaged or mismatched site when the high-fidelity replicative polymerases in the same family are ineffective. We report here the biochemical and structural properties of DNA Pol II that facilitate this translesion synthesis. DNA Pol II can extend primers past lesions either directly or by template skipping, in which small protein cavities outside of the active site accommodate looped-out template nucleotides 1 or 2 bp upstream. Because of multiple looping-out alternatives, mutation spectra of bypass synthesis are complicated. Moreover, translesion synthesis is enhanced by altered partitioning of DNA substrate between the polymerase active site and the proofreading exonuclease site. Compared to the replicative B family polymerases, DNA Pol II has subtle amino acid changes remote from the active site that allow it to replicate normal DNA with high efficiency yet conduct translesion synthesis when needed. C1 [Wang, Feng; Yang, Wei] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDK, Mol Biol Lab, NIH, 9000 Rockville Pike,Bldg 5,Room B1-03, Bethesda, MD 20892 USA. EM wei.yang@nih.gov RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU National Institute of Diabetes and Digestive and Kidney Diseases intramural research program at National Institutes of Health FX We thank S. Doublie for purified gp43 protein and the gp43-beta- clone, W. Konigsberg for the gp43 exo- clone, our labmates for technical support, D. Leahy and R. Craigie for critical reading of the manuscript, and F. Dyda for maintaining the X-ray equipment. The research is funded by the National Institute of Diabetes and Digestive and Kidney Diseases intramural research program at National Institutes of Health. NR 56 TC 45 Z9 45 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 24 PY 2009 VL 139 IS 7 BP 1279 EP 1289 DI 10.1016/j.cell.2009.11.043 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 536MO UT WOS:000273048700016 PM 20064374 ER PT J AU Liu, F Chen, X Allali-Hassani, A Quinn, AM Wasney, GA Dong, AP Barsyte, D Kozieradzki, I Senisterra, G Chau, I Siarheyeva, A Kireev, DB Jadhav, A Herold, JM Frye, SV Arrowsmith, CH Brown, PJ Simeonov, A Vedadi, M Jin, J AF Liu, Feng Chen, Xin Allali-Hassani, Abdellah Quinn, Amy M. Wasney, Gregory A. Dong, Aiping Barsyte, Dalia Kozieradzki, Ivona Senisterra, Guillermo Chau, Irene Siarheyeva, Alena Kireev, Dmitri B. Jadhav, Ajit Herold, J. Martin Frye, Stephen V. Arrowsmith, Cheryl H. Brown, Peter J. Simeonov, Anton Vedadi, Masoud Jin, Jian TI Discovery of a 2,4-Diamino-7-aminoalkoxyquinazoline as a Potent and Selective Inhibitor of Histone Lysine Methyltransferase G9a SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CHROMATIN-STRUCTURE; CANCER AB SAR exploration of the 2,4-diamino-6,7-dimethoxyquinazoline template led to the discovery of 8 (UNC0224) as it potent and selective G9a inhibitor. A high resolution X-ray crystal structure of the G9a-8 complex, the first cocrystal structure of G9a with a small molecule inhibitor, was obtained. The cocrystal structure validated our binding hypothesis and will enable structure-based design of novel inhibitors. 8 is a useful tool for investigating the biology of G9a and its roles in chromatin remodeling. C1 [Liu, Feng; Chen, Xin; Kireev, Dmitri B.; Herold, J. Martin; Frye, Stephen V.; Jin, Jian] Univ N Carolina, Ctr Integrated Chem Biol & Drug Discovery, Div Med Chem & Nat Prod, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. [Allali-Hassani, Abdellah; Wasney, Gregory A.; Dong, Aiping; Barsyte, Dalia; Kozieradzki, Ivona; Senisterra, Guillermo; Chau, Irene; Siarheyeva, Alena; Arrowsmith, Cheryl H.; Brown, Peter J.; Vedadi, Masoud] Univ Toronto, Struct Genom Consortium, Toronto, ON M5G 1L6, Canada. [Quinn, Amy M.; Jadhav, Ajit; Simeonov, Anton] Natl Human Genome Res Inst, NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Jin, J (reprint author), Univ N Carolina, Ctr Integrated Chem Biol & Drug Discovery, Div Med Chem & Nat Prod, Eshelman Sch Pharm, Chapel Hill, NC 27599 USA. EM jianjin@unc.edu RI Kireev, Dmitri/B-7225-2012; liu, feng/J-4669-2013 OI Kireev, Dmitri/0000-0001-8479-8555; FU Intramural NIH HHS [Z01 HG200319-05]; NIGMS NIH HHS [RC1 GM090732] NR 20 TC 117 Z9 117 U1 1 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD DEC 24 PY 2009 VL 52 IS 24 BP 7950 EP 7953 DI 10.1021/jm901543m PG 4 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 531ZJ UT WOS:000272712100008 PM 19891491 ER PT J AU Lin, X Parisiadou, L Gu, XL Wang, LZ Shim, H Sun, LX Xie, CS Long, CX Yang, WJ Ding, JH Chen, ZZ Gallant, PE Tao-Cheng, JH Rudow, G Troncoso, JC Liu, ZH Li, Z Cai, HB AF Lin, Xian Parisiadou, Loukia Gu, Xing-Long Wang, Lizhen Shim, Hoon Sun, Lixin Xie, Chengsong Long, Cai-Xia Yang, Wan-Jou Ding, Jinhui Chen, Zsu Zsu Gallant, Paul E. Tao-Cheng, Jung-Hwa Rudow, Gay Troncoso, Juan C. Liu, Zhihua Li, Zheng Cai, Huaibin TI Leucine-Rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced by Parkinson's-Disease-Related Mutant alpha-synuclein SO NEURON LA English DT Article ID COMMON LRRK2 MUTATION; LEWY BODIES; EXPRESSION; PROTEIN; BRAIN; MICE; LEUCINE-RICH-REPEAT-KINASE-2; LOCALIZATION; MICROTUBULES; GENE AB Mutations in alpha-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson's disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although overexpression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T alpha-synuclein transgenic mice. Moreover, we found that LRRK2 promoted the abnormal aggregation and somatic accumulation of alpha-synuclein in A53T mice, which likely resulted from the impairment of microtubule dynamics, Golgi organization, and the ubiquitin-proteasome pathway. Conversely, genetic ablation of LRRK2 preserved the Golgi structure and suppressed the aggregation and somatic accumulation of alpha-synuclein, and thereby delayed the progression of neuropathology in A53T mice. These findings demonstrate that overexpression of LRRK2 enhances alpha-synuclein-mediated cytotoxicity and suggest inhibition of LRRK2 expression as a potential therapeutic option for ameliorating alpha-synuclein-induced neurodegeneration. C1 [Lin, Xian; Parisiadou, Loukia; Gu, Xing-Long; Wang, Lizhen; Shim, Hoon; Sun, Lixin; Xie, Chengsong; Long, Cai-Xia; Yang, Wan-Jou; Cai, Huaibin] NIA, Unit Transgenesis, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Ding, Jinhui] NIA, Unit Bioinformat Core, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Gallant, Paul E.] Natl Inst Neurol Disorders & Stroke, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. [Tao-Cheng, Jung-Hwa] Natl Inst Neurol Disorders & Stroke, EM Facil, NIH, Bethesda, MD 20892 USA. [Liu, Zhihua] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Li, Zheng] NIMH, Unit Synapse Dev & Plast, Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Chen, Zsu Zsu] Univ Alabama, Dept Biol, Birmingham, AL 35233 USA. [Rudow, Gay; Troncoso, Juan C.] Johns Hopkins Univ, Sch Med, Dept Pathol, Div Neuropathol, Baltimore, MD 21205 USA. RP Cai, HB (reprint author), NIA, Unit Transgenesis, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM caih@mail.nih.gov RI gu, xinglong/A-3054-2011; Cai, Huaibin/H-3359-2013; Li, Zheng/I-8016-2014 OI gu, xinglong/0000-0002-0437-5606; Cai, Huaibin/0000-0002-8596-6108; Li, Zheng/0000-0002-2978-2531 FU National Institute on Aging; National Human Genome Research Institute (NHGRI); National Institute of Mental Health (NIMH); National Institutes of Health; Henry Jackson Foundation FX This work was supported in part by the intramural research programs of the National Institute on Aging, National Human Genome Research Institute (NHGRI), National Institute of Mental Health (NIMH), and National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health and the Henry Jackson Foundation. We thank the NHGRI and NIMH transgenic mouse facilities for blastocystic and pronuclear injections; the NINDS DNA Sequence Facility for sequencing DNA constructs; Dr. David Borchelt for kindly providing the tetO expression vector; Drs. Darren Moore, Valina Dawson, Ted Dawson (of the Johns Hopkins University School of Medicine), and Jean-Marc Taymans (Universiteit Leuven) for kindly providing LRRK2 antibodies; Drs. John Hardy and Andy Singleton for their helpful suggestions; and the NIH Fellows Editorial Board for editing this manuscript. NR 53 TC 244 Z9 247 U1 0 U2 13 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD DEC 24 PY 2009 VL 64 IS 6 BP 807 EP 827 DI 10.1016/j.neuron.2009.11.006 PG 21 WC Neurosciences SC Neurosciences & Neurology GA 541ON UT WOS:000273425800009 PM 20064389 ER PT J AU Omland, T de Lemos, JA Sabatine, MS Christophi, CA Rice, MM Jablonski, KA Tjora, S Domanski, MJ Gersh, BJ Rouleau, JL Pfeffer, MA Braunwald, E AF Omland, Torbjorn de Lemos, James A. Sabatine, Marc S. Christophi, Costas A. Rice, Madeline Murguia Jablonski, Kathleen A. Tjora, Solve Domanski, Michael J. Gersh, Bernard J. Rouleau, Jean L. Pfeffer, Marc A. Braunwald, Eugene CA Prevention Events Angiotensin Conv TI A Sensitive Cardiac Troponin T Assay in Stable Coronary Artery Disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID LONG-TERM MORTALITY; PROGNOSTIC VALUE; HEART; POPULATION; ELEVATION; TRIAL; RISK AB BACKGROUND In most patients with stable coronary artery disease, plasma cardiac troponin T levels are below the limit of detection for the conventional assay. The distribution and determinants of very low circulating troponin T levels, as well as their association with cardiovascular events, in such patients are unknown. METHODS We used a new, high-sensitivity assay to determine the concentration of cardiac troponin T in plasma samples from 3679 patients with stable coronary artery disease and preserved left ventricular function. Results of the assay were analyzed in relation to the incidence of cardiovascular events during a median follow-up period of 5.2 years. RESULTS With the highly sensitive assay, concentrations of cardiac troponin T were at or above the limit of detection (0.001 mu g per liter) in 3593 patients (97.7%) and at or above the 99th percentile for apparently healthy subjects (0.0133 mu g per liter) in 407 patients (11.1%). After adjustment for other independent prognostic indicators, there was a strong and graded increase in the cumulative incidence of cardiovascular death (adjusted hazard ratio per unit increase in the natural logarithm of the troponin T level, 2.09; 95% confidence interval [CI], 1.60 to 2.74; P<0.001) and of heart failure (adjusted hazard ratio, 2.20; 95% CI, 1.66 to 2.90; P<0.001) in this study group. Increased risk associated with higher levels of troponin T was evident well below the limit of detection of conventional cardiac troponin T assays and below the 99th percentile of values in a healthy population. There was no association between troponin T levels as measured with the highly sensitive assay and the incidence of myocardial infarction (adjusted hazard ratio, 1.16; 95% CI, 0.97 to 1.40; P = 0.11). CONCLUSIONS After adjustment for other independent prognostic indicators, cardiac troponin T concentrations as measured with a highly sensitive assay were significantly associated with the incidence of cardiovascular death and heart failure but not with myocardial infarction in patients with stable coronary artery disease. C1 [Omland, Torbjorn] Akershus Univ Hosp, Div Med, NO-1478 Lorenskog, Norway. [Tjora, Solve] Akershus Univ Hosp, Ctr Lab Med, NO-1478 Lorenskog, Norway. [Omland, Torbjorn] Univ Oslo, Akershus Univ Hosp, Fac Div, Oslo, Norway. [Omland, Torbjorn] Univ Oslo, Ctr Heart Failure Res, Oslo, Norway. [de Lemos, James A.] Univ Texas SW Med Ctr Dallas, Dept Med, Dallas, TX 75390 USA. [Sabatine, Marc S.; Pfeffer, Marc A.; Braunwald, Eugene] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Sabatine, Marc S.; Pfeffer, Marc A.; Braunwald, Eugene] Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. [Christophi, Costas A.; Rice, Madeline Murguia; Jablonski, Kathleen A.] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Domanski, Michael J.] NHLBI, Bethesda, MD 20892 USA. [Gersh, Bernard J.] Mayo Clin, Div Cardiovasc Dis, Dept Med, Rochester, MN USA. [Rouleau, Jean L.] Univ Montreal, Fac Med, Montreal, PQ H3C 3J7, Canada. [Rouleau, Jean L.] Univ Montreal, Montreal Heart Inst, Montreal, PQ, Canada. RP Omland, T (reprint author), Akershus Univ Hosp, Div Med, NO-1478 Lorenskog, Norway. EM torbjorn.omland@medisin.uio.no FU NHLBI NIH HHS [N01 HC065149-15, N01 HC065149] NR 21 TC 436 Z9 449 U1 2 U2 14 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 24 PY 2009 VL 361 IS 26 BP 2538 EP 2547 DI 10.1056/NEJMoa0805299 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 535WX UT WOS:000273003700009 PM 19940289 ER PT J AU Chien, YW Klugman, KP Morens, DM AF Chien, Yu-Wen Klugman, Keith P. Morens, David M. TI Bacterial Pathogens and Death during the 1918 Influenza Pandemic SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID STREPTOCOCCUS-PNEUMONIAE C1 [Chien, Yu-Wen; Klugman, Keith P.] Emory Univ, Atlanta, GA 30322 USA. [Morens, David M.] NIAID, Bethesda, MD 20892 USA. RP Chien, YW (reprint author), Emory Univ, Atlanta, GA 30322 USA. EM keith.klugman@emory.edu NR 5 TC 47 Z9 47 U1 0 U2 2 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 24 PY 2009 VL 361 IS 26 BP 2582 EP 2583 DI 10.1056/NEJMc0908216 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 535WX UT WOS:000273003700032 PM 20032332 ER PT J AU Liu, XQ Pawlyk, BS Adamian, M Olshevskaya, EV Dizhoor, AM Makino, CL Li, TS AF Liu, Xiaoqing Pawlyk, Basil S. Adamian, Michael Olshevskaya, Elena V. Dizhoor, Alexander M. Makino, Clint L. Li, Tiansen TI Increased Light Exposure Alleviates One Form of Photoreceptor Degeneration Marked by Elevated Calcium in the Dark SO PLOS ONE LA English DT Article ID DOMINANT CONE DEGENERATION; GUANYLATE-CYCLASE; RETINITIS-PIGMENTOSA; TRANSGENIC MICE; MOUSE MODEL; RHODOPSIN; MUTATION; DYSTROPHY; APOPTOSIS; DISEASE AB Background: In one group of gene mutations that cause photoreceptor degeneration in human patients, guanylyl cyclase is overactive in the dark. The ensuing excess opening of cGMP-gated cation channels causes intracellular calcium to rise to toxic levels. The Y99C mutation in guanylate cyclase-activating protein 1 (GCAP1) has been shown to act this way. We determined whether prolonged light exposure, which lowers cGMP levels through activation of phototransduction, might protect photoreceptors in a line of transgenic mice carrying the GCAP1-Y99C. Methodology/Principal Findings: We reared cohorts of GCAP1-Y99C transgenic mice under standard cyclic, constant dark and constant light conditions. Mouse eyes were analyzed by histology and by immunofluorescence for GFAP upregulation, a non-specific marker for photoreceptor degeneration. Full-field electroretinograms (ERGs) were recorded to assess retinal function. Consistent with our hypothesis, constant darkness accelerated disease, while continuous lighting arrested photoreceptor degeneration. Conclusions/Significance: In contrast to most forms of retinal degeneration, which are exacerbated by increased exposure to ambient light, a subset with mutations that cause overly active guanylyl cyclase and high intracellular calcium benefitted from prolonged light exposure. These findings may have therapeutic implications for patients with these types of genetic defects. C1 [Liu, Xiaoqing; Pawlyk, Basil S.; Adamian, Michael] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02115 USA. [Olshevskaya, Elena V.; Dizhoor, Alexander M.] Salus Univ, Penn Coll Optometry, Hafter Res Labs, Elkins Pk, PA USA. [Makino, Clint L.] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Howe Lab, Boston, MA USA. [Li, Tiansen] NEI, Neurodegenerat & Repair Lab, Bethesda, MD 20892 USA. RP Liu, XQ (reprint author), Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Berman Gund Lab Study Retinal Degenerat, Boston, MA 02115 USA. EM tiansen.li@nih.gov OI Makino, Clint/0000-0002-6005-9069 FU National Institutes of Health [EY10309, EY10581, EY11522, EY12944, EY14104]; Macular Vision Research Foundation; Foundation Fighting Blindness FX This work was supported by grants from the National Institutes of Health EY10309, EY10581 (TL), EY11522 (AD), EY12944 (CLM), EY14104 (core grant), the Macular Vision Research Foundation, and the Foundation Fighting Blindness. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 25 TC 5 Z9 5 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 24 PY 2009 VL 4 IS 12 AR e8438 DI 10.1371/journal.pone.0008438 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 537HN UT WOS:000273104000007 PM 20041177 ER PT J AU MacKellar, J Cushman, SW Periwal, V AF MacKellar, Jennifer Cushman, Samuel W. Periwal, Vipul TI Differential Effects of Thiazolidinediones on Adipocyte Growth and Recruitment in Zucker Fatty Rats SO PLOS ONE LA English DT Article ID ADIPOSE-TISSUE; INSULIN-RESISTANCE; PPAR-GAMMA; PIOGLITAZONE AB Background: Adipose tissue grows by two mechanisms: hyperplasia ( cell number increase) and hypertrophy ( cell size increase). Thiazolidinediones are insulin-sensitizing peroxisome proliferator-activated receptor gamma agonists that are known to affect the morphology of adipose tissue. Methodology: In this study, adipose cell-size probability distributions were measured in six Zucker fa/fa rats over a period of 24 days, from four weeks of age, using micro-biopsies to obtain subcutaneous ( inguinal) fat tissue from the animals. Three of the rats were gavaged daily with rosiglitazone, a thiazolidinedione, and three served as controls. These longitudinal probability distributions were analyzed to obtain the rate of increase in cell-size diameter in rosiglitazone-treated animals, and the hyperplasia induced by treatment quantitatively. Conclusions: We found that treatment leads to hypertrophy that leads to an approximately linear rate of cell diameter increase ( 2 mu m/day), and that the hyperplasia evident in treated animals occurs largely within the first eight days of treatment. The availability of additional lipid storage due to treatment may alleviate lipotoxicity and thereby promote insulin sensitivity. The hypothesis that a TZD regimen involving repeated treatments of limited duration may suffice for improvements in insulin sensitivity merits further investigation. C1 [MacKellar, Jennifer; Cushman, Samuel W.] NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. [Periwal, Vipul] NIDDKD, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP MacKellar, J (reprint author), NIDDKD, Diabet Branch, NIH, Bethesda, MD 20892 USA. EM vipulp@mail.nih.gov RI Periwal, Vipul/I-1728-2012 FU Intramural Research Program of the National Institutes of Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Diabetes and Digestive and Kidney Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 14 TC 10 Z9 10 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 24 PY 2009 VL 4 IS 12 AR e8196 DI 10.1371/journal.pone.0008196 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 537HN UT WOS:000273104000001 PM 20041138 ER PT J AU Mishra, PJ Song, B Mishra, PJ Wang, Y Humeniuk, R Banerjee, D Merlino, G Ju, JF Bertino, JR AF Mishra, Prasun J. Song, Bo Mishra, Pravin J. Wang, Yuan Humeniuk, Rita Banerjee, Debabrata Merlino, Glenn Ju, Jingfang Bertino, Joseph R. TI MiR-24 Tumor Suppressor Activity Is Regulated Independent of p53 and through a Target Site Polymorphism SO PLOS ONE LA English DT Article ID MIRNA EXPRESSION; DIHYDROFOLATE-REDUCTASE; CAENORHABDITIS-ELEGANS; MICRORNA POLYMORPHISMS; THYMIDYLATE SYNTHASE; CELL; GENES; PHARMACOGENOMICS; RNAS; DIFFERENTIATION AB MicroRNAs (miRNAs) are predicted to regulate approximately 30% of all human genes; however, only a few miRNAs have been assigned their targets and specific functions. Here we demonstrate that miR-24, a ubiquitously expressed miRNA, has an anti-proliferative effect independent of p53 function. Cell lines with differential p53 status were used as a model to study the effects of miR-24 on cell proliferation, cell cycle control, gene regulation and cellular transformation. Overexpression of miR-24 in six different cell lines, independent of p53 function, inhibited cell proliferation and resulted in G2/S cell cycle arrest. MiR-24 over expression in cells with wt-p53 upregulated TP53 and p21 protein; however, in p53-null cells miR-24 still induced cell cycle arrest without the involvement of p21. We show that miR-24 regulates p53-independent cellular proliferation by regulating an S-phase enzyme, dihydrofolate reductase (DHFR) a target of the chemotherapeutic drug methotrexate (MTX). Of interest, we found that a miR-24 target site polymorphism in DHFR 3' UTR that results in loss of miR-24-function and high DHFR levels in the cell imparts a growth advantage to immortalized cells and induces neoplastic transformation. Of clinical significance, we found that miR-24 is deregulated in human colorectal cancer tumors and a subset of tumors has reduced levels of miR-24. A novel function for miR-24 as a p53-independent cell cycle inhibitory miRNA is proposed. C1 [Mishra, Prasun J.; Merlino, Glenn] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Mishra, Prasun J.; Mishra, Pravin J.; Banerjee, Debabrata; Bertino, Joseph R.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Med & Pharmacol, Canc Inst New Jersey, Piscataway, NJ 08854 USA. [Song, Bo; Wang, Yuan; Ju, Jingfang] SUNY Stony Brook, Dept Pathol, Med Ctr, Translat Res Lab, Stony Brook, NY 11794 USA. [Humeniuk, Rita] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Mishra, PJ (reprint author), NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. EM bertinoj@umdnj.edu OI Ju, Jingfang/0000-0002-4821-7458 FU Center of Cancer Research, NCI [CA0810]; NIH [C5IL039280, CA114043] FX This work was supported in part by the Intramural Research Program of the Center of Cancer Research, NCI, NIH; in part by NCI Cancer Research Training Award C5IL039280 ( to PJM); in part by Stony-Brook Translational Research Laboratory Start-up fund and NIH CA114043 ( to JJ); and in part by NCI Grant CA0810 ( to JRB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 64 Z9 77 U1 2 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 24 PY 2009 VL 4 IS 12 AR e8445 DI 10.1371/journal.pone.0008445 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 537HN UT WOS:000273104000010 PM 20041160 ER PT J AU Wang, YG Mukhopadhyay, D Mathew, S Hasebe, T Heimeier, RA Azuma, Y Kolli, N Shi, YB Wilkinson, KD Dasso, M AF Wang, Yonggang Mukhopadhyay, Debaditya Mathew, Smita Hasebe, Takashi Heimeier, Rachel A. Azuma, Yoshiaki Kolli, Nagamalleswari Shi, Yun-Bo Wilkinson, Keith D. Dasso, Mary TI Identification and Developmental Expression of Xenopus laevis SUMO Proteases SO PLOS ONE LA English DT Article ID UBIQUITIN-LIKE PROTEINS; SMAD TRANSCRIPTIONAL ACTIVITY; CAENORHABDITIS-ELEGANS; STRUCTURAL BASIS; DOWN-REGULATION; GENE-REGULATION; SUMOYLATION; PATHWAY; YEAST; VERTEBRATE AB SUMO proteins are small ubiquitin-related modifiers. All SUMOs are synthesized as propeptides that are post-translationally cleaved prior to conjugation. After processing, SUMOs become covalently conjugated to cellular targets through a pathway that is similar to ubiquitination. Ubiquitin like protein proteases/Sentrin specific proteases (Ulp/SENPs) mediate both processing and deconjugation of SUMOs. The action of Ulp/SENPs makes SUMOylation a highly dynamic post-translational modification. To investigate how Ulp/SENPs are regulated in a developmental context, we isolated and characterized all Ulp/SENPs in Xenopus laevis. Xenopus possess homologues of mammalian SENP3, 5, 6 and 7. All of these enzymes reacted with HA-tagged vinyl sulfone derivatives of SUMO-2 (HA-SU2-VS) but not SUMO-1 ( HA-SU1-VS), suggesting that they act primarily on SUMO-2 and -3. In contrast, Xenopus possess a single member of the SENP1/SENP2 subfamily of Ulp/SENPs, most closely related to mammalian SENP1. Xenopus SENP1 reacted with HA-SU1-VS and HA-SU2-VS, suggesting that it acts on all SUMO paralogues. We analyzed the mRNA and protein levels for each of the Ulp/SENPs through development; we found that they show distinct patterns of expression that may involve both transcriptional and post-transcriptional regulation. Finally, we have characterized the developmental function of the most abundant Ulp/SENP found within Xenopus eggs, SENP3. Depletion of SENP3 using morpholino antisense oligonucleotides (morpholinos) caused accumulation of high molecular weight SUMO-2/3 conjugated species, defects in developing embryos and changes in the expression of some genes regulated by the transforming growth factor beta (TGF-beta) pathway. These findings collectively indicate that SUMO proteases are both highly regulated and essential for normal development. C1 [Wang, Yonggang; Mukhopadhyay, Debaditya; Mathew, Smita; Hasebe, Takashi; Heimeier, Rachel A.; Azuma, Yoshiaki; Shi, Yun-Bo; Dasso, Mary] NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. [Kolli, Nagamalleswari; Wilkinson, Keith D.] Emory Univ, Dept Biochem, Atlanta, GA 30322 USA. RP Wang, YG (reprint author), NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. EM mdasso@helix.nih.gov OI Dasso, Mary/0000-0002-5410-1371 FU National Institute of Child Health and Human Development; National Institutes of Health [5R01GM066355] FX This work was supported by National Institute of Child Health and Human Development intramural funds ( to Y. Wang, D. Mukhopadhyay, S. Mathew, T. Hasebe, R. Heimeier, Y. Azuma, Y.- B. Shi and M. Dasso) and by National Institutes of Health grant # 5R01GM066355 ( to N. Kolli and K. D. Wilkinson). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 54 TC 11 Z9 11 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 24 PY 2009 VL 4 IS 12 AR e8462 DI 10.1371/journal.pone.0008462 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 537HN UT WOS:000273104000022 PM 20041154 ER PT J AU McKnight, DA Fisher, LW AF McKnight, Dianalee A. Fisher, Larry W. TI Molecular evolution of dentin phosphoprotein among toothed and toothless animals SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID LINKED GLYCOPROTEINS SIBLINGS; DENTINOGENESIS IMPERFECTA; MATRIX METALLOPROTEINASES; MITOCHONDRIAL GENOMES; DIVERGENCE TIMES; GENE; EXPRESSION; PHYLOGENY; PHOSPHOPHORYN; SIALOPROTEIN AB Background: Dentin sialophosphoprotein (DSPP) is the largest member of the SIBLING family and is the most abundant noncollagenous protein in dentin. DSPP is also expressed in non-mineralized tissues including metabolically active ductal epithelia and some cancers. Its function, however, is poorly defined. The carboxy-terminal fragment, dentin phosphoprotein (DPP) is encoded predominantly by a large repetitive domain that requires separate cloning/sequencing reactions and is, therefore, often incomplete in genomic databases. Comparison of DPP sequences from at least one member of each major branch in the mammalian evolutionary tree (including some "toothless" mammals) as well as one reptile and bird may help delineate its possible functions in both dentin and ductal epithelia. Results: The BMP1-cleavage and translation-termination domains were sufficiently conserved to permit amplification/cloning/sequencing of most species' DPP. While the integrin-binding domain, RGD, was present in about half of species, only vestigial remnants of this tripeptide were identified in the others. The number of tandem repeats of the nominal SerSerAsp phosphorylation motif in toothed mammals (including baleen whale and platypus which lack teeth as adults), ranged from similar to 75 (elephant) to > 230 (human). These repeats were not perfect, however, and patterns of intervening sequences highlight the rapidity of changes among even closely related species. Two toothless anteater species have evolved different sets of nonsense mutations shortly after their BMP1 motifs suggesting that while cleavage may be important for DSPP processing in other tissues, the DPP domain itself may be required only in dentin. The lizard DSPP had an intact BMP1 site, a remnant RGD motif, as well as a distinctly different Ser/Asp-rich domain compared to mammals. Conclusions: The DPP domain of DSPP was found to change dramatically within mammals and was lost in two truly toothless animals. The defining aspect of DPP, the long repeating phosphorylation domain, apparently undergoes frequent slip replication and recombination events that rapidly change specific patterns but not its overall biochemical character in toothed animals. Species may have to co-evolve protein processing mechanisms, however, to handle increased lengths of DSP repeats. While the RGD domain is lost in many species, some evolutionary pressure to maintain integrin binding can be observed. C1 [McKnight, Dianalee A.; Fisher, Larry W.] NIDCR, Craniofacial & Skeletal Dis Branch, NIH, DHHS, Bethesda, MD 20892 USA. RP Fisher, LW (reprint author), NIDCR, Craniofacial & Skeletal Dis Branch, NIH, DHHS, Bethesda, MD 20892 USA. EM mcknightd@mail.nih.gov; lfisher@dir.nidcr.nih.gov FU NIH FX This research was supported by the Division of Intramural Research, NIDCR, of the Intramural Research Program of NIH. NR 44 TC 21 Z9 21 U1 1 U2 9 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 23 PY 2009 VL 9 AR 299 DI 10.1186/1471-2148-9-299 PG 16 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 543BJ UT WOS:000273544200001 PM 20030824 ER PT J AU Paoloni, M Davis, S Lana, S Withrow, S Sangiorgi, L Picci, P Hewitt, S Triche, T Meltzer, P Khanna, C AF Paoloni, Melissa Davis, Sean Lana, Susan Withrow, Stephen Sangiorgi, Luca Picci, Piero Hewitt, Stephen Triche, Timothy Meltzer, Paul Khanna, Chand TI Canine tumor cross-species genomics uncovers targets linked to osteosarcoma progression SO BMC GENOMICS LA English DT Article ID PEDIATRIC OSTEOSARCOMA; CELL-LINES; EXPRESSION PROFILES; FUNCTIONAL GENOMICS; INTERLEUKIN-8 GENE; OSTEOGENIC-SARCOMA; CANCER; CHEMOTHERAPY; BIOLOGY; DOG AB Background: Pulmonary metastasis continues to be the most common cause of death in osteosarcoma. Indeed, the 5-year survival for newly diagnosed osteosarcoma patients has not significantly changed in over 20 years. Further understanding of the mechanisms of metastasis and resistance for this aggressive pediatric cancer is necessary. Pet dogs naturally develop osteosarcoma providing a novel opportunity to model metastasis development and progression. Given the accelerated biology of canine osteosarcoma, we hypothesized that a direct comparison of canine and pediatric osteosarcoma expression profiles may help identify novel metastasis-associated tumor targets that have been missed through the study of the human cancer alone. Results: Using parallel oligonucleotide array platforms, shared orthologues between species were identified and normalized. The osteosarcoma expression signatures could not distinguish the canine and human diseases by hierarchical clustering. Cross-species target mining identified two genes, interleukin-8 (IL-8) and solute carrier family 1 (glial high affinity glutamate transporter), member 3 (SLC1A3), which were uniformly expressed in dog but not in all pediatric osteosarcoma patient samples. Expression of these genes in an independent population of pediatric osteosarcoma patients was associated with poor outcome (p = 0.020 and p = 0.026, respectively). Validation of IL-8 and SLC1A3 protein expression in pediatric osteosarcoma tissues further supported the potential value of these novel targets. Ongoing evaluation will validate the biological significance of these targets and their associated pathways. Conclusions: Collectively, these data support the strong similarities between human and canine osteosarcoma and underline the opportunities provided by a comparative oncology approach as a means to improve our understanding of cancer biology and therapies. C1 [Paoloni, Melissa; Khanna, Chand] NCI, Comparat Oncol Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Davis, Sean; Meltzer, Paul] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lana, Susan; Withrow, Stephen] Colorado State Univ, Vet Teaching Hosp, Anim Canc Ctr, Ft Collins, CO 80523 USA. [Sangiorgi, Luca; Picci, Piero] Rizzoli Orthoped Inst, Lab Oncol Res Bologna, I-40136 Bologna, Italy. [Hewitt, Stephen] NCI, Tissue Array Res Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Triche, Timothy] Univ So Calif, Childrens Hosp Los Angeles, Saban Res Inst, Los Angeles, CA 90027 USA. RP Paoloni, M (reprint author), NCI, Comparat Oncol Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM paolonim@mail.nih.gov; sdavis2@mail.nih.gov; Susan.Lana@ColoState.edu; Stephen.Withrow@ColoState.edu; luca.sangiorgi@ior.it; piero.picci@ior.it; hewitts@mail.nih.gov; triche@usc.edu; pmeltzer@mail.nih.gov; khannac@mail.nih.gov RI Picci, Piero/J-5979-2016; OI Hewitt, Stephen/0000-0001-8283-1788; Picci, Piero/0000-0002-8519-4101; Davis, Sean/0000-0002-8991-6458 NR 52 TC 90 Z9 91 U1 0 U2 17 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 23 PY 2009 VL 10 AR 625 DI 10.1186/1471-2164-10-625 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 543JI UT WOS:000273571600001 PM 20028558 ER PT J AU Nunemaker, CS Dishinger, JF Dula, SB Wu, RP Merrins, MJ Reid, KR Sherman, A Kennedy, RT Satin, LS AF Nunemaker, Craig S. Dishinger, John F. Dula, Stacey B. Wu, Runpei Merrins, Matthew J. Reid, Kendra R. Sherman, Arthur Kennedy, Robert T. Satin, Leslie S. TI Glucose Metabolism, Islet Architecture, and Genetic Homogeneity in Imprinting of [Ca2+](i) and Insulin Rhythms in Mouse Islets SO PLOS ONE LA English DT Article ID PANCREATIC BETA-CELLS; CYTOPLASMIC CA2+; IN-VIVO; ELECTRICAL-ACTIVITY; OXYGEN-CONSUMPTION; MICROFLUIDIC CHIP; SINGLE ISLETS; B-CELLS; OSCILLATIONS; SECRETION AB We reported previously that islets isolated from individual, outbred Swiss-Webster mice displayed oscillations in intracellular calcium ([Ca2+](i)) that varied little between islets of a single mouse but considerably between mice, a phenomenon we termed "islet imprinting." We have now confirmed and extended these findings in several respects. First, imprinting occurs in both inbred (C57BL/6J) as well as outbred mouse strains (Swiss-Webster; CD1). Second, imprinting was observed in NAD(P) H oscillations, indicating a metabolic component. Further, short-term exposure to a glucose-free solution, which transiently silenced [Ca2+](i) oscillations, reset the oscillatory patterns to a higher frequency. This suggests a key role for glucose metabolism in maintaining imprinting, as transiently suppressing the oscillations with diazoxide, a KATP-channel opener that blocks [Ca2+](i) influx downstream of glucose metabolism, did not change the imprinted patterns. Third, imprinting was not as readily observed at the level of single beta cells, as the [Ca2+](i) oscillations of single cells isolated from imprinted islets exhibited highly variable, and typically slower [Ca2+](i) oscillations. Lastly, to test whether the imprinted [Ca2+](i) patterns were of functional significance, a novel microchip platform was used to monitor insulin release from multiple islets in real time. Insulin release patterns correlated closely with [Ca2+](i) oscillations and showed significant mouseto- mouse differences, indicating imprinting. These results indicate that islet imprinting is a general feature of islets and is likely to be of physiological significance. While islet imprinting did not depend on the genetic background of the mice, glucose metabolism and intact islet architecture may be important for the imprinting phenomenon. C1 [Nunemaker, Craig S.; Dula, Stacey B.; Wu, Runpei] Univ Virginia, Dept Med, Div Endocrinol & Metab, Charlottesville, VA 22903 USA. [Dishinger, John F.; Reid, Kendra R.; Kennedy, Robert T.] Univ Michigan, Dept Chem, Ann Arbor, MI 48109 USA. [Merrins, Matthew J.; Satin, Leslie S.] Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Kennedy, Robert T.; Satin, Leslie S.] Univ Michigan, Brehm Diabet Ctr, Ann Arbor, MI 48109 USA. [Sherman, Arthur] NIH, Lab Biol Modeling, Bethesda, MD 20892 USA. RP Nunemaker, CS (reprint author), Univ Virginia, Dept Med, Div Endocrinol & Metab, Charlottesville, VA 22903 USA. EM lsatin@umich.edu RI Kennedy, Robert/G-9095-2016; OI Kennedy, Robert/0000-0003-2447-7471; Merrins, Matthew J./0000-0003-1599-9227 FU NIH [RO1 DK46409, R37 DK0469690, 1K01 DK081621]; NIH-NIDDK (National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases) FX Dr. Satin's laboratory is supported by RO1 DK46409 from the NIH. Dr. Kennedy's laboratory is supported by NIH R37 Grant DK0469690. Dr. Nunemaker's laboratory is supported by NIH 1K01 DK081621. Dr. Sherman was supported by the Intramural Research Program of the NIH-NIDDK (National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 53 TC 18 Z9 18 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 23 PY 2009 VL 4 IS 12 AR e8428 DI 10.1371/journal.pone.0008428 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 535UT UT WOS:000272998100015 PM 20037650 ER PT J AU Kerkar, SP Kemp, CD Duffy, A Kammula, US Schrump, DS Kwong, KF Quezado, M Goldspiel, BR Venkatesan, A Berger, A Walker, M Toomey, MA Steinberg, SM Giaccone, G Rosenberg, SA Avital, I AF Kerkar, Sid P. Kemp, Clinton D. Duffy, Austin Kammula, Udai S. Schrump, David S. Kwong, King F. Quezado, Martha Goldspiel, Barry R. Venkatesan, Aradhana Berger, Ann Walker, Melissa Toomey, Mary Ann Steinberg, Seth M. Giaccone, Guiseppe Rosenberg, Steven A. Avital, Itzhak TI The GYMSSA trial: a prospective randomized trial comparing gastrectomy, metastasectomy plus systemic therapy versus systemic therapy alone SO TRIALS LA English DT Article ID ADVANCED GASTRIC-CANCER; ADVANCED ESOPHAGOGASTRIC CANCER; QUALITY-OF-LIFE; PHASE-II TRIAL; IRINOTECAN FOLFOXIRI; SURGICAL RESECTION; HEPATIC RESECTION; FLUOROURACIL; OXALIPLATIN; ADENOCARCINOMA AB Background: The standard of care for metastatic gastric cancer (MGC) is systemic chemotherapy which leads to a median survival of 6-15 months. Survival beyond 3 years is rare. For selected groups of patients with limited MGC, retrospective studies have shown improved overall survival following gastrectomy and metastasectomies including peritoneal stripping with continuous hyperthermic peritoneal perfusion (CHPP), liver resection, and pulmonary resection. Median survival after liver resection for MGC is up to 34 months, with a five year survival rate of 24.5%. Similarly, reported median survival after pulmonary resection of MGC is 21 months with long term survival of greater than 5 years a possibility. Several case reports and small studies have documented evidence of long-term survival in select individuals who undergo CHPP for MGC. Design: The GYMSSA trial is a prospective randomized trial for patients with MGC. It is designed to compare two therapeutic approaches: gastrectomy with metastasectomy plus systemic chemotherapy (GYMS) versus systemic chemotherapy alone (SA). Systemic therapy will be composed of the FOLFOXIRI regimen. The aim of the study is to evaluate overall survival and potential selection criteria to determine those patients who may benefit from surgery plus systemic therapy. The study will be conducted by the Surgery Branch at the National Cancer Institute (NCI), National Institutes of Health (NIH) in Bethesda, Maryland. Surgeries and followup will be done at the NCI, and chemotherapy will be given by either the local oncologist or the medical oncology branch at NCI. C1 [Kerkar, Sid P.; Kemp, Clinton D.; Kammula, Udai S.; Schrump, David S.; Kwong, King F.; Walker, Melissa; Toomey, Mary Ann; Rosenberg, Steven A.; Avital, Itzhak] NCI, Surg Branch, CCR, Bethesda, MD 20892 USA. [Duffy, Austin] NCI, Med Oncol Branch, CCR, Bethesda, MD 20892 USA. [Quezado, Martha] NCI, Pathol Lab, CCR, Bethesda, MD 20892 USA. [Goldspiel, Barry R.; Giaccone, Guiseppe] NIH, Clin Ctr Pharm, Bethesda, MD 20892 USA. [Venkatesan, Aradhana] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Berger, Ann] NIH, Pain & Palliat Care Serv, Ctr Clin, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, CCR, Bethesda, MD 20892 USA. RP Avital, I (reprint author), NCI, Surg Branch, CCR, Bldg 10, Bethesda, MD 20892 USA. EM kerkars@mail.nih.gov; kempc@mail.nih.gov; duffya@mail.nih.gov; kammulau@mail.nih.gov; schrumpd@mail.nih.gov; kwongk2@mail.nih.gov; quezadom@mail.nih.gov; bgoldspiel@mail.nih.gov; venkatesana@mail.nih.gov; aberger@mail.nih.gov; walkerme@mail.nih.gov; toomeym@mail.nih.gov; steinbes@mail.nih.gov; giacconeg@mail.nih.gov; sar@nih.gov; avitali@mail.nih.gov RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU NIH, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA FX This study is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, Bethesda, MD, USA. NR 29 TC 21 Z9 27 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6215 J9 TRIALS JI Trials PD DEC 23 PY 2009 VL 10 AR 121 DI 10.1186/1745-6215-10-121 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 541WV UT WOS:000273452900001 PM 20030854 ER PT J AU Hofer, T Skeffington, LR Chapman, CM Rader, C AF Hofer, Thomas Skeffington, Lauren R. Chapman, Colby M. Rader, Christoph TI Molecularly Defined Antibody Conjugation through a Selenocysteine Interface SO BIOCHEMISTRY LA English DT Article ID SITE-SPECIFIC CONJUGATION; CANCER-THERAPY; MONOCLONAL-ANTIBODIES; MAMMALIAN-CELLS; AVIDIN MONOMER; DRUG; FRAGMENTS; PROTEINS; ATTACHMENT; PEGYLATION AB Antibody conjugates have broad utility in basic, preclinical, and clinical applications. Conventional antibody conjugation through the amine group of lysine or the thiol group of cysteine residues yields heterogeneous products of undefined stoichiometry and considerable batch-to-batch variability. To preserve the two hallmarks of the antibody molecule, precision and predictability, methods that enable site-specific antibody conjugation are in high demand. On the basis of a mammalian cell expression system, we describe the utilization of the 21st natural amino acid selenocysteine for the generation of IgG and Fab molecules with unique nucleophilic reactivity that affords site-specific conjugation to electrophilic derivatives of biotin, fluorescein, and poly(ethylene glycol). The resulting antibody conjugates were found to fully retain their antigen binding capability and, in the case of IgG, the ability to mediate effector functions. Gain of function was demonstrated in vitro and in vivo. While these antibody conjugates are relevant For a variety of proteomic, diagnostic, and therapeutic applications, they also constitute a proof of principle for the generation of molecularly defined antibody-drug conjugates and radioimmunoconjugates. Compared to other site-specific antibody conjugation methods, selenocysteine interface technology (i) only involves it minor modification at the C-terminus that does not interfere with disulfide bridges, (ii) does not require activation, and (iii) generates unique 1:1 stoichiometries of biological and chemical components. Collectively, our method affords the generation of highly defined antibody conjugates with broad utility from proteomic applications to therapeutic intervention. C1 [Hofer, Thomas; Skeffington, Lauren R.; Chapman, Colby M.; Rader, Christoph] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Rader, C (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bldg 10 CRC,Room 3-3150,9000 Rockville Pike, Bethesda, MD 20892 USA. EM raderc@mail.nih.gov FU Center for Cancer Research; National Cancer Institute, National Institutes of Health; National Cancer Institute; National Institutes of Health; Georgetown University FX This work was supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and by an Intramural Innovation Award from the Director of the National Cancer Institute. L.R.S. is it graduate student of the Graduate Partnerships Program of the National Institutes of Health and Georgetown University. C.M.C. was a summer student supported by the Introduction to Cancer Research Careers Program of the National Cancer Institute, NR 44 TC 46 Z9 50 U1 0 U2 2 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 22 PY 2009 VL 48 IS 50 BP 12047 EP 12057 DI 10.1021/bi901744t PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 531EH UT WOS:000272645400024 PM 19894757 ER PT J AU Peddada, SD Umbach, DM Harris, SF AF Peddada, Shyamal D. Umbach, David M. Harris, Shawn F. TI A response to information criterion-based clustering with order-restricted candidate profiles in short time-course microarray experiments SO BMC BIOINFORMATICS LA English DT Letter ID INFERENCE AB Background: For gene expression data obtained from a time-course microarray experiment, Liu et al. [1] developed a new algorithm for clustering genes with similar expression profiles over time. Performance of their proposal was compared with three other methods including the order-restricted inference based methodology of Peddada et al. [2,3]. In this note we point out several inaccuracies in Liu et al. [1] and conclude that the order-restricted inference based methodology of Peddada et al. (programmed in the software ORIOGEN) indeed operates at the desired nominal Type 1 error level, an important feature of a statistical decision rule, while being computationally substantially faster than indicated by Liu et al. [1]. Results: Application of ORIOGEN to the well-known breast cancer cell line data of Lobenhofer et al. [4] revealed that ORIOGEN software took only 21 minutes to run (using 100,000 bootstraps with p = 0.0025), substantially faster than the 72 hours found by Liu et al. [1] using Matlab. Also, based on a data simulated according to the model and parameters of simulation 1 (sigma(2) = 1, M = 5) in [1] we found that ORIOGEN took less than 30 seconds to run in stark contrast to Liu et al. who reported that their implementation of the same algorithm in R took 2979.29 seconds. Furthermore, for the simulation studies reported in [1], unlike the claims made by Liu et al. [1], ORIOGEN always maintained the desired false positive rate. According to Figure three in Liu et al. [1] their algorithm had a false positive rate ranging approximately from 0.20 to 0.70 for the scenarios that they simulated. Conclusions: Our comparisons of run times indicate that the implementations of ORIOGEN's algorithm in Matlab and R by Liu et al. [1] is inefficient compared to the publicly available JAVA implementation. Our results on the false positive rate of ORIOGEN suggest some error in Figure three of Liu et al. [1], perhaps due to a programming error. C1 [Peddada, Shyamal D.; Umbach, David M.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Harris, Shawn F.] SRA Int Inc, Durham, NC 27713 USA. RP Peddada, SD (reprint author), NIEHS, Biostat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM peddada@niehs.nih.gov; umbach@niehs.nih.gov; Shawn_Harris@sra.com RI Peddada, Shyamal/D-1278-2012 FU Intramural NIH HHS NR 7 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD DEC 22 PY 2009 VL 10 AR 438 DI 10.1186/1471-2105-10-438 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 551FM UT WOS:000274192200001 PM 20028515 ER PT J AU Chaitman, BR Hardison, RM Adler, D Gebhart, S Grogan, M Ocampo, S Sopko, G Ramires, JA Schneider, D Frye, RL AF Chaitman, Bernard R. Hardison, Regina M. Adler, Dale Gebhart, Suzanne Grogan, Mary Ocampo, Salvador Sopko, George Ramires, Jose A. Schneider, David Frye, Robert L. CA BARI 2D Study Grp TI The Bypass Angioplasty Revascularization Investigation 2 Diabetes Randomized Trial of Different Treatment Strategies in Type 2 Diabetes Mellitus With Stable Ischemic Heart Disease Impact of Treatment Strategy on Cardiac Mortality and Myocardial Infarction SO CIRCULATION LA English DT Article DE angioplasty; bypass; diabetes mellitus; myocardial infarction; prognosis ID CORONARY-ARTERY-DISEASE; PLASMINOGEN-ACTIVATOR INHIBITOR-1; GLUCOSE CONTROL; LIFE-EXPECTANCY; MEDICAL THERAPY; WALL THICKNESS; GRAFT-SURGERY; BARI; DESIGN; RATIONALE AB Background-The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial in 2368 patients with stable ischemic heart disease assigned before randomization to percutaneous coronary intervention or coronary artery bypass grafting strata reported similar 5-year all-cause mortality rates with insulin sensitization versus insulin provision therapy and with a strategy of prompt initial coronary revascularization and intensive medical therapy or intensive medical therapy alone with revascularization reserved for clinical indication(s). In this report, we examine the predefined secondary end points of cardiac death and myocardial infarction (MI). Methods and Results-Outcome data were analyzed by intention to treat; the Kaplan-Meier method was used to assess 5-year event rates. Nominal P values are presented. During an average 5.3-year follow-up, there were 316 deaths (43% were attributed to cardiac causes) and 279 first MI events. Five-year cardiac mortality did not differ between revascularization plus intensive medical therapy (5.9%) and intensive medical therapy alone groups (5.7%; P = 0.38) or between insulin sensitization (5.7%) and insulin provision therapy (6%; P = 0.76). In the coronary artery bypass grafting stratum (n = 763), MI events were significantly less frequent in revascularization plus intensive medical therapy versus intensive medical therapy alone groups (10.0% versus 17.6%; P = 0.003), and the composite end points of all-cause death or MI (21.1% versus 29.2%; P = 0.010) and cardiac death or MI (P = 0.03) were also less frequent. Reduction in MI (P = 0.001) and cardiac death/MI (P = 0.002) was significant only in the insulin sensitization group. Conclusions-In many patients with type 2 diabetes mellitus and stable ischemic coronary disease in whom angina symptoms are controlled, similar to those enrolled in the percutaneous coronary intervention stratum, intensive medical therapy alone should be the first-line strategy. In patients with more extensive coronary disease, similar to those enrolled in the coronary artery bypass grafting stratum, prompt coronary artery bypass grafting, in the absence of contraindications, intensive medical therapy, and an insulin sensitization strategy appears to be a preferred therapeutic strategy to reduce the incidence of MI. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305. (Circulation. 2009;120:2529-2540.) C1 [Chaitman, Bernard R.] St Louis Univ, Sch Med, St Louis, MO 63117 USA. [Hardison, Regina M.] Univ Pittsburgh, Pittsburgh, PA USA. [Adler, Dale] Brigham & Womens Hosp, Boston, MA 02115 USA. [Gebhart, Suzanne] Emory Univ, Santa Fe, NM USA. [Grogan, Mary] Brown Univ, Providence, RI 02912 USA. [Ocampo, Salvador] Mexican Inst Social Secur, Mexico City, DF, Mexico. [Sopko, George] Natl Inst Hlth, Bethesda, MD USA. [Ramires, Jose A.] Univ Sao Paulo, Inst Heart, Sao Paulo, Brazil. [Schneider, David] Univ Vermont, Fletcher Allen Hlth Care, Cardiovasc Res Labs, Colchester, VT USA. [Frye, Robert L.] Mayo Clin, Rochester, MN USA. RP Chaitman, BR (reprint author), St Louis Univ, Sch Med, 1034 S Brentwood Blvd,Suite 1550, St Louis, MO 63117 USA. EM chaitman@slu.edu FU NCATS NIH HHS [UL1 TR000454]; NHLBI NIH HHS [U01 HL061744-08, U01 HL061744, U01 HL061746, U01 HL061746-07, U01 HL061748, U01 HL061748-07, U01 HL063804, U01 HL063804-07] NR 41 TC 112 Z9 123 U1 2 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 22 PY 2009 VL 120 IS 25 BP 2529 EP U44 DI 10.1161/CIRCULATIONAHA.109.913111 PG 18 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 535LX UT WOS:000272970900004 PM 19920001 ER PT J AU Chen, XJ Koh, E Yoder, M Gumbiner, BM AF Chen, Xuejun Koh, Eunjin Yoder, Michael Gumbiner, Barry M. TI A Protocadherin-Cadherin-FLRT3 Complex Controls Cell Adhesion and Morphogenesis SO PLOS ONE LA English DT Article ID E-CADHERIN; PARAXIAL PROTOCADHERIN; TISSUE RECONSTRUCTION; DISSOCIATED CELLS; MECHANISM; ENDOCYTOSIS; PROTEINS; INVOLVEMENT; NEURONS; RND1 AB Background: Paraxial protocadherin (PAPC) and fibronectin leucine-rich domain transmembrane protein-3 (FLRT3) are induced by TGF beta signaling in Xenopus embryos and both regulate morphogenesis by inhibiting C-cadherin mediated cell adhesion. Principal Findings: We have investigated the functional and physical relationships between PAPC, FLRT3, and C-cadherin. Although neither PAPC nor FLRT3 are required for each other to regulate C-cadherin adhesion, they do interact functionally and physically, and they form a complex with cadherins. By itself PAPC reduces cell adhesion physiologically to induce cell sorting, while FLRT3 disrupts adhesion excessively to cause cell dissociation. However, when expressed together PAPC limits the cell dissociating and tissue disrupting activity of FLRT3 to make it effective in physiological cell sorting. PAPC counteracts FLRT3 function by inhibiting the recruitment of the GTPase RND1 to the FLRT3 cytoplasmic domain. Conclusions/Significance: PAPC and FLRT3 form a functional complex with cadherins and PAPC functions as a molecular "governor'' to maintain FLRT3 activity at the optimal level for physiological regulation of C-cadherin adhesion, cell sorting, and morphogenesis. C1 [Chen, Xuejun; Koh, Eunjin; Yoder, Michael; Gumbiner, Barry M.] Univ Virginia, Hlth Sci Ctr, Dept Cell Biol, Charlottesville, VA USA. RP Chen, XJ (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM gumbiner@virginia.edu FU US National Institutes of Health [R01GM52717] FX This work was supported by US National Institutes of Health grants R01GM52717 (www.nih.gov). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 34 Z9 35 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 22 PY 2009 VL 4 IS 12 AR e8411 DI 10.1371/journal.pone.0008411 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 535US UT WOS:000272998000016 PM 20027292 ER PT J AU Nasrin, N Kaushik, VK Fortier, E Wall, D Pearson, KJ de Cabo, R Bordone, L AF Nasrin, Nargis Kaushik, Virendar K. Fortier, Eric Wall, Daniel Pearson, Kevin J. de Cabo, Rafael Bordone, Laura TI JNK1 Phosphorylates SIRT1 and Promotes Its Enzymatic Activity SO PLOS ONE LA English DT Article ID EXTENDS LIFE-SPAN; OXIDATIVE STRESS; CALORIE RESTRICTION; CAENORHABDITIS-ELEGANS; HISTONE DEACETYLASE; CELL APOPTOSIS; LONGEVITY; TRANSCRIPTION; PATHWAYS; SURVIVAL AB SIRT1 is a NAD-dependent deacetylase that regulates a variety of pathways including the stress protection pathway. SIRT1 deacetylates a number of protein substrates, including histones, FOXOs, PGC-1 alpha, and p53, leading to cellular protection. We identified a functional interaction between cJUN N-terminal kinase (JNK1) and SIRT1 by coimmunoprecipitation of endogenous proteins. The interaction between JNK1 and SIRT1 was identified under conditions of oxidative stress and required activation of JNK1 via phosphorylation. Modulation of SIRT1 activity or protein levels using nicotinamide or RNAi did not modify JNK1 activity as measured by its ability to phosphorylate cJUN. In contrast, human SIRT1 was phosphorylated by JNK1 on three sites: Ser27, Ser47, and Thr530 and this phosphorylation of SIRT1 increased its nuclear localization and enzymatic activity. Surprisingly, JNK1 phosphorylation of SIRT1 showed substrate specificity resulting in deacetylation of histone H3, but not p53. These findings identify a mechanism for regulation of SIRT1 enzymatic activity in response to oxidative stress and shed new light on its role in the stress protection pathway. C1 [Nasrin, Nargis; Kaushik, Virendar K.; Fortier, Eric; Bordone, Laura] Novartis Inst BioMed Res Inc, Cardiovasc & Metab Dis Area, Cambridge, MA USA. [Kaushik, Virendar K.] Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer USDA, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [Pearson, Kevin J.; de Cabo, Rafael] NIA, NIH, Bethesda, MD 20892 USA. RP Nasrin, N (reprint author), Novartis Inst BioMed Res Inc, Cardiovasc & Metab Dis Area, Cambridge, MA USA. EM laura.bordone@novartis.com RI de Cabo, Rafael/J-5230-2016 OI , rafael/0000-0003-2830-5693; de Cabo, Rafael/0000-0002-3354-2442 FU National Institutes of Health (NIH); National Institute on Aging (NIA); Novartis Institutes for Biomedical Research FX This research was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute on Aging (NIA), and by internal funding from Novartis Institutes for Biomedical Research. Employees of the entities sponsoring the work were involved in conception, experimental design, analysis, and preparation of the paper. NR 24 TC 125 Z9 136 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 22 PY 2009 VL 4 IS 12 AR e8414 DI 10.1371/journal.pone.0008414 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 535US UT WOS:000272998000018 PM 20027304 ER PT J AU Shriner, D Adeyemo, A Gerry, NP Herbert, A Chen, GJ Doumatey, A Huang, HX Zhou, J Christman, MF Rotimi, CN AF Shriner, Daniel Adeyemo, Adebowale Gerry, Norman P. Herbert, Alan Chen, Guanjie Doumatey, Ayo Huang, Hanxia Zhou, Jie Christman, Michael F. Rotimi, Charles N. TI Transferability and Fine-Mapping of Genome-Wide Associated Loci for Adult Height across Human Populations SO PLOS ONE LA English DT Article ID BODY-MASS INDEX; LINKAGE DISEQUILIBRIUM; AFRICAN-AMERICAN; COMMON VARIANTS; FLIP-FLOP; STATURE; HERITABILITY; SCAN; GENE; REGIONS AB Human height is the prototypical polygenic quantitative trait. Recently, several genetic variants influencing adult height were identified, primarily in individuals of East Asian (Chinese Han or Korean) or European ancestry. Here, we examined 152 genetic variants representing 107 independent loci previously associated with adult height for transferability in a well-powered sample of 1,016 unrelated African Americans. When we tested just the reported variants originally identified as associated with adult height in individuals of East Asian or European ancestry, only 8.3% of these loci transferred (p-values <= 0.05 under an additive genetic model with directionally consistent effects) to our African American sample. However, when we comprehensively evaluated all HapMap variants in linkage disequilibrium (r(2) >= 0.3) with the reported variants, the transferability rate increased to 54.1%. The transferability rate was 70.8% for associations originally reported as genome-wide significant and 38.0% for associations originally reported as suggestive. An additional 23 loci were significantly associated but failed to transfer because of directionally inconsistent effects. Six loci were associated with adult height in all three groups. Using differences in linkage disequilibrium patterns between HapMap CEU or CHB reference data and our African American sample, we fine-mapped these six loci, improving both the localization and the annotation of these transferable associations. C1 [Shriner, Daniel; Adeyemo, Adebowale; Chen, Guanjie; Doumatey, Ayo; Huang, Hanxia; Zhou, Jie; Rotimi, Charles N.] NIH, Ctr Res Gen & Global Hlth, NHGRI, Bethesda, MD 20892 USA. [Gerry, Norman P.; Christman, Michael F.] Coriell Inst Med Res, Camden, NJ USA. [Herbert, Alan] Boston Univ, Sch Med, Dept Genet & Gen, Boston, MA 02118 USA. RP Shriner, D (reprint author), NIH, Ctr Res Gen & Global Hlth, NHGRI, Bldg 10, Bethesda, MD 20892 USA. EM shrinerda@mail.nih.gov; rotimic@mail.nih.gov OI Adeyemo, Adebowale/0000-0002-3105-3231 FU National Institutes of Health [S06GM008016-320107, S06GM008016-380111, 2M01RR010284]; Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health [Z01HG200362]; Coriell Institute FX The Howard University Family Study was supported by National Institutes of Health grants S06GM008016-320107 to CNR and S06GM008016-380111 to AA. Enrollment was carried out at the Howard University General Clinical Research Center, supported by National Institutes of Health grant 2M01RR010284. This research was supported in part by the Intramural Research Program of the Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health (Z01HG200362). Genotyping support was provided by the Coriell Institute for Medical Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 39 TC 35 Z9 35 U1 2 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 22 PY 2009 VL 4 IS 12 AR e8398 DI 10.1371/journal.pone.0008398 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 535US UT WOS:000272998000006 PM 20027299 ER PT J AU Strunnikova, NV Barb, J Sergeev, YV Thiagarajasubramanian, A Silvin, C Munson, PJ MacDonald, IM AF Strunnikova, Natalia V. Barb, Jennifer Sergeev, Yuri V. Thiagarajasubramanian, Ashwin Silvin, Christopher Munson, Peter J. MacDonald, Ian M. TI Loss-of-Function Mutations in Rab Escort Protein 1 (REP-1) Affect Intracellular Transport in Fibroblasts and Monocytes of Choroideremia Patients SO PLOS ONE LA English DT Article ID RETINAL-PIGMENT EPITHELIUM; MACULAR DEGENERATION; DRUSEN FORMATION; PLASMA-MEMBRANE; GENE-EXPRESSION; MOLECULAR-BASIS; CELLS; DISEASE; EXOCYTOSIS; RPE AB Background: Choroideremia (CHM) is a progressive X-linked retinopathy caused by mutations in the CHM gene, which encodes Rab escort protein-1 (REP-1), an escort protein involved in the prenylation of Rabs. Under-prenylation of certain Rabs, as a result of loss of function mutations in REP-1, could affect vesicular trafficking, exocytosis and secretion in peripheral cells of CHM patients. Methodology/Principal Findings: To evaluate this hypothesis, intracellular vesicle transport, lysosomal acidification and rates of proteolytic degradation were studied in monocytes (CD14+ fraction) and primary skin fibroblasts from the nine age-matched controls and thirteen CHM patients carrying 10 different loss-of-function mutations. With the use of pHrodo (TM) BioParticles (R) conjugated with E. coli, collagen I coated FluoSpheres beads and fluorescent DQ (TM) ovalbumin with BODYPY FL dye, we demonstrated for the first time that lysosomal pH was increased in monocytes of CHM patients and, as a consequence, the rates of proteolytic degradation were slowed. Microarray analysis of gene expression revealed that some genes involved in the immune response, small GTPase regulation, transcription, cell adhesion and the regulation of exocytosis were significantly up and down regulated in cells from CHM patients compared to controls. Finally, CHM fibroblasts secreted significantly lower levels of cytokine/growth factors such as macrophage chemoattractant protein-1 (MCP-1), pigment epithelial derived factor (PEDF), tumor necrosis factor (TNF) alpha, fibroblast growth factor (FGF) beta and interleukin (IL)-8. Conclusions/Significance: We demonstrated for the first time that peripheral cells of CHM patients had increased pH levels in lysosomes, reduced rates of proteolytic degradation and altered secretion of cytokines. Peripheral cells from CHM patients expose characteristics that were not previously recognized and could used as an alternative models to study the effects of different mutations in the REP-1 gene on mechanism of CHM development in human population. C1 [Strunnikova, Natalia V.; Sergeev, Yuri V.; Thiagarajasubramanian, Ashwin] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. [Barb, Jennifer; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. [Silvin, Christopher] NIH, Genet & Mol Biol Branch, NHGRI, Bethesda, MD 20892 USA. [MacDonald, Ian M.] Univ Alberta, Dept Ophthalmol, Edmonton, AB, Canada. RP Strunnikova, NV (reprint author), NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. EM Strunnikovan@nei.nih.gov OI MacDonald, Ian/0000-0001-7472-8385 FU National Institutes of Health (NIH) FX This study was supported by the Intramural NIH research program. The sponsor had no role in the design, data analysis, interpretation, or writing of the report. The manuscript was reviewed and cleared for publication by the Division of Intramural Research, National Institutes of Health prior to submission. NR 61 TC 21 Z9 21 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 22 PY 2009 VL 4 IS 12 AR e8402 DI 10.1371/journal.pone.0008402 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 535US UT WOS:000272998000009 PM 20027300 ER PT J AU Zerbino, DR McEwen, GK Margulies, EH Birney, E AF Zerbino, Daniel R. McEwen, Gayle K. Margulies, Elliott H. Birney, Ewan TI Pebble and Rock Band: Heuristic Resolution of Repeats and Scaffolding in the Velvet Short-Read de Novo Assembler SO PLOS ONE LA English DT Article ID SHORT DNA-SEQUENCES; GENOME; ALGORITHM; MILLIONS AB Background: Despite the short length of their reads, micro-read sequencing technologies have shown their usefulness for de novo sequencing. However, especially in eukaryotic genomes, complex repeat patterns are an obstacle to large assemblies. Principal Findings: We present a novel heuristic algorithm, Pebble, which uses paired-end read information to resolve repeats and scaffold contigs to produce large-scale assemblies. In simulations, we can achieve weighted median scaffold lengths (N50) of above 1 Mbp in Bacteria and above 100 kbp in more complex organisms. Using real datasets we obtained a 96 kbp N50 in Pseudomonas syringae and a unique 147 kbp scaffold of a ferret BAC clone. We also present an efficient algorithm called Rock Band for the resolution of repeats in the case of mixed length assemblies, where different sequencing platforms are combined to obtain a cost-effective assembly. Conclusions: These algorithms extend the utility of short read only assemblies into large complex genomes. They have been implemented and made available within the open-source Velvet short-read de novo assembler. C1 [Zerbino, Daniel R.; Birney, Ewan] European Bioinformat Inst, Cambridge, England. [McEwen, Gayle K.; Margulies, Elliott H.] NIH, Genome Technol Branch, NHGRI, Bethesda, MD 20892 USA. RP Zerbino, DR (reprint author), European Bioinformat Inst, Wellcome Trust Genome Campus, Cambridge, England. EM zerbino@ebi.ac.uk OI Birney, Ewan/0000-0001-8314-8497; Zerbino, Daniel/0000-0001-5350-3056 FU European Molecular Biology Laboratory; National Human Genome Research Institute FX D. R. Z. and E. B. are funded by European Molecular Biology Laboratory's central funds, G. K. M. and E. H. M by the Intramural Research Program of the National Human Genome Research Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 29 TC 93 Z9 93 U1 2 U2 16 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 22 PY 2009 VL 4 IS 12 AR e8407 DI 10.1371/journal.pone.0008407 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 535US UT WOS:000272998000012 PM 20027311 ER PT J AU Kanodia, JS Rikhy, R Kim, Y Lund, VK DeLotto, R Lippincott-Schwartz, J Shvartsman, SY AF Kanodia, Jitendra S. Rikhy, Richa Kim, Yoosik Lund, Viktor K. DeLotto, Robert Lippincott-Schwartz, Jennifer Shvartsman, Stanislav Y. TI Dynamics of the Dorsal morphogen gradient SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE computational modeling; Drosophila; systems biology; parameter estimation ID DORSOVENTRAL AXIS FORMATION; NEUROGENIC GENE-EXPRESSION; SHORT-GERM BEETLE; DROSOPHILA-EMBRYO; POSITIONAL INFORMATION; TRIBOLIUM-CASTANEUM; NUCLEAR; PROTEIN; NEUROECTODERM; EMBRYOGENESIS AB The dorsoventral (DV) patterning of the Drosophila embryo depends on the nuclear localization gradient of Dorsal (Dl), a protein related to the mammalian NF-kappa B transcription factors. Current understanding of how the Dl gradient works has been derived from studies of its transcriptional interpretation, but the gradient itself has not been quantified. In particular, it is not known whether the Dl gradient is stable or dynamic during the DV patterning of the embryo. To address this question, we developed a mathematical model of the Dl gradient and constrained its parameters by experimental data. Based on our computational analysis, we predict that the Dl gradient is dynamic and, to a first approximation, can be described as a concentration profile with increasing amplitude and constant shape. These time-dependent properties of the Dl gradient are different from those of the Bicoid and MAPK phosphorylation gradients, which pattern the anterior and terminal regions of the embryo. Specifically, the gradient of the nuclear levels of Bicoid is stable, whereas the pattern of MAPK phosphorylation changes in both shape and amplitude. We attribute these striking differences in the dynamics of maternal morphogen gradients to the differences in the initial conditions and chemistries of the anterior, DV, and terminal systems. C1 [Rikhy, Richa; Lippincott-Schwartz, Jennifer] NIH, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. [Kanodia, Jitendra S.; Kim, Yoosik; Shvartsman, Stanislav Y.] Princeton Univ, Dept Chem Engn, Princeton, NJ 08544 USA. [Kanodia, Jitendra S.; Kim, Yoosik; Shvartsman, Stanislav Y.] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08544 USA. [Lund, Viktor K.; DeLotto, Robert] Univ Copenhagen, Dept Mol Biol, DK-2200 Copenhagen, Denmark. RP Lippincott-Schwartz, J (reprint author), NIH, Cell Biol & Metab Branch, Bldg 32,18 Lib Dr, Bethesda, MD 20892 USA. EM jlippin@helix.nih.gov; stas@princeton.edu RI Rikhy, Richa/J-4481-2012; Kim, Yoosik/B-9009-2016; OI Kim, Yoosik/0000-0003-3064-4643; Rikhy, Richa/0000-0002-4262-0238 NR 40 TC 58 Z9 59 U1 2 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 22 PY 2009 VL 106 IS 51 BP 21707 EP 21712 DI 10.1073/pnas.0912395106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 535TM UT WOS:000272994200045 PM 19996178 ER PT J AU Boyer, M Yutin, N Pagnier, I Barrassi, L Fournous, G Espinosa, L Robert, C Azza, S Sun, SY Rossmann, MG Suzan-Monti, M La Scola, B Koonin, EV Raoult, D AF Boyer, Mickael Yutin, Natalya Pagnier, Isabelle Barrassi, Lina Fournous, Ghislain Espinosa, Leon Robert, Catherine Azza, Said Sun, Siyang Rossmann, Michael G. Suzan-Monti, Marie La Scola, Bernard Koonin, Eugene V. Raoult, Didier TI Giant Marseillevirus highlights the role of amoebae as a melting pot in emergence of chimeric microorganisms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE giant virus; horizontal gene transfer; nucleocytoplasmic large DNA virus; viral evolution ID COMPLETE GENOME SEQUENCE; LARGE DNA VIRUSES; MIMIVIRUS; ANNOTATION; PARASITE; DATABASE; PROTEIN; GENES AB Giant viruses such as Mimivirus isolated from amoeba found in aquatic habitats show biological sophistication comparable to that of simple cellular life forms and seem to evolve by similar mechanisms, including extensive gene duplication and horizontal gene transfer (HGT), possibly in part through a viral parasite, the virophage. We report here the isolation of "Marseille" virus, a previously uncharacterized giant virus of amoeba. The virions of Marseillevirus encompass a 368-kb genome, a minimum of 49 proteins, and some messenger RNAs. Phylogenetic analysis of core genes indicates that Marseillevirus is the prototype of a family of nucleocytoplasmic large DNA viruses (NCLDV) of eukaryotes. The genome repertoire of the virus is composed of typical NCLDV core genes and genes apparently obtained from eukaryotic hosts and their parasites or symbionts, both bacterial and viral. We propose that amoebae are "melting pots" of microbial evolution where diverse forms emerge, including giant viruses with complex gene repertoires of various origins. C1 [Sun, Siyang; Rossmann, Michael G.] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. [Boyer, Mickael; Pagnier, Isabelle; Barrassi, Lina; Fournous, Ghislain; Espinosa, Leon; Robert, Catherine; Azza, Said; Suzan-Monti, Marie; La Scola, Bernard; Raoult, Didier] Univ Aix Marseille 2, Unite Rech Malad Infect & Trop Emergentes, CNRS, Fac Med,UMR,Inst Rech Dev 6236, F-13385 Marseille 5, France. [Yutin, Natalya; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Rossmann, MG (reprint author), Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. EM mr@purdue.edu; didier.raoult@gmail.com RI Boyer, Mickael/F-6608-2013; LA SCOLA, Bernard/P-6477-2016; OI Boyer, Mickael/0000-0001-5384-1151; LA SCOLA, Bernard/0000-0001-8006-7704; Pagnier, Isabelle/0000-0002-1724-3450 FU Centre National de la Recherche Scientifique (CNRS); Conventions Industrielles de Formation par la Recherche; National Institutes of Health National Library of Medicine; National Institutes of Health [AI11219] FX We are grateful to Bernard Campagna for his technical assistance with electron microscopy, Valorie D. Bowman for collecting data for the cryo-EM reconstruction of Marseillevirus, Claude Nappez for anti-Marseillevirus monoclonal antibody production, Bernadette Giumelli and Thi Tien N'Guyen for technical assistance in genome sequencing, Philippe de Clocquement for protein identification, Angelique Campocasso for help in detection of viral RNA, Kira Makarova and Yuri Wolf for help with sequence analysis, Michele Merchat for providing water samples, and Christelle Desnues for reading the manuscript. This work was funded by the Centre National de la Recherche Scientifique (CNRS, credits re currents), a Conventions Industrielles de Formation par la Recherche fellowship (I. P.), Intramural Research Program of the National Institutes of Health National Library of Medicine (N.Y. and E. K), and National Institutes of Health Grant AI11219 (to S. S. and M. G. R.). NR 31 TC 145 Z9 149 U1 0 U2 27 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 22 PY 2009 VL 106 IS 51 BP 21848 EP 21853 DI 10.1073/pnas.0911354106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 535TM UT WOS:000272994200070 PM 20007369 ER PT J AU Udho, E Jakes, KS Buchanan, SK James, KJ Jiang, XX Klebba, PE Finkelstein, A AF Udho, Eshwar Jakes, Karen S. Buchanan, Susan K. James, Karron J. Jiang, Xiaoxu Klebba, Phillip E. Finkelstein, Alan TI Reconstitution of bacterial outer membrane TonB-dependent transporters in planar lipid bilayer membranes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE BtuB; Cir; FhuA; urea-denaturation ID COLICIN-I RECEPTOR; ESCHERICHIA-COLI; COBALAMIN TRANSPORTER; CRYSTAL-STRUCTURE; R-DOMAIN; FHUA; PROTEIN; CHANNEL; BTUB; COMPLEX AB Micronutrients such as siderophore-bound iron and vitamin B(12) cross the outer membrane of Gram-negative bacteria through a group of 22-stranded beta-barrel proteins. They share the unusual feature that their N-terminal end inserts from the periplasmic side into the beta-barrel and plugs the lumen. Transport results from energy-driven movement of TonB protein, which either pulls the plug out of the barrel or causes it to rearrange within the barrel. Attempts to reconstitute native plugged channels in an ion-conducting state in lipid bilayer membranes have so far been unsuccessful. We, however, have discovered that if the cis solution contained 4 M urea, then, with the periplasmic side of the channel facing that solution, macroscopic conductances and single channel events could be observed. These results were obtained with FhuA, Cir, and BtuB; for the former two, the channels were closed by removing the 4 M urea. Channels generated by 4 M urea exposure were not a consequence of general protein denaturation, as their ligand-binding properties were preserved. Thus, with FhuA, addition of ferrichrome (its siderophore) to the trans, extracellular-facing side reversibly inhibited 4 M urea-induced channel opening and blocked the channels. With Cir, addition of colicin la (the microbial toxin that targets Cir) to the trans, extracellular-facing side prevented 4 M urea-induced channel opening. We hypothesize that 4 M urea reversibly unfolds the FhuA and Cir plugs, thereby opening an ion-conducting pathway through these channels, and that this mimics to some extent the in vivo action of TonB on these plugs. C1 [Udho, Eshwar; Jakes, Karen S.; Finkelstein, Alan] Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA. [Buchanan, Susan K.] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [James, Karron J.] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada. [Jiang, Xiaoxu; Klebba, Phillip E.] Univ Oklahoma, Dept Chem & Biochem, Norman, OK 73019 USA. RP Udho, E (reprint author), Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10461 USA. EM eudho@aecom.yu.edu RI Jiang, xiaoxu/B-6996-2012 FU National Institutes of Health [GM29210, GM53836, GM008572]; National Science Foundation [MCB-0414694]; National Institute of Diabetes and Digestive and Kidney Diseases; Canadian Institutes of Health Research [MOP 14133, PRG 82674]; Canada Foundation for Innovation FX We thank Dr. James W. Coulton for his generous gift of FhuA protein and phage T5 and his helpful discussions throughout this work, and Dr. William Cramer for the gift of BtuB. This work was supported by National Institutes of Health Grants GM29210 (to A. F.), GM53836 (to P. E. K.) and GM008572 (to E. U.); National Science Foundation Grant MCB-0414694 (to P. E. K.); Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases (S. K. B.); Canadian Institutes of Health Research Grants MOP 14133 to J. W. Coulton (K. J. J.) and PRG 82674 (to K. J. J.); and the Canada Foundation for Innovation (K. J. J.). NR 37 TC 15 Z9 15 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 22 PY 2009 VL 106 IS 51 BP 21990 EP 21995 DI 10.1073/pnas.0910023106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 535TM UT WOS:000272994200094 PM 19959664 ER PT J AU Vogel, SS AF Vogel, Steven S. TI Channeling Calcium: A Shared Mechanism for Exocytosis-Endocytosis Coupling SO SCIENCE SIGNALING LA English DT Article ID COMPENSATORY ENDOCYTOSIS; DEPOLARIZATION; SECRETION; INFLUX; FORMS; CA2+ AB Cell surface area is maintained in most cells by coupling exocytotic activity to compensatory endocytosis, a process that specifically retrieves membrane inserted by exocytosis. Although such coupling mechanisms seem to be ubiquitous, the mechanisms through which these membrane trafficking events are linked have remained elusive. A mechanism for coupling exocytosis to endocytosis in fruit fly nerve terminals that depends on the exocytotic insertion of vesicular calcium channels into the plasma membrane has recently been identified. This coupling mechanism resembles one previously described in sea urchin eggs. Here, I compare the similarities and differences of the processes involved in linking exocytosis to endocytosis in these two invertebrate systems and speculate on whether the vertebrate coupling mechanism might also depend on vesicular channels. C1 NIAAA, NIH, Rockville, MD 20892 USA. RP Vogel, SS (reprint author), NIAAA, NIH, 5625 Fishers Lane, Rockville, MD 20892 USA. EM stevevog@mail.nih.gov RI Vogel, Steven/A-3585-2012; OI Vogel, Steven/0000-0002-3005-2667 FU National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism FX This work was supported by the intramural program of the National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism. NR 17 TC 6 Z9 6 U1 0 U2 2 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 22 PY 2009 VL 2 IS 102 AR pe80 DI 10.1126/scisignal.2102pe80 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 570BN UT WOS:000275646700003 PM 20029028 ER PT J AU Shehata, ML Cheng, S Osman, NF Bluemke, DA Lima, JAC AF Shehata, Monda L. Cheng, Susan Osman, Nael F. Bluemke, David A. Lima, Joao A. C. TI Myocardial tissue tagging with cardiovascular magnetic resonance SO JOURNAL OF CARDIOVASCULAR MAGNETIC RESONANCE LA English DT Review ID LEFT-VENTRICULAR FUNCTION; TAGGED MR-IMAGES; BUNDLE-BRANCH BLOCK; HARMONIC-PHASE MRI; HYPERTROPHIC CARDIOMYOPATHY; QUANTITATIVE ASSESSMENT; DILATED CARDIOMYOPATHY; DIASTOLIC DYSFUNCTION; STRAIN ANALYSIS; CARDIAC RESYNCHRONIZATION AB Cardiovascular magnetic resonance (CMR) is currently the gold standard for assessing both global and regional myocardial function. New tools for quantifying regional function have been recently developed to characterize early myocardial dysfunction in order to improve the identification and management of individuals at risk for heart failure. Of particular interest is CMR myocardial tagging, a non-invasive technique for assessing regional function that provides a detailed and comprehensive examination of intra-myocardial motion and deformation. Given the current advances in gradient technology, image reconstruction techniques, and data analysis algorithms, CMR myocardial tagging has become the reference modality for evaluating multidimensional strain evolution in the human heart. This review presents an in depth discussion on the current clinical applications of CMR myocardial tagging and the increasingly important role of this technique for assessing subclinical myocardial dysfunction in the setting of a wide variety of myocardial disease processes. C1 [Cheng, Susan; Lima, Joao A. C.] Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. [Bluemke, David A.] NIH, Dept Radiol, Bethesda, MD 20892 USA. [Shehata, Monda L.; Osman, Nael F.] Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. RP Lima, JAC (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. EM mshehat1@jhmi.edu; scheng32@jhmi.edu; nael@jhu.edu; bluemked@cc.nih.gov; jlima@jhmi.edu OI Bluemke, David/0000-0002-8323-8086 FU Intramural NIH HHS [ZIA EB000072-01, ZIA CL090019-01] NR 80 TC 72 Z9 74 U1 1 U2 7 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 21 PY 2009 VL 11 AR 55 DI 10.1186/1532-429X-11-55 PG 12 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 545TO UT WOS:000273759900001 PM 20025732 ER PT J AU Huang, JH Goedert, JJ Sundberg, EJ Cung, TDH Burke, PS Martin, MP Preiss, L Lifson, J Lichterfeld, M Carrington, M Yu, XG AF Huang, Jinghe Goedert, James J. Sundberg, Eric J. Cung, Thai Duong Hong Burke, Patrick S. Martin, Maureen P. Preiss, Liliana Lifson, Jeffrey Lichterfeld, Mathias Carrington, Mary Yu, Xu G. TI HLA-B*35-Px-mediated acceleration of HIV-1 infection by increased inhibitory immunoregulatory impulses SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CLASS-I MOLECULES; IMMUNODEFICIENCY VIRUS-REPLICATION; CD8(+) T-CELLS; MYELOMONOCYTIC CELLS; HLA; AIDS; RECEPTOR; INDIVIDUALS; RECOGNITION; PROGRESSION AB A subset of HLA-B*35 alleles, B*35-Px, are strongly associated with accelerated HIV-1 disease progression for reasons that are not understood. Interestingly, the alternative set of B*35 subtypes, B*35-PY, have no detectable impact on HIV-1 disease outcomes, even though they can present identical HIV-1 epitopes as B*35-Px molecules. Thus, the differential impact of these alleles on HIV-1 disease progression may be unrelated to interactions with HIV-1-specific CD8(+) T cells. Here, we show that the B*35-Px molecule B*3503 binds with greater affinity to immunoglobulin-like transcript 4 (ILT4), an inhibitory MHC class I receptor expressed on dendritic cells, than does the B*35-PY molecule B*3501, even though these two B*35 molecules differ by only one amino acid and present identical HIV-1 epitopes. The preferential recognition of B*3503 by ILT4 was associated with significantly stronger dendritic cell dysfunction in in vitro functional assays. Moreover, HIV-1-infected carriers of B*3503 had poor dendritic cell functional properties in ex vivo assessments when compared with carriers of the B*3501 allele. Differential interactions between HLA class I allele subtypes and immunoregulatory MHC class I receptors on dendritic cells thus provide a novel perspective for the understanding of MHC class I associations with HIV-1 disease progression and for the manipulation of host immunity against HIV-1. C1 [Huang, Jinghe; Cung, Thai Duong Hong; Burke, Patrick S.; Yu, Xu G.] Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02129 USA. [Huang, Jinghe; Cung, Thai Duong Hong; Burke, Patrick S.; Yu, Xu G.] Harvard Univ, Boston, MA 02129 USA. [Goedert, James J.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Sundberg, Eric J.] Boston Biomed Res Inst, Watertown, MA 02472 USA. [Martin, Maureen P.; Carrington, Mary] NCI, Canc & Inflammat Program, Expt Immunol Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Lifson, Jeffrey] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Preiss, Liliana] Res Triangle Inst Int, Rockville, MD 20852 USA. [Lichterfeld, Mathias] Massachusetts Gen Hosp, Div Infect Dis, Boston, MA 02114 USA. RP Yu, XG (reprint author), Massachusetts Gen Hosp, MIT, Ragon Inst, Boston, MA 02129 USA. EM xyu@partners.org RI Huang, Jinghe/O-1986-2015 FU CCR NIH HHS [HHSN261200800001C]; Intramural NIH HHS; NCI NIH HHS [HHSN261200800001E, N02CP55504]; NIAID NIH HHS [AI078799, R01 AI078799]; PHS HHS [HHSN261200800001E, HHSN266200400088C] NR 25 TC 41 Z9 42 U1 1 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD DEC 21 PY 2009 VL 206 IS 13 BP 2959 EP 2966 DI 10.1084/jem.20091386 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 535RE UT WOS:000272987500013 PM 20008523 ER PT J AU Ueda, T Compe, E Catez, P Kraemer, KH Egly, JM AF Ueda, Takahiro Compe, Emmanuel Catez, Philippe Kraemer, Kenneth H. Egly, Jean-Marc TI Both XPD alleles contribute to the phenotype of compound heterozygote xeroderma pigmentosum patients SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID RNA-POLYMERASE-II; NUCLEOTIDE EXCISION-REPAIR; FACTOR TFIIH; DNA-REPAIR; TRANSCRIPTION FACTOR; COCKAYNE-SYNDROME; SKIN-CANCER; RESPONSIVE GENES; RAR-ALPHA; TRICHOTHIODYSTROPHY AB Mutations in the XPD subunit of the DNA repair/transcription factor TFIIH result in the rare recessive genetic disorder xeroderma pigmentosum (XP). Many XP patients are compound heterozygotes with a "causative" XPD point mutation R683W and different second mutant alleles, considered "null alleles." However, there is marked clinical heterogeneity (including presence or absence of skin cancers or neurological degeneration) in these XPD/R683W patients, thus suggesting a contribution of the second allele. Here, we report XP patients carrying XPD/R683W and a second XPD allele either XPD/Q452X, /I455del, or /199insPP. We performed a systematic study of the effect of these XPD mutations on several enzymatic functions of TFIIH and found that each mutation exhibited unique biochemical properties. Although all the mutations inhibited the nucleotide excision repair (NER) by disturbing the XPD helicase function, each of them disrupted specific molecular steps during transcription: XPD/Q452X hindered the transactivation process, XPD/I455del disturbed RNA polymerase II phosphorylation, and XPD/199insPP inhibited kinase activity of the cdk7 subunit of TFIIH. The broad range and severity of clinical features in XP patients arise from a broad set of deficiencies in NER and transcription that result from the combination of mutations found on both XPD alleles. C1 [Ueda, Takahiro; Compe, Emmanuel; Catez, Philippe; Egly, Jean-Marc] Inst Genet & Biol Mol & Cellulaire, F-67404 Illkirch Graffenstaden, Cu Strasbourg, France. [Ueda, Takahiro; Kraemer, Kenneth H.] NCI, DNA Repair Sect, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20889 USA. [Compe, Emmanuel; Egly, Jean-Marc] Inst Rech Canc Appareil Digestif, F-67091 Strasbourg, France. RP Egly, JM (reprint author), Inst Genet & Biol Mol & Cellulaire, BP 10142, F-67404 Illkirch Graffenstaden, Cu Strasbourg, France. EM egly@igbmc.fr RI Compe, Emmanuel/N-8718-2016; OI Compe, Emmanuel/0000-0002-9189-7444 FU European Research Council; French League Against Cancer (Equipe Labellisee); French National Research Agency [ANR-08GENOPAT042]; U. S. National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD FX Work in J. M. Egly's laboratory is supported by a European Research Council Advanced Grant (2009). Funds from the French League Against Cancer (Equipe Labellisee) and the French National Research Agency (ANR-08GENOPAT042) supported this study. This research was supported in part by the Intramural Research Program of the U. S. National Institutes of Health, National Cancer Institute, Center for Cancer Research, Bethesda, MD. NR 56 TC 21 Z9 21 U1 0 U2 1 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 21 PY 2009 VL 206 IS 13 BP 3031 EP 3046 DI 10.1084/jem.20091892 PG 16 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 535RE UT WOS:000272987500019 PM 19934020 ER PT J AU Rios-Doria, D Chowell, G AF Rios-Doria, D. Chowell, G. TI Qualitative analysis of the level of cross-protection between epidemic waves of the 1918-1919 influenza pandemic SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE Mathematical model; Cross-immunity; Pandemic; Influenza; Reproduction number ID SPANISH FLU; TRANSMISSION; VIRUS; MORTALITY; DYNAMICS; IMPACT; AGE; SWITZERLAND; VACCINATION; FAMILIES AB The 1918-1919 influenza pandemic was composed of multiple waves with in a period of nine months in several regions of the world. Increasing our understanding of the mechanisms responsible for this multi-wave profile has important public health implications. We model the transmission dynamics of two strains of influenza interacting via cross-immunity to simulate two temporal waves of influenza and explore the impact of the basic reproduction number, as a measure of transmissibility associated to each influenza strain, cross-immunity and the timing of the onset of the second influenza epidemic on the pandemic profile. We use time series of case notifications during the 1918 influenza pandemic in Geneva, Switzerland, for illustration. We calibrate our mathematical model to the initial wave of infection to estimate the basic reproduction number of the first wave and the corresponding timing of onset of the second influenza variant. We use this information to explore the impact of cross-immunity levels on the dynamics of the second wave of influenza. Our results for the 1918 pandemic in Geneva, Switzerland, indicate that a second wave can occur whenever R(01) < 1.5 or when cross-immunity levels are less than 0.58 for our estimated R(02) of 2.4. We also explore qualitatively profiles of two-wave pandemics and compare them with real temporal profiles of the 1918 influenza pandemic in other regions of the world including several Scandinavian cities, New York City, England and Wales, and Sydney, Australia. Pandemic profiles are classified into three broad categories namely "right-handed", "left-handed", and "M-shape". Our results indicate that avoiding a second influenza epidemic is plausible given sufficient levels of cross-protection are attained via natural infection during a nearly ( herald) wave of infection or vaccination campaigns prior to a second wave. Furthermore, interventions aimed at mitigating the first pandemic wave may be counterproductive by increasing the chances of a second wave of infection that could potentially be more virulent than the first. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Rios-Doria, D.; Chowell, G.] Arizona State Univ, Math Computat & Modeling Sci Ctr, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. [Chowell, G.] NIH, Div Epidemiol & Populat Studies, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Rios-Doria, D (reprint author), Arizona State Univ, Math Computat & Modeling Sci Ctr, Sch Human Evolut & Social Change, Tempe, AZ 85287 USA. EM driosdor@asu.edu RI Chowell, Gerardo/F-5038-2012 OI Chowell, Gerardo/0000-0003-2194-2251 FU Mathematical and Theoretical Biology Institute FX We thank the anonymous referees for their valuable comments that helped to improve our manuscript. This study was partially supported by the Mathematical and Theoretical Biology Institute. NR 35 TC 20 Z9 20 U1 1 U2 8 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD DEC 21 PY 2009 VL 261 IS 4 BP 584 EP 592 DI 10.1016/j.jtbi.2009.08.020 PG 9 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 559CW UT WOS:000274799100008 PM 19703472 ER PT J AU Nelson, GM Ahlborn, GJ Allen, JW Ren, HZ Corton, JC Waalkes, MP Kitchin, KT Diwan, BA Knapp, G Delker, DA AF Nelson, Gail M. Ahlborn, Gene J. Allen, James W. Ren, Hongzu Corton, J. Christopher Waalkes, Michael P. Kitchin, Kirk T. Diwan, Bhalchandra A. Knapp, Geremy Delker, Don A. TI Transcriptional changes associated with reduced spontaneous liver tumor incidence in mice chronically exposed to high dose arsenic SO TOXICOLOGY LA English DT Article DE Sodium arsenite; C3H mouse; In utero; Liver tumor; Gene expression ID ACUTE PROMYELOCYTIC LEUKEMIA; ELEMENT-BINDING PROTEIN; COA DESATURASE-1 SCD1; DRINKING-WATER; IN-UTERO; DIMETHYLARSINIC ACID; HISTONE ACETYLATION; HEPATIC LIPOGENESIS; CALORIC RESTRICTION; METABOLIC SYNDROME AB Exposure of male C3H mice in utero (from gestational days 8-18) to 85 ppm sodium arsenite via the dams' drinking water has previously been shown to increase liver tumor incidence by 2 years of age. However, in our companion study (Ahlborn et al., 2009), continuous exposure to 85 ppm sodium arsenic (from gestational day 8 to postnatal day 365) did not result in increased tumor incidence, but rather in a significant reduction (0% tumor incidence). The purpose of the present study was to examine the gene expression responses that may lead to the apparent protective effect of continuous arsenic exposure. Genes in many functional categories including cellular growth and proliferation, gene expression, cell death, oxidative stress, protein ubiquitination, and mitochondrial dysfunction were altered by continuous arsenic treatment. Many of these genes are known to be involved in liver cancer. One such gene associated with rodent hepatocarcinogenesis, Scd1, encodes stearoyl-CoA desaturase and was down-regulated by continuous arsenic treatment. An overlap between the genes in our study affected by continuous arsenic exposure and those from the literature affected by long-term caloric restriction suggests that reduction in the spontaneous tumor incidence under both conditions may involve similar gene pathways such as fatty acid metabolism, apoptosis, and stress response. Published by Elsevier Ireland Ltd. C1 [Nelson, Gail M.; Ahlborn, Gene J.; Allen, James W.; Ren, Hongzu; Corton, J. Christopher; Kitchin, Kirk T.; Knapp, Geremy; Delker, Don A.] US EPA, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Ren, Hongzu; Corton, J. Christopher] US EPA, NHEERL Toxicogenom Core, Res Triangle Pk, NC 27711 USA. [Waalkes, Michael P.] NIEHS, NCI, Comparat Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. [Diwan, Bhalchandra A.] SAIC Frederick Inc, Basic Sci Program, Frederick, MD 21702 USA. RP Delker, DA (reprint author), Univ Utah, Sch Med, SOM 4R118,30 North,1900 East, Salt Lake City, UT 84132 USA. EM don.delker@hsc.utah.edu FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The authors would like to thank Dr. Julian Preston, Dr. Susan Hester and Dr. Shaeau-Fung Thai for their helpful support, suggestions, and data/manuscript reviews. NR 62 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD DEC 21 PY 2009 VL 266 IS 1-3 BP 6 EP 15 DI 10.1016/j.tox.2009.10.004 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 536LN UT WOS:000273046000002 PM 19822182 ER PT J AU Azzoli, CG Baker, S Temin, S Pao, W Aliff, T Brahmer, J Johnson, DH Laskin, JL Masters, G Milton, D Nordquist, L Pfister, DG Piantadosi, S Schiller, JH Smith, R Smith, TJ Strawn, JR Trent, D Giaccone, G AF Azzoli, Christopher G. Baker, Sherman, Jr. Temin, Sarah Pao, William Aliff, Timothy Brahmer, Julie Johnson, David H. Laskin, Janessa L. Masters, Gregory Milton, Daniel Nordquist, Luke Pfister, David G. Piantadosi, Steven Schiller, Joan H. Smith, Reily Smith, Thomas J. Strawn, John R. Trent, David Giaccone, Giuseppe TI American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID GROWTH-FACTOR-RECEPTOR; PHASE-III TRIAL; CISPLATIN PLUS GEMCITABINE; GENE COPY NUMBER; QUALITY-OF-LIFE; RANDOMIZED CONTROLLED-TRIALS; PLATINUM-BASED CHEMOTHERAPY; INDIVIDUAL PATIENT DATA; MESSENGER-RNA EXPRESSION; LEUKEMIA GROUP-B AB The purpose of this article is to provide updated recommendations for the treatment of patients with stage IV non-small-cell lung cancer. A literature search identified relevant randomized trials published since 2002. The scope of the guideline was narrowed to chemotherapy and biologic therapy. An Update Committee reviewed the literature and made updated recommendations. One hundred sixty-two publications met the inclusion criteria. Recommendations were based on treatment strategies that improve overall survival. Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life. For first-line therapy in patients with performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For patients with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with carboplatin-paclitaxel, except for patients with certain clinical characteristics. Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs. Data are insufficient to recommend routine use of molecular markers to select chemotherapy. J Clin Oncol 27:6251-6266. (c) 2009 by American Society of Clinical Oncology C1 Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Virginia Commonwealth Univ, Massey Canc Ctr, Richmond, VA 23284 USA. [Azzoli, Christopher G.] Amer Soc Clin Oncol, Alexandria, VA 22314 USA. Virginia Canc Ctr, Richmond, VA USA. Vanderbilt Ingram Canc Ctr, Nashville, TN USA. NW Oncol & Hematol Associates, Coral Springs, FL USA. Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Natl Canc Ctr, Bethesda, MD USA. Helen F Graham Canc Ctr, Newark, DE USA. Hematol Oncol Indiana PC, Indianapolis, IN USA. Nebraska Canc Specialists PC, Omaha, NE USA. Samuel Oschin Comprehens Canc Inst, Los Angeles, CA USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. RP Azzoli, CG (reprint author), Amer Soc Clin Oncol, 2318 Mill Rd,Suite 800, Alexandria, VA 22314 USA. EM guidelines@asco.org RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU National Library of Medicine FX Supported by the National Library of Medicine (T.J.S.). NR 157 TC 452 Z9 470 U1 9 U2 28 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 2009 VL 27 IS 36 BP 6251 EP 6266 DI 10.1200/JCO.2009.23.5622 PG 16 WC Oncology SC Oncology GA 534AI UT WOS:000272867500027 PM 19917871 ER PT J AU Suguitan, AL Marino, MP Desai, PD Chen, LM Matsuoka, Y Donis, RO Jin, H Swayne, DE Kemble, G Subbarao, K AF Suguitan, Amorsolo L., Jr. Marino, Michael P. Desai, Purvi D. Chen, Li-Mei Matsuoka, Yumiko Donis, Ruben O. Jin, Hong Swayne, David E. Kemble, George Subbarao, Kanta TI The influence of the multi-basic cleavage site of the H5 hemagglutinin on the attenuation, immunogenicity and efficacy of a live attenuated influenza A H5N1 cold-adapted vaccine virus SO VIROLOGY LA English DT Article DE Influenza; H5N1; HA cleavability; Attenuation; Pandemic; Immunogenicity; A/VietNam/1203/04; Live vaccine; Multi-basic cleavage site ID AVIAN INFLUENZA; GENE CONSTELLATION; TEMPERATURE SENSITIVITY; PROTEOLYTIC CLEAVAGE; PANDEMIC INFLUENZA; NEWCASTLE-DISEASE; HIGH VIRULENCE; AMINO-ACID; PATHOGENICITY; STRAINS AB A recombinant live attenuated influenza virus Delta H5N1 vaccine with a modified hemagglutinin I (HA) and intact neuraminidase genes from A/Vietnam/1203/04 (H5N1) and six remaining genome segments from A/Ann Arbor/6/60 (H2N2) cold-adapted (AA ca) virus was previously shown to be attenuated in chickens, mice and ferrets. Evaluation of the recombinant H5N1 viruses in mice indicated that three independent factors contributed to the attenuation of the Delta H5N1 vaccine: the attenuating mutations specified by the AA ca loci had the greatest influence, followed by the deletion of the H5 HA multi-basic cleavage site (MBS), and the constellation effects of the AA genes acting in concert with the H5N1 glycoproteins. Restoring the MBS in the H5 HA of the vaccine virus improved its immunogenicity and efficacy, likely as a consequence of increased virus replication, indicating that removal of the MBS had a deleterious effect on the immunogenicity and efficacy of the Delta H5N1 vaccine in mice. (C) 2009 Published by Elsevier Inc. C1 [Chen, Li-Mei; Matsuoka, Yumiko; Donis, Ruben O.] Ctr Dis Control & Prevent, Influenza Div, Natl Ctr Immunizat & Resp Dis, Atlanta, GA 30333 USA. [Jin, Hong; Kemble, George] MedImmune, Mountain View, CA 94043 USA. [Swayne, David E.] ARS, SE Poultry Res Lab, USDA, Athens, GA 30605 USA. [Suguitan, Amorsolo L., Jr.; Marino, Michael P.; Desai, Purvi D.; Subbarao, Kanta] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, Rm 3E13C1,33 North Dr,MSC 3203, Bethesda, MD 20892 USA. EM suguitanjra@medimmune.com; Michael.Marino@fda.hhs.gov; desaip@mail.nih.gov; bpr5@cdc.gov; matsuokay@niaid.nih.gov; rvd6@cdc.gov; jinh@medimmune.com; David.Swayne@ARS.USDA.GOV; kembleg@medimmune.com; ksubbarao@niaid.nih.gov FU NIAID; NIH FX We thank Jadon Jackson and the staff of the Comparative Medicine Branch, NIAID for superior technical Support for the animal studies performed at the NIH and Joan Beck for excellent assistance in performing studies in chickens at SEPRL. We are grateful to Dr. Le Quynh Mai, National Institute of Hygiene and Epidemiology (NIHE), Vietnam for providing the A/Vietnam/1203/2004 H5N1 wt virus used in this study which was made available to us by Drs. Nancy Cox and Alexander Klimov, Influenza Division, Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA. This research was supported by the Intramural Research Program of the NIAID, NIH and was performed as a Cooperative Research and Development Agreement (CRADA No: Al-0155) between the Laboratory of Infectious Diseases, NIAID and MedImmune. The findings and conclusions of this article are those of the authors and do not necessarily represent the views of the CDC. NR 33 TC 22 Z9 23 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD DEC 20 PY 2009 VL 395 IS 2 BP 280 EP 288 DI 10.1016/j.virol.2009.09.017 PG 9 WC Virology SC Virology GA 531EU UT WOS:000272647300012 PM 19833372 ER PT J AU Xiao, XD Chen, WZ Feng, Y Zhu, ZY Prabakaran, P Wang, YP Zhang, MY Longo, NS Dimitrov, DS AF Xiao, Xiaodong Chen, Weizao Feng, Yang Zhu, Zhongyu Prabakaran, Ponraj Wang, Yanping Zhang, Mei-Yun Longo, Nancy S. Dimitrov, Dimiter S. TI Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: Implications for evasion of immune responses and design of vaccine immunogens SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Germline; Antibody; Immune responses; HIV; Escape; Vaccine ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; CROSS-REACTIVE NEUTRALIZATION; EXTENSIVE SOMATIC MUTATION; AFFINITY B-CELLS; GERMINAL-CENTERS; ANTIGEN-BINDING; HENDRA VIRUSES; PHAGE LIBRARY; IN-VIVO AB Several human monoclonal antibodies (hmAbs) including b12, 2G12, and 2F5 exhibit relatively potent and broad HIV-1-neutralizing activity. However, their elicitation in vivo by vaccine immunogens based on the HIV-1 envelope glycoprotein (Env) has not been successful. We have hypothesized that HIV-1 has evolved a strategy to reduce or eliminate the immunogenicity of the highly conserved epitopes of such antibodies by using "holes" (absence or very weak binding to these epitopes of germline antibodies that is not sufficient to initiate and/or maintain an efficient immune response) in the human germline B cell receptor (BCR) repertoire. To begin to test this hypothesis we have designed germline-like antibodies corresponding most closely to b12, 2G12, and 2F5 as well as to X5, m44, and m46 which are cross-reactive but with relatively modest neutralizing activity as natively occurring antibodies due to size and/or other effects. The germline-like X5, m44, and m46 bound with relatively high affinity to all tested Envs. In contrast, germline-like b12, 2G12, and 2F5 lacked measurable binding to Envs in an ELISA assay although the corresponding mature antibodies did. These results provide initial evidence that Env structures containing conserved vulnerable epitopes may not initiate humoral responses by binding to germline antibodies. Even if such responses are initiated by very weak binding undetectable in our assay it is likely that they will be outcompeted by responses to structures Containing the epitopes of X5, m44, m46, and other antibodies that bind germline BCRs with much higher affinity/avidity. This hypothesis, if further supported by data, could contribute to our understanding of how HIV-1 evades immune responses and offer new concepts for design of effective vaccine immunogens. Published by Elsevier Inc. C1 [Xiao, Xiaodong; Chen, Weizao; Feng, Yang; Zhu, Zhongyu; Prabakaran, Ponraj; Wang, Yanping; Zhang, Mei-Yun; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. [Zhu, Zhongyu; Wang, Yanping; Zhang, Mei-Yun] NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Longo, Nancy S.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Dimitrov, DS (reprint author), NCI, Prot Interact Grp, Ctr Canc Res Nanobiol Program, NIH, Bldg 469,Rm 150B, Frederick, MD 21702 USA. EM dimiter.dimitrov@nih.gov RI Zhang, Mei-Yun/E-9908-2010 FU NIH; National Cancer Institute [N01-CO-12400]; Center for Cancer Research; Gates Foundation FX We thank Ruth Ruprecht, Hana Golding, Robert Blumenthal, Christopher Broder, Jorge Flores, Helen Quill, Nancy Miller, Garnett Kelsoe, and Barton Haynes for stimulating discussions and suggestions, Christopher Broder, Gerald Quinnan, Barton Haynes, Dennis Burton, and Tim Fouts for providing reagents, and John Owens for help. This work was supported by the intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, by Federal funds from the NIH, National Cancer Institute, under Contract No. N01-CO-12400, and by the Gates Foundation to D.S.D. NR 47 TC 117 Z9 118 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 18 PY 2009 VL 390 IS 3 BP 404 EP 409 DI 10.1016/j.bbrc.2009.09.029 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 529KY UT WOS:000272516700011 PM 19748484 ER PT J AU Pichu, S Ribeiro, JMC Mather, TN AF Pichu, Sivakamasundari Ribeiro, Jose M. C. Mather, Thomas N. TI Purification and characterization of a novel salivary antimicrobial peptide from the tick, Ixodes scapularis SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Ticks; Saliva; Ixodes scapularis; Antimicrobial peptide; Innate immunity ID AMERICAN DOG TICK; HARD TICK; DERMACENTOR-VARIABILIS; AMBLYOMMA-HEBRAEUM; INNATE IMMUNITY; DEFENSIN GENE; LYME-DISEASE; HEMOLYMPH; DROSOPHILA; HEMOCYTES AB A novel antimicrobial peptide was isolated from the saliva of the Lyme disease tick vector, Nodes scapularis, henceforth designated as ISAMP (I. scapularis Antimicrobial Peptide). ISAMP was purified using a sequential method including ultra filtration, gel filtration and reverse-phase high performance liquid chromatography. The purified peak had a molecular weight of 5.3 kDa by MALDI/TOF-MS and its amino acid sequence, determined by Edman degradation was PDxGxPxxVKAGRxPxxSI. A BLASTP search revealed that the protein is a putative 5.3 kDa secreted protein (AAM93656) from I. scapularis. The predicted protein is composed of 69 amino acids with no conserved domain motifs. Purified ISAMP was found to have antimicrobial activities against bacteria. Gene expression studies were carried out to observe ISAMP expression in different tick tissues. RT-PCR results indicated that the gene was expressed in hemocytes, fat body and salivary gland but virtually no expression was observed in the midgut. ISAMP is only similar to other Ixodid tick proteins, thus it is a member Of a unique family. Published by Elsevier Inc. C1 [Pichu, Sivakamasundari; Mather, Thomas N.] Univ Rhode Isl, Ctr Vector Borne Dis, Kingston, RI 02881 USA. [Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Mather, TN (reprint author), Univ Rhode Isl, Ctr Vector Borne Dis, 9 E Alumni Ave,Suite 7, Kingston, RI 02881 USA. EM tmather@uri.edu OI Ribeiro, Jose/0000-0002-9107-0818 FU National Institute of Health [AI 37230]; USDA [2006-34438-17306]; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH [P20 RR16457] FX We are particularly grateful to Drs. Marta Gomez-Chiarri, Roberta King, Shahid Karim, Assem Sayedahmed, and to Nathan Miller for helpful technical discussions. This work was supported by National Institute of Health Grant AI 37230 (TNM), a subcontract to USDA Special Grant 2006-34438-17306 (TNM), and by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH (JMCR). Experiments were supported by the URI Proteomics Core facility, made available by the RI-BRIN and RI-INBRE (NIH award P20 RR16457). Because J.M.C.R. is a government employee and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U.S. subject to a government use license. NR 33 TC 18 Z9 19 U1 0 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 18 PY 2009 VL 390 IS 3 BP 511 EP 515 DI 10.1016/j.bbrc.2009.09.127 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 529KY UT WOS:000272516700030 PM 19852941 ER PT J AU Shmueli, A Tsai, YC Yang, M Braun, MA Weissman, AM AF Shmueli, Ayelet Tsai, Yien Che Yang, Mei Braun, Mary A. Weissman, Allan M. TI Targeting of gp78 for ubiquitin-mediated proteasomal degradation by Hrd1: Cross-talk between E3s in the endoplasmic reticulum SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE RNF45; Autocrine motility factor receptor; KAI1; Atherosclerosis; Parkinson's disease; Pael-R ID MOTILITY FACTOR-RECEPTOR; LIGASE GP78; RING FINGER; MEMBRANE; DOMAIN; RETROTRANSLOCATION; SUBSTRATE; PROTEINS; PROMOTES; INSIG-1 AB There are an increasing number of ubiquitin ligases (E3s) implicated in endoplasmic Feticulum (ER)-associated degradation (ERAD) in mammals. The two for which the greatest amount of information exists are the RING finger proteins gp78 and Hrd1, which are the structural orthologs of the yeast ERAD E3 Hrd1p. We now report that Hrd1, also known as synoviolin, targets gp78 for proteasomal degradation independent of the ubiquitin ligase activity of gp78, without evidence of a reciprocal effect. This degradation is observed in mouse embryonic fibroblasts lacking Hrd1, as well as with acute manipulation of Hrd1. The significance of this is underscored by the diminished level of a gp78-specific substrate, Insig-1, when Hrd1 expression is decreased and gp78 levels are consequently increased. These finding demonstrate a previously unappreciated level of complexity of the ubiquitin system in ERAD and have potentially important ramifications for processes where gp78 is implicated including regulation of lipid metabolism, metastasis, cystic fibrosis and neurodegenerative disorders. Published by Elsevier Inc. C1 [Shmueli, Ayelet; Tsai, Yien Che; Yang, Mei; Braun, Mary A.; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Frederick, MD 21702 USA. RP Weissman, AM (reprint author), NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, Bldg 560 Rm 22-103,1050 Boyles St, Frederick, MD 21702 USA. EM shmuelia@mail.nih.gov; tsaiyien@mail.nih.gov; yangm6@mail.nih.gov; mabraun@andrew.cmu.edu; amw@nih.gov OI Tsai, Yien Che/0000-0001-9624-1092 FU US National Institutes of Health; National Cancer Institute; Center for Cancer Research; Michael J. Fox Foundation for Parkinson's Research FX The authors thank Toshihiro Nakajima for generously supplying Synoviolin MEFs; Dirk Bohmann, Robert M. Gernmill, Ryosuke Takahashi and Emmanuel J.H.J. Wiertz for providing critical plasmids; and Aaron Ciechanover, ZIatka Kostova, Jennifer Mariano and Jocelyn D. Weissman for invaluable discussions and comments. This research is supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research and in part by a grant from the Michael J. Fox Foundation for Parkinson's Research. NR 23 TC 32 Z9 32 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 18 PY 2009 VL 390 IS 3 BP 758 EP 762 DI 10.1016/j.bbrc.2009.10.045 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 529KY UT WOS:000272516700075 PM 19835843 ER PT J AU Zhou, YF Wang, SN Yu, ZX Hoyt, RF Sachdev, V Vincent, P Arai, AE Kwak, M Burkett, SS Horvath, KA AF Zhou, Yifu Wang, Suna Yu, Zuxi Hoyt, Robert F., Jr. Sachdev, Vandana Vincent, Pamela Arai, Andrew E. Kwak, Minjung Burkett, Sandra Sczerba Horvath, Keith A. TI Direct injection of autologous mesenchymal stromal cells improves myocardial function SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Mesenchymal stromal cells; Myocardial ischemia; Myocardial function ID COLONY-STIMULATING FACTOR; LEFT-VENTRICULAR FUNCTION; CORONARY-ARTERY-DISEASE; STEM-CELL; TOPCARE-AMI; REGENERATION ENHANCEMENT; PROGENITOR CELLS; HEART-FAILURE; TRANSPLANTATION; INFARCTION AB Cell-based therapies have been employed with conflicting results. Whether direct injection of ex-vivo expanded autologous marrow stromal cells (MSCs) would improve the function of ischemic myocardium and enhance angiogenesis is not well defined. in a porcine model of chronic ischemia, MSCs were isolated and cultured for 4 weeks. Sixteen animals were random divided into two groups to receive either direct intrannyocardial injection of autologous MSCs, or equal volumes and injections sites of saline. Cine MRI and epicardial echocardiography were performed just prior to the injections and again 6 weeks later at the time of sacrifice at which point tissue was also analyzed. Myocardial function as assessed by regional wall thickening (as measured by dobutamine stress echocardiograms) demonstrated a 40.9% improvement after cell treatment of the ischemic zone (p = 0.016) whereas the saline treated animals only had a 3.7% change (p = 0.82) compared to baseline. The left ventricular ejection fractions of MSC group showed 19.5% improvement from baseline 35.9 +/- 3.8% to 42.9 +/- 5.8% (p = 0.049). Increased vascularity was found in the MSC group compared to controls (0.80 +/- 0.30 vs 0.50 +/- 0.19 capillary/myocyte ratio, p = 0.018). Direct injection of autologous MSCs promotes angiogenesis and enhances the functional improvements following chronic myocardial ischemia. This suggests that the angiogenesis engendered by cell treatment may be physiologically meaningful by improving the contractility of ischemic myocardium. Published by Elsevier Inc. C1 [Zhou, Yifu; Wang, Suna; Yu, Zuxi; Hoyt, Robert F., Jr.; Sachdev, Vandana; Vincent, Pamela; Arai, Andrew E.; Kwak, Minjung; Burkett, Sandra Sczerba; Horvath, Keith A.] NHLBI, Cellular Biol Sect, Cardiothorac Surg Res Program, NIH, Bethesda, MD 20892 USA. RP Zhou, YF (reprint author), NHLBI, Cellular Biol Sect, Cardiothorac Surg Res Program, NIH, 10 Ctr Dr,MSC 1550,Bldg 10,Room 2N246, Bethesda, MD 20892 USA. EM zhouyifu@mail.nih.gov FU Intramural NIH HHS [Z99 HL999999, ZIA HL006136-01, ZIA HL006136-02] NR 25 TC 30 Z9 31 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 18 PY 2009 VL 390 IS 3 BP 902 EP 907 DI 10.1016/j.bbrc.2009.10.074 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 529KY UT WOS:000272516700101 PM 19852944 ER PT J AU Saito, H Okada, M Miki, T Wakamori, M Futatsugi, A Mori, Y Mikoshiba, K Suzuki, N AF Saito, Hiromitsu Okada, Motohiro Miki, Takafumi Wakamori, Minoru Futatsugi, Akira Mori, Yasuo Mikoshiba, Katsuhiko Suzuki, Noboru TI Knockdown of Ca(v)2.1 calcium channels is sufficient to induce neurological disorders observed in natural occurring Cacna1a mutants in mice SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Cacna1a; Knockdown; Ataxia; Seizures; Cerebellar atrophy; Dyskinesia ID EPISODIC ATAXIA TYPE-2; FAMILIAL HEMIPLEGIC MIGRAINE; CA2+ CHANNELS; P-TYPE; SYNAPTIC-TRANSMISSION; PURKINJE-CELLS; MUTATIONS; MOUSE; CURRENTS; NEURONS AB The CACNA1A gene encodes the poreforming, voltage-sensitive subunit of the voltage-dependent Ca(v)2.1 Calcium channel. Mutations in this gene have been linked to several human disorders, including familial hemiplegic migraine type 1, episodic ataxia type 2, and spinocerebellar ataxia type 6. In mice, mutations of the homolog Cacna1a cause recessively inherited phenotypes in tottering, roiling Nagoya, rocker, and leaner mice. Here we describe two knockdown mice with 28.4 +/- 3.4% and 13.8 +/- 3.3% of the wild-type Ca(v)2.1 quantity. 28.4 +/- 3.4% level mutants displayed ataxia, absence-like seizures and progressive cerebellar atrophy, although they had a normal life span. Mutants with 13.8 +/- 3.3% level exhibited ataxia severer than the 28.4 +/- 3.4% level Mutants, absence-like seizures and additionally paroxysmal dyskinesia, and died premature around 3 weeks of age. These results indicate that knock down of Ca(v)2.1 quantity to 13.8 +/- 3.3% of the wild-type level are sufficient to induce the all neurological disorders observed in natural occurring Cacna1a mutants. These knockdown animals with Ca(v)2.1 calcium channels intact can contribute to functional studies of the molecule in the disease. (C) 2009 Elsevier Inc. All rights reserved. C1 [Saito, Hiromitsu; Suzuki, Noboru] Mie Univ, Life Sci Res Ctr, Dept Anim Genom, Funct Genom Inst, Tsu, Mie 5148507, Japan. [Okada, Motohiro] Mie Univ, Grad Sch Med, Div Neurosci, Tsu, Mie 5148507, Japan. [Miki, Takafumi; Wakamori, Minoru; Mori, Yasuo] Kyoto Univ, Grad Sch Engn, Dept Synthet Chem & Biol Chem, Kyoto, Japan. [Wakamori, Minoru] Tohoku Univ, Grad Sch Dent, Dept Oral Biol, Sendai, Miyagi 980, Japan. [Futatsugi, Akira] NIDCR, NIH, Bethesda, MD 20892 USA. [Mikoshiba, Katsuhiko] RIKEN, Inst Phys & Chem Res, Dev Neurobiol Lab, Brain Sci Inst, Wako, Saitama 35101, Japan. [Mikoshiba, Katsuhiko] JST, Ca Oscillat Ptoject, Wako, Saitama, Japan. RP Suzuki, N (reprint author), Mie Univ, Life Sci Res Ctr, Dept Anim Genom, Funct Genom Inst, 2-174 Edobashi, Tsu, Mie 5148507, Japan. EM nsuzuki@doc.medic.mie-u.ac.jp RI Mikoshiba, Katsuhiko/N-7943-2015 NR 36 TC 12 Z9 12 U1 2 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD DEC 18 PY 2009 VL 390 IS 3 BP 1029 EP 1033 DI 10.1016/j.bbrc.2009.10.102 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 529KY UT WOS:000272516700123 PM 19854154 ER PT J AU Yutin, N Koonin, EV AF Yutin, Natalya Koonin, Eugene V. TI Evolution of DNA ligases of Nucleo-Cytoplasmic Large DNA viruses of eukaryotes: a case of hidden complexity SO BIOLOGY DIRECT LA English DT Article ID UNIVERSAL COMMON ANCESTOR; HORIZONTAL GENE-TRANSFER; COMPARATIVE GENOMICS; TOPOISOMERASE IB; ORIGIN; CELLS; VACCINIA; REPLICATION; FACTORIES; DOMAINS AB Background: Eukaryotic Nucleo-Cytoplasmic Large DNA Viruses (NCLDV) encode most if not all of the enzymes involved in their DNA replication. It has been inferred that genes for these enzymes were already present in the last common ancestor of the NCLDV. However, the details of the evolution of these genes that bear on the complexity of the putative ancestral NCLDV and on the evolutionary relationships between viruses and their hosts are not well understood. Results: Phylogenetic analysis of the ATP-dependent and NAD-dependent DNA ligases encoded by the NCLDV reveals an unexpectedly complex evolutionary history. The NAD-dependent ligases are encoded only by a minority of NCLDV (including mimiviruses, some iridoviruses and entomopoxviruses) but phylogenetic analysis clearly indicated that all viral NAD-dependent ligases are monophyletic. Combined with the topology of the NCLDV tree derived by consensus of trees for universally conserved genes suggests that this enzyme was represented in the ancestral NCLDV. Phylogenetic analysis of ATP-dependent ligases that are encoded by chordopoxviruses, most of the phycodnaviruses and Marseillevirus failed to demonstrate monophyly and instead revealed an unexpectedly complex evolutionary trajectory. The ligases of the majority of phycodnaviruses and Marseillevirus seem to have evolved from bacteriophage or bacterial homologs; the ligase of one phycodnavirus, Emiliana huxlei virus, belongs to the eukaryotic DNA ligase I branch; and ligases of chordopoxviruses unequivocally cluster with eukaryotic DNA ligase III. Conclusions: Examination of phyletic patterns and phylogenetic analysis of DNA ligases of the NCLDV suggest that the common ancestor of the extant NCLDV encoded an NAD-dependent ligase that most likely was acquired from a bacteriophage at the early stages of evolution of eukaryotes. By contrast, ATP-dependent ligases from different prokaryotic and eukaryotic sources displaced the ancestral NAD-dependent ligase at different stages of subsequent evolution. These findings emphasize complex routes of viral evolution that become apparent through detailed phylogenomic analysis but not necessarily in reconstructions based on phyletic patterns of genes. C1 [Yutin, Natalya; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM yutin@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gov FU DHHS (National Library of Medicine, National Institutes of Health) FX The authors thank Bernard Moss for providing results prior to publication and critical reading of the manuscript, and Tatiana Senkevich for helpful discussions. The authors' research is supported by the DHHS (National Library of Medicine, National Institutes of Health) intramural research program. NR 50 TC 23 Z9 24 U1 1 U2 5 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 2009 VL 4 AR 51 DI 10.1186/1745-6150-4-51 PG 14 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 546NU UT WOS:000273818300001 PM 20021668 ER PT J AU Kwon, H Thierry-Mieg, D Thierry-Mieg, J Kim, HP Oh, J Tunyaplin, C Carotta, S Donovan, CE Goldman, ML Tailor, P Ozato, K Levy, DE Nutt, SL Calame, K Leonard, WJ AF Kwon, Hyokjoon Thierry-Mieg, Danielle Thierry-Mieg, Jean Kim, Hyoung-Pyo Oh, Jangsuk Tunyaplin, Chainarong Carotta, Sebastian Donovan, Colleen E. Goldman, Matthew L. Tailor, Prafullakumar Ozato, Keiko Levy, David E. Nutt, Stephen L. Calame, Kathryn Leonard, Warren J. TI Analysis of Interleukin-21-Induced Prdm1 Gene Regulation Reveals Functional Cooperation of STAT3 and IRF4 Transcription Factors SO IMMUNITY LA English DT Article ID PLASMA-CELL DIFFERENTIATION; REPRESSOR BLIMP-1; IL-2 RECEPTOR; B-LYMPHOCYTES; FAMILY; CHAIN; IMMUNODEFICIENCY; HOMEOSTASIS; MODULATION; EXPRESSION AB Interleukin-21 (IL-21) is a pleiotropic cytokine that induces expression of transcription factor BLIMP1 (encoded by Prdm1), which regulates plasma cell differentiation and T cell homeostasis. We identified an IL-21 response element downstream of Prdm1 that binds the transcription factors STAT3 and IRF4, which are required for optimal Prdm1 expression. Genome-wide ChIP-Seq mapping of STAT3- and IRF4-binding sites showed that most regions with IL-21-induced STAT3 binding also bound IRF4 in vivo and furthermore revealed that the noncanonical TTCnnnTAA GAS motif critical in Prdm1 was broadly used for STAT3 binding. Comparing genome-wide expression array data to binding sites revealed that most IL-21-regulated genes were associated with combined STAT3-IRF4 sites rather than pure STAT3 sites. Correspondingly, ChIP-Seq analysis of Irf4(-/-) T cells showed greatly diminished STAT3 binding after IL-21 treatment, and lrf4(-/-) mice showed impaired IL-21-induced Tfh cell differentiation in vivo. These results reveal broad cooperative gene regulation by STAT3 and IRF4. C1 [Kwon, Hyokjoon; Kim, Hyoung-Pyo; Oh, Jangsuk; Donovan, Colleen E.; Goldman, Matthew L.; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Thierry-Mieg, Danielle; Thierry-Mieg, Jean] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Tunyaplin, Chainarong; Calame, Kathryn] Columbia Univ, Coll Phys & Surg, Dept Microbiol, New York, NY 10032 USA. [Carotta, Sebastian; Nutt, Stephen L.] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3050, Australia. [Tailor, Prafullakumar; Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. [Levy, David E.] NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. [Levy, David E.] NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RI THIERRY-MIEG, Jean/F-1975-2017; OI THIERRY-MIEG, Jean/0000-0002-0396-6789; Nutt, Stephen/0000-0002-0020-6637; Levy, David/0000-0002-7320-7788 FU Division of Intramural Research, National Heart, Lung. and Blood Institute; National Center for Biotechnology Information, National Library of Medicine FX We thank H C Morse III for NFS201 and NFS202 cells, D E Schones for valuable discussions and assistance with handling the Illumina raw ChIP-Seq data and for processing ChIP-Seq data, K Cui and T -Y Roh for help with Solexa sequencing, the NHLBI Affymetrix Core and N Raghavachan, X Xu, and D Liu for help with generating, analyzing. and handling Affymetrix data, and J -X Lin, H Young, K Zhao, and K -T Jeang for valuable discussions and/or critical comments. This work was supported by the Division of Intramural Research, National Heart, Lung. and Blood Institute, and by the National Center for Biotechnology Information, National Library of Medicine W J L is an inventor on patents and patent applications related to IL-21 NR 35 TC 181 Z9 184 U1 0 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD DEC 18 PY 2009 VL 31 IS 6 BP 941 EP 952 DI 10.1016/j.immuni.2009.10.008 PG 12 WC Immunology SC Immunology GA 543YE UT WOS:000273616400014 PM 20064451 ER PT J AU Martinez, GJ Zhang, ZM Chung, Y Reynolds, JM Lin, X Jetten, AM Feng, XH Dong, C AF Martinez, Gustavo J. Zhang, Zhengmao Chung, Yeonseok Reynolds, Joseph M. Lin, Xia Jetten, Anton M. Feng, Xin-Hua Dong, Chen TI Smad3 Differentially Regulates the Induction of Regulatory and Inflammatory T Cell Differentiation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR-BETA; TGF-BETA; GENERATION; PATHWAY AB Transforming growth factor beta (TGF-beta) is a crucial cytokine with pleiotropic functions on immune cells. In CD4(+) T cells, TGF-beta is required for induction of both regulatory T and Th17 cells. However, the molecular mechanism underlying this differential T cell fate decision remains unclear. In this study, we have evaluated the role of Smad3 in the development of Th17 and regulatory T cells. Smad3 was found to be dispensable for natural regulatory T cell function. However, induction of Foxp3 expression by TGF-beta in naive T cells was significantly reduced in the absence of this molecule. On the contrary, Smad3 deficiency led to enhanced Th17 differentiation in vitro and in vivo. Moreover, Smad3 was found to interact with retinoid acid receptor-related orphan receptor gamma t (ROR gamma t) and decrease its transcriptional activity. These results demonstrate that Smad3 is differentially involved in the reciprocal regulatory and inflammatory T cell generation. C1 [Zhang, Zhengmao; Feng, Xin-Hua] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. [Martinez, Gustavo J.; Chung, Yeonseok; Reynolds, Joseph M.; Dong, Chen] MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77054 USA. [Martinez, Gustavo J.; Feng, Xin-Hua] Univ Texas Hlth Sci Ctr Houston, Grad Sch Biomed Sci, Houston, TX 77030 USA. [Zhang, Zhengmao; Jetten, Anton M.] Baylor Coll Med, Michael E DeBakey Dept Surg, Houston, TX 77030 USA. [Lin, Xia] NIEHS, Cell Biol Sect, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Feng, XH (reprint author), Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA. EM xfeng@bcm.edu; cdong@mdanderson.org RI dong, chen /B-3181-2009; Huang, Xiaoyan/N-2561-2014; OI dong, chen /0000-0002-0084-9130; Jetten, Anton/0000-0003-0954-4445; Chung, Yeonseok/0000-0001-5780-4841 FU National Institutes of Health Research [RO1AR050772, RC2AR059010-01, RO1AR053591, RO1CA108454, RO1DK073932]; Division of Intramural Research at the NIEHS [Z01-ES-101586] FX This work was supported, in whole or in part, by National Institutes of Health Research Grants RO1AR050772 and RC2AR059010-01 (to C. D.), RO1AR053591 and RO1CA108454 (to X. H. F.), RO1DK073932 (to X. L.), and by National Institutes of Health Grant Z01-ES-101586 (to A. J.) through the Division of Intramural Research at the NIEHS. NR 14 TC 46 Z9 48 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 18 PY 2009 VL 284 IS 51 BP 35283 EP 35286 DI 10.1074/jbc.C109.078238 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 531EI UT WOS:000272645600004 PM 19887374 ER PT J AU Michailidis, E Marchand, B Kodama, EN Singh, K Matsuoka, M Kirby, KA Ryan, EM Sawani, AM Nagy, E Ashida, N Mitsuya, H Parniak, MA Sarafianos, SG AF Michailidis, Eleftherios Marchand, Bruno Kodama, Eiichi N. Singh, Kamlendra Matsuoka, Masao Kirby, Karen A. Ryan, Emily M. Sawani, Ali M. Nagy, Eva Ashida, Noriyuki Mitsuya, Hiroaki Parniak, Michael A. Sarafianos, Stefan G. TI Mechanism of Inhibition of HIV-1 Reverse Transcriptase by 4 '-Ethynyl-2-fluoro-2 '-deoxyadenosine Triphosphate, a Translocation-defective Reverse Transcriptase Inhibitor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DNA-POLYMERASE; NUCLEOSIDE ANALOGS; 3'-AZIDO-3'-DEOXYTHYMIDINE AZT; MOLECULAR-MECHANISMS; EXCISION PHENOTYPE; SELECTIVE ACTION; IN-VITRO; TYPE-1; RESISTANCE AB Nucleoside reverse transcriptase inhibitors (NRTIs) are employed in first line therapies for the treatment of human immunodeficiency virus (HIV) infection. They generally lack a 3'-hydroxyl group, and thus when incorporated into the nascent DNA they prevent further elongation. In this report we show that 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA), a nucleoside analog that retains a 3'-hydroxyl moiety, inhibited HIV-1 replication in activated peripheral blood mononuclear cells with an EC(50) of 0.05 nM, a potency several orders of magnitude better than any of the current clinically used NRTIs. This exceptional antiviral activity stems in part from a mechanism of action that is different from approved NRTIs. Reverse transcriptase (RT) can use EFdA-5'-triphosphate (EFdA-TP) as a substrate more efficiently than the natural substrate, dATP. Importantly, despite the presence of a 3'-hydroxyl, the incorporated EFdA monophosphate (EFdA-MP) acted mainly as a de facto terminator of further RT-catalyzed DNA synthesis because of the difficulty of RT translocation on the nucleic acid primer possessing 3'-terminal EFdA-MP. EFdA-TP is thus a translocation-defective RT inhibitor (TDRTI). This diminished translocation kept the primer 3'-terminal EFdA-MP ideally located to undergo phosphorolytic excision. However, net phosphorolysis was not substantially increased, because of the apparently facile reincorporation of the newly excised EFdA-TP. Our molecular modeling studies suggest that the 4'-ethynyl fits into a hydrophobic pocket defined by RT residues Ala-114, Tyr-115, Phe-160, and Met-184 and the aliphatic chain of Asp-185. These interactions, which contribute to both enhanced RT utilization of EFdA-TP and difficulty in the translocation of 3'-terminal EFdA-MP primers, underlie the mechanism of action of this potent antiviral nucleoside. C1 [Michailidis, Eleftherios; Marchand, Bruno; Singh, Kamlendra; Kirby, Karen A.; Ryan, Emily M.; Sawani, Ali M.; Sarafianos, Stefan G.] Univ Missouri, Dept Mol Microbiol & Immunol, Christopher Bond Life Sci Ctr, Columbia, MO 65211 USA. [Kodama, Eiichi N.; Matsuoka, Masao] Kyoto Univ, Inst Virus Res, Kyoto 6068507, Japan. [Nagy, Eva; Parniak, Michael A.] Univ Pittsburgh, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. [Ashida, Noriyuki] Yamasa Corp, Chiba 2880056, Japan. [Mitsuya, Hiroaki] Kumamoto Univ, Dept Hematol & Infect Dis, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NIH, Expt Retrovirol Sect, HIV AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Sarafianos, SG (reprint author), 471D Christopher S Bond Life Sci Ctr,1201 Rollins, Columbia, MO 65211 USA. EM sarafianoss@missouri.edu RI Kodama, Eiichi /C-4032-2009; OI Kodama, Eiichi /0000-0002-6622-2752; Matsuoka, Masao/0000-0002-0473-754X; Sarafianos, Stefan G/0000-0002-5840-154X; Kirby, Karen A./0000-0003-2468-4796 FU National Institutes of Health [AI076119, AI074389, AI076119-S1, AI076119-02S1, AI079801] FX This work was supported, in whole or in part, by National Institutes of Health Grants AI076119, AI074389, AI076119-S1, and AI076119-02S1 ( to S. G. S.) and AI079801 ( to M. A. P.). NR 50 TC 51 Z9 51 U1 0 U2 18 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 18 PY 2009 VL 284 IS 51 BP 35681 EP 35691 DI 10.1074/jbc.M109.036616 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 531EI UT WOS:000272645600046 PM 19837673 ER PT J AU Kato, GJ AF Kato, Gregory J. TI Vascular complications after splenectomy for hematologic disorders SO BLOOD LA English DT Letter ID HEMOLYSIS; THERAPY; DISEASE C1 NHLBI, Sickle Cell Vasc Dis Sect, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. RP Kato, GJ (reprint author), NHLBI, Sickle Cell Vasc Dis Sect, Pulm & Vasc Med Branch, NIH, 10 Ctr Dr,MSC 1476,Bldg 10 CRC,Room 5-5140, Bethesda, MD 20892 USA. EM gkato@mail.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [ZIA HL006014-01, ZIA HL006014-02] NR 7 TC 2 Z9 2 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 17 PY 2009 VL 114 IS 26 BP 5404 EP 5404 DI 10.1182/blood-2009-10-251439 PG 1 WC Hematology SC Hematology GA 533ZA UT WOS:000272863800026 PM 20018930 ER PT J AU Paran, N De Silva, FS Senkevich, TG Moss, B AF Paran, Nir De Silva, Frank S. Senkevich, Tatiana G. Moss, Bernard TI Cellular DNA Ligase I Is Recruited to Cytoplasmic Vaccinia Virus Factories and Masks the Role of the Vaccinia Ligase in Viral DNA Replication SO CELL HOST & MICROBE LA English DT Article ID POXVIRUS-INFECTED CELLS; TOPOISOMERASE-II; GENE; SITES; COLOCALIZATION; IDENTIFICATION; PROLIFERATION; TRANSCRIPTION; POLYPEPTIDE; TRANSLATION AB Vaccinia virus (VACV) encodes DNA polymerase and additional proteins that enable cytoplasmic replication. We confirmed the ability of VACV DNA ligase mutants to replicate and tested the hypothesis that cellular ligases compensate for loss of viral gene expression. RNA silencing of human DNA ligase I expression and a small molecule inhibitor of human DNA ligase I, but not other ligases with siRNA, or a specific inhibitor severely reduced replication of viral DNA in cells infected with VACV ligase-deficient mutants, indicating that the cellular enzyme plays a complementary role. Replication of ligase-deficient VACV was greatly reduced and delayed in resting primary cells, correlating with initial low levels of ligase I and subsequent viral induction and localization of ligase I in virus factories. These studies indicate that DNA ligation is essential for poxvinus replication and explain the ability of ligase deletion mutants to replicate in dividing cells but exhibit decreased pathogenicity in mice. Encoding its own ligase might allow VACV to "jump-start" DNA synthesis. C1 [Paran, Nir; De Silva, Frank S.; Senkevich, Tatiana G.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Division of Intramural Research, MAID; National Institutes of Health FX We thank A E Tomkinson, University of Maryland, Baltimore, for ligase inhibitors and to the following members of the National Institute of Allergy and Infectious Diseases (NIAID) A McBride for HFF cells, C Cotter for cell cultures, and M Gastinger, S. Becker, and L Koo for help with confocal microscopy imaging Research was supported by the Division of Intramural Research, MAID, National Institutes of Health. NR 35 TC 19 Z9 19 U1 1 U2 3 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 17 PY 2009 VL 6 IS 6 BP 563 EP 569 DI 10.1016/j.chom.2009.11.005 PG 7 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 543YF UT WOS:000273616500010 PM 20006844 ER PT J AU Yutin, N Wolf, YI Raoult, D Koonin, EV AF Yutin, Natalya Wolf, Yuri I. Raoult, Didier Koonin, Eugene V. TI Eukaryotic large nucleo-cytoplasmic DNA viruses: Clusters of orthologous genes and reconstruction of viral genome evolution SO VIROLOGY JOURNAL LA English DT Article ID GIANT VIRUSES; PROTEIN FAMILIES; MIMIVIRUS; SEQUENCE; SEARCH; ORIGIN; MODEL; LIFE; TREE; ACQUISITION AB Background: The Nucleo-Cytoplasmic Large DNA Viruses (NCLDV) comprise an apparently monophyletic class of viruses that infect a broad variety of eukaryotic hosts. Recent progress in isolation of new viruses and genome sequencing resulted in a substantial expansion of the NCLDV diversity, resulting in additional opportunities for comparative genomic analysis, and a demand for a comprehensive classification of viral genes. Results: A comprehensive comparison of the protein sequences encoded in the genomes of 45 NCLDV belonging to 6 families was performed in order to delineate cluster of orthologous viral genes. Using previously developed computational methods for orthology identification, 1445 Nucleo-Cytoplasmic Virus Orthologous Groups (NCVOGs) were identified of which 177 are represented in more than one NCLDV family. The NCVOGs were manually curated and annotated and can be used as a computational platform for functional annotation and evolutionary analysis of new NCLDV genomes. A maximum-likelihood reconstruction of the NCLDV evolution yielded a set of 47 conserved genes that were probably present in the genome of the common ancestor of this class of eukaryotic viruses. This reconstructed ancestral gene set is robust to the parameters of the reconstruction procedure and so is likely to accurately reflect the gene core of the ancestral NCLDV, indicating that this virus encoded a complex machinery of replication, expression and morphogenesis that made it relatively independent from host cell functions. Conclusions: The NCVOGs are a flexible and expandable platform for genome analysis and functional annotation of newly characterized NCLDV. Evolutionary reconstructions employing NCVOGs point to complex ancestral viruses. C1 [Yutin, Natalya; Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Raoult, Didier] Univ Aix Marseille 2, Fac Med, URMITE, CNRS,UMR IRD 6236, F-13385 Marseille 5, France. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM yutin@ncbi.nlm.nih.gov; wolf@ncbi.nlm.nih.gov; didier.raoult@gmail.com; koonin@ncbi.nlm.nih.gov FU NIH, National Library of Medicine FX We thank Pere Puigbo Avalos (NCBI), Liran Carmel (Hebrew University) and Miklos Csuros (Universite de Montreal) for their help with phylogenetic analysis and ancestral genome reconstruction. The research of NY, YIW and EVK is supported by the DHHS Intramural Program (NIH, National Library of Medicine). NR 53 TC 107 Z9 109 U1 2 U2 20 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 17 PY 2009 VL 6 AR 223 DI 10.1186/1743-422X-6-223 PG 13 WC Virology SC Virology GA 546NI UT WOS:000273817100002 PM 20017929 ER PT J AU Nagy, A Piszczek, G Sellers, JR AF Nagy, Attila Piszczek, Grzegorz Sellers, James R. TI Extensibility of the Extended Tail Domain of Processive and Nonprocessive Myosin V Molecules SO BIOPHYSICAL JOURNAL LA English DT Article ID COILED-COIL; STEPPING KINETICS; MOTOR; FORCE; PROTEIN; MODEL; TRANSPORT; BINDING; LOAD; TRIFLUOROETHANOL AB Myosin V is a single-molecule motor that moves organelles along actin. When myosin V pulls loads inside the cell in a highly viscous environment, the force on the motor is unlikely to be constant. We propose that the tether between the single-molecule motor and the cargo (i.e., the extended tail domain of the molecule) must be able to absorb the sudden mechanical motions of the motor and allow smooth relaxation of the motion of the cargo to a new position. To test this hypothesis, we compared the elastic properties of the extended tail domains of processive (mouse myosin Va) and nonprocessive (Drosophila myosin V) molecular motors. The extended tail domain of these myosins consists of mechanically strong coiled-coil regions interspersed with flexible loops. In this work we explored the mechanical properties of coiled-coil regions using atomic force microscopy. We found that the processive and nonprocessive coiled-coil fragments display different unfolding patterns. The unfolding of coiled-coil structures occurs much later during the atomic force microscopy stretch cycle for processive. myosin Va than for nonprocessive Drosophila myosin V, suggesting that this elastic tether between the cargo and motor may play an important role in sustaining the processive motions of this single-molecule motor. C1 [Nagy, Attila; Sellers, James R.] Natl Heart Lung & Blood Inst, Lab Mol Physiol, NIH, Bethesda, MD USA. [Piszczek, Grzegorz] Natl Heart Lung & Blood Inst, Biophys Facil, NIH, Bethesda, MD USA. RP Sellers, JR (reprint author), Natl Heart Lung & Blood Inst, Lab Mol Physiol, NIH, Bethesda, MD USA. EM sellersj@nhlbi.nih.gov NR 49 TC 7 Z9 7 U1 1 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD DEC 16 PY 2009 VL 97 IS 12 BP 3123 EP 3131 DI 10.1016/j.bpj.2009.09.033 PG 9 WC Biophysics SC Biophysics GA 532QV UT WOS:000272765400009 PM 20006949 ER PT J AU Bardakjian, TM Schneider, AS Ng, D Johnston, JJ Biesecker, LG AF Bardakjian, Tanya M. Schneider, Adele S. Ng, David Johnston, Jennifer J. Biesecker, Leslie G. TI Association of a de novo 16q copy number variant with a phenotype that overlaps with Lenz microphthalmia and Townes-Brocks syndromes SO BMC MEDICAL GENETICS LA English DT Article ID DENOVO INTERSTITIAL DELETION; SOX2 ANOPHTHALMIA SYNDROME; GRANULOMATOUS ARTHRITIS; GENE; MUTATIONS; IDENTIFICATION; DEFECTS; REGION; BIRTHS; SALL1 AB Background: Anophthalmia and microphthalmia are etiologically and clinically heterogeneous. Lenz microphthalmia is a syndromic form that is typically inherited in an X-linked pattern, though the causative gene mutation is unknown. Townes-Brocks syndrome manifests thumb anomalies, imperforate anus, and ear anomalies. We present a 13-year-old boy with a syndromic microphthalmia phenotype and a clinical diagnosis of Lenz microphthalmia syndrome. Case Presentation: The patient was subjected to clinical and molecular evaluation, including array CGH analysis. The clinical features included left clinical anophthalmia, right microphthalmia, anteriorly placed anus with fistula, chordee, ventriculoseptal defect, patent ductus arteriosus, posteriorly rotated ears, hypotonia, growth retardation with delayed bone age, and mental retardation. The patient was found to have an approximately 5.6 Mb deletion of 16q11.2q12.1 by microarray based-comparative genomic hybridization, which includes the SALL1 gene, which causes Townes-Brocks syndrome. Conclusions: Deletions of 16q11.2q12.2 have been reported in several individuals, although those prior reports did not note microphthalmia or anophthalmia. This region includes SALL1, which causes Townes-Brocks syndrome. In retrospect, this child has a number of features that can be explained by the SALL1 deletion, although it is not clear if the microphthalmia is a rare feature of Townes-Brocks syndrome or caused by other mechanisms. These data suggest that rare copy number changes may be a cause of syndromic microphthalmia allowing a personalized genomic medicine approach to the care of patients with these aberrations. C1 [Ng, David; Johnston, Jennifer J.; Biesecker, Leslie G.] NHGRI, NIH, Bethesda, MD 20892 USA. [Bardakjian, Tanya M.; Schneider, Adele S.] Albert Einstein Med Ctr, Dept Pediat, Philadelphia, PA 19141 USA. RP Biesecker, LG (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM BardakjianT@einstein.edu; schneida@einstein.edu; davidng@mail.nih.gov; jjohnsto@mail.nih.gov; leslieb@helix.nih.gov FU Albert B. Millett Memorial Fund; A Mellon Mid-Atlantic Charitable Trust; Rae S. Uber Trust; Gustavus and Louise Pfeiffer Research Foundation; National Human Genome Research Institute of the National Institutes of Health FX Funding for ASS and TMB was provided by the Albert B. Millett Memorial Fund, A Mellon Mid-Atlantic Charitable Trust, Rae S. Uber Trust, and the Gustavus and Louise Pfeiffer Research Foundation. Funding for JJJ, DN, and LGB was provided by the Intramural Research Program of the National Human Genome Research Institute of the National Institutes of Health. The authors are grateful to the family for their support of this description of their son and their support of the International Anophthalmia Children's Network. Aradhya Swaroop, Ph.D., of GeneDx Corp. provided information on the array platform. NR 37 TC 8 Z9 8 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD DEC 16 PY 2009 VL 10 AR 137 DI 10.1186/1471-2350-10-137 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 543SA UT WOS:000273597500001 PM 20003547 ER PT J AU Lieb, W Beiser, AS Vasan, RS Tan, ZS Au, R Harris, TB Roubenoff, R Auerbach, S DeCarli, C Wolf, PA Seshadri, S AF Lieb, Wolfgang Beiser, Alexa S. Vasan, Ramachandran S. Tan, Zaldy S. Au, Rhoda Harris, Tamara B. Roubenoff, Ronenn Auerbach, Sanford DeCarli, Charles Wolf, Philip A. Seshadri, Sudha TI Association of Plasma Leptin Levels With Incident Alzheimer Disease and MRI Measures of Brain Aging SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HIPPOCAMPAL SYNAPTIC PLASTICITY; CENTRAL-NERVOUS-SYSTEM; COGNITIVE FUNCTION; CENTRAL OBESITY; HEART-DISEASE; RISK; DEMENTIA; NEUROPATHOLOGY; MORTALITY; NEURONS AB Context The adipokine leptin facilitates long-term potentiation and synaptic plasticity in the hippocampus, promotes beta-amyloid clearance, and improves memory function in animal models of aging and Alzheimer disease (AD). Objective To relate baseline circulating leptin concentrations in a community-based sample of individuals without dementia to incident dementia and AD during follow-up and magnetic resonance imaging (MRI) measures of brain aging in survivors. Design, Setting, and Participants Prospective study of plasma leptin concentrations measured in 785 persons without dementia (mean [SD] age, 79 [5] years; 62% female), who were in the Framingham original cohort at the 22nd examination cycle (1990-1994). A subsample of 198 dementia-free survivors underwent volumetric brain MRI between 1999 and 2005, approximately 7.7 years after leptin was assayed. Two measures of brain aging, total cerebral brain volume and temporal horn volume (which is inversely related to hippocampal volume) were assessed. Main Outcome Measure Incidence of dementia and AD during follow-up until December 31, 2007. Results During a median follow-up of 8.3 years (range, 0-15.5 years), 111 participants developed incident dementia; 89 had AD. Higher leptin levels were associated with a lower risk of incident dementia and AD in multivariable models (hazard ratio per 1-SD increment in log leptin was 0.68 [95% confidence interval, 0.54-0.87] for all-cause dementia and 0.60 [95% confidence interval, 0.46-0.79] for AD). This corresponds to an absolute AD risk over a 12-year follow-up of 25% for persons in the lowest quartile (first quartile) vs 6% for persons in the fourth quartile of sex-specific leptin levels. In addition, a 1-SD elevation in plasma leptin level was associated with higher total cerebral brain volume and lower temporal horn volume, although the association of leptin level with temporal horn volume did not reach statistical significance. Conclusion Circulating leptin was associated with a reduced incidence of dementia and AD and with cerebral brain volume in asymptomatic older adults. JAMA. 2009;302(23):2565-2572 C1 [Beiser, Alexa S.; Au, Rhoda; Auerbach, Sanford; Wolf, Philip A.; Seshadri, Sudha] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. [Lieb, Wolfgang; Beiser, Alexa S.; Vasan, Ramachandran S.; Wolf, Philip A.; Seshadri, Sudha] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Beiser, Alexa S.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02118 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Epidemiol & Prevent Med, Boston, MA 02118 USA. [Tan, Zaldy S.] Brigham & Womens Hosp, Boston VA Healthcare Syst, Boston, MA 02115 USA. [Tan, Zaldy S.] Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. [Harris, Tamara B.] NIA, Intramural Res Program, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Roubenoff, Ronenn] Tufts Univ, Friedman Sch Nutr Sci & Policy, Boston, MA 02111 USA. [DeCarli, Charles] Univ Calif Davis, Dept Neurol, Sacramento, CA 95817 USA. [DeCarli, Charles] Univ Calif Davis, Ctr Neurosci, Sacramento, CA 95817 USA. RP Seshadri, S (reprint author), Boston Univ, Sch Med, Dept Neurol, 72 E Concord St,B602, Boston, MA 02118 USA. EM suseshad@bu.edu RI Lieb, Wolfgang/C-1990-2012; OI Ramachandran, Vasan/0000-0001-7357-5970 FU National Institutes of Health [N01-HC-25195, N01HV28178, RO1DK080739, 2K24HL04334]; National Heart, Lung, and Blood Institute; National Institute on Aging [R01 AG16495, AG08122, AG033193, AG031287]; National Institute of Neurological Disorders and Stroke [R01 NS17950] FX This work was supported by contracts N01-HC-25195, N01HV28178, RO1DK080739, and 2K24HL04334 (awarded to Dr Vasan) from the National Institutes of Health and the National Heart, Lung, and Blood Institute; grants R01 AG16495, AG08122, AG033193, and AG031287 from the National Institute on Aging; and grant R01 NS17950 from the National Institute of Neurological Disorders and Stroke. NR 45 TC 172 Z9 175 U1 2 U2 18 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 16 PY 2009 VL 302 IS 23 BP 2565 EP 2572 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 532HK UT WOS:000272737200024 PM 20009056 ER PT J AU Moriceau, S Shionoya, K Jakubs, K Sullivan, RM AF Moriceau, Stephanie Shionoya, Kiseko Jakubs, Katherine Sullivan, Regina M. TI Early-Life Stress Disrupts Attachment Learning: The Role of Amygdala Corticosterone, Locus Ceruleus Corticotropin Releasing Hormone, and Olfactory Bulb Norepinephrine SO JOURNAL OF NEUROSCIENCE LA English DT Review ID PITUITARY-ADRENAL AXIS; HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; ACTIVATES NORADRENERGIC NEURONS; MESSENGER-RNA EXPRESSION; IMMATURE RAT MODEL; INFANT RATS; POSTNATAL-DEVELOPMENT; MATERNAL-DEPRIVATION; BASOLATERAL AMYGDALA; CONDITIONED FEAR AB Infant rats require maternal odor learning to guide pups' proximity-seeking of the mother and nursing. Maternal odor learning occurs using a simple learning circuit including robust olfactory bulb norepinephrine (NE), release from the locus ceruleus (LC), and amygdala suppression by low corticosterone (CORT). Early-life stress increases NE but also CORT, and we questioned whether early-life stress disrupted attachment learning and its neural correlates [2-deoxyglucose (2-DG) autoradiography]. Neonatal rats were normally reared or stressed-reared during the first 6 d of life by providing the mother with insufficient bedding for nest building and were odor-0.5 mA shock conditioned at 7 d old. Normally reared paired pups exhibited typical odor approach learning and associated olfactory bulb enhanced 2-DG uptake. However, stressed-reared pups showed odor avoidance learning and both olfactory bulb and amygdala 2-DG uptake enhancement. Furthermore, stressed-reared pups had elevated CORT levels, and systemic CORT antagonist injection reestablished the age-appropriate odor-preference learning, enhanced olfactory bulb, and attenuated amygdala 2-DG. We also assessed the neural mechanism for stressed-reared pups' abnormal behavior in a more controlled environment by injecting normally reared pups with CORT. This was sufficient to produce odor aversion, as well as dual amygdala and olfactory bulb enhanced 2-DG uptake. Moreover, we assessed a unique cascade of neural events for the aberrant effects of stress rearing: the amygdala-LC-olfactory bulb pathway. Intra-amygdala CORT or intra-LC corticotropin releasing hormone (CRH) infusion supported aversion learning with intra-LC CRH infusion associated with increased olfactory bulb NE (microdialysis). These results suggest that early-life stress disturbs attachment behavior via a unique cascade of events (amygdala-LC-olfactory bulb). C1 [Moriceau, Stephanie; Sullivan, Regina M.] Emot Brain Inst, Nathan Kline Inst, Orangeburg, NY 10962 USA. [Moriceau, Stephanie; Sullivan, Regina M.] NYU, Langone Med Ctr, Ctr Child Study, New York, NY 10016 USA. [Sullivan, Regina M.] NYU, Ctr Neural Sci, New York, NY 10003 USA. [Moriceau, Stephanie; Shionoya, Kiseko; Jakubs, Katherine; Sullivan, Regina M.] Univ Oklahoma, Dept Zool, Norman, OK 73019 USA. [Shionoya, Kiseko] Univ Lyon, CNRS, Lab Neurosci Sensorielles, F-69007 Lyon, France. [Jakubs, Katherine] NIH, Bethesda, MD 20892 USA. RP Moriceau, S (reprint author), Emot Brain Inst, Nathan Kline Inst, 140 Old Orangeburg Rd, Orangeburg, NY 10962 USA. EM SMoriceau@nki.rfmh.org OI Sullivan, Regina/0000-0002-2406-8857 FU National Institutes of Health [DC003906, DC009910]; National Science Foundation [IOB0850527]; Leon Levy Foundation; Hope for Depression Foundation FX This work was funded by National Institutes of Health Grants DC003906 and DC009910, National Science Foundation Grant IOB0850527, the Leon Levy Foundation, and the Hope for Depression Foundation (R.M.S.). NR 118 TC 44 Z9 46 U1 2 U2 13 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 16 PY 2009 VL 29 IS 50 BP 15745 EP 15755 DI 10.1523/JNEUROSCI.4106-09.2009 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 533PP UT WOS:000272837000016 PM 20016090 ER PT J AU McHale, K Mabuchi, H AF McHale, Kevin Mabuchi, Hideo TI Precise Characterization of the Conformation Fluctuations of Freely Diffusing DNA: Beyond Rouse and Zimm SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; 3-DIMENSIONAL PARTICLE TRACKING; QUASI-ELASTIC SCATTERING; POLYMER SOLUTIONS; MONOMER DYNAMICS; SINGLE; MOLECULES; VISCOELASTICITY; MICROSCOPE; SYSTEM AB We studied the dynamics of single freely diffusing fluorescence-labeled double-stranded lambda-phage DNA molecules using dual-color 3-dimensional feedback tracking microscopy and intramolecular fluorescence correlation spectroscopy. Our technique is independently sensitive to the molecule's diffusion coefficient D and radius of gyration R(g) and is concentration insensitive, providing greater precision for characterizing the molecule's intramolecular motion than other methods. We measured D = 0.80 +/- 0.05 mu m(2)/s and R(g) approximate to 420 nm, consistent with the Kirkwood-Riseman prediction for a flexible polymer with strong hydrodynamic interactions (HI), but we find the statistics of intramolecular motion inconsistent with the Zimm model for such a polymer. We address a dispute in the experimental literature, finding that previous measurements on double-stranded DNA likely lacked the sensitivity to distinguish between the Zimm model and the HI-free Rouse model. Finally, we observe fluorescence fluctuations with a correlation time of over 2 s that cannot be explained by either model and propose that they may be signatures of excluded volume interactions. C1 [McHale, Kevin; Mabuchi, Hideo] Stanford Univ, Edward L Ginzton Lab, Stanford, CA 94305 USA. RP McHale, K (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mchalekl@niddk.nih.gov NR 49 TC 13 Z9 13 U1 2 U2 15 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 16 PY 2009 VL 131 IS 49 BP 17901 EP 17907 DI 10.1021/ja906979j PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 536FJ UT WOS:000273028800041 PM 19911791 ER PT J AU Kojima, C Ramirez, DC Tokar, EJ Himeno, S Drobna, Z Styblo, M Mason, RP Waalkes, MP AF Kojima, Chikara Ramirez, Dario C. Tokar, Erik J. Himeno, Seiichiro Drobna, Zuzana Styblo, Miroslav Mason, Ronald P. Waalkes, Michael P. TI Requirement of Arsenic Biomethylation for Oxidative DNA Damage SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID INDUCED MALIGNANT-TRANSFORMATION; HUMAN UROTHELIAL CELLS; ABERRANT GENE-EXPRESSION; EPITHELIAL-CELLS; MATRIX METALLOPROTEINASES; METHYLATED ARSENICALS; HUMAN HEPATOCYTES; CHRONIC EXPOSURE; BLADDER-CANCER; LOW-LEVEL AB Inorganic arsenic is an environmental carcinogen that may act through multiple mechanisms including formation of methylated derivatives in vivo. Sodium arsenite (up to 5.0 mu M) renders arsenic methylation-competent TRL1215 rat liver epithelial cells tumorigenic in nude mice at 18 weeks of exposure and arsenic methylation-deficient RWPE-1 human prostate epithelial cells tumorigenic at 30 weeks of exposure. We assessed the role of arsenic biomethylation in oxidative DNA damage (ODD) using a recently developed immuno-spin trapping method. Immuno-spin trapping was used to measure ODD after chronic exposure of cultured TRL1215 vs RWPE-1 cells, or of methylation-competent UROtsa/F35 vs methylation-deficient UROtsa human urothelial cells, to sodium arsenite. Secreted matrix metalloproteinase (MMP)-2 and -9 activity, as analyzed by zymography, cellular invasiveness by using a transwell assay, and colony formation by using soft agar assay were compared in cells exposed to arsenite with and without selenite, an arsenic biomethylation inhibitor, to assess the role of ODD in the transition to an in vitro cancer phenotype. Exposure of methylation-competent TRL1215 cells to up to 1.0 mu M sodium arsenite was followed by a substantial increase in ODD at 5-18 weeks (eg, at 16 weeks with 1.0 mu M arsenite, 1138% of control, 95% confidence interval [CI] = 797% to 1481%), whereas exposure of methylation-deficient RWPE-1 cells to up to 5.0 mu M arsenite did not increase ODD for a 30-week period. Inhibition of arsenic biomethylation with sodium selenite abolished arsenic-induced ODD and invasiveness, colony formation, and MMP-2 and -9 hypersecretion in TRL1215 cells. Arsenic induced ODD in methylation-competent UROtsa/F35 cells (eg, at 16 weeks, with 1.0 mu M arsenite 225% of control, 95% CI = 188% to 262%) but not in arsenic methylation-deficient UROtsa cells, and ODD levels corresponded to the levels of increased invasiveness, colony formation, and hypersecretion of active MMP-2 and -9 seen after transformation to an in vitro cancer phenotype. Arsenic biomethylation appears to be obligatory for arsenic-induced ODD and appears linked in some cells with the accelerated transition to an in vitro cancer phenotype. C1 [Kojima, Chikara; Tokar, Erik J.; Waalkes, Michael P.] NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Ctr Canc Res,NCI, Res Triangle Pk, NC 27709 USA. [Ramirez, Dario C.; Mason, Ronald P.] NIEHS, Pharmacol Lab, Div Intramural Res, Res Triangle Pk, NC 27709 USA. [Himeno, Seiichiro] Tokushima Bunri Univ, Fac Pharmaceut Sci, Lab Mol Nutr & Toxicol, Yamashiro, Tokushima 770, Japan. [Drobna, Zuzana; Styblo, Miroslav] Univ N Carolina, Dept Nutr, Sch Publ Hlth & Med, Chapel Hill, NC USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Ctr Canc Res,NCI, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov RI RAMIREZ, DARIO/K-3312-2013 OI RAMIREZ, DARIO/0000-0001-6725-3326 FU National Cancer Institute; Center for Cancer Research; National Institute of Environmental Health Sciences FX Intramural Research Program of the National Cancer Institute, Center for Cancer Research (C.K., E.J.T., M.P.W.); National Institute of Environmental Health Sciences (D.C.R., R.P.M.). NR 51 TC 63 Z9 67 U1 0 U2 6 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 16 PY 2009 VL 101 IS 24 BP 1670 EP 1681 DI 10.1093/jnci/djp414 PG 12 WC Oncology SC Oncology GA 534YL UT WOS:000272933400006 PM 19933942 ER PT J AU Hauptmann, M Stewart, PA Lubin, JH Freeman, LEB Hornung, RW Herrick, RF Hoover, RN Fraumeni, JF Blair, A Hayes, RB AF Hauptmann, Michael Stewart, Patricia A. Lubin, Jay H. Freeman, Laura E. Beane Hornung, Richard W. Herrick, Robert F. Hoover, Robert N. Fraumeni, Joseph F., Jr. Blair, Aaron Hayes, Richard B. TI Mortality From Lymphohematopoietic Malignancies and Brain Cancer Among Embalmers Exposed to Formaldehyde SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID SURROGATE RESPONDENTS; OCCUPATIONAL-EXPOSURE; BRITISH PATHOLOGISTS; WORKERS; LEUKEMIA; VALIDITY; COHORT; DEATH AB Excess mortality from lymphohematopoietic malignancies, in particular myeloid leukemia, and brain cancer has been found in surveys of anatomists, pathologists, and funeral industry workers, all of whom may have worked with formaldehyde. We investigated the relation of mortality to work practices and formaldehyde exposure levels among these professionals to address cancer risk in the funeral industry. Professionals employed in the funeral industry who died between January 1, 1960, and January 1, 1986, from lymphohematopoietic malignancies (n = 168) or brain tumors (n = 48) (ie, case subjects) were compared with deceased matched control subjects (n = 265) with regard to lifetime work practices and exposures in the funeral industry, which were obtained by interviews with next of kin and coworkers, and to estimated levels of formaldehyde exposure. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by use of logistic regression. All statistical tests were two-sided. Mortality from myeloid leukemia increased statistically significantly with increasing number of years of embalming (P for trend = .020) and with increasing peak formaldehyde exposure (P for trend = .036). Compared with subjects who performed fewer than 500 lifetime embalmings, mortality from myeloid leukemia was elevated among those who performed embalmings for more than 34 years (OR = 3.9, 95% CI = 1.2 to 12.5, P = .024), who performed more than 3068 embalmings (OR = 3.0, 95% CI = 1.0 to 9.2, P = .057), and those whose estimated cumulative formaldehyde exposure exceeded 9253 parts per million-hours (OR = 3.1; 95% CI = 1.0 to 9.6, P = .047). These exposures were not related to other lymphohematopoietic malignancies or to brain cancer. Duration of embalming practice and related formaldehyde exposures in the funeral industry were associated with statistically significantly increased risk for mortality from myeloid leukemia. C1 [Hauptmann, Michael; Stewart, Patricia A.; Lubin, Jay H.; Freeman, Laura E. Beane; Hoover, Robert N.; Fraumeni, Joseph F., Jr.; Blair, Aaron; Hayes, Richard B.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hauptmann, Michael] Netherlands Canc Inst, Dept Bioinformat & Stat, Amsterdam, Netherlands. [Stewart, Patricia A.] Stewart Exposure Assessments, Arlington, VA USA. [Hornung, Richard W.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Herrick, Robert F.] Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. [Hayes, Richard B.] NYU, Med Ctr, Dept Environm Med, New York, NY 10016 USA. RP Freeman, LEB (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM freemala@mail.nih.gov RI Beane Freeman, Laura/C-4468-2015; OI Beane Freeman, Laura/0000-0003-1294-4124; Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute; National Institutes of Health; Department of Health and Human Services FX Intramural Research Program of the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. NR 34 TC 68 Z9 70 U1 0 U2 12 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 16 PY 2009 VL 101 IS 24 BP 1696 EP 1708 DI 10.1093/jnci/djp416 PG 13 WC Oncology SC Oncology GA 534YL UT WOS:000272933400008 PM 19933446 ER PT J AU Menigatti, M Cattaneo, E Sabates-Bellver, J Ilinsky, VV Went, P Buffoli, F Marquez, VE Jiricny, J Marra, G AF Menigatti, Mirco Cattaneo, Elisa Sabates-Bellver, Jacob Ilinsky, Valery V. Went, Philip Buffoli, Federico Marquez, Victor E. Jiricny, Josef Marra, Giancarlo TI The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis SO MOLECULAR CANCER LA English DT Article ID PTP-SL; SIGNALING PATHWAY; DNA METHYLATION; HUMAN CANCER; KINASES; CELLS; INACTIVATION; PROGRESSION; MICE; IDENTIFICATION AB Background: Tumor development in the human colon is commonly accompanied by epigenetic changes, such as DNA methylation and chromatin modifications. These alterations result in significant, inheritable changes in gene expression that contribute to the selection of tumor cells with enhanced survival potential. Results: A recent high-throughput gene expression analysis conducted by our group identified numerous genes whose transcription was markedly diminished in colorectal tumors. One of these, the protein-tyrosine phosphatase receptor type R (PTPRR) gene, was dramatically downregulated from the earliest stages of cellular transformation. Here, we show that levels of both major PTPRR transcript variants are markedly decreased (compared with normal mucosal levels) in precancerous and cancerous colorectal tumors, as well in colorectal cancer cell lines. The expression of the PTPRR-1 isoform was inactivated in colorectal cancer cells as a result of de novo CpG island methylation and enrichment of transcription-repressive histone-tail marks, mainly H3K27me3. De novo methylation of the PTPRR-1 transcription start site was demonstrated in 29/36 (80%) colorectal adenomas, 42/44 (95%) colorectal adenocarcinomas, and 8/8 (100%) liver metastases associated with the latter tumors. Conclusions: Epigenetic downregulation of PTPRR seems to be an early alteration in colorectal cell transformation, which is maintained during the clonal selection associated with tumor progression. It may represent a preliminary step in the constitutive activation of the RAS/RAF/MAPK/ERK signalling, an effect that will later be consolidated by mutations in genes encoding key components of this pathway. C1 [Menigatti, Mirco; Cattaneo, Elisa; Sabates-Bellver, Jacob; Ilinsky, Valery V.; Jiricny, Josef; Marra, Giancarlo] Univ Zurich, Inst Mol Canc Res, CH-8006 Zurich, Switzerland. [Went, Philip] Triemli Hosp Zurich, Dept Pathol, Zurich, Switzerland. [Buffoli, Federico] Poliambulanza Hosp Brescia, Gastroenterol Unit, Brescia, Italy. [Marquez, Victor E.] NCI, Med Chem Lab, Frederick, MD 21701 USA. RP Marra, G (reprint author), Univ Zurich, Inst Mol Canc Res, CH-8006 Zurich, Switzerland. EM menigatti@imcr.uzh.ch; cattaneo@imcr.uzh.ch; jacob.sabates@roche.com; vilinsky@ya.ru; Philip.Went@triemli.stzh.ch; febuffo@tin.it; marquezv@mail.nih.gov; jiricny@imcr.uzh.ch; marra@imcr.uzh.ch RI Went, Philip/C-8203-2009 FU Swiss National Science Foundation; Zurich Cancer League; Sassella-Stiftung Zurich; University Research Priority Program System Biology/Functional Genomics; NIH, National Cancer Institute, Center for Cancer Research FX The study was supported by grants from the Swiss National Science Foundation (to GM and EC), the Zurich Cancer League (to JS-B), the Sassella-Stiftung Zurich (to VVI), and the University Research Priority Program System Biology/Functional Genomics (to MM and JJ). This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (to VEM). We thank Ritva Haider for technical assistance; and Marian Everett Kent for editorial assistance. NR 51 TC 17 Z9 17 U1 0 U2 0 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 16 PY 2009 VL 8 AR 124 DI 10.1186/1476-4598-8-124 PG 11 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 539TL UT WOS:000273280900001 PM 20015382 ER PT J AU Gattinoni, L Klebanoff, CA Restifo, NP AF Gattinoni, Luca Klebanoff, Christopher A. Restifo, Nicholas P. TI Pharmacologic Induction of CD8(+) T Cell Memory: Better Living Through Chemistry SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID TRANSCRIPTION FACTOR; STEM-CELLS; INTERLEUKIN-7 RECEPTOR; IN-VIVO; WNT; IMMUNITY; DIFFERENTIATION; IMMUNOTHERAPY; LYMPHOCYTES; MAINTENANCE AB The generation of a robust population of memory T cells is critical for effective vaccine and cell-based therapies to prevent and treat infectious diseases and cancer. A series of recent papers have established a new, cell-intrinsic approach in which small molecules target key metabolic and developmental pathways to enhance the formation and maintenance of highly functional CD8(+) memory T cells. These findings raise the exciting new possibility of using small molecules, many of which are already approved for human use, for the pharmacologic induction of immunologic memory. C1 [Gattinoni, Luca; Klebanoff, Christopher A.; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gattinoni, L (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM gattinol@mail.nih.gov; restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Restifo, Nicholas/A-5713-2008; Klebanoff, Christopher/D-9581-2011; OI Gattinoni, Luca/0000-0003-2239-3282; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [ZIA BC010763-05, Z99 CA999999] NR 36 TC 35 Z9 36 U1 0 U2 1 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 1946-6234 J9 SCI TRANSL MED JI Sci. Transl. Med. PD DEC 16 PY 2009 VL 1 IS 11 AR 11ps12 DI 10.1126/scitranslmed.3000302 PG 6 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 590XZ UT WOS:000277263100002 PM 20371454 ER PT J AU Halloran, ME Holmes, EC AF Halloran, M. Elizabeth Holmes, Edward C. TI Invited Commentary: Evaluating Vaccination Programs Using Genetic Sequence Data SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE communicable diseases; disease notification; disease transmission; infectious; genetic variation; hepatitis B virus; molecular sequence data; vaccination ID HEPATITIS-B VIRUS; EFFICACY; VACCINES; DYNAMICS AB Genomic data will become an increasingly important component of epidemiologic studies in coming years. The authors of the accompanying Journal article, van Ballegooijen et al. (Am J Epidemiol. 2009;170(12):1455-1463), are to be commended for attempting to use the coalescent analysis of viral sequence data to evaluate a hepatitis B vaccination program. Coalescent theory attempts to link the phylogenetic history of populations with rates of population growth and decline. In particular, under certain assumptions, a reduction in genetic diversity can be interpreted as a reduction in disease incidence. However, the authors of this commentary contend that van Ballegooijen et al.'s interpretation of changes in viral genetic diversity as a measure of hepatitis B vaccine effectiveness has major limitations. Because of the potential use of these methods in future vaccination studies, the authors discuss the utility of these methods and the data requirements needed for them to be convincing. First, data sets should be large enough to provide sufficient epidemiologic-scale resolution. Second, data need to reflect sufficiently fine-grained temporal sampling. Third, other processes that can potentially influence genetic diversity and confuse demographic inferences should be considered. C1 [Halloran, M. Elizabeth] Fred Hutchinson Canc Res Ctr, Ctr Stat & Quantitat Infect Dis, Seattle, WA 98109 USA. [Halloran, M. Elizabeth] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [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 Halloran, ME (reprint author), Fred Hutchinson Canc Res Ctr, Ctr Stat & Quantitat Infect Dis, 1100 Fairview Ave N,M2-C200, Seattle, WA 98109 USA. EM betz@u.washington.edu OI Holmes, Edward/0000-0001-9596-3552 FU NIAID NIH HHS [R01 AI32042, R01 AI032042] NR 11 TC 5 Z9 5 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 15 PY 2009 VL 170 IS 12 BP 1464 EP 1466 DI 10.1093/aje/kwp366 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 528RF UT WOS:000272463600002 PM 19910381 ER PT J AU Sempos, CT Goldbourt, U AF Sempos, Christopher T. Goldbourt, Uri TI Harold A. Kahn (1920-2009): A Remembrance of a Life Devoted to Public Health Obituary SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Biographical-Item ID HEART DISEASE; FRAMINGHAM; PREVALENCE C1 [Sempos, Christopher T.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Goldbourt, Uri] Tel Aviv Univ, Sackler Fac Med, Dept Epidemiol & Prevent Med, IL-69978 Tel Aviv, Israel. RP Sempos, CT (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Room 3B01, Bethesda, MD 20892 USA. EM semposch@mail.nih.gov NR 15 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 15 PY 2009 VL 170 IS 12 BP 1530 EP 1532 DI 10.1093/aje/kwp346 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 528RF UT WOS:000272463600011 PM 19965894 ER PT J AU Sebastiani, P Hadley, EC Province, M Christensen, K Rossi, W Perls, TT Ash, AS AF Sebastiani, Paola Hadley, Evan C. Province, Michael Christensen, Kaare Rossi, Winifred Perls, Thomas T. Ash, Arlene S. TI A Family Longevity Selection Score: Ranking Sibships by Their Longevity, Size, and Availability for Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE aged; 80 and over; family data; longevity; Shannon information ID CORONARY-HEART-DISEASE; RISK SCORE; MORTALITY; CENTENARIANS; SIBLINGS AB Family studies of exceptional longevity can potentially identify genetic and other factors contributing to long life and healthy aging. Although such studies seek families that are exceptionally long lived, they also need living members who can provide DNA and phenotype information. On the basis of these considerations, the authors developed a metric to rank families for selection into a family study of longevity. Their measure, the family longevity selection score (FLOSS), is the sum of 2 components: 1) an estimated family longevity score built from birth-, gender-, and nation-specific cohort survival probabilities and 2) a bonus for older living siblings. The authors examined properties of FLoSS-based family rankings by using data from 3 ongoing studies: the New England Centenarian Study, the Framingham Heart Study, and screenees for the Long Life Family Study. FLoSS-based selection yields families with exceptional longevity, satisfactory sibship sizes and numbers of living siblings, and high ages. Parameters in the FLOSS formula can be tailored for studies of specific populations or age ranges or with different conditions. The first component of the FLOSS also provides a conceptually sound survival measure to characterize exceptional longevity in individuals or families in various types of studies and correlates well with later-observed longevity. C1 [Hadley, Evan C.; Rossi, Winifred] NIA, Div Geriatr & Clin Gerontol, Bethesda, MD 20892 USA. [Sebastiani, Paola] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. [Province, Michael] Washington Univ, Dept Biostat, St Louis, MO USA. [Christensen, Kaare] Univ So Denmark, Danish Aging Res Ctr, Inst Publ Hlth, Odense, Denmark. [Perls, Thomas T.] Boston Univ, Div Geriatr, Dept Med, Med Ctr, Boston, MA USA. [Ash, Arlene S.] Boston Univ, Sch Med, Dept Med, Hlth Care Res Unit,Sect Gen Internal Med, Boston, MA 02118 USA. RP Hadley, EC (reprint author), NIA, Div Geriatr & Clin Gerontol, Gateway Bldg,MSC 9205,7201 Wisconsin Ave, Bethesda, MD 20892 USA. EM evan.hadley@nih.gov RI Christensen, Kaare/C-2360-2009; OI Christensen, Kaare/0000-0002-5429-5292; Perls, Thomas/0000-0002-2492-4334; sebastiani, paola/0000-0001-6419-1545 FU National Heart, Lung, and Blood Institute in collaboration with Boston University; [U01AG023755]; [U01AG023746]; [U01AG023712] FX Funded by grants U01AG023755 (P. S., T. P., A. S. A.), U01AG023746 (M. P.), and U01AG023712 (K. C.). The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with Boston University. NR 11 TC 37 Z9 39 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD DEC 15 PY 2009 VL 170 IS 12 BP 1555 EP 1562 DI 10.1093/aje/kwp309 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 528RF UT WOS:000272463600014 PM 19910380 ER PT J AU Ahmad, F Lindh, R Tang, Y Ruishalme, I Ost, A Sahachartsiri, B Stralfors, P Degerman, E Manganiello, VC AF Ahmad, Faiyaz Lindh, Rebecka Tang, Yan Ruishalme, Iida Ost, Anita Sahachartsiri, Bobby Stralfors, Peter Degerman, Eva Manganiello, Vincent C. TI Differential regulation of adipocyte PDE3B in distinct membrane compartments by insulin and the beta(3)-adrenergic receptor agonist CL316243: effects of caveolin-1 knockdown on formation/maintenance of macromolecular signalling complexes SO BIOCHEMICAL JOURNAL LA English DT Article DE adipocyte; beta(3)-adrenergic receptor; caveolin-1; insulin; protein kinase A (PKA); phosphodiesterase 3 (PDE3) ID NUCLEOTIDE PHOSPHODIESTERASE 3B; HORMONE-SENSITIVE LIPASE; PROTEIN-KINASE B; RAT ADIPOCYTES; INDUCED PHOSPHORYLATION; PLASMA-MEMBRANE; ACTIVATION; TRANSLOCATION; CELLS; MICE AB In adipocytes, PDE3B (phosphodiesterase 3B) is an important regulatory effector in signalling pathways controlled by insulin and cAMP-increasing hormones. Stimulation of 3T3-L1 adipocytes with insulin or the beta(3)-adrenergic receptor agonist CL316243 (termed CL) indicated that insulin preferentially phosphorylated/activated PDE3B associated with internal membranes (endoplasmic reticulum/Golgi), whereas CL preferentially phosphorylated/activated PDE3B associated with caveolae. siRNA (small interfering RNA)-mediated KD (knockdown) of CAV-1 (caveolin-1) in 3T3-L1 adipocytes resulted in down-regulation of expression of membrane-associated PDE3B. Insulin-induced activation of PDE3B was reduced, whereas CL-mediated activation was almost totally abolished. Similar results were obtained in adipocytes from Cav-1-deficient mice. siRNA-mediated KID of CAV-1 in 3T3-L1 adipocytes also resulted in inhibition of CL-stimulated phosphorylation of HSL (hormone-sensitive lipase) and perilipin A, and of lipolysis. Superose 6 gel-filtration chromatography of solubilized membrane proteins from adipocytes stimulated with insulin or CL demonstrated the reversible assembly of distinct macromolecular complexes that contained P-32-phosphorylated PDE3B and signalling molecules thought to be involved in its activation. Insulin- and CL-induced macromolecular complexes were enriched in cholesterol, and contained certain common signalling proteins [14-3-3, PP2A (protein phosphatase 2A) and cav-1]. The complexes present in insulin-stimulated cells contained tyrosine-phosphorylated IRS-1 (insulin receptor substrate 1) and its downstream signalling proteins, whereas CL-activated complexes contained beta(3)-adrenergic receptor, PKA-RII [PKA (cAMP-dependent protein kinase)-regulatory subunit] and HSL. Insulin- and CL-mediated macromolecular complex formation was significantly inhibited by CAV-1 KID. These results suggest that cav-1 acts as a molecular chaperone or scaffolding molecule in cholesterol-rich lipid rafts that may be necessary for the proper stabilization and activation of PDE3B in response to CL and insulin. C1 [Ahmad, Faiyaz; Tang, Yan; Sahachartsiri, Bobby; Manganiello, Vincent C.] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Lindh, Rebecka; Degerman, Eva] Lund Univ, Dept Expt Med Sci, S-22184 Lund, Sweden. [Ruishalme, Iida; Ost, Anita; Stralfors, Peter] Linkoping Univ, Div Cell Biol, SE-58185 Linkoping, Sweden. [Ruishalme, Iida; Ost, Anita; Stralfors, Peter] Linkoping Univ, Diabet Res Ctr, SE-58185 Linkoping, Sweden. RP Ahmad, F (reprint author), NHLBI, Translat Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM Ahmadf@nhlbi.nih.gov FU NHLBI [HL002540-15]; Swedish Medical Research Council [3362] FX Part of this work was supported by the NHLBI (National Heart, Lung and Blood Institute) Intramural Research Programme [project number HL002540-15]. E.D. was supported, in part, by the Swedish Medical Research Council [grant number 3362]. NR 37 TC 24 Z9 24 U1 0 U2 3 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 15 PY 2009 VL 424 BP 399 EP 410 DI 10.1042/BJ20090842 PN 3 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 538VF UT WOS:000273211600008 PM 19747167 ER PT J AU Zharikova, OL Fokina, VM Nanovskaya, TN Hill, RA Mattison, DR Hankins, GDV Ahmed, MS AF Zharikova, Olga L. Fokina, Valentina M. Nanovskaya, Tatiana N. Hill, Ronald A. Mattison, Donald R. Hankins, Gary D. V. Ahmed, Mahmoud S. TI Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Glyburide; Human placenta; Human liver; Enzymes; Glyburide metabolism ID HUMAN LIVER-MICROSOMES; HUMAN CYTOCHROME-P450 ISOFORMS; ENDOTHELIN RECEPTOR ANTAGONIST; IN-VITRO; TRANSPLACENTAL TRANSFER; LIQUID-CHROMATOGRAPHY; ACTIVE METABOLITES; HUMAN SERUM; GLIBENCLAMIDE; PHARMACOKINETICS AB One of the factors affecting the pharmacokinetics (PK) of a drug during pregnancy is the activity of hepatic and placental metabolizing enzymes. Recently, we reported on the biotransformation of glyburide by human hepatic and placental microsomes to six metabolites that are structurally identical between the two tissues. Two of the metabolites, 4-trans-(M1) and 3-cis-hydroxycyclohexyl glyburide (M2b), were previously identified in plasma and urine of patients treated with glyburide and are pharmacologically active. The aim of this investigation was to identify the major human hepatic and placental CYP450 isozymes responsible for the formation of each metabolite of glyburide. This was achieved by the use of chemical inhibitors selective for individual CYP isozymes and antibodies raised against them. The identification was confirmed by the kinetic constants for the biotransformation of glyburide by cDNA-expressed enzymes. The data revealed that the major hepatic isozymes responsible for the formation of each metabolite are as follows: CYP3A4 (ethylene-hydroxylated glyburide (M5), 3-trans-(M3) and 2-trans-(M4) cyclohexyl glyburide); CYP2C9 (M1, M2a (4-cis-) and M215); CYP2C8 (M1 and M2b); and CYP2C19 (M2a). Human placental microsomal CYP19/aromatase was the major isozyme responsible for the biotransformation of glyburide to predominantly M5. The formation of significant amounts of M5 by CYP19 in the placenta could render this metabolite more accessible to the fetal circulation. The multiplicity of enzymes biotransforming glyburide and the metabolites formed underscores the potential for its drug interactions in vivo. (C) 2009 Elsevier Inc. All rights reserved. C1 [Zharikova, Olga L.; Fokina, Valentina M.; Nanovskaya, Tatiana N.; Hankins, Gary D. V.; Ahmed, Mahmoud S.] Univ Texas Med Branch, Dept Obstet & Gynecol, Galveston, TX 77555 USA. [Hill, Ronald A.] NE Louisiana Univ, Coll Pharm, Monroe, LA 71209 USA. [Mattison, Donald R.] NICHD, Obstet Fetal Pharmacol Res Units OPRU Network, Ctr Res Mother & Children, Bethesda, MD USA. RP Ahmed, MS (reprint author), Univ Texas Med Branch, Dept Obstet & Gynecol, 301 Univ Blvd, Galveston, TX 77555 USA. EM maahmed@utmb.edu RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 FU NICHD [U10-HD0478]; University of Texas Medical Branch, Galveston, Texas FX This investigation was supported by the Obstetric-Fetal Pharmacology Research Units Network (OPRU, U10-HD0478, NICHD). The authors appreciate the assistance of the medical staff of the Labor and Delivery Ward of the John Sealy Hospital, the Perinatal Research Group, and the Publication, Grant, & Media Support Office of the Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, Texas. NR 42 TC 26 Z9 26 U1 0 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD DEC 15 PY 2009 VL 78 IS 12 BP 1483 EP 1490 DI 10.1016/j.bcp.2009.08.003 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 514MZ UT WOS:000271400300008 PM 19679108 ER PT J AU Li, QL Wang, YL Bryant, SH AF Li, Qingliang Wang, Yanli Bryant, Stephen H. TI A novel method for mining highly imbalanced high-throughput screening data in PubChem SO BIOINFORMATICS LA English DT Article ID DRUG-LIKE COMPOUNDS; CHEMICAL BIOLOGY; NIH ROADMAP; CLASSIFICATION; ASSAYS; KNOWLEDGE; MODELS AB Motivation: The comprehensive information of small molecules and their biological activities in PubChem brings great opportunities for academic researchers. However, mining high-throughput screening (HTS) assay data remains a great challenge given the very large data volume and the highly imbalanced nature with only small number of active compounds compared to inactive compounds. Therefore, there is currently a need for better strategies to work with HTS assay data. Moreover, as luciferase-based HTS technology is frequently exploited in the assays deposited in PubChem, constructing a computational model to distinguish and filter out potential interference compounds for these assays is another motivation. Results: We used the granular support vector machines (SVMs) repetitive under sampling method (GSVM-RU) to construct an SVM from luciferase inhibition bioassay data that the imbalance ratio of active/inactive is high (1/377). The best model recognized the active and inactive compounds at the accuracies of 86.60% and 88.89 with a total accuracy of 87.74%, by cross-validation test and blind test. These results demonstrate the robustness of the model in handling the intrinsic imbalance problem in HTS data and it can be used as a virtual screening tool to identify potential interference compounds in luciferase-based HTS experiments. Additionally, this method has also proved computationally efficient by greatly reducing the computational cost and can be easily adopted in the analysis of HTS data for other biological systems. C1 [Li, Qingliang; Wang, Yanli; Bryant, Stephen H.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov RI Li, Qingliang/N-5169-2015 OI Li, Qingliang/0000-0002-6453-236X FU National Institutes of Health, National Library of Medicine FX Intramural Research Program of the National Institutes of Health, National Library of Medicine. NR 33 TC 28 Z9 29 U1 1 U2 18 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD DEC 15 PY 2009 VL 25 IS 24 BP 3310 EP 3316 DI 10.1093/bioinformatics/btp589 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 528RJ UT WOS:000272464000015 PM 19825798 ER PT J AU Wang, DY Iera, J Baker, H Hogan, P Ptak, R Yang, L Hartman, T Buckheit, RW Desjardins, A Yang, A Legault, P Yedavalli, V Jeang, KT Appella, DH AF Wang, Deyun Iera, Jaclyn Baker, Heather Hogan, Priscilla Ptak, Roger Yang, Lu Hartman, Tracy Buckheit, Robert W., Jr. Desjardins, Alexandre Yang, Ao Legault, Pascale Yedavalli, Venkat Jeang, Kuan-Teh Appella, Daniel H. TI Multivalent binding oligomers inhibit HIV Tat-TAR interaction critical for viral replication SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE HIV; RNA; TAR; Multivalency ID HUMAN-IMMUNODEFICIENCY-VIRUS; SMALL MOLECULES; TARGETING RNA; BIOLOGICAL EVALUATION; LIGANDS; PROTEIN; RECOGNITION; TRANSCRIPTION; ANTAGONIST; CONJUGATE AB We describe the development of a new type of scaffold to target RNA structures. Multivalent binding oligomers (MBOs) are molecules in which multiple sidechains extend from a polyamine backbone such that favorable RNA binding occurs. We have used this strategy to develop MBO-based inhibitors to prevent the association of a protein-RNA complex, Tat-TAR, that is essential for HIV replication. In vitro binding assays combined with model cell-based assays demonstrate that the optimal MBOs inhibit Tat-TAR binding at low micromolar concentrations. Antiviral studies are also consistent with the in vitro and cell-based assays. MBOs provide a framework for the development of future RNA-targeting molecules. Published by Elsevier Ltd. C1 [Wang, Deyun; Iera, Jaclyn; Baker, Heather; Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Hogan, Priscilla; Ptak, Roger] So Res Inst, Frederick, MD 21701 USA. [Yang, Lu; Hartman, Tracy; Buckheit, Robert W., Jr.] ImQuest Biosci Inc, Frederick, MD 21704 USA. [Desjardins, Alexandre; Yang, Ao; Legault, Pascale] Univ Montreal, Dept Biochim, Montreal, PQ H3C 3J7, Canada. [Yedavalli, Venkat; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, NIH, DHHS, Bethesda, MD 20892 USA. RP Appella, DH (reprint author), NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov RI Jeang, Kuan-Teh/A-2424-2008; Desjardins, Alexandre/K-6378-2012 FU Intramural Research Programs (IRPs) of NIDDK and NIAID; Intramural AIDS Targeted Antiviral Program (IATAP) at NIH; Canadian Institutes for Health Research [HOP-83068]; Fonds de la Recherche en Sante du Quebec; Universite de Montreal; Universite de Montreal Research Group on Drug Development FX The authors would like to thank Dr. Jim Turpin (NIAID), Dr. Lisa Jenkins (NCI), and Mr. George Lieman (NCI) for helpful comments on this manuscript. This research was supported in part by the Intramural Research Programs (IRPs) of NIDDK and NIAID, and the Intramural AIDS Targeted Antiviral Program (IATAP) at NIH. This work was supported in part by a grant from the Canadian Institutes for Health Research (HOP-83068 to P. L.). A. D. was supported by graduate scholarships from the Fonds de la Recherche en Sante du Quebec and the Universite de Montreal. A.Y. was supported by a post-doctoral fellowship from the Universite de Montreal Research Group on Drug Development. P. L. holds a Canada Research Chair in Structural Biology of RNA. NR 50 TC 10 Z9 10 U1 4 U2 11 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 2009 VL 19 IS 24 BP 6893 EP 6897 DI 10.1016/j.bmcl.2009.10.078 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 518VU UT WOS:000271724200014 PM 19896372 ER PT J AU Yim, PB Clarke, ML McKinstry, M Lacerda, SHD Pease, LF Dobrovolskaia, MA Kang, HG Read, TD Sozhamannan, S Hwang, JS AF Yim, Peter B. Clarke, Matthew L. McKinstry, Michael Lacerda, Silvia H. De Paoli Pease, Leonard F., III Dobrovolskaia, Marina A. Kang, HyeongGon Read, Timothy D. Sozhamannan, Shanmuga Hwang, Jeeseong TI Quantitative Characterization of Quantum Dot-Labeled Lambda Phage for Escherichia coli Detection SO BIOTECHNOLOGY AND BIOENGINEERING LA English DT Article DE phage; bacteria detection; fluorescence; nanocrystal; microscopy; electron-spray differential mobility assay ID DIFFERENTIAL MOBILITY ANALYSIS; BACTERIOPHAGE-LAMBDA; BACILLUS-ANTHRACIS; RAPID DETECTION; O157-H7; PROTEIN; PATHOGENS; SURFACE AB We characterize CdSe/ZnS quantum dot (QD) binding to genetically modified bacteriophage as a model for bacterial detection. Interactions among QDs, lambda (lambda) phage, and Escherichia coli are examined by several cross-validated methods. Flow and image-based cytometry clarify fluorescent labeling of bacteria, with image-based cytometry additionally reporting the number of decorated phage bound to cells. Transmission electron microscopy, image-based cytometry, and electrospray differential mobility analysis allow quantization of QDs attached to each phage (4-17 QDs) and show that lambda phage used in this study exhibits enhanced QD binding to the capsid by nearly a factor of four compared to bacteriophage T7. Additionally, the characterization methodology presented can be applied to the quantitative characterization of other fluorescent nanocrystal-biological conjugates. Biotechnol. Bioeng. 2009; 104: 1059-1067. Published 2009 Wiley Periodicals, Inc. C1 [Yim, Peter B.; Clarke, Matthew L.; Lacerda, Silvia H. De Paoli; Pease, Leonard F., III; Kang, HyeongGon; Hwang, Jeeseong] NIST, Gaithersburg, MD 20899 USA. [McKinstry, Michael; Sozhamannan, Shanmuga] USN, Biol Def Res Directorate, Med Res Ctr, Silver Spring, MD USA. [Pease, Leonard F., III] Univ Utah, Dept Chem Engn, Salt Lake City, UT 84112 USA. [Dobrovolskaia, Marina A.] SAIC Frederick NCI Frederick, Nanotechnol Characterizat Lab, Frederick, MD USA. [Read, Timothy D.] Emory Univ, Sch Med, Div Infect Dis, Dept Human Genet, Atlanta, GA USA. RP Hwang, JS (reprint author), NIST, 100 Bur Dr,Mailstop 8443, Gaithersburg, MD 20899 USA. EM jch@nist.gov RI Read, Timothy/E-6240-2011; Nanotechnology Characterization Lab, NCL/K-8454-2012 FU National Institute of Standards and Technology Advanced Technology Program; NRC postdoctoral fellowship program; Defense Threat Reduction Agency, Department of Defense of the U.S. Government [8.10084_08_NM_B] FX The authors thank Dr. Georgeta Crivat, Dr. Zhenping Zhou, Dr. Jianyong Tang, Dr. John Woodward, Dr. Lori Goldner, Dr. Garnett Bryant, and Dr. Paul DeRose at NIST; and Dr. Anil Patri at the Nanotechnology Characterization Laboratory (NCL) at SAIC-Frederick/NCI-Frederick and Daniel Nelson at the University of Maryland Biotechnology Institute for useful discussions and acknowledge Mike Zachariah, Mike Tarlov, and De-Hao Tsai for their assistance with ES-DMA training. JH was supported by the National Institute of Standards and Technology Advanced Technology Program. MC was supported by the NRC postdoctoral fellowship program. This work was supported by funds from the Defense Threat Reduction Agency, Department of Defense of the U.S. Government (BDRD authors; grant # 8.10084_08_NM_B). NR 31 TC 30 Z9 30 U1 1 U2 30 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0006-3592 J9 BIOTECHNOL BIOENG JI Biotechnol. Bioeng. PD DEC 15 PY 2009 VL 104 IS 6 BP 1059 EP 1067 DI 10.1002/bit.22488 PG 9 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 546LX UT WOS:000273813400002 PM 19634184 ER PT J AU Camacho, C Coulouris, G Avagyan, V Ma, N Papadopoulos, J Bealer, K Madden, TL AF Camacho, Christiam Coulouris, George Avagyan, Vahram Ma, Ning Papadopoulos, Jason Bealer, Kevin Madden, Thomas L. TI BLAST plus : architecture and applications SO BMC BIOINFORMATICS LA English DT Article ID PSI-BLAST; PROTEIN-SEQUENCE; DNA-SEQUENCES; SEARCHES; TOOL AB Background: Sequence similarity searching is a very important bioinformatics task. While Basic Local Alignment Search Tool (BLAST) outperforms exact methods through its use of heuristics, the speed of the current BLAST software is suboptimal for very long queries or database sequences. There are also some shortcomings in the user-interface of the current command-line applications. Results: We describe features and improvements of rewritten BLAST software and introduce new command-line applications. Long query sequences are broken into chunks for processing, in some cases leading to dramatically shorter run times. For long database sequences, it is possible to retrieve only the relevant parts of the sequence, reducing CPU time and memory usage for searches of short queries against databases of contigs or chromosomes. The program can now retrieve masking information for database sequences from the BLAST databases. A new modular software library can now access subject sequence data from arbitrary data sources. We introduce several new features, including strategy files that allow a user to save and reuse their favorite set of options. The strategy files can be uploaded to and downloaded from the NCBI BLAST web site. Conclusion: The new BLAST command-line applications, compared to the current BLAST tools, demonstrate substantial speed improvements for long queries as well as chromosome length database sequences. We have also improved the user interface of the command-line applications. C1 [Camacho, Christiam; Coulouris, George; Avagyan, Vahram; Ma, Ning; Papadopoulos, Jason; Bealer, Kevin; Madden, Thomas L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Madden, TL (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bldg 38A,8600 Rockville Pike, Bethesda, MD 20894 USA. EM camacho@ncbi.nlm.nih.gov; coulouri@ncbi.nlm.nih.gov; avagyanv@ncbi.nlm.nih.gov; maning@ncbi.nlm.nih.gov; jasonp@boo.net; kevinbealer@gmail.com; madden@ncbi.nlm.nih.gov FU NIH; National Library of Medicine FX A number of people contributed to this project. Richa Agarwala, Alejandro Schaffer, and Mike DiCuccio offered ideas and feedback. Mike Gertz, Aleksandr Morgulis, and Ilya Dondoshansky contributed some of the code used in the core of BLAST. Denis Vakatov, Aaron Ucko and other members of the NCBI C++ toolkit group offered assistance as well as the C++ toolkit used to build BLAST+. Eugene Yaschenko, Kurt Rodarmer and Ty Roach provided help in using the NCBI SRA Software Development Toolkit. David Lipman and Jim Ostell originally suggested the need for a rewritten version of BLAST and provided encouragement and feedback. Greg Boratyn, Maureen Madden and John Spouge read the manuscript and offered helpful suggestions.; This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. Funding to pay the Open Access publication charges for this article was provided by the National Institutes of Health. NR 24 TC 1599 Z9 1622 U1 21 U2 163 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD DEC 15 PY 2009 VL 10 AR 421 DI 10.1186/1471-2105-10-421 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 542YD UT WOS:000273534300001 PM 20003500 ER PT J AU Kaufmann, PG AF Kaufmann, Peter G. TI Psychosocial Interventions in Breast Cancer To Light a Candle SO CANCER LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; PSYCHOLOGICAL INTERVENTION; COMBINED PHARMACOTHERAPIES; BEHAVIORAL INTERVENTIONS; ALCOHOL DEPENDENCE; CLINICAL-TRIAL; DISEASE; HEALTH C1 NHLBI, Clin Applicat & Prevent Branch, Bethesda, MD 20892 USA. RP Kaufmann, PG (reprint author), NHLBI, Clin Applicat & Prevent Branch, 6701 Rockledge Dr Suite 10106,Rockledge 2, Bethesda, MD 20892 USA. EM kaufmannp@nhlbi.nih.gov NR 14 TC 3 Z9 3 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 15 PY 2009 VL 115 IS 24 BP 5617 EP 5619 DI 10.1002/cncr.24659 PG 3 WC Oncology SC Oncology GA 529UX UT WOS:000272545400004 PM 19824082 ER PT J AU Adams, SA Smith, ER Hardin, J Prabhu-Das, I Fulton, J Hebert, JR AF Adams, Swann A. Smith, Emily R. Hardin, James Prabhu-Das, Irene Fulton, Jeanette Hebert, James R. TI Racial Differences in Follow-Up of Abnormal Mammography Findings Among Economically Disadvantaged Women SO CANCER LA English DT Article DE mammography; health status disparities; African Americans; medically uninsured; breast neoplasms ID BREAST-CANCER SURVIVAL; AFRICAN-AMERICAN; SCREENING MAMMOGRAPHY; UNITED-STATES; WHITE WOMEN; DIAGNOSIS; RACE; CARE; CARCINOMA; DELAY AB BACKGROUND: In the United States, and particularly in South Carolina, African-American women suffer disproportionately higher mortality rates from breast cancer than European-American women. The timeliness of patient adherence to the follow-up of mammographic abnormalities may influence prognosis and survival. The objective of the current investigation was to examine racial differences in the completion and completion time of a diagnostic workup after the finding of a suspicious breast abnormality. METHODS: Study participants of the Best Chance Network, a statewide service program that provides free mammography screening to economically disadvantaged and medically underserved women, were included in the study. Racial differences in tumor characteristics and adherence to recommended workup were tested using chi-square tests and t tests. Logistic and Cox regression modeling was used to assess the relation between workup completion and other factors among African-American women and European-American women. RESULTS: Completion of the workup was associated with the number of previous procedures and income, and no significant differences were noted by race. The amount of time to completion of the workup was influenced by previous procedures, income, and race. After accounting for completion time, African-American women were 12% less likely than European-American women to complete the recommended workup (hazard ratio, 0.88; P = .01). CONCLUSIONS: The results from this study established a racial disparity in the time to completion of a diagnostic workup among Best Chance Network participants. These findings highlight the importance of understanding the factors associated with delays in and adherence to completing the recommended workup when breast abnormalities are detected in mammograms. Cancer 2009;115:5788-97. (C) 2009 American Cancer Society. C1 [Adams, Swann A.] Univ S Carolina, Canc Prevent & Control Program, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, Columbia, SC 29208 USA. [Adams, Swann A.; Smith, Emily R.; Hebert, James R.] S Carolina Statewide Canc Prevent & Control Progr, Columbia, SC USA. [Prabhu-Das, Irene] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Fulton, Jeanette] S Carolina Comprehens Breast Ctr, Columbia, SC USA. RP Adams, SA (reprint author), Univ S Carolina, Canc Prevent & Control Program, Arnold Sch Publ Hlth, Dept Epidemiol & Biostat, 915 Greene St, Columbia, SC 29208 USA. EM swann.adams@sc.edu RI Arp Adams, Swann/C-7337-2015; Hardin, James/Q-7617-2016 OI Arp Adams, Swann/0000-0001-5779-6802; Hardin, James/0000-0003-0506-5500 FU University of South Carolina; Office of Research and Health Sciences; National Cancer Institute [1 U01 CA114601-01] FX Supported by the University of South Carolina, Office of Research and Health Sciences. We also acknowledge funding of the South Carolina Cancer Disparities Community Network through grant 1 U01 CA114601-01 from the National Cancer Institute (Community Networks Program). NR 53 TC 27 Z9 27 U1 2 U2 11 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD DEC 15 PY 2009 VL 115 IS 24 BP 5788 EP 5797 DI 10.1002/cncr.24633 PG 10 WC Oncology SC Oncology GA 529UX UT WOS:000272545400024 PM 19859902 ER PT J AU Gheeya, JS Chen, QR Benjamin, CD Cheuk, AT Tsang, P Chung, JY Metaferia, BB Badgett, TC Johansson, P Wei, JS Hewitt, SM Khan, J AF Gheeya, Jinesh S. Chen, Qing-Rong Benjamin, Christopher D. Cheuk, Adam T. Tsang, Patricia Chung, Joon-Yong Metaferia, Belhu B. Badgett, Thomas C. Johansson, Peter Wei, Jun S. Hewitt, Stephen M. Khan, Javed TI Screening a panel of drugs with diverse mechanisms of action yields potential therapeutic agents against neuroblastoma SO CANCER BIOLOGY & THERAPY LA English DT Article DE neuroblastoma; drug screening; anti-cancer agents; chemotherapy; apoptosis; cucurbitacin I; STAT3 ID NF-KAPPA-B; CELL-CYCLE ARREST; SYNTHETIC TRITERPENOID CDDO; PROTEASOME INHIBITOR PS-341; ANTITUMOR-ACTIVITY; TOPOISOMERASE-II; CANCER CELLS; HUMAN GLIOBLASTOMA; APOPTOSIS; GROWTH AB Neuroblastoma (NB) is the most common extracranial solid tumor in children. Despite current aggressive therapy, the survival rate for high risk NB remains less than 40%. To identify novel effective chemo-agents against NB, we screened a panel of 96 drugs against two NB cell lines, SK-N-AS and SH-SY5Y. We found 30 compounds that were active against NB cell lines at <= 10 mu M concentration. More interestingly, 17 compounds are active at <= 1 mu M concentration, and they act through a wide spectrum of diverse mechanisms such as mitotic inhibition, topoisomerase inhibition, targeting various biological pathways, and unknown mechanisms. The majority of these active compounds also induced caspase 3/7 by more than 2-fold. Of these 17 active compounds against NB cell lines at sub-micromolar concentration, eleven compounds are not currently used to treat NB. among them, nine are FDA approved compounds, and three agents are undergoing clinical trials for various malignancies. Furthermore, we identified four agents active against these NB cell lines that have not yet been tested in the clinical setting. Finally we demonstrated that Cucurbitacin I inhibits neuroblastoma cell growth through inhibition of STAT3 pathway. These drugs thus represent potential novel therapeutic agents for patients with NB, and further validation studies are needed to translate them to the clinic. C1 [Gheeya, Jinesh S.; Chen, Qing-Rong; Benjamin, Christopher D.; Cheuk, Adam T.; Tsang, Patricia; Metaferia, Belhu B.; Badgett, Thomas C.; Johansson, Peter; Wei, Jun S.; Khan, Javed] NCI, Oncogenom Sect, Pediat Oncol Branch, Adv Technol Ctr, Gaithersburg, MD USA. [Chung, Joon-Yong; Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, Gaithersburg, MD USA. RP Khan, J (reprint author), NCI, Oncogenom Sect, Pediat Oncol Branch, Adv Technol Ctr, Gaithersburg, MD USA. EM khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014; Johansson, Peter/K-1053-2014; OI Khan, Javed/0000-0002-5858-0488; Johansson, Peter/0000-0001-7015-5452; Gheeya, Jinesh/0000-0002-5246-6262; Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU Intramural NIH HHS [Z99 CA999999] NR 58 TC 18 Z9 18 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD DEC 15 PY 2009 VL 8 IS 24 BP 2386 EP 2395 DI 10.4161/cbt.8.24.10184 PG 10 WC Oncology SC Oncology GA 551RI UT WOS:000274226300018 PM 19946221 ER PT J AU Green, JE AF Green, J. E. TI Our Inner Mouse: Genomic Insights from Mouse Mammary Cancer Models To Guide Pre-clinical Testing SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 [Green, J. 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 483S EP 483S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700010 ER PT J AU Powles, T Diem, S Wickerham, L Cox, D Amewou-Atisso, M Agnusdei, D Murain, D Mitlak, B Cummings, S AF Powles, T. Diem, S. Wickerham, L. Cox, D. Amewou-Atisso, M. Agnusdei, D. Murain, D. Mitlak, B. Cummings, S. TI Effects of Arzoxifene on Breast Cancer Incidence in Postmenopausal Women with Osteoporosis or with Low Bone Mass SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Parkside Oncol Clin, London, England. Univ Minnesota, Minneapolis, MN USA. NSABP, Pittsburgh, PA USA. Eli Lilly & Co, Indianapolis, IN 46285 USA. Univ Calif San Francisco, San Francisco, CA 94143 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 499S EP 499S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700056 ER PT J AU Lee, HY Lewin, A Wen, ML Ryseck, R Fargnoli, J Poruchynsky, MS Fojo, T Mudenda, B Rugo, HS AF Lee, H. Y. Lewin, A. Wen, M-L Ryseck, R. Fargnoli, J. Poruchynsky, M. S. Fojo, T. Mudenda, B. Rugo, H. S. TI Antiangiogenic (AG) Synergy with Ixabepilone (IXA): Translation of Preclinical Studies to the Clinical Setting. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Bristol Myers Squibb Co, Princeton, NJ USA. Bristol Myers Squibb Co, Wallingford, CT 06492 USA. NCI, Bethesda, MD 20892 USA. UCSF Comprehens Canc Ctr, San Francisco, CA 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 511S EP 512S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920700088 ER PT J AU Julian, TB Anderson, SJ Golesorkhi, N Fourchotte, V Zheng, P Mamounas, EP Brown, AM Boudros, E Bear, HD Constantino, JP Wolmark, N AF Julian, T. B. Anderson, S. J. Golesorkhi, N. Fourchotte, V Zheng, P. Mamounas, E. P. Brown, A. M. Boudros, E. Bear, H. D. Constantino, J. P. Wolmark, N. TI Predictive Factors for Positive Non-Sentinel Nodes Following a Positive Sentinel Node Biopsy: NSABP B-32. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 [Julian, T. B.; Anderson, S. J.; Golesorkhi, N.; Fourchotte, V; Zheng, P.; Mamounas, E. P.; Brown, A. M.; Boudros, E.; Bear, H. D.; Constantino, J. P.; Wolmark, N.] 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 513S EP 513S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700091 ER PT J AU Grubbs, C Juliana, M Bode, A Iwata, K Ruppert, M Lubet, R AF Grubbs, C. Juliana, M. Bode, A. Iwata, K. Ruppert, M. Lubet, R. TI Use of MMTV-Neu/P53 KO Transgenic Mice To Screen for Potential Chemopreventive Agents. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Univ Alabama, Birmingham, AL USA. Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. OSI Pharmaceut, Long Isl City, NY USA. W Virginia Univ, Morgantown, WV 26506 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 551S EP 552S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920700199 ER PT J AU Disis, ML Cecil, D Gad, E Park, K Lai, V Lubet, R Lu, H AF Disis, M. L. Cecil, D. Gad, E. Park, K. Lai, V Lubet, R. Lu, H. TI Preventing the Development of Breast Cancer by Immunizing with Multi-Antigen Vaccines Targeting Proteins Associated with Oncogenesis SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Univ Washington, Seattle, WA 98195 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 552S EP 553S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920700202 ER PT J AU Lubet, R Bode, A Juliana, M Steele, V Grubbs, C AF Lubet, R. Bode, A. Juliana, M. Steele, V Grubbs, C. TI Preventive Effects of Lapatinib, a Combined EGFR 1 and EGFR 2 Inhibitor, on Methylinitrosourea-Induced ER plus and MMTV-Neu/P53 KO ER- Mammary Cancers. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 NCI, Bethesda, MD 20892 USA. Univ Minnesota, Hormel Inst, Austin, MN 55912 USA. Univ Alabama, 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 552S EP 552S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700200 ER PT J AU Bode, AM Li, J Cho, YY Lubet, RA Grubbs, C AF Bode, A. M. Li, J. Cho, Y. Y. Lubet, R. A. Grubbs, C. TI Lapatinib Suppresses RTK-Mediated Signaling through Multiple Signaling Pathways. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Univ Minnesota, Austin, MN USA. NCI, Bethesda, MD 20892 USA. Univ Alabama, 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 580S EP 580S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920700283 ER PT J AU Parker, JS Prat, A Cheang, MCU Lenburg, ME Paik, S Perou, CM AF Parker, J. S. Prat, A. Cheang, M. C. U. Lenburg, M. E. Paik, S. Perou, C. M. TI Breast Cancer Molecular Subtypes Predict Response to Anthracycline/Taxane-Based Chemotherapy SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Univ N Carolina, Chapel Hill, NC USA. Boston Univ, Sch Med, Boston, MA 02118 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. RI Prat, Aleix/P-8561-2014 OI Prat, Aleix/0000-0003-2377-540X 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 598S EP 598S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920701054 ER PT J AU Anderson, WF Jatoi, I Rosenberg, PS AF Anderson, W. F. Jatoi, I Rosenberg, P. S. TI Male Breast Cancer: A Population-Based Comparison with Female Breast Cancer SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 NCI, Rockville, MD USA. Natl Naval 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 617S EP 617S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920701109 ER PT J AU Bennett, CN Tomlinson, CC Hollingshead, MG Green, JE AF Bennett, C. N. Tomlinson, C. C. Hollingshead, M. G. Green, J. E. TI Accelerating Combination Drug Therapies for Triple Negative Breast Cancer through Comparative Pre-Clinical Testing of Human Xenografts and a Mouse Breast Cancer Model SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX ID TRANSGENIC MICE; MAMMARY; IDENTIFICATION; PROGRESSION; CARCINOMAS; PROSTATE; GENE C1 NCI, NIH, Bethesda, MD 20892 USA. NCI, NIH, Frederick, MD 21701 USA. NR 6 TC 0 Z9 0 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 646S EP 646S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920701198 ER PT J AU Ziegler, RG Fuhrman, BJ Xu, X Gail, MH Keefer, LK Veenstra, TD Hoover, RN AF Ziegler, R. G. Fuhrman, B. J. Xu, X. Gail, M. H. Keefer, L. K. Veenstra, T. D. Hoover, R. N. TI In Asian-American Women, Westernization Influences Estrogen Metabolism, but Not Total Endogenous Estrogen Production SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 NCI, Bethesda, MD 20892 USA. SAIC Frederick Inc, Frederick, MD USA. NCI, Frederick, MD 21701 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 666S EP 666S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920701260 ER PT J AU Capala, J Chernomordik, V Hassan, M Zielinski, R Gandjbakhche, A AF Capala, J. Chernomordik, V Hassan, M. Zielinski, R. Gandjbakhche, A. TI Quantitative Analysis of HER2 Receptors Expression In Vivo by Near-Infrared Optical Imaging SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 [Capala, J.; Chernomordik, V; Hassan, M.; Zielinski, R.; Gandjbakhche, A.] 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 765S EP 765S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920701548 ER PT J AU Berg, P Uzturk, G Awate, S Stevenson, H Schwartz, A AF Berg, P. Uzturk, G. Awate, S. Stevenson, H. Schwartz, A. TI Role of BP1, a Novel Transcription Factor, in Antiestrogen Resistance SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 George Washington Univ, Washington, DC USA. NIH, Bethesda, MD 20892 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 813S EP 813S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920702103 ER PT J AU Mitchell, BD Ni, X Wickerham, DL Sontag, A Muram, D AF Mitchell, B. D. Ni, X. Wickerham, D. L. Sontag, A. Muram, D. TI Incidence Rates of Invasive Breast Cancer in Postmenopausal Women with and without a Family History of Breast Cancer and Stratified by Breast Cancer Risk Score SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 Lilly USA LLC, Indianapolis, IN USA. NSABP, 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 844S EP 845S PG 2 WC Oncology SC Oncology GA 534TR UT WOS:000272920702192 ER PT J AU Kil, WJ Camphausen, K AF Kil, W. J. Camphausen, K. TI Increased Radiation Resistance of Breast Cancer Cells by Endocrine Disrupting Chemical Bisphenol A SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 [Kil, W. J.; Camphausen, K.] NCI, Bethesda, MD 20892 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 847S EP 847S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920702199 ER PT J AU Iwamoto, T Bianchini, G Coutant, C Shiang, CY Matsuoka, J Symmans, WF Hortobagyi, GN Simon, R Pusztai, L AF Iwamoto, T. Bianchini, G. Coutant, C. Shiang, C. Y. Matsuoka, J. Symmans, W. F. Hortobagyi, G. N. Simon, R. Pusztai, L. TI Different Biological Processes Are Associated with Prognosis and Chemotherapy Sensitivity in the Different Molecular Subtypes of Breast Cancer. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 UT MD Anderson Canc Ctr, Houston, TX USA. Okayama Univ, Grad Sch Med & Dent, Okayama, Japan. NCI, Bethesda, MD 20892 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 864S EP 864S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920702247 ER PT J AU Hendrix, A Maynard, D Pauwels, P Braems, G Denys, H Van den Broecke, R Van Belle, S Cocquyt, V Bracke, M Seabra, M Gahl, W De Wever, O Westbroek, W AF Hendrix, A. Maynard, D. Pauwels, P. Braems, G. Denys, H. Van den Broecke, R. Van Belle, S. Cocquyt, V Bracke, M. Seabra, M. Gahl, W. De Wever, O. Westbroek, W. TI The Secretory Small GTPase Rab27B Regulates Invasive Tumor Growth and Metastasis through Extracellular Heat Shock Protein 90 alpha. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX C1 NHGRI, Bethesda, MD 20892 USA. Univ Ghent, B-9000 Ghent, Belgium. Univ London Imperial Coll Sci Technol & Med, London, England. RI de wever, olivier/J-3094-2013 OI de wever, olivier/0000-0002-5453-760X 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 871S EP 871S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920702266 ER PT J AU De, K Bandyopadhyay, A Chang, A Elkahloun, AG Cornell, JE Yang, J Wang, L Yeh, IT Goins, BA Sun, L AF De, K. Bandyopadhyay, A. Chang, A. Elkahloun, A. G. Cornell, J. E. Yang, J. Wang, L. Yeh, I-T Goins, B. A. Sun, L. TI Stable Spontaneous Fusion of Estrogen Receptor (ER) Positive and ER Negative Breast Cancer Cells Generates an Efficient Model for Breast Cancer Brain Metastasis. SO CANCER RESEARCH LA English DT Meeting Abstract CT 32nd Annual San Antonio Breast Cancer Symposium CY DEC 09-13, 2009 CL San Antonio, TX 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 SU 3 BP 872S EP 872S PG 1 WC Oncology SC Oncology GA 534TR UT WOS:000272920702269 ER PT J AU Li, SH Hawthorne, VS Neal, CL Sanghera, S Xu, J Yang, J Guo, H Steeg, PS Yu, DH AF Li, Shau-Hsuan Hawthorne, Valerie S. Neal, Christopher L. Sanghera, Sartaj Xu, Jia Yang, Jun Guo, Hua Steeg, Patricia S. Yu, Dihua TI Upregulation of Neutrophil Gelatinase-Associated Lipocalin by ErbB2 through Nuclear Factor-KB Activation SO CANCER RESEARCH LA English DT Article ID CANCER-RELATED ANEMIA; PRIMARY BREAST-CANCER; KAPPA-B; CELLS; NGAL; ERYTHROPOIETIN; OVEREXPRESSION; SUPPRESSION; EXPRESSION; GROWTH AB ErbB2 (HER2, neu) is a receptor tyrosine kinase overexpressed in about 25% of invasive breast carcinomas. Neutrophil gelatinase-associated lipocalin (NGAL) is a secreted glycoprotein expressed in a variety of cancers, including breast carcinomas. NGAL can inhibit erythroid cell production, leading to anemia. Anemia usually occurs in cancer patients and negatively affects quality of life. However, current treatment for cancer-related anemia has potential complications. ErbB2, NGAL, and anemia have all been associated with increased metastasis and poor prognosis in breast cancer patients, although the relationship between ErbB2 and NGAL expression is not clear. Here, using breast cancer cell lines in vitro and transgenic mice carrying the activated c-neu oncogene driven by a mouse mammary tumor virus (MMTV-neu) in vivo, we show that ErbB2 overexpression leads to NGAL upregulation, which is dependent on nuclear factor-kappa B (NF-kappa B) activity. MMTV-neu transgenic mice developed anemia after tumor onset, and anemia progression could be partially arrested by a NF-kappa B inhibitor and ErbB2-targeted therapy. Taken together, upregulation of NGAL by ErbB2 through NF-kappa B activation is involved in cancer-related anemia, and the ErbB2, NF-kappa B, and NGAL pathways may serve as potential therapeutic targets for cancer-related anemia. [Cancer Res 2009;69(24):9163-8] C1 [Yu, Dihua] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Unit 108, Houston, TX 77030 USA. [Steeg, Patricia S.] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Yu, DH (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Unit 108, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM dyu@mdanderson.org FU NIH [P30-CA 16672, 1101-CA109570, 1101-CA112567, P01-CA099031, P50 CA116199]; DOD Center of Excellence [W81, XXV11-06-2-0033, W81XWH-08-1-0712]; Susan G. Komen Breast Cancer Foundation [KG091020]; Chang Gong Memorial Hospital; Chang Gung University College of Medicine, Kaolisiung, Taiwan FX The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 20 TC 23 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 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 BP 9163 EP 9168 DI 10.1158/0008-5472.CAN-09-2483 PG 6 WC Oncology SC Oncology GA 534TP UT WOS:000272920500003 PM 19951994 ER PT J AU Binet, R Ythier, D Robles, AI Collado, M Larrieu, D Fonti, C Brambilla, E Brambilla, C Serrano, M Harris, CC Pedeux, R AF Binet, Romuald Ythier, Damien Robles, Ana I. Collado, Manuel Larrieu, Delphine Fonti, Claire Brambilla, Elisabeth Brambilla, Christian Serrano, Manuel Harris, Curtis C. Pedeux, Remy TI WNT16B Is a New Marker of Cellular Senescence That Regulates p53 Activity and the Phosphoinositide 3-Kinase/AKT Pathway SO CANCER RESEARCH LA English DT Article ID HUMAN-CELLS; REPLICATIVE SENESCENCE; HUMAN FIBROBLASTS; TELOMERE DYSFUNCTION; SIGNALING PATHWAY; INDUCTION; SUPPRESSION; EXPRESSION; APOPTOSIS; DISEASE AB Senescence is a tumor suppression mechanism that is induced by several stimuli, including oncogenic signaling and telomere shortening, and controlled by the p53/p21(WAF1) signaling pathway. Recently, a critical role for secreted factors has emerged, suggesting that extracellular signals are necessary for the onset and maintenance of senescence. Conversely, factors secreted by senescent cells may promote tumor growth. By using expression profiling techniques, we searched for secreted factors that were overexpressed in fibroblasts undergoing replicative senescence. We identified WNT16B, a member of the WNT family of secreted proteins. We found that WNT16B is overexpressed in cells undergoing stress-induced premature senescence and oncogene-induced senescence in both MRC5 cell line and the in vivo murine model of K-Ras(V12)-induced senescence. By small interfering RNA experiments, we observed that both p53 and WNT16B are necessary for the onset of replicative senescence. WNT16B expression is required for the full transcriptional activation of p21(WAF1) Moreover, WNT16B regulates activation of the phosphoinositide 3-kinase (PI3K)/AKT pathway. Overall, we identified WNT16B as a new marker of senescence that regulates p53 activity and the PI3K/AKT pathway and is necessary for the onset of replicative senescence. [Cancer Res 2009;69(24):9183-91] C1 [Binet, Romuald; Ythier, Damien; Larrieu, Delphine; Fonti, Claire; Brambilla, Elisabeth; Brambilla, Christian; Pedeux, Remy] UJF, INSERM, Ctr Rech, U823,Inst Albert Bonniot, La Tronche, France. [Robles, Ana I.; Harris, Curtis C.] NCI, Ctr Canc Res, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. [Collado, Manuel; Serrano, Manuel] Spanish Natl Canc Res Ctr, Madrid, Spain. RP Pedeux, R (reprint author), Fac Med, INSERM, U917, MICA, Room 117,Bldg 2,2 Ave Pr Leon Bernard, F-35043 Rennes, France. EM remy.pedeux@univ-rennes1.fr RI Binet, Romuald/I-7938-2012; Brambilla, Elisabeth/L-8796-2013; BRAMBILLA, CHRISTIAN/K-2285-2013; Serrano, Manuel/H-2634-2015; Collado, Manuel/K-8140-2014 OI Binet, Romuald/0000-0003-0636-2195; Serrano, Manuel/0000-0001-7177-9312; Collado, Manuel/0000-0002-0330-0880 FU Institut National de la Sante et de la Recherche Medicale; "Agir a dom," I'Association pour la Recherche contre le Cancer; Marie Curie International Reintegration (EU) [MIRG-CT-2006-042148]; La Fondation pour hi Recherche Medicale (Prix Mariane Josso); INCa; French Ministry of Education and Research; International Association for the Study of Lung Cancer FX We thank Thibault Voeltzel for providing MRC5 fibroblasts, Dr. Stephanie Corde kind Antoine Dorenlot for their help in the X-radiation experiments. and Dr. Teck Teh for providing the pEGFP/IRES-WNIT16A plasmid. NR 42 TC 52 Z9 55 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 BP 9183 EP 9191 DI 10.1158/0008-5472.CAN-09-1016 PG 9 WC Oncology SC Oncology GA 534TP UT WOS:000272920500006 PM 19951988 ER PT J AU Suva, ML Riggi, N Janiszewska, M Radovanovic, I Provero, P Stehle, JC Baumer, K Le Bitoux, MA Marino, D Cironi, L Marquez, VE Clement, V Stamenkovic, I AF Suva, Mario-Luca Riggi, Nicolo Janiszewska, Michalina Radovanovic, Ivan Provero, Paolo Stehle, Jean-Christophe Baumer, Karine Le Bitoux, Marie-Aude Marino, Denis Cironi, Luisa Marquez, Victor E. Clement, Virginie Stamenkovic, Ivan TI EZH2 Is Essential for Glioblastoma Cancer Stem Cell Maintenance SO CANCER RESEARCH LA English DT Article ID TUMOR-INITIATING CELLS; PROSTATE-CANCER; POLYCOMB; REPRESSION; GENE; DIFFERENTIATION; IDENTIFICATION; TEMOZOLOMIDE; PROTEINS; RENEWAL AB Overexpression of the polycomb group protein enhancer of zeste homologue 2 (EZH2) occurs in diverse malignancies, including prostate cancer, breast cancer, and glioblastoma multiforme (GBM). Based on its ability to modulate transcription of key genes implicated in cell cycle control, DNA repair, and cell differentiation, EZH2 is believed to play a crucial role in tissue-specific stem cell maintenance and tumor development. Here, we show that targeted pharmacologic disruption of EZH2 by the S-adenosylhomocysteine hydrolase inhibitor 3-deazaneplanocin A (DZNep), or its specific downregulation by short hairpin RNA (shRNA), strongly impairs GBM cancer stem cell (CSC) self-renewal in vitro and tumor-initiating capacity in vivo. Using genome-wide expression analysis of DZNep-treated GBM CSCs, we found the expression of c-myc, recently reported to be essential for GBM CSCs, to be strongly repressed upon EZH2 depletion. Specific shRNA-mediated downregulation of EZH2 in combination with chromatin immunoprecipitation experiments revealed that c-myc is a direct target of EZH2 in GBM CSCs. Taken together, our observations provide evidence that direct transcriptional regutation of c-myc by EZH2 may constitute a novel mechanism underlying GBM CSC maintenance and suggest that EZH2 may be a valuable new therapeutic target for GBM management. [Cancer Res 2009;69(24):9211-8] C1 [Suva, Mario-Luca; Riggi, Nicolo; Janiszewska, Michalina; Stehle, Jean-Christophe; Baumer, Karine; Le Bitoux, Marie-Aude; Cironi, Luisa; Stamenkovic, Ivan] Univ Lausanne, Inst Pathol, Div Expt Pathol, CH-1011 Lausanne, Switzerland. [Radovanovic, Ivan; Clement, Virginie] Univ Geneva, Dept Neurosurg, Geneva, Switzerland. [Provero, Paolo] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Marquez, Victor E.] NCI, Ctr Canc Res, Frederick, MD 21701 USA. RP Stamenkovic, I (reprint author), Univ Lausanne, Inst Pathol, Div Expt Pathol, 25 Rue Bugnon, CH-1011 Lausanne, Switzerland. EM Ivan.Stamenkovic@chuv.ch FU Foods National de la Recherche Scientifique [3100A0-105833]; OncoSuisse [01656-02-2005]; National Center of Competence in Research Molecular Oncology FX Grant support: Foods National de la Recherche Scientifique grant 3100A0-105833, OncoSuisse grant 01656-02-2005, and a grant from National Center of Competence in Research Molecular Oncology (L Stamenkovic). NR 28 TC 215 Z9 224 U1 2 U2 19 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 2009 VL 69 IS 24 BP 9211 EP 9218 DI 10.1158/0008-5472.CAN-09-1622 PG 8 WC Oncology SC Oncology GA 534TP UT WOS:000272920500009 PM 19934320 ER PT J AU Kim, SS Cao, L Baek, HJ Lim, SC Li, CL Wang, RH Xu, XL Cho, KH Deng, CX AF Kim, Sang Soo Cao, Liu Baek, Hye Jung Lim, Sung-Chul Li, Cuiling Wang, Rui-Hong Xu, Xiaoling Cho, Kwan Ho Deng, Chu-Xia TI Impaired Skin and Mammary Gland Development and Increased gamma-Irradiation-Induced Tumorigenesis in Mice Carrying a Mutation of S1152-ATM Phosphorylation Site in Brca1 SO CANCER RESEARCH LA English DT Article ID DNA-DAMAGE RESPONSE; CELL-CYCLE CHECKPOINT; CONDITIONAL KNOCKOUT MICE; GENETIC INSTABILITY; ATAXIA-TELANGIECTASIA; TUMOR-FORMATION; IN-VIVO; ATM; BREAST; HYPERPLASIA AB The tumor suppressor BRCA1 interacts with many proteins and undergoes multiple modifications on DNA damage. ATM, a key molecule of the DNA damage response, phosphorylates S1189 of BRCA1 after gamma-irradiation. S1189 of BRCA1 is known as a unique ATM phosphorylation site in BRCA1 exon 11. To study the functions of ATM-dependent phosphorylation of BRCA1-S1189, we generated a mouse model carrying a mutation of S1152A (S1152 in mouse Brca1 corresponds to S1189 in human BRCA1) by gene targeting. Brca1(S1152A/S1152A) mice were born at the expected ratio, unlike that seen in previous studies of Brca1-null mice. However, 36% of Brca1(S1152A/S1152A) mice exhibited aging-like phenotypes including growth retardation, skin abnormalities, and delay of the mammary gland morphogenesis, with an increase in apoptosis. Mutant mice were hypersensitive to high doses of gamma-irradiation, displaying shortened life span and reduction in intestinal villus size, associated with increased apoptosis. Aging-unaffected 18-month-old Brca1(S1152A/S1152A) female mice also showed mammary gland abnormalities with increased levels of cyclin D1 and phospho-ER-alpha, such as Brcal-Delta 11 mutation. On low-dose gamma-irradiation, they suffered a marked increase in tumor formation with an abnormal coat pattern. Furthermore, Brca1(S1152A/S1152A) embryonic fibroblasts failed to accumulate p53 on gamma-irradiation with delayed phosphorylation of p53-S23. These observations indicate that ATM-mediated phosphorylation of S1189 is required for BRCA1 functions in the modulation of DNA damage response and in the suppression of tumor formation by regulating p53 and apoptosis. [Cancer Res 2009;69(24):9291-300] C1 [Kim, Sang Soo; Baek, Hye Jung; Cho, Kwan Ho] Natl Canc Ctr, Radiat Med Branch, Goyang 410769, Gyenggi, South Korea. [Kim, Sang Soo; Cao, Liu; Li, Cuiling; Wang, Rui-Hong; Xu, Xiaoling; Deng, Chu-Xia] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Lim, Sung-Chul] Chosun Univ, Dept Pathol, Coll Med, Kwangju, South Korea. RP Kim, SS (reprint author), Natl Canc Ctr, Radiat Med Branch, 809 Madu 1 Dong, Goyang 410769, Gyenggi, South Korea. EM sangsookim@ncc.re.kr RI deng, chuxia/N-6713-2016 FU National Institute of Diabetes, Digestive, and Kidney Diseases. NIH (Bethesda, MD); National Cancer Center of Korea [NCC-0910020]; Korea Healthcare Technology RD Project [A090095]; National Research Foundation of Kore [2009-0070609] FX Grant support: Intramural Research Program of the National Institute of Diabetes, Digestive, and Kidney Diseases. NIH (Bethesda, MD) to C.-X. Deng, and the National Cancer Center of Korea (NCC-0910020), the Korea Healthcare Technology R&D Project (A090095), and the National Research Foundation of Korea (2009-0070609) to S.S. Kim. NR 40 TC 8 Z9 9 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 BP 9291 EP 9300 DI 10.1158/0008-5472.CAN-09-2418 PG 10 WC Oncology SC Oncology GA 534TP UT WOS:000272920500018 PM 19996295 ER PT J AU Zhu, Y Stevens, RG Hoffman, AE FitzGerald, LM Kwon, EM Ostrander, EA Davis, S Zheng, TZ Stanford, JL AF Zhu, Yong Stevens, Richard G. Hoffman, Aaron E. FitzGerald, Liesel M. Kwon, Erika M. Ostrander, Elaine A. Davis, Scott Zheng, Tongzhang Stanford, Janet L. TI Testing the Circadian Gene Hypothesis in Prostate Cancer: A Population-Based Case-Control Study SO CANCER RESEARCH LA English DT Article ID NON-HODGKINS-LYMPHOMA; DNA-DAMAGE RESPONSE; BREAST-CANCER; TUMOR-SUPPRESSOR; HEALTHY-YOUNG; SHIFT-WORK; IN-VIVO; RISK; CLOCK; NPAS2 AB Circadian genes are responsible for maintaining the ancient adaptation of a 24-hour circadian rhythm and influence a variety of cancer-related biological pathways, including the regulation of sex hormone levels. However, few studies have been undertaken to investigate the role of circadian genes in the development of prostate cancer, the most common cancer type among men (excluding nonmelanoma skin cancer). The current genetic association study tested the circadian gene hypothesis in relation to prostate cancer by genotyping a total of 41 tagging and amino acid-altering single nucleotide polymorphisms (SNP) in 10 circadian-related genes in a population-based case-control study of Caucasian men (n = 1,308 cases and 1,266 controls). Our results showed that at least one SNP in nine core circadian genes (rs885747 and rs2289591 in PFR1; rs7602358 in PER2; rs1012477 in PER3; rs1534891 in CSNK1E; rs12315175 in CRY1; rs2292912 in CRY2; rs7950226 in ARNTL; rs11133373 in CLOCK, and rs1369481, rs895521, and rs17024926 in NPAS2) was significantly associated with susceptibility to prostate cancer (either overall risk or risk of aggressive disease), and the risk estimate for four SNPs in three genes (rs885747 and rs2289591 in PER1, rs1012477 in PER3, and rs11133373 in CLOCK) varied by disease aggressiveness. Further analyses of haplotypes were consistent with these genotyping results. Findings from this candidate gene association study support the hypothesis of a link between genetic variants in circadian genes and prostate cancer risk, warranting further confirmation and mechanistic investigation of circadian biomarkers in prostate tumorigenesis. [Cancer Res 2009;69(24):9315-22] C1 [Zhu, Yong; Hoffman, Aaron E.; Zheng, Tongzhang] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Stevens, Richard G.] Univ Connecticut, Ctr Hlth, Dept Community Med & Hlth Care, Farmington, CT USA. [FitzGerald, Liesel M.; Davis, Scott; Stanford, Janet L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Kwon, Erika M.; Ostrander, Elaine A.] NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Zhu, Y (reprint author), Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. EM yong.zhu@yale.edu; jstanfor@fhcrc.org OI Ostrander, Elaine/0000-0001-6075-9738 FU NIH [R01 CA56678, R01 CA082664, R01 CA092579, R01 CA122676, R01 CA110937]; Fred Hutchinson Cancer Research Center, Yale University; National Human Genorne Research Institute FX Grant support: NIH (grants R01 CA56678, R01 CA082664, R01 CA092579, R01 CA 122676, and R01 CA110937), with additional support from the Fred Hutchinson Cancer Research Center, Yale University, and the National Human Genorne Research Institute. NR 43 TC 59 Z9 65 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD DEC 15 PY 2009 VL 69 IS 24 BP 9315 EP 9322 DI 10.1158/0008-5472.CAN-09-0648 PG 8 WC Oncology SC Oncology GA 534TP UT WOS:000272920500021 PM 19934327 ER PT J AU Rapisarda, A Shoemaker, RH Melillo, G AF Rapisarda, Annamaria Shoemaker, Robert H. Melillo, Giovanni TI Antiangiogenic agents and HIF-1 inhibitors meet at the crossroads SO CELL CYCLE LA English DT Article DE hypoxia; HIF-1; tumor microenvironment; antiangiogenic agents; cancer therapeutics ID HYPOXIA-INDUCIBLE-FACTOR; CHEMOKINE RECEPTOR CXCR4; FACTOR-I INHIBITION; TOPOISOMERASE-I; CANCER-THERAPY; FACTOR 1-ALPHA; TRANSCRIPTIONAL ACTIVATION; FACTOR-1; TUMOR; ANGIOGENESIS AB Novel molecularly targeted therapies aim at exploiting oncogenic and non-oncogenic alterations that epitomize potential vulnerable aspects of tumorigenesis, with the hope to ultimately target cancer cells and spare normal tissues. Hypoxia, a decrease in tissue oxygen levels, is a feature of the tumor micro-environment that has attracted considerable interest for its potential contribution to increasing the tumorigenicity of cancer cells, by selecting more aggressive and metastatic clones and by activating pathways that contribute to cancer cells survival, all of which may have important therapeutic implications. In this article, we discuss how two therapeutic strategies, which have been developed over the last few years to target aspects dependent on or associated with intra-tumor hypoxia, may provide the rationale for a novel combination strategy aimed at blocking compensatory circuits that maintain cancer cells survival and propagate the cancer phenotype. We hypothesized that concurrent inhibition of HIF-1 and VEGF, which are mechanistically linked to intratumor hypoxia, represents a logical therapeutic combination that may find applications in a number of solid tumors, irrespective of their underlying genetic alterations. Indeed, intrinsic limitations of HIF-1 inhibitors and mechanisms of acquired resistance to anti-VEGF therapies may counterbalance each other in combination approaches that block vicious compensatory pathways exploited by cancer cells to overcome environmental stresses. C1 [Rapisarda, Annamaria; Melillo, Giovanni] SAIC Frederick Inc, Frederick, MD USA. [Shoemaker, Robert H.] NCI, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. RP Melillo, G (reprint author), SAIC Frederick Inc, Frederick, MD USA. EM melillog@mail.nih.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400] FX The authors would like to thank members of the Tumor Hypoxia Laboratory for helpful discussion and Dominic Scudiero and members of his laboratory for conducting the HIF-1 HTS. This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. N01-CO-12400. The content of this publication does not necessarily reflect the 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 Developmental Therapeutics Program, DCTD, of the National Cancer Institute, NIH. NR 43 TC 14 Z9 15 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD DEC 15 PY 2009 VL 8 IS 24 BP 4040 EP 4043 DI 10.4161/cc.8.24.10145 PG 4 WC Cell Biology SC Cell Biology GA 539CZ UT WOS:000273232300018 PM 19923892 ER PT J AU Azad, NS Aragon-Ching, JB Kong, HH AF Azad, Nilofer S. Aragon-Ching, Jeanny B. Kong, Heidi H. TI Sorafenib-Related Hand-Foot Skin Reaction Improves, Not Worsens, with Continued Treatment Response SO CLINICAL CANCER RESEARCH LA English DT Letter C1 [Azad, Nilofer S.; Aragon-Ching, Jeanny B.; Kong, Heidi H.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Azad, NS (reprint author), NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 1 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 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD DEC 15 PY 2009 VL 15 IS 24 BP 7749 EP 7750 DI 10.1158/1078-0432.CCR-09-1836 PG 2 WC Oncology SC Oncology GA 533VM UT WOS:000272853500039 PM 20008856 ER PT J AU Collignon, P Powers, JH Chiller, TM Aidara-Kane, A Aarestrup, FM AF Collignon, Peter Powers, John H. Chiller, Tom M. Aidara-Kane, Awa Aarestrup, Frank M. TI Critically Important Antimicrobial - or Not? Reply SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Collignon, Peter] Canberra Hosp, Infect Dis Unit, Dept Microbiol, Woden, ACT 2607, Australia. [Collignon, Peter] Australian Natl Univ, Sch Clin Med, Woden, ACT, Australia. [Powers, John H.] NIAID, Sci Applicat Int Corp, Collaborat Clin Res Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Powers, John H.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Powers, John H.] George Washington Univ, Sch Med, Washington, DC USA. [Chiller, Tom M.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Aidara-Kane, Awa] WHO, Dept Food Safety Zoonoses & Foodborne Dis, CH-1211 Geneva, Switzerland. [Aarestrup, Frank M.] Tech Univ Denmark, Head Community Reference Lab Antimicrobial Resist, Copenhagen, Denmark. [Aarestrup, Frank M.] Tech Univ Denmark, WHO, Collaborating Ctr Antimicrobial Resistance Foodbo, Copenhagen, Denmark. RP Collignon, P (reprint author), Canberra Hosp, Infect Dis Unit, Dept Microbiol, POB 11, Woden, ACT 2607, Australia. EM peter.collignon@act.gov.au NR 3 TC 0 Z9 0 U1 1 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD DEC 15 PY 2009 VL 49 IS 12 BP 1962 EP U204 DI 10.1086/648503 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 523KA UT WOS:000272070800035 ER PT J AU Srikanta, D Sen, SK Conlin, EM Batzer, MA AF Srikanta, Deepa Sen, Shurjo K. Conlin, Erin M. Batzer, Mark A. TI Internal priming: An opportunistic pathway for L1 and Alu retrotransposition in hominins SO GENE LA English DT Article DE L1 elements; Alu elements; Target primed reverse transcription; Double-strand break repair ID STRAND BREAK REPAIR; REVERSE TRANSCRIPTION; HUMAN LINE-1; ALTERNATIVE PATHWAY; CHIMPANZEE LINEAGES; MEDIATED DELETION; HUMAN GENOME; IN-VITRO; DNA; ELEMENT AB Retrotransposons, specifically Alu and L1 elements, have been especially successful in their expansion throughout primate genomes. While most of these elements integrate through an endonuclease-mediated process termed target primed reverse transcription, a minority integrate using alternative methods. Here we present evidence for one such mechanism, which we term internal priming and demonstrate that loci integrating through this mechanism are qualitatively different from "classical" insertions. Previous examples of this mechanism are limited to cell culture assays, which show that reverse transcription can initiate upstream of the 3' poly-A tail during retrotransposon integration. To detect whether this mechanism occurs in vivo as well as in cell culture, we have analyzed the human genome for internal priming events using recently integrated L1 and Alu elements. Our examination of the human genome resulted in the recovery of twenty events involving internal priming insertions, which are structurally distinct from both classical TPRT-mediated insertions and non-classical insertions. We suggest two possible mechanisms by which these internal priming loci are created and provide evidence supporting a role in staggered DNA double-strand break repair. Also, we demonstrate that the internal priming process is associated with inter-chromosomal duplications and the insertion of filler DNA. (c) 2009 Elsevier B.V. All rights reserved. C1 [Srikanta, Deepa; Conlin, Erin M.; Batzer, Mark A.] Louisiana State Univ, Biol Computat & Visualizat Ctr, Dept Biol Sci, Baton Rouge, LA 70803 USA. [Sen, Shurjo K.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Batzer, MA (reprint author), Louisiana State Univ, Biol Computat & Visualizat Ctr, Dept Biol Sci, 202 Life Sci Bldg, Baton Rouge, LA 70803 USA. EM mbatzer@lsu.edu FU LSU Biograds [08-10]; National Science Foundation [BCS-0218338]; National Institutes of Health [RO1 GM59290] FX The authors would like to thank all members of the Batzer laboratory for their support and feedback. They would especially like to thank J.A. Walker, K. Han and M. Konkel for suggestions and advice. They are grateful to T.J. Meyer, C. Faulk and J. Huang for their useful comments during the preparation of the manuscript. This research was supported by LSU Biograds #08-10 (D. S.), National Science Foundation grant BCS-0218338 (M.A.B.), and National Institutes of Health RO1 GM59290 (M.A.B.). NR 46 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD DEC 15 PY 2009 VL 448 IS 2 BP 233 EP 241 DI 10.1016/j.gene.2009.05.014 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 522BH UT WOS:000271972200019 PM 19501635 ER PT J AU Moreno, LM Mansilla, MA Bullard, SA Cooper, ME Busch, TD Machida, J Johnson, MK Brauer, D Krahn, K Daack-Hirsch, S L'Heureux, J Valencia-Ramirez, C Rivera, D Lopez, AM Moreno, MA Hing, A Lammer, EJ Jones, M Christensen, K Lie, RT Jugessur, A Wilcox, AJ Chines, P Pugh, E Doheny, K Arcos-Burgos, M Marazita, ML Murray, JC Lidral, AC AF Moreno, Lina M. Mansilla, Maria Adela Bullard, Steve A. Cooper, Margaret E. Busch, Tamara D. Machida, Junichiro Johnson, Marla K. Brauer, David Krahn, Katherine Daack-Hirsch, Sandy L'Heureux, Jamie Valencia-Ramirez, Consuelo Rivera, Dora Maria Lopez, Ana Moreno, Manuel A. Hing, Anne Lammer, Edward J. Jones, Marilyn Christensen, Kaare Lie, Rolv T. Jugessur, Astanand Wilcox, Allen J. Chines, Peter Pugh, Elizabeth Doheny, Kim Arcos-Burgos, Mauricio Marazita, Mary L. Murray, Jeffrey C. Lidral, Andrew C. TI FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate SO HUMAN MOLECULAR GENETICS LA English DT Article ID CASE-PARENT TRIOS; OROFACIAL CLEFTS; GENE VARIANTS; GENOME SCAN; MATERNAL SMOKING; THYROID DYSGENESIS; CANDIDATE GENES; SONIC HEDGEHOG; 4 POPULATIONS; ORAL CLEFTS AB Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22-q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22-q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22-q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E - 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E - 13) and rs4460498 (P = 6.51E - 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5' and 3' of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies. C1 [Moreno, Lina M.; Bullard, Steve A.; Busch, Tamara D.; Machida, Junichiro; Krahn, Katherine; Lidral, Andrew C.] Univ Iowa, Coll Dent, Dept Orthodont, Iowa City, IA 52242 USA. [Moreno, Lina M.] Univ Iowa, Coll Dent, Dows Inst Dent Res, Iowa City, IA 52242 USA. [Mansilla, Maria Adela; Johnson, Marla K.; Brauer, David; Daack-Hirsch, Sandy; L'Heureux, Jamie; Murray, Jeffrey C.] Univ Iowa, Dept Pediat, Roy C Carver Coll Med, Iowa City, IA 52242 USA. [Cooper, Margaret E.] Univ Pittsburgh, Sch Dent Med, Dept Oral Biol, Ctr Craniofacial & Dent Genet, Pittsburgh, PA 15260 USA. [Valencia-Ramirez, Consuelo; Rivera, Dora; Maria Lopez, Ana] Univ Antioquia, Coll Dent, Medellin, Colombia. [Moreno, Manuel A.] Lab Genet Forense & Huellas Digitales DNA, Medellin, Colombia. [Hing, Anne] Univ Washington, Dept Pediat, Seattle, WA 98195 USA. [Hing, Anne] Childrens Hosp & Reg Med Ctr, Craniofacial Ctr, Seattle, WA 98195 USA. [Lammer, Edward J.] Univ Alabama, Dept Genet, Birmingham, AL 35294 USA. [Lammer, Edward J.] Univ Alabama, Dept Pediat, Birmingham, AL 35294 USA. [Jones, Marilyn] Childrens Hosp Oakland, Res Inst, Oakland, CA 94609 USA. [Christensen, Kaare] Univ So Denmark, Dept Epidemiol, DK-5230 Odense, Denmark. [Lie, Rolv T.] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Sect Epidemiol & Med Stat, Bergen, Norway. [Jugessur, Astanand] Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic 3052, Australia. [Wilcox, Allen J.] NIEHS, Epidemiol Branch, Durham, NC 27709 USA. [Chines, Peter] NHGRI, Div Intramural Res, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Pugh, Elizabeth; Doheny, Kim] Johns Hopkins Univ, Sch Med, Inst Med Genet, CIDR, Baltimore, MD 21224 USA. [Arcos-Burgos, Mauricio] Univ Miami, Leonard M Miller Sch Med, Dept Psychiat & Behav Sci, Miami, FL 33136 USA. [Marazita, Mary L.] Univ Pittsburgh, Sch Med, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA 15260 USA. [Marazita, Mary L.] Univ Pittsburgh, Sch Med, Clin & Translat Sci Inst, Pittsburgh, PA 15260 USA. RP Lidral, AC (reprint author), Univ Iowa, Coll Dent, Dept Orthodont, 2174 Med Labs, Iowa City, IA 52242 USA. EM andrew-lidral@uiowa.edu RI Christensen, Kaare/C-2360-2009 OI Wilcox, Allen/0000-0002-3376-1311; Christensen, Kaare/0000-0002-5429-5292 FU National Institutes of Health [RO1-DE014667-8, KO2-AEO15291, N01-HG-65403]; March of Dimes Basil O'Connor award [FY 98-0718, 6-FY01-616]; Cleft Palate Foundation Grant; American Association of Orthodontics Foundation Faculty Development Award [DE-08559, DE-11948, P50-DE-16215, R01-DE016148, R21-DE016930, R01-DE09886, R01-DE012472]; Fogarty [1RO3-TW-007644]; Intramural Research Program of the National Institute of Environmental Health Sciences FX This work was supported by the National Institutes of Health [RO1-DE014667-8, KO2-AEO15291, a March of Dimes Basil O'Connor award # FY 98-0718 and Research Grant # 6-FY01-616, a Cleft Palate Foundation Grant and an American Association of Orthodontics Foundation Faculty Development Award to A. C. L., DE-08559 to J. C. M., DE-11948 to K. C., P50-DE-16215 to M. L. M. and J. C. M., R01-DE016148 to M. L. M., R21-DE016930 to M. L. M., R01-DE09886 to M. L. M., R01-DE012472 to M. L. M. and Fogarty 1RO3-TW-007644 to J. C. M.]; and also by the Intramural Research Program of the National Institute of Environmental Health Sciences, National Institutes of Health. Genotyping services were provided by the Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, Contract Number N01-HG-65403. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Dental and Craniofacial Research, or the National Institutes of Health. NR 68 TC 70 Z9 72 U1 0 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD DEC 15 PY 2009 VL 18 IS 24 BP 4879 EP 4896 DI 10.1093/hmg/ddp444 PG 18 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 523ME UT WOS:000272077200018 PM 19779022 ER PT J AU Rageul, J Mottier, S Jarry, A Shah, Y Theoleyre, S Masson, D Gonzalez, FJ Laboisse, CL Denis, MG AF Rageul, Julie Mottier, Stephanie Jarry, Anne Shah, Yatrik Theoleyre, Sandrine Masson, Damien Gonzalez, Frank J. Laboisse, Christian L. Denis, Marc G. TI KLF4-dependent, PPAR gamma-induced expression of GPA33 in colon cancer cell lines SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE GPA33; PPAR gamma; KLF4; regulation; colon cancer ID ACTIVATED-RECEPTOR-GAMMA; KRUPPEL-LIKE FACTOR; MONOCLONAL-ANTIBODY A33; ORGAN-SPECIFIC EXPRESSION; PHASE-I TRIAL; COLORECTAL-CARCINOMA; EPITHELIAL-CELLS; SURFACE TARGET; ANTIGEN A33; CYCLIN D1 AB The glycoprotein A33 (GPA33) is a colon cancer antigen. Phase I trials with (131)I and (125)I monoclonal antibody A33 in colon carcinoma patients showed excellent localization to colorectal cancer and some evidence of tumor response. Using DNA microarrays, we have identified the GPA33 gene as a target of PPAR gamma in HT29-Cl.16E colon cancer cells. Treatment of HT29-Cl.16E, Caco2, SW1116 and LS174T colon cancer cells with the PPAR gamma agonist GW7845 induced a 2- to 6-fold increase in GPA33 mRNA as determined by real-time PCR. This induction was also found in HT29-Cl.16E cells treated with rosiglitazone and ciglitazone and was prevented by cotreatment with the PPAR gamma antagonist GW9662, indicating that this regulation was PPAR gamma dependent. No canonical PPAR responsive element was found in the GPA33 promoter. We therefore analyzed the expression of transcription factors involved in GPA33 expression. CDX1, CDX2 and KLF5 expression was not modified by PPAR gamma activation. By contrast, a significant increase in KLF4 was seen, both at mRNA and protein levels. Furthermore, chromatin immunoprecipitation studies demonstrated that an increased amount of KLF4 protein was bound to the GPA33 promoter in cells treated with rosiglitazone. Finally, downregulation of KLF4 expression by siRNA reduced rosiglitazone-induced GPA33 expression. This indicates that PPAR gamma activation induces KLF4 expression, which in turn increases GPA33 expression. We also demonstrate that PPAR gamma activation leads to increased (p21(WAF1/Cip1) and keratin 19) or decreased (cyclin D1) expression of known KLF4 targets, suggesting that KLF4 is a nodal player in a network of PPAR gamma-regulated genes. (C) 2009 UICC C1 [Rageul, Julie; Mottier, Stephanie; Theoleyre, Sandrine; Denis, Marc G.] Univ Rennes 1, CNRS, Fac Med, IFR140,UMR 6061, F-35043 Rennes, France. [Jarry, Anne; Laboisse, Christian L.] Univ Nantes, Fac Med, EA Biometadys, Nantes, France. [Shah, Yatrik; Gonzalez, Frank J.] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Masson, Damien] Univ Nantes, INSERM, Fac Med, U913, Nantes, France. RP Denis, MG (reprint author), Univ Rennes 1, CNRS, Fac Med, IFR140,UMR 6061, 2 Ave Pr Leon Bernard, F-35043 Rennes, France. EM marc.denis@univ-rennes1.fr RI Masson, Damien/K-2730-2015; jarry, anne/O-5964-2015; Denis, Marc/K-8049-2015 OI Denis, Marc/0000-0001-5865-3248 FU Ligue Departementale Contre le Cancer [35, 44, 56]; Association Pour la Recherche Contre le Cancer [ARC-3732]; Region Bretagne [ACOMB 2627] FX Grant sponsor: Ligue Departementale Contre le Cancer: Grant numbers: 35, 44, 56; Grant sponsor: Association Pour la Recherche Contre le Cancer; Grant number: ARC-3732; Grant sponsor: Region Bretagne; Grant number: ACOMB 2627. NR 56 TC 27 Z9 31 U1 1 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 15 PY 2009 VL 125 IS 12 BP 2802 EP 2809 DI 10.1002/ijc.24683 PG 8 WC Oncology SC Oncology GA 523CJ UT WOS:000272049000007 PM 19551868 ER PT J AU Yang, XR Pfeiffer, RM Wheeler, W Yeager, M Chanock, S Tucker, MA Goldstein, AM AF Yang, Xiaohong Rose Pfeiffer, Ruth M. Wheeler, William Yeager, Meredith Chanock, Stephen Tucker, Margaret A. Goldstein, Alisa M. TI Identification of modifier genes for cutaneous malignant melanoma in melanoma-prone families with and without CDKN2A mutations SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE modifier gene; cutaneous malignant melanoma; high-risk family; CDKN2A; pathway ID POPULATION-BASED PREVALENCE; DYSPLASTIC NEVI; CDK4 MUTATIONS; POLYMORPHISMS; RISK; ASSOCIATION; VARIANTS; SUSCEPTIBILITY; PENETRANCE; LESIONS AB CDKN2A is a major susceptibility gene for cutaneous malignant melanoma (CMM), but the variable penetrance and clinical manifestations among mutation carriers suggest the existence of modifier factors. The goal of this study was to identify modifier genes for CMM in CMM-prone families with or without CDKN2A mutations. We genotyped 537 individuals (107 CMM) from 28 families (19 CDKN2A +, 9 CDKN2A -) for 1,536 SNPs in 152 genes involved in DNA repair, apoptosis and immune response pathways. We used conditional logistic regression to account for family ascertainment and differences in disease prevalence among families. Pathway- and gene-based permutation analyses were used to assess the risk of CMM associated with genes in the 5 pathways (DNA repair, apoptosis, TNF/NF kappa B, TH1:TH2 and other immune regulation). Our analyses identified some candidate genes such as FAS, BCL7A, CASP14, TRAF6, WRN, IL9, IL10RB, TNFSF8, TNFRSF9 and JAK3 that were associated with CMM risk (p < 0.01, gene-based test). After correction for multiple comparisons, IL9 remained significant (Bonferroni p < 0.05). The effects of some genes were stronger in CDKN2A-positive families (BCL7A and IL9), while some were stronger in CDKN2A-negative families (BCL2L1). Our findings support the hypothesis that common genetic polymorphisms in DNA repair, apoptosis and immune response pathways may modify the risk of CMM in CMM-prone families with or without CDKN2A mutations. Published 2009 UICC. This article is a US Government work, and, as such, is in the public domain in the United States of America. C1 [Yang, Xiaohong Rose] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD USA. RP Yang, XR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bldg EPS,Rm 7014,6120 Execut Blvd, Rockville, MD 20852 USA. EM royang@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; Tucker, Margaret/B-4297-2015 FU NIH; NCI; DCEG FX Grant sponsors: NIH, NCI, DCEG. NR 31 TC 18 Z9 18 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD DEC 15 PY 2009 VL 125 IS 12 BP 2912 EP 2917 DI 10.1002/ijc.24622 PG 6 WC Oncology SC Oncology GA 523CJ UT WOS:000272049000020 PM 19626699 ER PT J AU Shiels, MS Cole, SR Kirk, GD Poole, C AF Shiels, Meredith S. Cole, Stephen R. Kirk, Gregory D. Poole, Charles TI A Meta-Analysis of the Incidence of Non-AIDS Cancers in HIV-Infected Individuals SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT American-Association-for-Cancer-Research Frontiers in Cancer Research Meeting CY NOV 17, 2008 CL National Harbor, MD SP Amer Assoc Canc Res DE AIDS; cancer; epidemiology; HIV; meta-analysis ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; NEW-YORK-CITY; HUMAN-PAPILLOMAVIRUS INFECTION; WOMENS INTERAGENCY HIV; UNITED-STATES; LUNG-CANCER; DEFINING CANCERS; HOMOSEXUAL-MEN; RISK-FACTORS AB Objective: To estimate summary standardized incidence ratios (SIRS) of non-AIDS cancers among HIV-infected individuals compared with general population rates overall and stratified by gender, AIDS, and highly active antiretroviral therapy (HAART) era. Design: A meta-analysis using SIRS from 18 studies of non-AIDS cancer in HIV-infected individuals. Methods: SIRS for non-AIDS cancers in HIV-infected individuals and 95% confidence limits (CLs) were abstracted from each study. Random effects meta-analyses were used to estimate summary SIRS. Modifications by gender, AIDS, and HAART era were estimated with meta-regression. Results: Four thousand seven hundred ninety-seven non-AIDS cancers occurred among 625,716 HIV-infected individuals. SIRS for several cancers were elevated., In particular, cancers associated with infections, such as anal (SIR = 28; 95% CL 21 to 35), liver (SIR = 5.6; 95% CL 4.0 to 7.7), and Hodgkin lymphoma (SIR = 11; 95% CL 8.8 to 15) and smoking, such as lung (SIR = 2.6; 95% CL 2.1 to 3.1), kidney (SIR = 1.7; 95% CL 1.3 to 2.2), and laryngeal (SIR = 1.5; 95% CL 1.1 to 2.0). AIDS was associated with greater SIRS for Hodgkin lymphoma, leukemia, lung, brain, and all non-AIDS cancers combined. Conclusions: HIV-infected individuals may be at an increased risk of developing non-AIDS cancers, particularly those associated with infections and smoking. An association with advanced immune suppression was suggested for certain cancers. C1 [Shiels, Meredith S.; Kirk, Gregory D.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Cole, Stephen R.; Poole, Charles] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Shiels, MS (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7063, Bethesda, MD 20892 USA. EM shielsms@mail.nih.gov FU NCI NIH HHS [T32 CA009314, T32 CA009314-28S3, T32 CA009314-23]; NIAID NIH HHS [P30 AI-50410, P30 AI050410, P30 AI050410-11] NR 57 TC 201 Z9 203 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD DEC 15 PY 2009 VL 52 IS 5 BP 611 EP 622 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 526SO UT WOS:000272314100013 PM 19770804 ER PT J AU Qiu, XY Setlow, P AF Qiu, Xiangyun Setlow, Peter TI Structural and Genetic Analysis of X-Ray Scattering by Spores of Bacillus subtilis SO JOURNAL OF BACTERIOLOGY LA English DT Article ID COAT PROTEIN; RESISTANCE; GERMINATION; PREDATION; PATTERN; LAYERS; ACID AB Dormant spores of Bacillus subtilis exhibit two prominent X-ray scattering peaks. These peaks persisted in spores lacking most alpha/beta-type small, acid-soluble protein or the CotE protein responsible for assembly of much spore coat protein, but they were absent from spores of strains lacking the late sporulation-specific transcription factor GerE. C1 [Setlow, Peter] Univ Connecticut, Ctr Hlth, Dept Mol Microbial & Struct Biol, Farmington, CT 06030 USA. [Qiu, Xiangyun] NICHHD, Lab Phys & Struct Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Setlow, P (reprint author), Univ Connecticut, Ctr Hlth, Dept Mol Microbial & Struct Biol, Farmington, CT 06030 USA. EM setlow@nso2.uchc.edu FU Army Research Office; NIH FX This work was supported by a grant from the Army Research Office (P. S.) and by the Intramural Research Program of NIH, Program in Physical Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (X. Q.). NR 23 TC 1 Z9 1 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD DEC 15 PY 2009 VL 191 IS 24 BP 7620 EP 7622 DI 10.1128/JB.01200-09 PG 3 WC Microbiology SC Microbiology GA 522WI UT WOS:000272030400026 PM 19837800 ER PT J AU Ozato, K Yoshimi, R Chang, TH Wang, HS Atsumi, T Morse, HC AF Ozato, Keiko Yoshimi, Ryusuke Chang, Tsung-Hsien Wang, Hongsheng Atsumi, Toru Morse, Herbert C., III TI Comment on "Gene Disruption Study Reveals a Nonredundant Role for TRIM21/Ro52 in NF-kappa B-Dependent Cytokine Expression in Fibroblasts SO JOURNAL OF IMMUNOLOGY LA English DT Letter C1 [Ozato, Keiko; Yoshimi, Ryusuke; Chang, Tsung-Hsien; Atsumi, Toru] NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. [Wang, Hongsheng; Morse, Herbert C., III] NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. RP Ozato, K (reprint author), NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. OI Morse, Herbert/0000-0002-9331-3705; Yoshimi, Ryusuke/0000-0002-3945-307X FU Intramural NIH HHS [Z01 AI001057-01] NR 4 TC 7 Z9 7 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2009 VL 183 IS 12 BP 7619 EP 7619 DI 10.4049/jimmunol.0990103 PG 1 WC Immunology SC Immunology GA 533YE UT WOS:000272861300001 PM 20007569 ER PT J AU Cuburu, N Kweon, MN Hervouet, C Cha, HR Pang, YYS Holmgren, J Stadler, K Schiller, JT Anjuere, F Czerkinsky, C AF Cuburu, Nicolas Kweon, Mi-Na Hervouet, Catherine Cha, Hye-Ran Pang, Yuk-Ying S. Holmgren, Jan Stadler, Konrad Schiller, John T. Anjuere, Fabienne Czerkinsky, Cecil TI Sublingual Immunization with Nonreplicating Antigens Induces Antibody-Forming Cells and Cytotoxic T Cells in the Female Genital Tract Mucosa and Protects against Genital Papillomavirus Infection SO JOURNAL OF IMMUNOLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; IMMUNOGLOBULIN-A ANTIBODIES; HERPES-SIMPLEX VIRUS-2; TOXIN B-SUBUNIT; CHOLERA-TOXIN; IMMUNE-RESPONSES; SECRETING CELLS; DENDRITIC CELLS; INTRACELLULAR NEUTRALIZATION; INTRANASAL IMMUNIZATION AB We have recently reported that the sublingual (s.l.) mucosa is an efficient site for inducing systemic and mucosal immune responses. In this study, the potential of s.l. immunization to induce remote Ab responses and CD8(+) cytotoxic responses in the female genital tract was examined in mice by using a nonreplicating Ag, OVA, and cholera toxin (CT) as an adjuvant. Sublingual administration of OVA and CT induced Ag-specific IgA and IgG Abs in blood and in cervicovaginal secretions. These responses were associated with large numbers of IgA Ab-secreting cells (ASCs) in the genital mucosa. Genital ASC responses were similar in magnitude and isotype distribution after s.l., intranasal, or vaginal immunization and were superior to those seen after intragastric immunization. Genital, but not blood or spleen, IgA ASC responses were inhibited by treatment with anti-CCL28 Abs, suggesting that the chemokine CCL28 plays a major role in the migration of IgA ASC progenitors to the reproductive tract mucosa. Furthermore, s.l. immunization with OVA induced OVA-specific effector CD8(+) cytolytic T cells in the genital mucosa, and these responses required coadministration of the CT adjuvant. Furthermore, s.l. administration of human papillomavirus virus-like particles with or without the CT adjuvant conferred protection against genital challenge with human papillomavirus pseudovirions. Taken together, these findings underscore the potential or s.l. immunization as an efficient vaccination strategy for inducing genital immune responses and should impact on the development or vaccines against sexually transmitted diseases. The Journal of Immunology, 2009, 183: 7851-7859. C1 [Czerkinsky, Cecil] Seoul Natl Univ, Int Vaccine Inst, Div Sci Lab, Seoul 151818, South Korea. [Cuburu, Nicolas; Hervouet, Catherine; Anjuere, Fabienne; Czerkinsky, Cecil] Univ Nice Sophia Antipolis, INSERM, UMR 721, Fac Med Pasteur, Nice, France. [Cuburu, Nicolas; Pang, Yuk-Ying S.; Schiller, John T.] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. [Holmgren, Jan] Dept Microbiol & Immunol, Gothenburg, Sweden. [Holmgren, Jan] Univ Gothenburg, Vaccine Res Inst, Gothenburg, Sweden. RP Czerkinsky, C (reprint author), Seoul Natl Univ, Int Vaccine Inst, Div Sci Lab, Res Pk, Seoul 151818, South Korea. EM cczerkinsky@ivi.int RI CZERKINSKY, CECIL/G-6520-2015; Anjuere-Casile, Fabienne/O-5779-2016 OI Anjuere-Casile, Fabienne/0000-0003-3144-8652 FU Bill and Melinda Gates Foundation; INSERM (France); Agence Nationale de Recherches sur le SIDA (France); Association Ensemble Contre le SIDA (SIDACTION) (France); Association Faire face an SIDA (France); Swedish Science Council (Medicine) [K2000-06X-03382]; Knut and Alice Wallenberg Foundation (Sweden); Republic of Korea, Kuwait, and Sweden (SIDA) FX This work was supported by the Bill and Melinda Gates Foundation, INSERM (France), the Agence Nationale de Recherches sur le SIDA (France), the Association Ensemble Contre le SIDA (SIDACTION) (France), the Association Faire face an SIDA (France), the Swedish Science Council (Medicine) Grant K2000-06X-03382, and the Knut and Alice Wallenberg Foundation (Sweden). The International Vaccine Institute is supported in part by grants from the governments of the Republic of Korea, Kuwait, and Sweden (SIDA). NR 60 TC 57 Z9 58 U1 3 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2009 VL 183 IS 12 BP 7851 EP 7859 DI 10.4049/jimmunol.0803740 PG 9 WC Immunology SC Immunology GA 533YE UT WOS:000272861300029 PM 19933861 ER PT J AU Mielke, LA Elkins, KL Wei, L Starr, R Tsichlis, PN O'Shea, JJ Watford, WT AF Mielke, Lisa A. Elkins, Karen L. Wei, Lai Starr, Robyn Tsichlis, Philip N. O'Shea, John J. Watford, Wendy T. TI Tumor Progression Locus 2 (Map3k8) Is Critical for Host Defense against Listeria monocytogenes and IL-1 beta Production SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TNF-ALPHA PRODUCTION; NF-KAPPA-B; INNATE IMMUNE-RESPONSES; C-TYPE LECTIN; TPL2 KINASE; MURINE LISTERIOSIS; ERK ACTIVATION; BETA-GLUCANS; MICE LACKING; I RECEPTOR AB Tumor progression locus 2 (Tpl2, also known as Map3k8 and Cot) is a serine-threonine kinase critical in innate immunity, linking toll-like receptors (TLRs) to TNF production through its activation of ERK. Tpl2(-/-) macrophages have abrogated TNF production but overproduce IL-12 in response to TLR ligands. Despite enhanced IL-12 production, Tpl2(-/-) T cells have impaired IFN-gamma production. Therefore, the role of Tpl2 in a bona fide bacterial infection where all of these cytokines are important in host defense is unclear. To address this issue,we infected Tpl2(-/-) mice with the model pathogen Listeria monocytogenes. We found that Tpl2(-/-) mice infected i.v. with L. monocytogenes had increased pathogen burdens compared with wild-type mice and rapidly succumbed to infection. Enhanced susceptibility correlated with impaired signaling through TLR2 and nucleotide-binding oligomerization domain 2, two receptors previously shown. to mediate Listeria recognition. Surprisingly, TNF production in response to infection was not significantly impaired, even though Tpl2 has been implicated in the regulation of TNF. We found that the role of Tpl2 has cell-type specific effects in regulating TNF and transduces signals from some, but not all, pattern recognition receptors (PRR). In contrast to the cell-type- and receptor-specific regulation of TNF, we found that Tpl2 is essential for IL-1 beta production from both macrophages and dendritic cells. These studies implicate Tpl2 as an important mediator for collaboration of pattern recognition receptors with danger-associated molecular patterns to induce TNF and IL-1 beta production and optimal host defense. The Journal of Immunology, 2009, 183: 7984-7993. C1 [Mielke, Lisa A.; Wei, Lai; O'Shea, John J.; Watford, Wendy T.] Natl Inst Arthrit Musculoskeletal & Skin Dis, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Mielke, Lisa A.] Royal Melbourne Hosp, Walter & Eliza Hall Inst Med Res, Div Mol Med, Parkville, Vic 3050, Australia. [Mielke, Lisa A.] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia. [Elkins, Karen L.] US FDA, Ctr Biol Evaluat & Res, Lab Mycobacterial Dis & Cellular Immunol, Div Bacterial Parasit & Allergen Prod, Rockville, MD 20852 USA. [Starr, Robyn] St Vincents Inst Med Res, Signal Transduct Lab, Fitzroy, Vic 3065, Australia. [Tsichlis, Philip N.] Tufts Univ New England Med Ctr, Mol Oncol Res Inst, Boston, MA 02111 USA. RP Watford, WT (reprint author), Univ Georgia, Coll Vet Med, Dept Infect Dis, Athens, GA 30602 USA. EM watfordw@uga.edu RI Wei, Lai/D-1088-2014 FU National Institutes of Health [R01 CA095431, 1 K22 AR53953-01] FX P.N.T. is supported by National Institutes of Health Grant R01 CA095431. W.T.W. is supported by National Institutes of Health Grant 1 K22 AR53953-01. NR 60 TC 43 Z9 44 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2009 VL 183 IS 12 BP 7984 EP 7993 DI 10.4049/jimmunol.0901336 PG 10 WC Immunology SC Immunology GA 533YE UT WOS:000272861300043 PM 19933865 ER PT J AU Weldon, S McNally, P McElvaney, NG Elborn, JS McAuley, DF Wartelle, J Belaaouaj, A Levine, RL Taggart, CC AF Weldon, Sinead McNally, Paul McElvaney, Noel G. Elborn, J. Stuart McAuley, Danny F. Wartelle, Julien Belaaouaj, Abderrazzaq Levine, Rodney L. Taggart, Clifford C. TI Decreased Levels of Secretory Leucoprotease Inhibitor in the Pseudomonas-Infected Cystic Fibrosis Lung Are Due to Neutrophil Elastase Degradation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LEUKOCYTE PROTEASE INHIBITOR; RESPIRATORY EPITHELIAL SURFACE; LEUKOPROTEASE INHIBITOR; PROTEINASE-INHIBITOR; BACTERIAL LIPOPOLYSACCHARIDE; MACROPHAGE RESPONSES; AIRWAY INFLAMMATION; AERUGINOSA; ANTILEUKOPROTEASE; SLPI AB Secretory leucoprotease inhibitor (SLPI) is a neutrophil serine protease inhibitor constitutively expressed at many mucosal surfaces, including that of the lung. Originally identified as a serine protease inhibitor, it is now evident that SLPI also has antimicrobial and anti-inflammatory functions, and therefore plays an important role in host defense. Previous work has shown that some host defense proteins such as SLPI and elafin are susceptible to proteolytic degradation. Consequently, we investigated the status of SLPI in the cystic fibrosis (CF) lung. A major factor that contributes to the high mortality rate among CF patients is Pseudomonas aeruginosa infection. In this study, we report that. P. aeruginosa-positive CF bronchoalveolar lavage fluid, which contains lower SLPI levels and higher neutrophil elastase (NE) activity compared with P. aeruginosa-negative samples, was particularly effective at cleaving recombinant human SLPI. Additionally, we found that only NE inhibitors were able to prevent SLPI cleavage, thereby implicating NE in this process. NE in excess was found to cleave recombinant SLPI at two novel sites in the NH(2)-terminal region and abrogate its ability to bind LPS and NF-kappa B consensus binding sites but not its ability to inhibit activity of the serine protease cathepsin G. In conclusion, this study provides evidence that SLPI is cleaved and inactivated by NE present in P. aeruginosa-positive CF lung secretions and that P. aeruginosa infection contributes to inactivation of the host defense screen in the CF lung. The Journal of Immunology, 2009, 183: 8148-8156. C1 [Weldon, Sinead; Elborn, J. Stuart; McAuley, Danny F.; Taggart, Clifford C.] Queens Univ Belfast, Ctr Infect & Immun, Sch Med Dent & Biomed Sci, Belfast BT9 7BL, Antrim, North Ireland. [McNally, Paul; McElvaney, Noel G.] Beaumont Hosp, Royal Coll Surg Ireland, Resp Res Div, Dublin 9, Ireland. [Wartelle, Julien; Belaaouaj, Abderrazzaq] Univ Reims, Inst Natl Sante & Rech Med, Programme Avenir EA Inflammat & Immun Resp Epithe, Inst Federatif Rech 53, Reims, France. [Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Taggart, CC (reprint author), Queens Univ Belfast, Ctr Infect & Immun, Sch Med Dent & Biomed Sci, 97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland. EM c.taggart@qub.ac.uk RI McElvaney, Noel/A-6809-2010; Taggart, Clifford/G-4492-2014; Weldon, Sinead/J-5451-2014; Levine, Rodney/D-9885-2011; OI Weldon, Sinead/0000-0001-5628-6624; McNally, Paul/0000-0001-7102-1712; elborn, joseph/0000-0002-2323-442X FU Northern Ireland Chest Heart and Stroke Association [CT 2008 107]; American Alpha One Foundation FX This study was supported in part by funding from the Northern Ireland Chest Heart and Stroke Association (CT 2008 107) and the American Alpha One Foundation. NR 50 TC 51 Z9 52 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD DEC 15 PY 2009 VL 183 IS 12 BP 8148 EP 8156 DI 10.4049/jimmunol.0901716 PG 9 WC Immunology SC Immunology GA 533YE UT WOS:000272861300060 PM 20007580 ER PT J AU Tran, NBC Nguyen, TH Anders, KL Wolbers, M Le, BL Lu, TMH Tran, TH Nguyen, TH Farrar, J Whitehead, S Simmons, CP AF Tran Nguyen Bich Chau Nguyen Trong Hieu Anders, Katherine L. Wolbers, Marcel Le Bich Lien Lu Thi Minh Hieu Tran Tinh Hien Nguyen Thanh Hung Farrar, Jeremy Whitehead, Stephen Simmons, Cameron P. TI Dengue Virus Infections and Maternal Antibody Decay in a Prospective Birth Cohort Study of Vietnamese Infants SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID RISK-FACTORS; HEMORRHAGIC-FEVER; SOUTHERN VIETNAM; SHOCK SYNDROME; CHILDREN; SEROPREVALENCE; RESPONSES; THAILAND; AGE AB Dengue hemorrhagic fever can occur in primary dengue virus (DENV) infection of infants. The decay of maternally derived DENV immunoglobulin (Ig) G and the incidence of DENV infection were determined in a prospectively studied cohort of 1244 Vietnamese infants. Higher concentrations of total IgG and DENV-reactive IgG were found in cord plasma relative to maternal plasma. Maternally derived DENV-neutralizing and E protein-reactive IgG titers declined to below measurable levels in 190% of infants by 6 months of age. In contrast, IgG reactive with whole DENV virions persisted until 12 months of age in 20% of infants. Serological surveillance identified 10 infants with asymptomatic DENV infection for an incidence of 1.7 cases per 100 person-years. DENV-neutralizing antibodies remained measurable for >= 1 year after infection. These results suggest that whereas DENV infection in infants is frequently subclinical, there is a window between 4 and 12 months of age where virion-binding but nonneutralizing IgG could facilitate antibody-dependent enhancement. C1 [Simmons, Cameron P.] Univ Oxford, Clin Res Unit, Hosp Trop Dis, Ho Chi Minh City, Vietnam. [Nguyen Trong Hieu] Hong Vuong Hosp, Dept Neonatol, Ho Chi Minh City, Vietnam. [Le Bich Lien; Lu Thi Minh Hieu; Nguyen Thanh Hung] Childrens Hosp 1, Dept Dengue Haemorrhag Fever, Ho Chi Minh City, Vietnam. [Anders, Katherine L.; Wolbers, Marcel; Farrar, Jeremy; Simmons, Cameron P.] Univ Oxford, Ctr Trop Med, Oxford, England. [Whitehead, Stephen] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Simmons, CP (reprint author), Univ Oxford, Clin Res Unit, Hosp Trop Dis, 190 Ben Ham Tu, Ho Chi Minh City, Vietnam. EM csimmons@oucru.org OI Simmons, Cameron P./0000-0002-9039-7392; Farrar, Jeremy/0000-0002-2700-623X FU Wellcome Trust FX Financial support: Wellcome Trust. NR 21 TC 5 Z9 6 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1899 EI 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD DEC 15 PY 2009 VL 200 IS 12 BP 1893 EP 1900 DI 10.1086/648407 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 520UH UT WOS:000271874000012 PM 19911991 ER PT J AU Bock, NA Kocharyan, A Liu, JV Silva, AC AF Bock, Nicholas A. Kocharyan, Ara Liu, Junjie V. Silva, Afonso C. TI Visualizing the entire cortical myrelination pattern in marmosets with magnetic resonance imaging SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Brain anatomy; Non-human primate; Myeloarchitecture; Magnetic resonance imaging; Magnetization-prepared rapidly acquired gradient echo sequence; Gallyas silver staining ID MONKEY CALLITHRIX-JACCHUS; HIGH-RESOLUTION MRI; DORSOLATERAL FRONTAL-CORTEX; MIDDLE TEMPORAL AREA; NONPHOSPHORYLATED NEUROFILAMENT; EXTRASTRIATE CORTICES; AUDITORY-CORTEX; CEREBRAL-CORTEX; CONNECTIONS; ORGANIZATION AB Myeloarchitecture, the pattern of myelin density across the cerebral cortex, has long been visualized in histological sections to identify distinct anatomical areas of the cortex. In humans, two-dimensional (2D) magnetic resonance imaging (MRI) has been used to visualize myeloarchitecture in select areas of the cortex, such as the stripe of Gennari in the primary visual cortex and Heschl's gyrus in the primary auditory cortex. Here, we investigated the use of MRI contrast based on longitudinal relaxation time (T(1)) to visualize myeloarchitecture in vivo over the entire cortex of the common marmoset (Callithrix jacchus), a small non-human primate that is becoming increasingly important in neuroscience and neurobiology research. Using quantitative T(1) mapping, we found that T(1) at 7T in a cortical region with a high myelin content was 15% shorter than T(1) in a region with a low myelin content. To maximize this T(1) contrast for imaging cortical myelination patterns, we optimized a magnetization-prepared rapidly acquired gradient echo (MP-RAGE) sequence. In whole-brain, 3D T(1)-weighted images made in vivo with the sequence, we identified six major cortical areas with high myelination and confirmed the results with histological sections stained for myelin. We also identified several subtle features of myeloarchitecture, showing the sensitivity of our technique. The ability to image myeloarchitecture over the entire cortex may prove useful in studies of longitudinal changes of the topography of the cortex associated with development and neuronal plasticity, as well as for guiding and confirming the location of functional measurements. Published by Elsevier B.V. C1 [Bock, Nicholas A.; Kocharyan, Ara; Liu, Junjie V.; Silva, Afonso C.] NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Bock, Nicholas A.] McMaster Univ, Hamilton, ON, Canada. RP Silva, AC (reprint author), 10 Ctr Dr,Bldg 10,Room BD106, Bethesda, MD 20892 USA. EM bockn@mcmaster.ca; silvaa@mail.nih.gov RI Silva, Afonso/A-7129-2009 FU Intramural Research Program of the NIH; NINDS (Alan P. Koretsky, Scientific Director) FX We wish to acknowledge the excellent assistance of Man Feng Zhang for animal handling and Laura Banevicius, Leanne Radecki, and Britni Rowe for image segmentation. This research was supported by the Intramural Research Program of the NIH, NINDS (Alan P. Koretsky, Scientific Director). NR 45 TC 52 Z9 52 U1 0 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD DEC 15 PY 2009 VL 185 IS 1 BP 15 EP 22 DI 10.1016/j.jneumeth.2009.08.022 PG 8 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 528UR UT WOS:000272473000002 PM 19737577 ER PT J AU Firth, C Charleston, MA Duffy, S Shapiro, B Holmes, EC AF Firth, Cadhla Charleston, Michael A. Duffy, Siobain Shapiro, Beth Holmes, Edward C. TI Insights into the Evolutionary History of an Emerging Livestock Pathogen: Porcine Circovirus 2 SO JOURNAL OF VIROLOGY LA English DT Article ID MULTISYSTEMIC WASTING-SYNDROME; RETROSPECTIVE SEROLOGICAL SURVEY; TYPE-2 PCV2; RNA VIRUSES; GENETIC-CHARACTERIZATION; PHYLOGENETIC ANALYSIS; MOLECULAR EVOLUTION; CRETACEOUS ORIGIN; NORTHERN-IRELAND; PCR DETECTION AB Porcine circovirus 2 (PCV2) is the primary etiological agent of postweaning multisystemic wasting syndrome (PMWS), one of the most economically important emerging swine diseases worldwide. Virulent PCV2 was first identified following nearly simultaneous outbreaks of PMWS in North America and Europe in the 1990s and has since achieved global distribution. However, the processes responsible for the emergence and spread of PCV2 remain poorly understood. Here, phylogenetic and cophylogenetic inferences were utilized to address key questions on the time scale, processes, and geographic diffusion of emerging PCV2. The results of these analyses suggest that the two genotypes of PCV2 (PCV2a and PCV2b) are likely to have emerged from a common ancestor approximately 100 years ago and have been on independent evolutionary trajectories since that time, despite cocirculating in the same host species and geographic regions. The patterns of geographic movement of PCV2 that we recovered appear to mimic those of the global pig trade and suggest that the movement of asymptomatic animals is likely to have facilitated the rapid spread of virulent PCV2 around the globe. We further estimated the rate of nucleotide substitution for PCV2 to be on the order of 1.2 x 10(-3) substitutions/site/year, the highest yet recorded for a single-stranded DNA virus. This high rate of evolution may allow PCV2 to maintain evolutionary dynamics closer to those of single-stranded RNA viruses than to those of double-stranded DNA viruses, further facilitating the rapid emergence of PCV2 worldwide. C1 [Firth, Cadhla] Penn State Univ, Dept Biol, Mueller Lab, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Charleston, Michael A.] Univ Sydney, Sch Informat Technol, Sydney, NSW 2006, Australia. [Charleston, Michael A.] Univ Sydney, Ctr Math Biol, Sydney, NSW 2006, Australia. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Firth, C (reprint author), Penn State Univ, Dept Biol, Mueller Lab, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM cbr134@psu.edu RI Duffy, Siobain/A-9104-2009; OI Duffy, Siobain/0000-0003-0753-223X; Shapiro, Beth/0000-0002-2733-7776; Holmes, Edward/0000-0001-9596-3552 FU Natural Sciences and Engineering Research Council (Canada); NIH [R01 GM080533] FX We thank Andrew Read, Anton Nekrutenko, and Bryan Grenfell for their insight into PCV2 evolution and emergence; Sergei Kosakovsky Pond for his technical advice and support; and Maia Rabaa for her editorial assistance and invaluable contribution to all things swine. NR 73 TC 77 Z9 83 U1 1 U2 13 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC 15 PY 2009 VL 83 IS 24 BP 12813 EP 12821 DI 10.1128/JVI.01719-09 PG 9 WC Virology SC Virology GA 521PB UT WOS:000271932900016 PM 19812157 ER PT J AU Satheshkumar, PS Moss, B AF Satheshkumar, P. S. Moss, Bernard TI Characterization of a Newly Identified 35-Amino-Acid Component of the Vaccinia Virus Entry/Fusion Complex Conserved in All Chordopoxviruses SO JOURNAL OF VIROLOGY LA English DT Article ID ENTRY-FUSION COMPLEX; CELL-CELL FUSION; INTRACELLULAR MATURE VIRION; COMPLETE DNA-SEQUENCE; OPEN READING FRAME; MEMBRANE-PROTEIN; MONOCLONAL-ANTIBODIES; POXVIRUS ENTRY; HOST-CELLS; L1 PROTEIN AB The original annotation of the vaccinia virus (VACV) genome was limited to open reading frames (ORFs) of at least 65 amino acids. Here, we characterized a 35-amino-acid ORF (O3L) located between ORFs O2L and I1L. ORFs similar in length to O3L were found at the same genetic locus in all vertebrate poxviruses. Although amino acid identities were low, the presence of a characteristic N-terminal hydrophobic domain strongly suggested that the other poxvirus genes were orthologs. Further studies demonstrated that the O3 protein was expressed at late times after infection and incorporated into the membrane of the mature virion. An O3L deletion mutant was barely viable, producing tiny plaques and a 3-log reduction in infectious progeny. A mutant VACV with a regulated O3L gene had a similar phenotype in the absence of inducer. There was no apparent defect in virus morphogenesis, though O3-deficient virus had low infectivity. The impairment was shown to be at the stage of virus entry, as cores were not detected in the cytoplasm after virus adsorption. Furthermore, O3-deficient virus did not induce fusion of infected cells when triggered by low pH. These characteristics are hallmarks of a group of proteins that form the entry/fusion complex (EFC). Affinity purification experiments demonstrated an association of O3 with EFC proteins. In addition, the assembly or stability of the EFC was impaired when expression of O3 was repressed. Thus, O3 is the newest recognized component of the EFC and the smallest VACV protein shown to have a function. C1 [Satheshkumar, P. S.; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 33 North Dr,MSC 3210, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 51 TC 28 Z9 29 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC 15 PY 2009 VL 83 IS 24 BP 12822 EP 12832 DI 10.1128/JVI.01744-09 PG 11 WC Virology SC Virology GA 521PB UT WOS:000271932900017 PM 19812151 ER PT J AU Moreno-Fernandez, ME Zapata, W Blackard, JT Franchini, G Chougnet, CA AF Moreno-Fernandez, Maria E. Zapata, Wildeman Blackard, Jason T. Franchini, Genoveffa Chougnet, Claire A. TI Human Regulatory T Cells Are Targets for Human Immunodeficiency Virus (HIV) Infection, and Their Susceptibility Differs Depending on the HIV Type 1 Strain SO JOURNAL OF VIROLOGY LA English DT Article ID LONG TERMINAL REPEAT; NF-KAPPA-B; PERIPHERAL-BLOOD; IN-VITRO; CD4(+); FOXP3; DISEASE; INDIVIDUALS; ACTIVATION; EXPRESSION AB Regulatory T cells (Treg) are a subpopulation of CD4(+) T cells characterized by the suppressive activity they exert on effector immune responses, including human immunodeficiency virus (HIV)-specific immune responses. Because Treg express CXCR4 and CCR5, they represent potential targets for HIV; however, Treg susceptibility to HIV infection is still unclear. We therefore performed an extensive study of Treg susceptibility to HIV, using lab strains and primary isolates with either CCR5 or CXCR4 tropism. Furthermore, we quantified HIV infection at early and late time points of the virus life cycle. We found that Treg were clearly susceptible to HIV infection. Circulating Treg were not preferentially infected with HIV compared to effector T cells (Teff) in vivo. Conversely, in vitro infection with either CCR5-using (R5) or CXCR4-using (X4) viruses occurred with different dynamics. For instance, HIV infection by R5 viruses (lab strains and primary isolates) resulted in lower levels of infection in Treg compared with Teff at both early and late time points. In contrast, X4 viruses induced higher levels of infection in Treg compared to Teff at early time points, but this difference disappeared at the late time points of the virus life cycle. Our results suggest that the relative susceptibility of Treg to HIV infection compared to Teff varies, depending on both viral and host factors. These variations may play an important role in HIV pathogenesis. C1 [Moreno-Fernandez, Maria E.; Zapata, Wildeman; Chougnet, Claire A.] Univ Cincinnati, Div Mol Immunol, Cincinnati Childrens Hosp, Dept Pediat,Res Fdn,Coll Med, Cincinnati, OH 45229 USA. [Zapata, Wildeman] Univ Antioquia, Grp Inmunovirol, Medellin, Antioquia, Colombia. [Blackard, Jason T.] Univ Cincinnati, Div Digest Dis, Coll Med, Cincinnati, OH 45267 USA. [Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. RP Chougnet, CA (reprint author), Univ Cincinnati, Div Mol Immunol, Cincinnati Childrens Hosp, Dept Pediat,Res Fdn,Coll Med, Cincinnati, OH 45229 USA. EM Claire.Chougnet@cchmc.org FU NIH [RO1 AI068524]; University of Cincinnati, College of Medicine FX This study was supported by NIH grant RO1 AI068524 ( to C. C.) and the Dean's Scholar Award from the University of Cincinnati, College of Medicine ( to J.T.B.). NR 36 TC 43 Z9 45 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD DEC 15 PY 2009 VL 83 IS 24 BP 12925 EP 12933 DI 10.1128/JVI.01352-09 PG 9 WC Virology SC Virology GA 521PB UT WOS:000271932900026 PM 19828616 ER PT J AU Boudreau, HE Emerson, SU Korzeniowska, A Jendrysik, MA Leto, TL AF Boudreau, Howard E. Emerson, Suzanne U. Korzeniowska, Agnieszka Jendrysik, Meghan A. Leto, Thomas L. TI Hepatitis C Virus (HCV) Proteins Induce NADPH Oxidase 4 Expression in a Transforming Growth Factor beta-Dependent Manner: a New Contributor to HCV-Induced Oxidative Stress SO JOURNAL OF VIROLOGY LA English DT Article ID SMOOTH-MUSCLE-CELLS; NF-KAPPA-B; CORE PROTEIN; NAD(P)H OXIDASE; MESENCHYMAL TRANSITION; TRANSGENIC MICE; TGF-BETA; HEPATOCELLULAR-CARCINOMA; SIGNAL-TRANSDUCTION; GENE-EXPRESSION AB Viral hepatitis-induced oxidative stress accompanied by increased levels of transforming growth factor beta (TGF-beta) and hepatic fibrosis are hallmarks of hepatitis C virus (HCV) infection. The mechanisms of redox regulation in the pathogenesis of HCV-induced liver disease are not clearly understood. The results of our current studies suggest that reactive oxygen species (ROS) derived from Nox4, a member of the NADPH oxidase (Nox) family, could play a role in HCV-induced liver disease. We found that the expression of HCV (genotype 1a) cDNA constructs (full-length and subgenomic), core protein alone, viral RNA, or replicating HCV (JFH-AM2) induced Nox4 mRNA expression and ROS generation in human hepatocyte cell lines (Huh-7, Huh-7.5, HepG2, and CHL). Conversely, hepatocytes expressing Nox4 short hairpin RNA (shRNA) or an inactive dominant negative form of Nox4 showed decreased ROS production when cells were transfected with HCV. The promoters of both human and murine Nox4 were used to demonstrate transcriptional regulation of Nox4 mRNA by HCV, and a luciferase reporter tied to an similar to 2-kb promoter region of Nox4 identified HCV-responsive regulatory regions modulating the expression of Nox4. Furthermore, the human Nox4 promoter was responsive to TGF-beta 1, and the HCV core-dependent induction of Nox4 was blocked by antibody against TGF-beta or the expression of dominant negative TGF-beta receptor type II. These findings identified HCV as a regulator of Nox4 gene expression and subsequent ROS production through an autocrine TGF-beta-dependent mechanism. Collectively, these data provide evidence that HCV-induced Nox4 contributes to ROS production and may be related to HCV-induced liver disease. C1 [Leto, Thomas L.] NIAID, Host Def Lab, NIH, Rockville, MD 20852 USA. RP Leto, TL (reprint author), NIAID, Host Def Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM tleto@nih.gov FU U.S. National Institutes of Health Intramural Research Program; National Institutes of Allergy and Infectious Diseases FX The U.S. National Institutes of Health Intramural Research Program, National Institutes of Allergy and Infectious Diseases, supported this work. NR 75 TC 64 Z9 65 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD DEC 15 PY 2009 VL 83 IS 24 BP 12934 EP 12946 DI 10.1128/JVI.01059-09 PG 13 WC Virology SC Virology GA 521PB UT WOS:000271932900027 PM 19812163 ER PT J AU Ammann, CG Messer, RJ Varvel, K DeBuysscher, BL LaCasse, RA Pinto, AK Hasenkrug, KJ AF Ammann, Christoph G. Messer, Ronald J. Varvel, Kimberly DeBuysscher, Blair L. LaCasse, Rachel A. Pinto, Amelia K. Hasenkrug, Kim J. TI Effects of Acute and Chronic Murine Norovirus Infections on Immune Responses and Recovery from Friend Retrovirus Infection SO JOURNAL OF VIROLOGY LA English DT Article ID REGULATORY T-CELLS; LEUKEMIA-VIRUS; MICE; CD4(+); IDENTIFICATION; COINFECTION; DYSFUNCTION; KINETICS; ANTIBODY; MOLONEY AB Murine norovirus (MNV) is a highly infectious but generally nonpathogenic agent that is commonly found in research mouse colonies in both North America and Europe. In the present study, the effects of acute and chronic infections with MNV on immune responses and recovery from concurrent Friend virus (FV) infections were investigated. No significant differences in T-cell or NK-cell responses, FV-neutralizing antibody responses, or long-term recovery from FV infection were observed. We conclude that concurrent MNV infections had no major impacts on FV infections. C1 [Ammann, Christoph G.; Messer, Ronald J.; Varvel, Kimberly; DeBuysscher, Blair L.; LaCasse, Rachel A.; Hasenkrug, Kim J.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Pinto, Amelia K.] Washington Univ, Dept Pathol & Immunol, Sch Med, St Louis, MO 63110 USA. RP Hasenkrug, KJ (reprint author), 903 S 4th St, Hamilton, MT 59840 USA. EM khasenkrug@nih.gov OI Ammann, Christoph/0000-0002-6267-1286 FU NIAID; NIH FX This work was supported by the Division of Intramural Research of the NIAID, NIH. NR 34 TC 15 Z9 15 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD DEC 15 PY 2009 VL 83 IS 24 BP 13037 EP 13041 DI 10.1128/JVI.01445-09 PG 5 WC Virology SC Virology GA 521PB UT WOS:000271932900039 PM 19812147 ER PT J AU Kang, HS Kim, YS ZeRuth, G Beak, JY Gerrish, K Kilic, G Sosa-Pineda, B Jensen, J Foley, J Jetten, AM AF Kang, Hong Soon Kim, Yong-Sik ZeRuth, Gary Beak, Ju Youn Gerrish, Kevin Kilic, Gamze Sosa-Pineda, Beatriz Jensen, Jan Foley, Julie Jetten, Anton M. TI Transcription Factor Glis3, a Novel Critical Player in the Regulation of Pancreatic beta-Cell Development and Insulin Gene Expression SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ZINC-FINGER PROTEIN; NEONATAL DIABETES-MELLITUS; POLYCYSTIC KIDNEY-DISEASE; CONGENITAL HYPOTHYROIDISM; FATE SPECIFICATION; ENDOCRINE PANCREAS; PROGENITOR CELLS; ZIC GENES; DIFFERENTIATION; MOUSE AB In this study, we report that the Kruppel-like zinc finger transcription factor Gli-similar 3 (Glis3) is induced during the secondary transition of pancreatic development, a stage of cell lineage specification and extensive patterning, and that Glis3(zf/zf) mutant mice develop neonatal diabetes, evidenced by hyperglycemia and hypoinsulinemia. The Glis3(zf/zf) mutant mouse pancreas shows a dramatic loss of beta and delta cells, contrasting a smaller relative loss of alpha, PP, and epsilon cells. In addition, Glis3(zf/zf) mutant mice develop ductal cysts, while no significant changes were observed in acini. Gene expression profiling and immunofluorescent staining demonstrated that the expression of pancreatic hormones and several transcription factors important in endocrine cell development, including Ngn3, MafA, and Pdx1, were significantly decreased in the developing pancreata of Glis3(zf/zf) mutant mice. The population of pancreatic progenitors appears not to be greatly affected in Glis3(zf/zf) mutant mice; however, the number of neurogenin 3 (Ngn3)-positive endocrine cell progenitors is significantly reduced. Our study indicates that Glis3 plays a key role in cell lineage specification, particularly in the development of mature pancreatic beta cells. In addition, we provide evidence that Glis3 regulates insulin gene expression through two Glis-binding sites in its proximal promoter, indicating that Glis3 also regulates beta-cell function. C1 [Kang, Hong Soon; Kim, Yong-Sik; ZeRuth, Gary; Beak, Ju Youn; Jetten, Anton M.] NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Gerrish, Kevin] NIEHS, Microarray Lab Core, NIH, Res Triangle Pk, NC 27709 USA. [Kim, Yong-Sik; Jensen, Jan] Cleveland Clin, Dept Stem Cell Biol & Regenerat Med, Lerner Res Inst, Cleveland, OH 44195 USA. [Kilic, Gamze; Sosa-Pineda, Beatriz] St Jude Childrens Hosp, Dept Genet & Tumor Cell Biol, Memphis, TN 38105 USA. [Foley, Julie] NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, Div Intramural Res, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jensen, Jan/0000-0003-0657-4032; Jetten, Anton/0000-0003-0954-4445 FU NIEHS, NIH [Z01-ES-100485] FX This research was supported by the Intramural Research Program of the NIEHS, NIH (Z01-ES-100485). NR 57 TC 53 Z9 55 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC 15 PY 2009 VL 29 IS 24 BP 6366 EP 6379 DI 10.1128/MCB.01259-09 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 522QI UT WOS:000272013000004 PM 19805515 ER PT J AU Sekine, H Mimura, J Oshima, M Okawa, H Kanno, J Igarashi, K Gonzalez, FJ Ikuta, T Kawajiri, K Fujii-Kuriyama, Y AF Sekine, Hiroki Mimura, Junsei Oshima, Motohiko Okawa, Hiromi Kanno, Jun Igarashi, Katsuhide Gonzalez, Frank J. Ikuta, Togo Kawajiri, Kaname Fujii-Kuriyama, Yoshiaki TI Hypersensitivity of Aryl Hydrocarbon Receptor-Deficient Mice to Lipopolysaccharide-Induced Septic Shock SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NUCLEAR TRANSLOCATOR ARNT; NF-KAPPA-B; AH RECEPTOR; DIOXIN RECEPTOR; TRANSCRIPTION; ACTIVATION; TOXICITY; PROTEINS; LACKING; GENES AB Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, is known to mediate a wide variety of pharmacological and toxicological effects caused by polycyclic aromatic hydrocarbons. Recent studies have revealed that AhR is involved in the normal development and homeostasis of many organs. Here, we demonstrate that AhR knockout (AhR KO) mice are hypersensitive to lipopolysaccharide (LPS)-induced septic shock, mainly due to the dysfunction of their macrophages. In response to LPS, bone marrow-derived macrophages (BMDM) of AhR KO mice secreted an enhanced amount of interleukin-1 beta (IL-1 beta). Since the enhanced IL-1 beta secretion was suppressed by supplementing Plasminogen activator inhibitor-2 (Pai-2) expression through transduction with Pai-2-expressing adenoviruses, reduced Pai-2 expression could be a cause of the increased IL-1 beta secretion by AhR KO mouse BMDM. Analysis of gene expression revealed that AhR directly regulates the expression of Pai-2 through a mechanism involving NF-kappa B but not AhR nuclear translocator (Arnt), in an LPS-dependent manner. Together with the result that administration of the AhR ligand 3-methylcholanthrene partially protected mice with wild-type AhR from endotoxin-induced death, these results raise the possibility that an appropriate AhR ligand may be useful for treating patients with inflammatory disorders. C1 [Sekine, Hiroki; Mimura, Junsei; Oshima, Motohiko; Okawa, Hiromi; Fujii-Kuriyama, Yoshiaki] Univ Tsukuba, Ctr Tsukuba Adv Res Alliance, Tsukuba, Ibaraki 3058577, Japan. [Sekine, Hiroki; Mimura, Junsei; Oshima, Motohiko; Okawa, Hiromi; Fujii-Kuriyama, Yoshiaki] Univ Tsukuba, Inst Basic Med Sci, Tsukuba, Ibaraki 3058577, Japan. [Kanno, Jun; Igarashi, Katsuhide] Natl Inst Hlth Sci, Div Mol Toxicol, Setagaya Ku, Tokyo 1588501, Japan. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ikuta, Togo; Kawajiri, Kaname] Saitama Canc Ctr, Res Inst Clin Oncol, Ina, Saitama 3620806, Japan. [Sekine, Hiroki; Mimura, Junsei; Oshima, Motohiko; Okawa, Hiromi; Fujii-Kuriyama, Yoshiaki] Japan Sci & Technol Agcy, SORST, Kawaguchi, Saitama 3320012, Japan. RP Fujii-Kuriyama, Y (reprint author), 5-18-7 Honkomagome,Bunkyo Ku, Tokyo 1130021, Japan. EM y.k_fujii@nifty.com RI Mimura, Junsei/E-7893-2013 FU Japan Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan; Ministry of Health, Labor and Welfare, Japan FX This work was funded in part by Solution Oriented Research for Science and Technology from Japan Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan, and by a grant for Scientific Research from the Ministry of Health, Labor and Welfare, Japan. NR 32 TC 54 Z9 56 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC 15 PY 2009 VL 29 IS 24 BP 6391 EP 6400 DI 10.1128/MCB.00337-09 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 522QI UT WOS:000272013000006 PM 19822660 ER PT J AU Ginsburg, DS Govind, CK Hinnebusch, AG AF Ginsburg, Daniel S. Govind, Chhabi K. Hinnebusch, Alan G. TI NuA4 Lysine Acetyltransferase Esa1 Is Targeted to Coding Regions and Stimulates Transcription Elongation with Gcn5 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; CHROMATIN REMODELER RSC; IN-VIVO; SACCHAROMYCES-CEREVISIAE; SRB MEDIATOR; HISTONE ACETYLATION; ACTIVATOR GCN4P; PHO5 PROMOTER; COMPLEX; YEAST AB NuA4, the major H4 lysine acetyltransferase (KAT) complex in Saccharomyces cerevisiae, is recruited to promoters and stimulates transcription initiation. NuA4 subunits contain domains that bind methylated histones, suggesting that histone methylation should target NuA4 to coding sequences during transcription elongation. We show that NuA4 is cotranscriptionally recruited, dependent on its physical association with elongating polymerase II (Pol II) phosphorylated on the C-terminal domain by cyclin-dependent kinase 7/Kin28, but independently of subunits (Eaf1 and Tra1) required for NuA4 recruitment to promoters. Whereas histone methylation by Set1 and Set2 is dispensable for NuA4's interaction with Pol II and targeting to some coding regions, it stimulates NuA4-histone interaction and H4 acetylation in vivo. The NuA4 KAT, Esa1, mediates increased H4 acetylation and enhanced RSC occupancy and histone eviction in coding sequences and stimulates the rate of transcription elongation. Esa1 cooperates with the H3 KAT in SAGA, Gcn5, to enhance these functions. Our findings delineate a pathway for acetylation-mediated nucleosome remodeling and eviction in coding sequences that stimulates transcription elongation by Pol II in vivo. C1 [Ginsburg, Daniel S.; Govind, Chhabi K.; Hinnebusch, Alan G.] NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NIH, Bldg 6,Room 230, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov FU NIH FX This work was supported by the Intramural Research Program of the NIH. NR 65 TC 54 Z9 56 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC 15 PY 2009 VL 29 IS 24 BP 6473 EP 6487 DI 10.1128/MCB.01033-09 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 522QI UT WOS:000272013000013 PM 19822662 ER PT J AU Tripathi, BK Zelenka, PS AF Tripathi, Brajendra K. Zelenka, Peggy S. TI Cdk5-Dependent Regulation of Rho Activity, Cytoskeletal Contraction, and Epithelial Cell Migration via Suppression of Src and p190RhoGAP SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID CYCLIN-DEPENDENT KINASE-5; INTEGRIN-LINKED KINASE; LIGHT-CHAIN KINASE; ACTIN CYTOSKELETON; SMOOTH-MUSCLE; MYOSIN PHOSPHATASE; ADHESION DYNAMICS; FOCAL ADHESIONS; WOUND CLOSURE; IN-VIVO AB Cdk5 regulates adhesion and migration in a variety of cell types. We previously showed that Cdk5 is strongly activated during stress fiber formation and contraction in spreading cells. Here we determine the mechanism linking Cdk5 to stress fiber contractility and its relevance to cell migration. Immunofluorescence showed that Cdk5 colocalized with phosphorylated myosin regulatory light chain (pMRLC) on contracting stress fibers. Inhibiting Cdk5 activity by various means significantly reduced pMRLC level and cytoskeletal contraction, with loss of central stress fibers. Blocking Cdk5 activity also reduced Rho-Rho kinase (ROCK) signaling, which is the principal pathway of myosin phosphorylation under these conditions. Next, we examined the effect of Cdk5 activity on Src, a known regulator of Rho. Inhibiting Cdk5 activity increased Src activation and phosphorylation of its substrate, p190RhoGAP, an upstream inhibitor of Rho. Inhibiting both Cdk5 and Src activity completely reversed the effect of Cdk5 inhibition on Rho and prevented the loss of central stress fibers, demonstrating that Cdk5 exerts its effects on Rho-ROCK signaling by suppressing Src activity. Moreover, inhibiting either Cdk5 or ROCK activity increased cell migration to an equal extent, while inhibiting both kinases produced no additional effect, demonstrating that Cdk5-dependent regulation of ROCK activity is a physiological determinant of migration rate. C1 [Tripathi, Brajendra K.; Zelenka, Peggy S.] NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Zelenka, PS (reprint author), NEI, Mol & Dev Biol Lab, NIH, 5635 Fishers Lane,Room 1127, Bethesda, MD 20892 USA. EM zelenkap@nei.nih.gov FU National Eye Institute Intramural Research Program [Z01-EY000238-20] FX This work was supported by the National Eye Institute Intramural Research Program Z01-EY000238-20. NR 49 TC 16 Z9 16 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD DEC 15 PY 2009 VL 29 IS 24 BP 6488 EP 6499 DI 10.1128/MCB.01098-09 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 522QI UT WOS:000272013000014 PM 19822667 ER PT J AU Haubenberger, D Hotzy, C Pirker, W Katzenschlager, R Brucke, T Zimprich, F Auff, E Zimprich, A AF Haubenberger, Dietrich Hotzy, Christoph Pirker, Walter Katzenschlager, Regina Bruecke, Thomas Zimprich, Fritz Auff, Eduard Zimprich, Alexander TI Role of LINGO1 Polymorphisms in Parkinson's Disease SO MOVEMENT DISORDERS LA English DT Article DE essential tremor; Parkinson's disease; LINGO1; genetics; association study ID ESSENTIAL TREMOR; RISK; GENE AB A clinical overlap between Parkinson's disease (PD) and essential tremor (ET) has prompted a discussion whether these conditions share common genetic susceptibility factors. Recently, the first genome-wide association study in ET revealed a significant association with a variant in the LINGO1 gene. LINGO1 has also been demonstrated to play a role in the survival of dopaminergic neurons in an animal model of PD, and therefore constitutes a potential candidate gene for PD. In this study, SNPs rs9652490, rs11856808, and rs7177008 of LINGO1 were genotyped in a total of 694 Austrian subjects (349 PD, 345 controls). No association could be found between genotype or allele counts and PD. Neither did a subgroup analysis in tremor-dominant patients with PD reveal a significant association. This study on LINGO1-variants in PD argues against a major role of LINGO1 gene variations for PD. (C) 2009 Movement Disorder Society C1 [Haubenberger, Dietrich; Hotzy, Christoph; Pirker, Walter; Zimprich, Fritz; Auff, Eduard; Zimprich, Alexander] Med Univ Vienna, Dept Neurol, Vienna, Austria. [Katzenschlager, Regina] SMZ Ost Donauspital, Dept Neurol, Vienna, Austria. [Bruecke, Thomas] Wilhelminenspital Stadt Wien, Dept Neurol, Vienna, Austria. RP Haubenberger, D (reprint author), NINDS, Human Control Sect, MNB, NIH, 10 Ctr Dr Bldg 10,Room 7037, Bethesda, MD 20892 USA. EM dietrich.haubenberger@meduniwien.ac.at RI Zimprich, Alexander/A-5232-2017 OI Zimprich, Alexander/0000-0002-1668-5177 FU Department of Neurology, Medical University of Vienna, Austria FX This study was supported by the Department of Neurology, Medical University of Vienna, Austria. NR 15 TC 20 Z9 20 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD DEC 15 PY 2009 VL 24 IS 16 BP 2404 EP 2407 DI 10.1002/mds.22768 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 541SJ UT WOS:000273440200014 PM 19908305 ER PT J AU O'Farrell, CA Martin, KL Hutton, M Delatycki, MB Cookson, MR Lockhart, PJ AF O'Farrell, C. A. Martin, K. L. Hutton, M. Delatycki, M. B. Cookson, M. R. Lockhart, P. J. TI MUTANT TORSINA INTERACTS WITH TYROSINE HYDROXYLASE IN CULTURED CELLS SO NEUROSCIENCE LA English DT Article DE dystonia; dopamine; catecholaminergic neurons; inclusion body ID TRANSGENIC MOUSE MODEL; DYT1 DYSTONIA MUTATION; EARLY-ONSET DYSTONIA; NUCLEAR-ENVELOPE; CAENORHABDITIS-ELEGANS; ALPHA-SYNUCLEIN; PROTEIN; DOPAMINE; LOCALIZATION; NEURONS AB A specific mutation (Delta E302/303) in the torsinA gene underlies most cases of dominantly inherited early-onset torsion dystonia. This mutation causes the protein to aggregate and form intracellular inclusion bodies in cultured cells and animal models. Co-expression of the wildtype and mutant proteins resulted in the redistribution of the wildtype protein from the endoplasmic reticulum to inclusion bodies in cultured HEK293 cells, and this was associated with increased interaction between the two proteins. Expression of Delta E302/303 but not wildtype torsinA in primary postnatal midbrain neurons resulted in the formation of intracellular inclusion bodies, predominantly in dopaminergic neurons. Tyrosine hydroxylase, was sequestered in these inclusions and this process was mediated by increased protein-protein interaction between mutant torsinA and tyrosine hydroxylase. Analysis in an inducible neuroblastoma cell culture model demonstrated altered tyrosine hydroxylase activity in the presence of the mutant but not wildtype torsinA protein. Our results suggest that the interaction of tyrosine hydroxylase and mutant torsinA may contribute to the phenotype and reported dopaminergic dysfunction in torsinA-mediated dystonia. (C) 2009 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Lockhart, P. J.] Royal Childrens Hosp, Murdoch Childrens Res Inst, Bruce Lefroy Ctr Genet Hlth Res, Parkville, Vic 3052, Australia. [O'Farrell, C. A.] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA. [Hutton, M.] Merck Res Labs, Boston, MA 02115 USA. [Delatycki, M. B.; Lockhart, P. J.] Univ Melbourne, Royal Childrens Hosp, Dept Paediat, Parkville, Vic, Australia. [Cookson, M. R.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Lockhart, PJ (reprint author), Royal Childrens Hosp, Murdoch Childrens Res Inst, Bruce Lefroy Ctr Genet Hlth Res, 10th Floor,Flemington Rd, Parkville, Vic 3052, Australia. EM paul.lockhart@mcri.edu.au RI Delatycki, Martin/A-5409-2013; Lockhart, Paul/E-7753-2011 OI Lockhart, Paul/0000-0003-2531-8413 FU National Health & Medical Research Council (NHMRC Australia) [436976, 334346, 546452]; NIH FX This work was supported in part by National Health & Medical Research Council (NHMRC Australia) project grant #436976 (to PJL and MBD) and by the Intramural Research Program of the NIH, National Institute on Aging. PJL is an NHMRC RD Wright Fellow (Fellowship #334346) and MBD is an NHMRC Practitioner Fellow (Fellowship #546452). We thank our laboratory colleagues for helpful comments and assistance. NR 58 TC 11 Z9 11 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD DEC 15 PY 2009 VL 164 IS 3 BP 1127 EP 1137 DI 10.1016/j.neuroscience.2009.09.017 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 520NM UT WOS:000271852000022 PM 19761814 ER PT J AU Carol, H Lock, R Houghton, PJ Morton, CL Kolb, EA Gorlick, R Reynolds, CP Maris, JM Keir, ST Billups, CA Smith, MA AF Carol, Hernan Lock, Richard Houghton, Peter J. Morton, Christopher L. Kolb, E. Anders Gorlick, Richard Reynolds, C. Patrick Maris, John M. Keir, Stephen T. Billups, Catherine A. Smith, Malcolm A. TI Initial Testing (Stage 1) of the Kinesin Spindle Protein Inhibitor Ispinesib by the Pediatric Preclinical Testing Program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; ispinesib; preclinical testing ID PHASE-II; IN-VIVO; CANCER MODELS; AGENTS; EG5; CHEMOTHERAPY; THERAPIES; CARCINOMA; SB-715992; RECURRENT AB Background. Ispinesib is a highly specific inhibitor of kinesin spindle protein (KSP, HsEg5), a mitotic kinesin required for separation of the spindle poles. Here we report the activity of ispinesib against the in vitro and in vivo panels of the Pediatric Preclinical Testing Program (PPTP). Procedures. Ispinesib was tested against the PPTP in vitro panel cell lines at concentrations from 0.1 nM to 1 mu M and against the in vivo tumor panel xenografts by intraperitoneal administration (5 or 10 mg/kg) every 4 clays for 3 closes repeated at day 2]. Results. Ispinesib was highly potent against the PPTP's in vitro cell lines with a median IC(50) of 4.1 W. Ispinesib (10 mg/kg) induced unexplained toxicity in mice bearing osteosarcoma xenografts and exceeded the MTD in 12 of 40 non-osteosarcoma xenografts. Ispinesib induced significant tumor growth delay in 88% (23/26) of evaluable xenografts. Using a time to event measure of efficacy, ispinesib had intermediate and high levels of activity against 4 (24%) and 5 (26%) of the 19 evaluable solid tumor xenografts, respectively. Ispinesib induced maintained complete responses (CR) in a rhabdoid turner, a Wilms tumor and a Ewing sarcoma xenograft. Ispinesib (5 mg/kg) produced 2 complete and 2 partial responses among 6 evaluable xenografts in the ALL panel. The in vivo pattern of activity was distinctive from that previously reported for vincristine. Conclusions. Ispinesib demonstrated broad in vivo antitumor activity, including maintained complete responses for several xenografts, although with high toxicity rates at the doses studied. Pediatr Blood Cancer 2009;53:1255-1263. (C) 2009 Wiley-Liss, Inc. C1 [Lock, Richard] St Jude Childrens Hosp, Dept Mol Pharmacol, Memphis, TN 38105 USA. [Carol, Hernan; Lock, Richard] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Kolb, E. Anders; Gorlick, Richard] Childrens Hosp Montefiore, Bronx, NY USA. [Reynolds, C. Patrick] Univ So Calif, Dev Therapeut Program, USC CHLA Inst Pediat Clin Res, Los Angeles, CA USA. [Reynolds, C. Patrick] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Maris, John M.] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Houghton, PJ (reprint author), St Jude Childrens Hosp, Dept Mol Pharmacol, 332 N Lauderdale St, Memphis, TN 38105 USA. EM peter.houghton@stjude.org RI Houghton, Peter/E-3265-2011; Carol, Hernan/F-5750-2013; Lock, Richard/G-4253-2013; OI Carol, Hernan/0000-0002-9443-8032; Reynolds, C. Patrick/0000-0002-2827-8536 FU National Cancer Institute [NO1-CM42216, CA21765, CA108786] FX Grant sponsor: National Cancer Institute; Grant numbers: NO1-CM42216, CA21765, CA108786. NR 31 TC 20 Z9 21 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD DEC 15 PY 2009 VL 53 IS 7 BP 1255 EP 1263 DI 10.1002/pbc.22056 PG 9 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 513ZV UT WOS:000271363800016 PM 19554570 ER PT J AU Tang, TTT Yang, F Chen, BS Lu, Y Ji, YY Roche, KW Lu, B AF Tang, Tina Tze-Tsang Yang, Feng Chen, Bo-Shiun Lu, Yuan Ji, Yuanyuan Roche, Katherine W. Lu, Bai TI Dysbindin regulates hippocampal LTP by controlling NMDA receptor surface expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE glutamate receptor; schizophrenia; synaptic plasticity ID LONG-TERM POTENTIATION; LYSOSOME-RELATED ORGANELLES; SYNAPTIC PLASTICITY; SUBUNIT COMPOSITION; DIFFERENTIAL ROLES; SCHIZOPHRENIA; TRAFFICKING; SYNAPSES; NEURONS; DTNBP1 AB Abnormalities in NMDA receptor (NMDAR) function have been implicated in schizophrenia. Here, we show that dysbindin, a schizophrenia-susceptibility gene widely expressed in the forebrain, controls the surface expression of NMDARs in a subunit-specific manner. Imaging analyses revealed a marked increase in surface NR2A, but not NR2B, in hippocampal neurons derived from dysbindin-null mutant mice (Dys-/-). Exogenous expression of dysbindin reduced NR2A surface expression in both wild-type and Dys-/- neurons. Biotinylation experiments also revealed an increase in surface expression of endogenous NR2A in Dys-/- neurons. Disruption of the dysbindin gene dramatically increased NR2A-mediated synaptic currents, without affecting AMPA receptor currents, in hippocampal CA1 neurons. The Dys-/- hippocampal slices exhibited an enhanced LTP, whereas basal synaptic transmission, presynaptic properties, and LTD were normal. Thus, dysbindin controls hippocampal LTP by selective regulation of the surface expression of NR2A. These results reveal subunit-specific regulation of NMDARs by dysbindin, providing an unexpected link between these two proteins implicated in schizophrenia. C1 [Tang, Tina Tze-Tsang; Chen, Bo-Shiun; Roche, Katherine W.] NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. [Yang, Feng; Ji, Yuanyuan; Lu, Bai] NICHHD, Sect Neural Dev & Plast, NIH, Bethesda, MD 20892 USA. [Lu, Yuan; Lu, Bai] NIMH, Gene Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Tang, Tina Tze-Tsang] Univ Bristol, Sch Med Sci, Dept Anat, MRC,Ctr Synapt Plast, Bristol BS8 1TD, Avon, England. RP Roche, KW (reprint author), NINDS, Receptor Biol Sect, NIH, Bethesda, MD 20892 USA. EM rochek@ninds.nih.gov; bailu@mail.nih.gov RI Chen, Bo-Shiun/E-2736-2010; Yang, Feng/C-9530-2011; Lu, Bai/A-4018-2012; Chen, Bo-Shiun/H-4633-2012; yu, yan/C-2322-2012; OI Roche, Katherine/0000-0001-7282-6539 FU Intramural Research Programs of NINDS; National Institute of Mental Health FX We thank Dr. Stefano Vicini for GFP-NR2A and GFPNR2B cDNAs. We also thank the National Institute of Neurological Disorders and Stroke (NINDS) Light Imaging Facility (LIF). This work is supported by the Intramural Research Programs of NINDS and the National Institute of Mental Health. NR 43 TC 55 Z9 57 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 15 PY 2009 VL 106 IS 50 BP 21395 EP 21400 DI 10.1073/pnas.0910499106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533AW UT WOS:000272795300069 PM 19955431 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI The Retrovirology Open Access experience SO RETROVIROLOGY LA English DT Editorial Material AB The Retrovirology Open Access experience after publishing more than 500 articles is discussed. C1 NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM kjeang@niaid.nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 5 TC 1 Z9 1 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 15 PY 2009 VL 6 AR 115 DI 10.1186/1742-4690-6-115 PG 2 WC Virology SC Virology GA 539VE UT WOS:000273286000001 PM 20003491 ER PT J AU de Gonzalez, AB Mahesh, M Kim, KP Bhargavan, M Lewis, R Mettler, F Land, C AF de Gonzalez, Amy Berrington Mahesh, Mahadevappa Kim, Kwang-Pyo Bhargavan, Mythreyi Lewis, Rebecca Mettler, Fred Land, Charles TI Projected Cancer Risks From Computed Tomographic Scans Performed in the United States in 2007 SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CUMULATIVE RADIATION-EXPOSURE; IONIZING-RADIATION; POOLED ANALYSIS; CT; ANGIOGRAPHY AB Background: The use of computed tomographic (CT) scans in the United States (US) has increased more than 3-fold since 1993 to approximately 70 million scans annually. Despite the great medical benefits, there is concern about the potential radiation-related cancer risk. We conducted detailed estimates of the future cancer risks from current CT scan use in the US according to age, sex, and scan type. Methods: Risk models based on the National Research Council's "Biological Effects of Ionizing Radiation" report and organ-specific radiation doses derived from a national survey were used to estimate age-specific cancer risks for each scan type. These models were combined with age- and sex-specific scan frequencies for the US in 2007 obtained from survey and insurance claims data. We estimated the mean number of radiation-related incident cancers with 95% uncertainty limits (UL) using Monte Carlo simulations. Results: Overall, we estimated that approximately 29 000 (95% UL, 15 000-45 000) future cancers could be related to CT scans performed in the US in 2007. The largest contributions were from scans of the abdomen and pelvis (n=14000) (95% UL, 6900-25000), chest (n=4100) (95% UL, 1900-8100), and head (n=4000) (95% UL, 1100-8700), as well as from chest CT angiography (n = 2700) (95% UL, 1300-5000). One-third of the projected cancers were due to scans performed at the ages of 35 to 54 years compared with 15% due to scans performed at ages younger than 18 years, and 66% were in females.. Conclusions: These detailed estimates highlight several areas of CT scan use that make large contributions to the total cancer risk, including several scan types and age groups with a high frequency of use or scans involving relatively high doses, in which risk-reduction efforts may be warranted. C1 [de Gonzalez, Amy Berrington; Land, Charles] NCI, Radiat Epidemiol Branch, DCEG, Bethesda, MD 20892 USA. [Mahesh, Mahadevappa; Bhargavan, Mythreyi] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [Kim, Kwang-Pyo] Kyung Hee Univ, Dept Nucl Engn, Gyeonggi Do, South Korea. [Bhargavan, Mythreyi; Lewis, Rebecca] Amer Coll Radiol, Res Dept, Reston, VA USA. [Mettler, Fred] New Mexico Vet Adm Healthcare Syst, Dept Radiol & Nucl Med, Albuquerque, NM USA. RP de Gonzalez, AB (reprint author), NCI, Radiat Epidemiol Branch, DCEG, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM berringtona@mail.nih.gov FU Siemens Medical Systems, Malvern, Pennsylvania FX Dr Maliesh has received funding from Siemens Medical Systems, Malvern, Pennsylvania. NR 39 TC 481 Z9 484 U1 3 U2 23 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9926 EI 1538-3679 J9 ARCH INTERN MED JI Arch. Intern. Med. PD DEC 14 PY 2009 VL 169 IS 22 BP 2071 EP 2077 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 530XJ UT WOS:000272625800005 ER PT J AU Smith-Bindman, R Lipson, J Marcus, R Kim, KP Mahesh, M Gould, R de Gonzalez, AB Miglioretti, DL AF Smith-Bindman, Rebecca Lipson, Jafi Marcus, Ralph Kim, Kwang-Pyo Mahesh, Mahadevappa Gould, Robert de Gonzalez, Amy Berrington Miglioretti, Diana L. TI Radiation Dose Associated With Common Computed Tomography Examinations and the Associated Lifetime Attributable Risk of Cancer SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID ATOMIC-BOMB SURVIVORS; CORONARY-ANGIOGRAPHY; CT ANGIOGRAPHY; EXPOSURE; REDUCTION; UK AB Background: Use of computed tomography (CT) for diagnostic evaluation has increased dramatically over the past 2 decades. Even though CT is associated with substantially higher radiation exposure than conventional radiography, typical doses are not known. We sought to estimate the radiation dose associated with common CT studies in clinical practice and quantify the potential cancer risk associated with these examinations. Methods: We conducted a retrospective cross-sectional study describing radiation dose associated with the I I most common types of diagnostic CT studies performed on 1119 consecutive adult patients at 4 San Francisco Bay Area institutions in California between January I and May 30, 2008. We estimated lifetime attributable risks of cancer by study type from these measured doses. Results: Radiation doses varied significantly between the different types of CT studies. The overall median effective doses ranged from 2 millisieverts (mSv) for a routine he-ad CT scan to 31 mSv for a multiphase abdomen and pelvis CT scan. Within each type of CT study, effective dose varied significantly within and across institutions, with a mean 13-fold variation between the highest and lowest dose for each study type. The estimated number of CT scans that will lead to the development of a cancer varied widely depending on the specific type of CT examination and the patient's age and sex. An estimated I in 270 women who underwent CT coronary angiography at age 40 years will develop cancer from that CT scan (I in 600 men), compared with an estimated I in 8100 women who had a routine head CT scan at the same age (I in 11080 men). For 20-year-old patients, the risks were approximately doubled, and for 60-year-old patients, they were approximately 50% lower. Conclusion: Radiation doses from commonly performed diagnostic CT examinations are higher and more variable than generally quoted, highlighting the need for greater standardization across institutions. C1 [Smith-Bindman, Rebecca; Lipson, Jafi; Gould, Robert] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94115 USA. [Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94115 USA. [Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Obstet Gynecol & Reprod Sci, San Francisco, CA 94115 USA. [Marcus, Ralph] Univ Calif San Francisco, Sch Med, San Francisco, CA 94115 USA. [Kim, Kwang-Pyo] Kyung Hee Univ, Dept Nucl Engn, Gyeonggi Do, South Korea. [Mahesh, Mahadevappa] Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD USA. [de Gonzalez, Amy Berrington] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Miglioretti, Diana L.] Univ Washington, Grp Hlth Res Inst, Grp Hlth Cooperat, Seattle, WA 98195 USA. [Miglioretti, Diana L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Smith-Bindman, Rebecca; Lipson, Jafi; Gould, Robert] Univ Calif San Francisco, Dept Biomed Imaging, San Francisco, CA 94115 USA. RP Smith-Bindman, R (reprint author), Univ Calif San Francisco, Dept Radiol, 350 Parnassus Ave,Ste 307, San Francisco, CA 94115 USA. EM rebecca.smith-bindman@radiology.ucsf.edu FU National Institutes of Health (NIH) National Institute of Biomedical Imaging and BioEngineering [T32 EB001631]; NIH National Cancer Institute [CA125036, CA 131698]; UCSF School of Medicine Bridge Funding Program FX This study was funded by the National Institutes of Health (NIH) National Institute of Biomedical Imaging and BioEngineering training grant T32 EB001631, NIH National Cancer Institute grants CA125036 and CA 131698, and the UCSF School of Medicine Bridge Funding Program. NR 37 TC 922 Z9 941 U1 6 U2 49 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD DEC 14 PY 2009 VL 169 IS 22 BP 2078 EP 2086 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 530XJ UT WOS:000272625800006 PM 20008690 ER PT J AU Poliakov, E Gentleman, S Chander, P Cunningham, FX Grigorenko, BL Nemuhin, AV Redmond, TM AF Poliakov, Eugenia Gentleman, Susan Chander, Preethi Cunningham, Francis X., Jr. Grigorenko, Bella L. Nemuhin, Alexander V. Redmond, T. Michael TI Biochemical evidence for the tyrosine involvement in cationic intermediate stabilization in mouse beta-carotene 15, 15 '-monooxygenase SO BMC BIOCHEMISTRY LA English DT Article ID SQUALENE-HOPENE CYCLASES; FUNCTIONAL-ANALYSIS; REACTION-MECHANISM; VISUAL CYCLE; CATALYTIC MECHANISM; OXIDATIVE CLEAVAGE; MOLECULAR ANALYSIS; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; PI INTERACTIONS AB Background: beta-carotene 15,15'-monooxygenase (BCMO1) catalyzes the crucial first step in vitamin A biosynthesis in animals. We wished to explore the possibility that a carbocation intermediate is formed during the cleavage reaction of BCMO1, as is seen for many isoprenoid biosynthesis enzymes, and to determine which residues in the substrate binding cleft are necessary for catalytic and substrate binding activity. To test this hypothesis, we replaced substrate cleft aromatic and acidic residues by site-directed mutagenesis. Enzymatic activity was measured in vitro using His-tag purified proteins and in vivo in a beta-carotene-accumulating E. coli system. Results: Our assays show that mutation of either Y235 or Y326 to leucine (no cation-pi stabilization) significantly impairs the catalytic activity of the enzyme. Moreover, mutation of Y326 to glutamine (predicted to destabilize a putative carbocation) almost eliminates activity (9.3% of wt activity). However, replacement of these same tyrosines with phenylalanine or tryptophan does not significantly impair activity, indicating that aromaticity at these residues is crucial. Mutations of two other aromatic residues in the binding cleft of BCMO1, F51 and W454, to either another aromatic residue or to leucine do not influence the catalytic activity of the enzyme. Our ab initio model of BCMO1 with beta-carotene mounted supports a mechanism involving cation-pi stabilization by Y235 and Y326. Conclusions: Our data are consistent with the formation of a substrate carbocation intermediate and cation-pi stabilization of this intermediate by two aromatic residues in the substrate-binding cleft of BCMO1. C1 [Poliakov, Eugenia; Gentleman, Susan; Chander, Preethi; Redmond, T. Michael] NEI, NIH, Bethesda, MD 20892 USA. [Cunningham, Francis X., Jr.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Grigorenko, Bella L.; Nemuhin, Alexander V.] Moscow MV Lomonosov State Univ, Dept Chem, Moscow, Russia. RP Redmond, TM (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM poliakove@nei.nih.gov; sgman@helix.nih.gov; chanderp@nei.nih.gov; BuddyX@umd.edu; anem@lcc.chem.msu.ru; nemukhin@ncisgi.ncifcrf.gov; redmond@helix.nih.gov RI Nemukhin, Alexander/P-9662-2015; OI Redmond, T. Michael/0000-0002-1813-5291 FU National Eye Institute, NIH FX The authors gratefully recognize the contribution of Dr. J. Von Lintig to the bacterial BCMO1 expression system. EP thanks Dr. Murali C. Krishna for EPR analyses. This work was supported by the Intramural Research Program of the National Eye Institute, NIH. NR 63 TC 11 Z9 15 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2091 J9 BMC BIOCHEM JI BMC Boichem. PD DEC 14 PY 2009 VL 10 AR 31 DI 10.1186/1471-2091-10-31 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 540JU UT WOS:000273328300001 PM 20003456 ER PT J AU Hall, KD AF Hall, Kevin D. TI The energy cost of protein turnover is arbitrarily distributed between maintenance requirements and protein retention efficiency - Comments by Hall SO BRITISH JOURNAL OF NUTRITION LA English DT Editorial Material ID GROWING PIGS; FAT; DEPOSITION; OBESITY; MODEL C1 NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. RP Hall, KD (reprint author), NIDDK, Lab Biol Modeling, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov RI Hall, Kevin/F-2383-2010 NR 11 TC 3 Z9 3 U1 0 U2 2 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 0007-1145 J9 BRIT J NUTR JI Br. J. Nutr. PD DEC 14 PY 2009 VL 102 IS 11 BP 1695 EP 1696 DI 10.1017/S0007114509991905 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 532QM UT WOS:000272764500020 PM 19967793 ER PT J AU Parameswar, AR Park, IH Saksena, R Kovac, P Nahm, MH Demchenko, AV AF Parameswar, Archana R. Park, In Ho Saksena, Rina Kovac, Pavol Nahm, Moon H. Demchenko, Alexei V. TI Synthesis, Conjugation, and Immunological Evaluation of the Serogroup 6 Pneumococcal Oligosaccharides SO CHEMBIOCHEM LA English DT Article DE carbohydrates; glycoconjugates; oligosaccharides; Streptococcus pneumoniae; synthetic vaccines ID STREPTOCOCCUS-PNEUMONIAE TYPE-6A; CAPSULAR POLYSACCHARIDE; SEROTYPES 6A; GROUP MIGRATION; VACCINES; ANTIBODIES; GLYCOSIDES; VIRULENCE; PROTEIN; MICE AB The first synthesis of the newly discovered oligosaccharide of pneumococcal serotype 6C and its spacer-containing analogue is reported. Conjugation of the spacer-containing oligosaccharides of pneumococcal saccharides 6A, 6B, 6C and derivatives thereof with bovine serum albumin (BSA) protein carrier was carried out by using squaric-acid approach to obtain the oligosaccharide-protein conjugates in excellent yields. The conjugates have been tested with a rabbit antiserum pool (Pool B) used for pneumococcal serotyping. The results showed that synthetic carbohydrate conjugates express epitopes found in native capsular polysaccharides of serotypes 6A, 6B, and 6C. C1 [Parameswar, Archana R.; Demchenko, Alexei V.] Univ Missouri, Dept Chem & Biochem, St Louis, MO 63121 USA. [Park, In Ho; Nahm, Moon H.] Univ Alabama, Dept Pathol, Birmingham, AL 35294 USA. [Park, In Ho; Nahm, Moon H.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. [Saksena, Rina; Kovac, Pavol] NIDDK, LBC, NIH, Bethesda, MD 20892 USA. RP Demchenko, AV (reprint author), Univ Missouri, Dept Chem & Biochem, 1 Univ Blvd, St Louis, MO 63121 USA. EM demchenkoa@umsl.edu RI Kovac, Pavol/B-8813-2008; OI Kovac, Pavol/0000-0001-5044-3449; Nahm, Moon/0000-0002-6922-1042; Demchenko, Alexei/0000-0003-3515-212X FU NSF [CHE-0547566]; NIH [Al-067494, Al-031473, Al-30021] FX The work was supported with NSF (CHE-0547566) and NIH awards (Al-067494) to A. VD. and NIH funds (Al-031473, Al-30021) to M.H.N. NR 44 TC 11 Z9 11 U1 4 U2 11 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1439-4227 J9 CHEMBIOCHEM JI ChemBioChem PD DEC 14 PY 2009 VL 10 IS 18 BP 2893 EP 2899 DI 10.1002/cbic.200900587 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 538CF UT WOS:000273161000012 PM 19856369 ER PT J AU Meaburn, KJ Gudla, PR Khan, S Lockett, SJ Misteli, T AF Meaburn, Karen J. Gudla, Prabhakar R. Khan, Sameena Lockett, Stephen J. Misteli, Tom TI Disease-specific gene repositioning in breast cancer SO JOURNAL OF CELL BIOLOGY LA English DT Article ID FINE-NEEDLE-ASPIRATION; EWING SARCOMA-CELLS; GENOME ORGANIZATION; CHROMOSOME-22 TERRITORIES; NUCLEAR ARCHITECTURE; X-CHROMOSOME; BIOPSY; LOCI; DIFFERENTIATION; TRANSCRIPTION AB Genomes are nonrandomly organized within the three-dimensional space of the cell nucleus. Here, we have identified several genes whose nuclear positions are altered in human invasive breast cancer compared with normal breast tissue. The changes in positioning are gene specific and are not a reflection of genomic instability within the cancer tissue. Repositioning events are specific to cancer and do not generally occur in noncancerous breast disease. Moreover, we show that the spatial positions of genes are highly consistent between individuals. Our data indicate that cancer cells have disease-specific gene distributions. These interphase gene positioning patterns may be used to identify cancer tissues. C1 [Meaburn, Karen J.; Khan, Sameena; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Gudla, Prabhakar R.; Lockett, Stephen J.] Sci Applicat Int Corp Frederick Inc, Opt Microscopy & Anal Lab, Adv Technol Program, Frederick, MD 21702 USA. [Gudla, Prabhakar R.; Lockett, Stephen J.] NCI, Frederick, MD 21702 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov OI Meaburn, Karen/0000-0002-1327-5957 FU National Institutes of Health, National Cancer Institute, Center for Cancer Research; National Cancer Institute, National Institutes of Health [HHSN261200800001E]; Department of Defense [BC073689] FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and with federal funds from the National Cancer Institute, National Institutes of Health, under Contract HHSN261200800001E. K. J. Meaburn was supported by an Idea Award from the Department of Defense (BC073689). NR 33 TC 50 Z9 55 U1 2 U2 6 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD DEC 14 PY 2009 VL 187 IS 6 BP 801 EP 812 DI 10.1083/jcb.200909127 PG 12 WC Cell Biology SC Cell Biology GA 531WJ UT WOS:000272702500008 PM 19995938 ER PT J AU Polevoy, G Wei, HC Wong, R Szentpetery, Z Kim, YJ Goldbach, P Steinbach, SK Balla, T Brill, JA AF Polevoy, Gordon Wei, Ho-Chun Wong, Raymond Szentpetery, Zsofia Kim, Yeun Ju Goldbach, Philip Steinbach, Sarah K. Balla, Tamas Brill, Julie A. TI Dual roles for the Drosophila PI 4-kinase Four wheel drive in localizing Rab11 during cytokinesis SO JOURNAL OF CELL BIOLOGY LA English DT Article ID NEURONAL CALCIUM SENSOR-1; PHOSPHATIDYLINOSITOL 4-KINASE; CLEAVAGE-FURROW; GOLGI-COMPLEX; SCHIZOSACCHAROMYCES-POMBE; MICROTUBULE ORGANIZATION; MEMBRANE TRAFFICKING; ACTIN CYTOSKELETON; TRANSFER PROTEINS; CONTRACTILE RING AB Successful completion of cytokinesis relies on addition of new membrane, and requires the recycling endosome regulator Rab11, which localizes to the midzone. Despite the critical role of Rab11 in this process, little is known about the formation and composition of Rab11-containing organelles. Here, we identify the phosphatidylinositol (PI) 4-kinase III beta Four wheel drive (Fwd) as a key regulator of Rab11 during cytokinesis in Drosophila melanogaster spermatocytes. We show Fwd is required for synthesis of PI 4-phosphate (PI4P) on Golgi membranes and for formation of PI4P-containing secretory organelles that localize to the midzone. Fwd binds and colocalizes with Rab11 on Golgi membranes, and is required for localization of Rab11 in dividing cells. A kinase-dead version of Fwd also binds Rab11 and partially restores cytokinesis to fwd mutant flies. Moreover, activated Rab11 partially suppresses loss of fwd. Our data suggest Fwd plays catalytic and noncatalytic roles in regulating Rab11 during cytokinesis. C1 [Polevoy, Gordon; Wei, Ho-Chun; Wong, Raymond; Goldbach, Philip; Steinbach, Sarah K.; Brill, Julie A.] Hosp Sick Children, Program Dev & Stem Cell Biol, Toronto, ON M5G 1L7, Canada. [Wong, Raymond; Brill, Julie A.] Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A8, Canada. [Goldbach, Philip; Brill, Julie A.] Univ Toronto, Dept Mol Genet, Toronto, ON M5S 1A8, Canada. [Szentpetery, Zsofia; Kim, Yeun Ju; Balla, Tamas] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Signal Transduct, Program Dev Neurosci, NIH, Bethesda, MD 20847 USA. RP Brill, JA (reprint author), Hosp Sick Children, Program Dev & Stem Cell Biol, Toronto, ON M5G 1L7, Canada. EM julie.brill@sickkids.ca OI Balla, Tamas/0000-0002-9077-3335; Brill, Julie/0000-0002-5925-9901 FU SickKids Restracomp awards; Ontario Graduate Scholarship; National Institutes of Health; Terry Fox Foundation [16425]; Canadian Institutes of Health Research Institute of Genetics [IG1-93477] FX We are grateful for SickKids Restracomp awards (to H.- C. Wei and R. Wong), an Ontario Graduate Scholarship (to R. Wong), the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (to T. Balla, Z. Szentpetery, and Y. J. Kim), and grants from the Terry Fox Foundation (National Cancer Institute of Canada # 16425) and the Canadian Institutes of Health Research Institute of Genetics (# IG1-93477) (to J. A. Brill). The authors declare no competing interests. NR 77 TC 55 Z9 55 U1 1 U2 7 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD DEC 14 PY 2009 VL 187 IS 6 BP 847 EP 858 DI 10.1083/jcb.200908107 PG 12 WC Cell Biology SC Cell Biology GA 531WJ UT WOS:000272702500011 PM 19995935 ER PT J AU Schulz, TA Choi, MG Raychaudhuri, S Mears, JA Ghirlando, R Hinshaw, JE Prinz, WA AF Schulz, Timothy A. Choi, Mal-Gi Raychaudhuri, Sumana Mears, Jason A. Ghirlando, Rodolfo Hinshaw, Jenny E. Prinz, William A. TI Lipid-regulated sterol transfer between closely apposed membranes by oxysterol-binding protein homologues SO JOURNAL OF CELL BIOLOGY LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; PLASMA-MEMBRANE; ENDOPLASMIC-RETICULUM; ANALYTICAL ULTRACENTRIFUGATION; GOLGI STRUCTURE; CONTACT SITES; TRANSPORT; CHOLESTEROL; METABOLISM; TRAFFICKING AB Sterols are transferred between cellular membranes by vesicular and poorly understood nonvesicular pathways. Oxysterol-binding protein-related proteins (ORPs) have been implicated in sterol sensing and nonvesicular transport. In this study, we show that yeast ORPs use a novel mechanism that allows regulated sterol transfer between closely apposed membranes, such as organelle contact sites. We find that the core lipid-binding domain found in all ORPs can simultaneously bind two membranes. Using Osh4p/Kes1p as a representative ORP, we show that ORPs have at least two membrane-binding surfaces; one near the mouth of the sterol-binding pocket and a distal site that can bind a second membrane. The distal site is required for the protein to function in cells and, remarkably, regulates the rate at which Osh4p extracts and delivers sterols in a phosphoinositide-dependent manner. Together, these findings suggest a new model of how ORPs could sense and regulate the lipid composition of adjacent membranes. C1 [Schulz, Timothy A.; Choi, Mal-Gi; Raychaudhuri, Sumana; Mears, Jason A.; Hinshaw, Jenny E.; Prinz, William A.] NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Prinz, WA (reprint author), NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. EM wprinz@helix.nih.gov RI Ghirlando, Rodolfo/A-8880-2009; OI Raychaudhuri, Sumana/0000-0002-3164-0057 FU National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 51 TC 95 Z9 98 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD DEC 14 PY 2009 VL 187 IS 6 BP 889 EP 903 DI 10.1083/jcb.200905007 PG 15 WC Cell Biology SC Cell Biology GA 531WJ UT WOS:000272702500014 PM 20008566 ER PT J AU Berezhkovskii, AM Barzykin, AV Zitserman, VY AF Berezhkovskii, Alexander M. Barzykin, Alexander V. Zitserman, Vladimir Yu. TI One-dimensional description of diffusion in a tube of abruptly changing diameter: Boundary homogenization based approach SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article DE diffusion; kinetic theory; particle traps; pipes ID DENDRITIC SPINES; CALCIUM DYNAMICS; CROSS-SECTION; NARROW ESCAPE AB Reduction of three-dimensional (3D) description of diffusion in a tube of variable cross section to an approximate one-dimensional (1D) description has been studied in detail previously only in tubes of slowly varying diameter. Here we discuss an effective 1D description in the opposite limiting case when the tube diameter changes abruptly, i.e., in a tube composed of any number of cylindrical sections of different diameters. The key step of our approach is an approximate description of the particle transitions between the wide and narrow parts of the tube as trapping by partially absorbing boundaries with appropriately chosen trapping rates. Boundary homogenization is used to determine the trapping rate for transitions from the wide part of the tube to the narrow one. This trapping rate is then used in combination with the condition of detailed balance to find the trapping rate for transitions in the opposite direction, from the narrow part of the tube to the wide one. Comparison with numerical solution of the 3D diffusion equation allows us to test the approximate 1D description and to establish the conditions of its applicability. We find that suggested 1D description works quite well when the wide part of the tube is not too short, whereas the length of the narrow part can be arbitrary. Taking advantage of this description in the problem of escape of diffusing particle from a cylindrical cavity through a cylindrical tunnel we can lift restricting assumptions accepted in earlier theories: We can consider the particle motion in the tunnel and in the cavity on an equal footing, i.e., we can relax the assumption of fast intracavity relaxation used in all earlier theories. As a consequence, the dependence of the escape kinetics on the particle initial position in the system can be analyzed. Moreover, using the 1D description we can analyze the escape kinetics at an arbitrary tunnel radius, whereas all earlier theories are based on the assumption that the tunnel is narrow. C1 [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Barzykin, Alexander V.] Royal Bank Scotland, London EC2M 4AA, England. [Zitserman, Vladimir Yu.] Russian Acad Sci, Joint Inst High Temp, Moscow 125412, Russia. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bldg 10, Bethesda, MD 20892 USA. EM berezh@helix.nih.gov FU NIH, Center for Information Technology FX A. M. B. was supported by the Intramural Research Program of the NIH, Center for Information Technology. NR 34 TC 25 Z9 25 U1 0 U2 4 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 14 PY 2009 VL 131 IS 22 AR 224110 DI 10.1063/1.3271998 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 533DO UT WOS:000272803000015 PM 20001027 ER PT J AU Knight, HM Pickard, BS Maclean, A Malloy, MP Soares, DC Mcrae, AF Condie, A White, A Hawkins, W McGhee, K van Beck, M MacIntyre, DJ Starr, JM Deary, IJ Visscher, PM Porteous, DJ Cannon, RE St Clair, D Muir, WJ Blackwood, DHR AF Knight, Helen M. Pickard, Benjamin S. Maclean, Alan Malloy, Mary P. Soares, Dinesh C. McRae, Allan F. Condie, Alison White, Angela Hawkins, William McGhee, Kevin van Beck, Margaret MacIntyre, Donald J. Starr, John M. Deary, Ian J. Visscher, Peter M. Porteous, David J. Cannon, Ronald E. St Clair, David Muir, Walter J. Blackwood, Douglas H. R. TI A Cytogenetic Abnormality and Rare Coding Variants Identify ABCA13 as a Candidate Gene in Schizophrenia, Bipolar Disorder, and Depression SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; POSTMORTEM ORBITOFRONTAL CORTEX; GLUTAMATE-RECEPTOR GENE; FATTY-ACIDS; COMMON DISEASES; ATP HYDROLYSIS; PROTEIN; TRANSPORTER; PREDICTION; FAMILY AB Schizophrenia and bipolar disorder are leading causes of morbidity across all Populations, with heritability estimates of similar to 80% indicating a substantial genetic component. Population genetics and genome-wide association studies Suggest an overlap of genetic risk factors between these illnesses but it is unclear how this genetic component is divided between common gene polymorphisms, rare genomic copy number variants, and rare gene sequence mutations. We report evidence that the lipid transporter gene ABCA13 is a susceptibility factor for both schizophrenia and bipolar disorder. After the initial discovery of its disruption by a chromosome abnormality in a person with schizophrenia, we resequenced ABCA13 exons in 100 cases with schizophrenia and 100 controls. Multiple rare coding variants were identified including one nonsense and nine missense mutations and compound heterozygosity/homozygosity in six cases. Variants were genotyped in additional schizophrenia, bipolar, depression (n > 1600), and control (n > 950) cohorts and the frequency of all rare variants combined was greater than controls in schizophrenia (OR = 1.93, p = 0.0057) and bipolar disorder (OR = 2.71, p = 0.00007). The population attributable risk of these mutations was 2.2% for schizophrenia and 4.0% for bipolar disorder. In a Study of 21 families of mutation carriers, we genotyped affected and unaffected relatives and found significant linkage (LOD = 4.3) of rare variants with a phenotype including schizophrenia, bipolar disorder, and major depression. These data identify a candidate gene, highlight the genetic overlap between schizophrenia, bipolar disorder, and depression, and suggest that rare coding variants may contribute significantly to risk of these disorders. C1 [Knight, Helen M.; Maclean, Alan; Malloy, Mary P.; McGhee, Kevin; van Beck, Margaret; MacIntyre, Donald J.; Muir, Walter J.; Blackwood, Douglas H. R.] Univ Edinburgh, Royal Edinburgh Hosp, Div Psychiat, Edinburgh EH10 5HF, Midlothian, Scotland. [McRae, Allan F.; Visscher, Peter M.] Queensland Inst Med Res, Brisbane, Qld 4006, Australia. [Condie, Alison; White, Angela; Hawkins, William] Western Gen Hosp, Wellcome Trust Clin Res Facil, Edinburgh EH4 2XU, Midlothian, Scotland. [Starr, John M.] Univ Edinburgh, Ctr Cognit Ageing & Cognit Epidemiol, Geriatr Med Unit, Royal Victoria Hosp, Edinburgh EH4 2DN, Midlothian, Scotland. [Knight, Helen M.; Pickard, Benjamin S.; Maclean, Alan; Malloy, Mary P.; Soares, Dinesh C.; McGhee, Kevin; Porteous, David J.; Muir, Walter J.; Blackwood, Douglas H. R.] Univ Edinburgh, Western Gen Hosp, Inst Genet & Mol Med, Mol Med Ctr, Edinburgh EH4 2XU, Midlothian, Scotland. [Deary, Ian J.] Univ Edinburgh, Dept Psychol, Ctr Cognit Ageing & Cognit Epidemiol, Edinburgh EH8 9JZ, Midlothian, Scotland. [Cannon, Ronald E.] NIEHS, Canc Biol Grp, Natl Ctr Toxicogen, Res Triangle Pk, NC 27709 USA. [St Clair, David] Univ Aberdeen, Inst Med Sci, Aberdeen AB25 2ZD, Scotland. RP Pickard, BS (reprint author), Univ Strathclyde, Strathclyde Inst Pharm & Biomed Sci, John Arbuthnott Bldg,27 Taylor St, Glasgow G4 0NR, Lanark, Scotland. EM benjamin.pickard@strath.ac.uk RI Starr, John/C-8951-2011; Soares, Dinesh/A-4425-2012; Deary, Ian/C-6297-2009; Porteous, David/C-7289-2013; McRae, Allan/J-2644-2014; Pickard, Benjamin/K-3923-2014; OI Soares, Dinesh/0000-0001-7557-0495; Visscher, Peter/0000-0002-2143-8760; Porteous, David/0000-0003-1249-6106; McRae, Allan/0000-0001-5286-5485; Pickard, Benjamin/0000-0002-2374-6329; MacIntyre, Donald J/0000-0001-6963-1335 FU Biotechnology and Biological Sciences Research Council; Chief Scientist Office [CZB/4/498]; Medical Research Council [, G0100266, G0900627]; Wellcome Trust NR 81 TC 60 Z9 62 U1 0 U2 6 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 11 PY 2009 VL 85 IS 6 BP 833 EP 846 DI 10.1016/j.ajhg.2009.11.003 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 533BN UT WOS:000272797100007 PM 19944402 ER PT J AU Volkening, K Leystra-Lantz, C Yang, WC Jaffee, H Strong, MJ AF Volkening, Kathryn Leystra-Lantz, Cheryl Yang, Wenchang Jaffee, Howard Strong, Michael J. TI Tar DNA binding protein of 43 kDa (TDP-43), 14-3-3 proteins and copper/zinc superoxide dismutase (SOD1) interact to modulate NFL mRNA stability. Implications for altered RNA processing in amyotrophic lateral sclerosis (ALS) SO BRAIN RESEARCH LA English DT Article DE TDP-43; 14-3-3; Copper/zinc superoxide dismutase 1 (SOD1); Amyotrophic lateral sclerosis; RNA binding protein ID FRONTOTEMPORAL LOBAR DEGENERATION; MAMMALIAN STRESS GRANULES; MOTOR-NEURON DISEASE; DESTABILIZING ELEMENT; NEUROFILAMENT LIGHT; NUCLEAR IMPORT; ALDOLASE-C; TRANSPORT; STAUFEN; BODIES AB Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease characterized by progressive motor neuron degeneration in association with neurofilament (NF) aggregate formation. This process is accompanied by an alteration in the stoichiometry of NF subunit protein expression such that the steady state levels of the low molecular weight NF (NFL) mRNA levels are selectively suppressed. We have previously shown that each of TDP-43, 14-3-3 and mutant SOD1 can function as NFL mRNA 3'UTR binding proteins that directly affect the stability of NFL transcripts. in this study, we demonstrate that the interaction of TDP-43 with the NFL mRNA 3' UTR involves ribonucleotide (UG) motifs present on stem loops of the 3'UTR as well as the RRM1 and RRM2 motifs of TDP-43. Ex vivo, TDP-43, 14-3-3 and SOD1 proteins interact to modulate NFL mRNA stability, although in vivo, only TDP-43 and either mutant or wild-type SOD1 co-localize in ALS motor neurons. TDP-43 was observed to co-localize to RNA transport granules (Staufen immunoreactive) in both control and ALS spinal motor neurons. In contrast, both stress granules (TIA-1 immunoreactive) and processing bodies (P-bodies; XRN-1 immunoreactive) were more prevalent in ALS motor neurons than in controls and demonstrated strong co-localization with TDP-43. Using RNA-IP-PCR, we further demonstrate that NFL mRNA is preferentially sequestered to both stress granules and P-bodies in ALS. These data suggest that NFL mRNA processing is fundamentally altered in ALS spinal motor neurons to favour compartmentalization within both stress granules and P-bodies, and that TDP-43 plays a fundamental role in this process. (C) 2009 Elsevier B.V. All rights reserved. C1 [Volkening, Kathryn; Leystra-Lantz, Cheryl; Yang, Wenchang; Strong, Michael J.] John P Robarts Res Inst, Mol Brain Res Grp, London, ON N6A 5K8, Canada. [Jaffee, Howard] NINDS, Prot Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. [Strong, Michael J.] Univ Western Ontario, Dept Clin Neurol Sci, London, ON N6A 5A5, Canada. RP Strong, MJ (reprint author), Univ Western Ontario, Univ Hosp, London Hlth Sci Ctr, Room C7-120,339 Windermere Rd, London, ON N6A 5A5, Canada. EM mstrong@uwo.ca RI Strong, Michael/H-9689-2012 FU Canadian Institute of Health Research (CIHR); Michael Halls' Endowment Fund FX This research was funded by the Canadian Institute of Health Research (CIHR) and the Michael Halls' Endowment Fund. NR 52 TC 92 Z9 94 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD DEC 11 PY 2009 VL 1305 BP 168 EP 182 DI 10.1016/j.brainres.2009.09.105 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 538EQ UT WOS:000273167500017 PM 19815002 ER PT J AU Newman, JD Kenkel, WM Aronoff, EC Bock, NA Zametkin, MR Silva, AC AF Newman, John D. Kenkel, William M. Aronoff, Emily C. Bock, Nicholas A. Zametkin, Molly R. Silva, Afonso C. TI A combined histological and MRI brain atlas of the common marmoset monkey, Callithrix jacchus SO BRAIN RESEARCH REVIEWS LA English DT Review DE Primate neuroanatomy; Callitrichidae; Female; Forebrain; Thalamus; Midbrain; Brainstem; Magnetic resonance imaging ID VISUAL AREA; CORTEX; EXPRESSION; PRIMATE; CONNECTIONS; MODEL AB The common marmoset, Callithrix jacchus, is of growing importance for research in neuroscience and related fields. In the present work, we describe a combined histological and magnetic resonance imaging (MRI) atlas constructed from the brains of two adult female marmosets Histological sections were processed from Nissl staining and digitized to produce an atlas in a large format that facilitates visualization of structures with significant detail Naming of identifiable brain structures was performed utilizing current terminology The histological sections and a simplified schematic atlas are available online at http//udn nichd nih.gov/brainatlas_home html. Published by Elsevier B V C1 [Newman, John D.; Kenkel, William M.; Aronoff, Emily C.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Dev Neuroethol, Lab Comparat Ethol, Poolesville, MD 20837 USA. [Bock, Nicholas A.; Silva, Afonso C.] NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. [Zametkin, Molly R.] NIMH, Nonhuman Primate Res Core, Intramural Res Program, Poolesville, MD 20837 USA. RP Newman, JD (reprint author), Box 529, Poolesville, MD 20837 USA. RI Silva, Afonso/A-7129-2009 FU NIH; NICHD; NINDS FX The authors wish to thank Ms. Julie Mackel and Ms Deborah Bernhards for technical assistance. This research was supported by the Intramural Research Program of the NIH, NICHD, and NINDS NR 41 TC 30 Z9 31 U1 1 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0173 J9 BRAIN RES REV JI Brain Res. Rev. PD DEC 11 PY 2009 VL 62 IS 1 BP 1 EP 18 DI 10.1016/j.brainresrev.2009.09.001 PG 18 WC Neurosciences SC Neurosciences & Neurology GA 534TJ UT WOS:000272919900001 PM 19744521 ER PT J AU Benca, R Duncan, MJ Frank, E McClung, C Nelson, RJ Vicentic, A AF Benca, Ruth Duncan, Marilyn J. Frank, Ellen McClung, Colleen Nelson, Randy J. Vicentic, Aleksandra TI Biological rhythms, higher brain function, and behavior: Gaps, opportunities, and challenges SO BRAIN RESEARCH REVIEWS LA English DT Review ID NIGHT-EATING SYNDROME; TOTAL SLEEP-DEPRIVATION; BIPOLAR-I-DISORDER; SEROTONIN TRANSPORTER GENE; MILD COGNITIVE IMPAIRMENT; WHITE-CROWNED SPARROW; CIRCADIAN CLOCK GENE; LOCUS-COERULEUS; LIGHT THERAPY; SLOW WAVES AB Increasing evidence suggests that disrupted temporal organization impairs behavior, cognition, and affect, further, disruption of circadian clock genes impairs sleep-wake cycle and social rhythms which may be implicated in mental disorders. Despite this strong evidence, a gap in understanding the neural mechanisms of this interaction obscures whether biological rhythms disturbances are the underlying causes or merely symptoms of mental disorder. Here, we review current understanding, emerging concepts, gaps, and opportunities pertinent to (1) the neurobiology of the interactions between circadian oscillators and the neural circuits subserving higher brain function and behaviors of relevance to mental health, (2) the most promising approaches to determine how biological rhythms regulate brain function and behavior under normal and pathological conditions, (3) the gaps and challenges to advancing knowledge on the link between disrupted circadian rhythms/sleep and psychiatric disorders, and (4) the novel strategies for translation of basic science discoveries in circadian biology to clinical settings to define risk, prevent or delay onset of mental illnesses, design diagnostic tools, and propose new therapeutic strategies. The review is organized around five themes pertinent to (1) the impact of molecular clocks on physiology and behavior, (2) the interactions between circadian signals and cognitive functions, (3) the interface of circadian rhythms with sleep, (4) a clinical perspective on the relationship between circadian rhythm abnormalities and affective disorders, and (5) the pre-clinical models of circadian rhythm abnormalities and mood disorders Published by Elsevier B V C1 [Vicentic, Aleksandra] NIMH, Div Neurosci & Basic Behav Sci, Rockville, MD 20892 USA. [Benca, Ruth] Univ Wisconsin, Dept Psychiat & Psychol, Madison, WI 53792 USA. [Duncan, Marilyn J.] Univ Kentucky, Med Ctr, Dept Anat & Neurobiol, Lexington, KY 40536 USA. [Frank, Ellen] Univ Pittsburgh, Sch Med, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. [McClung, Colleen] Univ Texas SW Med Ctr Dallas, Dept Psychiat, Dallas, TX 75390 USA. [Nelson, Randy J.] Ohio State Univ, Dept Psychol, Columbus, OH 43210 USA. [Nelson, Randy J.] Ohio State Univ, Dept Neurosci, Columbus, OH 43210 USA. RP Vicentic, A (reprint author), NIMH, Div Neurosci & Basic Behav Sci, Rockville, MD 20892 USA. OI Nelson, Randy/0000-0002-8194-4016 FU NIMH NIH HHS [HHSN278200551009C]; None [HHSN278200551009C] NR 120 TC 38 Z9 38 U1 4 U2 22 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0173 J9 BRAIN RES REV JI Brain Res. Rev. PD DEC 11 PY 2009 VL 62 IS 1 BP 57 EP 70 DI 10.1016/j.brainresrev.2009.09.005 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 534TJ UT WOS:000272919900005 PM 19766673 ER PT J AU Mathas, S Misteli, T AF Mathas, Stephan Misteli, Tom TI The Dangers of Transcription SO CELL LA English DT Editorial Material ID TRANSLOCATIONS AB Transcription is obviously essential, but even a good thing can be dangerous at times. In this issue, Lin et al. (2009) provide evidence that binding of the transcription machinery may predispose genome regions to breakage and translocations that may lead to cancer. C1 [Mathas, Stephan] Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. [Mathas, Stephan] Charite, D-13353 Berlin, Germany. [Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Mathas, S (reprint author), Max Delbruck Ctr Mol Med, D-13125 Berlin, Germany. EM stephan.mathas@charite.de; mistelit@mail.nih.gov RI Mathas, Stephan/I-5589-2015 FU Intramural NIH HHS [Z01 BC010309-10] NR 5 TC 7 Z9 7 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 11 PY 2009 VL 139 IS 6 BP 1047 EP 1049 DI 10.1016/j.cell.2009.11.037 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 530WK UT WOS:000272622800005 PM 20005797 ER PT J AU Muller, F Mutch, NJ Schenk, WA Smith, SA Esterl, L Spronk, HM Schmidbauer, S Gahl, WA Morrissey, JH Renne, T AF Muller, Felicitas Mutch, Nicola J. Schenk, Wolfdieter A. Smith, Stephanie A. Esterl, Lucie Spronk, Henri M. Schmidbauer, Stefan Gahl, William A. Morrissey, James H. Renne, Thomas TI Platelet Polyphosphates Are Proinflammatory and Procoagulant Mediators In Vivo SO CELL LA English DT Article ID COAGULATION-FACTOR-XII; BLOOD-COAGULATION; CONTACT-PHASE; INORGANIC POLYPHOSPHATE; THROMBUS FORMATION; INTRINSIC PATHWAY; ACTIVATION; DEFICIENCY; DISEASE; SYSTEM AB Platelets play a central role in thrombosis, hemostasis, and inflammation. We show that activated platelets release inorganic polyphosphate (polyP), a polymer of 60-100 phosphate residues that directly bound to and activated the plasma protease factor XII. PolyP-driven factor XII activation triggered release of the inflammatory mediator bradykinin by plasma kallikrein-mediated kininogen processing. PolyP increased vascular permeability and induced fluid extravasation in skin microvessels of mice. Mice deficient in factor XII or bradykinin receptors were resistant to polyP-induced leakage. PolyP initiated clotting of plasma via the contact pathway. Ablation of intrinsic coagulation pathway proteases factor XII and factor XI protected mice from polyP-triggered lethal pulmonary embolism. Targeting polyP with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Addition of polyP restored defective plasma clotting of Hermansky-Pudlak Syndrome patients, who lack platelet polyP. The data identify polyP as a new class of mediator having fundamental roles in platelet-driven proinflammatory and procoagulant disorders. C1 [Muller, Felicitas; Esterl, Lucie; Renne, Thomas] Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden. [Muller, Felicitas; Esterl, Lucie; Renne, Thomas] Karolinska Inst, Ctr Mol Med, S-17176 Stockholm, Sweden. [Mutch, Nicola J.] Univ Leeds, Fac Biol Sci, Dept Cardiovasc Med, Leeds LS2 9JT, W Yorkshire, England. [Schenk, Wolfdieter A.] Univ Wurzburg, Inst Inorgan Chem, D-97074 Wurzburg, Germany. [Smith, Stephanie A.; Morrissey, James H.] Univ Illinois, Coll Med, Urbana, IL 61801 USA. [Spronk, Henri M.] Maastricht Univ, Dept Internal Med, Lab Clin Thrombosis & Haemostasis, NL-6200 MD Maastricht, Netherlands. [Schmidbauer, Stefan] CSL Behring GmbH, D-35041 Marburg, Germany. [Gahl, William A.] NHGRI, Human Biochem Genet Sect, Bethesda, MD 20892 USA. RP Renne, T (reprint author), Karolinska Inst, Dept Mol Med & Surg, S-17176 Stockholm, Sweden. EM thomas@renne.net FU Deutsche Forschungsgemeinschaft [SFB 688]; EU; NIH [R01 HL47014]; National Human Genome Research Institute, NIH FX This work was supported in part by grants from the Deutsche Forschungsgemeinschaft (SFB 688) and the EU-funded ERARE program (T. R.); by NIH grant R01 HL47014 (J.H.M.); and by the Intramural Research Program of the National Human Genome Research Institute, NIH (W. A. G.). We thank Dr. T. Staffel (BK Giulini, Ludwigshafen, Germany) for donating synthetic polyP. We are grateful to Dr. David Gailani (Vanderbilt University, Nashville, TN, USA) for providing FXI null mice and Dr. Alan E. Mast (Blood Center of Wisconsin, Milwaukee, WI, USA) for anti-TFPI antibodies. We cordially thank Dr. Ulrich Walter (Julius-Maximilians-University Wurzburg, Wurzburg, Germany) for continuous mentoring and support. F. M. is supported by a Rudolf-Marx Grant of the Society for Thrombosis and Hemostasis Research (GTH). Three of the authors (N.J.M., S. A. S., and J.H.M.) are coinventors on pending patent applications on medical uses of polyP. NR 41 TC 310 Z9 312 U1 12 U2 44 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD DEC 11 PY 2009 VL 139 IS 6 BP 1143 EP 1156 DI 10.1016/j.cell.2009.11.001 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 530WK UT WOS:000272622800016 PM 20005807 ER PT J AU Mutoh, S Osabe, M Inoue, K Moore, R Pedersen, L Perera, L Rebolloso, Y Sueyoshi, T Negishi, M AF Mutoh, Shingo Osabe, Makoto Inoue, Kaoru Moore, Rick Pedersen, Lee Perera, Lalith Rebolloso, Yvette Sueyoshi, Tatsuya Negishi, Masahiko TI Dephosphorylation of Threonine 38 Is Required for Nuclear Translocation and Activation of Human Xenobiotic Receptor CAR (NR1I3) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CONSTITUTIVE ACTIVE/ANDROSTANE RECEPTOR; MOUSE PRIMARY HEPATOCYTES; DRUG-METABOLISM; X-RECEPTOR; CYP2B GENE; LIVER; HETERODIMER; INDUCTION AB Upon activation by therapeutics, the nuclear xenobiotic/constitutive active/androstane receptor (CAR) regulates various liver functions ranging from drug metabolism and excretion to energy metabolism. CAR can also be a risk factor for developing liver diseases such as hepatocellular carcinoma. Here we have characterized the conserved threonine 38 of human CAR as the primary residue that regulates nuclear translocation and activation of CAR. Protein kinase C phosphorylates threonine 38 located on the alpha-helix spanning from residues 29-42 that constitutes a part of the first zinc finger and continues into the region between the zinc fingers. Molecular dynamics study has revealed that this phosphorylation may destabilize this helix, thereby inactivating CAR binding to DNA as well as sequestering it in the cytoplasm. We have found, in fact, that helix-stabilizing mutations reversed the effects of phosphorylation. Immunohistochemical study using an anti-phosphothreonine 38 peptide antibody has, in fact, demonstrated that the classic CAR activator phenobarbital dephosphorylates the corresponding threonine 48 of mouse CAR in the cytoplasm of mouse liver and translocates CAR into the nucleus. These results define CAR as a cell signal-regulated constitutive active nuclear receptor. These results also provide phosphorylation/dephosphorylation of the threonine as the primary drug target for CAR activation. C1 [Mutoh, Shingo; Osabe, Makoto; Inoue, Kaoru; Moore, Rick; Sueyoshi, Tatsuya; Negishi, Masahiko] NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Pedersen, Lee; Perera, Lalith] NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Rebolloso, Yvette] NIEHS, Cellular & Mol Pathol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov RI perera, Lalith/B-6879-2012; Pedersen, Lee/E-3405-2013 OI perera, Lalith/0000-0003-0823-1631; Pedersen, Lee/0000-0003-1262-9861 FU National Institutes of Health Intramural Research Program [Z01ES71005-01] FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Program Z01ES71005-01 through the NIEHS. NR 20 TC 65 Z9 71 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 11 PY 2009 VL 284 IS 50 BP 34785 EP 34792 DI 10.1074/jbc.M109.048108 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528JG UT WOS:000272439600034 PM 19858220 ER PT J AU Luo, Y Jian, W Stavreva, D Fu, XQ Hager, G Bungert, J Huang, SM Qiu, Y AF Luo, Yi Jian, Wei Stavreva, Diana Fu, Xueqi Hager, Gordon Bungert, Joerg Huang, Suming Qiu, Yi TI Trans-regulation of Histone Deacetylase Activities through Acetylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURE; IN-VIVO; COMPLEX; TRANSCRIPTION; PROTEIN; YEAST; METHYLATION; INHIBITION; REPRESSION; DOMAINS AB HDAC1 and -2 are highly conserved enzymes and often coexist in the same coregulator complexes. Understanding the regulation of histone deacetylase activities is extremely important because these enzymes play key roles in epigenetic regulation in normal and cancer cells. We previously showed that HDAC1 is required for glucocorticoid receptor-mediated transcription activation and that its activity is regulated through acetylation by p300 during the induction cycle. Here, we showed that HDAC2 is also required for glucocorticoid receptor-mediated gene activation. HDAC2, however, is regulated through a different mechanism from that of HDAC1. HDAC2 is not acetylated by p300, although 5 of 6 acetylated lysine residues in HDAC1 are also present in HDAC2. More importantly, the activity of HDAC2 is inhibited by acetylated HDAC1. Additionally, we showed that acetylated HDAC1 can trans-regulate HDAC2 through heterodimerization. Thus, this study uncovered fundamental differences between HDAC1 and HDAC2. It also unveiled a new mechanism of collaborative regulation by HDAC1/2 containing coregulator complexes. C1 [Luo, Yi; Jian, Wei; Qiu, Yi] Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. [Bungert, Joerg; Huang, Suming] Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. [Stavreva, Diana; Hager, Gordon] NCI, Lab Receptor Biol & Gene Express, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Luo, Yi; Fu, Xueqi] Jilin Univ, Coll Life Sci, Changchun 130023, Peoples R China. RP Qiu, Y (reprint author), Rm 356,1376 Mowry Rd, Gainesville, FL 32610 USA. EM qiuy@ufl.edu FU National Institutes of Health [R01 HL090589, R01 HL091929, R01 DK52356]; Florida Department of Health FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 HL090589 and R01 HL091929 (to S. H.) and R01 DK52356 (to J. B.). This work was also supported by grants from the Florida Department of Health (to Y. Q. and S. H.). NR 37 TC 29 Z9 30 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 11 PY 2009 VL 284 IS 50 BP 34901 EP 34910 DI 10.1074/jbc.M109.038356 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528JG UT WOS:000272439600045 PM 19822520 ER PT J AU Das, K Bandwar, RP White, KL Feng, JY Sarafianos, SG Tuske, S Tu, XY Clark, AD Boyer, PL Hou, XR Gaffney, BL Jones, RA Miller, MD Hughes, SH Arnold, E AF Das, Kalyan Bandwar, Rajiv P. White, Kirsten L. Feng, Joy Y. Sarafianos, Stefan G. Tuske, Steven Tu, Xiongying Clark, Arthur D., Jr. Boyer, Paul L. Hou, Xiaorong Gaffney, Barbara L. Jones, Roger A. Miller, Michael D. Hughes, Stephen H. Arnold, Eddy TI Structural Basis for the Role of the K65R Mutation in HIV-1 Reverse Transcriptase Polymerization, Excision Antagonism, and Tenofovir Resistance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; THYMIDINE ANALOG MUTATIONS; IN-VITRO SELECTION; MOLECULAR-MECHANISMS; PRIMER UNBLOCKING; NUCLEOSIDE ANALOG; COMBINATION THERAPY; DRUG-RESISTANCE; AZT RESISTANCE; DNA AB K65R is a primary reverse transcriptase (RT) mutation selected in human immunodeficiency virus type 1-infected patients taking antiretroviral regimens containing tenofovir disoproxil fumarate or other nucleoside analog RT drugs. We determined the crystal structures of K65R mutant RT crosslinked to double-stranded DNA and in complexes with tenofovir diphosphate (TFV-DP) or dATP. The crystals permit substitution of TFV-DP with dATP at the dNTP-binding site. The guanidinium planes of the arginines K65R and Arg72 were stacked to form a molecular platform that restricts the conformational adaptability of both of the residues, which explains the negative effects of the K65R mutation on nucleotide incorporation and on excision. Furthermore, the guanidinium planes of K65R and Arg72 were stacked in two different rotameric conformations in TFV-DP- and dATP-bound structures that may help explain how K65R RT discriminates the drug from substrates. These K65R-mediated effects on RT structure and function help us to visualize the complex interaction with other key nucleotide RT drug resistance mutations, such as M184V, L74V, and thymidine analog resistance mutations. C1 [Das, Kalyan; Bandwar, Rajiv P.; Sarafianos, Stefan G.; Tuske, Steven; Tu, Xiongying; Clark, Arthur D., Jr.; Arnold, Eddy] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Das, Kalyan; Bandwar, Rajiv P.; Sarafianos, Stefan G.; Tuske, Steven; Tu, Xiongying; Clark, Arthur D., Jr.; Hou, Xiaorong; Gaffney, Barbara L.; Jones, Roger A.; Arnold, Eddy] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. [White, Kirsten L.; Feng, Joy Y.; Miller, Michael D.] Gilead Sci Inc, Foster City, CA 94404 USA. [Boyer, Paul L.; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. RP Arnold, E (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. EM arnold@cabm.rutgers.edu RI Tu, Xiongying/H-7983-2012; OI Sarafianos, Stefan G/0000-0002-5840-154X FU National Institutes of Health [AI 27690]; NCI; Center for Cancer Research; NIGMS; [P01 GM066671] FX This work was supported, in whole or in part, by National Institutes of Health MERIT Award AI 27690 and Grant P01 GM066671 (to E.A.) for support of RT structural studies and by the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research, and NIGMS (to S.H.H.). NR 54 TC 48 Z9 48 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 11 PY 2009 VL 284 IS 50 BP 35092 EP 35100 DI 10.1074/jbc.M109.022525 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 528JG UT WOS:000272439600063 PM 19812032 ER PT J AU Rigby, ST Van Nostrand, KP Rose, AE Gorelick, RJ Mathews, DH Bambara, RA AF Rigby, Sean T. Van Nostrand, Keith P. Rose, April E. Gorelick, Robert J. Mathews, David H. Bambara, Robert A. TI Factors That Determine the Efficiency of HIV-1 Strand Transfer Initiated at a Specific Site SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV-1; reverse transcriptase; RNase H; nucleocapsid protein recombination ID HUMAN-IMMUNODEFICIENCY-VIRUS; TRANSCRIPTASE RNASE-H; TYPE-1 REVERSE-TRANSCRIPTASE; NUCLEOCAPSID PROTEIN; RETROVIRAL RECOMBINATION; INTERNAL REGIONS; IN-VITRO; CLEAVAGE SPECIFICITY; POLYPURINE TRACT; DNA-SYNTHESIS AB Human immunodeficiency virus-1 employs strand transfer for recombination between two viral genomes. We have previously provided evidence that strand transfer proceeds by an invasion-mediated mechanism in which a DNA segment on the original RNA template is invaded by a second RNA template at a gap site. The initial RNA-DNA hybrid then expands until the DNA is fully transferred. Ribonuclease H (RNase H) cleavages and nucleocapsid protein (NC) were required for long-distance propagation of the hybrid. Evaluation was performed on a unique substrate, with a short gap serving as a precreated invasion site. In our current work, this substrate provided an opportunity for us to test what factors influence a specific invasion site to support transfer, and to distinguish factors that influence invasion site creation from those that impact later steps. RNase H can act in a polymerization-dependent or polymerization-independent mode. Polymerization-dependent and polymerization-independent RNase H were found to be important in creating efficiently used invasion sites in the primer-donor complex, with or without NC. Propagation and terminus transfer steps, emanating from a precreated invasion site in the presence of NC, were stimulated by polymerization-dependent, but not polymerization-independent, RNase H. RNase H can carry out primary and secondary cleavages during synthesis. While both modes of cleavage promoted invasion, only primary cleavage promoted propagation in the presence of NC in our system. These observations suggest that once invasion is initiated at a short gap, it can propagate through an adjacent region interrupted only by nicks, with help by NC. We considered the possibility that propagation solely by strand exchange was a significant contributor to transfers. However, it did not promote transfer even if synthetic progress of reverse transcriptase was intentionally slowed, consistent with strand exchange by random walk in which rate declines precipitously with distance. (C) 2009 Published by Elsevier Ltd. C1 [Rigby, Sean T.; Van Nostrand, Keith P.; Rose, April E.; Mathews, David H.; Bambara, Robert A.] Univ Rochester, Sch Med & Dent, Dept Biochem & Biophys, Rochester, NY 14642 USA. [Gorelick, Robert J.] NCI, AIDS & Canc Virus Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Bambara, Robert A.] Univ Rochester, Med Ctr, Wilmot Canc Ctr, Rochester, NY 14642 USA. RP Bambara, RA (reprint author), Univ Rochester, Sch Med & Dent, Dept Biochem & Biophys, Rochester, NY 14642 USA. EM robert-bambara@urmc.rochester.edu FU National Institutes of Health [GM 049573, HG 004002, N01-CO-12400]; [5T32 AI 049815] FX This work was supported by grants from the National Institutes of Health: GM 049573 (R.A.B.), HG 004002 (D.H.M.), and Training in HIV Replication and Pathogenesis 5T32 AI 049815 (S.T.R.). This work was also funded, in part, by National Institutes of Health contract N01-CO-12400 (R.J.G.). We thank Dr. Vandana Basu-Purohit for H539 RT mutants, and Dr. Stuart F. J. Le Grice for E478Q RT. We express our appreciation to Dr. Mark N. Hanson for the development of the PCIS substrate. Thanks to Dr. Lisa M. Demeter, Dr. Baek Kim, and the members of the Bambara Laboratory for helpful discussions. We thank Cody Spencer for contributions to the early stages of this project. We also thank Dr. Jeffrey DeStefano, Dr. Lata Balakrishnan, and Dr. Dorota Piekna-Przybylska for reviewing the manuscript. NR 47 TC 4 Z9 4 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD DEC 11 PY 2009 VL 394 IS 4 BP 694 EP 707 DI 10.1016/j.jmb.2009.10.036 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 530OT UT WOS:000272602900011 PM 19853618 ER PT J AU Giraud, G Ramqvist, T Pastrana, DV Pavot, V Lindau, C Kogner, P Orrego, A Buck, CB Allander, T Holm, S Gustavsson, B Dalianis, T AF Giraud, Geraldine Ramqvist, Torbjorn Pastrana, Diana V. Pavot, Vincent Lindau, Cecilia Kogner, Per Orrego, Abiel Buck, Christopher B. Allander, Tobias Holm, Stefan Gustavsson, Bengt Dalianis, Tina TI DNA from KI, WU and Merkel Cell Polyomaviruses Is Not Detected in Childhood Central Nervous System Tumours or Neuroblastomas SO PLOS ONE LA English DT Article ID RESPIRATORY-TRACT INFECTIONS; NONMELANOMA SKIN-CANCER; JC VIRUS; BK VIRUS; BRAIN-TUMORS; CARCINOMA; EXPRESSION; CHILDREN; DISEASE; ANTIGEN AB Background: BK and JC polyomaviruses (BKV and JCV) are potentially oncogenic and have in the past inconclusively been associated with tumours of the central nervous system (CNS), while BKV has been hinted, but not confirmed to be associated with neuroblastomas. Recently three new polyomaviruses (KIPyV, WUPyV and MCPyV) were identified in humans. So far KIPyV and WUPyV have not been associated to human diseases, while MCPyV was discovered in Merkel Cell carcinomas and may have neuroepithelial cell tropism. However, all three viruses can be potentially oncogenic and this compelled us to investigate for their presence in childhood CNS and neuroblastomas. Methodology: The presence of KI, WU and MCPyV DNA was analysed, by a joint WU and KI specific PCR (covering part of VP1) and by a MCPyV specific regular and real time quantitative PCR (covering part of Large T) in 25 CNS tumour biopsies and 31 neuroblastoma biopsies from the Karolinska University Hospital, Sweden. None of the three new human polyomaviruses were found to be associated with any of the tumours, despite the presence of PCR amplifiable DNA assayed by a S14 housekeeping gene PCR. Conclusion: In this pilot study, the presence of MCPyV, KI and WU was not observed in childhood CNS tumours and neuroblastomas. Nonetheless, we suggest that additional data are warranted in tumours of the central and peripheral nervous systems and we do not exclude that other still not yet detected polyomaviruses could be present in these tumours. C1 [Giraud, Geraldine; Ramqvist, Torbjorn; Pavot, Vincent; Orrego, Abiel; Dalianis, Tina] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Pastrana, Diana V.; Buck, Christopher B.] NCI, Cellular Oncol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Lindau, Cecilia; Allander, Tobias] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Kogner, Per; Holm, Stefan] Karolinska Inst, Dept Women & Child Hlth, Stockholm, Sweden. [Gustavsson, Bengt] Karolinska Inst, Dept Neurosci, Stockholm, Sweden. [Dalianis, Tina] Swedish Inst Infect Dis Control, Dept Virol, Solna, Sweden. RP Giraud, G (reprint author), Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. EM geraldine.giraud@ki.se OI Buck, Christopher/0000-0003-3165-8094; Kogner, Per/0000-0002-2202-9694 FU Swedish Children's Cancer Foundation [PROJ07/004]; Swedish Cancer Foundation [08 0278]; Swedish Research Council [K2008-57X-15282-04-3]; Stockholm City Council [75034]; Karolinska Institutet; Stockholm Cancer Society [081041]; King Gustav V's Jubilee Foundation [084052] FX This investigation was supported financially by: the Swedish Children's Cancer Foundation (project number PROJ07/004) http://www.barncancerfonden.se/, the Swedish Cancer Foundation (project number 08 0278) http://www.cancerfonden.se/, the Swedish Research Council (VR) (project number K2008-57X-15282-04-3) http://www.vr.se/, The Stockholm City Council (project number 75034) http://international.stockholm.se/Politics-and-organisation/Organisation /The-City-Council/, Karolinska Institutet http://ki.se/, the Stockholm Cancer Society (project number 081041) http://www.radiumhemmetsforskningsfonder.com/, and the King Gustav V's Jubilee Foundation (project number 084052) http://www.radiumhemmetsforskningsfonder.com/. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 50 TC 16 Z9 16 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 11 PY 2009 VL 4 IS 12 AR e8239 DI 10.1371/journal.pone.0008239 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533NH UT WOS:000272830200001 PM 20011509 ER PT J AU Abdulla, MA Ahmed, I Assawamakin, A Bhak, J Brahmachari, SK Calacal, GC Chaurasia, A Chen, CH Chen, JM Chen, YT Chu, JY Cutiongco-de la Paz, EMC De Ungria, MCA Delfin, FC Edo, J Fuchareon, S Ghang, H Gojobori, T Han, JS Ho, SF Hoh, BP Huang, W Inoko, H Jha, P Jinam, TA Jin, L Jung, J Kangwanpong, D Kampuansai, J Kennedy, GC Khurana, P Kim, HL Kim, K Kim, S Kim, WY Kimm, K Kimura, R Koike, T Kulawonganunchai, S Kumar, V Lai, PS Lee, JY Lee, S Liu, ET Majumder, PP Mandapati, KK Marzuki, S Mitchell, W Mukerji, M Naritomi, K Ngamphiw, C Niikawa, N Nishida, N Oh, B Oh, S Ohashi, J Oka, A Ong, R Padilla, CD Palittapongarnpim, P Perdigon, HB Phipps, ME Png, E Sakaki, Y Salvador, JM Sandraling, Y Scaria, V Seielstad, M Sidek, MR Sinha, A Srikummool, M Sudoyo, H Sugano, S Suryadi, H Suzuki, Y Tabbada, KA Tan, A Tokunaga, K Tongsima, S Villamor, LP Wang, E Wang, Y Wang, HF Wu, JY Xiao, HS Xu, SH Yang, JO Shugart, YY Yoo, HS Yuan, WT Zhao, GP Zilfalil, BA AF Abdulla, Mahmood Ameen Ahmed, Ikhlak Assawamakin, Anunchai Bhak, Jong Brahmachari, Samir K. Calacal, Gayvelline C. Chaurasia, Amit Chen, Chien-Hsiun Chen, Jieming Chen, Yuan-Tsong Chu, Jiayou Cutiongco-de la Paz, Eva Maria C. De Ungria, Maria Corazon A. Delfin, Frederick C. Edo, Juli Fuchareon, Suthat Ghang, Ho Gojobori, Takashi Han, Junsong Ho, Sheng-Feng Hoh, Boon Peng Huang, Wei Inoko, Hidetoshi Jha, Pankaj Jinam, Timothy A. Jin, Li Jung, Jongsun Kangwanpong, Daoroong Kampuansai, Jatupol Kennedy, Giulia C. Khurana, Preeti Kim, Hyung-Lae Kim, Kwangjoong Kim, Sangsoo Kim, Woo-Yeon Kimm, Kuchan Kimura, Ryosuke Koike, Tomohiro Kulawonganunchai, Supasak Kumar, Vikrant Lai, Poh San Lee, Jong-Young Lee, Sunghoon Liu, Edison T. Majumder, Partha P. Mandapati, Kiran Kumar Marzuki, Sangkot Mitchell, Wayne Mukerji, Mitali Naritomi, Kenji Ngamphiw, Chumpol Niikawa, Norio Nishida, Nao Oh, Bermseok Oh, Sangho Ohashi, Jun Oka, Akira Ong, Rick Padilla, Carmencita D. Palittapongarnpim, Prasit Perdigon, Henry B. Phipps, Maude Elvira Png, Eileen Sakaki, Yoshiyuki Salvador, Jazelyn M. Sandraling, Yuliana Scaria, Vinod Seielstad, Mark Sidek, Mohd Ros Sinha, Amit Srikummool, Metawee Sudoyo, Herawati Sugano, Sumio Suryadi, Helena Suzuki, Yoshiyuki Tabbada, Kristina A. Tan, Adrian Tokunaga, Katsushi Tongsima, Sissades Villamor, Lilian P. Wang, Eric Wang, Ying Wang, Haifeng Wu, Jer-Yuarn Xiao, Huasheng Xu, Shuhua Yang, Jin Ok Shugart, Yin Yao Yoo, Hyang-Sook Yuan, Wentao Zhao, Guoping Zilfalil, Bin Alwi CA HUGO Pan Asian SNP Consortium Indian Genome Variation Consortium TI Mapping Human Genetic Diversity in Asia SO SCIENCE LA English DT Article ID POPULATION-STRUCTURE; WIDE ANALYSIS; ADMIXTURE; GEOGRAPHY; UYGHURS; HISTORY; EUROPE AB Asia harbors substantial cultural and linguistic diversity, but the geographic structure of genetic variation across the continent remains enigmatic. Here we report a large-scale survey of autosomal variation from a broad geographic sample of Asian human populations. Our results show that genetic ancestry is strongly correlated with linguistic affiliations as well as geography. Most populations show relatedness within ethnic/linguistic groups, despite prevalent gene flow among populations. More than 90% of East Asian (EA) haplotypes could be found in either Southeast Asian (SEA) or Central-South Asian (CSA) populations and show clinal structure with haplotype diversity decreasing from south to north. Furthermore, 50% of EA haplotypes were found in SEA only and 5% were found in CSA only, indicating that SEA was a major geographic source of EA populations. C1 [Jin, Li] Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200433, Peoples R China. [Abdulla, Mahmood Ameen; Edo, Juli; Jinam, Timothy A.; Phipps, Maude Elvira] Univ Malaya, Fac Med, Dept Mol Med, Kuala Lumpur 50603, Malaysia. [Abdulla, Mahmood Ameen; Edo, Juli; Jinam, Timothy A.; Phipps, Maude Elvira] Univ Malaya, Fac Arts & Social Sci, Dept Anthropol, Kuala Lumpur 50603, Malaysia. [Ahmed, Ikhlak; Brahmachari, Samir K.; Chaurasia, Amit; Jha, Pankaj; Mukerji, Mitali; Scaria, Vinod; Sinha, Amit; Indian Genome Variation Consortium] CSIR, Inst Genom & Integrat Biol, Delhi 110007, India. [Assawamakin, Anunchai; Fuchareon, Suthat] Mahidol Univ, Puttamonthon 73170, Nakornpathom, Thailand. [Assawamakin, Anunchai; Kulawonganunchai, Supasak; Ngamphiw, Chumpol; Tongsima, Sissades] Natl Ctr Genet Engn & Biotechnol, Genome Inst, Biostat & Informat Lab, Pathum Thani 12120, Thailand. [Bhak, Jong; Ghang, Ho; Kim, Woo-Yeon; Lee, Sunghoon; Oh, Sangho; Yang, Jin Ok; Yoo, Hyang-Sook] KRIBB, KOBIC, Taejon 305806, South Korea. [Calacal, Gayvelline C.; De Ungria, Maria Corazon A.; Delfin, Frederick C.; Perdigon, Henry B.; Salvador, Jazelyn M.; Tabbada, Kristina A.; Villamor, Lilian P.] Univ Philippines, Nat Sci Res Inst, DNA Anal Lab, Quezon City 1101, Philippines. [Chen, Chien-Hsiun; Chen, Yuan-Tsong; Ho, Sheng-Feng; Wu, Jer-Yuarn] Acad Sinica, Inst Biomed Sci, Taipei 115, Taiwan. [Chen, Jieming; Kumar, Vikrant; Liu, Edison T.; Ong, Rick; Png, Eileen; Seielstad, Mark; Tan, Adrian] Genome Inst Singapore, Singapore 138672, Singapore. [Chu, Jiayou] Chinese Acad Med Sci, Inst Med Biol, Kunming, Peoples R China. [Cutiongco-de la Paz, Eva Maria C.; Padilla, Carmencita D.] Univ Philippines Manila, Natl Inst Hlth, Inst Human Genet, Ermita Manila 1000, Philippines. [Gojobori, Takashi; Koike, Tomohiro; Suzuki, Yoshiyuki] Res Org Informat & Syst, Ctr Informat Biol, Mishima, Shizuoka 4118540, Japan. [Gojobori, Takashi; Koike, Tomohiro; Suzuki, Yoshiyuki] Res Org Informat & Syst, DNA Data Bank Japan, Natl Inst Genet, Mishima, Shizuoka 4118540, Japan. [Gojobori, Takashi] Natl Inst Adv Ind Sci & Technol, Biomed Informat Res Ctr, Koto Ku, Tokyo 1350064, Japan. [Han, Junsong; Xiao, Huasheng] Natl Engn Ctr Biochip Shanghai, Shanghai 201203, Peoples R China. [Hoh, Boon Peng; Sidek, Mohd Ros; Zilfalil, Bin Alwi] Univ Sains Malaysia, Sch Med Sci, Ctr Human Genome, Kubang Kerian 16150, Kelantan, Malaysia. [Huang, Wei; Wang, Ying; Wang, Haifeng; Yuan, Wentao; Zhao, Guoping] Chinese Natl Human Genome Ctr Shanghai, MOST Shanghai Lab Dis & Hlth Genom, Shanghai 201203, Peoples R China. [Inoko, Hidetoshi; Oka, Akira] Tokai Univ, Sch Med, Dept Mol Life Sci, Div Mol Med Sci & Mol Med, Isehara, Kanagawa A2591193, Japan. [Jin, Li] Fudan Univ, Sch Life Sci, MOE Key Lab Contemporary Anthropol, Shanghai 200433, Peoples R China. [Jung, Jongsun; Kim, Hyung-Lae; Kim, Kwangjoong; Lee, Jong-Young; Oh, Bermseok] Korea Natl Inst Hlth, Seoul 122701, South Korea. [Kangwanpong, Daoroong; Kampuansai, Jatupol; Srikummool, Metawee] Chiang Mai Univ, Fac Sci, Dept Biol, Chiang Mai 50202, Thailand. [Kennedy, Giulia C.; Wang, Eric] Affymetrix, Genom Collaborat, Santa Clara, CA 95051 USA. [Kennedy, Giulia C.; Wang, Eric] Veracyte, San Francisco, CA 94080 USA. [Khurana, Preeti; Mandapati, Kiran Kumar] Ctr Genom Applicat, New Delhi 110020, India. [Kim, Sangsoo] Soongsil Univ, Seoul 156743, South Korea. [Kimm, Kuchan] Eulji Univ, Coll Med, Taejon 301832, South Korea. [Kimura, Ryosuke; Nishida, Nao; Ohashi, Jun; Tokunaga, Katsushi] Univ Tokyo, Grad Sch Med, Dept Human Genet, Bunkyo Ku, Tokyo 1130033, Japan. [Lai, Poh San] Natl Univ Singapore, Natl Univ Hosp, Yong Loo Lin Sch Med, Dept Paediat, Singapore 119074, Singapore. [Lai, Poh San] DSO Natl Labs, Def Med & Environm Res Inst, Populat Genet Lab, Singapore 117510, Singapore. [Majumder, Partha P.] Indian Stat Inst, Kolkata 700108, India. [Marzuki, Sangkot; Sandraling, Yuliana; Sudoyo, Herawati; Suryadi, Helena] Eijkman Inst Mol Biol, Jakarta 10430, Indonesia. [Mitchell, Wayne] Informat Expt Therapeut Ctr, Singapore 138669, Singapore. [Mitchell, Wayne] Nanyang Technol Univ, Sch Comp Engn, Div Informat Sci, Singapore 639798, Singapore. [Naritomi, Kenji] Univ Ryukyus, Fac Med, Dept Med Genet, Okinawa 9030215, Japan. [Palittapongarnpim, Prasit] Natl Sci & Technol Dev Agcy, Pathum Thani 12120, Thailand. [Phipps, Maude Elvira] Monash Univ, Bandar Sunway 46150, Selangor, Malaysia. [Sakaki, Yoshiyuki] RIKEN, Genom Sci Ctr, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. Univ Hong Kong, Dept Biochem, Pokfulam, Hong Kong, Peoples R China. [Sugano, Sumio] Univ Tokyo, Grad Sch Frontier Sci, Dept Med Genome Sci, Lab Funct Genom,Shirokanedai Lab,Minato Ku, Tokyo 1088639, Japan. [Jin, Li; Xu, Shuhua] Chinese Acad Sci, Shanghai Inst Biol Sci, Max Planck Soc, Partner Inst Computat Biol, Shanghai 200031, Peoples R China. [Shugart, Yin Yao] NIMH, Genom Res Branch, NIH, Bethesda, MD 20892 USA. [Niikawa, Norio] Hlth Sci Univ Hokkaido, Res Inst Personalized Hlth Sci, Tobetsu 0610293, Japan. RP Jin, L (reprint author), Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, 220 Handan Rd, Shanghai 200433, Peoples R China. EM ljin007@gmail.com; liue@gis.a-star.edu.sg; seielstadm@gis.a-star.edu.sg; xushua@picb.ac.cn RI Mitchell, Wayne/C-5219-2008; Ganju, Shahji/F-3409-2012; Scaria, Vinod/B-2819-2008; Liu, Edison/C-4141-2008; XU, SHUHUA/D-5345-2009; MOE Key Lab at Fudan University, Contemp Anthropology/A-1772-2010; Fudan Anthropology, MOE KeyLab/A-9454-2010; Tongsima, Sissades/F-4891-2011; EDO, JULI A/L EDO/B-8721-2010; Jin, Li/C-1468-2009; Kimura, Ryosuke/B-3354-2015; Hoh, Boon-Peng/H-8682-2016; OI Seielstad, Mark/0000-0001-5783-1401; Scaria, Vinod/0000-0001-7644-7181; Ahmed, Ikhlak/0000-0002-5753-9627; Chen, Jieming/0000-0003-3767-9486; XU, SHUHUA/0000-0002-1975-1002; Tongsima, Sissades/0000-0002-1491-1839; Jin, Li/0000-0002-4546-2415; Hoh, Boon-Peng/0000-0001-9249-4965; Phipps, Maude/0000-0001-8314-068X NR 26 TC 225 Z9 240 U1 10 U2 100 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 11 PY 2009 VL 326 IS 5959 BP 1541 EP 1545 DI 10.1126/science.1177074 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 530WS UT WOS:000272623600059 ER PT J AU Kolibab, K Parra, M Yang, AL Perera, LP Derrick, SC Morris, SL AF Kolibab, Kristopher Parra, Marcela Yang, Amy L. Perera, Liyanage P. Derrick, Steven C. Morris, Sheldon L. TI A practical in vitro growth inhibition assay for the evaluation of TB vaccines SO VACCINE LA English DT Article DE Tuberculosis; In vitro assay; Vaccine; Mouse; Cytokines ID MYCOBACTERIUM-TUBERCULOSIS INFECTION; INTRACELLULAR GROWTH; INTERFERON-GAMMA; IMMUNE-RESPONSES; IFN-GAMMA; CELLS; CD4(+); MICE; BCG; IMMUNOGENICITY AB New vaccines and novel immunization strategies are needed to improve the control of the global tuberculosis epidemic. To facilitate vaccine development, we have been creating in vitro mycobacterial intra-macrophage growth inhibition assays. Here we describe the development of an in vitro assay designed for BSL-2 laboratories which measures the capacity of vaccine-induced immune splenocytes to control the growth of isoniazid-resistant Mycobacterium bovis BCG (INH(r) BCG). The use of the INH(r) BCG as the infecting organism allows the discrimination of BCG bacilli used in murine vaccinations from BCG used in the in vitro assay. In this study, we showed that protective immune responses evoked by four different types of Mycobacterium tuberculosis vaccines [BCG, an ESAT6/Antigen 85B fusion protein formulated in DDA/MPL adjuvant, a DNA vaccine expressing the same fusion protein, and a TB Modified Vaccinia Ankara construct expressing four TB antigens (MVA-4TB)] were detected. Importantly, the levels of vaccine-induced protective immunity seen in the in vitro assay correlated with the results from in vivo protection studies in the mouse model of pulmonary tuberculosis. Furthermore, the growth inhibition data for the INH(r) BCG assay was similar to the previously reported results for a M. tuberculosis infection assay. The cytokine expression profiles at day 7 of the INHr BCG growth inhibition studies were also similar but not identical to the cytokine patterns detected in earlier M. tuberculosis co-culture assays. Overall, we have shown that a BSL-2 compatible in vitro growth inhibition assay using INHr BCG as the intra-macrophage target organism should be useful in developing and evaluating new TB immunization strategies. Published by Elsevier Ltd. C1 [Morris, Sheldon L.] US FDA, Lab Mycobacterial Dis & Cellular Immunol, CBER, Bethesda, MD 20892 USA. [Perera, Liyanage P.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Morris, SL (reprint author), US FDA, Lab Mycobacterial Dis & Cellular Immunol, CBER, Bldg 29 Room 502,29 Lincol Dr, Bethesda, MD 20892 USA. EM sheldon.morris@fda.hhs.gov FU National Institute of Allergy and Infectious Diseases; National Institutes of Health; Department of Health and Human Services [IAA 227-06-1322] FX This project was funded in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services under IAA 227-06-1322. NR 26 TC 12 Z9 12 U1 2 U2 2 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 11 PY 2009 VL 28 IS 2 BP 317 EP 322 DI 10.1016/j.vaccine.2009.10.047 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 559YS UT WOS:000274869300005 PM 19879231 ER PT J AU Voordouw, ACG Beyer, WEP Smith, DJ Sturkenbom, MCJM Stricker, BHC AF Voordouw, A. C. G. Beyer, W. E. P. Smith, D. J. Sturkenbom, M. C. J. M. Stricker, B. H. Ch. TI Evaluation of serological trials submitted for annual re-licensure of influenza vaccines to regulatory authorities between 1992 and 2002 SO VACCINE LA English DT Article DE Seasonal influenza vaccine; Annual update trial; Serology; CHMP criteria; Regulatory requirement ID SINGLE RADIAL HEMOLYSIS; ANTIBODY-RESPONSE; ELDERLY ADULTS; SERUM ANTIBODY; VACCINATION; IMMUNOGENICITY; INDIVIDUALS; INFECTION; EFFICACY; SAFETY AB Background: As part of the regulatory requirements, serological evaluation of trivalent inactivated influenza vaccines must be performed before annual re-licensure in the European Union. These studies are typically set up as uncontrolled, open label trials including 2 groups of at least 50 healthy adults and healthy elderly. Methods: The serological data submitted to the Dutch Medicines Evaluation Board (MEB) for annual re-licensure purposes between 1992 and 2002, were analysed with respect to their ability to assess the immunogenic properties of the vaccines. The trials in this meta-analysis were selected by strictly applying the inclusion and exclusion criteria described in the Committee of Human Medicinal Products (CHMP) Note for Guidance on harmonisation of requirements for influenza vaccines. To select the final dataset additional exclusion criteria were defined: age outside the inclusion criterion of the trial, incomplete demographics, co-morbid conditions, antibody determination by SRH assay, incomplete dataset and sample size smaller than 50 subjects. Results: Out of 51 trials retrieved from the archives, 48 age-defined trials including 2510 adults and 2008 elderly fulfilled all the in- and exclusion criteria. A large proportion of vaccinees already met the threshold for seroprotection at baseline. Post-vaccination, the serological response was shown to be age dependent. Previous influenza vaccinations significantly affected pre-vaccination but not post-vaccination titres. Conclusions: The annual update trials performed for regulatory purposes have serious methodological limitations. which affect their ability to identify influenza vaccines with low immunogenicity. To establish clinical (protective) efficacy different trials and different assessment criteria are needed. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Voordouw, A. C. G.] Med Evaluat Board, NL-2500 BC The Hague, Netherlands. [Voordouw, A. C. G.; Sturkenbom, M. C. J. M.; Stricker, B. H. Ch.] Erasmus Univ, Pharmacoepidemiol Unit, Dept Internal Med, Med Ctr, Rotterdam, Netherlands. [Voordouw, A. C. G.; Sturkenbom, M. C. J. M.; Stricker, B. H. Ch.] Erasmus Univ, Dept Epidemiol & Biostat, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Beyer, W. E. P.; Smith, D. J.] Erasmus Univ, Dept Virol, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Smith, D. J.] Univ Cambridge, Dept Zool, Cambridge, England. [Sturkenbom, M. C. J. M.] Erasmus Univ, Dept Med Informat, Med Ctr, NL-3000 DR Rotterdam, Netherlands. [Stricker, B. H. Ch.] Inspectorate Hlth Care, Drug Safety Unit, The Hague, Netherlands. [Smith, D. J.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Voordouw, ACG (reprint author), Med Evaluat Board, POB 16229, NL-2500 BC The Hague, Netherlands. EM ac.voordouw@cbg-meb.nl FU The Netherlands Organisation for Health Research and Development [2200.0090]; NIH Director's Pioneer [DP1-0D000490-01]; European Union [223498 EMPERIE] FX We acknowledge the valuable discussions concerning this manuscript with members of the Vaccine Working Party of the European Medicines Agency (EMEA), London.; The conclusions drawn reflect the scientific opinions of the authors only.; This study was supported by a grant from The Netherlands Organisation for Health Research and Development (ZonMw), project number 2200.0090. DJS was supported by an NIH Director's Pioneer Award DP1-0D000490-01 and FP7 grant 223498 EMPERIE from the European Union. None of the data have been presented previously. Conflict of interest: None of the authors have a commercial or other association that might pose a conflict of interest. NR 23 TC 11 Z9 11 U1 0 U2 2 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 11 PY 2009 VL 28 IS 2 BP 392 EP 397 DI 10.1016/j.vaccine.2009.09.138 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 559YS UT WOS:000274869300015 PM 19878750 ER PT J AU Belele, CL English, MA Chahal, J Burnetti, A Finckbeiner, SM Gibney, G Kirby, M Sood, R Liu, PP AF Belele, Christiane L. English, Milton A. Chahal, Jagman Burnetti, Anthony Finckbeiner, Steven M. Gibney, Gretchen Kirby, Martha Sood, Raman Liu, P. Paul TI Differential requirement for Gata1 DNA binding and transactivation between primitive and definitive stages of hematopoiesis in zebrafish SO BLOOD LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; IN-VIVO; TRANSGENIC ZEBRAFISH; CELL-DEVELOPMENT; GENE; PROTEIN; EMBRYOS; ERYTHROPOIESIS; EXPRESSION; MUTATION AB The transcription factor Gata1 is required for the development of erythrocytes and megakaryocytes. Previous studies with a complementation rescue approach showed that the zinc finger domains are required for both primitive and definitive hematopoiesis. Here we report a novel zebrafish gata1 mutant with an N-ethyl-N-nitrosourea-induced point mutation in the C-finger (gata1(T301K)). The Gata1 protein with this mutation bound to its DNA target sequence with reduced affinity and transactivated inefficiently in a reporter assay. gata1(T301K/T301K) fish had a decreased number of erythrocytes during primitive hematopoiesis but normal adult hematopoiesis. We crossed the gata1(T301K/T301K) fish with those carrying the R339X mutation, also known as vlad tepes (vlt), which abolishes DNA binding and transactivation activities. As we reported previously, gata1(vlt/vlt) embryos were "bloodless" and died approximately 11 to 15 days after fertilization. Interestingly, the gata1(T301K/vlt) fish had nearly a complete block of primitive hematopoiesis, but they resumed hematopoiesis between 7 and 14 days after fertilization and grew to phenotypically normal fish with normal adult hematopoiesis. Our findings suggest that the impact of Gata1 on hematopoiesis correlates with its DNA-binding ability and that primitive hematopoiesis is more sensitive to reduction in Gata1 function than definitive hematopoiesis. (Blood. 2009; 114: 5162-5172) C1 [Belele, Christiane L.; English, Milton A.; Chahal, Jagman; Burnetti, Anthony; Finckbeiner, Steven M.; Kirby, Martha; Sood, Raman; Liu, P. Paul] NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. [Gibney, Gretchen] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Liu, PP (reprint author), 49 Convent Dr,49-3A26, Bethesda, MD 20892 USA. EM rsood@mail.nih.gov; pliu@nhgri.nih.gov RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU National Human Genome Research Institute, National Institutes of Health; United Negro College Merck FX This study was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. M. A. E. was supported by a fellowship from United Negro College Fund/Merck. NR 41 TC 11 Z9 11 U1 1 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 10 PY 2009 VL 114 IS 25 BP 5162 EP 5172 DI 10.1182/blood-2009-05-224709 PG 11 WC Hematology SC Hematology GA 530SH UT WOS:000272612100008 PM 19843882 ER PT J AU Liu, J Yu, LM Coppin, JF Tokar, EJ Diwan, BA Waalkes, MP AF Liu, Jie Yu, Limei Coppin, Jean-Francois Tokar, Erik J. Diwan, Bhalchandra A. Waalkes, Michael P. TI Fetal arsenic exposure appears to facilitate endocrine disruption by postnatal diethylstilbestrol in neonatal mouse adrenal SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Arsenic; Diethylstilbestrol; Carcinogenesis; Gene expression; Neonatal tissues; Adrenal ID ABERRANT GENE-EXPRESSION; IN-UTERO; GESTATIONAL EXPOSURE; DRINKING-WATER; ADULT MICE; LIVER; CARCINOGENESIS; CANCER; TUMORS; ESTROGEN AB Fetal exposure of mice to arsenic and subsequent postnatal diethylstilbestrol (DES) facilitates production of urogenital system and liver tumors in the offspring when they reach adulthood. The adrenal is a target of endocrine disruption that could influence tumor formation at other sites. Thus, we examined possible fetal arsenic-induced adrenal effects as a potential basis of arsenic enhancement of DES carcinogenesis. Pregnant CDI mice were given drinking water containing 85 ppm arsenic as sodium arsenite or unaltered water from day 8 to day 18 of gestation and were allowed to deliver normally. Groups of offspring were subsequently injected s.c. on postpartum days 1-5 with DES (2 mu g/pup/day) and killed on postnatal day 12. Total RNA was isolated from the whole adrenal glands, and the expression of various genes was analyzed by real-time RT-PCR. Fetal arsenic exposure greatly enhanced DES-induced, estrogen-linked gene expression, such as estrogen receptor-a and trefoil factors. Expression of genes involved with steroid metabolism and/or methionine metabolism was also increased. including genes encoding for 17 beta-hydroxysteroid dehydrogenase type 5 (HSD 17 beta 5) and androstenedione 15 alpha-hydroxylase (Cyp2a4). The transcripts for homocysteine cycling genes (betaine-homocysteine methyltransferase and thioether S-methyltransferase) and developmental marker genes (alpha-fetoprotein, insulin-like growth factor 2 and IGF binding protein-1), were also higher with arsenic plus DES than either treatment alone. Thus, exposure of the mouse to arsenic during a critical period of fetal development may potentially alter adrenal genetic programming, leading to endocrine disruption and potentially enhancing tumor formation together with DES at other sites much later in life. Functional studies, such as changes in circulating steroids, would greatly support this hypothesis, and are planned. (C) 2009 Published by Elsevier Ireland Ltd. C1 [Liu, Jie; Yu, Limei; Coppin, Jean-Francois; Tokar, Erik J.; Waalkes, Michael P.] NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Res Triangle Pk, NC 27709 USA. [Yu, Limei] Zunyi Med Coll, Zunyi, Peoples R China. [Diwan, Bhalchandra A.] NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, NCI, Mail Drop F0-09, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research [HHSN261200800001E] FX The authors thank Drs. Wei Qu and Larry Keefer for their critical review of this manuscript. This research was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, and by National Institutes of Health, Basic Science Program 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 32 TC 6 Z9 6 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD DEC 10 PY 2009 VL 182 IS 2-3 BP 253 EP 258 DI 10.1016/j.cbi.2009.07.023 PG 6 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 522SC UT WOS:000272017800022 PM 19665456 ER PT J AU Kadan-Lottick, NS Brouwers, P Breiger, D Kaleita, T Dziura, J Northrup, V Chen, L Nicoletti, M Bostrom, B Stork, L Neglia, JP AF Kadan-Lottick, Nina S. Brouwers, Pim Breiger, David Kaleita, Thomas Dziura, James Northrup, Veronika Chen, Lu Nicoletti, Megan Bostrom, Bruce Stork, Linda Neglia, Joseph P. TI Comparison of Neurocognitive Functioning in Children Previously Randomly Assigned to Intrathecal Methotrexate Compared With Triple Intrathecal Therapy for the Treatment of Childhood Acute Lymphoblastic Leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NERVOUS-SYSTEM LEUKEMIA; LONG-TERM SURVIVORS; CRANIAL IRRADIATION; ONCOLOGY GROUP; CANCER-GROUP; CHEMOTHERAPY; SEQUELAE; DYSFUNCTION; RADIATION AB Purpose For the majority of children with acute lymphoblastic leukemia (ALL), CNS prophylaxis consists of either intrathecal (IT) methotrexate or triple IT therapy (ie, methotrexate with both cytarabine and hydrocortisone). The long-term neurotoxicities of these two IT strategies have not yet been directly compared. Patients and Methods In this multisite study, 171 children with standard-risk ALL, age 1 to 9.99 years at diagnosis, previously randomly assigned to IT methotrexate (n = 82) or to triple IT therapy (n = 89) on CCG 1952, underwent neurocognitive evaluation by a licensed psychologist at a mean of 5.9 years after random assignment. Results Patients who received IT methotrexate had a mean Processing Speed Index that was 3.6 points lower, about one fourth of a standard deviation, than those who received triple IT therapy (P = .04) after analysis was adjusted for age, sex, and time since diagnosis. Likewise, 19.5% of children in the IT methotrexate group had a Processing Speed Index score in the below-average range compared with 6.9% in the triple IT therapy group (P = .02). Otherwise, the groups performed similarly on tests of full-scale intelligence quotient, academic achievement, attention/concentration, memory, and visual motor integration. The association of treatment with measures of cognitive functioning was not modified by sex or age at diagnosis. In the post-therapy period, there were no group differences in special education services, neurologic events, or use of psychotropic medications. Conclusion This study did not show any clinically meaningful differences in neurocognitive functioning between patients previously randomly assigned to IT methotrexate or triple IT therapy except for a small difference in processing speed in the IT methotrexate group. C1 Yale Univ, Sch Med, Sect Pediat Hematol Oncol, New Haven, CT USA. Yale Ctr Clin Invest, New Haven, CT USA. Texas Childrens Canc Ctr, Houston, TX USA. NIMH, Rockville, MD 20857 USA. Univ Washington, Sch Med, Seattle, WA USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. Childrens Oncol Grp Operat Ctr, Arcadia, CA USA. Childrens Hosp & Clin, Minneapolis, MN USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. Oregon Hlth & Sci Univ, Portland, OR 97201 USA. RP Kadan-Lottick, NS (reprint author), 333 Cedar St,LMP 2073,POB 208064, New Haven, CT 06520 USA. EM Nina.Kadan-Lottick@Yale.Edu FU American Cancer Society [RSGPB-03-167-01-PBP]; National Center for Research Resources [KL2 RR024138]; National Institutes of Health (NIH); NIH Roadmap for Medical Research; Children's Oncology Group Chair [U10 CA98543]; Statistics and Data Center [U10 CA98413]; CCOP [U10 CA95861] FX Supported in part by Grant No. RSGPB-03-167-01-PBP from the American Cancer Society (J. N.); Clinical and Translational Science Award Grant No. KL2 RR024138 from the National Center for Research Resources, a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research (N. K.-L.); the Children's Oncology Group Chair Grant No. U10 CA98543; the Statistics and Data Center Grant No. U10 CA98413; and the CCOP Grant No. U10 CA95861. NR 27 TC 42 Z9 42 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 10 PY 2009 VL 27 IS 35 BP 5986 EP 5992 DI 10.1200/JCO.2009.23.5408 PG 7 WC Oncology SC Oncology GA 531GQ UT WOS:000272652700023 PM 19884541 ER PT J AU Dodd, LE Korn, EL Freidlin, B Rubinstein, L Dancey, J Jaffe, CC Mooney, M AF Dodd, Lori E. Korn, Edward L. Freidlin, Boris Rubinstein, Lawrence Dancey, Janet Jaffe, C. Carl Mooney, Margaret TI Are Onsite Image Evaluations the Solution or Are We Trading One Problem for Another? Reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter C1 [Dodd, Lori E.] NIAID, NIH, Bethesda, MD 20892 USA. [Korn, Edward L.; Freidlin, Boris; Rubinstein, Lawrence; Mooney, Margaret] NCI, NIH, Bethesda, MD 20892 USA. [Dancey, Janet] Ontario Inst Canc Res, Toronto, ON, Canada. [Jaffe, C. Carl] Boston Med Ctr, Boston, MA USA. RP Dodd, LE (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. NR 2 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 10 PY 2009 VL 27 IS 35 BP E265 EP E265 DI 10.1200/JCO.2009.25.4342 PG 1 WC Oncology SC Oncology GA 531GQ UT WOS:000272652700046 ER PT J AU Vanan, I Redner, A Atlas, M Marin, L Kadkade, P Bandovic, J Jaffe, ES AF Vanan, Issai Redner, Arlene Atlas, Mark Marin, Lorraine Kadkade, Prajoy Bandovic, Jela Jaffe, Elaine S. TI Solitary Extramedullary Plasmacytoma of the Vocal Cord in an Adolescent SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LARYNX; FOLD; BONE C1 [Vanan, Issai; Redner, Arlene; Atlas, Mark] Schneider Childrens Hosp, Div Hematol Oncol & Stem Cell Transplantat, New Hyde Pk, NY USA. [Marin, Lorraine] Long Isl Jewish Med Ctr, Dept Radiat Med, New Hyde Pk, NY 11042 USA. [Kadkade, Prajoy] Long Isl Jewish Med Ctr, Dept Otorhinolaryngol, New Hyde Pk, NY 11042 USA. [Bandovic, Jela] Long Isl Jewish Med Ctr, Dept Pathol, New Hyde Pk, NY 11042 USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Vanan, I (reprint author), Schneider Childrens Hosp, Div Hematol Oncol & Stem Cell Transplantat, New Hyde Pk, NY USA. NR 15 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD DEC 10 PY 2009 VL 27 IS 35 BP E244 EP E247 DI 10.1200/JCO.2009.23.7461 PG 4 WC Oncology SC Oncology GA 531GQ UT WOS:000272652700034 PM 19858382 ER PT J AU La Regina, G Sarkar, T Bai, RL Edler, MC Saletti, R Coluccia, A Piscitelli, F Minelli, L Gatti, V Mazzoccoli, C Palermo, V Mazzoni, C Falcone, C Scovassi, AI Giansanti, V Campiglia, P Porta, A Maresca, B Hamel, E Brancale, A Novellino, E Silvestri, R AF La Regina, Giuseppe Sarkar, Taradas Bai, Ruoli Edler, Michael C. Saletti, Roberto Coluccia, Antonio Piscitelli, Francesco Minelli, Lara Gatti, Valerio Mazzoccoli, Carmela Palermo, Vanessa Mazzoni, Cristina Falcone, Claudio Scovassi, Anna Ivana Giansanti, Vincenzo Campiglia, Pietro Porta, Amalia Maresca, Bruno Hamel, Ernest Brancale, Andrea Novellino, Ettore Silvestri, Romano TI New Arylthioindoles and Related Bioisosteres at the Sulfur Bridging Group. 4. Synthesis, Tubulin Polymerization, Cell Growth Inhibition, and Molecular Modeling Studies SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POTENT ANTITUBULIN AGENTS; BIOLOGICAL EVALUATION; COLCHICINE; MICROTUBULE; BINDING; YEAST; INDOLES; ANALOGS AB New arylthioindoles along with the corresponding ketone and methylene compounds were potent tubulin assembly inhibitors. As growth inhibitors of MCF-7 cells, sulfur derivatives were superior or sometimes equivalent to the ketones, while methylene derivatives were substantially less effective. Esters 24, 27-29, 36, 39, and 41 showed similar to 50% of inhibition oil human HeLa and HCT116/chr3 cells at 0.5 mu M, and these compounds inhibited the growth of HEK, M 14, and U937 cells with IC(50)'S ill the 78220 nM range. While murine macrophage J744.1 cell growth was significantly less affected (20% at higher concentrations), four other nontransformed cell lines remained sensitive to these esters. The effect of drug treatment oil cell morphology was examined by time-lapse microscopy. In a protocol set up to evaluate toxicity on the Saccharomyces cerevisiae BY4741 wild type strain, compounds 24 and 54 strongly reduced cell growth, and 29, 36, and 39 also showed significant inhibition. C1 [La Regina, Giuseppe; Piscitelli, Francesco; Minelli, Lara; Gatti, Valerio; Mazzoccoli, Carmela; Silvestri, Romano] Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, Inst Pasteur, Fdn Cenci Bolognetti, I-00185 Rome, Italy. [Saletti, Roberto; Coluccia, Antonio; Brancale, Andrea] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales. [Sarkar, Taradas; Bai, Ruoli; Edler, Michael C.; Hamel, Ernest] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Novellino, Ettore] Univ Naples Federico 2, Dipartimento Chim Farmaceut & Tossicol, I-80131 Naples, Italy. [Scovassi, Anna Ivana; Giansanti, Vincenzo] CNR, Ist Genet Mol, I-27100 Pavia, Italy. [Palermo, Vanessa; Mazzoni, Cristina; Falcone, Claudio] Univ Roma La Sapienza, Dipartimento Biol Cellulare & Sviluppo, I-00185 Rome, Italy. [Campiglia, Pietro] Univ Salerno, Dipartimento Sci Farmaceut, Sez Chim Tecnol, I-84084 Salerno, Italy. [Porta, Amalia; Maresca, Bruno] Univ Salerno, Dipartimento Sci Farmaceut, Sez Biomed, I-84084 Salerno, Italy. [Mazzoccoli, Carmela] Ctr Riferimento Oncol Basilicata, Ist Ricovero & Cura Carattere Sci, I-85028 Potenza, Italy. RP Silvestri, R (reprint author), Univ Roma La Sapienza, Dipartimento Chim & Tecnol Farmaco, Inst Pasteur, Fdn Cenci Bolognetti, Piazzale Aldo Moro 5, I-00185 Rome, Italy. EM romano.silvestri@uniroma1.it RI scovassi, anna ivana/F-2458-2010; La Regina, Giuseppe/I-2161-2012; Porta, Amalia/E-9540-2012; Brancale, Andrea/N-9445-2014; OI La Regina, Giuseppe/0000-0003-3252-1161; Porta, Amalia/0000-0001-5947-9472; Brancale, Andrea/0000-0002-9728-3419; /0000-0002-7940-8206; Scovassi, Anna Ivana/0000-0003-3484-9881; Silvestri, Romano/0000-0003-2489-0178; Mazzoni, Cristina/0000-0002-1504-6189 FU Istituto Pasteur-Fondazione Cenci Bolognetti; Progetti di Ricerca di Universita; Sapienza Universita di Roma; FIRC; Fondazione Banca del Monte di Lombardia (Pavia, Italy); Associazione Italiana per la Ricerca sul Cancro FX This research was funded in part by Istituto Pasteur-Fondazione Cenci Bolognetti, and Progetti di Ricerca di Universita, Sapienza Universita di Roma. A.C. thanks Istituto Pasteur-Fondazione Cenci Bolognetti for his Borsa di Studio per Ricerche all'Estero. G.L.R. was supported by a fellowship from FIRC. L.M. thanks Progetti di Ricerca di Universita, Sapienza Universita di Roma, for her Contralto di Collaborazione Esterna per Progetti di Ricerca (Bando 2/2007, Dipartimento di Studi Farmaceutici). This research was also partially Supported by it grant of the Fondazione Banca del Monte di Lombardia (Pavia, Italy) to A.I.S. V.G. is a Ph.D. student from the University of Pavia (Dottorato in Scienze biomolecolari e biotecnologie). NR 32 TC 46 Z9 46 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD DEC 10 PY 2009 VL 52 IS 23 BP 7512 EP 7527 DI 10.1021/jm900016t PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 527AK UT WOS:000272338000020 PM 19601594 ER PT J AU Zhang, Y Lee, YS Rothman, RB Dersch, CM Deschamps, JR Jacobson, AE Rice, KC AF Zhang, Yi Lee, Yong Sok Rothman, Richard B. Dersch, Christina M. Deschamps, Jeffrey R. Jacobson, Arthur E. Rice, Kenner C. TI Probes for Narcotic Receptor Mediated Phenomena. 39. Enantiomeric N-Substituted Benzofuro[2,3-c]pyridin-6-ols: Synthesis and Topological Relationship to Oxide-Bridged Phenylmorphans SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHENETHYL ANALOGS; AFFINITY; ISOMERS; INVERSION AB Enantiomers of N-substituted benzofuro[2,3-c]pyridin-6-ols have been synthesized, and the subnanomolar affinity and potent agonist activity of the known racemic N-phenethyl substituted benzofuro[2,3-c]pyridin-6-ol can now be ascribed to the 4aS,9aR enantiomer. The energy-minimized structures suggest that the active enantiomer bears a greater three-dimensional resemblance to morphine than to an ostensibly structurally similar oxide-bridged phenylmorphan. Structural features of the conformers of N-substituted benzofuro[2,3-c]pyridin-6-ols were compared to provide the rationale for their binding affinity. C1 [Zhang, Yi; Jacobson, Arthur E.; Rice, Kenner C.] NIDA, Drug Design & Synth Sect, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Zhang, Yi; Jacobson, Arthur E.; Rice, Kenner C.] NIAAA, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rothman, Richard B.; Dersch, Christina M.] 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, Struct Matter Lab, Washington, DC 20375 USA. [Lee, Yong Sok] NIH, Ctr Mol Modeling, Div Computat Biosci, CIT,DHHS, Bethesda, MD 20892 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 National Institute of Diabetes and Digestive and Kidney Diseases; National Institute on Drug Abuse (NIDA) [Y1-DA6002]; National Institute of Alcohol Abuse and Alcoholism; NIH Intramural Research Program through the Center for Information Technology FX The research of the Drug Design and Synthesis Section, CBRB, NIDA and NIAAA, 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 (NIDA),and the National Institute of Alcohol Abuse and Alcoholism, and NIDA supported the research of the Clinical Psychopharmacology Section. We thank Dr. John Lloyd (NIDDK) for the mass spectral data, Dr. Amy Newman (NIDA) for the use of her laboratory for some of this work, and NIDA for Support Of the X-ray crystallographic studies (NIDA Contract Y1-DA6002). The quantum chemical study utilized PC/Linux clusters at the Center for Molecular Modeling of the NIH (http://cit.nih.gov), and this research was Supported by the NIH Intramural Research Program through the Center for Information Technology. NR 23 TC 6 Z9 6 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD DEC 10 PY 2009 VL 52 IS 23 BP 7570 EP 7579 DI 10.1021/jm9004225 PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 527AK UT WOS:000272338000024 PM 19627147 ER PT J AU Tosh, DK Chinn, M Ivanov, AA Klutz, AM Gao, ZG Jacobson, KA AF Tosh, Dilip K. Chinn, Moshe Ivanov, Andrei A. Klutz, Athena M. Gao, Zhan-Guo Jacobson, Kenneth A. TI Functionalized Congeners of A(3) Adenosine Receptor-Selective Nucleosides Containing a Bicyclo[3.1.0]hexane Ring System SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HIGH-AFFINITY; PHARMACOLOGICAL CHARACTERIZATION; RHEUMATOID-ARTHRITIS; MOLECULAR PROBES; PARTIAL AGONISTS; HIGHLY POTENT; ANTAGONISTS; LIGANDS; RADIOLIGAND; DERIVATIVES AB (N)-Methanocarba nucleosides containing bicyclo[3.1.0]hexane replacement of the ribose ring previously demonstrated selectivity Lis A(3) adenosine receptor (AR) agonists (5'-uronamides) or antagonists (5'-truncated). Here, these two series were modified in parallel at the adenine C2 position. N-6-3-Chlorobenzyl-5'-N-methyluronamides derivatives with functionalized 2-alkynyl chains of varying length terminating in a reactive carboxylate, ester, or amine group were full, potent human A(3)AR agonists. Flexibility of chain substitution allowed the conjugation with a fluorescent cyanine dye (Cy5) and biotin, resulting in binding K-i values of 17 and 36 nM, respectively. The distal end of the chain was predicted by homology modeling to bind at the A(3)AR extracellular regions. Corresponding L-nucleosides were nearly inactive in AR binding. In the 5'-truncated nucleoside series, 2-Cl analogues were more potent at A(3)AR than 2-H and 2-F, functional efficacy in adenylate cyclase inhibition varied, and introduction of a 2-alkynyl chain greatly reduced affinity. SAR parallels between the two series lost stringency at distal positions. The most potent and selective novel compounds were amine congener 15 (K-i = 2.1 nM) and truncated Partial agonist 22 (K-i = 4.9 nM). C1 [Tosh, Dilip K.; Chinn, Moshe; Ivanov, Andrei A.; Klutz, Athena M.; Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, NIH, LBC, Bethesda, MD 20892 USA. [Ivanov, Andrei A.] Emory Univ, Sch Med, Dept Biochem, Rollins Res Ctr, Atlanta, GA 30322 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, NIH, LBC, Bldg 8A,Rm BIA 19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU NIH, National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Dr. John Lloyd and Dr. Noel Whittaker (NIDDK) for mass spectral determinations. This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases, Dr. Dilip Tosh thanks Can-Fite Biopharma for financial support. NR 52 TC 31 Z9 32 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 EI 1520-4804 J9 J MED CHEM JI J. Med. Chem. PD DEC 10 PY 2009 VL 52 IS 23 BP 7580 EP 7592 DI 10.1021/jm900426g PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 527AK UT WOS:000272338000025 PM 19499950 ER PT J AU Ghosh, AK Kulkarni, S Anderson, DD Hong, L Baldridge, A Wang, YF Chumanevich, AA Kovalevsky, AY Tojo, Y Amano, M Koh, Y Tang, J Weber, IT Mitsuya, H AF Ghosh, Arun K. Kulkarni, Sarang Anderson, David D. Hong, Lin Baldridge, Abigail Wang, Yuan-Fang Chumanevich, Alexander A. Kovalevsky, Andrey Y. Tojo, Yasushi Amano, Masayuki Koh, Yasuhiro Tang, Jordan Weber, Irene T. Mitsuya, Hiroaki TI Design, Synthesis, Protein-Ligand X-ray Structure, and Biological Evaluation of a Series of Novel Macrocyclic Human Immunodeficiency Virus-1 Protease Inhibitors to Combat Drug Resistance SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RESOLUTION CRYSTAL-STRUCTURES; HIV-1 PROTEASE; TYPE-1 PROTEASE; METATHESIS CATALYSTS; HYDROGEN-BONDS; WILD-TYPE; POTENT; COMPLEXES; MUTANTS; GENERATION AB The structure-based design, synthesis, and biological evaluation of a series of nonpeptidic macrocyclic HIV protease inhibitors are described. The inhibitors are designed to effectively fill in the hydrophobic pocket in the S1'-S2' subsites and retain all major hydrogen bonding interactions with the protein backbone similar to darunavir (1) or inhibitor 2. The ring size, the effect of methyl substitution, and unsaturation within the macrocyclic ring structure were assessed. In general, cyclic inhibitors were significantly more potent than their acyclic homologues, saturated rings were less active than their unsaturated analogues and a preference for 10- and 13-membered macrocylic rings was revealed. The addition of methyl substituents resulted in a reduction of potency. Both inhibitors 14b and 14c exhibited marked enzyme inhibitory and antiviral activity, and they exerted potent activity against multidrug-resistant HIV-1 variants. Protein-ligand X-ray structures of inhibitors 2 and 14c provided critical molecular insights into the ligand-binding site interactions. C1 [Ghosh, Arun K.; Kulkarni, Sarang; Anderson, David D.; Baldridge, Abigail] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Ghosh, Arun K.; Kulkarni, Sarang; Anderson, David D.; Baldridge, Abigail] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA. [Hong, Lin; Tang, Jordan] Oklahoma Med Res Fdn, Prot Studies Program, Oklahoma City, OK 73104 USA. [Tang, Jordan] Univ Oklahoma, Hlth Sci Ctr, Dept Biochem & Mol Biol, Oklahoma City, OK 73104 USA. [Wang, Yuan-Fang; Chumanevich, Alexander A.; Kovalevsky, Andrey Y.; Weber, Irene T.] Georgia State Univ, Dept Biol, Atlanta, GA 30303 USA. [Tojo, Yasushi; Amano, Masayuki; Koh, Yasuhiro; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Hematol, Kumamoto 8608556, Japan. [Tojo, Yasushi; Amano, Masayuki; Koh, Yasuhiro; Mitsuya, Hiroaki] Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 8608556, Japan. [Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA. RP Ghosh, AK (reprint author), Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. EM akghosh@purdue.edu RI Amano, Masayuki/N-7407-2016; OI Amano, Masayuki/0000-0003-0516-9502; Kovalevsky, Andrey/0000-0003-4459-9142 FU National Institutes of Health [GM53386, GM062920]; Center for Cancer Research, National Cancer Institute, National Institutes of Health; Ministry of Education, Culture, Sports, Science, and Technology of Japan; Ministry of Health, Welfare, and Labor of Japan [H15-AIDS-001]; U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [DE-AC02-06CH11357] FX The research was supported by grants from the National Institutes of Health (GM53386, A.K.G., and GM062920, I.T.W.). This work was also supported by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, National Institutes of Health, and in part by a Grant-in-Aid for Scientific Research (Priority Areas) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Monbu Kagakusho), a Grant for Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan (Kosei Rohdosho: H15-AIDS-001), and the Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo: no. 78, Kumamoto University) of Monbu-Kagakusho. We thank the staff at the SER-CAT beamline at the Advanced Photon Source, Argonne National Laboratory, for assistance during X-ray data collection. 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 no. DE-AC02-06CH11357. We thank Dr. John Harwood, Purdue University, for many helpful discussions Surrounding NMR spectroscopy. NR 38 TC 27 Z9 28 U1 1 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD DEC 10 PY 2009 VL 52 IS 23 BP 7689 EP 7705 DI 10.1021/jm900695w PG 17 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 527AK UT WOS:000272338000034 PM 19746963 ER PT J AU Knepper, MA Mindell, JA AF Knepper, Mark A. Mindell, Joseph A. TI STRUCTURAL BIOLOGY Molecular coin slots for urea SO NATURE LA English DT Editorial Material ID TRANSPORT C1 [Knepper, Mark A.] NHLBI, Epithelial Syst Biol Lab, NIH, Bethesda, MD 20892 USA. [Mindell, Joseph A.] NINDS, Membrane Transport Biophys Unit, NIH, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Epithelial Syst Biol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Mindell, Joseph/0000-0002-6952-8247 NR 9 TC 8 Z9 9 U1 4 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD DEC 10 PY 2009 VL 462 IS 7274 BP 733 EP 734 DI 10.1038/462733a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529ZZ UT WOS:000272559900026 PM 20010678 ER PT J AU Roche, KW AF Roche, Katherine W. TI Robert J. Wenthold (1948-2009) OBITUARY SO NEURON LA English DT Biographical-Item C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Roche, KW (reprint author), NINDS, NIH, Bethesda, MD 20892 USA. EM rochek@ninds.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD DEC 10 PY 2009 VL 64 IS 5 BP 603 EP 604 DI 10.1016/j.neuron.2009.11.025 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 537OW UT WOS:000273123700006 ER PT J AU Ito, I Bazhenov, M Ong, RCY Raman, B Stopfer, M AF Ito, Iori Bazhenov, Maxim Ong, Rose Chik-ying Raman, Baranidharan Stopfer, Mark TI Frequency Transitions in Odor-Evoked Neural Oscillations SO NEURON LA English DT Article ID OLFACTORY NETWORK DYNAMICS; HIPPOCAMPUS IN-VITRO; MOTH MANDUCA-SEXTA; CAT VISUAL-CORTEX; ANTENNAL LOBES; PROJECTION NEURONS; SPHINX MOTH; SYNAPTIC INHIBITION; GAMMA-OSCILLATIONS; OUTPUT NEURONS AB In many species, sensory stimuli elicit the oscillatory synchronization of groups of neurons. What determines the properties of these oscillations? In the olfactory system of the moth, we found that odors elicited oscillatory synchronization through a neural mechanism like that described in locust and Drosophila. During responses to long odor pulses, oscillations suddenly slowed as net olfactory receptor neuron (ORN) output decreased; thus, stimulus intensity appeared to determine oscillation frequency. However, changing the concentration of the odor had little effect upon oscillatory frequency. Our recordings in vivo and computational models based on these results suggested that the main effect of increasing odor concentration was to recruit additional, less well-tuned ORNs whose firing rates were tightly constrained by adaptation and saturation. Thus, in the periphery, concentration is encoded mainly by the size of the responsive ORN population, and oscillation frequency is set by the adaptation and saturation of this response. C1 [Ito, Iori; Ong, Rose Chik-ying; Raman, Baranidharan; Stopfer, Mark] NICHHD, NIH, Bethesda, MD 20892 USA. [Bazhenov, Maxim] Univ Calif Riverside, Dept Cell Biol & Neurosci, Riverside, CA 92521 USA. [Ong, Rose Chik-ying] Chinese Univ Hong Kong, Dept Biochem, Hong Kong, Hong Kong, Peoples R China. [Raman, Baranidharan] Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. RP Stopfer, M (reprint author), NICHHD, NIH, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov RI NAMEKAWA, IORI/A-3172-2009 FU Japan Society for the Promotion of Science [00169, 70510]; National Research Council; NIH-NIDCD; NIH-NINDS; NIH-NICHD FX We are grateful to members of the Stopfer and Bazhenov laboratories for helpful discussions and to Dr. Marit Stranden for sensilla lessons. We also thank Dr. Kui Sun for her excellent animal care. Microscopy imaging was performed at the Microscopy & Imaging Core (National Institute of Child Health and Human Development, NIH) with the kind assistance of Dr. Vincent Schram. This work was supported by the Japan Society for the Promotion of Science (00169, 70510) to I.I., Joint NIH-NIST postdoctoral fellowship award by National Research Council to B.R., grants from NIH-NIDCD and NIH-NINDS to M.B. and an intramural grant from NIH-NICHD to M.S. NR 66 TC 45 Z9 45 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 EI 1097-4199 J9 NEURON JI Neuron PD DEC 10 PY 2009 VL 64 IS 5 BP 692 EP 706 DI 10.1016/j.neuron.2009.10.004 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 537OW UT WOS:000273123700014 PM 20005825 ER PT J AU Hsieh, MM Kang, EM Fitzhugh, CD Link, MB Bolan, CD Kurlander, R Childs, RW Rodgers, GP Powell, JD Tisdale, JF AF Hsieh, Matthew M. Kang, Elizabeth M. Fitzhugh, Courtney D. Link, M. Beth Bolan, Charles D. Kurlander, Roger Childs, Richard W. Rodgers, Griffin P. Powell, Jonathan D. Tisdale, John F. TI Allogeneic Hematopoietic Stem-Cell Transplantation for Sickle Cell Disease. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID VERSUS-HOST-DISEASE; BONE-MARROW TRANSPLANTATION; PULMONARY-HYPERTENSION; IN-VITRO; T-CELLS; ANEMIA; CHIMERISM; RAPAMYCIN; CAMPATH-1H; SIROLIMUS AB Background: Myeloablative allogeneic hematopoietic stem-cell transplantation is curative in children with sickle cell disease, but in adults the procedure is unduly toxic. Graft rejection and graft-versus-host disease (GVHD) are additional barriers to its success. We performed nonmyeloablative stem-cell transplantation in adults with sickle cell disease. Methods: Ten adults (age range, 16 to 45 years) with severe sickle cell disease underwent nonmyeloablative transplantation with CD34+ peripheral-blood stem cells, mobilized by granulocyte colony-stimulating factor (G-CSF), which were obtained from HLA-matched siblings. The patients received 300 cGy of total-body irradiation plus alemtuzumab before transplantation, and sirolimus was administered afterward. Results: All 10 patients were alive at a median follow-up of 30 months after transplantation (range, 15 to 54). Nine patients had long-term, stable donor lymphohematopoietic engraftment at levels that sufficed to reverse the sickle cell disease phenotype. Mean (+/-SE) donor-recipient chimerism for T cells (CD3+) and myeloid cells (CD14+15+) was 53.3+/-8.6% and 83.3+/-10.3%, respectively, in the nine patients whose grafts were successful. Hemoglobin values before transplantation and at the last follow-up assessment were 9.0+/-0.3 and 12.6+/-0.5 g per deciliter, respectively. Serious adverse events included the narcotic-withdrawal syndrome and sirolimus-associated pneumonitis and arthralgia. Neither acute nor chronic GVHD developed in any patient. Conclusions: A protocol for nonmyeloablative allogeneic hematopoietic stem-cell transplantation that includes total-body irradiation and treatment with alemtuzumab and sirolimus can achieve stable, mixed donor-recipient chimerism and reverse the sickle cell phenotype. (ClinicalTrials.gov number, NCT00061568.) N Engl J Med 2009;361:2309-17. C1 [Hsieh, Matthew M.; Fitzhugh, Courtney D.; Link, M. Beth; Rodgers, Griffin P.; Tisdale, John F.] NIDDKD, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. [Bolan, Charles D.; Childs, Richard W.] NHLBI, Hematol Branch, Bethesda, MD 20892 USA. [Kang, Elizabeth M.] NIAID, Host Def Lab, Bethesda, MD 20892 USA. [Kurlander, Roger] Ctr Clin, Dept Lab Med, Bethesda, MD USA. [Powell, Jonathan D.] Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD USA. RP Tisdale, JF (reprint author), 9000 Rockville Pike,Bldg 10,Rm 9N 116, Bethesda, MD 20892 USA. EM johntis@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [P30 CA006973]; NIAID NIH HHS [R01 AI077610] NR 36 TC 161 Z9 162 U1 4 U2 13 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 10 PY 2009 VL 361 IS 24 BP 2309 EP 2317 DI 10.1056/NEJMoa0904971 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 529VS UT WOS:000272547600005 PM 20007560 ER PT J AU Calado, RT Young, NS AF Calado, Rodrigo T. Young, Neal S. TI Mechanisms of Disease: Telomere Diseases. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID IDIOPATHIC PULMONARY-FIBROSIS; DOMINANT DYSKERATOSIS-CONGENITA; BONE-MARROW-TRANSPLANTATION; HEMATOPOIETIC STEM-CELLS; GENOME-WIDE ASSOCIATION; CORONARY-ARTERY-DISEASE; ACUTE MYELOID-LEUKEMIA; APLASTIC-ANEMIA; MYELODYSPLASTIC SYNDROMES; CHROMOSOMAL INSTABILITY C1 [Calado, Rodrigo T.; Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Calado, RT (reprint author), 10 Ctr Dr,Bldg 10-CRC,Rm 3E-5140, Bethesda, MD 20892 USA. EM calador@nhlbi.nih.gov RI Calado, Rodrigo/G-2619-2011 FU Intramural NIH HHS [Z99 HL999999] NR 101 TC 311 Z9 324 U1 3 U2 26 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 10 PY 2009 VL 361 IS 24 BP 2353 EP 2365 DI 10.1056/NEJMra0903373 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 529VS UT WOS:000272547600009 PM 20007561 ER PT J AU Zhu, LC Li, H Liang, Y Wang, XH Xie, HC Zhang, TY Ito, Y AF Zhu, Licai Li, He Liang, Yong Wang, Xiaohong Xie, Huichun Zhang, Tianyou Ito, Yoichiro TI Application of high-speed counter-current chromatography and preparative high-performance liquid chromatography mode for rapid isolation of anthraquinones from Morinda officinalis How. SO SEPARATION AND PURIFICATION TECHNOLOGY LA English DT Article DE Morinda officinalis How.; Anthraquinones; High-speed counter-current chromatography; Preparative high-performance liquid chromatography ID MEDICINAL-PLANT; 3 FLAVONOIDS; ROOTS; CONSTITUENTS; PURIFICATION; SEPARATION; CULTURES; RATS; L. AB Five anthraquinones including alizarin-l-methylether, 1,2-dimethoxy-3-hydroxyanthraquinone, 1-hydroxy-3-hydroxymethylanthraquinone, rubiadin-1-methylether and anthragallol-2-methylether were isolated and purified by high-speed counter-current chromatography (HSCCC) and followed by preparative high-performance liquid chromatography (prep-HPLC) mode from Morinda officinalis How. n-Hexane-ethyl acetate-methanol-water (6:4:5:5, v/v/v/v) was employed as the two-phase solvent system in HSCCC. Consequently, partially purified fraction "1" (90.6 mg, containing alizarin-1-methylether and 1,2-dimethoxy-3-hydroxyanthraquinone), partially purified fraction "2" (52.5mg, containing 1-hydroxy-3-hydroxymethylanthraquinone and rubiadin-l-methylether) and 19.8 mg anthragallol-2-methylether were obtained from 300 mg of the crude extract. Then the partially purified fractions were further separated by prep-HPLC, which recovered 54.9 mg alizarin-1-methylether, 10.2 mg 1,2-dimethoxy-3-hydroxyanthraquinone, 16.4 mg 1-hydroxy-3-hydroxymethylanthraquinone and 18.2 mg rubiadin-l-methylether. The purity of each compound was over 96%, as determined by HPLC. The structures of five anthraquinones were identified by MS and (1)H NMR. It is the first report of discovering 1,2-dimethoxy-3-hydroxyanthraquinone from the plant of M. officinalis How. The results demonstrated that this separation mode can integrate the advantages of HSCCC and prep-HPLC to improve separation efficiency, and adopted method was a feasible, economical and efficient technique for rapid preparative isolation of complicated natural products. (C) 2009 Elsevier B.V. All rights reserved. C1 [Zhu, Licai; Li, He; Liang, Yong; Wang, Xiaohong; Xie, Huichun] S China Normal Univ, Sch Chem & Environm, Guangzhou 510631, Guangdong, Peoples R China. [Zhang, Tianyou] Beijing Inst New Technol Applicat, Beijing 100035, Peoples R China. [Ito, Yoichiro] NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Liang, Y (reprint author), S China Normal Univ, Sch Chem & Environm, Guangzhou 510631, Guangdong, Peoples R China. EM liangy@scnu.edu.cn FU Bureau of Science and Technology of Guangzhou [2005Z3-E5091] FX The authors acknowledge the Bureau of Science and Technology of Guangzhou (fund no. 2005Z3-E5091) for financial support. NR 19 TC 22 Z9 23 U1 3 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5866 J9 SEP PURIF TECHNOL JI Sep. Purif. Technol. PD DEC 10 PY 2009 VL 70 IS 2 BP 147 EP 152 DI 10.1016/j.seppur.2009.09.009 PG 6 WC Engineering, Chemical SC Engineering GA 531MX UT WOS:000272671800002 ER PT J AU Bansal, S Khandelwal, S Meyers, LA AF Bansal, Shweta Khandelwal, Shashank Meyers, Lauren Ancel TI Exploring biological network structure with clustered random networks SO BMC BIOINFORMATICS LA English DT Article ID PROTEIN INTERACTION NETWORKS; RANDOM GRAPH MODELS; P-ASTERISK MODELS; COMPLEX NETWORKS; COMMUNITY STRUCTURE; SOCIAL NETWORKS; FOOD-WEB; ATTRIBUTES; STABILITY; PATTERNS AB Background: Complex biological systems are often modeled as networks of interacting units. Networks of biochemical interactions among proteins, epidemiological contacts among hosts, and trophic interactions in ecosystems, to name a few, have provided useful insights into the dynamical processes that shape and traverse these systems. The degrees of nodes (numbers of interactions) and the extent of clustering (the tendency for a set of three nodes to be interconnected) are two of many well-studied network properties that can fundamentally shape a system. Disentangling the interdependent effects of the various network properties, however, can be difficult. Simple network models can help us quantify the structure of empirical networked systems and understand the impact of various topological properties on dynamics. Results: Here we develop and implement a new Markov chain simulation algorithm to generate simple, connected random graphs that have a specified degree sequence and level of clustering, but are random in all other respects. The implementation of the algorithm (ClustRNet: Clustered Random Networks) provides the generation of random graphs optimized according to a local or global, and relative or absolute measure of clustering. We compare our algorithm to other similar methods and show that ours more successfully produces desired network characteristics. Finding appropriate null models is crucial in bioinformatics research, and is often difficult, particularly for biological networks. As we demonstrate, the networks generated by ClustRNet can serve as random controls when investigating the impacts of complex network features beyond the byproduct of degree and clustering in empirical networks. Conclusion: ClustRNet generates ensembles of graphs of specified edge structure and clustering. These graphs allow for systematic study of the impacts of connectivity and redundancies on network function and dynamics. This process is a key step in unraveling the functional consequences of the structural properties of empirical biological systems and uncovering the mechanisms that drive these systems. C1 [Bansal, Shweta] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Bansal, Shweta] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Meyers, Lauren Ancel] Univ Texas Austin, Sect Integrat Biol, Austin, TX 78712 USA. [Meyers, Lauren Ancel] Santa Fe Inst, External Fac, Santa Fe, NM 87501 USA. RP Bansal, S (reprint author), Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM shweta@sbansal.com; shrew@alumni.cs.utexas.edu; laurenmeyers@mail.utexas.edu OI Bansal, Shweta/0000-0002-1740-5421 FU University of Texas at Austin; McDonnell Foundation; NSF [DEB-0749097] FX The authors acknowledge valuable feedback from Joel Miller, Mark Newman, Erik Volz, Alberto Segre Ted Herman, and two anonymous reviewers. SB acknowledges financial support from the University of Texas at Austin. LAM acknowledges support from the McDonnell Foundation and NSF grant DEB-0749097. NR 56 TC 39 Z9 40 U1 1 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD DEC 9 PY 2009 VL 10 AR 405 DI 10.1186/1471-2105-10-405 PG 15 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 540KX UT WOS:000273331500002 PM 20003212 ER PT J AU Dickert, NW Wendler, D AF Dickert, Neal W. Wendler, David TI The Investigator-Participant Relationship Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID CARE RESPONSIBILITIES; MEDICAL RESEARCHERS; CLINICAL CARE C1 [Dickert, Neal W.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Wendler, David] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Dickert, NW (reprint author), Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. EM njr@emory.edu NR 2 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 9 PY 2009 VL 302 IS 22 BP 2435 EP 2436 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 529MD UT WOS:000272520500020 ER PT J AU Ballard-Barbash, R Neuhouser, ML AF Ballard-Barbash, Rachel Neuhouser, Marian L. TI Challenges in Design and Interpretation of Observational Research on Health Behaviors and Cancer Survival SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; SOY INTERVENTION; BREAST; RISK; EPIDEMIOLOGY C1 [Ballard-Barbash, Rachel] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Neuhouser, Marian L.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. RP Ballard-Barbash, R (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, EPN 4005,6130 Execut Blvd, Bethesda, MD 20892 USA. EM barbashr@mail.nih.gov NR 14 TC 3 Z9 3 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD DEC 9 PY 2009 VL 302 IS 22 BP 2483 EP 2484 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 529MD UT WOS:000272520500031 PM 19996407 ER PT J AU Shew, WL Yang, HD Petermann, T Roy, R Plenz, D AF Shew, Woodrow L. Yang, Hongdian Petermann, Thomas Roy, Rajarshi Plenz, Dietmar TI Neuronal Avalanches Imply Maximum Dynamic Range in Cortical Networks at Criticality SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CELL ASSEMBLIES; CORTEX; VARIABILITY; RESPONSES; CIRCUITS; OSCILLATIONS; MODULATION; CULTURES; LAYERS; CHAOS AB Spontaneous neuronal activity is a ubiquitous feature of cortex. Its spatiotemporal organization reflects past input and modulates future network output. Here we study whether a particular type of spontaneous activity is generated by a network that is optimized for input processing. Neuronal avalanches are a type of spontaneous activity observed in superficial cortical layers in vitro and in vivo with statistical properties expected from a network operating at "criticality." Theory predicts that criticality and, therefore, neuronal avalanches are optimal for input processing, but until now, this has not been tested in experiments. Here, we use cortex slice cultures grown on planar microelectrode arrays to demonstrate that cortical networks that generate neuronal avalanches benefit from a maximized dynamic range, i.e., the ability to respond to the greatest range of stimuli. By changing the ratio of excitation and inhibition in the cultures, we derive a network tuning curve for stimulus processing as a function of distance from criticality in agreement with predictions from our simulations. Our findings suggest that in the cortex, (1) balanced excitation and inhibition establishes criticality, which maximizes the range of inputs that can be processed, and (2) spontaneous activity and input processing are unified in the context of critical phenomena. C1 [Plenz, Dietmar] NIMH, Sect Crit Brain Dynam, Lab Syst Neurosci, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. [Yang, Hongdian; Roy, Rajarshi] Univ Maryland, Inst Phys Sci & Technol, College Pk, MD 20742 USA. RP Plenz, D (reprint author), NIMH, Sect Crit Brain Dynam, Lab Syst Neurosci, Porter Neurosci Res Ctr, Room 3A-100,35 Convent Dr, Bethesda, MD 20892 USA. EM plenzd@mail.nih.gov RI Yang, Hongdian/D-1450-2015; OI Shew, Woodrow/0000-0003-0679-1766 FU Department of Defense Multidisciplinary University Research Initiative [ONR N000140710734]; Swiss National Science Foundation [PBEL2-110211] FX This work was supported by the Intramural Research Program of the National Institute of Mental Health. R. R. acknowledges support from a Department of Defense Multidisciplinary University Research Initiative grant (ONR N000140710734) to the University of Maryland. T. P. is also grateful to the Swiss National Science Foundation (Grant PBEL2-110211) for financial support. We thank Craig Stewart for help with preparing the cultures. NR 30 TC 164 Z9 164 U1 1 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 9 PY 2009 VL 29 IS 49 BP 15595 EP 15600 DI 10.1523/JNEUROSCI.3864-09.2009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 532HF UT WOS:000272736400026 PM 20007483 ER PT J AU Xia, MH Bi, K Huang, RL Cho, MH Sakamuru, S Miller, SC Li, H Sun, Y Printen, J Austin, CP Inglese, J AF Xia, Menghang Bi, Kun Huang, Ruili Cho, Ming-Hsuang Sakamuru, Srilatha Miller, Susanne C. Li, Hua Sun, Yi Printen, John Austin, Christopher P. Inglese, James TI Identification of small molecule compounds that inhibit the HIF-1 signaling pathway SO MOLECULAR CANCER LA English DT Article ID INDUCIBLE FACTOR-I; ENDOTHELIAL GROWTH-FACTOR; HIGH-THROUGHPUT; FACTOR 1-ALPHA; CANCER-THERAPY; HYPOXIA; HIF-1-ALPHA; HYDROXYLATION; TRANSCRIPTION; ACTIVATION AB Background: Hypoxia-inducible factor-1 (HIF-1) is the major hypoxia-regulated transcription factor that regulates cellular responses to low oxygen environments. HIF-1 is composed of two subunits: hypoxia-inducible HIF-1 alpha and constitutively-expressed HIF-1 beta. During hypoxic conditions, HIF-1 alpha heterodimerizes with HIF-1 beta and translocates to the nucleus where the HIF-1 complex binds to the hypoxia-response element (HRE) and activates expression of target genes implicated in cell growth and survival. HIF-1 alpha protein expression is elevated in many solid tumors, including those of the cervix and brain, where cells that are the greatest distance from blood vessels, and therefore the most hypoxic, express the highest levels of HIF-1 alpha. Therapeutic blockade of the HIF-1 signaling pathway in cancer cells therefore provides an attractive strategy for development of anticancer drugs. To identify small molecule inhibitors of the HIF-1 pathway, we have developed a cell-based reporter gene assay and screened a large compound library by using a quantitative high-throughput screening (qHTS) approach. Results: The assay is based upon a beta-lactamase reporter under the control of a HRE. We have screened approximate 73,000 compounds by qHTS, with each compound tested over a range of seven to fifteen concentrations. After qHTS we have rapidly identified three novel structural series of HIF-1 pathway Inhibitors. Selected compounds in these series were also confirmed as inhibitors in a HRE beta-lactamase reporter gene assay induced by low oxygen and in a VEGF secretion assay. Three of the four selected compounds tested showed significant inhibition of hypoxia-induced HIF-1 alpha accumulation by western blot analysis. Conclusion: The use of beta-lactamase reporter gene assays, in combination with qHTS, enabled the rapid identification and prioritization of inhibitors specific to the hypoxia induced signaling pathway. C1 [Xia, Menghang; Huang, Ruili; Cho, Ming-Hsuang; Sakamuru, Srilatha; Miller, Susanne C.; Austin, Christopher P.; Inglese, James] NIH, NIH Chem Genom Ctr, Bethesda, MD 20892 USA. [Bi, Kun; Printen, John] Invitrogen Discovery Sci, Madison, WI 53719 USA. [Li, Hua; Sun, Yi] Univ Michigan, Ctr Comprehens Canc, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. RP Xia, MH (reprint author), NIH, NIH Chem Genom Ctr, Bldg 10, Bethesda, MD 20892 USA. EM mxia@mail.nih.gov; Kun.Bi@invitrogen.com; huangru@mail.nih.gov; chomi@mail.nih.gov; sakamurus@mail.nih.gov; smille10@umd.edu; huali@med.umich.edu; sunyi@med.umich.edu; John.Printen@Invitrogen.com; austinc@mail.nih.gov; jinglese@mail.nih.gov FU Molecular Libraries Initiative of the NIH Roadmap; National Human Genome Research Institute, National Institutes of Health FX We thank S. Michael, C. Klumpp and Paul Shinn for assistance with automated screening, and Dr. Ron Johnson for critical reading for the manuscript. This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. NR 34 TC 11 Z9 11 U1 0 U2 6 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 9 PY 2009 VL 8 AR 117 DI 10.1186/1476-4598-8-117 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 536PF UT WOS:000273055600001 PM 20003191 ER PT J AU Himmel, DM Maegley, KA Pauly, TA Bauman, JD Das, K Dharia, C Clark, AD Ryan, K Hickey, MJ Love, RA Hughes, SH Bergqvist, S Arnold, E AF Himmel, Daniel M. Maegley, Karen A. Pauly, Tom A. Bauman, Joseph D. Das, Kalyan Dharia, Chhaya Clark, Arthur D., Jr. Ryan, Kevin Hickey, Michael J. Love, Robert A. Hughes, Stephen H. Bergqvist, Simon Arnold, Eddy TI Structure of HIV-1 Reverse Transcriptase with the Inhibitor beta-Thujaplicinol Bound at the RNase H Active Site SO STRUCTURE LA English DT Article ID DOUBLE-STRANDED DNA; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; RIBONUCLEASE-H; ANGSTROM RESOLUTION; SUBSTRATE-SPECIFICITY; MAXIMUM-LIKELIHOOD; RNA/DNA HYBRID; DIKETO ACID; MECHANISM AB Novel inhibitors are needed to counteract the rapid emergence of drug-resistant HIV variants. HIV-1 reverse transcriptase (RT) has both DNA polymerase and RNase H (RNH) enzymatic activities, but approved drugs that inhibit RT target the polymerase. Inhibitors that act against new targets, such as RNH, should be effective against all of the current drug-resistant variants. Here, we present 2.80 angstrom and 2.04 angstrom resolution crystal structures of an RNH inhibitor, beta-thujaplicinol, bound at the RNH active site of both HIV-1 RT and an isolated RNH domain. beta-thujaplicinol chelates two divalent metal ions at the RNH active site. We provide biochemical evidence that beta-thujaplicinol is a slow-binding RNH inhibitor with noncompetitive kinetics and suggest that it forms a tropylium ion that interacts favorably with RT and the RNA:DNA substrate. C1 [Himmel, Daniel M.; Bauman, Joseph D.; Das, Kalyan; Dharia, Chhaya; Clark, Arthur D., Jr.; Arnold, Eddy] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Himmel, Daniel M.; Bauman, Joseph D.; Das, Kalyan; Dharia, Chhaya; Clark, Arthur D., Jr.; Arnold, Eddy] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. [Maegley, Karen A.; Pauly, Tom A.; Ryan, Kevin; Hickey, Michael J.; Love, Robert A.; Bergqvist, Simon] Pfizer Global Res & Dev, La Jolla Labs, San Diego, CA 92121 USA. [Hughes, Stephen H.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Arnold, E (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. EM arnold@cabm.rutgers.edu FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [AI 27690, R37 AI027690] NR 54 TC 68 Z9 69 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD DEC 9 PY 2009 VL 17 IS 12 BP 1625 EP 1635 DI 10.1016/j.str.2009.09.016 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 532QB UT WOS:000272763400011 PM 20004166 ER PT J AU Sagara, I Ellis, RD Dicko, A Niambele, MB Kamate, B Guindo, O Sissoko, MS Fay, MP Guindo, MA Kante, O Saye, R Miura, K Long, C Mullen, GED Pierce, M Martin, LB Rausch, K Dolo, A Diallo, DA Miller, LH Doumbo, OK AF Sagara, Issaka Ellis, Ruth D. Dicko, Alassane Niambele, Mohamed B. Kamate, Beh Guindo, Ousmane Sissoko, Mahamadou S. Fay, Michael P. Guindo, Merepen A. Kante, Ousmane Saye, Renion Miura, Kazutoyo Long, Carole Mullen, Gregory E. D. Pierce, Mark Martin, Laura B. Rausch, Kelly Dolo, Amagana Diallo, Dapa A. Miller, Louis H. Doumbo, Ogobara K. TI A randomized and controlled Phase 1 study of the safety and immunogenicity of the AMA1-C1/Alhydrogel (R) + CPG 7909 vaccine for Plasmodium falciparum malaria in semi-immune Malian adults SO VACCINE LA English DT Article DE Malaria; Vaccine; AMA1-C1; CPG ID APICAL MEMBRANE ANTIGEN-1; IMMUNOSTIMULATORY CPG-OLIGODEOXYNUCLEOTIDES; PLASMODIUM-FALCIPARUM MALARIA; TOLL-LIKE RECEPTOR-9; BLOOD-STAGE VACCINE; CLINICAL MALARIA; ANTIBODY-RESPONSES; CONTROLLED-TRIAL; AMA1 VACCINE; PROTECTION AB A double blind, randomized and controlled Phase 1 clinical trial was conducted to assess the safety and immunogenicity in malaria-exposed adults of the Plasmodium falciparum blood stage vaccine candidate Apical Membrane Antigen 1-Combination 1 (AMA1-C1)/Alhydrogel(R) with and without the novel adjuvant CPG 7909. Participants were healthy adults 18-45 years old living in the village of Donegubougou, Mali. A total of 24 participants received 2 doses one month apart of either 80 mu g AMA1-C1 /Alhydrogel(R) or 80 mu g AMA1-C1/Alhydrogel(R) + 564 mu g CPG 7909. The study started in October 2007 and completed follow up in May 2008. Both vaccines were well tolerated, with only mild local adverse events and no systemic adverse events judged related to vaccination. The difference in antibody responses were over 2-fold higher in the group receiving CPG 7909 for all time points after second vaccination and the differences are statistically significant (all p < 0.05). This is the first use of the novel adjuvant CPG 7909 in a malaria-exposed population. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Sagara, Issaka; Dicko, Alassane; Niambele, Mohamed B.; Kamate, Beh; Guindo, Ousmane; Sissoko, Mahamadou S.; Guindo, Merepen A.; Kante, Ousmane; Saye, Renion; Dolo, Amagana; Diallo, Dapa A.; Doumbo, Ogobara K.] Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, Bamako, Mali. [Ellis, Ruth D.; Miura, Kazutoyo; Mullen, Gregory E. D.; Pierce, Mark; Martin, Laura B.; Rausch, Kelly; Miller, Louis H.] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Long, Carole] NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD USA. RP Sagara, I (reprint author), Univ Bamako, Fac Med Pharm & Dent, Malaria Res & Training Ctr, BP 1805, Bamako, Mali. EM isagara@icermali.org; ellisru@niaid.nih.gov RI Martin, Laura/N-1789-2013 OI Martin, Laura/0000-0002-4431-4381 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health; GIA Reference Center FX This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. We thank Pr. Marnadou Dembele, Dr. Mohamed Keita, Dr. Mamadou Traore, PPD study monitors, MAID DSMB, Etsegenet Meshesha, Dick Sakai, Drissa Sow, and the volunteers in the villages for their support. We would also like to acknowledge Hong Zhou, Sam Moretz, Ababacar Diouf and Greg Tullo for the GIA work and the PATH/Malaria Vaccine Initiative for their support of the GIA Reference Center. CPG 7909 was supplied by Coley Pharmaceuticals, a Pfizer Company. NR 38 TC 44 Z9 45 U1 0 U2 2 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 9 PY 2009 VL 27 IS 52 BP 7292 EP 7298 DI 10.1016/j.vaccine.2009.10.087 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 541KP UT WOS:000273414900010 PM 19874925 ER PT J AU Traore, B Kone, Y Doumbo, S Doumtabe, D Traore, A Crompton, PD Mircetic, M Huang, CY Kayentao, K Dicko, A Sagara, I Ellis, RD Miura, K Guindo, A Miller, LH Doumbo, OK Pierce, SK AF Traore, Boubacar Kone, Younoussou Doumbo, Safiatou Doumtabe, Didier Traore, Abdramane Crompton, Peter D. Mircetic, Marko Huang, Chiung-Yu Kayentao, Kassoum Dicko, Alassane Sagara, Issaka Ellis, Ruth D. Miura, Kazutoyo Guindo, Agnes Miller, Louis H. Doumbo, Ogobara K. Pierce, Susan K. TI The TLR9 agonist CpG fails to enhance the acquisition of Plasmodium falciparum-specific memory B cells in semi-immune adults in Mali SO VACCINE LA English DT Article DE Memory B cells; Plasmodium falciparum; Malaria; Toll-like receptor 9 ID CHRONIC VIRAL-INFECTION; MALARIA; ACTIVATION; RESPONSES; VACCINE; INDIVIDUALS; EXHAUSTION; ANTIBODY; HUMANS AB Antibodies play a key role in controlling blood stage malaria infections, and an effective blood stage malaria vaccine will likely require that it induce vaccine-specific memory B cells (MBCs). Our previous studies showed that the addition of the TLR9 agonist CpG to Plasmodium falciparum protein subunit vaccines greatly increased their efficacy in inducing MBCs in nonimmune U.S. volunteers. Here we show that in contrast the same CpG-containing malaria vaccine did not enhance the acquisition of MBCs in semi-immune adults living in Mali. Understanding the molecular basis of this apparent refractoriness to TLR9 agonist will be of significant interest in vaccine design. Published by Elsevier Ltd. C1 [Traore, Boubacar; Kone, Younoussou; Doumbo, Safiatou; Doumtabe, Didier; Traore, Abdramane; Kayentao, Kassoum; Dicko, Alassane; Sagara, Issaka; Guindo, Agnes; Doumbo, Ogobara K.] Malaria Res & Training Ctr, Fac Med Pharm & Odontostomatol, Dept Epidemiol Parasit Dis DEAP, Bamako, Mali. [Huang, Chiung-Yu] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Crompton, Peter D.; Mircetic, Marko; Pierce, Susan K.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Ellis, Ruth D.; Miura, Kazutoyo; Miller, Louis H.] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD USA. RP Traore, B (reprint author), Malaria Res & Training Ctr, Fac Med Pharm & Odontostomatol, Dept Epidemiol Parasit Dis DEAP, BP 1805, Bamako, Mali. EM Bouba.traore@mrtcbko.org; spierce@nih.gov RI Crompton, Peter/N-1130-2016 FU National institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Intramural Research Program of the National institute of Allergy and Infectious Diseases, National Institutes of Health. The authors are grateful for the gracious participation of the study volunteers of Donegoubougou and the diligent efforts of the members of the Malaria Vaccine Development Branch and the Malaria Research and Training Center clinical trial teams. Thanks to Coley Pharmaceuticals, a Pfizer Company, for supplying CPG 7909. NR 24 TC 30 Z9 31 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD DEC 9 PY 2009 VL 27 IS 52 BP 7299 EP 7303 DI 10.1016/j.vaccine.2009.08.023 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 541KP UT WOS:000273414900011 PM 19712767 ER PT J AU Osorio, A Milne, RL Pita, G Peterlongo, P Heikkinen, T Simard, J Chenevix-Trench, G Spurdle, AB Beesley, J Chen, X Healey, S Neuhausen, SL Ding, YC Couch, FJ Wang, X Lindor, N Manoukian, S Barile, M Viel, A Tizzoni, L Szabo, CI Foretova, L Zikan, M Claes, K Greene, MH Mai, P Rennert, G Lejbkowicz, F Barnett-Griness, O Andrulis, IL Ozcelik, H Weerasooriya, N Gerdes, AM Thomassen, M Cruger, DG Caligo, MA Friedman, E Kaufman, B Laitman, Y Cohen, S Kontorovich, T Gershoni-Baruch, R Dagan, E Jernstrom, H Askmalm, MS Arver, B Malmer, B Domchek, SM Nathanson, KL Brunet, J Cajal, TRY Yannoukakos, D Hamann, U Hogervorst, FBL Verhoef, S Garcia, EBG Wijnen, JT van den Ouweland, A Easton, DF Peock, S Cook, M Oliver, CT Frost, D Luccarini, C Evans, DG Lalloo, F Eeles, R Pichert, G Cook, J Hodgson, S Morrison, PJ Douglas, F Godwin, AK Sinilnikova, OM Barjhoux, L Stoppa-Lyonnet, D Moncoutier, V Giraud, S Cassini, C Olivier-Faivre, L Revillion, F Peyrat, JP Muller, D Fricker, JP Lynch, HT John, EM Buys, S Daly, M Hopper, JL Terry, MB Miron, A Yassin, Y Goldgar, D Singer, CF Gschwantler-Kaulich, D Pfeiler, G Spiess, AC Hansen, TV Johannsson, OT Kirchhoff, T Offit, K Kosarin, K Piedmonte, M Rodriguez, GC Wakeley, K Boggess, JF Basil, J Schwartz, PE Blank, SV Toland, AE Montagna, M Casella, C Imyanitov, EN Allavena, A Schmutzler, RK Versmold, B Engel, C Meindl, A Ditsch, N Arnold, N Niederacher, D Deissler, H Fiebig, B Varon-Mateeva, R Schaefer, D Froster, UG Caldes, T de la Hoya, M McGuffog, L Antoniou, AC Nevanlinna, H Radice, P Benitez, J AF Osorio, A. Milne, R. L. Pita, G. Peterlongo, P. Heikkinen, T. Simard, J. Chenevix-Trench, G. Spurdle, A. B. Beesley, J. Chen, X. Healey, S. Neuhausen, S. L. Ding, Y. C. Couch, F. J. Wang, X. Lindor, N. Manoukian, S. Barile, M. Viel, A. Tizzoni, L. Szabo, C. I. Foretova, L. Zikan, M. Claes, K. Greene, M. H. Mai, P. Rennert, G. Lejbkowicz, F. Barnett-Griness, O. Andrulis, I. L. Ozcelik, H. Weerasooriya, N. Gerdes, A-M Thomassen, M. Cruger, D. G. Caligo, M. A. Friedman, E. Kaufman, B. Laitman, Y. Cohen, S. Kontorovich, T. Gershoni-Baruch, R. Dagan, E. Jernstrom, H. Askmalm, M. S. Arver, B. Malmer, B. Domchek, S. M. Nathanson, K. L. Brunet, J. Ramon y Cajal, T. Yannoukakos, D. Hamann, U. Hogervorst, F. B. L. Verhoef, S. Gomez Garcia, E. B. Wijnen, J. T. van den Ouweland, A. Easton, D. F. Peock, S. Cook, M. Oliver, C. T. Frost, D. Luccarini, C. Evans, D. G. Lalloo, F. Eeles, R. Pichert, G. Cook, J. Hodgson, S. Morrison, P. J. Douglas, F. Godwin, A. K. Sinilnikova, O. M. Barjhoux, L. Stoppa-Lyonnet, D. Moncoutier, V. Giraud, S. Cassini, C. Olivier-Faivre, L. Revillion, F. Peyrat, J-P Muller, D. Fricker, J-P Lynch, H. T. John, E. M. Buys, S. Daly, M. Hopper, J. L. Terry, M. B. Miron, A. Yassin, Y. Goldgar, D. Singer, C. F. Gschwantler-Kaulich, D. Pfeiler, G. Spiess, A-C Hansen, Thomas v. O. Johannsson, O. T. Kirchhoff, T. Offit, K. Kosarin, K. Piedmonte, M. Rodriguez, G. C. Wakeley, K. Boggess, J. F. Basil, J. Schwartz, P. E. Blank, S. V. Toland, A. E. Montagna, M. Casella, C. Imyanitov, E. N. Allavena, A. Schmutzler, R. K. Versmold, B. Engel, C. Meindl, A. Ditsch, N. Arnold, N. Niederacher, D. Deissler, H. Fiebig, B. Varon-Mateeva, R. Schaefer, D. Froster, U. G. Caldes, T. de la Hoya, M. McGuffog, L. Antoniou, A. C. Nevanlinna, H. Radice, P. Benitez, J. CA KConFab OCGN SWE-BRCA HEBON EMBRACE GEMO Breast Cancer Family Registry CIMBA TI Evaluation of a candidate breast cancer associated SNP in ERCC4 as a risk modifier in BRCA1 and BRCA2 mutation carriers. Results from the Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA) SO BRITISH JOURNAL OF CANCER LA English DT Article DE BRCA1; BRCA2; ERCC4; breast cancer ID EXCISION-REPAIR; OVARIAN-CANCER; POLYMORPHISMS; GENES; NUCLEOTIDE AB BACKGROUND: In this study we aimed to evaluate the role of a SNP in intron I of the ERCC4 gene (rs744154), previously reported to be associated with a reduced risk of breast cancer in the general population, as a breast cancer risk modifier in BRCA1 and BRCA2 mutation carriers. METHODS: We have genotyped rs744154 in 9408 BRCA1 and 5632 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and assessed its association with breast cancer risk using a retrospective weighted cohort approach. RESULTS: We found no evidence of association with breast cancer risk for BRCA1 (per-allele HR: 0.98, 95% CI: 0.93-1.04, P = 0.5) or BRCA2 (per-allele HR: 0.97, 95% CI: 0.89-1.06, P = 0.5) mutation carriers. CONCLUSION: This SNP is not a significant modifier of breast cancer risk for mutation carriers, though weak associations cannot be ruled out. British Journal of Cancer (2009) 101, 2048-2054. doi: 10.1038/sj.bjc.6605416 www.bjcancer.com Published online 17 November 2009 (C) 2009 Cancer Research UK C1 [Osorio, A.; Benitez, J.] Spanish Natl Canc Res Ctr, Human Genet Grp, Madrid, Spain. [Milne, R. L.] Spanish Natl Canc Res Ctr, Genet & Mol Epidemiol Grp, Madrid, Spain. [Pita, G.; Benitez, J.] Spanish Natl Canc Res Ctr, Human Canc Genet Programme, Genotyping Unit, Madrid, Spain. [Peterlongo, P.; Manoukian, S.; Radice, P.] Fdn IRCCS Ist Nazl Tumori, Milan, Italy. [Peterlongo, P.; Tizzoni, L.; Radice, P.] Fdn Ist FIRC Oncol Mol, Milan, Italy. [Heikkinen, T.; Nevanlinna, H.] Helsinki Univ Cent Hosp, Dept Obstet & Gynaecol, Helsvinki, Finland. [Simard, J.] Ctr Hosp Univ Quebec, Canc Genom Lab, Canada Res Chair Oncogenet, Quebec City, PQ, Canada. [Simard, J.] Univ Laval, Quebec City, PQ, Canada. [Chenevix-Trench, G.; Spurdle, A. B.; Beesley, J.; Chen, X.; Healey, S.] Queensland Inst Med Res, Div Genet & Populat Hlth, Brisbane, Qld 4006, Australia. [KConFab] Peter MacCallum Canc Ctr, Div Res, Melbourne, Vic, Australia. [Neuhausen, S. L.; Ding, Y. C.] Univ Calif Irvine, Sch Med, Dept Epidemiol, Irvine, CA 92717 USA. [Couch, F. J.; Wang, X.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN USA. [Couch, F. J.] Mayo Clin, Dept Hlth Sci Res, Rochester, MN USA. [Lindor, N.] Mayo Clin, Dept Med Genet, Rochester, MN USA. [Barile, M.] Ist Europeo Oncol, Milan, Italy. [Viel, A.] IRCCS, Ctr Riferimento Oncol, Aviano, PN, Italy. [Tizzoni, L.] Consortium Genom Technol, Milan, Italy. [Szabo, C. I.] Mayo Clin, Coll Med, Dept Lab Med & Pathol, Rochester, MN USA. [Foretova, L.] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Zikan, M.] Charles Univ Prague, Fac Med 1, Dept Biochem & Expt Oncol, Prague, Czech Republic. [Claes, K.] Ghent Univ Hosp, Ctr Med Genet, B-9000 Ghent, Belgium. [Greene, M. H.; Mai, P.] NCI, Clin Genet Branch, Rockville, MD USA. [Rennert, G.; Lejbkowicz, F.; Barnett-Griness, O.] Carmel Hosp, CHS Natl Canc Control Ctr, Haifa, Israel. [Rennert, G.; Lejbkowicz, F.; Barnett-Griness, O.] Technion Israel Inst Technol, Fac Med, Haifa, Israel. [Andrulis, I. L.; Weerasooriya, N.; OCGN] Ontario Canc Genet Network, Toronto, ON, Canada. [Andrulis, I. L.; Ozcelik, H.] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Fred A Litwin Ctr Canc Genet, Toronto, ON M5G 1X5, Canada. [Gerdes, A-M; Thomassen, M.] Odense Univ Hosp, Clin Genet BFG, DK-5000 Odense, Denmark. [Cruger, D. G.] Vejle Hosp, Dept Clin Genet, Vijle, Denmark. [Caligo, M. A.] Univ Pisa, Dept Oncol, Div Pathol, Pisa, Italy. [Caligo, M. A.] Univ Hosp Pisa, Pisa, Italy. [Friedman, E.; Kaufman, B.; Laitman, Y.; Cohen, S.; Kontorovich, T.] Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Friedman, E.; Kaufman, B.] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Gershoni-Baruch, R.] Rambam Med Ctr, Haifa, Israel. [Dagan, E.] Univ Haifa, Fac Social Welf & Hlth Sci, Dept Nursing, IL-31999 Haifa, Israel. [Dagan, E.] Inst Human Genet, Haifa, Israel. [Jernstrom, H.] Lund Univ, Dept Oncol, Lund, Sweden. [Askmalm, M. S.] Linkoping Univ Hosp, Dept Oncol, S-58185 Linkoping, Sweden. [Arver, B.] Karolinska Univ Hosp, Dept Oncol, Stockholm, Sweden. [Malmer, B.] Umea Univ, Dept Radiat Sci, Umea, Sweden. [Domchek, S. M.; Nathanson, K. L.] Univ Penn, Abramson Canc Ctr, Philadelphia, PA 19104 USA. [Brunet, J.] Hosp Dr Josep Trueta IdiBGi, Inst Catalan Oncol, Programa Consejo Genet Canc, Girona, Spain. [Ramon y Cajal, T.] Hosp Santa Creu & Sant Pau, Med Oncol Serv, Barcelona, Spain. [Yannoukakos, D.] Demokritos Natl Ctr Sci Res, IRRP, Mol Diagnost Lab, GR-15310 Athens, Greece. [Hamann, U.] Deutsch Krebsforschungszentrum, D-6900 Heidelberg, Germany. [Hogervorst, F. B. L.; Verhoef, S.] Netherlands Canc Inst, Family Canc Clin, Dept Clin Mol Genet, Amsterdam, Netherlands. [Gomez Garcia, E. B.] Univ Med Ctr, Dept Genet & Cell Biol, Maastricht, Netherlands. [Gomez Garcia, E. B.] Res Inst Growth & Dev, Maastricht, Netherlands. [Wijnen, J. T.] Leiden Univ, Med Ctr, Dept Clin Mol Genet, Leiden, Netherlands. [Wijnen, J. T.] Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. [van den Ouweland, A.] Erasmus Univ, Med Ctr, Dept Mol Genet, Rotterdam, Netherlands. [Easton, D. F.; Peock, S.; Cook, M.; Oliver, C. T.; Frost, D.; McGuffog, L.; Antoniou, A. C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England. [Luccarini, C.] Univ Cambridge, Dept Oncol, Cambridge, England. [Evans, D. G.; Lalloo, F.] St Marys Hosp, Acad Unit Med Genet, Manchester M13 0JH, Lancs, England. [Evans, D. G.; Lalloo, F.] St Marys Hosp, Reg Genet Serv, Manchester M13 0JH, Lancs, England. [Eeles, R.] Inst Canc Res, Translat Canc Genet Team, London SW3 6JB, England. [Eeles, R.] Royal Marsden NHS Fdn Trust, London, England. [Pichert, G.] Guys Hosp, London SE1 9RT, England. [Cook, J.] Sheffield Childrens Hosp, Sheffield Clin Genet Serv, Sheffield, S Yorkshire, England. [Hodgson, S.] Univ London, St Georges Hosp, Dept Canc Genet, London, England. [Morrison, P. J.] Belfast City Hosp, No Ireland Reg Genet Ctr, Belfast BT9 7AD, Antrim, North Ireland. [Douglas, F.] Newcastle Upon Tyne Hosp NHS Trust, Inst Human Genet, Ctr Life, Newcastle Upon Tyne, Tyne & Wear, England. [Godwin, A. K.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Sinilnikova, O. M.; Barjhoux, L.; Giraud, S.] Hosp Civils Lyon, Ctr Leon Berard, Unite Mixte Genet Constitut Canc Frequents, Lyon, France. [Sinilnikova, O. M.; Barjhoux, L.] Univ Lyon, Lab Genet Mol Signalisat & Canc, CNRS, UMR5201, Lyon, France. [Stoppa-Lyonnet, D.; Moncoutier, V.; GEMO] Univ Paris 05, Inst Curie, Serv Gent Oncol, INSERM,U509, Paris, France. [Cassini, C.; Olivier-Faivre, L.] Ctr Genet, Dijon, France. [Cassini, C.; Olivier-Faivre, L.] CLCC Georges Francois Leclerc, Dijon, France. [Revillion, F.; Peyrat, J-P] Ctr Oscar Lambret, Human Mol Oncol Lab, F-59020 Lille, France. [Muller, D.; Fricker, J-P] CLCC Paul Strauss, Unite Oncogenet, Strasbourg, France. [Lynch, H. T.] Creighton Univ, Dept Prevent Med, Omaha, NE 68178 USA. [John, E. M.] No Calif Canc Ctr, Fremont, CA USA. [Buys, S.] Huntsman Canc Inst, Salt Lake City, UT USA. [Daly, M.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Hopper, J. L.] Univ Melbourne, Melbourne, Vic, Australia. [Terry, M. B.] Columbia Univ, New York, NY USA. [Miron, A.; Yassin, Y.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Goldgar, D.] Univ Utah, Dept Dermatol, Salt Lake City, UT USA. [Singer, C. F.; Gschwantler-Kaulich, D.; Pfeiler, G.; Spiess, A-C] Med Univ Vienna, Dept OB GYN, Div Special Gynecol, Vienna, Austria. [Hansen, Thomas v. O.] Odense Univ Hosp, Dept Biochem Pharmacol & Genet, DK-5000 Odense, Denmark. [Johannsson, O. T.] Landspitali Univ Hosp, Dept Oncol, Reykjavik, Iceland. [Kirchhoff, T.; Offit, K.; Kosarin, K.] Mem Sloan Kettering Canc Ctr, Dept Med, Clin Genet Serv, New York, NY 10021 USA. [Piedmonte, M.] Roswell Pk Canc Inst, GOG Stat & Data Ctr, Buffalo, NY 14263 USA. [Rodriguez, G. C.] Evanston NW Healthcare, NorthShore Univ Hlth Syst, Evanston, IL USA. [Wakeley, K.] Tufts Univ, New England Med Ctr, Boston, MA 02111 USA. [Boggess, J. F.] Univ N Carolina, Chapel Hill, NC USA. [Basil, J.] St Elizabeth Hosp, Edgewood, KY USA. [Schwartz, P. E.] Yale Univ, Sch Med, New Haven, CT USA. [Blank, S. V.] NYU, Sch Med, New York, NY USA. [Toland, A. E.] Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Dept Internal Med & Mol Virol, Columbus, OH 43210 USA. [Toland, A. E.] Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Dept Immunol, Columbus, OH 43210 USA. [Toland, A. E.] Ohio State Univ, Ctr Comprehens Canc, Div Human Canc Genet, Dept Med Genet, Columbus, OH 43210 USA. [Montagna, M.] IRCCS, Inst Oncol Veneto, Padua, Italy. [Casella, C.] Dept Oncol & Surg Sci, Padua, Italy. [Imyanitov, E. N.] NN Petrov Oncol Res Inst, St Petersburg, Russia. [Allavena, A.] Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. [Schmutzler, R. K.; Versmold, B.] Univ Cologne, Dept Obstet & Gynaecol, Div Mol Gynaecooncol, Cologne, Germany. [Engel, C.] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany. [Meindl, A.] Tech Univ Munich, Dept Obstet & Gynaecol, Munich, Germany. [Ditsch, N.] Univ Munich, Dept Obstet & Gynaecol, Munich, Germany. [Arnold, N.] Univ Schleswig Holstein, Dept Obstet & Gynaecol, Lubeck, Germany. [Niederacher, D.] Univ Dusseldorf, Dept Obstet & Gynaecol, Mol Genet Lab, Dusseldorf, Germany. [Deissler, H.] Univ Ulm, Dept Obstet & Gynaecol, Ulm, Germany. [Fiebig, B.] Univ Regensburg, Inst Human Genet, Regensburg, Germany. [Varon-Mateeva, R.] Humboldt Univ, Inst Human Genet, Charite, Berlin, Germany. [Schaefer, D.] Goethe Univ Frankfurt, Inst Human Genet, Frankfurt, Germany. [Froster, U. G.] Univ Leipzig, Inst Human Genet, Leipzig, Germany. [Caldes, T.; de la Hoya, M.] Hosp Clin San Carlos, Madrid, Spain. RP Osorio, A (reprint author), Spanish Natl Canc Ctr CNIO, Human Genet Grp, C Melchor Fernandez Almagro 3, Madrid 28029, Spain. EM aosorio@cnio.es RI Spurdle, Amanda/A-4978-2011; Arnold, Norbert/E-3012-2010; Toland, Amanda/E-4202-2011; montagna, marco/E-2225-2012; Andrulis, Irene/E-7267-2013; Ligtenberg, Marjolijn/N-9666-2013; manoukian, siranoush/E-7132-2017; Hoogerbrugge, Nicoline/O-1016-2013; Radice, Paolo/O-3119-2013; Ditsch, Nina/F-6267-2014; Osorio, Ana/I-4324-2014; Ehrencrona, Hans/M-5619-2014; GLADIEFF, Laurence/O-5129-2014 OI Evans, Gareth/0000-0002-8482-5784; Nordling, Margareta/0000-0002-4047-4994; Eeles, Rosalind/0000-0002-3698-6241; Nathanson, Katherine/0000-0002-6740-0901; Brunet, Joan/0000-0003-1945-3512; Nevanlinna, Heli/0000-0002-0916-2976; Kirchhoff, Tomas/0000-0002-9055-2364; Yannoukakos, Drakoulis/0000-0001-7509-3510; Spurdle, Amanda/0000-0003-1337-7897; Arnold, Norbert/0000-0003-4523-8808; montagna, marco/0000-0002-4929-2150; Ligtenberg, Marjolijn/0000-0003-1290-1474; manoukian, siranoush/0000-0002-6034-7562; Osorio, Ana/0000-0001-8124-3984; Ehrencrona, Hans/0000-0002-5589-3622; GLADIEFF, Laurence/0000-0002-6980-9719 FU Canadian Institutes of Health Research; Cancer Research UK [10118, C1287/A10118, C1287/A8874, C5047/A8385, C8197/A10123]; Intramural NIH HHS [NIH0014262027]; NCI NIH HHS [P50 CA116201, CA 27469, CA 37517, CA116167, CA122340, CA128978, CA74415, N02-CP-11019-50, N02CP11019, N02CP65504, P50CA116201, R01 CA074415, R01 CA116167, R01 CA122340, R01 CA128978, RFA-CA-06-503, U01 CA069398, U01 CA069417, U01 CA069446, U01 CA069467, U01 CA069631, U01 CA069638, U01 CA116167, U01 CA69398, U01 CA69417, U01 CA69446, U01 CA69467, U01 CA69631, U01 CA69638, U10 CA027469, U10 CA037517]; Associazione Italiana per la Ricerca sul Cancro NR 19 TC 11 Z9 11 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD DEC 8 PY 2009 VL 101 IS 12 BP 2048 EP 2054 DI 10.1038/sj.bjc.6605416 PG 7 WC Oncology SC Oncology GA 529ZH UT WOS:000272557800015 PM 19920816 ER PT J AU Mok, SC Bonome, T Vathipadiekal, V Bell, A Johnson, ME Wong, KK Park, DC Hao, K Yip, DKP Donninger, H Ozbun, L Samimi, G Brady, J Randonovich, M Pise-Masison, CA Barrett, JC Wong, WH Welch, WR Berkowitz, RS Birrer, MJ AF Mok, Samuel C. Bonome, Tomas Vathipadiekal, Vinod Bell, Aaron Johnson, Michael E. Wong, Kwong-kwok Park, Dong-Choon Hao, Ke Yip, Daniel K. P. Donninger, Howard Ozbun, Laurent Samimi, Goli Brady, John Randonovich, Mike Pise-Masison, Cindy A. Barrett, J. Carl Wong, Wing H. Welch, William R. Berkowitz, Ross S. Birrer, Michael J. TI A Gene Signature Predictive for Outcome in Advanced Ovarian Cancer Identifies a Survival Factor: Microfibril-Associated Glycoprotein 2 SO CANCER CELL LA English DT Article ID EXPRESSION PATTERNS; ENDOTHELIAL-CELLS; ADHESION; STATISTICS; CENTROSOME; INTEGRINS; INTERACTS; MAGP-2; TUMORS AB Advanced stage papillary serous tumors of the ovary are responsible for the majority of ovarian cancer deaths, yet the molecular determinants modulating patient survival are poorly characterized. Here, we identify and validate a prognostic gene expression signature correlating with survival in a series of microdissected serous ovarian tumors. Independent evaluation confirmed the association of a prognostic gene microfibril-associated glycoprotein 2 (MAGP2) with poor prognosis, whereas in vitro mechanistic analyses demonstrated its ability to prolong tumor cell survival and stimulate endothelial cell motility and survival via the alpha(V)beta(3) integrin receptor. Increased MAGP2 expression correlated with microvessel density suggesting a proangiogenic role in vivo. Thus, MAGP2 may serve as a survival-associated target. C1 [Bonome, Tomas; Vathipadiekal, Vinod; Bell, Aaron; Donninger, Howard; Ozbun, Laurent; Samimi, Goli; Barrett, J. Carl; Birrer, Michael J.] NCI, Cell & Canc Biol Branch, NIH, Rockville, MD 20892 USA. [Mok, Samuel C.; Wong, Kwong-kwok] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Samimi, Goli] NCI, Canc Prevent Fellowship Program, NIH, Rockville, MD 20892 USA. [Brady, John; Randonovich, Mike; Pise-Masison, Cindy A.] NCI, Cellular Oncol Lab, NIH, Rockville, MD 20892 USA. [Johnson, Michael E.; Park, Dong-Choon; Berkowitz, Ross S.] Harvard Univ, Sch Med, Dept Obstet Gynecol & Reprod Biol, Brigham & Womens Hosp,Div Gynecol Oncol, Boston, MA 02115 USA. [Welch, William R.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Park, Dong-Choon] Catholic Univ Korea, St Vincent Hosp, Dept Obstet & Gynecol, Suwon 442723, Gyeonggi Do, South Korea. [Hao, Ke; Wong, Wing H.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Yip, Daniel K. P.] Univ S Florida, Dept Physiol & Biophys, Tampa, FL 33612 USA. [Berkowitz, Ross S.] Dana Farber Harvard Canc Ctr, Gillette Ctr Womens Canc, Boston, MA 02115 USA. RP Birrer, MJ (reprint author), NCI, Cell & Canc Biol Branch, NIH, Rockville, MD 20892 USA. EM mbirrer@partners.org RI Yip, Kay-Pong/H-4639-2012; OI Yip, Kay-Pong/0000-0003-4364-6701; Vathipadiekal, Vinod/0000-0002-8181-6890; Wong, Kwong-Kwok/0000-0002-0375-6669 FU National Institutes of Health, Department of Health and Human Services [P50CA105009, R33CA103595, RO1CA133057]; Ovarian Cancer Research Fund, Inc.; National Institutes of Health, National Cancer Institute FX This study was supported in part by Dana-Farber Ovarian Cancer SPORE grant P50CA105009, R33CA103595, and RO1CA133057 from the National Institutes of Health, Department of Health and Human Services, the Ovarian Cancer Research Fund, Inc., and the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 31 TC 82 Z9 84 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 EI 1878-3686 J9 CANCER CELL JI Cancer Cell PD DEC 8 PY 2009 VL 16 IS 6 BP 521 EP 532 DI 10.1016/j.ccr.2009.10.018 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 531UD UT WOS:000272693700011 PM 19962670 ER PT J AU Velagaleti, RS Massaro, J Vasan, RS Robins, SJ Kannel, WB Levy, D AF Velagaleti, Raghava S. Massaro, Joseph Vasan, Ramachandran S. Robins, Sander J. Kannel, William B. Levy, Daniel TI Relations of Lipid Concentrations to Heart Failure Incidence The Framingham Heart Study SO CIRCULATION LA English DT Article DE epidemiology; heart failure; hypercholesterolemia; lipids; risk factors ID HIGH-DENSITY-LIPOPROTEIN; UNRECOGNIZED MYOCARDIAL-INFARCTION; LEFT-VENTRICULAR HYPERTROPHY; HIGH BLOOD-PRESSURE; CHOLESTEROL LEVELS; SERUM-CHOLESTEROL; PHYSICIANS HEALTH; RISK-FACTORS; DISEASE; PLASMA AB Background-The relations of lipid concentrations to heart failure (HF) risk have not been elucidated comprehensively. Methods and Results-In 6860 Framingham Heart Study participants (mean age, 44 years; 54% women) free of baseline coronary heart disease, we related high-density lipoprotein cholesterol (HDL-C) and non-HDL-C to HF incidence during long-term follow-up, adjusting for clinical covariates and myocardial infarction at baseline and updating these at follow-up examinations. We evaluated dyslipidemia-specific population burden of HF by calculating population attributable risks. During follow-up (mean of 26 years), 680 participants (49% women) developed HF. Unadjusted HF incidence in the low (<160 mg/dL) versus high (>= 190 mg/dL) non-HDL-C groups was 7.9% and 13.8%, respectively, whereas incidence in the high (>= 55 [men], >= 65 [women] mg/dL) versus low (<40 [men], <50 [women] mg/dL) HDL-C groups was 6.1% and 12.8%, respectively. In multivariable models, baseline non-HDL-C and HDL-C, modeled as continuous measures, carried HF hazards (confidence intervals) of 1.19 (1.11 to 1.27) and 0.82 (0.75 to 0.90), respectively, per SD increment. In models updating lipid concentrations every 8 years, the corresponding hazards (confidence intervals) were 1.23 (1.16 to 1.31) and 0.77 (0.70 to 0.85). Participants with high baseline non-HDL-C and those with low HDL-C experienced a 29% and 40% higher HF risk, respectively, compared with those in the desirable categories; the population attributable risks for high non-HDL-C and low HDL-C were 7.5% and 15%, respectively. Hazards associated with non-HDL-C and HDL-C remained statistically significant after additional adjustment for interim myocardial infarction. Conclusions-Dyslipidemia carries HF risk independent of its association with myocardial infarction, suggesting that lipid modification may be a means for reducing HF risk. (Circulation. 2009; 120:2345-2351.) C1 [Levy, Daniel] NHLBI, Framingham Heart Study, Ctr Populat Studies, Framingham, MA 01702 USA. [Massaro, Joseph] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [Vasan, Ramachandran S.] Boston Univ, Sch Med, Dept Preventat Med & Cardiol, Boston, MA 02118 USA. [Levy, Daniel] NHLBI, Ctr Populat Studies, Bethesda, MD 20892 USA. RP Levy, D (reprint author), NHLBI, Framingham Heart Study, Ctr Populat Studies, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM levyd@nih.gov OI Massaro, Joseph/0000-0002-2682-4812; Ramachandran, Vasan/0000-0001-7357-5970 FU National Institutes of Health [NO1-HC-25195] FX The Framingham Heart Study is supported by National Institutes of Health contract NO1-HC-25195. NR 47 TC 39 Z9 40 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 8 PY 2009 VL 120 IS 23 BP 2345 EP 2351 DI 10.1161/CIRCULATIONAHA.109.830984 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 528TA UT WOS:000272468600007 PM 19933936 ER PT J AU Kranz, G Shamim, EA Lin, PT Kranz, GS Voller, B Hallett, M AF Kranz, G. Shamim, E. A. Lin, P. T. Kranz, G. S. Voller, B. Hallett, M. TI Blepharospasm and the modulation of cortical excitability in primary and secondary motor areas SO NEUROLOGY LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; CRANIAL DYSTONIA; FACIAL-MUSCLES; SILENT PERIOD; BLINK REFLEX; CORTEX; INHIBITION; NUCLEUS; HEALTH AB Background: Traditionally, benign essential blepharospasm (BEB) is considered a disorder caused by basal ganglia dysfunction. Electrophysiologic and brain imaging studies suggest pathologic changes in excitability in the primary motor cortex (MC), anterior cingulate (AC), and secondary motor areas, such as premotor (PMC) and supplementary motor cortices (SMA). Methods: In this pilot study of 7 patients with BEB, we experimentally reduced cortical excitability of 4 areas: MC (first dorsal interosseus area), PMC, SMA, and AC, each with 3 noninvasive techniques: low-frequency repetitive transcranial magnetic stimulation (lfrTMS), continuous theta burst stimulation (cTBS), and cathodal transcranial direct current stimulation (tDCS). Primary outcome was the clinical effects on blepharospasm (blink rate observation by an investigator blinded to the intervention and subjective rating by the patient); secondary outcome was the blink reflex recovery curve (BRR). Results: lfrTMS resulted in a significant improvement over all 4 brain areas for physician rating, patient rating, and BRR, whereas cTBS and tDCS showed only trends for improvement in physician rating, but no improvements for patient rating and BRR. lfrTMS had a significantly higher effect over AC than MC for physician rating, but no differences were seen for other pairwise comparisons of stimulated brain areas. Conclusions: Electrophysiologic and clinical improvements by functional inhibition of the medial frontal areas using low-frequency repetitive transcranial magnetic stimulation suggests that hypersensitivity of the anterior cingulate is directly or indirectly involved in the pathophysiology of benign essential blepharospasm. Inhibition of these areas using low-frequency repetitive transcranial magnetic stimulation could provide a therapeutic tool and is worthy of a larger study. Neurology (R) 2009; 73: 2031-2036 C1 [Kranz, G.; Voller, B.] Med Univ Vienna, Dept Neurol, A-1090 Vienna, Austria. [Kranz, G.; Shamim, E. A.; Lin, P. T.; Hallett, M.] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Shamim, E. A.] Georgetown Univ Hosp, Dept Neurol, Washington, DC 20007 USA. [Shamim, E. A.] Kaiser Permanente, Dept Neurol, Suitland, MD USA. [Lin, P. T.] Santa Clara Valley Med Ctr, Dept Neurol, San Jose, CA 95128 USA. [Kranz, G. S.] Univ Vienna, Inst Psychol, A-1010 Vienna, Austria. RP Kranz, G (reprint author), Med Univ Vienna, Dept Neurol, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. EM gottfried.kranz@meduniwien.ac.at OI Voller, Bernhard/0000-0001-5809-874X FU Intramural NIH HHS NR 24 TC 13 Z9 13 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD DEC 8 PY 2009 VL 73 IS 23 BP 2031 EP 2036 DI 10.1212/WNL.0b013e3181c5b42d PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 528SJ UT WOS:000272466800018 PM 19996078 ER PT J AU Xua, J Gannon, PJ Emmorey, K Smith, JF Braun, AR AF Xua, Jiang Gannon, Patrick J. Emmorey, Karen Smith, Jason F. Braun, Allen R. TI Symbolic gestures and spoken language are processed by a common neural system SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE evolution; fMRI; perisylvian; communication; modality-independent ID CORTICAL ORGANIZATION; SIGN-LANGUAGE; BRAIN; SPEECH; APHASIA; RECOGNITION; INTEGRATION; PERCEPTION; ACTIVATION; NETWORK AB Symbolic gestures, such as pantomimes that signify actions (e. g., threading a needle) or emblems that facilitate social transactions (e. g., finger to lips indicating "be quiet''), play an important role in human communication. They are autonomous, can fully take the place of words, and function as complete utterances in their own right. The relationship between these gestures and spoken language remains unclear. We used functional MRI to investigate whether these two forms of communication are processed by the same system in the human brain. Responses to symbolic gestures, to their spoken glosses (expressing the gestures' meaning in English), and to visually and acoustically matched control stimuli were compared in a randomized block design. General Linear Models (GLM) contrasts identified shared and unique activations and functional connectivity analyses delineated regional interactions associated with each condition. Results support a model in which bilateral modality-specific areas in superior and inferior temporal cortices extract salient features from vocal-auditory and gestural-visual stimuli respectively. However, both classes of stimuli activate a common, left-lateralized network of inferior frontal and posterior temporal regions in which symbolic gestures and spoken words may be mapped onto common, corresponding conceptual representations. We suggest that these anterior and posterior perisylvian areas, identified since the mid-19th century as the core of the brain's language system, are not in fact committed to language processing, but may function as a modality-independent semiotic system that plays a broader role in human communication, linking meaning with symbols whether these are words, gestures, images, sounds, or objects. C1 [Xua, Jiang; Braun, Allen R.] Natl Inst Deafness & Other Commun Disorders, Language Sect, NIH, Bethesda, MD 20892 USA. [Gannon, Patrick J.] Hofstra Univ, Sch Med, Dept Sci Educ, Hempstead, NY 11549 USA. [Emmorey, Karen] San Diego State Univ, Lab Language & Cognit Neurosci, San Diego, CA 92120 USA. [Smith, Jason F.] Natl Inst Deafness & Other Commun Disorders, Brain Imaging & Modeling Sect, NIH, Bethesda, MD 20892 USA. RP Braun, AR (reprint author), Natl Inst Deafness & Other Commun Disorders, Language Sect, NIH, Bldg 10,Room 8S235A, Bethesda, MD 20892 USA. EM brauna@nidcd.nih.gov FU NIDCD FX The authors thank Drs. Susan Goldin-Meadow and Jeffrey Solomon for their important contributions. This research was supported by the Intramural program of the NIDCD. NR 43 TC 1 Z9 1 U1 5 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 8 PY 2009 VL 106 IS 49 BP 20664 EP 20669 DI 10.1073/pnas.0909197106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529XP UT WOS:000272553000023 ER PT J AU Chua, J Rikhy, R Lippincott-Schwartz, J AF Chua, Jennifer Rikhy, Richa Lippincott-Schwartz, Jennifer TI Dynamin 2 orchestrates the global actomyosin cytoskeleton for epithelial maintenance and apical constriction SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE deacetylated cortactin; actin; polarity; morphogenesis; epithelial cells ID CELL-SHAPE; ACTIN DYNAMICS; CORTACTIN; ENDOCYTOSIS; GTPASE; MORPHOGENESIS; JUNCTIONS; NETWORK; BINDING; PROTEIN AB The mechanisms controlling cell shape changes within epithelial monolayers for tissue formation and reorganization remain unclear. Here, we investigate the role of dynamin, a large GTPase, in epithelial morphogenesis. Depletion of dynamin 2 (Dyn2), the only dynamin in epithelial cells, prevents establishment and maintenance of epithelial polarity, with no junctional formation and abnormal actin organization. Expression of Dyn2 mutants shifted to a non-GTP state, by contrast, causes dramatic apical constriction without disrupting polarity. This is due to Dyn2's interactions with deacetylated cortactin and downstream effectors, which cause enhanced actomyosin contraction. Neither inhibitors of endocytosis nor GTP-shifted Dyn2 mutants induce apical constriction. This suggests that GTPase-dependent changes in Dyn2 lead to interactions with different effectors that may differentially modulate endocytosis and/or actomyosin dynamics in polarized cells. We propose this enables Dyn2 to coordinate, in a GTPase-dependent manner, membrane recycling and actomyosin contractility during epithelial morphogenesis. C1 [Chua, Jennifer; Rikhy, Richa; Lippincott-Schwartz, Jennifer] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. RP Lippincott-Schwartz, J (reprint author), NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM JLippin@helix.nih.gov RI Rikhy, Richa/J-4481-2012; OI Rikhy, Richa/0000-0002-4262-0238 NR 31 TC 24 Z9 26 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 8 PY 2009 VL 106 IS 49 BP 20770 EP 20775 DI 10.1073/pnas.0909812106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529XP UT WOS:000272553000041 PM 19948954 ER PT J AU Taimen, P Pfleghaar, K Shimi, T Moller, D Ben-Harush, K Erdos, MR Adam, SA Herrmann, H Medalia, O Collins, FS Goldman, AE Goldman, RD AF Taimen, Pekka Pfleghaar, Katrin Shimi, Takeshi Moeller, Dorothee Ben-Harush, Kfir Erdos, Michael R. Adam, Stephen A. Herrmann, Harald Medalia, Ohad Collins, Francis S. Goldman, Anne E. Goldman, Robert D. TI A progeria mutation reveals functions for lamin A in nuclear assembly, architecture, and chromosome organization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE centromere; chromatin; Rabl; senescence; telomere ID CELL-PROLIFERATION; DNA-REPLICATION; LIVING CELLS; CHROMATIN; TELOMERES; ENVELOPE; MITOSIS; LOCALIZATION; ARRANGEMENTS; CENTROMERE AB Numerous mutations in the human A-type lamin gene (LMNA) cause the premature aging disease, progeria. Some of these are located in the alpha-helical central rod domain required for the polymerization of the nuclear lamins into higher order structures. Patient cells with a mutation in this domain, 433G>A (E145K) show severely lobulated nuclei, a separation of the A-and B-type lamins, alterations in pericentric heterochromatin, abnormally clustered centromeres, and mislocalized telomeres. The induction of lobulations and the clustering of centromeres originate during postmitotic nuclear assembly in daughter cells and this early G1 configuration of chromosomes is retained throughout interphase. In vitro analyses of E145K-lamin A show severe defects in the assembly of protofilaments into higher order lamin structures. The results show that this central rod domain mutation affects nuclear architecture in a fashion distinctly different from the changes found in the most common form of progeria caused by the expression of LA Delta 50/progerin. The study also emphasizes the importance of lamins in nuclear assembly and chromatin organization. C1 [Taimen, Pekka; Pfleghaar, Katrin; Shimi, Takeshi; Adam, Stephen A.; Goldman, Anne E.; Goldman, Robert D.] Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. [Moeller, Dorothee; Herrmann, Harald] German Canc Res Ctr, Div Mol Genet, D-69120 Heidelberg, Germany. [Ben-Harush, Kfir; Medalia, Ohad] Ben Gurion Univ Negev, Dept Life Sci, IL-84120 Beer Sheva, Israel. [Ben-Harush, Kfir; Medalia, Ohad] NIBN, IL-84120 Beer Sheva, Israel. [Erdos, Michael R.; Collins, Francis S.] NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. RP Goldman, RD (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Cell & Mol Biol, Chicago, IL 60611 USA. EM francis.collins@gmail.com; r-goldman@northwestern.edu FU National Institute on Aging; Ellison Foundation; European Commission; Fritz-Thysen Stiftung; German-Israel Foundation; Sigrid Juselius Foundation; Orion-Farmos Research Foundation; Cancer Society of Southwestern Finland; Finnish Cultural Foundation; Deutsche Forschungsgemeinschaft FX We thank D. R. Foltz (University of Virginia, Charlottesville, VA) for the YFP-CENP A HeLa line and D. Parry for a helpful discussion. R. D. G. was supported by the National Institute on Aging and the Ellison Foundation; H. H. by the European Commission; O. M. by the Fritz-Thysen Stiftung; H. H. and O. M. by the German-Israel Foundation; P. T. by the Sigrid Juselius Foundation, Orion-Farmos Research Foundation, Cancer Society of Southwestern Finland, and Finnish Cultural Foundation; and K. P. by the Deutsche Forschungsgemeinschaft. NR 46 TC 83 Z9 86 U1 1 U2 12 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 8 PY 2009 VL 106 IS 49 BP 20788 EP 20793 DI 10.1073/pnas.0911895106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529XP UT WOS:000272553000044 PM 19926845 ER PT J AU Cicala, C Martinelli, E McNally, JP Goode, DJ Gopaul, R Hiatt, J Jelicic, K Kottilil, S Macleod, K O'Shea, A Patel, N Van Ryk, D Wei, DL Pascuccio, M Yi, L McKinnon, L Izulla, P Kimani, J Kaul, R Fauci, AS Arthos, J AF Cicala, Claudia Martinelli, Elena McNally, Jonathan P. Goode, Diana J. Gopaul, Ravindra Hiatt, Joseph Jelicic, Katija Kottilil, Shyamasundaran Macleod, Katilyn O'Shea, Angeline Patel, Nikita Van Ryk, Donald Wei, Danlan Pascuccio, Massimiliano Yi, Ling McKinnon, Lyle Izulla, Preson Kimani, Joshua Kaul, Rupert Fauci, Anthony S. Arthos, James TI The integrin alpha(4)beta(7) forms a complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to infection by HIV-1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE integrin receptor; transmission; gut-associated lymphoid tissues (GALT) ID IMMUNODEFICIENCY-VIRUS TYPE-1; MUCOSAL HOMING RECEPTOR; RETINOIC ACID; GENITAL-TRACT; TRANSMISSION; DEPLETION; ALPHA-4-BETA-7; LYMPHOCYTES; ROLES; LFA-1 AB Both activated and resting CD4(+) T cells in mucosal tissues play important roles in the earliest phases of infection after sexual transmission of HIV-1, a process that is inefficient. HIV-1 gp120 binds to integrin alpha(4)beta(7) (alpha(4)beta(7)), the gut mucosal homing receptor. We find that alpha(4)beta(high)(7) CD4(+) T cells are more susceptible to productive infection than are alpha(4)beta(low-neg)(7) CD4(+) T cells in part because this cellular subset is enriched with metabolically active CD4(+) T cells. alpha(4)beta(high)(7) CD4(+) T cells are CCR5(high) and CXCR4(low); on these cells, alpha(4)beta(7) appears in a complex with CD4. The specific affinity of gp120 for alpha(4)beta(7) provides a mechanism for HIV-1 to target activated cells that are critical for efficient virus propagation and dissemination following sexual transmission. C1 [Cicala, Claudia; Martinelli, Elena; McNally, Jonathan P.; Goode, Diana J.; Gopaul, Ravindra; Hiatt, Joseph; Jelicic, Katija; Kottilil, Shyamasundaran; Macleod, Katilyn; O'Shea, Angeline; Patel, Nikita; Van Ryk, Donald; Wei, Danlan; Pascuccio, Massimiliano; Fauci, Anthony S.; Arthos, James] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Yi, Ling] NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [McKinnon, Lyle; Kaul, Rupert] Univ Toronto, Dept Med, Toronto, ON M5S 1A8, Canada. [Izulla, Preson; Kimani, Joshua] Univ Nairobi, Dept Med Microbiol, Nairobi, Kenya. RP Cicala, C (reprint author), NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. EM ccicala@niaid.nih.gov; afauci@niaid.nih.gov OI Hiatt, Joseph/0000-0002-8015-9614 FU National Institutes of Health FX We thank Audrey Kinter, Sundararajan Venkatesan, and Oliver Laeyendecker, for useful discussions; John Weddle for figure preparation; Owen Schwartz, Juraj Kabat, and Lily Koo for assistance with imaging experiments; Kathleen Kelly for sharing results ahead of publication; the National Institutes of Health AIDS Research and Reference Reagent Program for numerous reagents; and Stephen Shaw for providing the mAb Act-1. Support for this work was provided by the Intramural Research Program of the National Institutes of Health. NR 32 TC 130 Z9 132 U1 3 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD DEC 8 PY 2009 VL 106 IS 49 BP 20877 EP 20882 DI 10.1073/pnas.0911796106 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 529XP UT WOS:000272553000059 PM 19933330 ER PT J AU Tseng, KY Chambers, RA Lipska, BK AF Tseng, Kuei Y. Chambers, R. Andrew Lipska, Barbara K. TI The neonatal ventral hippocampal lesion as a heuristic neurodevelopmental model of schizophrenia SO BEHAVIOURAL BRAIN RESEARCH LA English DT Review DE Schizophrenia; Neurodevelopment; Dopamine; Interneurons ID DORSOLATERAL PREFRONTAL CORTEX; DOPAMINE-GLUTAMATE INTERACTIONS; MEDIAL TEMPORAL-LOBE; MK-801-INDUCED MOTOR HYPERACTIVITY; DUAL DIAGNOSIS SCHIZOPHRENIA; GABA-IMMUNOREACTIVE NEURONS; DEVELOPMENTAL ANIMAL-MODEL; WORKING-MEMORY PERFORMANCE; DENDRITIC SPINE DENSITY; LONG-TERM POTENTIATION AB Traditionally, animal models of schizophrenia were predominantly pharmacological constructs focused on phenomena linked to dopamine and glutamate neurotransmitter systems, and were created by direct perturbations of these systems. A number of developmental models were subsequently generated that allowed testing of hypotheses about the origin of the disease, mimicked a wider array of clinical and neurobiological features of schizophrenia, and opened new avenues for developing novel treatment strategies. The most thoroughly characterized (similar to 100 primary research articles) is the neonatal ventral hippocampal lesion (NVHL) model, which is the subject of this review. We highlight its advantages and limitations, and how it may offer clues about the extent to which positive, negative, cognitive, and other aspects of schizophrenia, including addiction vulnerability, represent inter-related pathophysiological mechanisms. (C) 2008 Elsevier B.V. All rights reserved. C1 [Tseng, Kuei Y.] RFUMS Chicago Med Sch, Dept Cellular & Mol Pharmacol, N Chicago, IL 60064 USA. [Chambers, R. Andrew] Indiana Univ, Sch Med, Inst Psychiat Res, Lab Translat Neurosci Dual Diag & Dev, Indianapolis, IN 46202 USA. [Lipska, Barbara K.] NIMH, Bethesda, MD 20892 USA. RP Tseng, KY (reprint author), RFUMS Chicago Med Sch, Dept Cellular & Mol Pharmacol, N Chicago, IL 60064 USA. EM kuei-yuan.tseng@rosalindfranklin.edu RI Lipska, Barbara/E-4569-2017 FU Rosalind Franklin University/Chicago Medical School Start-up funds; NIDA [K08-DA019850]; National Institutes of Health FX We thank Dr. Daniel R. Weinberger for his creativity and vision and many other contributions that led to generating the NVHL model. The authors are supported by Rosalind Franklin University/Chicago Medical School Start-up funds (K.Y.T), NIDA K08-DA019850 (R.A.C.) and the Intramural Program of the National Institutes of Health, NIMH (B.K.L.). We thank Dr. James McCutcheon and Dr. Michela Marinelli for helpful comments. NR 156 TC 157 Z9 158 U1 2 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD DEC 7 PY 2009 VL 204 IS 2 SI SI BP 295 EP 305 DI 10.1016/j.bbr.2008.11.039 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 499FR UT WOS:000270203800005 PM 19100784 ER PT J AU Wust, S Tischner, D John, M Tuckermann, JP Menzfeld, C Hanisch, UK van den Brandt, J Luhder, F Reichardt, HM AF Wuest, Simone Tischner, Denise John, Michael Tuckermann, Jan P. Menzfeld, Christiane Hanisch, Uwe-Karsten van den Brandt, Jens Luehder, Fred Reichardt, Holger M. TI Therapeutic and Adverse Effects of a Non-Steroidal Glucocorticoid Receptor Ligand in a Mouse Model of Multiple Sclerosis SO PLOS ONE LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; DNA-BINDING; IN-VIVO; T-CELLS; INFLAMMATION; REPRESSION; APOPTOSIS; METHYLPREDNISOLONE; TRANSACTIVATION AB Background: Dissociating glucocorticoid receptor (GR) ligands hold great promise for treating inflammatory disorders since it is assumed that they exert beneficial activities mediated by transrepression but avoid adverse effects of GR action requiring transactivation. Here we challenged this paradigm by investigating 2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride (CpdA), a dissociating non-steroidal GR ligand, in the context of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). Methodology/Principal Findings: CpdA inhibited pro-inflammatory mediators in myelin-specific T cells and fibroblasts in a GR-dependent manner while gene activation was abolished. However, it also induced massive apoptosis in various cell types even in the absence of the GR by engaging a Bcl-2- and caspase-dependent pathway. (1)H NMR spectroscopy corroborated these findings by revealing that CpdA dissolved in buffered solutions rapidly decomposes into aziridine intermediates known to act as alkylating pro-apoptotic agents. Importantly, the dichotomy of CpdA action also became evident in vivo. Administration of high-dose CpdA to mice was lethal while treatment of EAE with low to intermediate amounts of CpdA dissolved in water significantly ameliorated the disease. The beneficial effect of CpdA required expression of the GR in T cells and was achieved by down regulating LFA-1 and CD44 on peripheral Th cells and by repressing IL-17 production. Conclusions/Significance: CpdA has significant therapeutic potential although adverse effects severely compromise its application in vivo. Hence, non-steroidal GR ligands require careful analysis prior to their translation into new therapeutic concepts. C1 [Wuest, Simone; Luehder, Fred] Univ Gottingen & Gemeinnutzige Hertie Stiftung, Inst Multiple Sclerosis Res, Gottingen, Germany. [Tischner, Denise; van den Brandt, Jens; Reichardt, Holger M.] Univ Gottingen, Sch Med, Dept Cellular & Mol Immunol, Gottingen, Germany. [John, Michael] Univ Gottingen, Inst Inorgan Chem, Gottingen, Germany. [Tuckermann, Jan P.] Fritz Lipmann Inst, Leibniz Inst Age Res, Jena, Germany. [Menzfeld, Christiane; Hanisch, Uwe-Karsten] Univ Gottingen, Dept Neuropathol, Sch Med, Gottingen, Germany. RP Wust, S (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM fred.luehder@med.uni-goettingen.de; hreichardt@med.uni-goettingen.de FU Gemeinnutzige Hertie-Stiftung [1.01.1/06/010]; Deutsche Forschungsgemeinschaft [Re1631/1-3, Tu220/3-1] FX This work was supported by grants from the Gemeinnutzige Hertie-Stiftung (1.01.1/06/010) and the Deutsche Forschungsgemeinschaft (Re1631/1-3, Tu220/3-1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 37 TC 42 Z9 43 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 7 PY 2009 VL 4 IS 12 AR e8202 DI 10.1371/journal.pone.0008202 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533NB UT WOS:000272829500019 PM 19997594 ER PT J AU Metcalf, CJE Bjornstad, ON Grenfell, BT Andreasen, V AF Metcalf, C. Jessica E. Bjornstad, Ottar N. Grenfell, Bryan T. Andreasen, Viggo TI Seasonality and comparative dynamics of six childhood infections in pre-vaccination Copenhagen SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE measles; susceptible reconstruction; time-series susceptible-infected-recovered ID MEASLES EPIDEMICS; MODEL; DETERMINISM; DIPHTHERIA; SYNCHRONY; PERTUSSIS; OUTBREAKS; IMMUNITY; DISEASES; RATES AB Seasonal variation in infection transmission is a key determinant of epidemic dynamics of acute infections. For measles, the best-understood strongly immunizing directly transmitted childhood infection, the perception is that term-time forcing is the main driver of seasonality in developed countries. The degree to which this holds true across other acute immunizing childhood infections is not clear. Here, we identify seasonal transmission patterns using a unique long-term dataset with weekly incidence of six infections including measles. Data on age-incidence allow us to quantify the mean age of infection. Results indicate correspondence between dips in transmission and school holidays for some infections, but there are puzzling discrepancies, despite close correspondence between average age of infection and age of schooling. Theoretical predictions of the relationship between amplitude of seasonality and basic reproductive rate of infections that should result from term-time forcing are also not upheld. We conclude that where yearly trajectories of susceptible numbers are perturbed, e. g. via waning of immunity, seasonality is unlikely to be entirely driven by term-time forcing. For the three bacterial infections, pertussis, scarlet fever and diphtheria, there is additionally a strong increase in transmission during the late summer before the end of school vacations. C1 [Metcalf, C. Jessica E.; Grenfell, Bryan T.] Princeton Univ, Woodrow Wilson Sch, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Metcalf, C. Jessica E.; Bjornstad, Ottar N.; Grenfell, Bryan T.] Penn State Univ, Ctr Infect Dis Dynam, Mueller Lab 208, University Pk, PA 16802 USA. [Bjornstad, Ottar N.; Grenfell, Bryan T.; Andreasen, Viggo] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Andreasen, Viggo] Roskilde Univ Ctr, Dept Sci, DK-4000 Roskilde, Denmark. RP Metcalf, CJE (reprint author), Princeton Univ, Woodrow Wilson Sch, Dept Ecol & Evolutionary Biol, Eno Hall, Princeton, NJ 08544 USA. EM cjm53@psu.edu RI Bjornstad, Ottar/I-4518-2012 FU Danish Medical Research Council [271-07-0555]; Bill and Melinda Gates Foundation; RAPIDD program of the Science & Technology Directorate; National Institute of Health [NIH/GM R01-GM083983-01] FX This work was funded by the Danish Medical Research Council (V. A.; grant 271-07-0555), the Bill and Melinda Gates Foundation (C. J. E. M., B. G., O. N. B.), the RAPIDD program of the Science & Technology Directorate (B. G.) and the National Institute of Health (B. G., O. N. B.; grant NIH/GM R01-GM083983-01). NR 29 TC 38 Z9 38 U1 1 U2 15 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P R SOC B JI Proc. R. Soc. B-Biol. Sci. PD DEC 7 PY 2009 VL 276 IS 1676 BP 4111 EP 4118 DI 10.1098/rspb.2009.1058 PG 8 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 509YO UT WOS:000271055400004 PM 19740885 ER PT J AU Diabate, A Dao, A Yaro, AS Adamou, A Gonzalez, R Manoukis, NC Traore, SF Gwadz, RW Lehmann, T AF Diabate, Abdoulaye Dao, Adama Yaro, Alpha S. Adamou, Abdoulaye Gonzalez, Rodrigo Manoukis, Nicholas C. Traore, Sekou F. Gwadz, Robert W. Lehmann, Tovi TI Spatial swarm segregation and reproductive isolation between the molecular forms of Anopheles gambiae SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE molecular forms; Anopheles gambiae; reproductive isolation; swarms ID INCIPIENT SPECIATION; BURKINA-FASO; GENETIC DIFFERENTIATION; CHROMOSOMAL FORMS; WEST-AFRICA; COMPLEX; DIPTERA; CULICIDAE; S.S; SELECTION AB Anopheles gambiae, the major malaria vector in Africa, can be divided into two subgroups based on genetic and ecological criteria. These two subgroups, termed the M and S molecular forms, are believed to be incipient species. Although they display differences in the ecological niches they occupy in the field, they are often sympatric and readily hybridize in the laboratory to produce viable and fertile offspring. Evidence for assortative mating in the field was recently reported, but the underlying mechanisms awaited discovery. We studied swarming behaviour of the molecular forms and investigated the role of swarm segregation in mediating assortative mating. Molecular identification of 1145 males collected from 68 swarms in Doneguebougou, Mali, over 2 years revealed a strict pattern of spatial segregation, resulting in almost exclusively monotypic swarms with respect to molecular form. We found evidence of clustering of swarms composed of individuals of a single molecular form within the village. Tethered M and S females were introduced into natural swarms of the M form to verify the existence of possible mate recognition operating within-swarm. Both M and S females were inseminated regardless of their form under these conditions, suggesting no within-mate recognition. We argue that our results provide evidence that swarm spatial segregation strongly contributes to reproductive isolation between the molecular forms in Mali. However this does not exclude the possibility of additional mate recognition operating across the range distribution of the forms. We discuss the importance of spatial segregation in the context of possible geographic variation in mechanisms of reproductive isolation. C1 [Diabate, Abdoulaye; Gonzalez, Rodrigo; Manoukis, Nicholas C.; Gwadz, Robert W.; Lehmann, Tovi] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. [Dao, Adama; Yaro, Alpha S.; Adamou, Abdoulaye; Traore, Sekou F.] Malaria Res & Training Ctr, Bamako, Mali. RP Diabate, A (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM a_diabate@hotmail.com OI Manoukis, Nicholas/0000-0001-5062-7256 FU Intramural Research Program of the Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We are grateful to F. Tripet and D. Huestis for useful comments and suggestions to improve the manuscript and to NIAID intramural editor B. R. Marshall for assistance. Special thanks go to M. Diallo, K. Yaya and the villagers from Doneguebougou for their help in collecting swarms. NR 45 TC 62 Z9 62 U1 2 U2 12 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P R SOC B JI Proc. R. Soc. B-Biol. Sci. PD DEC 7 PY 2009 VL 276 IS 1676 BP 4215 EP 4222 DI 10.1098/rspb.2009.1167 PG 8 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 509YO UT WOS:000271055400016 PM 19734189 ER PT J AU Terracciano, A Balaci, L Thayer, J Scally, M Kokinos, S Ferrucci, L Tanaka, T Zonderman, AB Sanna, S Olla, N Zuncheddu, MA Naitza, S Busonero, F Uda, M Schlessinger, D Abecasis, GR Costa, PT AF Terracciano, Antonio Balaci, Lenuta Thayer, Jason Scally, Matthew Kokinos, Sarah Ferrucci, Luigi Tanaka, Toshiko Zonderman, Alan B. Sanna, Serena Olla, Nazario Zuncheddu, Maria Antonietta Naitza, Silvia Busonero, Fabio Uda, Manuela Schlessinger, David Abecasis, Goncalo R. Costa, Paul T., Jr. TI Variants of the Serotonin Transporter Gene and NEO-PI-R Neuroticism: No Association in the BLSA and SardiNIA Samples SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE personality; depression; anxiety; 5-HTT; GWA ID PROMOTER POLYMORPHISM 5-HTTLPR; ANXIETY-RELATED TRAITS; PERSONALITY-TRAITS; REGULATORY REGION; MAJOR DEPRESSION; HARM AVOIDANCE; FUNCTIONAL POLYMORPHISM; CHARACTER INVENTORY; TEMPERAMENT; METAANALYSIS AB The polymorphism in the serotonin transporter gene promoter region (5-HTTLPR) is by far the most studied variant hypothesized to influence Neuroticism-related personality traits. The results of previous studies have been mixed and appear moderated by the personality questionnaire used. Studies that used the TCI to assess Harm Avoidance or the EPQ to assess Neuroticism have found no association with the 5-HTTLPR. However, studies that used the NEO-PI-R or related instruments (NEO-PI, NEO-FFI) to measure Neuroticism have found some evidence of association. This study examines the association of variants in the serotonin transporter gene in a sample from a genetically isolated population within Sardinia (Italy) that is several times larger than previous samples that used the NEO-PI-R (N = 3,913). The association was also tested in a sample (N = 548) from the Baltimore Longitudinal Study of Aging (BLSA), in which repeated NEO-PI-R assessments were obtained. In the SardiNIA sample, we found no significant association of the 5-HTTLPR genotypes with Neuroticism or its facets (Anxiety, Angry-Hostility, Depression, Self-Consciousness, Impulsiveness, and Vulnerability). In the BLSA sample, we found lower scores on Neuroticism traits for the heterozygous group, which is inconsistent with previous studies. We also examined eight SNPs in the SardiNIA (N = 3,972) and nine SNPs in the BLSA (N = 1,182) that map within or near the serotonin transporter gene (SLC6A4), and found no association. Along with other large studies that used different phenotypic measures and found no association, this study substantially increases the evidence against a link between 5-HTT variants and Neuroticism-related traits. (C) 2009 Wiley-Liss, Inc. C1 [Terracciano, Antonio; Thayer, Jason; Scally, Matthew; Kokinos, Sarah; Ferrucci, Luigi; Zonderman, Alan B.; Schlessinger, David; Costa, Paul T., Jr.] NIA, NIH, DHHS, Baltimore, MD 21224 USA. [Balaci, Lenuta; Sanna, Serena; Olla, Nazario; Zuncheddu, Maria Antonietta; Naitza, Silvia; Busonero, Fabio; Uda, Manuela] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Tanaka, Toshiko] Medstar Res Inst, Baltimore, MD USA. [Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. RP Terracciano, A (reprint author), NIA, NIH, DHHS, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM terraccianoa@mail.nih.gov RI Abecasis, Goncalo/B-7840-2010; terracciano, antonio/B-1884-2008; Naitza, Silvia/D-5620-2017; OI sanna, serena/0000-0002-3768-1749; Abecasis, Goncalo/0000-0003-1509-1825; Costa, Paul/0000-0003-4375-1712; Zonderman, Alan B/0000-0002-6523-4778 FU Intramural Research Program of the NIH, National Institute on Aging; RD contract FX We thank the individuals who participated in this study; The SardiNIA team thanks Monsignore Piseddu (Bishop of Ogliastra), the mayors of the four Sardinian towns (Lanusei, Ilbono, Arzana and Elini), and the head of the Public Health Unit ASL4 for cooperation. We thank Prof. Antonio Cao for his leadership of the SardlNlA project. This research was supported entirely by the Intramural Research Program of the NIH, National Institute on Aging. A portion of that support was through a R&D contract with MedStar Research Institute. NR 52 TC 22 Z9 23 U1 5 U2 13 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD DEC 5 PY 2009 VL 150B IS 8 BP 1070 EP 1077 DI 10.1002/ajmg.b.30932 PG 8 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 529KX UT WOS:000272516600004 PM 19199283 ER PT J AU Close, TJ Bhat, PR Lonardi, S Wu, YH Rostoks, N Ramsay, L Druka, A Stein, N Svensson, JT Wanamaker, S Bozdag, S Roose, ML Moscou, MJ Chao, SAM Varshney, RK Szucs, P Sato, K Hayes, PM Matthews, DE Kleinhofs, A Muehlbauer, GJ DeYoung, J Marshall, DF Madishetty, K Fenton, RD Condamine, P Graner, A Waugh, R AF Close, Timothy J. Bhat, Prasanna R. Lonardi, Stefano Wu, Yonghui Rostoks, Nils Ramsay, Luke Druka, Arnis Stein, Nils Svensson, Jan T. Wanamaker, Steve Bozdag, Serdar Roose, Mikeal L. Moscou, Matthew J. Chao, Shiaoman Varshney, Rajeev K. Szuecs, Peter Sato, Kazuhiro Hayes, Patrick M. Matthews, David E. Kleinhofs, Andris Muehlbauer, Gary J. DeYoung, Joseph Marshall, David F. Madishetty, Kavitha Fenton, Raymond D. Condamine, Pascal Graner, Andreas Waugh, Robbie TI Development and implementation of high-throughput SNP genotyping in barley SO BMC GENOMICS LA English DT Article ID DENSITY CONSENSUS MAP; HORDEUM-VULGARE L.; DART MARKERS; GENOME; STRESS; SSR; DNA; POPULATION; WHEAT; RICE AB Background: High density genetic maps of plants have, nearly without exception, made use of marker datasets containing missing or questionable genotype calls derived from a variety of genic and non-genic or anonymous markers, and been presented as a single linear order of genetic loci for each linkage group. The consequences of missing or erroneous data include falsely separated markers, expansion of cM distances and incorrect marker order. These imperfections are amplified in consensus maps and problematic when fine resolution is critical including comparative genome analyses and map-based cloning. Here we provide a new paradigm, a high-density consensus genetic map of barley based only on complete and error-free datasets and genic markers, represented accurately by graphs and approximately by a best-fit linear order, and supported by a readily available SNP genotyping resource. Results: Approximately 22,000 SNPs were identified from barley ESTs and sequenced amplicons; 4,596 of them were tested for performance in three pilot phase Illumina GoldenGate assays. Data from three barley doubled haploid mapping populations supported the production of an initial consensus map. Over 200 germplasm selections, principally European and US breeding material, were used to estimate minor allele frequency (MAF) for each SNP. We selected 3,072 of these tested SNPs based on technical performance, map location, MAF and biological interest to fill two 1536-SNP "production" assays (BOPA1 and BOPA2), which were made available to the barley genetics community. Data were added using BOPA1 from a fourth mapping population to yield a consensus map containing 2,943 SNP loci in 975 marker bins covering a genetic distance of 1099 cM. Conclusion: The unprecedented density of genic markers and marker bins enabled a high resolution comparison of the genomes of barley and rice. Low recombination in pericentric regions is evident from bins containing many more than the average number of markers, meaning that a large number of genes are recombinationally locked into the genetic centromeric regions of several barley chromosomes. Examination of US breeding germplasm illustrated the usefulness of BOPA1 and BOPA2 in that they provide excellent marker density and sensitivity for detection of minor alleles in this genetically narrow material. C1 [Close, Timothy J.; Bhat, Prasanna R.; Svensson, Jan T.; Wanamaker, Steve; Roose, Mikeal L.; Moscou, Matthew J.; Madishetty, Kavitha; Fenton, Raymond D.; Condamine, Pascal] Univ Calif Riverside, Dept Bot & Plant Sci, Riverside, CA 92521 USA. [Lonardi, Stefano; Wu, Yonghui; Bozdag, Serdar] Univ Calif Riverside, Dept Comp Sci, Riverside, CA 92521 USA. [Rostoks, Nils; Ramsay, Luke; Druka, Arnis; Marshall, David F.; Waugh, Robbie] Scottish Crop Res Inst, Dundee DD2 5DA, Scotland. [Stein, Nils; Varshney, Rajeev K.; Graner, Andreas] Leibniz Inst Plant Genet & Crop Plant Res IPK, D-06466 Gatersleben, Germany. [Chao, Shiaoman] USDA ARS, Biosci Res Lab, Fargo, ND 58105 USA. [Szuecs, Peter; Hayes, Patrick M.] Oregon State Univ, Dept Crop & Soil Sci, Corvallis, OR 97331 USA. [Sato, Kazuhiro] Okayama Univ, Bioresources Res Inst, Kurashiki, Okayama 7100046, Japan. [Matthews, David E.] Cornell Univ, USDA ARS, Ithaca, NY 14853 USA. [Kleinhofs, Andris] Washington State Univ, Dept Crop & Soil Sci, Pullman, WA 99164 USA. [Muehlbauer, Gary J.] Univ Minnesota, Dept Agron & Plant Genet, St Paul, MN 55108 USA. [DeYoung, Joseph] Univ Calif Los Angeles, So Calif Genotyping Consortium, Los Angeles, CA 90095 USA. [Bhat, Prasanna R.] Monsanto Res Ctr, Bangalore 560092, Karnataka, India. [Wu, Yonghui] Google, Mountain View, CA 94043 USA. [Stein, Nils] Latvian State Univ, Fac Biol, LV-1586 Riga, Latvia. [Svensson, Jan T.] Univ Copenhagen, DK-1871 Frederiksberg C, Denmark. [Bozdag, Serdar] NCI, NIH, Neurooncol Branch, Bethesda, MD 20892 USA. [Moscou, Matthew J.] Iowa State Univ, Dept Plant Pathol, Ames, IA 50011 USA. [Varshney, Rajeev K.] Int Crops Res Inst Semi Arid Trop, Patancheru 502324, Andhra Pradesh, India. [Condamine, Pascal] NetSocial Mkt, F-15600 Le Puech, Montmurat, France. RP Close, TJ (reprint author), Univ Calif Riverside, Dept Bot & Plant Sci, Riverside, CA 92521 USA. EM timothy.close@ucr.edu; prasannarb@gmail.com; stelo@cs.ucr.edu; yonghui@cs.ucr.edu; nrostoks@latnet.lv; Luke.Ramsay@scri.ac.uk; arnisdruka@aol.com; stein@ipk-gatersleben.de; jsv@life.ku.dk; steve.wanamaker@ucr.edu; sbozdag@cs.ucr.edu; mikeal.roose@ucr.edu; moscou@iastate.edu; Shiaoman.Chao@ars.usda.gov; r.k.varshney@cgiar.org; Peter.Szucs@oregonstate.edu; kazsato@rib.okayama-U.ac.jp; hayesp@css.orst.edu; Matthews@greengenes.cit.cornell.edu; andyk@wsu.edu; Gary.J.Muehlbauer-1@tc.umn.edu; Jdeyoung@mednet.ucla.edu; D.F.Marshall@scri.sari.ac.uk; kavithavcs@yahoo.com; raymond.fenton@ucr.edu; pascalcondamine@yahoo.fr; a_graner@IPK-Gatersleben.de; rwaugh@scri.sari.ac.uk RI Marshall, David/F-2471-2011; svensson, jan/D-1815-2009; Varshney, Rajeev/C-5295-2014; Moscou, Matthew/D-5266-2011; OI Marshall, David/0000-0001-9309-2570; Varshney, Rajeev/0000-0002-4562-9131; Moscou, Matthew/0000-0003-2098-6818; Rostoks, Nils/0000-0002-4047-2438 FU NSF DBI [0321756]; USDA-CSREES-NRI [2006-55606-16722]; Biotechnology and Biological Sciences Research Council; Scottish Executive Environment and Rural Affairs Department; Leibniz Institute of Plant Genetics; Crop Plant Research FX This research was supported by NSF DBI Grant No. 0321756 "Coupling EST and Bacterial Artificial Chromosome Resources to Access the Barley Genome", USDA-CSREES-NRI Grant No. 2006-55606-16722 "Barley Coordinated Agricultural Project: Leveraging Genomics, Genetics, and Breeding for Gene Discovery and Barley Improvement", the Biotechnology and Biological Sciences Research Council and Scottish Executive Environment and Rural Affairs Department, and core funding from the Leibniz Institute of Plant Genetics and Crop Plant Research. NR 26 TC 314 Z9 318 U1 9 U2 97 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 4 PY 2009 VL 10 AR 582 DI 10.1186/1471-2164-10-582 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 535PW UT WOS:000272983700001 PM 19961604 ER PT J AU Wang, MY Fu, ZM Zhang, J Wu, J Jiang, LQ Khazan, B Telljohann, R Krug, A Monticone, R Van Eyk, J Lakatta, E AF Wang, Mingyi Fu, Zongming Zhang, Jing Wu, James Jiang, Liqun Khazan, Benjamin Telljohann, Richard Krug, Alexander Monticone, Robert Van Eyk, Jennifer Lakatta, Edward TI Milk Fat Globule-EGF-Factor 8 (MFG-E8): A Novel Protein Orchestrator of Inflammatory Vascular Smooth Muscle Cell Proliferation and Invasion SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT Basic Cardiovascular Sciences Conference 2009 CY JUL, 2009 CL Las Vegas, NV C1 [Wang, Mingyi; Zhang, Jing; Wu, James; Jiang, Liqun; Khazan, Benjamin; Telljohann, Richard; Krug, Alexander; Monticone, Robert; Lakatta, Edward] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. [Fu, Zongming; Van Eyk, Jennifer] Johns Hopkins Univ, Hopkins Nhlbi Prote Ctr, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD DEC 4 PY 2009 VL 105 IS 12 MA 5188 BP E62 EP E62 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 527PO UT WOS:000272379200039 ER PT J AU Rid, A Schmidt, H AF Rid, A. Schmidt, H. TI The newly revised declaration of Helsinki: what do the changes mean from an ethical perspective? SO DEUTSCHE MEDIZINISCHE WOCHENSCHRIFT LA German DT Editorial Material DE research ethics; Declaration of Helsinki; international research ID INTERNATIONAL RESEARCH; CARE DEBATE; STANDARD C1 [Rid, A.] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Rid, A.] Univ Zurich, Inst Biomed Eth, CH-8006 Zurich, Switzerland. [Schmidt, H.] LSE Hlth, London, England. [Schmidt, H.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. RP Rid, A (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. NR 15 TC 1 Z9 1 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0012-0472 J9 DEUT MED WOCHENSCHR JI Dtsch. Med. Wochenschr. PD DEC 4 PY 2009 VL 134 IS 49 BP 2525 EP 2528 DI 10.1055/s-0029-1243058 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 532NW UT WOS:000272757400008 PM 19941238 ER PT J AU Namkung, Y Dipace, C Urizar, E Javitch, JA Sibley, DR AF Namkung, Yoon Dipace, Concetta Urizar, Eneko Javitch, Jonathan A. Sibley, David R. TI G Protein-coupled Receptor Kinase-2 Constitutively Regulates D-2 Dopamine Receptor Expression and Signaling Independently of Receptor Phosphorylation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADENYLATE-CYCLASE; DESENSITIZATION; TRAFFICKING; SENSITIZATION; ARRESTINS; MEMBRANE; BINDING; EZRIN; GAMMA; GRKS AB We investigated the regulatory effects of GRK2 on D2 dopamine receptor signaling and found that this kinase inhibits both receptor expression and functional signaling in a phosphorylation-independent manner, apparently through different mechanisms. Overexpression of GRK2 was found to suppress receptor expression at the cell surface and enhance agonist-induced internalization, whereas short interfering RNA knockdown of endogenous GRK2 led to an increase in cell surface receptor expression and decreased agonist-mediated endocytosis. These effects were not due to GRK2-mediated phosphorylation of the D2 receptor as a phosphorylation-null receptor mutant was regulated similarly, and overexpression of a catalytically inactive mutant of GRK2 produced the same effects. The suppression of receptor expression is correlated with constitutive association of GRK2 with the receptor complex as we found that GRK2 and several of its mutants were able to co-immunoprecipitate with the D-2 receptor. Agonist pretreatment did not enhance the ability of GRK2 to co-immunoprecipitate with the receptor. We also found that overexpression of GRK2 attenuated the functional coupling of the D2 receptor and that this activity required the kinase activity of GRK2 but did not involve receptor phosphorylation, thus suggesting the involvement of an additional GRK2 substrate. Interestingly, we found that the suppression of functional signaling also required the G beta gamma binding activity of GRK2 but did not involve the GRK2 N-terminal RH domain. Our results suggest a novel mechanism by which GRK2 negatively regulates G protein-coupled receptor signaling in a manner that is independent of receptor phosphorylation. C1 [Namkung, Yoon; Sibley, David R.] NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. [Dipace, Concetta; Urizar, Eneko; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Ctr Mol Recognit, New York, NY 10032 USA. [Dipace, Concetta; Urizar, Eneko; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Dipace, Concetta; Urizar, Eneko; Javitch, Jonathan A.] Columbia Univ Coll Phys & Surg, Dept Pharmacol, New York, NY 10032 USA. RP Sibley, DR (reprint author), NINDS, Mol Neuropharmacol Sect, NIH, Rm 4S-04,MSC 9405,5625 Fishers Lane, Bethesda, MD 20892 USA. EM sibley@helix.nih.gov FU National Institutes of Health [MH54137 and DA022413]; NINDS competitive fellowship; Lieber Center for Schizophrenia Research and Treatment FX This work was supported, in whole or in part, by the National Institutes of Health through the intramural research program of NINDS (to D. R. S.), Grants MH54137 and DA022413 (to J. A. J.), and a NINDS competitive fellowship (to Y. N.). This work was also supported by the Lieber Center for Schizophrenia Research and Treatment (to J. A. J.). NR 33 TC 39 Z9 40 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 4 PY 2009 VL 284 IS 49 BP 34103 EP 34115 DI 10.1074/jbc.M109.055707 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524TE UT WOS:000272165200043 PM 19815545 ER PT J AU Das, B Heimeier, RA Buchholz, DR Shi, YB AF Das, Biswajit Heimeier, Rachel A. Buchholz, Daniel R. Shi, Yun-Bo TI Identification of Direct Thyroid Hormone Response Genes Reveals the Earliest Gene Regulation Programs during Frog Metamorphosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RETINOIC ACID RECEPTORS; BETA-A GENE; XENOPUS-LAEVIS; AMPHIBIAN METAMORPHOSIS; MATRIX-METALLOPROTEINASE; TRANSCRIPTIONAL ACTIVATION; POSTEMBRYONIC DEVELOPMENT; EXPRESSION PROGRAM; BRAIN-DEVELOPMENT; DUAL FUNCTIONS AB Thyroid hormone (T3) is essential for normal development and organ function throughout vertebrates. Its effects are mainly mediated through transcriptional regulation by T3 receptor (TR). The identification and characterization of the immediate early, direct target genes are thus of critical importance in understanding the molecular pathways induced by T3. Unfortunately, this has been hampered by the difficulty to study gene regulation by T3 in uterus-enclosed mammalian embryos. Here we used Xenopus metamorphosis as a model for vertebrate postembryonic development to identify direct T3 response genes in vivo. We took advantage of the ability to easily induce metamorphosis with physiological levels of T3 and to carry out microarray analysis in Xenopus laevis and genome-wide sequence analysis in Xenopus tropicalis. This allowed us to identify 188 up-regulated and 249 down-regulated genes by T3 in the absence of new protein synthesis in whole animals. We further provide evidence to show that these genes contain functional TREs that are bound by TR in tadpoles and that their promoters are regulated by TR in vivo. More importantly, gene ontology analysis showed that the direct up-regulated genes are enriched in categories important for transcriptional regulation and protein degradation-dependent signaling processes but not DNA replication. Our findings thus revealed the existence of interesting pathways induced by T3 at the earliest step of metamorphosis. C1 [Das, Biswajit; Heimeier, Rachel A.; Shi, Yun-Bo] Eunice Kennedy Shriver NICHD, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, Program Cellular Regulat & Metab,NIH, Bethesda, MD 20892 USA. [Buchholz, Daniel R.] Univ Cincinnati, Dept Biol Sci, Cincinnati, OH 45221 USA. RP Shi, YB (reprint author), NICHD, Lab Gene Regulat & Dev, Program Cellular Regulat & Metab, NIH, Bldg 18T,Rm 106, Rockville, MD 20852 USA. EM shi@helix.nih.gov FU National Institutes of Health Intramural Research Program of NICHD FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program of NICHD. NR 72 TC 47 Z9 47 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 4 PY 2009 VL 284 IS 49 BP 34167 EP 34178 DI 10.1074/jbc.M109.066084 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524TE UT WOS:000272165200049 PM 19801647 ER PT J AU Rostovtseva, TK Boukari, H Antignani, A Shiu, B Banerjee, S Neutzner, A Youle, RJ AF Rostovtseva, Tatiana K. Boukari, Hacene Antignani, Antonella Shiu, Brian Banerjee, Soojay Neutzner, Albert Youle, Richard J. TI Bax Activates Endophilin B1 Oligomerization and Lipid Membrane Vesiculation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; GIANT PHOSPHOLIPID-VESICLES; FLUCTUATION SPECTROSCOPY; PROTEIN FAMILY; DOMAIN; CURVATURE; MECHANISM; DYNAMICS; FISSION; BIF-1 AB Endophilins participate in membrane scission events that occur during endocytosis and intracellular organelle biogenesis through the combined activity of an N-terminal BAR domain that interacts with membranes and a C-terminal SH3 domain that mediates protein binding. Endophilin B1 (Endo B1) was identified to bind Bax, a Bcl-2 family member that promotes apoptosis, through yeast two-hybrid protein screens. Although Endo B1 does not bind Bax in healthy cells, during apoptosis, Endo B1 interacts transiently with Bax and promotes cytochrome c release from mitochondria. To explore the molecular mechanism of action of Endo B1, we have analyzed its interaction with Bax in cell-free systems. Purified recombinant Endo B1 in solution displays a Stokes radius indicating a tetrameric quarternary structure. However, when incubated with purified Bax, it assembles into oligomersmore than 4-fold greater in molecular weight. Although Endo B1 oligomerization is induced by Bax, Bax does not stably associate with the high molecular weight Endo B1 complex. Endo B1 oligomerization requires its C-terminal Src homology 3 domain and is not induced by Bcl-xL. Endo B1 combined with Bax reduces the size and changes the morphology of giant unilamellar vesicles by inducing massive vesiculation of liposomes. This activity of purified Bax protein to induce cell-free assembly of Endo B1 may reflect its activity in cells that regulates apoptosis and/or mitochondrial fusion. C1 [Antignani, Antonella; Shiu, Brian; Banerjee, Soojay; Youle, Richard J.] NINDS, Biochem Sect, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Eunice Kennedy Shriver NICHD, Lab Phys & Struct Biol, Bethesda, MD 20892 USA. [Boukari, Hacene] Eunice Kennedy Shriver NICHD, Lab Integrat & Med Biophys, Program Phys Biol, Bethesda, MD 20892 USA. [Neutzner, Albert] Univ Basel Hosp, Dept Biomed, CH-4031 Basel, Switzerland. RP Youle, RJ (reprint author), NINDS, Biochem Sect, Surg Neurol Branch, NIH, 35 Convent Dr,2C-917, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov OI Neutzner, Albert/0000-0001-9254-5558 FU Eunice Kennedy Shriver NICHD; NINDS FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Programs of the Eunice Kennedy Shriver NICHD (to T.K.R., H.B., and B.S.) and NINDS (to A.A., S.B., and R.J.Y.). NR 42 TC 20 Z9 22 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD DEC 4 PY 2009 VL 284 IS 49 BP 34390 EP 34399 DI 10.1074/jbc.M109.021873 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 524TE UT WOS:000272165200069 PM 19805544 ER PT J AU Lloyd-Smith, JO George, D Pepin, KM Pitzer, VE Pulliam, JRC Dobson, AP Hudson, PJ Grenfell, BT AF Lloyd-Smith, James O. George, Dylan Pepin, Kim M. Pitzer, Virginia E. Pulliam, Juliet R. C. Dobson, Andrew P. Hudson, Peter J. Grenfell, Bryan T. TI Epidemic Dynamics at the Human-Animal Interface SO SCIENCE LA English DT Review ID ACUTE RESPIRATORY SYNDROME; TRANSMISSION DYNAMICS; INFECTIOUS-DISEASES; SYNDROME CORONAVIRUS; RISK-FACTORS; HOST-RANGE; HONG-KONG; EMERGENCE; INFLUENZA; PATHOGENS AB Few infectious diseases are entirely human-specific: Most human pathogens also circulate in animals or else originated in nonhuman hosts. Influenza, plague, and trypanosomiasis are classic examples of zoonotic infections that transmit from animals to humans. The multihost ecology of zoonoses leads to complex dynamics, and analytical tools, such as mathematical modeling, are vital to the development of effective control policies and research agendas. Much attention has focused on modeling pathogens with simpler life cycles and immediate global urgency, such as influenza and severe acute respiratory syndrome. Meanwhile, vector-transmitted, chronic, and protozoan infections have been neglected, as have crucial processes such as cross-species transmission. Progress in understanding and combating zoonoses requires a new generation of models that addresses a broader set of pathogen life histories and integrates across host species and scientific disciplines. C1 [Lloyd-Smith, James O.] Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. [Lloyd-Smith, James O.; George, Dylan; Pitzer, Virginia E.; Pulliam, Juliet R. C.; Hudson, Peter J.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [George, Dylan] Colorado State Univ, Dept Biol, Ft Collins, CO 80523 USA. [Pepin, Kim M.; Pitzer, Virginia E.; Hudson, Peter J.; Grenfell, Bryan T.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Dobson, Andrew P.; Grenfell, Bryan T.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Dobson, Andrew P.; Grenfell, Bryan T.] Princeton Univ, Woodrow Wilson Sch, Princeton, NJ 08544 USA. RP Lloyd-Smith, JO (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolutionary Biol, Los Angeles, CA 90095 USA. EM jlloydsmith@ucla.edu RI Pulliam, Juliet/A-6516-2008; Lloyd-Smith, James/K-4080-2012 OI Pulliam, Juliet/0000-0003-3314-8223; Lloyd-Smith, James/0000-0001-7941-502X FU Science and Technology Directorate, U. S. Department of Homeland Security; Fogarty International Center, NIH FX This work was supported by the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate, U. S. Department of Homeland Security, and the Fogarty International Center, NIH. We are grateful to O. Bjornstad, E. McKenzie, M. Poss, A. Read, and L. Simonsen for valuable comments and to B. Gee for assistance with figure preparation. J. L.-S. is grateful for the support of the De Logi Chair in Biological Sciences. NR 51 TC 181 Z9 183 U1 6 U2 110 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 4 PY 2009 VL 326 IS 5958 BP 1362 EP 1367 DI 10.1126/science.1177345 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 527EX UT WOS:000272351100031 PM 19965751 ER PT J AU Tsai, HT Caporaso, NE Kyle, RA Katzmann, JA Dispenzieri, A Hayes, RB Marti, GE Albitar, M Ghia, P Rajkumar, SV Landgren, O AF Tsai, Huei-Ting Caporaso, Neil E. Kyle, Robert A. Katzmann, Jerry A. Dispenzieri, Angela Hayes, Richard B. Marti, Gerald E. Albitar, Maher Ghia, Paolo Rajkumar, S. Vincent Landgren, Ola TI Evidence of serum immunoglobulin abnormalities up to 9.8 years before diagnosis of chronic lymphocytic leukemia: a prospective study SO BLOOD LA English DT Article ID UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; MULTIPLE-MYELOMA; CIRCULATING CD20; LIGHT; SURVIVAL; MARKER; PROTEINS; DISEASE; RISK AB Immune-related deficiencies are well-known complications of chronic lymphocytic leukemia (CLL). Although recent data indicate that almost all CLL patients are preceded by a monoclonal B-cell lymphocytosis precursor state, patterns of immune defects preceding CLL diagnosis are unclear. We identified 109 persons who developed CLL from the prospective and nationwide Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial with 77 469 participants, with serially collected prediagnostic serum samples. We assayed monoclonal (M)-proteins, kappa/lambda free light chains (FLCs) in prediagnostic obtained up to 9.8 years before CLL diagnosis. The prevalence of an abnormal FLC ratio, M-protein, and hypogammaglobulinemia before CLL diagnosis was 38% (95% confidence interval, 29%-47%), 13% (7%-21%), and 3% (1%-8%), respectively. M-proteins and abnormal FLC ratios were detected up to 9.8 years before CLL diagnosis in a total of 48 persons (44%). Hypogammaglobulinemia was not present until 3 years before the diagnosis of CLL. Among 37 patients with information on tumor cell immunophenotype, an association between immunophenotype and involved FLC (P = .024, Fisher exact test) was observed. Among 61 persons with a normal FLC ratio and without an M-protein, 17 had elevated kappa and/or lambda FLC levels, indicating polyclonal B-cell activation in 17 of 109 (16%) patients. These findings support a role for chronic immune stimulation in CLL genesis. (Blood. 2009; 114: 4928-4932) C1 [Landgren, Ola] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Tsai, Huei-Ting; Caporaso, Neil E.; Landgren, Ola] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Kyle, Robert A.; Katzmann, Jerry A.; Dispenzieri, Angela; Rajkumar, S. Vincent] Mayo Clin, Div Hematol & Internal Med, Rochester, MN USA. [Kyle, Robert A.; Katzmann, Jerry A.; Dispenzieri, Angela] Mayo Clin, Div Clin Biochem & Immunol, Rochester, MN USA. [Kyle, Robert A.; Katzmann, Jerry A.; Dispenzieri, Angela] Mayo Clin, Div Lab Med & Pathol, Rochester, MN USA. [Hayes, Richard B.] NYU, Inst Canc, Langone Med Ctr, Dept Environm Med,Div Epidemiol, New York, NY 10003 USA. [Marti, Gerald E.] NIH, Ctr Biol Evaluat & Res, US FDA, Bethesda, MD 20892 USA. [Albitar, Maher] Quest Diagnost, Nichols Inst, San Juan Capistrano, CA USA. [Ghia, Paolo] Univ Vita Salute San Raffaele, Lab Cell Neoplasia B, Div Mol Oncol, Milan, Italy. [Ghia, Paolo] Univ Vita Salute San Raffaele, Dept Oncol, Unit Lymphoid Malignancies, Milan, Italy. [Ghia, Paolo] Ist Sci San Raffaele, Milan, Italy. RP Landgren, O (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10 Rm 13N240F, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov RI Ghia, Paolo/K-7138-2016; OI Ghia, Paolo/0000-0003-3750-7342; Rajkumar, S. Vincent/0000-0002-5862-1833; Hayes, Richard/0000-0002-0918-661X; Dispenzieri, Angela/0000-0001-8780-9512 FU National Cancer Institute and the Intramural Research Program of the National Institutes of Health [CA62242, CA 107476] FX This work was supported in part by Research Grants CA62242 and CA 107476 from the National Cancer Institute and the Intramural Research Program of the National Institutes of Health. NR 31 TC 34 Z9 34 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 3 PY 2009 VL 114 IS 24 BP 4928 EP 4932 DI 10.1182/blood-2009-08-237651 PG 5 WC Hematology SC Hematology GA 527WX UT WOS:000272403000006 PM 19828698 ER PT J AU Bajenoff, M Germain, RN AF Bajenoff, Marc Germain, Ronald N. TI B-cell follicle development remodels the conduit system and allows soluble antigen delivery to follicular dendritic cells SO BLOOD LA English DT Article ID LYMPH-NODE CORTEX; FIBROBLASTIC RETICULAR CELLS; HIGH ENDOTHELIAL VENULES; TISSUE-INDUCER CELLS; SUBCAPSULAR SINUS; IMMUNE-RESPONSE; T-CELLS; MICROENVIRONMENTS; NETWORKS; LYMPHOTOXIN AB Afferent lymph is transported throughout lymph nodes (LNs) by the conduit system. Whereas this conduit network is dense in the T-cell zone, it is sparse in B-cell follicles. In this study, we show that this differential organization emerges during lymph node development. Neonatal LNs lack B follicles, but have a developed T-cell zone and a dense conduit network. As new T and B cells enter the developing LN, the conduit network density is maintained in the T, but not the B zone, leading to a profound remodeling of the follicular network that nevertheless maintains its connectivity. In adults, the residual follicular conduits transport soluble antigen to deep regions, where follicular dendritic cells are abundant and appear to replace the fibroblastic reticular cells that enwrap conduits in the T zone. This strategic location correlates with the capacity of the follicular dendritic cells to capture antigen even in the absence of antigen-specific antibodies. Together, these results describe how the stromal organization of the T and B regions of LNs diverges during development, giving rise to distinct antigen transport and delivery modes in the 2 compartments. (Blood. 2009; 114: 4989-4997) C1 [Bajenoff, Marc] Univ Nice Sophia Antipolis, INSERM, U924, CNRS, Valbonne, France. [Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Bajenoff, M (reprint author), Ctr Immunol Marseille Luminy, Parc Sci & Technol Marseille Luminy,Case 906, F-13288 Marseille, France. EM bajenoff@ciml.univ-mrs.fr FU Inserm, Centre National de la Recherche Scientifique, Agence Nationale de la Recherche; National Institutes of Health, National Institute of Allergy and Infectious Diseases FX This work was supported by grants from Inserm, Centre National de la Recherche Scientifique, Agence Nationale de la Recherche, and funds from the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 37 TC 48 Z9 49 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 3 PY 2009 VL 114 IS 24 BP 4989 EP 4997 DI 10.1182/blood-2009-06-229567 PG 9 WC Hematology SC Hematology GA 527WX UT WOS:000272403000015 PM 19713459 ER PT J AU Scheinberg, P Melenhorst, JJ Brenchley, JM Hill, BJ Hensel, NF Chattopadhyay, PK Roederer, M Picker, LJ Price, DA Barrett, AJ Douek, DC AF Scheinberg, Phillip Melenhorst, Jan J. Brenchley, Jason M. Hill, Brenna J. Hensel, Nancy F. Chattopadhyay, Pratip K. Roederer, Mario Picker, Louis J. Price, David A. Barrett, A. John Douek, Daniel C. TI The transfer of adaptive immunity to CMV during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor SO BLOOD LA English DT Article ID BONE-MARROW-TRANSPLANTATION; CYTOMEGALOVIRUS-SPECIFIC CD4(+); ADOPTIVE TRANSFER; CYCLOSPORINE-A; CENTRAL MEMORY; CLONAL COMPOSITION; VIRUS; LYMPHOCYTES; RECIPIENTS; INFECTION AB The successful reconstitution of adaptive immunity to human cytomegalovirus (CMV) in hematopoietic stem cell transplantation (HSCT) recipients is central to the reduction of viral reactivation-related morbidity and mortality. Here, we characterized the magnitude, specificity, phenotype, function, and clonotypic composition of CMV-specific T-cell responses in 18 donor-recipient pairs both before and after HSCT. The principal findings were: (1) the specificity of CMV-specific T-cell responses in the recipient after HSCT mirrors that in the donor; (2) the maintenance of these targeting patterns reflects the transfer of epitope-specific T-cell clonotypes from donor to recipient; (3) less differentiated CD27(+)CD57(-) CMV-specific memory T cells are more likely to persist in the recipient after HSCT compared with more terminally differentiated CD27(-)CD57(+) CMV-specific memory T cells; (4) the presence of greater numbers of less differentiated CD8(+) CMV-specific T cells in the donor appears to confer protection against viral reactivation in the recipient after HSCT; and (5) CMV-specific T cells acquire a more differentiated phenotype and a restricted functional profile after HSCT. Overall, these findings define the immunologic factors that influence the successful adoptive transfer of antigen-specific T-cell immunity during HSCT, which enables the identification of recipients at particular risk of CMV reactivation after HSCT. (Blood. 2009; 114: 5071-5080) C1 [Hill, Brenna J.; Price, David A.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Scheinberg, Phillip; Melenhorst, Jan J.; Hensel, Nancy F.; Barrett, A. John] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Brenchley, Jason M.] NIAID, Immunopathogenesis Unit, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Chattopadhyay, Pratip K.; Roederer, Mario] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Picker, Louis J.] Oregon Hlth & Sci Univ, Vaccine & Gene Therapy Inst, Beaverton, OR USA. [Price, David A.] Cardiff Univ, Sch Med, Dept Med Biochem & Immunol, Cardiff, S Glam, Wales. RP Douek, DC (reprint author), NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr, Bethesda, MD 20892 USA. EM ddouek@mail.nih.gov RI Chattopadhyay, Pratip/B-9227-2008; Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Scheinberg, Phillip/0000-0002-9047-4538; Chattopadhyay, Pratip/0000-0002-5457-9666 FU National Institutes of Health, National Heart, Lung and Blood Institute and National Institute of Allergy and Infectious Diseases; Medical Research Council (United Kingdom) FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung and Blood Institute and National Institute of Allergy and Infectious Diseases. D. A. P. is a Medical Research Council (United Kingdom) Senior Clinical Fellow. NR 47 TC 49 Z9 50 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD DEC 3 PY 2009 VL 114 IS 24 BP 5071 EP 5080 DI 10.1182/blood-2009-04-214684 PG 10 WC Hematology SC Hematology GA 527WX UT WOS:000272403000025 PM 19776383 ER PT J AU Sweetland, S Green, J Liu, B de Gonzalez, AB Canonico, M Reeves, G Beral, V AF Sweetland, Sian Green, Jane Liu, Bette de Gonzalez, Amy Berrington Canonico, Marianne Reeves, Gillian Beral, Valerie CA Million Women Study Collaborators TI Duration and magnitude of the postoperative risk of venous thromboembolism in middle aged women: prospective cohort study SO BRITISH MEDICAL JOURNAL LA English DT Article ID DEEP-VEIN THROMBOSIS; PULMONARY-EMBOLISM; TOTAL HIP; KNEE REPLACEMENT; TIME-COURSE; PROPHYLAXIS; SURGERY; PREVENTION; CANCER; CARE AB Objective To examine the duration and magnitude of increased risk of venous thromboembolism after different types of surgery. Design Prospective cohort study ( Million Women Study). Setting Questionnaire data from the Million Women Study linked with hospital admission and death records. Participants 947 454 middle aged women in the United Kingdom recruited in 1996-2001 and followed by record linkage to routinely collected NHS data on hospital admissions and deaths. During follow-up 239 614 admissions were for surgery; 5419 women were admitted, and a further 270 died, from venous thromboembolism. Main outcome measures Adjusted relative risks and standardised incidence rates for hospital admission or death from venous thromboembolism ( pulmonary embolism or deep vein thrombosis), by time since and type of surgery. Results Compared with not having surgery, women were 70 times more likely to be admitted with venous thromboembolism in the first six weeks after an inpatient operation ( relative risk 69.1, 95% confidence interval 63.1 to 75.6) and 10 times more likely after a day case operation (9.6, 8.0 to 11.5). The risks were lower but still substantially increased 7-12 weeks after surgery (19.6, 16.6 to 23.1 and 5.5, 4.3 to 7.0, respectively). This pattern of risk was similar for pulmonary embolism (n=2487) and deep venous thrombosis (n=3529). The postoperative risks of venous thromboembolism varied considerably by surgery type, with highest relative risks after inpatient surgery for hip or knee replacement and for cancer - 1-6 weeks after surgery the relative risks were, respectively, 220.6 (187.8 to 259.2) and 91.6 (73.9 to 113.4). Conclusion The risk of deep vein thrombosis and pulmonary embolism after surgery is substantially increased in the first 12 postoperative weeks, and varies considerably by type of surgery. An estimated 1 in 140 middle aged women undergoing inpatient surgery in the UK will be admitted with venous thromboembolism during the 12 weeks after surgery ( 1 in 45 after hip or knee replacement and 1 in 85 after surgery for cancer), compared with 1 in 815 after day case surgery and only 1 in 6200 women during a 12 week period without surgery. C1 [Sweetland, Sian; Green, Jane; de Gonzalez, Amy Berrington; Canonico, Marianne; Reeves, Gillian; Beral, Valerie] Univ Oxford, Canc Epidemiol Unit, Oxford OX3 7LF, England. [de Gonzalez, Amy Berrington] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Canonico, Marianne] INSERM, Cardiovasc Epidemiol Unit, U780, Villejuif, France. RP Beral, V (reprint author), Univ Oxford, Canc Epidemiol Unit, Richard Doll Bldg, Oxford OX3 7LF, England. EM pa.valerie.beral@ceu.ox.ac.uk RI Liu, Bette/A-7581-2013; Beral, Valerie/B-2979-2013; Canonico, Marianne/F-9138-2013; OI Balkwill, Angela/0000-0002-6327-6245; Liu, Bette/0000-0002-0787-5825 FU Cancer Research UK [C570/A5028]; Medical Research Council [G0700474] FX This study was funded by Cancer Research UK ( grant No C570/A5028) and the Medical Research Council ( grant No G0700474). Marianne Canonico was additionally supported by Leem Recherche. The funders did not participate in the study design and conduct, in the collection, management, analysis and interpretation of the data, nor was there any funder input into the preparation, review or approval of this manuscript. NR 32 TC 121 Z9 123 U1 1 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8146 J9 BRIT MED J JI Br. Med. J. PD DEC 3 PY 2009 VL 339 AR b4583 DI 10.1136/bmj.b4583 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 528NT UT WOS:000272453400004 PM 19959589 ER PT J AU Tiwari, S Goyal, AK Mishra, N Khatri, K Vaidya, B Mehta, A Wu, YM Vyas, SP AF Tiwari, Shaija Goyal, Amit K. Mishra, Neeraj Khatri, Kapil Vaidya, Bhuvaneshwar Mehta, Abhinav Wu, Yimin Vyas, Suresh P. TI Development and characterization of novel carrier gel core liposomes based transmission blocking malaria vaccine SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE CpGODN; Gel core liposomes; Pfs25; Vaccine adjuvant; Poly acrylic acid ID MUCOSAL IMMUNE-RESPONSES; TOLL-LIKE RECEPTORS; CPG MOTIFS; PLASMODIUM-FALCIPARUM; BACTERIAL-DNA; IN-VIVO; POLY(ACRYLIC ACID); ANTIBODY-RESPONSES; ANTIGEN; OLIGODEOXYNUCLEOTIDES AB The aim of present work was to investigate the potential utility of novel carrier gel core liposomes for intramuscular delivery of transmission blocking malaria antigen Pfs25 and to evaluate the effect of co-administration of vaccine adjuvant CpGODN on immune enhancement of recombinant protein antigen Pfs25. In the present work we have prepared gel core liposomes containing core of biocompatible polymer poly acrylic acid in phospholipid bilayer by reverse phase evaporation method and characterized for various in vitro parameters. In process stability of the encapsulated antigen was evaluated by SDS-PAGE followed by western blotting. The immune stimulating ability was studied by measuring anti-Pfs25 antibody titer in serum of Balb/c mice following intramuscular administration of various formulations. A Significant and perdurable immune responses was obtained after intramuscular administration of gel core liposomes encapsulated Pfs25 as compared to Pfs25 loaded conventional liposomes. Moreover co-administration of CpGODN in liposomes (conventional and gel core) was found to further increase the immunogenicity of vaccine. The result indicates high potential of gel core liposomes for their use as a carrier adjuvant for intramuscular delivery of recombinant antigen Pfs25 based transmission blocking malaria vaccine. (C) 2009 Elsevier B.V. All rights reserved. C1 [Tiwari, Shaija; Goyal, Amit K.; Mishra, Neeraj; Khatri, Kapil; Vaidya, Bhuvaneshwar; Mehta, Abhinav; Vyas, Suresh P.] Dr Hari Singh Gour Vishwavidyalaya, Dept Pharmaceut Sci, Drug Delivery Res Lab, Sagar 470003, MP, India. [Wu, Yimin] NIAID, Malaria Vaccine Dev Branch, Rockville, MD USA. RP Vyas, SP (reprint author), Dr Hari Singh Gour Vishwavidyalaya, Dept Pharmaceut Sci, Drug Delivery Res Lab, Sagar 470003, MP, India. EM vyas_sp@rediffmail.com FU Senior Research Fellowship FX Authors are thankful to AIIMS, New Delhi for conducting electron microscopy experiments. Authors AG, KK and NM are thankful to the Department of Biotechnology, New Delhi, Council for Scientific and Industrial Research and Indian Council of Medical Research, New Delhi respectively for providing the financial assistance in the form of Senior Research Fellowship. NR 51 TC 19 Z9 20 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD DEC 3 PY 2009 VL 140 IS 2 BP 157 EP 165 DI 10.1016/j.jconrel.2009.08.004 PG 9 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 529EE UT WOS:000272497900012 PM 19686788 ER PT J AU Rerks-Ngarm, S Pitisuttithum, P Nitayaphan, S Kaewkungwal, J Chiu, J Paris, R Premsri, N Namwat, C de Souza, M Adams, E Benenson, M Gurunathan, S Tartaglia, J McNeil, JG Francis, DP Stablein, D Birx, DL Chunsuttiwat, S Khamboonruang, C Thongcharoen, P Robb, ML Michael, NL Kunasol, P Kim, JH AF Rerks-Ngarm, Supachai Pitisuttithum, Punnee Nitayaphan, Sorachai Kaewkungwal, Jaranit Chiu, Joseph Paris, Robert Premsri, Nakorn Namwat, Chawetsan de Souza, Mark Adams, Elizabeth Benenson, Michael Gurunathan, Sanjay Tartaglia, Jim McNeil, John G. Francis, Donald P. Stablein, Donald Birx, Deborah L. Chunsuttiwat, Supamit Khamboonruang, Chirasak Thongcharoen, Prasert Robb, Merlin L. Michael, Nelson L. Kunasol, Prayura Kim, Jerome H. CA MOPH-TAVEG Investigators TI Vaccination with ALVAC and AIDSVAX to Prevent HIV-1 Infection in Thailand SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; RECOMBINANT GLYCOPROTEIN-120 VACCINE; IMMUNE-RESPONSES; CANARYPOX VACCINE; PHASE-I/II; SUBTYPE-E; NEUTRALIZING ANTIBODIES; SIMIAN IMMUNODEFICIENCY; HIV-1-UNINFECTED ADULTS; CANDIDATE VACCINE AB BACKGROUND The development of a safe and effective vaccine against the human immunodeficiency virus type 1 (HIV-1) is critical to pandemic control. METHODS In a community-based, randomized, multicenter, double-blind, placebo-controlled efficacy trial, we evaluated four priming injections of a recombinant canarypox vector vaccine (ALVAC-HIV [vCP1521]) plus two booster injections of a recombinant glycoprotein 120 subunit vaccine (AIDSVAX B/E). The vaccine and placebo injections were administered to 16,402 healthy men and women between the ages of 18 and 30 years in Rayong and Chon Buri provinces in Thailand. The volunteers, primarily at heterosexual risk for HIV infection, were monitored for the coprimary end points: HIV-1 infection and early HIV-1 viremia, at the end of the 6-month vaccination series and every 6 months thereafter for 3 years. RESULTS In the intention-to-treat analysis involving 16,402 subjects, there was a trend toward the prevention of HIV-1 infection among the vaccine recipients, with a vaccine efficacy of 26.4% (95% confidence interval [CI], -4.0 to 47.9; P = 0.08). In the per-protocol analysis involving 12,542 subjects, the vaccine efficacy was 26.2% (95% CI, -13.3 to 51.9; P = 0.16). In the modified intention-to-treat analysis involving 16,395 subjects (with the exclusion of 7 subjects who were found to have had HIV-1 infection at baseline), the vaccine efficacy was 31.2% (95% CI, 1.1 to 52.1; P = 0.04). Vaccination did not affect the degree of viremia or the CD4+ T-cell count in subjects in whom HIV-1 infection was subsequently diagnosed. CONCLUSIONS This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk. Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research. (ClinicalTrials.gov number, NCT00223080.) C1 [Robb, Merlin L.; Michael, Nelson L.; Kim, Jerome H.] Walter Reed Army Inst Res, US Mil HIV Res Program, Rockville, MD 20850 USA. [Rerks-Ngarm, Supachai; Paris, Robert; Namwat, Chawetsan; Chunsuttiwat, Supamit; Khamboonruang, Chirasak; Thongcharoen, Prasert; Kunasol, Prayura] Minist Publ Hlth, Dept Dis Control, Nonthaburi, Thailand. [Pitisuttithum, Punnee] Mahidol Univ, Vaccine Trials Ctr, Bangkok 10700, Thailand. [Kaewkungwal, Jaranit] Mahidol Univ, Fac Trop Med, Data Management Unit, Bangkok, Thailand. [Chiu, Joseph; Paris, Robert; de Souza, Mark; Benenson, Michael] Armed Forces Res Inst Med Sci, US Army Med Component, Bangkok 10400, Thailand. [Adams, Elizabeth] NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. [Gurunathan, Sanjay; Tartaglia, Jim; McNeil, John G.] Sanofi Pasteur, Swiftwater, PA USA. [Francis, Donald P.] Global Solut Infect Dis, San Francisco, CA USA. [Stablein, Donald] Emmes Corp, Rockville, MD USA. [Birx, Deborah L.] Ctr Dis Control & Prevent, Global AIDS Program, Atlanta, GA USA. [Kim, Jerome H.] US Army Med Mat Dev Act, Ft Detrick, MD USA. RP Kim, JH (reprint author), Walter Reed Army Inst Res, US Mil HIV Res Program, 1600 E Gude Dr, Rockville, MD 20850 USA. EM jkim@hivresearch.org FU U. S. Army Medical Research and Materiel Command [Y1-AI-2642-12]; National Institute of Allergy and Infectious Diseases [Y1-AI-2642-12]; Henry M. Jackson Foundation [W81XWH-07-2-0067]; U. S. Department of Defense [W81XWH-07-2-0067] FX Supported in part by an Interagency Agreement (Y1-AI-2642-12) between the U. S. Army Medical Research and Materiel Command and the National Institute of Allergy and Infectious Diseases and by a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the U. S. Department of Defense. Sanofi Pasteur provided the ALVAC-HIV vaccine, and Global Solutions for Infectious Diseases (VaxGen) provided the reagents for the immunogenicity assays. NR 48 TC 1476 Z9 1504 U1 20 U2 137 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 3 PY 2009 VL 361 IS 23 BP 2209 EP 2220 DI 10.1056/NEJMoa0908492 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 525ZM UT WOS:000272257100004 PM 19843557 ER PT J AU Sax, PE Tierney, C Collier, AC Fischl, MA Mollan, K Peeples, L Godfrey, C Jahed, NC Myers, L Katzenstein, D Farajallah, A Rooney, JF Ha, B Woodward, WC Koletar, SL Johnson, VA Geiseler, PJ Daar, ES AF Sax, Paul E. Tierney, Camlin Collier, Ann C. Fischl, Margaret A. Mollan, Katie Peeples, Lynne Godfrey, Catherine Jahed, Nasreen C. Myers, Laurie Katzenstein, David Farajallah, Awny Rooney, James F. Ha, Belinda Woodward, William C. Koletar, Susan L. Johnson, Victoria A. Geiseler, P. Jan Daar, Eric S. CA AIDS Clinical Trials Grp Study TI Abacavir-Lamivudine versus Tenofovir-Emtricitabine for Initial HIV-1 Therapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID RANDOMIZED-TRIAL; INFECTED ADULTS; NAIVE PATIENTS; LOPINAVIR/RITONAVIR; ZIDOVUDINE; DF; EFAVIRENZ; EFFICACY; SAFETY AB BACKGROUND The use of fixed-dose combination nucleoside reverse-transcriptase inhibitors (NRTIs) with a nonnucleoside reverse-transcriptase inhibitor or a ritonavir-boosted protease inhibitor is recommended as initial therapy in patients with human immunodeficiency virus type 1 (HIV-1) infection, but which NRTI combination has greater efficacy and safety is not known. METHODS In a randomized, blinded equivalence study involving 1858 eligible patients, we compared four once-daily anti-retroviral regimens as initial therapy for HIV-1 infection: abacavir-lamivudine or tenofovir disoproxil fumarate (DF)-emtricitabine plus efavirenz or ritonavir-boosted atazanavir. The primary efficacy end point was the time from randomization to virologic failure (defined as a confirmed HIV-1 RNA level >= 1000 copies per milliliter at or after 16 weeks and before 24 weeks, or = 200 copies per milliliter at or after 24 weeks). RESULTS A scheduled interim review by an independent data and safety monitoring board showed significant differences in virologic efficacy, according to the NRTI combination, among patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more. At a median follow-up of 60 weeks, among the 797 patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the time to virologic failure was significantly shorter in the abacavir-lamivudine group than in the tenofovir DF-emtricitabine group (hazard ratio, 2.33; 95% confidence interval, 1.46 to 3.72; P<0.001), with 57 virologic failures (14%) in the abacavir-lamivudine group versus 26 (7%) in the tenofovir DF-emtricitabine group. The time to the first adverse event was also shorter in the abacavir-lamivudine group (P<0.001). There was no significant difference between the study groups in the change from the baseline CD4 cell count at week 48. CONCLUSIONS In patients with screening HIV-1 RNA levels of 100,000 copies per milliliter or more, the times to virologic failure and the first adverse event were both significantly shorter in patients randomly assigned to abacavir-lamivudine than in those assigned to tenofovir DF-emtricitabine. (ClinicalTrials.gov number, NCT00118898.) C1 [Sax, Paul E.] Brigham & Womens Hosp, Div Infect Dis, Boston, MA 02115 USA. [Sax, Paul E.] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. [Sax, Paul E.] Harvard Univ, Sch Med, Boston, MA USA. [Tierney, Camlin; Mollan, Katie; Peeples, Lynne] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Collier, Ann C.] Univ Washington, Harborview Med Ctr, Seattle, WA 98104 USA. [Fischl, Margaret A.] Univ Miami, Sch Med, Miami, FL USA. [Godfrey, Catherine] NIAID, Div Aids, Bethesda, MD 20892 USA. [Jahed, Nasreen C.] Social & Sci Syst, Silver Spring, MD USA. [Myers, Laurie] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Katzenstein, David] Stanford Univ, Palo Alto, CA 94304 USA. [Rooney, James F.] Gilead Sci Inc, Foster City, CA 94404 USA. [Geiseler, P. Jan] Univ So Calif, Los Angeles, CA USA. [Daar, Eric S.] Univ Calif Los Angeles, Los Angeles, CA USA. [Daar, Eric S.] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Los Angeles, CA USA. [Farajallah, Awny] Bristol Myers Squibb Co, Plainsboro, NJ USA. [Ha, Belinda] GlaxoSmithKline, Res Triangle Pk, NC USA. [Woodward, William C.] Abbott Labs, Abbott Pk, IL 60064 USA. [Koletar, Susan L.] Ohio State Univ, Columbus, OH 43210 USA. [Johnson, Victoria A.] Univ Alabama Birmingham, Sch Med, Birmingham, AL USA. [Johnson, Victoria A.] Birmingham Vet Affairs Med Ctr, Birmingham, AL USA. RP Sax, PE (reprint author), Brigham & Womens Hosp, Div Infect Dis, 75 Francis St, Boston, MA 02115 USA. EM psax@partners.org FU GlaxoSmithKline; Pfizer; Merck Laboratories; Abbott Laboratories; Bristol-Myers Squibb; Gilead Sciences; Tibotec; Johnson Johnson; Koronis; Schering-Plough; Bionor Immuno AS; Cytheris; Siemens Medical Solutions Diagnostics and Roche Diagnostics; Boehringer Ingelheim; Panacos Pharmaceuticals; National Institute of Allergy and Infectious Diseases, National Institutes of Health [AI38858, AI68636, AI68634]; National Center for Research Resources FX Dr. Sax reports receiving grant support from GlaxoSmithKline, Pfizer, and Merck Laboratories and consulting fees from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Laboratories, and Tibotec and serving as a member of the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents; Dr. Tierney, serving on a data and safety monitoring board for Tibotec; Dr. Collier, receiving grant support from Johnson & Johnson (Tibotec), Koronis, Merck Laboratories, Schering-Plough, and Gilead Sciences and consulting fees from GlaxoSmithKline, Pfizer, Merck Laboratories; Dr. Fischl, receiving grant support from Abbott Laboratories, Bionor Immuno AS, Bristol-Myers Squibb, Cytheris, GlaxoSmithKline, and Tibotec and grant support and lecture and consulting fees from Merck Laboratories; Dr. Katzenstein, receiving grant support from Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, and Gilead Sciences; Dr. Farajallah, being an employee of Bristol-Myers Squibb; Dr. Rooney, being an employee of Gilead Sciences; Dr. Ha, being an employee of GlaxoSmithKline; Dr. Woodward, being an employee of Abbott Laboratories; Dr. Johnson, receiving grant support from Siemens Medical Solutions Diagnostics and Roche Diagnostics; Dr. Geiseler, receiving lecture fees from Cubist Pharmaceuticals; Dr. Daar, receiving grant support from Abbott Laboratories, Merck Laboratories, GlaxoSmithKline, and Gilead Sciences and consulting fees from Abbott Laboratories, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Sciences, Pfizer, Merck Laboratories, Tibotec, Boehringer Ingelheim, and Schering-Plough, and serving as a member of the data and safety monitoring board for Ardea Biosciences and of the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents; and Dr. Koletar, receiving grant support from Panacos Pharmaceuticals. No other potential conflict of interest relevant to this article was reported. Supported by grants (AI38858, to the AIDS Clinical Trials Group [ACTG] Central Group; AI68636, to the ACTG Network; and AI68634 and AI38855, to the ACTG Statistical and Data Analysis Center) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, with additional support from the General Clinical Research Center units funded by the National Center for Research Resources. NR 16 TC 171 Z9 171 U1 0 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 3 PY 2009 VL 361 IS 23 BP 2230 EP 2240 DI 10.1056/NEJMoa0906768 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 525ZM UT WOS:000272257100006 PM 19952143 ER PT J AU Lauer, MS AF Lauer, Michael S. TI Radiation Exposure from Medical Imaging Procedures REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NHLBI, Bethesda, MD 20892 USA. RP Lauer, MS (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 NR 6 TC 0 Z9 0 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 EI 1533-4406 J9 NEW ENGL J MED JI N. Engl. J. Med. PD DEC 3 PY 2009 VL 361 IS 23 BP 2292 EP 2292 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 525ZM UT WOS:000272257100023 ER PT J AU Chowell, G Viboud, C Wang, XH Bertozzi, SM Miller, MA AF Chowell, Gerardo Viboud, Cecile Wang, Xiaohong Bertozzi, Stefano M. Miller, Mark A. TI Adaptive Vaccination Strategies to Mitigate Pandemic Influenza: Mexico as a Case Study SO PLOS ONE LA English DT Article ID BACTERIAL PNEUMONIA; SOCIAL CONTACTS; MORTALITY; SPREAD; EPIDEMIC; PATTERNS; IMPACT; AGE; TRANSMISSIBILITY; PREPAREDNESS AB Background: We explore vaccination strategies against pandemic influenza in Mexico using an age-structured transmission model calibrated against local epidemiological data from the Spring 2009 A(H1N1) pandemic. Methods and Findings: In the context of limited vaccine supplies, we evaluate age-targeted allocation strategies that either prioritize youngest children and persons over 65 years of age, as for seasonal influenza, or adaptively prioritize age groups based on the age patterns of hospitalization and death monitored in real-time during the early stages of the pandemic. Overall the adaptive vaccination strategy outperformed the seasonal influenza vaccination allocation strategy for a wide range of disease and vaccine coverage parameters. Conclusions: This modeling approach could inform policies for Mexico and other countries with similar demographic features and vaccine resources issues, with regard to the mitigation of the S-OIV pandemic. We also discuss logistical issues associated with the implementation of adaptive vaccination strategies in the context of past and future influenza pandemics. C1 [Chowell, Gerardo; Wang, Xiaohong] Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Tempe, AZ 85287 USA. [Chowell, Gerardo; Viboud, Cecile; Miller, Mark A.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Bertozzi, Stefano M.] Ctr Evaluat Res & Surveys, Natl Inst Publ Hlth, Cuernavaca, Morelos, Mexico. [Bertozzi, Stefano M.] Univ Calif Berkeley, Berkeley, CA 94720 USA. RP Chowell, G (reprint author), Arizona State Univ, Sch Human Evolut & Social Change, Math Computat & Modeling Sci Ctr, Tempe, AZ 85287 USA. EM gchowell@asu.edu RI Chowell, Gerardo/F-5038-2012 OI Chowell, Gerardo/0000-0003-2194-2251 FU Quantitative Immunization and Vaccine-Related Research (QUIVER) program of the WHO; Fogarty International Center; National Institutes of Health FX The study was funded by the Quantitative Immunization and Vaccine-Related Research (QUIVER) program of the WHO and the intra-mural program of the Fogarty International Center, 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 52 TC 38 Z9 38 U1 4 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 3 PY 2009 VL 4 IS 12 AR e8164 DI 10.1371/journal.pone.0008164 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MW UT WOS:000272829000014 PM 19997603 ER PT J AU Vaiana, SM Best, RB Yau, WM Eaton, WA Hofrichter, J AF Vaiana, Sara M. Best, Robert B. Yau, Wai-Ming Eaton, William A. Hofrichter, James TI Evidence for a Partially Structured State of the Amylin Monomer SO BIOPHYSICAL JOURNAL LA English DT Article ID ISLET AMYLOID POLYPEPTIDE; INTRAMOLECULAR CONTACT FORMATION; TYPE-2 DIABETES-MELLITUS; PROTEIN-FOLDING KINETICS; ALPHA-HELICAL STATES; LOOP FORMATION; NMR-SPECTROSCOPY; MOLECULAR-BASIS; DYNAMICS; PEPTIDE AB Islet amyloid polypeptide (amylin) is the main component in amyloid deposits formed in type II diabetes. We used triplet quenching to probe the dynamics of contact formation between the N-terminal disulfide loop and a C-terminal tryptophan in monomeric amylins from human and rat. Quenching rates measured in the absence of denaturant are four times larger than those in 6 M guanidinium chloride, indicating a decrease in the average end-to-end distance (collapse) at low denaturant concentrations. We were surprised to find an even greater (sevenfold) increase in quenching rates on removal of denaturant for a hydrophilic control peptide containing the disulfide loop compared to the same peptide without the loop (twofold change). These results suggest that collapse is driven by backbone-backbone and backbone-side chain interactions involving the disulfide loop portion of the chain rather than by the formation of side-chain hydrophobic contacts. Molecular dynamics simulations of the control peptide show that the collapse results from hydrogen-bonding interactions between the central residues of the chain and the disulfide loop. The quenching experiments also indicate that the monomer of the human, amyloidogenic form of amylin is more compact than the rat form, which does not form amyloid. We discuss these newly observed differences between human and rat amylin in solution and their possible relation to aggregation and to the physiological function of amylin binding to the calcitonin receptor. C1 [Vaiana, Sara M.; Yau, Wai-Ming; Eaton, William A.; Hofrichter, James] NIDDK, Chem Phys Lab, NIH, Bethesda, MD USA. [Best, Robert B.] Univ Cambridge, Dept Chem, Cambridge CB2 1EW, England. RP Vaiana, SM (reprint author), Arizona State Univ, Dept Phys, Tempe, AZ 85287 USA. EM sara.vaiana@asu.edu; jameshof@niddk.nih.gov RI Best, Robert/H-7588-2016 OI Best, Robert/0000-0002-7893-3543 FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Royal Society University FX S.M.V., W.M.Y., W.A.E., and J.H. were supported by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, and made use of the Biowulf cluster at the National Institutes of Health. R.B.B. is supported by a .Royal Society University Research Fellowship NR 47 TC 29 Z9 29 U1 4 U2 28 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD DEC 2 PY 2009 VL 97 IS 11 BP 2948 EP 2957 DI 10.1016/j.bpj.2009.08.041 PG 10 WC Biophysics SC Biophysics GA 526GA UT WOS:000272274500012 PM 19948124 ER PT J AU Jang, H Arce, FT Capone, R Ramachandran, S Lal, R Nussinov, R AF Jang, Hyunbum Arce, Fernando Teran Capone, Ricardo Ramachandran, Srinivasan Lal, Ratnesh Nussinov, Ruth TI Misfolded Amyloid Ion Channels Present Mobile beta-Sheet Subunits in Contrast to Conventional Ion Channels SO BIOPHYSICAL JOURNAL LA English DT Article ID PRION PROTEIN-FRAGMENT; ALZHEIMERS-DISEASE; ZN2+-SENSITIVE CHANNEL; MOLECULAR-DYNAMICS; COMMON MECHANISM; LIPID-BILAYERS; 3D STRUCTURE; CONGO RED; FIBRILS; PROTOFILAMENTS AB In Alzheimers disease, calcium permeability through cellular membranes appears to underlie neuronal cell death. It is increasingly accepted that calcium permeability involves toxic ion channels. We modeled Alzheimer's disease ion channels of different sizes (12-mer to 36-mer) in the lipid bilayer using molecular dynamics simulations. Our A beta channels consist of the solid-state NMR-based U-shaped beta-strand-turn-beta-strand motif. In the simulations we obtain ion-permeable channels whose subunit morphologies and shapes are consistent with electron microscopy/atomic force microscopy. In agreement with imaged channels, the simulations indicate that beta-sheet channels break into loosely associated mobile beta-sheet subunits. The preferred channel sizes (16- to 24-mer) are compatible with electron microscopy/atomic force microscopy-derived dimensions. Mobile subunits were also observed for beta-sheet channels formed by cytolytic PG-1 beta-hairpins. The emerging picture from our large-scale simulations is that toxic ion channels formed by beta-sheets spontaneously break into loosely interacting dynamic units that associate and dissociate leading to toxic ionic flux. This sharply contrasts intact conventional gated ion channels that consist of tightly interacting alpha-helices that robustly prevent ion leakage, rather than hydrogen-bonded beta-strands. The simulations suggest why conventional gated channels evolved to consist of interacting a-helices rather than hydrogen-bonded beta-strands that tend to break in fluidic bilayers. Nature designs folded channels but not misfolded toxic channels. C1 [Jang, Hyunbum; Nussinov, Ruth] NCI, Ctr Canc Res Nanobiol Program, SAIC Frederick, Frederick, MD 21701 USA. [Arce, Fernando Teran; Capone, Ricardo; Ramachandran, Srinivasan; Lal, Ratnesh] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Arce, Fernando Teran; Capone, Ricardo; Ramachandran, Srinivasan; Lal, Ratnesh] Univ Chicago, Ctr Nanomed, Chicago, IL 60637 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Jang, H (reprint author), NCI, Ctr Canc Res Nanobiol Program, SAIC Frederick, Frederick, MD 21701 USA. EM jangh2@mail.nih.gov RI Capone, Ricardo/D-1943-2010 OI Capone, Ricardo/0000-0002-7327-9837 FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research FX This work was supported by the National Cancer Institute, National Institutes of Health (N01-CO-12400), and the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 59 TC 52 Z9 53 U1 2 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD DEC 2 PY 2009 VL 97 IS 11 BP 3029 EP 3037 DI 10.1016/j.bpj.2009.09.014 PG 9 WC Biophysics SC Biophysics GA 526GA UT WOS:000272274500021 PM 19948133 ER PT J AU Cofta-Woerpel, L Randhawa, V McFadden, HG Fought, A Bullard, E Spring, B AF Cofta-Woerpel, Ludmila Randhawa, Veenu McFadden, H. Gene Fought, Angela Bullard, Emily Spring, Bonnie TI ACCISS study rationale and design: activating collaborative cancer information service support for cervical cancer screening SO BMC PUBLIC HEALTH LA English DT Article ID NATIONAL TRENDS SURVEY; INCOME MINORITY WOMEN; ABNORMAL PAP-SMEARS; FOLLOW-UP; PSYCHOMETRIC PROPERTIES; HEALTH INFORMATION; PATIENT EDUCATION; DECISION-MAKING; PUBLIC-HEALTH; COMMUNICATION AB Background: High-quality cancer information resources are available but underutilized by the public. Despite greater awareness of the National Cancer Institute's Cancer Information Service among low-income African Americans and Hispanics compared with Caucasians, actual Cancer Information Service usage is lower than expected, paralleling excess cancer-related morbidity and mortality for these subgroups. The proposed research examines how to connect the Cancer Information Service to low-income African-American and Hispanic women and their health care providers. The study will examine whether targeted physician mailing to women scheduled for colposcopy to follow up an abnormal Pap test can increase calls to the Cancer Information Service, enhance appropriate medical follow-up, and improve satisfaction with provider-patient communication. Methods/Design: The study will be conducted in two clinics in ethnically diverse low-income communities in Chicago. During the formative phase, patients and providers will provide input regarding materials planned for use in the experimental phase of the study. The experimental phase will use a two-group prospective randomized controlled trial design. African American and Hispanic women with an abnormal Pap test will be randomized to Usual Care (routine colposcopy reminder letter) or Intervention (reminder plus provider recommendation to call the Cancer Information Service and sample questions to ask). Primary outcomes will be: 1) calls to the Cancer Information Service; 2) timely medical follow-up, operationalized by whether the patient keeps her colposcopy appointment within six months of the abnormal Pap; and 3) patient satisfaction with provider-patient communication at follow-up. Discussion: The study examines the effectiveness of a feasible, sustainable, and culturally sensitive strategy to increase awareness and use of the Cancer Information Service among an underserved population. The goal of linking a public service (the Cancer Information Service) with real-life settings of practice (the clinics), and considering input from patients, providers, and Cancer Information Service staff, is to ensure that the intervention, if proven effective, can be incorporated into existing care systems and sustained. The approach to study design and planning is aimed at bridging the gap between research and practice/service. C1 [McFadden, H. Gene; Fought, Angela; Spring, Bonnie] Northwestern Univ, Dept Prevent Med, Chicago, IL 60611 USA. [Cofta-Woerpel, Ludmila] Univ Texas MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77230 USA. [Cofta-Woerpel, Ludmila] NCI, Canc Informat Serv, Unit 1330, Houston, TX 77230 USA. [Randhawa, Veenu] Access Community Hlth Network, Maternal Program, Chicago, IL 60606 USA. [Randhawa, Veenu] Access Community Hlth Network, Child Hlth Program, Chicago, IL 60606 USA. [Bullard, Emily] Univ Kansas, Med Ctr, NCI, Canc Informat Serv, Kansas City, KS 66160 USA. RP Spring, B (reprint author), Northwestern Univ, Dept Prevent Med, 680 N Lakeshore Dr,Suite 1220, Chicago, IL 60611 USA. EM lcwoerpel@mdanderson.org; veenu_r@yahoo.com; h-mcfadden@northwestern.edu; ajfought@northwestern.edu; ebullard@kumc.edu; bspring@northwestern.edu FU NCI [R21 CA126450]; NCI's Cancer Information Service FX This study is funded by NCI grant R21 CA126450 awarded to Dr. Bonnie Spring. We extend our gratitude to providers and patients in the Erie Family Health Center and the Prentice Ambulatory Clinic in Chicago, IL, for participating in the research. We thank NCI's Cancer Information Service for collaborating on the study and for unyielding support of this project. We also thank Alfred Rademaker, Ph. D., Director of the Biostatistics Core for the Robert Lurie Comprehensive Cancer Center, for conducting the study's power analyses and developing the analytic plan. NR 55 TC 1 Z9 2 U1 5 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD DEC 2 PY 2009 VL 9 AR 444 DI 10.1186/1471-2458-9-444 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 533NA UT WOS:000272829400001 PM 19951443 ER PT J AU Das, BB Antony, S Gupta, S Dexheimer, TS Redon, CE Garfield, S Shiloh, Y Pommier, Y AF Das, Benu Brata Antony, Smitha Gupta, Shalu Dexheimer, Thomas S. Redon, Christophe E. Garfield, Susan Shiloh, Yosef Pommier, Yves TI Optimal function of the DNA repair enzyme TDP1 requires its phosphorylation by ATM and/or DNA-PK SO EMBO JOURNAL LA English DT Article DE camptothecin; DNA repair; gamma H2AX; Topoisomerase 1; XRCC1 ID DOUBLE-STRAND BREAKS; DEPENDENT PROTEIN-KINASE; BASE EXCISION-REPAIR; I CLEAVAGE COMPLEXES; TOPOISOMERASE-I; PHOSPHODIESTERASE TDP1; ATAXIA-TELANGIECTASIA; SPINOCEREBELLAR ATAXIA; COVALENT COMPLEXES; AXONAL NEUROPATHY AB Human tyrosyl-DNA phosphodiesterase (TDP1) hydrolyzes the phosphodiester bond at a DNA 3' end linked to a tyrosyl moiety. This type of linkage is found at stalled topoisomerase I (Top1)-DNA covalent complexes, and TDP1 has been implicated in the repair of such complexes. Here we show that Top1-associated DNA double-stranded breaks (DSBs) induce the phosphorylation of TDP1 at S81. This phosphorylation is mediated by the protein kinases: ataxia-telangiectasia-mutated (ATM) and DNA-dependent protein kinase (DNA-PK). Phosphorylated TDP1 forms nuclear foci that co-localize with those of phosphorylated histone H2AX (gamma H2AX). Both Top1-induced replication-and transcription-mediated DNA damages induce TDP1 phosphorylation. Furthermore, we show that S81 phosphorylation stabilizes TDP1, induces the formation of XRCC1 (X-ray cross-complementing group 1)-TDP1 complexes and enhances the mobilization of TDP1 to DNA damage sites. Finally, we provide evidence that TDP1-S81 phosphorylation promotes cell survival and DNA repair in response to CPT-induced DSBs. Together; our findings provide a new mechanism for TDP1 post-translational regulation by ATM and DNA-PK. The EMBO Journal (2009) 28, 3667-3680. doi: 10.1038/emboj.2009.302; Published online 22 October 2009 C1 [Pommier, Yves] NCI, Mol Pharmacol Lab, Div Basic Sci, NIH,Ctr Canc Res, Bethesda, MD 20892 USA. [Garfield, Susan] NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Shiloh, Yosef] Tel Aviv Univ, Sackler Sch Med, David & Inez Meyers Lab Canc Genet, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Div Basic Sci, NIH,Ctr Canc Res, Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov FU NCI Intramural Program; Center for Cancer Research; National Cancer Institute; NIH; A-T Medical Research Foundation; Israel Cancer Research Fund FX The authors thank Dr Cornelius F Boerkoel (Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, British Columbia, Canada) for kindly providing the TDP1+/+ and TDP1-/- primary MEFs cells. This study was supported by funds from the NCI Intramural Program, Center for Cancer Research, National Cancer Institute, NIH, and by the A-T Medical Research Foundation (YS). YS is a Research Professor of Israel Cancer Research Fund. NR 68 TC 52 Z9 55 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD DEC 2 PY 2009 VL 28 IS 23 BP 3667 EP 3680 DI 10.1038/emboj.2009.302 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 526HG UT WOS:000272277700005 PM 19851285 ER PT J AU Taniguchi, S Nakazawa, T Tanimura, A Kiyama, Y Tezuka, T Watabe, AM Katayama, N Yokoyama, K Inoue, T Izumi-Nakaseko, H Kakuta, S Sudo, K Iwakura, Y Umemori, H Inoue, T Murphy, NP Hashimoto, K Kano, M Manabe, T Yamamoto, T AF Taniguchi, Sachiko Nakazawa, Takanobu Tanimura, Asami Kiyama, Yuji Tezuka, Tohru Watabe, Ayako M. Katayama, Norikazu Yokoyama, Kazumasa Inoue, Takeshi Izumi-Nakaseko, Hiroko Kakuta, Shigeru Sudo, Katsuko Iwakura, Yoichiro Umemori, Hisashi Inoue, Takafumi Murphy, Niall P. Hashimoto, Kouichi Kano, Masanobu Manabe, Toshiya Yamamoto, Tadashi TI Involvement of NMDAR2A tyrosine phosphorylation in depression-related behaviour SO EMBO JOURNAL LA English DT Article DE DARPP-32; depression-related behaviour; NMDA receptor; Src; tyrosine phosphorylation ID D-ASPARTATE RECEPTOR; ANTIDEPRESSANT ACTIVITY; SYNAPTIC-TRANSMISSION; NEOSTRIATAL NEURONS; SUBUNIT NR2A; MOUSE; MICE; PLASTICITY; KINASE; SRC AB Major depressive and bipolar disorders are serious illnesses that affect millions of people. Growing evidence implicates glutamate signalling in depression, though the molecular mechanism by which glutamate signalling regulates depression-related behaviour remains unknown. In this study, we provide evidence suggesting that tyrosine phosphorylation of the NMDA receptor, an ionotropic glutamate receptor, contributes to depression-related behaviour. The NR2A subunit of the NMDA receptor is tyrosine-phosphorylated, with Tyr 1325 as its one of the major phosphorylation site. We have generated mice expressing mutant NR2A with a Tyr-1325-Phe mutation to prevent the phosphorylation of this site in vivo. The homozygous knock-in mice show antidepressant-like behaviour in the tail suspension test and in the forced swim test. In the striatum of the knock-in mice, DARPP-32 phosphorylation at Thr 34, which is important for the regulation of depression-related behaviour, is increased. We also show that the Tyr 1325 phosphorylation site is required for Src-induced potentiation of the NMDA receptor channel in the striatum. These data argue that Tyr 1325 phosphorylation regulates NMDA receptor channel properties and the NMDA receptor-mediated downstream signalling to modulate depression-related behaviour. The EMBO Journal (2009) 28, 3717-3729. doi: 10.1038/emboj.2009.300; Published online 15 October 2009 C1 [Nakazawa, Takanobu] Univ Tokyo, Div Oncol, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan. [Tanimura, Asami; Hashimoto, Kouichi; Kano, Masanobu] Univ Tokyo, Dept Neurophysiol, Grad Sch Med, Tokyo 1088639, Japan. [Kiyama, Yuji; Watabe, Ayako M.; Katayama, Norikazu; Izumi-Nakaseko, Hiroko; Manabe, Toshiya] Univ Tokyo, Div Neuronal Network, Inst Med Sci, Tokyo 1088639, Japan. [Kakuta, Shigeru; Sudo, Katsuko; Iwakura, Yoichiro] Univ Tokyo, Ctr Expt Med & Syst Biol, Inst Med Sci, Tokyo 1088639, Japan. [Umemori, Hisashi] Univ Michigan, Sch Med, Mol & Behav Neurosci Inst, Ann Arbor, MI USA. [Umemori, Hisashi] Univ Michigan, Sch Med, Dept Biol Chem, Ann Arbor, MI USA. [Inoue, Takafumi] Waseda Univ, Fac Sci & Engn, Dept Life Sci & Biosci, Tokyo, Japan. [Murphy, Niall P.] Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Hatos Ctr Neuropharmacol, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90024 USA. [Hashimoto, Kouichi; Manabe, Toshiya] Japan Sci & Technol Agcy JST, Kawaguchi, Saitama, Japan. [Yamamoto, Tadashi] NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Nakazawa, T (reprint author), Univ Tokyo, Div Oncol, Inst Med Sci, Minato Ku, 4-6-1 Shirokanedai, Tokyo 1088639, Japan. EM takanobunakazawa-tky@umin.ac.jp RI Iwakura, Yoichiro/E-5457-2011; Nakazawa, Takanobu/E-1012-2014; OI Iwakura, Yoichiro/0000-0002-9934-5775; Nakazawa, Takanobu/0000-0002-5049-9140; Inoue, Takafumi/0000-0002-2728-0060 FU Ministry of Education, Science, Sports, Culture and Technology of Japan FX We thank J. Miyazaki for providing the mice carrying the CAG-cre transgene and S. Nakanishi for providing cDNAs of the rats NR1E and NR2A. We thank S. Kida for helpful discussion. We also thank the editorial assistance of the NIH Fellows Editorial Board. This research was supported in part by Grants-in-Aid for Scientific Research (TN, TY, AMW, and TM); by Global COE Program (Integrative Life Science Based on the Study of Biosignaling Mechanisms) (TY); by Center for Brain Medical Science, 21st Century COE Program (TM); and by Global COE Program (Comprehensive Center of Education and Research for Chemical Biology of the Diseases) (TM) from the Ministry of Education, Science, Sports, Culture and Technology of Japan. NR 48 TC 36 Z9 37 U1 1 U2 4 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0261-4189 EI 1460-2075 J9 EMBO J JI Embo J. PD DEC 2 PY 2009 VL 28 IS 23 BP 3717 EP 3729 DI 10.1038/emboj.2009.300 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 526HG UT WOS:000272277700009 PM 19834457 ER PT J AU Peng, AW Belyantseva, IA Hsu, PD Friedman, TB Heller, S AF Peng, Anthony W. Belyantseva, Inna A. Hsu, Patrick D. Friedman, Thomas B. Heller, Stefan TI Twinfilin 2 Regulates Actin Filament Lengths in Cochlear Stereocilia SO JOURNAL OF NEUROSCIENCE LA English DT Article ID HAIR-CELL STEREOCILIA; MYOSIN-XVA; INNER-EAR; POSTNATAL-DEVELOPMENT; HAMSTER COCHLEA; CROSS-LINKS; ELONGATION; WHIRLIN; MOUSE; GENE AB Inner ear sensory hair cells convert mechanical stimuli into electrical signals. This conversion happens in the exquisitely mechanosensitive hair bundle that protrudes from the cell's apical surface. In mammals, cochlear hair bundles are composed of 50-100 actin-filled stereocilia, which are organized in three rows in a staircase manner. Stereocilia actin filaments are uniformly oriented with their barbed ends toward stereocilia tips. During development, the actin core of each stereocilium undergoes elongation due to addition of actin monomers to the barbed ends of the filaments. Here we show that in the mouse cochlea the barbed end capping protein twinfilin 2 is present at the tips of middle and short rows of stereocilia from postnatal day 5 (P5) onward, which correlates with a time period when these rows stop growing. The tall stereocilia rows, which do not display twinfilin 2 at their tips, continue to elongate between P5 and P15. When we expressed twinfilin 2 in LLC/PK1-CL4 (CL4) cells, we observed a reduction of espin-induced microvilli length, pointing to a potent function of twinfilin 2 in suppressing the elongation of actin filaments. Overexpression of twinfilin 2 in cochlear inner hair cells resulted in a significant reduction of stereocilia length. Our results suggest that twinfilin 2 plays a role in the regulation of stereocilia elongation by restricting excessive elongation of the shorter row stereocilia thereby maintaining the mature staircase architecture of cochlear hair bundles. C1 [Peng, Anthony W.; Hsu, Patrick D.; Heller, Stefan] Stanford Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, Stanford, CA 94305 USA. [Peng, Anthony W.; Hsu, Patrick D.; Heller, Stefan] Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA. [Peng, Anthony W.] MIT, Cambridge, MA 02139 USA. [Belyantseva, Inna A.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, Sect Human Genet, NIH, Rockville, MD 20850 USA. RP Heller, S (reprint author), Stanford Univ, Sch Med, Dept Otolaryngol Head & Neck Surg, 801 Welch Rd, Stanford, CA 94305 USA. EM hellers@stanford.edu OI Peng, Anthony/0000-0002-2208-6779 FU National Institute on Deafness and Other Communication Disorders [R01 DC4563, P30 DC010363]; [1 Z01-DC-000048-11 LMG]; [T3 2 DC000020]; [F31 DC009168] FX This work was supported by National Institute on Deafness and Other Communication Disorders Grants R01 DC4563 and P30 DC010363 (to S. H.), intramural funds 1 Z01-DC-000048-11 LMG (to T. B. F.), and, in part, when the work commenced at the Massachusetts Eye and Ear Infirmary in Boston, MA, by Training Grant T3 2 DC000020; support was continued by F31 DC009168 (to A. W. P.). We thank Dr. Pekka Lappalainen (Helsinki University) for providing antibodies to twinfilin and Andrew Guzzetta (Stanford) for expert help with mass spectrometry. NR 24 TC 37 Z9 39 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD DEC 2 PY 2009 VL 29 IS 48 BP 15083 EP 15088 DI 10.1523/JNEUROSCI.2782-09.2009 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 527IW UT WOS:000272361700007 PM 19955359 ER PT J AU Kefas, B Comeau, L Floyd, DH Seleverstov, O Godlewski, J Schmittgen, T Jiang, JM diPierro, CG Li, YQ Chiocca, EA Lee, J Fine, H Abounader, R Lawler, S Purow, B AF Kefas, Benjamin Comeau, Laurey Floyd, Desiree H. Seleverstov, Oleksandr Godlewski, Jakub Schmittgen, Tom Jiang, Jinmai diPierro, Charles G. Li, Yunqing Chiocca, E. Antonio Lee, Jeongwu Fine, Howard Abounader, Roger Lawler, Sean Purow, Benjamin TI The Neuronal MicroRNA miR-326 Acts in a Feedback Loop with Notch and Has Therapeutic Potential against Brain Tumors SO JOURNAL OF NEUROSCIENCE LA English DT Article ID CELL-LINES; PROTEIN-KINASE; STEM-CELLS; ACTIVATION; EXPRESSION; APOPTOSIS; NEUROGENESIS; GLIOBLASTOMA; INHIBITION; RECEPTOR AB Little is known of microRNA interactions with cellular pathways. Few reports have associated microRNAs with the Notch pathway, which plays key roles in nervous system development and in brain tumors. We previously implicated the Notch pathway in gliomas, the most common and aggressive brain tumors. While investigating Notch mediators, we noted microRNA-326 was upregulated following Notch-1 knockdown. This neuronally expressed microRNA was not only suppressed by Notch but also inhibited Notch proteins and activity, indicating a feedback loop. MicroRNA-326 was downregulated in gliomas via decreased expression of its host gene. Transfection of microRNA-326 into both established and stem cell-like glioma lines was cytotoxic, and rescue was obtained with Notch restoration. Furthermore, miR-326 transfection reduced glioma cell tumorigenicity in vivo. Additionally, we found microRNA-326 partially mediated the toxic effects of Notch knockdown. This work demonstrates a microRNA-326/Notch axis, shedding light on the biology of Notch and suggesting microRNA-326 delivery as a therapy. C1 [Purow, Benjamin] Univ Virginia Hlth Syst, Old Med Sch, Dept Neurol, Div Neurooncol, Charlottesville, VA 22908 USA. [Godlewski, Jakub; Chiocca, E. Antonio; Lawler, Sean] Ohio State Univ, Med Ctr, Dept Neurol Surg, Dardinger Lab Neurooncol & Neurosci, Columbus, OH 43210 USA. [Schmittgen, Tom; Jiang, Jinmai] Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. [diPierro, Charles G.] Univ VIrginia Hlth Syst, Dept Pathol, Charlottesville, VA 22908 USA. [Li, Yunqing] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. [Li, Yunqing] Hugo W Moser Res Inst Kennedy Krieger, Baltimore, MD 21205 USA. [Lee, Jeongwu; Fine, Howard] Natl Inst Neurol Disorders & Stroke, Neurooncol Branch, NCI, NIH, Bethesda, MD 20892 USA. RP Purow, B (reprint author), Univ Virginia Hlth Syst, Old Med Sch, Dept Neurol, Div Neurooncol, Room 4814,21 Hosp Dr, Charlottesville, VA 22908 USA. EM bwp5g@virginia.edu FU National Institutes of Health [R01CA136803]; University of Virginia Neurology Department and Cancer Center FX This work was supported by National Institutes of Health Grant R01CA136803 (B. P.) and by startup funding from the University of Virginia Neurology Department and Cancer Center (B. P.). We thank Joanne Lannigan and Michael Solga for assistance with flow cytometry. We are grateful to Spyros Artavanis-Tsakonas for his kind gift of the Notch-1 expression vector and to S. Diane Hayward for her kind gift of the CBF1-luciferase reporter plasmid. NR 33 TC 109 Z9 113 U1 1 U2 11 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 2 PY 2009 VL 29 IS 48 BP 15161 EP 15168 DI 10.1523/JNEUROSCI.4966-09.2009 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 527IW UT WOS:000272361700016 PM 19955368 ER PT J AU Woloshin, S Schwartz, LM Kramer, BS AF Woloshin, Steven Schwartz, Lisa M. Kramer, Barnett S. TI Promoting Healthy Skepticism in the News: Helping Journalists Get It Right SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID PRESS RELEASES C1 [Woloshin, Steven; Schwartz, Lisa M.] Dartmouth Inst Hlth Policy & Clin Practice, Ctr Med Media, Hanover, NH USA. [Woloshin, Steven; Schwartz, Lisa M.] Vet Affairs Med Ctr, VA Outcomes Grp 111B, White River Jct, VT USA. [Kramer, Barnett S.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Schwartz, LM (reprint author), Vet Affairs Med Ctr, VA Outcomes Grp, Mail Code 111B,215 N Main St, White River Jct, VT 05009 USA. EM lisa.schwartz@dartmouth.edu FU NCI NIH HHS [R01 CA104721, R01CA104721] NR 16 TC 17 Z9 17 U1 0 U2 3 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 2 PY 2009 VL 101 IS 23 BP 1596 EP 1599 DI 10.1093/jnci/djp409 PG 4 WC Oncology SC Oncology GA 528RT UT WOS:000272465100001 PM 19933445 ER PT J AU Shneider, NA Brown, MN Smith, CA Pickel, J Alvarez, FJ AF Shneider, Neil A. Brown, Meghan N. Smith, Courtney A. Pickel, James Alvarez, Francisco J. TI Gamma motor neurons express distinct genetic markers at birth and require muscle spindle-derived GDNF for postnatal survival SO NEURAL DEVELOPMENT LA English DT Article ID VESICULAR GLUTAMATE TRANSPORTERS; TRANSCRIPTION FACTOR EGR3; MAMMALIAN SPINAL-CORD; MICE LACKING GDNF; HORSERADISH-PEROXIDASE; NEUROTROPHIC FACTOR; PERONEAL MOTONEURONS; ALPHA-MOTONEURONS; TIBIALIS ANTERIOR; CAT AB Background: Gamma motor neurons (gamma-MNs) selectively innervate muscle spindle intrafusal fibers and regulate their sensitivity to stretch. They constitute a distinct subpopulation that differs in morphology, physiology and connectivity from alpha-MNs, which innervate extrafusal muscle fibers and exert force. The mechanisms that control the differentiation of functionally distinct fusimotor neurons are unknown. Progress on this question has been limited by the absence of molecular markers to specifically distinguish and manipulate gamma-MNs. Recently, it was reported that early embryonic gamma-MN precursors are dependent on GDNF. Using this knowledge we characterized genetic strategies to label developing gamma-MNs based on GDNF receptor expression, showed their strict dependence for survival on muscle spindle-derived GDNF and generated an animal model in which gamma-MNs are selectively lost. Results: In mice heterozygous for both the Hb9::GFP transgene and a tau-lacZ-labeled (TLZ) allele of the GDNF receptor Gfr alpha 1, we demonstrated that small motor neurons with high Gfr alpha 1-TLZ expression and lacking Hb9::GFP display structural and synaptic features of gamma-MNs and are selectively lost in mutants lacking target muscle spindles. Loss of muscle spindles also results in the downregulation of Gfra1 expression in some large diameter MNs, suggesting that spindle-derived factors may also influence populations of alpha-MNs with beta-skeletofusimotor collaterals. These molecular markers can be used to identify gamma-MNs from birth to the adult and to distinguish gamma- from beta-motor axons in the periphery. We also found that postnatal gamma-MNs are also distinguished by low expression of the neuronal nuclear protein (NeuN). With these markers of gamma-MN identity, we show after conditional elimination of GDNF from muscle spindles that the survival of gamma-MNs is selectively dependent on spindle-derived GDNF during the first 2 weeks of postnatal development. Conclusion: Neonatal gamma-MNs display a unique molecular profile characterized by the differential expression of a series of markers - Gfr alpha 1, Hb9::GFP and NeuN - and the selective dependence on muscle spindle-derived GDNF. Deletion of GDNF expression from muscle spindles results in the selective elimination of gamma-MNs with preservation of the spindle and its sensory innervation. This provides a mouse model with which to explore the specific role of gamma-fusimotor activity in motor behaviors. C1 [Shneider, Neil A.] Columbia Univ, Dept Neurol, Ctr Motor Neuron Biol & Dis, New York, NY 10032 USA. [Shneider, Neil A.; Brown, Meghan N.] Natl Inst Neurol Disorders & Stroke, Sect Dev Neurobiol, NIH, Bethesda, MD 20892 USA. [Smith, Courtney A.; Alvarez, Francisco J.] Wright State Univ, Dept Neurosci Cell Biol & Physiol, Dayton, OH 45435 USA. [Pickel, James] Natl Inst Mental Hlth Transgen Core, NIH, Bethesda, MD 20892 USA. RP Shneider, NA (reprint author), Columbia Univ, Dept Neurol, Ctr Motor Neuron Biol & Dis, New York, NY 10032 USA. EM ns327@columbia.edu; mnbrown@gmail.com; courtney.smith@wright.edu; pickel@nih.gov; francisco.alvarez@wright.edu RI Alvarez, Francisco/H-4929-2011; OI Shneider, Neil/0000-0002-3223-7366 FU National Institute of Neurological Disorders and Stroke intramural program; Columbia University Center for Motor Neuron Biology and Disease; National Institutes of Health [NS047357] FX This work was supported by the National Institute of Neurological Disorders and Stroke intramural program (MNB and NAS), the Columbia University Center for Motor Neuron Biology and Disease (NAS) and by National Institutes of Health Grant NS047357 (CAS and FJA). We thank Chris Henderson, Tom Jessell, George Mentis and Michael O'Donovan for their support and critical comments on this manuscript. We also thank Ms Jackie Sisco with her help preparing semithin histological sections of muscle spindles. NR 62 TC 43 Z9 44 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1749-8104 J9 NEURAL DEV JI Neural Dev. PD DEC 2 PY 2009 VL 4 AR 42 DI 10.1186/1749-8104-4-42 PG 21 WC Developmental Biology; Neurosciences SC Developmental Biology; Neurosciences & Neurology GA 539UB UT WOS:000273282800001 PM 19954518 ER PT J AU Chhikara, M Wang, SB Kern, SJ Ferreyra, GA Barb, JJ Munson, PJ Danner, RL AF Chhikara, Maneesha Wang, Shuibang Kern, Steven J. Ferreyra, Gabriela A. Barb, Jennifer J. Munson, Peter J. Danner, Robert L. TI Carbon Monoxide Blocks Lipopolysaccharide-Induced Gene Expression by Interfering with Proximal TLR4 to NF-kappa B Signal Transduction in Human Monocytes SO PLOS ONE LA English DT Article ID ISCHEMIA-REPERFUSION INJURY; INDUCED LUNG INJURY; THERAPEUTIC APPLICATIONS; ISCHEMIA/REPERFUSION INJURY; INFLAMMATORY RESPONSE; INDUCED ACTIVATION; ENDOTHELIAL-CELLS; HEME OXYGENASE; MAPK PATHWAY; PPAR-GAMMA AB Carbon monoxide (CO) is an endogenous messenger that suppresses inflammation, modulates apoptosis and promotes vascular remodeling. Here, microarrays were employed to globally characterize the CO (250 ppm) suppression of early (1 h) LPS-induced inflammation in human monocytic THP-1 cells. CO suppressed 79 of 101 immediate-early genes induced by LPS; 19% (15/79) were transcription factors and most others were cytokines, chemokines and immune response genes. The prototypic effects of CO on transcription and protein production occurred early but decreased rapidly. CO activated p38 MAPK, ERK1/2 and Akt and caused an early and transitory delay in LPS-induced JNK activation. However, selective inhibitors of these kinases failed to block CO suppression of LPS-induced IL-1 beta, an inflammation marker. Of CO-suppressed genes, 81% (64/79) were found to have promoters with putative NF-kappa B binding sites. CO was subsequently shown to block LPS-induced phosphorylation and degradation of IkB alpha in human monocytes, thereby inhibiting NF-kappa B signal transduction. CO broadly suppresses the initial inflammatory response of human monocytes to LPS by reshaping proximal events in TLR4 signal transduction such as stress kinase responses and early NF-kappa B activation. These rapid, but transient effects of CO may have therapeutic applications in acute pulmonary and vascular injury. C1 [Chhikara, Maneesha; Wang, Shuibang; Kern, Steven J.; Ferreyra, Gabriela A.; Danner, Robert L.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Barb, Jennifer J.; Munson, Peter J.] NIH, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Chhikara, M (reprint author), NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. EM rdanner@cc.nih.gov FU National Institutes of Health Clinical Center FX This study was supported by intramural funds from the National Institutes of Health Clinical Center. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 28 Z9 29 U1 0 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD DEC 2 PY 2009 VL 4 IS 12 AR e8139 DI 10.1371/journal.pone.0008139 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 533MU UT WOS:000272828800029 PM 19956541 ER PT J AU Andrus, MB Wong, Y Liu, J Beebe, K Neckers, LM AF Andrus, Merritt B. Wong, Yong Liu, Jing Beebe, Kristin Neckers, Leonard M. TI Synthesis and evaluation of 8,9-amido analogs of geldanamycin SO TETRAHEDRON LETTERS LA English DT Article DE Glycolate aldol; Ansamycin; Geldanamycin; Amide isostere; Heat-shock protein ID GLYCOLATE ALDOL REACTIONS; HSP90 MOLECULAR CHAPERONE; WADSWORTH-EMMONS REACTION; HERBIMYCIN-A; BIOLOGICAL EVALUATION; ANTITUMOR AGENT; INHIBITORS; ESTERS; (-)-O-QUINOGELDANAMYCIN; (+)-GELDANAMYCIN AB Amido analogs of geldanamycin, an ansamycin anticancer agent, were designed, synthesized, and assayed with SKBR3 cells, in which stability of HER2 receptor tyrosine kinase is dependent on the chaperone Hsp90. An amide was employed as a trisubstituted alkene isostere at the C8,9 position, which provided for a simplified, convergent synthesis through two major fragments, an aniline-amine left-hand portion and a dicarboxylic acid right-hand piece. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Andrus, Merritt B.; Wong, Yong; Liu, Jing] Brigham Young Univ, Dept Chem & Biochem, Provo, UT 84602 USA. [Beebe, Kristin; Neckers, Leonard M.] NCI, Rockville, MD 20892 USA. RP Andrus, MB (reprint author), Brigham Young Univ, Dept Chem & Biochem, C100 BNSN, Provo, UT 84602 USA. EM mbandrus@chem.byu.edu RI liu, jing/G-3957-2011 FU Brigham Young University Cancer Research Center FX We are grateful for the support provided by the Brigham Young University Cancer Research Center and Dr. Yong-Sok Lee of the Center for Molecular Modeling, NIH, for conformer calculations. NR 38 TC 7 Z9 7 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD DEC 2 PY 2009 VL 50 IS 48 BP 6705 EP 6708 DI 10.1016/j.tetlet.2009.09.091 PG 4 WC Chemistry, Organic SC Chemistry GA 514QU UT WOS:000271410800024 ER PT J AU Lee, TL Chan, WY Rennert, OM AF Lee, Tin-Lap Chan, Wai-Yee Rennert, Owen M. TI Assessing the Safety of Nanomaterials by Genomic Approach Could Be Another Alternative SO ACS NANO LA English DT Letter C1 [Lee, Tin-Lap; Chan, Wai-Yee; Rennert, Owen M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genom, Lab Clin Genom, NIH, Bethesda, MD 20892 USA. RP Lee, TL (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Dev Genom, Lab Clin Genom, NIH, Bethesda, MD 20892 USA. EM leetl@mail.nih.gov RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 NR 2 TC 5 Z9 5 U1 0 U2 2 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 2009 VL 3 IS 12 BP 3830 EP 3830 PG 1 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary SC Chemistry; Science & Technology - Other Topics; Materials Science GA 533ST UT WOS:000272846000010 PM 20025301 ER PT J AU Miller, M Dauter, Z Cherry, S Tropea, JE Wlodawer, A AF Miller, Maria Dauter, Zbigniew Cherry, Scott Tropea, Joseph E. Wlodawer, Alexander TI Structure of the Taz2 domain of p300: insights into ligand binding SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID TRANSACTIVATION DOMAIN; TERNARY COMPLEX; P53; PHOSPHORYLATION; ACTIVATION; CBP/P300; PROTEINS; MDM2; ACETYLTRANSFERASE; ONCOPROTEIN AB CBP and its paralog p300 are histone acetyl transferases that regulate gene expression by interacting with multiple transcription factors via specialized domains. The structure of a segment of human p300 protein (residues 1723-1836) corresponding to the extended zinc-binding Taz2 domain has been investigated. The crystal structure was solved by the SAD approach utilizing the anomalous diffraction signal of the bound Zn ions. The structure comprises an atypical helical bundle stabilized by three Zn ions and closely resembles the solution structures determined previously for shorter peptides. Residues 1813-1834 from the current construct form a helical extension of the C-terminal helix and make extensive crystal-contact interactions with the peptide-binding site of Taz2, providing additional insights into the mechanism of the recognition of diverse transactivation domains (TADs) by Taz2. On the basis of these results and molecular modeling, a hypothetical model of the binding of phosphorylated p53 TAD1 to Taz2 has been proposed. C1 [Miller, Maria; Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. [Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne, IL 60439 USA. RP Miller, M (reprint author), NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM mariami@mail.nih.gov RI Miller, Maria/I-1636-2013 OI Miller, Maria/0000-0003-0252-5348 FU U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; NIH; National Cancer Institute; Center for Cancer Research FX We would like to thank Dr Stewart Durell for critical reading of the manuscript. We acknowledge the use of beamline 22-ID of the Southeast Regional Collaborative Access Team (SER-CAT), located at the Advanced Photon Source, Argonne National Laboratory. Use of the APS was supported by the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences, under Contract No. W-31-109-Eng-38. This project was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 24 TC 9 Z9 9 U1 0 U2 5 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD DEC PY 2009 VL 65 BP 1301 EP 1308 DI 10.1107/S0907444909040153 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 521HX UT WOS:000271912500008 PM 19966416 ER PT J AU Radaev, S Agniswamy, J Sun, PD AF Radaev, Sergei Agniswamy, Johnson Sun, Peter D. TI A case of structure determination using pseudosymmetry SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID GROUP-A STREPTOCOCCUS; MAC PROTEIN; OPSONOPHAGOCYTOSIS; IDENTIFICATION; EVASION; INSIGHT AB Here, a case is presented of an unusual structure determination which was facilitated by the use of pseudosymmetry. Group A streptococcus uses cysteine protease Mac-1 (also known as IdeS) to evade the host immune system. Native Mac-1 was crystallized in the orthorhombic space group P2(1)2(1)2. Surprisingly, crystals of the inactive C94A mutant of Mac-1 displayed monoclinic symmetry with space group P2(1), despite the use of native orthorhombic Mac-1 microcrystals for seeding. Attempts to solve the structure of the C94A mutant by MAD phasing in the monoclinic space group did not produce an interpretable map. The native Patterson map of the C94A mutant showed two strong peaks along the (1 0 1) diagonal, indicating possible translational pseudosymmetry in space group P2(1). Interestingly, one-third of the monoclinic reflections obeyed pseudo-orthorhombic P2(1)2(1)2 symmetry similar to that of the wild-type crystals and could be indexed and processed in this space group. The pseudo-orthorhombic and monoclinic unit cells were related by the following vector operations: a(m) = b(o) - c(o), b(m) = a(o) and c(m) = -2c(o) - b(o). The pseudo-orthorhombic subset of data produced good SAD phases, leading to structure determination with one monomer in the asymmetric unit. Subsequently, the structure of the Mac-1 mutant in the monoclinic form was determined by molecular replacement, which showed six molecules forming three translationally related dimers aligned along the (1 0 1) diagonal. Knowing the geometric relationship between the pseudo-orthorhombic and the monoclinic unit cells, all six molecules can be generated in the monoclinic unit cell directly without the use of molecular replacement. The current case provides a successful example of the use of pseudosymmetry as a powerful phase-averaging method for structure determination by anomalous diffraction techniques. In particular, a structure can be solved in a higher pseudosymmetry subcell in which an NCS operator becomes a crystallographic operator. The geometrical relationships between the subcell and parental cell can be used to generate a complete molecular representation of the parental asymmetric unit for refinement. C1 [Radaev, Sergei; Sun, Peter D.] NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, Rockville, MD 20852 USA. [Agniswamy, Johnson] Georgia State Univ, Dept Biol, Atlanta, GA 30302 USA. RP Sun, PD (reprint author), NIAID, Struct Immunol Sect, Immunogenet Lab, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM psun@nih.gov FU National Institute of Allergy and Infectious Diseases; National Institutes of Health FX All X-ray diffraction data were collected on the Southeast Regional Collaborative Access Team (SER-CAT) 22-ID beamline at the Advanced Photon Source, Argonne National Laboratory. Supporting institutions are listed at http://www.ser-cat.org. This research was supported by the intramural research program of National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 22 TC 2 Z9 2 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD DEC PY 2009 VL 65 BP 1334 EP 1340 DI 10.1107/S0907444909039912 PN 12 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 521HX UT WOS:000271912500012 PM 19966420 ER PT J AU Del Tongo, C Carretta, D Fulgenzi, G Catini, C Minciacchi, D AF Del Tongo, Claudia Carretta, Donatella Fulgenzi, Gianluca Catini, Claudio Minciacchi, Diego TI Parvalbumin-positive GABAergic interneurons are increased in the dorsal hippocampus of the dystrophic mdx mouse SO ACTA NEUROPATHOLOGICA LA English DT Article DE Duchenne muscular dystrophy; Mutant mouse strain; Dystrophin; Immunohistochemistry; Dentate gyrus ID DUCHENNE MUSCULAR-DYSTROPHY; CALCIUM-BINDING PROTEINS; TEMPORAL-LOBE EPILEPSY; CENTRAL-NERVOUS-SYSTEM; BRAIN-STEM NEURONS; RAT HIPPOCAMPUS; SYNAPTIC PLASTICITY; GABA(A) RECEPTORS; CALRETININ IMMUNOREACTIVITY; GLYCOPROTEIN COMPLEX AB Duchenne muscular dystrophy (DMD) is characterized by variable alterations of the dystrophin gene and by muscle weakness and cognitive impairment. We postulated an association between cognitive impairment and architectural changes of the hippocampal GABAergic system. We investigated a major subpopulation of GABAergic neurons, the parvalbumin-immunopositive (PV-I) cells, in the dorsal hippocampus of the mdx mouse, an acknowledged model of DMD. PV-I neurons were quantified and their distribution was compared in CA1, CA2, CA3, and dentate gyrus in wild-type and mdx mice. The cell morphology and topography of PV-I neurons were maintained. Conversely, the number of PV-I neurons was significantly increased in the mdx mouse. The percent increase of PV-I neurons was from 45% for CA2, up to 125% for the dentate gyrus. In addition, the increased parvalbumin content in the mdx hippocampus was confirmed by Western blot. A change in the hippocampus processing abilities is the expected functional counterpart of the modification displayed by PV-I GABAergic neurons. Altered hippocampal functionality can be responsible for part of the cognitive impairment in DMD. C1 [Del Tongo, Claudia; Carretta, Donatella; Catini, Claudio; Minciacchi, Diego] Univ Florence, Dept Anat Histol & Forens Med, I-50134 Florence, Italy. [Fulgenzi, Gianluca] Univ Polytech Marche, Dept Expt Pathol & Innovat Therapies, Ancona, Italy. [Fulgenzi, Gianluca] NCI, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Minciacchi, D (reprint author), Univ Florence, Dept Anat Histol & Forens Med, Viale Morgagni 85, I-50134 Florence, Italy. EM diego@unifi.it OI Fulgenzi, Gianluca/0000-0003-2646-7728 NR 65 TC 12 Z9 12 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD DEC PY 2009 VL 118 IS 6 BP 803 EP 812 DI 10.1007/s00401-009-0567-3 PG 10 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 519ZD UT WOS:000271808600009 PM 19588159 ER PT J AU Karschner, EL Schwilke, EW Lowe, RH Darwin, WD Pope, HG Herning, R Cadet, JL Huestis, MA AF Karschner, Erin L. Schwilke, Eugene W. Lowe, Ross H. Darwin, W. David Pope, Harrison G. Herning, Ronald Cadet, Jean L. Huestis, Marilyn A. TI Do Delta 9-tetrahydrocannabinol concentrations indicate recent use in chronic cannabis users? SO ADDICTION LA English DT Article DE Blood; cannabinoids; cannabis; chronic use; driving; tetrahydrocannabinol ID APPARENT HALF-LIFE; BLOOD CANNABINOIDS; MARIJUANA USE; PLASMA; THC; METABOLISM; SMOKING; THCCOOH; DRUGS; TIME AB Aims To quantify blood Delta 9-tetrahydrocannabinol (THC) concentrations in chronic cannabis users over 7 days of continuous monitored abstinence. Participants Twenty-five frequent, long-term cannabis users resided on a secure clinical research unit at the US National Institute on Drug Abuse under continuous medical surveillance to prevent cannabis self-administration. Measurements Whole blood cannabinoid concentrations were determined by two-dimensional gas chromatography-mass spectrometry. Findings Nine chronic users (36%) had no measurable THC during 7 days of cannabis abstinence; 16 had at least one positive THC >= 0.25 ng/ml, but not necessarily on the first day. On day 7, 6 full days after entering the unit, six participants still displayed detectable THC concentrations [mean +/- standard deviation (SD), 0.3 +/- 0.7 ng/ml] and all 25 had measurable carboxy-metabolite (6.2 +/- 8.8 ng/ml). The highest observed THC concentrations on admission (day 1) and day 7 were 7.0 and 3.0 ng/ml, respectively. Interestingly, five participants, all female, had THC-positive whole blood specimens over all 7 days. Body mass index did not correlate with time until the last THC-positive specimen (n = 16; r = -0.2; P = 0.445). Conclusions Substantial whole blood THC concentrations persist multiple days after drug discontinuation in heavy chronic cannabis users. It is currently unknown whether neurocognitive impairment occurs with low blood THC concentrations, and whether return to normal performance, as documented previously following extended cannabis abstinence, is accompanied by the removal of residual THC in brain. These findings also may impact on the implementation of per se limits in driving under the influence of drugs legislation. C1 [Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Pope, Harrison G.] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Pope, Harrison G.] McLean Hosp, Biol Psychiat Lab, Belmont, MA 02178 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, Biomed Res Ctr, Suite 200,251 Bayview Blvd,Room 05A-721, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU National Institute on Drug Abuse; National Institutes of Health FX The authors would like to thank Allan J. Barnes for data analysis support and Kathleen Demuth, Janeen Nichels and John Etter for clinical research assistance. This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 45 TC 40 Z9 40 U1 2 U2 9 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD DEC PY 2009 VL 104 IS 12 BP 2041 EP 2048 DI 10.1111/j.1360-0443.2009.02705.x PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 517OO UT WOS:000271625500014 PM 19804462 ER PT J AU Pegoraro, G Misteli, T AF Pegoraro, Gianluca Misteli, Tom TI The central role of chromatin maintenance in aging SO AGING-US LA English DT Article DE chromatin; DNA repair; progeria; histones; epigenetics ID GILFORD-PROGERIA-SYNDROME; DOUBLE-STRAND BREAKS; EXTENDS LIFE-SPAN; SACCHAROMYCES-CEREVISIAE; CELL-CYCLE; S-PHASE; NUCLEAR ARCHITECTURE; CALORIE RESTRICTION; GENOMIC INSTABILITY; GENOTOXIC STRESS AB Epigenetic regulation of chromatin and the DNA damage response are now well appreciated key players in human aging. What contributions chromatin and DAN repair make to aging, whether they are causal, and how these relate to other aging pathways, however, is unclear. Novel insights into the aging-related molecular mechanisms that link chromatin and DNA damage repair have recently been gained by studying models of both premature and physiological aging. Here we discuss these findings and we propose a broad framework for the role of chromatin in aging to reconcile apparently contradicting evidence obtained in various experimental systems. C1 [Pegoraro, Gianluca; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, 41 Lib Dr,Bldg 41,B610, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov OI Pegoraro, Gianluca/0000-0003-2843-9464 FU Intramural NIH HHS [Z01 BC010309-10] NR 56 TC 26 Z9 26 U1 0 U2 8 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD DEC PY 2009 VL 1 IS 12 BP 1017 EP 1022 PG 6 WC Cell Biology SC Cell Biology GA 579VA UT WOS:000276403100006 PM 20157584 ER PT J AU Carey, JW Mejia, R Bingham, T Ciesielski, C Gelaude, D Herbst, JH Sinunu, M Sey, E Prachand, N Jenkins, RA Stall, R AF Carey, James W. Mejia, Roberto Bingham, Trista Ciesielski, Carol Gelaude, Deborah Herbst, Jeffrey H. Sinunu, Michele Sey, Ekow Prachand, Nikhil Jenkins, Richard A. Stall, Ron TI Drug Use, High-Risk Sex Behaviors, and Increased Risk for Recent HIV Infection among Men who Have Sex with Men in Chicago and Los Angeles SO AIDS AND BEHAVIOR LA English DT Article DE Recent HIV infection; Men who have sex with men; Drug use; Viagra (R); Poppers; Methamphetamine; Sexual risk behavior ID HUMAN-IMMUNODEFICIENCY-VIRUS; SILDENAFIL VIAGRA USE; SUBSTANCE USE; UNITED-STATES; SAN-FRANCISCO; YOUNG MEN; PREVENTION PROGRAMS; METHAMPHETAMINE USE; ENZYME-IMMUNOASSAY; BISEXUAL MEN AB We examined how drugs, high-risk sexual behaviors, and socio-demographic variables are associated with recent HIV infection among men who have sex with men (MSM) in a case-control study. Interviewers collected risk factor data among 111 cases with recent HIV infection, and 333 HIV-negative controls from Chicago and Los Angeles. Compared with controls, cases had more unprotected anal intercourse (UAI) with both HIV-positive and HIV-negative partners. MSM with lower income or prior sexually transmitted infections (STI) were more likely to be recently HIV infected. Substances associated with UAI included amyl nitrate ("poppers"), methamphetamine, Viagra(A (R)) (or similar PDE-5 inhibitors), ketamine, and gamma hydroxybutyrate (GHB). Cases more frequently used Viagra(A (R)), poppers, and methamphetamine during UAI compared with controls. In multivariate analysis, income, UAI with HIV-positive partners, Viagra(A (R)), and poppers remained associated with recent HIV seroconversion. Better methods are needed to prevent HIV among MSM who engage in high-risk sex with concurrent drug use. C1 [Carey, James W.; Mejia, Roberto; Gelaude, Deborah; Herbst, Jeffrey H.; Sinunu, Michele] Ctr Dis Control & Prevent, Prevent Res Branch, Div HIV AIDS Prevent, Atlanta, GA 30333 USA. [Bingham, Trista; Sey, Ekow] Los Angeles Cty Dept Hlth Serv, HIV Epidemiol Program, Los Angeles, CA 90005 USA. [Ciesielski, Carol] US Ctr Dis Control & Prevent, Global AIDS Program, APO, AP 96546 USA. [Prachand, Nikhil] Chicago Dept Publ Hlth HIV Surveillance Epidemiol, Chicago, IL 60604 USA. [Jenkins, Richard A.] NIDA, Prevent Res Branch, NIH, Bethesda, MD 20892 USA. [Stall, Ron] Univ Pittsburgh, Dept Behav Community Hlth Sci, Sch Publ Hlth, Pittsburgh, PA 15261 USA. RP Carey, JW (reprint author), Ctr Dis Control & Prevent, Prevent Res Branch, Div HIV AIDS Prevent, 1600 Clifton Rd,Mailstop E-37, Atlanta, GA 30333 USA. EM jfc9@cdc.gov NR 64 TC 70 Z9 71 U1 3 U2 14 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD DEC PY 2009 VL 13 IS 6 BP 1084 EP 1096 DI 10.1007/s10461-008-9403-3 PG 13 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 526NX UT WOS:000272298900008 PM 18498049 ER PT J AU Yawn, BP Nichols, WL Rick, ME AF Yawn, Barbara P. Nichols, William L. Rick, Margaret E. TI Diagnosis and Management of Von Willebrand Disease: Guidelines for Primary Care SO AMERICAN FAMILY PHYSICIAN LA English DT Article ID BLEEDING DISORDERS; WOMEN; PATHOPHYSIOLOGY; MENORRHAGIA; PUERPERIUM; PREGNANCY; THERAPY AB Von Willebrand disease is an inherited condition characterized by deficiency of von Willebrand factor, which is essential in hemostasis. The National Heart, Lung, and Blood Institute has released new evidence-based guidelines for the diagnosis and management of the disease. There are three major subtypes of von Willebrand disease, classified as partial quantitative deficiency (low levels) of von Willebrand factor (type 1), qualitative deficiency (type 2), or virtually complete deficiency (type 3). Diagnosis is usually made by reviewing the patient's personal and family history of bleeding and by clinical evaluation for more common reasons for bleeding, supplemented with laboratory tests. Assessment may be used to determine bleeding risk before surgery and other invasive procedures, and to diagnose reasons for unexplained hemorrhaging. Von Willebrand factor levels of 30 IU per dL or lower are required for the definite diagnosis of inherited von Willebrand disease. Persons with levels of 30 to 50 TU per dL may not have the disease, but may need agents to increase von Willebrand factor levels during invasive procedures or childbirth. Treatment is tailored to the subtype of the disease: increasing plasma concentration of von Willebrand factor by releasing endogenous stores with desmopressin or replacing nonexistent or ineffective von Willebrand factor by using human plasma-derived, viral-inactivated concentrates; treatment is often combined with hemostatic agents that have mechanisms other than increasing von Willebrand factor. Regular prophylaxis is seldom required, and treatment is initiated before planned invasive procedures or in response to bleeding. (Am Fam Physician. 2009;80(11):1261-1268, 1269-1270. Copyright (C) 2009 American Academy of Family Physicians.) C1 [Yawn, Barbara P.] Olmsted Med Ctr, Rochester, MN 55904 USA. [Nichols, William L.] Mayo Clin, Rochester, MN USA. [Rick, Margaret E.] NIH, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Yawn, BP (reprint author), Olmsted Med Ctr, 210 9th St SE, Rochester, MN 55904 USA. EM yawnx002@umn.edu NR 27 TC 14 Z9 14 U1 0 U2 2 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD DEC 1 PY 2009 VL 80 IS 11 BP 1261 EP 1268 PG 8 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 533IW UT WOS:000272818100013 PM 19961139 ER PT J AU Margolis, KL Dunn, K Simpson, LM Ford, CE Williamson, JD Gordon, DJ Einhorn, PT Probstfield, JL AF Margolis, Karen L. Dunn, Kay Simpson, Lara M. Ford, Charles E. Williamson, Jeff D. Gordon, David J. Einhorn, Paula T. Probstfield, Jeffrey L. CA ALLHAT Collaborative Res Grp TI Coronary heart disease in moderately hypercholesterolemic, hypertensive black and non-black patients randomized to pravastatin versus usual care: The Antihypertensive and Lipid Lowering to Prevent Heart Attack Trial (ALLHAT-LLT) SO AMERICAN HEART JOURNAL LA English DT Article ID CYSTATHIONINE BETA-SYNTHASE; CARDIOVASCULAR-DISEASE; CHOLESTEROL LEVELS; AFRICAN-AMERICANS; RISK; EFFICACY; HOMOCYSTEINE; POLYMORPHISM; EVENTS; METAANALYSIS AB Background In previous analyses in ALLHAT, blacks had a significantly lower risk of coronary heart disease (CHD) in the pravastatin group compared to the usual care group, whereas non-blacks had no benefit from pravastatin. No previous statin trial has reported results separately in blacks. Objectives The study aimed to determine if apparent racial differences in CHD in ALLHAT are explained by differences in baseline characteristics, adherence during the trial, or achieved blood pressure and lipid lowering. Methods This was a prespecified subgroup analysis of a randomized controlled trial. Hypertensive, moderately hypercholesterolemic participants were assigned to open-label pravastatin (40 mg/d) or usual care. The outcome was a composite of nonfatal myocardial infarction and fatal CHD. We performed intention-to-treat survival analyses using Cox proportional hazards models, adjusting for baseline covariates (age, sex, aspirin use, history of CHD and diabetes, and baseline hypertension treatment) and time-varying levels of blood pressure and total cholesterol. Results After adjustment for baseline characteristics, there remained a significant interaction between race and treatment group (P = .02). In stratified models, blacks in the pravastatin group had a 29% lower risk of CHD (hazard ratio [HR] 0.71, 95% CI 0.57-0.90, P = .005) compared to those in the usual care group, whereas non-blacks had no benefit (HR 1.00, 95% CI 0.85-1.19, P = .95). With further adjustment for achieved blood pressure and total cholesterol, the HR in blacks was 0.65 (95% CI 0.45-0.96, P = .03) and in non-blacks was 1.07 (95% CI 0.81-1.41, P = .65). Conclusions Our results suggest that pravastatin is effective in preventing CHD in blacks. (Am Heart J 2009; 158: 948-55.) C1 [Margolis, Karen L.] HealthPartners Res Fdn, Minneapolis, MN 55440 USA. [Dunn, Kay; Simpson, Lara M.; Ford, Charles E.] Univ Texas Houston Hlth Sci Ctr, Sch Publ Hlth, Coordinating Ctr Clin Trials, Houston, TX USA. [Williamson, Jeff D.] Wake Forest Univ, Bowman Gray Sch Med, J Paul Sticht Ctr Aging, Winston Salem, NC USA. [Gordon, David J.; Einhorn, Paula T.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Gordon, David J.; Einhorn, Paula T.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Probstfield, Jeffrey L.] Univ Washington, Sch Med, Div Cardiol, Seattle, WA USA. RP Margolis, KL (reprint author), HealthPartners Res Fdn, Box 1524,Mail Stop 21111R, Minneapolis, MN 55440 USA. EM karen.l.margolis@healthpartners.com FU NHLBI NIH HHS [N01 HC035130] NR 24 TC 8 Z9 8 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD DEC PY 2009 VL 158 IS 6 BP 948 EP 955 DI 10.1016/j.ahj.2009.10.001 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 536NM UT WOS:000273051100010 PM 19958861 ER PT J AU Masulli, M Patti, L Riccardi, G Vaccaro, O Annuzzi, G Ebbesson, SOE Fabsitz, RR Howard, WJ Otvos, JD Roman, MJ Wang, H Weissman, NJ Howard, BV Rivellese, AA AF Masulli, Maria Patti, Lidia Riccardi, Gabriele Vaccaro, Olga Annuzzi, Giovanni Ebbesson, Sven O. E. Fabsitz, Richard R. Howard, Wm. James Otvos, James D. Roman, Mary J. Wang, Hone Weissman, Neil J. Howard, Barbara V. Rivellese, Angela A. TI Relation Among Lipoprotein Subfractions and Carotid Atherosclerosis in Alaskan Eskimos (from the GOCADAN Study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LOW-DENSITY-LIPOPROTEIN; INTIMA-MEDIA THICKNESS; LDL PARTICLE-SIZE; SUBCLINICAL ATHEROSCLEROSIS; INSULIN-RESISTANCE; NATIVES; PREVALENCE; MORTALITY AB Studies have been inconsistent regarding whether lipoprotein particle subfraction measures are useful indicators of cardiovascular risk. The present study evaluated the relation between lipoprotein particle concentrations and size, analyzed using nuclear magnetic resonance spectroscopy and measures of carotid atherosclerosis in a population with high cardiovascular risk but little hyperlipidemia. In this cross-sectional, population-based sample of Alaska Eskimos >= 35 years old (n = 656), a greater carotid intimal medial thickness was associated with greater low-density lipoprotein (LDL) cholesterol (p = 0.03) and total LDL particle concentration (p = 0.04), independently of other traditional risk factors. The effects of LDL cholesterol and LDL particle concentration on intimal medial thickness were additive (p = 0.015). Carotid plaque was associated with greater levels of LDL cholesterol (p = 0.01), greater concentrations of large LDL particles (p = 0.003), and a reduction in the size of the very-low-density lipoprotein particles (p = 0.03). The effects of LDL cholesterol and large LDL particles on the plaque score were additive. In conclusion, the carotid intimal medial thickness was associated with greater LDL particle concentrations. The association was strongest in those with greater LDL cholesterol levels. Plaque was associated with greater concentrations of LDL cholesterol, large LDL particles, and smaller very-low-density lipoprotein particles. It might be beneficial to determine the lipoprotein subfractions in populations with little hyperlipidemia. (C) 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104:1516-1521) C1 [Howard, Barbara V.] MedStar Res Inst, Hyattsville, MD USA. [Masulli, Maria; Patti, Lidia; Riccardi, Gabriele; Vaccaro, Olga; Annuzzi, Giovanni; Rivellese, Angela A.] Univ Naples Federico 2, Naples, Italy. [Ebbesson, Sven O. E.] Norton Sound Hlth Corp, Nome, AK USA. [Fabsitz, Richard R.] NHLBI, Bethesda, MD 20892 USA. [Howard, Wm. James] Washington Hosp Ctr, Washington, DC 20010 USA. [Otvos, James D.] LipoScience, Raleigh, NC USA. [Roman, Mary J.] Weill Cornell Med Coll, New York, NY USA. [Wang, Hone; Weissman, Neil J.; Howard, Barbara V.] MedStar Res Inst, Hyattsville, MD USA. RP Howard, BV (reprint author), MedStar Res Inst, Hyattsville, MD USA. EM Barbara.v.howard@medstar.net RI riccardi, gabriele/A-9269-2012; OI Patti, Lidia/0000-0002-0674-4188 FU National Heart, Lung, and Blood Institute, Bethesda, MD [HL064244-07] FX This work was supported by Grant HL064244-07 From the National Heart, Lung, and Blood Institute, Bethesda, MD. NR 24 TC 10 Z9 10 U1 0 U2 1 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 1 PY 2009 VL 104 IS 11 BP 1516 EP 1521 DI 10.1016/j.amjcard.2009.07.021 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 531BK UT WOS:000272637500011 PM 19932785 ER PT J AU Roberts, WC Ko, JM Vowels, TJ AF Roberts, William Clifford Ko, Jong Mi Vowels, Travis James TI Natural History of Syphilitic Aortitis SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID UNTREATED SYPHILIS; TUSKEGEE; HEART AB No large studies of cardiovascular syphilis at necropsy have been reported since 1964. We examined at necropsy 90 patients who had characteristic morphologic findings of syphilitic aortitis. None had ever undergone cardiovascular surgery. With the exception of 2 cases seen more recently, the hearts and aortas of the 90 patients were examined and categorized by one of us (W.C.R.) from 1966 to 1990. All 90 had extensive involvement of the tubular portion of the ascending aorta by the syphilitic process, which spared the sinuses of Valsalva in all but 4 patients. The aortic arch was also involved in 49 (91%) of 54 patients and the descending thoracic aorta in 47 (90%) of 52 patients. Syphilis was the cause of death in 23 (26%) of the 90 patients. It was secondary to rupture of the ascending or descending thoracic aorta in 12, severe aortic regurgitation leading to heart failure in 10, and severe narrowing of the aortic ostium of the right coronary artery in 1 patient. Of the 40 patients who had undergone serologic testing for syphilis, 28 (70%) had a positive (reactive) finding. Those patients with a negative or nonreactive test or who did not undergo a serologic test for syphilis had morphologic and histologic findings in the aorta at necropsy similar to the findings of those patients who had had a positive serologic test for syphilis. In conclusion, cardiovascular syphilis has not disappeared. In patients with dilated ascending aortas, with or without aortic regurgitation, a serologic test for syphilis is recommended. If the findings are positive or if characteristic morphologic features of cardiovascular syphilis are suspected, irrespective of the results of the serologic tests, antibiotic therapy appears desirable. (C) 2009 Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104:1578-1587) C1 [Roberts, William Clifford; Ko, Jong Mi; Vowels, Travis James] Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, Dallas, TX USA. [Roberts, William Clifford] NHLBI, Pathol Branch, NIH, Bethesda, MD 20892 USA. [Vowels, Travis James] Univ Texas Austin, Austin, TX 78712 USA. RP Roberts, WC (reprint author), Baylor Univ, Med Ctr, Baylor Heart & Vasc Inst, Dallas, TX USA. EM wc.roberts@baylorhealth.edu NR 9 TC 25 Z9 28 U1 0 U2 5 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 1 PY 2009 VL 104 IS 11 BP 1578 EP 1587 DI 10.1016/j.amjcard.2009.07.031 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 531BK UT WOS:000272637500022 PM 19932796 ER PT J AU Tanofsky-Kraff, M Han, JC Anandalingam, K Shomaker, LB Columbo, KM Wolkoff, LE Kozlosky, M Elliott, C Ranzenhofer, LM Roza, CA Yanovski, SZ Yanovski, JA AF Tanofsky-Kraff, Marian Han, Joan C. Anandalingam, Kavitha Shomaker, Lauren B. Columbo, Kelli M. Wolkoff, Laura E. Kozlosky, Merel Elliott, Camden Ranzenhofer, Lisa M. Roza, Caroline A. Yanovski, Susan Z. Yanovski, Jack A. TI The FTO gene rs9939609 obesity-risk allele and loss of control over eating SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID BODY-MASS INDEX; ENERGY-INTAKE; PHYSICAL-ACTIVITY; ADULT OBESITY; FAT MASS; DISORDER EXAMINATION; DIETARY RESTRAINT; FOOD-INTAKE; CHILDREN; BINGE AB Background: Children with rs9939609 FTO variant alleles (homozygous = AA and heterozygous = AT) are predisposed to greater adiposity than are those with 2 wild-type alleles (TT). Objective: Because FTO is highly expressed in hypothalamic regions that are important for appetite, FTO genotype may affect energy balance by influencing eating behavior. Loss of control (LOC) eating, a behavior commonly reported by overweight youth, predicts excessive weight gain in children. However, the relation between FTO genotype and LOC eating has not been previously examined. Design: Two-hundred eighty-nine youth aged 6-19 y were genotyped for rs9939609, underwent body-composition measurements, and were interviewed to determine the presence or absence of LOC eating. A subset (n = 190) participated in a lunch buffet test meal designed to model an LOC eating episode. Subjects with AA and AT genotypes were grouped together for comparison with wild-type TT subjects. Results: Subjects with at least one A allele (67.7%) had significantly greater body mass indexes, body mass index z scores (P < 0.01), and fat mass (P < 0.05). Of the AA/AT subjects, 34.7% reported LOC compared with 18.2% of the TT subjects (P = 0.002). Although total energy intake at the test meal did not differ significantly by genotype (P = 0.61), AA/AT subjects consumed a greater percentage of energy from fat than did the TT subjects (P < 0.01). Conclusions: Children and adolescents with 1 or 2 FTO rs9939609 obesity-risk alleles report more frequent LOC eating episodes and select foods higher in fat at a buffet meal. Both LOC eating and more frequent selection of energy-dense, palatable foods may be mechanisms through which variant FTO alleles lead to excess body weight. Am J Clin Nutr 2009;90:1483-8. C1 [Tanofsky-Kraff, Marian; Han, Joan C.; Anandalingam, Kavitha; Shomaker, Lauren B.; Columbo, Kelli M.; Wolkoff, Laura E.; Elliott, Camden; Ranzenhofer, Lisa M.; Roza, Caroline A.; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Growth & Obes, Program Dev Endocrinol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. [Tanofsky-Kraff, Marian; Shomaker, Lauren B.; Columbo, Kelli M.; Wolkoff, Laura E.; Elliott, Camden; Ranzenhofer, Lisa M.] Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. [Kozlosky, Merel] NIH, Dept Nutr, Ctr Clin, Bethesda, MD 20892 USA. [Yanovski, Susan Z.] NIDDK, Div Digest Dis & Nutr, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Yanovski, JA (reprint author), NICHD, Unit Growth & Obes, PDEGEN, NIH,Hatfield Clin Res Ctr, 10 Ctr Dr,Room 1-3330,MSC 1103, Bethesda, MD 20892 USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU Intramural Research Program, National Institute of Child Health, National Institutes of Health [Z01-HD-00641]; NCMHD; Uniformed Services University of the Health Sciences [R072IC] FX Supported by the Intramural Research Program, National Institute of Child Health, National Institutes of Health (grant Z01-HD-00641 to JAY), and supplemental funding from NCMHD (to JAY) and the Uniformed Services University of the Health Sciences (grant R072IC to MTK). NR 51 TC 101 Z9 105 U1 0 U2 11 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC 1 PY 2009 VL 90 IS 6 BP 1483 EP 1488 DI 10.3945/ajcn.2009.28439 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 522XZ UT WOS:000272034900007 PM 19828706 ER PT J AU Delmonico, MJ Harris, TB Visser, M Park, SW Conroy, MB Velasquez-Mieyer, P Boudreau, R Manini, TM Nevitt, M Newman, AB Goodpaster, BH AF Delmonico, Matthew J. Harris, Tamara B. Visser, Marjolein Park, Seok Won Conroy, Molly B. Velasquez-Mieyer, Pedro Boudreau, Robert Manini, Todd M. Nevitt, Michael Newman, Anne B. Goodpaster, Bret H. CA Health Aging & Body Composition St TI Longitudinal study of muscle strength, quality, and adipose tissue infiltration SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID SKELETAL-MUSCLE; BODY-COMPOSITION; OLDER-ADULTS; INSULIN-RESISTANCE; DIABETES-MELLITUS; FAT DISTRIBUTION; WEIGHT CHANGE; MASS; WOMEN; AGE AB Background: Sarcopenia is thought to be accompanied by increased muscle fat infiltration. However, no longitudinal studies have examined concomitant changes in muscle mass, strength, or fat infiltration in older adults. Objective: We present longitudinal data on age-related changes in leg composition, strength, and muscle quality (MQ) in ambulatory, well-functioning men and women. We hypothesized that muscle cross-sectional area (CSA) and strength would decrease and muscular fat infiltration would increase over 5 y. Design: Midthigh muscle, subcutaneous fat (SF), and intermuscular fat (IMF) CSAs and isokinetic leg muscle torque (MT) and MQ (MT/quadriceps CSA) were examined over 5 y in the Health, Aging, and Body Composition study cohort (n = 1678). Results: Men experienced a 16.1% loss of MT, whereas women experienced a 13.4% loss. Adjusted annualized decreases in MT were 2-5 times greater than the loss of muscle CSA in those who lost weight and in those who remained weight-stable. Weight gain did not prevent the loss of MT, despite a small increase in muscle CSA. Only those who gained weight had an increase in SF (P < 0.001), whereas those who lost weight also lost SF (P < 0.001). There was an age-related increase in IMF in men and women (P < 0.001), and IMF increased in those who lost weight, gained weight, or remained weight-stable (all P < 0.001). Conclusions: Loss of leg MT in older adults is greater than muscle CSA loss, which suggests a decrease in MQ. Additionally, aging is associated with an increase in IMF regardless of changes in weight or SF. Am J Clin Nutr 2009;90:1579-85. C1 [Delmonico, Matthew J.; Conroy, Molly B.; Boudreau, Robert; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Conroy, Molly B.; Newman, Anne B.; Goodpaster, Bret H.] Univ Pittsburgh, Dept Med, Pittsburgh, PA 15261 USA. [Delmonico, Matthew J.] Univ Rhode Isl, Dept Kinesiol, Kingston, RI 02881 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Visser, Marjolein] Vrije Univ Amsterdam, Inst Hlth Sci, Amsterdam, Netherlands. [Visser, Marjolein] Vrije Univ Amsterdam Med Ctr, EMGO Inst, Amsterdam, Netherlands. [Park, Seok Won] Pochon CHA Univ, Dept Internal Med, Pochon, South Korea. [Velasquez-Mieyer, Pedro] Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN USA. [Manini, Todd M.] Univ Florida, Dept Aging & Geriatr Res, Gainesville, FL USA. [Nevitt, Michael] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Delmonico, MJ (reprint author), Univ Rhode Isl, MPH Dept Kinesiol, 25 W Independence Way,Room 214, Kingston, RI 02881 USA. EM delmonico@uri.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Boudreau, Robert/0000-0003-0162-5187 FU National Institute on Aging [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; Intramural Research Program of the NIH, National Institute on Aging FX Supported by National Institute on Aging contracts N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 and in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 29 TC 285 Z9 288 U1 1 U2 28 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC 1 PY 2009 VL 90 IS 6 BP 1579 EP 1585 DI 10.3945/ajcn.2009.28047 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 522XZ UT WOS:000272034900019 PM 19864405 ER PT J AU SanGiovanni, JP Agron, E Meleth, AD Reed, GF Sperduto, RD Clemons, TE Chew, EY AF SanGiovanni, John Paul Agron, Elvira Meleth, A. Dhananjayan Reed, George F. Sperduto, Robert D. Clemons, Traci E. Chew, Emily Y. CA AREDS Res Grp TI omega-3 Long-chain polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular degeneration and central geographic atrophy: AREDS report 30, a prospective cohort study from the Age-Related Eye Disease Study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID DIETARY-FAT; DOCOSAHEXAENOIC ACID; LIPID MEDIATORS; FISH INTAKE; RISK; MACULOPATHY; INFLAMMATION; ASSOCIATION; CONSUMPTION; RETINA AB Background: omega-3 (n-3) Long-chain polyunsaturated fatty acids (LCPUFAs) affect processes implicated in vascular and neural retinal pathogenesis and thus may influence the risk of developing age-related macular degeneration (AMD). Objective: We investigated whether omega-3 LCPUFA intake was associated with a reduced likelihood of developing central geographic atrophy (CGA) and neovascular (NV) AMD. Design: We undertook a nested cohort study within a multicenter phase 3 clinical trial, the Age-Related Eye Disease Study (AREDS), to study progression to advanced AMD in 1837 persons at moderate-to-high risk of this condition. The AREDS was designed to assess the clinical course, prognosis, risk factors, and nutrient-based treatments of AMD and ran from November 1992 to December 2005. We obtained baseline data on omega-3 LCPUFA intake with a validated food-frequency questionnaire. Trained fundus graders ascertained AMD status from annual stereoscopic color photographs by using standardized methods at a single reading center across a 12-y period. We applied multivariable repeated-measures logistic regression with the incorporation of generalized estimating equation methods, because this permitted determination of progression to outcome at each visit. Results: Participants who reported the highest omega-3 LCPUFA intake (median: 0.11% of total energy intake) were 30% less likely than their peers to develop CGA and NV AMD. The respective odds ratios were 0.65 (95% CI: 0.45, 0.92; P <= 0.02) and 0.68 (95% CI: 0.49, 0.94; P <= 0.02). Conclusions: The 12-y incidence of CGA and NV AMD in participants at moderate-to-high risk of these outcomes was lowest for those reporting the highest consumption of omega-3 LCPUFAs. If these results are generalizable, they may guide the development of low-cost and easily implemented preventive interventions for progression to advanced AMD. This trial was registered at clinicaltrials.gov as NCT00594672. Am J Clin Nutr 2009;90:1601-7. C1 [SanGiovanni, John Paul] NEI, Clin Trials Branch, NIH, CRC, Bethesda, MD 20892 USA. [Clemons, Traci E.] EMMES Corp, Rockville, MD USA. [Meleth, A. Dhananjayan] George Washington Univ, Dept Ophthalmol, Washington, DC USA. RP SanGiovanni, JP (reprint author), NEI, Clin Trials Branch, NIH, CRC, 10 Ctr Dr,MSC 1204,Bldg 10,Room 3-2521, Bethesda, MD 20892 USA. EM jpsangio@post.harvard.edu FU National Eye Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD FX Supported by the National Eye Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD. NR 32 TC 68 Z9 70 U1 1 U2 8 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD DEC 1 PY 2009 VL 90 IS 6 BP 1601 EP 1607 DI 10.3945/ajcn.2009.27594 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 522XZ UT WOS:000272034900022 PM 19812176 ER PT J AU Weinberg, CR Shi, M AF Weinberg, Clarice R. Shi, Min TI The Genetics of Preterm Birth: Using What We Know to Design Better Association Studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE association analysis; genetics; logistic model; log-linear model; models; statistical; power comparisons; premature birth; study design ID PATERNAL FACTORS; DELIVERY; RISK; PREGNANCY; WEIGHT; GENES; FETAL; RECURRENCE; COHORT; TRIADS AB Women delivering preterm are at greatly increased risk of another preterm birth in subsequent pregnancies, reflecting effects of the environment, genetics, or both. Recent literature tells an increasingly coherent story about genetic susceptibility. Women who change partners after delivering preterm retain their elevated risk, whereas fathers who change partners do not. Women who themselves were preterm are at increased risk, an association not seen in fathers. Women with a half-sister who delivered preterm are at increased risk only if the shared parent was the mother. Concordance for preterm delivery is elevated in monozygotic compared with dizygotic twin mothers but not in monozygotic twin fathers. Several mechanisms could be operating: mitochondrial genes, maternal genes, or fetal genes expressing only the maternally derived copy. The authors compare 3 study designs for their ability to detect variants and to distinguish among mechanisms underlying heritability of this common outcome. The case-parent triad design offers robustness against self-selection and genetic population stratification, providing for estimation of genetic effects that are fetal, maternal, or that depend on the parent of origin. A case-base approach compares case-mothers with randomly sampled baby-mother pairs and permits estimation of the same relative risk parameters. Both designs offer important advantages over the commonly applied case-mother/control-mother design. C1 [Weinberg, Clarice R.; Shi, Min] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), Natl Inst Environm Hlth Sci, Biostat Branch, Mail Drop A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. EM weinber2@niehs.nih.gov FU NIH; National Institute of Environmental Health Sciences [Z01-ES040007] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01-ES040007). NR 31 TC 16 Z9 16 U1 0 U2 2 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 1 PY 2009 VL 170 IS 11 BP 1373 EP 1381 DI 10.1093/aje/kwp325 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 523JR UT WOS:000272069900006 PM 19854804 ER PT J AU von Ehrenstein, OS Mikolajczyk, RT Zhang, J AF von Ehrenstein, Ondine S. Mikolajczyk, Rafael T. Zhang, Jun TI Timing and Trajectories of Fetal Growth Related to Cognitive Development in Childhood SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE child development; cohort studies; fetal development; intelligence tests; ultrasonics ID FOR-GESTATIONAL-AGE; INTRAUTERINE GROWTH; PRENATAL EXPOSURE; DUTCH FAMINE; IN-UTERO; LATER LIFE; DISEASE; CHILDREN; INFANTS; INTELLIGENCE AB The authors investigated timing and trajectories of fetal growth in relation to childhood development in the National Institute of Child Health and Human Development-Scandinavian Study of Successive Small-for-Gestational Age Births (1986-1988) (n = 1,059). Fetal size was assessed by ultrasound at 17, 25, and 33 gestational weeks and at birth. Bayley Scales of Infant Development and the Wechsler Preschool and Primary Scale of Intelligence-Revised tests were conducted at ages 1 and 5 years, respectively, producing mental and psychomotor development indexes and verbal and performance intelligence quotients. Relative fetal size was calculated as a standard deviation score at each data point; growth trajectories were explored with longitudinal mixture models. Fetal size at 17, 25, and 33 weeks was positively associated with mental development index; larger size at 33 weeks and at birth was associated with higher verbal intelligence quotient scores (2.61, 95% confidence interval: 1.06, 4.15 and 1.90, 95% confidence interval: 0.67, 3.13 increase per 1 standard deviation score, respectively); findings were similar for performance intelligence quotient. Seven trajectories were identified; scores were lower for "small" and "medium-to-small" trajectories than for "medium" and "big" (representing normal size) trajectories: mental development index (P < 0.01), performance intelligence quotient (P < 0.001), and verbal intelligence quotient (P < 0.001). Overall, larger fetal size in the second and third trimesters was positively associated with childhood development. Fetal growth trajectories may matter beyond birth. C1 [von Ehrenstein, Ondine S.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90095 USA. [Mikolajczyk, Rafael T.] Univ Bielefeld, Sch Publ Hlth, Bielefeld, Germany. [Mikolajczyk, Rafael T.; Zhang, Jun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. RP von Ehrenstein, OS (reprint author), Univ Calif Los Angeles, Sch Publ Hlth, POB 951772, Los Angeles, CA 90095 USA. EM ovehren@ucla.edu OI Mikolajczyk, Rafael/0000-0003-1271-7204 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland.; National Institutes of Health, Bethesda, Maryland. FX This work was supported in part by the Intramural Research Program at the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. NR 37 TC 6 Z9 8 U1 0 U2 2 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 1 PY 2009 VL 170 IS 11 BP 1388 EP 1395 DI 10.1093/aje/kwp296 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 523JR UT WOS:000272069900009 PM 19889710 ER PT J AU Aziz, NM AF Aziz, Noreen M. TI Long-term cancer survivors: Research issues and care needs in a key phase of the survivorship spectrum SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Editorial Material ID ADULT CANCERS C1 NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH,DHHS, Bethesda, MD 20892 USA. RP Aziz, NM (reprint author), NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, NIH,DHHS, Bethesda, MD 20892 USA. EM na45f@nih.gov NR 19 TC 6 Z9 6 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD DEC PY 2009 VL 84 IS 12 BP 782 EP 784 DI 10.1002/ajh.21579 PG 3 WC Hematology SC Hematology GA 528XY UT WOS:000272481500002 PM 19937803 ER PT J AU Zhao, Q Gu, DF Chen, J Bazzano, LA Rao, DC Hixson, JE Jaquish, CE Cao, J Chen, JC Li, JX Rice, T He, J AF Zhao, Qi Gu, Dongfeng Chen, Jing Bazzano, Lydia A. Rao, Dabeeru C. Hixson, James E. Jaquish, Cashell E. Cao, Jie Chen, Jichun Li, Jianxin Rice, Treva He, Jiang TI Correlation Between Blood Pressure Responses to Dietary Sodium and Potassium Intervention in a Chinese Population SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article ID SALT SENSITIVITY; HYPERTENSION; GENSALT; TRIAL AB BACKGROUND Blood pressure (BP) responses to dietary sodium and potassium intake vary among individuals. We examined the correlation between BP responses to dietary low-sodium, high-sodium, and potassium supplementation interventions in a feeding study. METHODS A total of 1,906 Chinese aged 1 6 years participated in the dietary intervention that included a 7-day low-salt intervention (51.3 mmol/day), a 7-day high-salt intervention (307.8 mmol/day), and a 7-day high-salt plus potassium supplementation (60 mmol/day) intervention. BP was measured nine times during the 3-day baseline observation and during the last 3 days of each intervention phase using a random-zero sphygmomanometer. RESULTS The correlation coefficients (95% confidence intervals (CIs)) of the BP responses to low-sodium and high-sodium interventions were -0.47 (-0.51 to -0.44), -0.47 (-0.50 to -0.43), and -0.45 (-0.49 to -0.42) for systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP), respectively (all P < 0.0001). The correlation coefficients (95% Cl) of the BP responses to high-sodium intervention and potassium supplementation were -0.52 (-0.56 to -0.49), -0.48 (-0.52 to 0.45), and -0.52 (-0.55 to -0.48) for SBP, DBP, and MAP, respectively (all P < 0.0001). The kappa coefficients were moderate, varying from 0.28 to 0.34, between BP responses to low-sodium and high-sodium interventions (all P < 0.0001). CONCLUSIONS These results indicate there is a moderate correlation between BP responses to low-sodium and to high-sodium interventions, and BP responses to high-sodium intervention and potassium supplementation. Furthermore, our study suggests that individuals who were more sensitive to high-sodium diet might benefit more from a low-sodium and/or high-potassium intervention aimed at lowering BP levels. C1 [Zhao, Qi; Chen, Jing; Bazzano, Lydia A.; He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70118 USA. [Gu, Dongfeng; Cao, Jie; Chen, Jichun; Li, Jianxin] Fuwai Hosp, Dept Evidence Based Med, Beijing, Peoples R China. [Gu, Dongfeng; Cao, Jie; Chen, Jichun; Li, Jianxin] Chinese Acad Med Sci, Cardiovasc Inst, Beijing 100037, Peoples R China. [Gu, Dongfeng; Cao, Jie; Chen, Jichun; Li, Jianxin] Peking Union Med Coll, Chinese Natl Ctr Cardiovasc Dis Control & Res, Beijing 100021, Peoples R China. [Chen, Jing; Bazzano, Lydia A.; He, Jiang] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Chen, Jing; Bazzano, Lydia A.; He, Jiang] Tulane Univ, Sch Med, Tulane Hypertens & Renal Ctr Excellence, New Orleans, LA 70112 USA. [Rao, Dabeeru C.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Hixson, James E.] Univ Texas Houston, Sch Publ Hlth, Ctr Human Genet, Houston, TX USA. [Jaquish, Cashell E.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. RP He, J (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70118 USA. EM jhe@tulane.edu FU National Heart, Lung, and Blood Institute [U01HL072507, R01HL087263, R01HL090682, K08HL091108]; National Institutes of Health, Bethesda, MD FX The Genetic Epidemiology Network of Salt Sensitivity is supported by research grants (U01HL072507, R01HL087263, and R01HL090682) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. Upsher-Smith Laboratories, Maple Grove, MN has provided Klor-Con M20 potassium tablets for the GenSalt study. L.A.B. was supported by a career development grant (K08HL091108) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD. NR 19 TC 5 Z9 8 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD DEC PY 2009 VL 22 IS 12 BP 1281 EP 1286 DI 10.1038/ajh.2009.176 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 524NL UT WOS:000272149900011 PM 19763120 ER PT J AU Chen, WY Kim, MS Shanbhag, S Arai, A VanRyzin, C McDonnell, NB Merke, DP AF Chen, Wuyan Kim, Mimi S. Shanbhag, Sujata Arai, Andrew VanRyzin, Carol McDonnell, Nazli B. Merke, Deborah P. TI The Phenotypic Spectrum of Contiguous Deletion of CYP21A2 and Tenascin XB: Quadricuspid Aortic Valve and Other Midline Defects SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE congenital adrenal hyperplasia; CAH; CYP21A2; tenascin-X; TNXB; Ehlers-Danlos syndrome; EDS; hypermobility; aortic valve; TNX; contiguous deletion syndrome ID EHLERS-DANLOS-SYNDROME; CONGENITAL ADRENAL-HYPERPLASIA; DEFICIENCY; GENE; COLLAGEN; MUSCLE; FORM; TNXB AB Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disorder and is the most common cause of ambiguous genitalia in the newborn. The genes encoding 21-hydroxylase, CYP21A2, and tenascin-X (TNX), TNXB, are located within the HLA complex, in a region of high gene density termed the RCCX module. The module has multiple pseudogenes as well as tandem repeat sequences that promote misalignment during meiosis leading to complex gene rearrangements, deletions and gene conversion events. CYP21A2 mutations cause CAH, and TNX deficiency has been identified as a cause of hypermobility type Ehlers-Danlos syndrome (EDS). Here we report on a three-generation family with a heterozygous deletion encompassing CYP21A2 and TNXB that initially came to medical attention due to the diagnosis of CAH in the proposita. Southern blotting and PCR-based analysis of the RCCX module revealed a CYP21A2 deletion extending into TNXB in one allele and a CYP21A2 point mutation in the other allele. Family history is notable for joint hypermobility. Additional radiological and clinical investigations showed a quadricuspid aortic valve, single kidney, bicornuate uterus and a bifid uvula in the proposita, and mitral valve prolapse in her mother. These findings further delineate the phenotype of the CAH-TNX contiguous gene deletion syndrome and point to an intersection of connective tissue dysplasias with a common gene-mediated endocrine disorder. Published 2009 Wiley-Liss, Inc. C1 [Chen, Wuyan] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Kim, Mimi S.; VanRyzin, Carol; Merke, Deborah P.] NIH, Ctr Clin, Baltimore, MD USA. [Shanbhag, Sujata; Arai, Andrew] NHLBI, NIH, Baltimore, MD USA. [Merke, Deborah P.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod Biol & Med Branch, Bethesda, MD USA. [McDonnell, Nazli B.] NIA, Clin Res Branch, Bethesda, MD 20892 USA. RP Merke, DP (reprint author), Bldg 10 CRC,1-2740,10 Ctr Dr, Bethesda, MD 20892 USA. EM dmerke@nih.gov FU NIA/NICHD/NIH; Congenital Adrenal Hyperplasia Research, Education and Support (CARES) Foundation; NICHD IRB [06CH0011] FX We thank the family who participated in this research. We thank the NIA Core Lab Staff for DNA extraction and purification, and LCI staff Ronnie Black and Tina Roberson for help with sample transmittals. We are indebted to Dr. C.Y. Yu (Center for Molecular and Human Genetics, Columbus Children's Research Institute, Columbus, OH) for a kind gift of probes for the RCCX module. We thank Dr. Michel Bernier for assistance with the preparation of the figures. Patient samples and clinical data were collected under NICHD IRB# 06CH0011 (Clinical Trials number NCT00250159). All work was supported by funds originating at the intramural programs of NIA/NICHD/NIH and (in part) by the Congenital Adrenal Hyperplasia Research, Education and Support (CARES) Foundation. NR 26 TC 8 Z9 8 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD DEC PY 2009 VL 149A IS 12 BP 2803 EP 2808 DI 10.1002/ajmg.a.33092 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 529RN UT WOS:000272535000026 PM 19921645 ER PT J AU Eberlein, M Chahla, MF Baierlein, SA Mahon, RT AF Eberlein, Michael Chahla, Mayy F. Baierlein, Sammy A. Mahon, Richard T. TI A Fall in Ghana SO AMERICAN JOURNAL OF MEDICINE LA English DT Editorial Material ID SEVERE TYPHOID-FEVER; TRAVELERS; DISEASE C1 [Eberlein, Michael] NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. [Eberlein, Michael] Johns Hopkins Univ, Sch Med, Div Pulm & Crit Care Med, Baltimore, MD USA. [Chahla, Mayy F.] Johns Hopkins Univ, Sch Med, Div Hosp Med, Baltimore, MD USA. [Baierlein, Sammy A.] St Clara Hosp, Dept Surg, Basel, Switzerland. [Mahon, Richard T.] Natl Naval Med Ctr, Div Pulm & Crit Care, Bethesda, MD USA. RP Eberlein, M (reprint author), NIH, Dept Crit Care Med, 10 Ctr Dr,Room 2C145, Bethesda, MD 20892 USA. EM eberleinmh@cc.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD DEC PY 2009 VL 122 IS 12 BP 1088 EP 1092 DI 10.1016/j.amjmed.2009.09.002 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 526YW UT WOS:000272333700012 PM 19958884 ER PT J AU Hilmer, SN Mager, DE Simonsick, EM Ling, SM Windham, BG Harris, TB Shorr, RI Bauer, DC Abernethy, DR AF Hilmer, Sarah N. Mager, Donald E. Simonsick, Eleanor M. Ling, Shari M. Windham, B. Gwen Harris, Tamara B. Shorr, Ronald I. Bauer, Douglas C. Abernethy, Darrell R. CA Hlth ABC Study TI Drug Burden Index Score and Functional Decline in Older People SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Clinical pharmacology; Geriatrics; Physical function ID LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE; SUBSEQUENT DISABILITY; COGNITIVE PERFORMANCE; BENZODIAZEPINE USE; ADULTS; STRENGTH; AGE; MEDICATIONS; PREDICTOR AB BACKGROUND: The Drug Burden Index (DBI), a measure of exposure to anticholinergic and sedative medications, has been independently associated with physical and cognitive function in a cross-sectional analysis of community-dwelling older persons participating in the Health, Aging and Body Composition study. Here we evaluate the association between DBI and functional outcomes in Health, Aging and Body Composition study participants over 5 years. METHODS: DBI was calculated at years 1 (baseline), 3, and 5, and a measure of the area under the curve for DBI (AUCDB) over the whole study period was devised and calculated. Physical performance was measured using the short physical performance battery, usual gait speed, and grip strength. The association of DBI at each time point and AUCDB with year 6 function was analyzed in data from participants with longitudinal functional measures, controlling for sociodemographics, comorbidities, and baseline function. RESULTS: Higher DBI at years 1, 3, and 5 was consistently associated with poorer function at year 6. On multivariate analysis, a 1-unit increase in AUCDB predicted decreases in short physical performance battery score of .08 (P = .01), gait speed of .01 m/s (P = .004), and grip strength of .27 kg (P = .004) at year 6. CONCLUSION: Increasing exposure to medication with anticholinergic and sedative effects, measured with DBI, is associated with lower objective physical function over 5 years in community-dwelling older people. (C) 2009 Elsevier Inc. All rights reserved. The American Journal of Medicine (2009) 122, 1142-1149 C1 [Hilmer, Sarah N.; Mager, Donald E.; Simonsick, Eleanor M.; Ling, Shari M.; Windham, B. Gwen; Harris, Tamara B.; Abernethy, Darrell R.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Hilmer, Sarah N.; Mager, Donald E.; Simonsick, Eleanor M.; Ling, Shari M.; Windham, B. Gwen; Harris, Tamara B.; Abernethy, Darrell R.] NIA, Intramural Res Program, Bethesda, MD 20892 USA. [Hilmer, Sarah N.] Royal N Shore Hosp, Sydney, NSW, Australia. [Hilmer, Sarah N.] Univ Sydney, Sydney, NSW 2006, Australia. [Mager, Donald E.] SUNY Buffalo, Buffalo, NY 14260 USA. [Shorr, Ronald I.] Univ Florida, Gainesville, FL USA. [Bauer, Douglas C.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Abernethy, Darrell R.] US Pharmacopeia, Rockville, MD USA. RP Abernethy, DR (reprint author), 3740 Thomas Point Rd, Annapolis, MD 21403 USA. EM abernethy3@version.net OI Hilmer, Sarah/0000-0002-5970-1501 FU National Institutes of Health, National Institute on Aging, and National Institute on Aging [NO1-AG-6-2101, NO1-AG-6-2103, NO1-AG-6-2106] FX Supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging, and National Institute on Aging Contracts NO1-AG-6-2101, NO1-AG-6-2103, and NO1-AG-6-2106. NR 27 TC 48 Z9 49 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD DEC PY 2009 VL 122 IS 12 BP 1142 EP U97 DI 10.1016/j.amjmed.2009.02.021 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 526YW UT WOS:000272333700022 PM 19958893 ER PT J AU Bailit, J Zhang, J Quintero, VHG Gregory, K Wilkins, I Ramirez, MM Reddy, U Vanveldhuisen, P Burkman, R Branch, W Hoffman, M Haberman, S Kominiarek, M Landy, H Hatjis, C Troendle, J AF Bailit, Jennifer Zhang, Jun Quintero, Victor Hugo Gonzalez Gregory, Kimberly Wilkins, Isabelle Ramirez, Mildred M. Reddy, Uma Vanveldhuisen, Paul Burkman, Ronald Branch, Ware Hoffman, Matthew Haberman, Shoshana Kominiarek, Michelle Landy, Helain Hatjis, Christos Troendle, James TI Maternal outcomes by labor onset type SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Bailit, Jennifer] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Zhang, Jun; Troendle, James] NICHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Quintero, Victor Hugo Gonzalez] Miami Univ, Dept Obstet Gynecol, MFM Div, Miami, FL USA. [Gregory, Kimberly] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Wilkins, Isabelle] Univ Illinois, Chicago, IL USA. [Ramirez, Mildred M.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Reddy, Uma] NICHD, NIH, Bethesda, MD USA. [Vanveldhuisen, Paul] Emmes Corp, Rockville, MD USA. [Burkman, Ronald] Tufts Univ, Baystate Med Ctr, Springfield, MA USA. [Branch, Ware] Univ Utah, Salt Lake City, UT USA. [Hoffman, Matthew] Christiana Hosp, Newark, DE USA. [Haberman, Shoshana] Maimonides Hosp, Brooklyn, NY 11219 USA. [Kominiarek, Michelle] Indiana Univ, Indianapolis, IN 46204 USA. [Landy, Helain] Georgetown Univ Hosp, Washington, DC 20007 USA. [Hatjis, Christos] Childrens Hosp, Med Ctr, Akron, OH 44308 USA. [Branch, Ware] Intermt Hlth, Salt Lake City, UT USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 143 BP S67 EP S67 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500143 ER PT J AU Bailit, J Zhang, J Quintero, VHG Gregory, K Hibbard, J Ramirez, M Reddy, U Vanveldhuisen, P Burkman, R Branch, W Hoffman, M Habermanm, S Kominiarek, M Landy, H Hatjis, C Troendle, J AF Bailit, Jennifer Zhang, Jun Gonzalez Quintero, Victor Hugo Gregory, Kimberly Hibbard, Judith Ramirez, Mildred Reddy, Uma Vanveldhuisen, Paul Burkman, Ronald Branch, Ware Hoffman, Matthew Habermanm, Shoshana Kominiarek, Michelle Landy, Helain Hatjis, Christos Troendle, James TI Neonatal outcomes by labor onset type and gestational age SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Bailit, Jennifer] Case Western Reserve Univ, Metrohlth Med Ctr, Dept Gynecol & Obstet, Cleveland, OH 44106 USA. [Zhang, Jun; Troendle, James] NICHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Gonzalez Quintero, Victor Hugo] Univ Miami, Dept Obstet Gynecol, MFM Div, Miami, FL USA. [Gregory, Kimberly] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Hibbard, Judith] Univ Illinois, Chicago, IL USA. [Ramirez, Mildred] Univ Texas Houston, Hlth Sci Ctr, Houston, TX USA. [Reddy, Uma] NICHD, NIH, Bethesda, MD USA. [Vanveldhuisen, Paul] Emmes Corp, Rockville, MD USA. [Burkman, Ronald] Tufts Univ, Baystate Med Ctr, Medford, MA 02155 USA. [Branch, Ware] Univ Utah, Salt Lake City, UT USA. [Hoffman, Matthew] Christiana Hosp, Newark, DE USA. [Habermanm, Shoshana] Maimonides Hosp, Brooklyn, NY 11219 USA. [Kominiarek, Michelle] Indiana Univ, Indianapolis, IN 46204 USA. [Landy, Helain] Georgetown Univ Hosp, Washington, DC 20007 USA. [Hatjis, Christos] Childrens Hosp & Med Ctr, Akron, OH USA. [Branch, Ware] Intermt Hlth, Salt Lake City, UT USA. [Landy, Helain] Medstar Hlth, Washington, DC USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 29 BP S17 EP S18 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500030 ER PT J AU Borowski, K Clark, E AF Borowski, Kristi Clark, Erin TI Neonatal genetic variation in steroid metabolism genes and perinatal outcomes in single and multiple courses of corticosteroids SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Borowski, Kristi; Clark, Erin] Eunice Kennedy Shriver NICHD, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 733 BP S264 EP S265 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500726 ER PT J AU Bukowski, R Fofanov, V Koshinsky, H Rojas, M Fofanov, Y AF Bukowski, Radek Fofanov, Viacheslav Koshinsky, Heather Rojas, Mark Fofanov, Yuriy TI Metagenomics of preterm birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Bukowski, Radek] NICHD, Genom & Prote Network Preterm Birth Res, Bethesda, MD USA. [Fofanov, Yuriy] Univ Houston, Houston, TX 77004 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 473 BP S178 EP S178 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500469 ER PT J AU Casey, B AF Casey, Brian TI Does maternal BMI modify the beneficial effects of treatment in women with mild gestational diabetes? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Casey, Brian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 257 BP S107 EP S107 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500256 ER PT J AU Chaiworapongsa, T Romero, R Kusanovic, JP Savasan, ZA Mazaki-Tovi, S Kim, SK Vaisbuch, E Tarca, AL Mittal, P Ogge, G Madan, I Dong, Z Yeo, L Hassan, SS AF Chaiworapongsa, Tinnakorn Romero, Roberto Kusanovic, Juan Pedro Savasan, Zeynep Alpay Mazaki-Tovi, Shali Kim, Sun Kwon Vaisbuch, Edi Tarca, Adi L. Mittal, Pooja Ogge, Giovanna Madan, Ichchha Dong, Zhong Yeo, Lami Hassan, Sonia S. TI Fetal death: a condition with a disparity in SVEGFR-2 between the maternal and fetal compartments SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology C1 [Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Savasan, Zeynep Alpay; Mazaki-Tovi, Shali; Vaisbuch, Edi; Tarca, Adi L.; Mittal, Pooja; Madan, Ichchha; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Sch Med, Detroit, MI USA. [Romero, Roberto; Kim, Sun Kwon; Ogge, Giovanna; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto; Kim, Sun Kwon; Ogge, Giovanna; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. RI Ogge, Giovanna/G-6109-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 792 BP S284 EP S285 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500785 ER PT J AU Chaiworapongsa, T Romero, R Kusanovic, JP Savasan, ZA Kim, SK Mazaki-Tovi, S Vaibuch, E Ogge, G Madan, I Dong, Z Yeo, L Mittal, P Hassan, SS AF Chaiworapongsa, Tinnakorn Romero, Roberto Kusanovic, Juan Pedro Savasan, Zeynep Alpay Kim, Sun Kwon Mazaki-Tovi, Shali Vaibuch, Edi Ogge, Giovanna Madan, Ichchha Dong, Zhong Yeo, Lami Mittal, Pooja Hassan, Sonia S. TI Fetal death is associated with increased concentration of anti-angiogenic factors SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology C1 [Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Savasan, Zeynep Alpay; Mazaki-Tovi, Shali; Vaibuch, Edi; Madan, Ichchha; Yeo, Lami; Mittal, Pooja; Hassan, Sonia S.] Wayne State Univ, Sch Med, Detroit, MI USA. [Romero, Roberto; Kim, Sun Kwon; Ogge, Giovanna; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto; Kim, Sun Kwon; Ogge, Giovanna; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. RI Ogge, Giovanna/G-6109-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 791 BP S284 EP S284 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500784 ER PT J AU Chetty-John, S Zhang, J Chen, Z Albert, P Sun, LP Klebanoff, M Grewal, U AF Chetty-John, Shilpa Zhang, Jun Chen, Zhen Albert, Paul Sun, Liping Klebanoff, Mark Grewal, Una TI Long-term physical and neurological development in newborns with isolated single umbilical artery SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Chetty-John, Shilpa] NHGRI, NIH, Bethesda, MD 20892 USA. [Zhang, Jun; Chen, Zhen; Albert, Paul; Sun, Liping; Klebanoff, Mark; Grewal, Una] NICHD, NIH, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 107 BP S55 EP S55 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500107 ER PT J AU Clark, EAS AF Clark, Erin A. S. TI Association of candidate gene polymorphisms with death and cerebral palsy following preterm birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Clark, Erin A. S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 730 BP S263 EP S264 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500723 ER PT J AU Clark, EAS AF Clark, Erin A. S. TI Association of candidate gene polymorphisms and magnesium sulfate exposure with psychomotor delay at age 2 following preterm birth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Clark, Erin A. S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 62 BP S36 EP S36 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500063 ER PT J AU Conde-Agudelo, A Romero, R AF Conde-Agudelo, Agustin Romero, Roberto TI Maternal periodontal disease and risk of preeclampsia: a systematic review and meta-analysis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology C1 [Conde-Agudelo, Agustin; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 794 BP S285 EP S285 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500787 ER PT J AU Conde-Agudelo, A Romero, R AF Conde-Agudelo, Agustin Romero, Roberto TI Supplementation with vitamins C and E during pregnancy for the prevention of preeclampsia: a systematic review and meta-analysis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology C1 [Conde-Agudelo, Agustin; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 793 BP S285 EP S285 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500786 ER PT J AU Conde-Agudelo, A Romero, R AF Conde-Agudelo, Agustin Romero, Roberto TI Fetal fibronectin as a predictor of spontaneous preterm delivery in multiple gestations: a systematic review and meta-analysis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Conde-Agudelo, Agustin; Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 526 BP S196 EP S196 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500522 ER PT J AU Costantine, M AF Costantine, Maged TI Customized vs population-based approach to evaluate fetal overgrowth SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Costantine, Maged] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 382 BP S148 EP S148 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500379 ER PT J AU Digiulio, D Romero, R Kusanovic, JP Gomez, R Kim, CJ Seok, K Gotsch, F Mazaki-Tovi, S Vaisbuch, E Sanders, K Bik, E Chaiworapongsa, T Relman, D AF Digiulio, Daniel Romero, Roberto Kusanovic, Juan Pedro Gomez, Ricardo Kim, Chong Jai Seok, Kimberley Gotsch, Francesca Mazaki-Tovi, Shali Vaisbuch, Edi Sanders, Katherine Bik, Elizabeth Chaiworapongsa, Tinnakorn Relman, David TI A molecular investigation of the microbial diversity and burden in preterm PROM reveals a high rate of infection with a broad range of organisms including gastrointestinal tract microbiota SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Digiulio, Daniel; Bik, Elizabeth] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Romero, Roberto; Gotsch, Francesca] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto; Gotsch, Francesca] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Kusanovic, Juan Pedro; Kim, Chong Jai; Mazaki-Tovi, Shali; Vaisbuch, Edi; Chaiworapongsa, Tinnakorn] Wayne State Univ, Sch Med, Detroit, MI USA. [Gomez, Ricardo] Catholic Univ Chile, CEDIP, Sotero Rio Hosp, Puente Alto, Chile. [Gomez, Ricardo] Catholic Univ Chile, CEDIP, Sotero Rio Hosp, Santiago, Chile. [Seok, Kimberley] Vet Affairs Palo Alto Hlth Care Syst, Palo Alto, CA USA. [Relman, David] Stanford Univ, VA Palo Alto Hlth Care Syst, Palo Alto, CA 94304 USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 535 BP S198 EP S199 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500531 ER PT J AU Dong, YL Siller, RB Shi, SQ Shi, L Balducci, J Chambliss, L Romero, R Garfield, R AF Dong, Yuan-Lin Siller, Rafael Buerba Shi, Shao-Qing Shi, Leili Balducci, James Chambliss, Linda Romero, Roberto Garfield, Robert TI A role for myometrial membrane progesterone receptors in pregnancy maintenance and the control of human parturition: evidence derived from studies of expression (mRNA and protein), immunolocalization, binding and contractility SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Dong, Yuan-Lin; Siller, Rafael Buerba; Shi, Shao-Qing; Shi, Leili; Balducci, James; Chambliss, Linda; Garfield, Robert] St Josephs Hosp, Med Ctr, Phoenix, AZ USA. [Romero, Roberto] NICHD, NIH, Detroit, MI USA. [Romero, Roberto] Wayne State Univ, Perinatol Res Branch, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 300 BP S121 EP S121 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500299 ER PT J AU Durnwald, C AF Durnwald, Celeste TI Glycemic characteristics of women treated for mild gestational diabetes and perinatal outcomes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Durnwald, Celeste] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 259 BP S107 EP S107 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500258 ER PT J AU Eller, A Branch, W Lu, L Zhang, J Wilkins, I Hibbard, J Burkman, R Bailit, J Quintero, VHG Gregory, K Haberman, S Hatjis, C Hoffman, M Kominiarek, M Landy, H Ramirez, M Reddy, U Troendle, J Vanveldhuisen, P AF Eller, Alexandra Branch, Ware Lu, Li Zhang, Jim Wilkins, Isabelle Hibbard, Judith Burkman, Ronald Bailit, Jennifer Quintero, Victor Hugo Gonzalez Gregory, Kimberly Haberman, Shoshana Hatjis, Christos Hoffman, Mathew Kominiarek, Michelle Landy, Helain Ramirez, Mildred Reddy, Uma Troendle, James Vanveldhuisen, Paul TI The impact of epidural timing on mode of delivery in nulliparous women at term SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Eller, Alexandra; Branch, Ware] Univ Utah, Salt Lake City, UT USA. [Eller, Alexandra; Branch, Ware] Intermt Healthcare, Salt Lake City, UT USA. [Lu, Li; Vanveldhuisen, Paul] Emmes Corp, Rockville, MD USA. [Zhang, Jim] Natl Inst Hlth, Bethesda, MD USA. [Wilkins, Isabelle; Hibbard, Judith; Kominiarek, Michelle] Univ Illinois, Chicago, IL 60680 USA. [Burkman, Ronald] Tufts Univ, Medford, MA 02155 USA. [Bailit, Jennifer] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Quintero, Victor Hugo Gonzalez] Univ Miami, Dept Obstet Gynecol, MFM Div, Miami, FL USA. [Gregory, Kimberly] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Haberman, Shoshana] Maimonides Hosp, Brooklyn, NY 11219 USA. [Hatjis, Christos] Childrens Hosp Med Ctr, Akron, OH USA. [Hoffman, Mathew] Christiana Care Hlth Syst, Delaware, OH USA. [Landy, Helain] Georgetown Univ, Washington, DC USA. [Ramirez, Mildred] Univers Texas Hlth Sci Ctr, Houston, TX USA. [Reddy, Uma; Troendle, James] NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 172 BP S77 EP S77 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500172 ER PT J AU Gonzalez-Quintero, VH Zhang, J Landy, H Reddy, U Ramirez, M Burkman, R Bailit, J Troendle, J Vanveldhuisen, P Hibbard, J Haberman, S Branch, W Kominiarek, M Hoffman, M Fanning, J Gregory, K AF Gonzalez-Quintero, Victor Hugo Zhang, Jun Landy, Helain Reddy, Uma Ramirez, Mildred Burkman, Ronald Bailit, Jennifer Troendle, James Vanveldhuisen, Paul Hibbard, Judith Haberman, Shoshana Branch, Waren Kominiarek, Michelle Hoffman, Matthew Fanning, James Gregory, Kimberly TI Labor patterns in women with a successful vaginal birth after cesarean (VBAC) in the US: the consortium on safe labor SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Gonzalez-Quintero, Victor Hugo] Univ Miami, Miami, FL USA. [Zhang, Jun; Troendle, James] NIH, Bethesda, MD 20892 USA. [Landy, Helain] Georgetown Univ, Washington, DC USA. [Reddy, Uma] Univ Maryland Baltimore Cty, Bethesda, MD USA. [Ramirez, Mildred] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Burkman, Ronald] Tufts Univ, Springfield, MA USA. [Bailit, Jennifer] MetroHlth, Cleveland, OH USA. [Vanveldhuisen, Paul] EMMES Corp, Rockville, MD USA. [Hibbard, Judith] Univ Illinois, Chicago, IL USA. [Haberman, Shoshana] Maimonides Hosp, Brooklyn, NY 11219 USA. [Hoffman, Matthew] Christiana Hosp, Newark, DE USA. [Fanning, James] Summa Hlth Syst, Toledo, OH USA. [Gregory, Kimberly] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Kominiarek, Michelle] Univ Illinois, Indianapolis, IN USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 677 BP S244 EP S245 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500670 ER PT J AU Harper, M AF Harper, Margaret TI Low maternal omega-3 levels prior to 22 weeks' gestation are associated with preterm delivery and low fish intake SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Harper, Margaret] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 454 BP S172 EP S172 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500451 ER PT J AU Hauth, J AF Hauth, John TI Vitamin C and E supplementation to prevent preterm premature rupture of membranes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Hauth, John] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 465 BP S175 EP S176 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500461 ER PT J AU Hibbard, JU Wilkins, I Zhang, J Bailit, J Burkman, R Branch, W Gonzalez-Quintero, V Gregory, K Haberman, S Hatjis, C Hoffman, M Kominiarek, M Landy, H Ramirez, M Reddy, U Troendle, J Vanveldhuisen, P AF Hibbard, Judith U. Wilkins, Isabelle Zhang, Jun Bailit, Jennifer Burkman, Ronald Branch, Ware Gonzalez-Quintero, Victor Gregory, Kimberly Haberman, Shoshana Hatjis, Christos Hoffman, Matthew Kominiarek, Michelle Landy, Helain Ramirez, Mildred Reddy, Uma Troendle, James Vanveldhuisen, Paul TI Respiratory morbidity in the late preterm neonate (LPN) SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Hibbard, Judith U.; Wilkins, Isabelle] Univ Illinois, Chicago, IL USA. [Zhang, Jun] NICHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Bailit, Jennifer] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Burkman, Ronald] Tufts Univ, Springfield, MA USA. [Branch, Ware] Univ Utah, Salt Lake City, UT USA. [Branch, Ware] Intermt Healthcare, Salt Lake City, UT USA. [Gonzalez-Quintero, Victor] Univ Miami, Miami, FL USA. [Gregory, Kimberly] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Haberman, Shoshana] Maimonides Hosp, Brooklyn, NY 11219 USA. [Hatjis, Christos] Childrens Hosp, Med Ctr, Akron, OH 44308 USA. [Hoffman, Matthew] Christiana Care Hlth Syst, Newark, DE USA. [Kominiarek, Michelle] Indiana Univ, Indianapolis, IN 46204 USA. [Landy, Helain] Georgetown Univ, Washington, DC USA. [Ramirez, Mildred] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Reddy, Uma; Troendle, James] NIH, Bethesda, MD 20892 USA. [Vanveldhuisen, Paul] Emmes Corp, Rockville, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 187 BP S82 EP S82 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500187 ER PT J AU Incerti, M Roberson, R Nold, C Abebe, D Spong, C AF Incerti, Maddalena Roberson, Robin Nold, Christopher Abebe, Daniel Spong, Catherine TI Role of brain-derived neurotrophic factor in Down syndrome SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology C1 [Incerti, Maddalena; Roberson, Robin; Abebe, Daniel; Spong, Catherine] NIH, Bethesda, MD 20892 USA. [Nold, Christopher] Univ Connecticut, Ctr Hlth, Farmington, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 704 BP S255 EP S255 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500697 ER PT J AU Incerti, M Roberson, R Nold, C Toso, L Vink, J Abebe, D Spong, C AF Incerti, Maddalena Roberson, Robin Nold, Christopher Toso, Laura Vink, Joy Abebe, Daniel Spong, Catherine TI Prenatal treatment with neuroprotective peptides restores DYRK1A expression in a mouse model of Down syndrome SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology C1 [Incerti, Maddalena; Roberson, Robin; Toso, Laura; Abebe, Daniel; Spong, Catherine] NIH, Bethesda, MD 20892 USA. [Nold, Christopher] Univ Connecticut, Ctr Hlth, Farmington, CT USA. [Vink, Joy] Columbia Univ, Med Ctr, New York, NY USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 703 BP S255 EP S255 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500696 ER PT J AU Incerti, M Vink, J Roberson, R Benassou, I Abebe, D Spong, C AF Incerti, Maddalena Vink, Joy Roberson, Robin Benassou, Ines Abebe, Daniel Spong, Catherine TI Brain-derived neurotrophic factor in normal development and as a mediator of fetal alcohol syndrome SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Incerti, Maddalena; Roberson, Robin; Benassou, Ines; Abebe, Daniel; Spong, Catherine] NIH, Bethesda, MD 20892 USA. [Vink, Joy] Columbia Univ, Med Ctr, New York, NY 10027 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 220 BP S93 EP S93 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500219 ER PT J AU Incerti, M Vink, J Benassou, I Roberson, R Abebe, D Spong, C AF Incerti, Maddalena Vink, Joy Benassou, Ines Roberson, Robin Abebe, Daniel Spong, Catherine TI Prevention of the alcohol-induced changes in brain-derived neurotrophic factor expression using neuroprotective peptides in a model of fetal alcohol syndrome SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Incerti, Maddalena; Benassou, Ines; Roberson, Robin; Abebe, Daniel; Spong, Catherine] NIH, Bethesda, MD 20892 USA. [Vink, Joy] Columbia Univ, Med Ctr, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 54 BP S31 EP S31 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500055 ER PT J AU Kim, SK Romero, R Chaiworapongsa, T Kusanovic, JP Mazaki-Tovi, S Vaisbuch, E Mittal, P Ogge, G Alpay-Savasan, Z Madan, I Dong, Z Yeo, L Hassan, SS AF Kim, Sun Kwon Romero, Roberto Chaiworapongsa, Tinnakorn Kusanovic, Juan Pedro Mazaki-Tovi, Shali Vaisbuch, Edi Mittal, Pooja Ogge, Giovanna Alpay-Savasan, Zeynep Madan, Ichchha Dong, Zhong Yeo, Lami Hassan, Sonia S. TI Evidence for intersection between the angiogenic and inflammatory pathways in preterm labor and preterm PROM SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Kim, Sun Kwon; Romero, Roberto; Ogge, Giovanna; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Kim, Sun Kwon; Romero, Roberto; Ogge, Giovanna; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Vaisbuch, Edi; Mittal, Pooja; Alpay-Savasan, Zeynep; Madan, Ichchha; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Sch Med, Bethesda, MD USA. RI Ogge, Giovanna/G-6109-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 73 BP S41 EP S42 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500074 ER PT J AU Kominiarek, M Vanveldhuisen, P Hibbard, J Landy, H Haberman, S Zhang, J Wilkins, I Bailit, J Branch, W Burkman, R Quintero, VHG Gregory, K Hatiis, C Hoffman, M Ramirez, M Reddy, U Troendle, J AF Kominiarek, Michelle Vanveldhuisen, Paul Hibbard, Judith Landy, Helain Haberman, Shoshana Zhang, Jun Wilkins, Isabelle Bailit, Jennifer Branch, Ware Burkman, Ronald Quintero, Victor Hugo Gonzalez Gregory, Kimberly Hatiis, Christos Hoffman, Matthew Ramirez, Mildred Reddy, Uma Troendle, James TI The maternal body mass index (BMI): a strong predictor of the success of a vaginal delivery SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Kominiarek, Michelle] Indiana Univ Clarian Hlth, Indianapolis, IN USA. [Vanveldhuisen, Paul] EMMES Corp, Rockville, MD USA. [Landy, Helain; Wilkins, Isabelle] Univ Illinois, Chicago, IL USA. [Landy, Helain] Georgetown Univ, Washington, DC USA. [Haberman, Shoshana] Maimonides Hosp, Brooklyn, NY 11219 USA. [Zhang, Jun; Troendle, James] NICHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Bailit, Jennifer] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Branch, Ware] Intermt Healthcare Univ Utah, Salt Lake City, UT USA. [Burkman, Ronald] Tufts Univ, Springfield, MA USA. [Quintero, Victor Hugo Gonzalez] Univ Miami, Miami, FL USA. [Gregory, Kimberly] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Hatiis, Christos] Childrens Hosp, Med Ctr, Akron, OH 44308 USA. [Hoffman, Matthew] Christiana Care Hlth Syst, Newark, DC USA. [Ramirez, Mildred] Univ Texas Houston, Hlth Sci Ctr, Houston, TX USA. [Reddy, Uma] NICHD, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 295 BP S119 EP S119 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500294 ER PT J AU Landon, MB AF Landon, Mark B. TI The relationship between maternal glycemia and perinatal outcome SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Landon, Mark B.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, MFMU Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 52 BP S28 EP S29 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500053 ER PT J AU Leveno, K AF Leveno, Ken TI Antecedents to cerebral palsy in preterm infants SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Leveno, Ken] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 481 BP S181 EP S181 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500477 ER PT J AU Madan, I Romero, R Kusanovic, JP Mittal, P Chaiworapongsa, T Dong, Z Mazaki-Tovi, S Vaisbuch, E Savasan, ZA Yeo, L Hassan, SS AF Madan, Ichchha Romero, Roberto Kusanovic, Juan Pedro Mittal, Pooja Chaiworapongsa, Tinnakorn Dong, Zhong Mazaki-Tovi, Shali Vaisbuch, Edi Savasan, Zeynep Alpay Yeo, Lami Hassan, Sonia S. TI The frequency and clinical significance of intra-amniotic infection in women with placenta previa and vaginal bleeding: an unexpected observation SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Madan, Ichchha; Kusanovic, Juan Pedro; Mittal, Pooja; Chaiworapongsa, Tinnakorn; Mazaki-Tovi, Shali; Vaisbuch, Edi; Savasan, Zeynep Alpay; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Sch Med, Detroit, MI USA. [Romero, Roberto; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 171 BP S76 EP S76 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500171 ER PT J AU Mazaki-Tovi, S Romero, R Vaisbuch, E Kusanovic, JP Chaiworapongsa, T Kim, SK Mittal, P Dong, Z Pacora, P Yeo, L Hassan, SS AF Mazaki-Tovi, Shali Romero, Roberto Vaisbuch, Edi Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Kim, Sun Kwon Mittal, Pooja Dong, Zhong Pacora, Percy Yeo, Lami Hassan, Sonia S. TI Retinol-binding protein-4: a novel adipokine implicated in the genesis of LGA in the absence of gestational diabetes mellitus SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Mazaki-Tovi, Shali; Vaisbuch, Edi; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Mittal, Pooja; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Sch Med, Detroit, MI USA. [Romero, Roberto; Kim, Sun Kwon; Dong, Zhong; Pacora, Percy] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 272 BP S112 EP S112 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500271 ER PT J AU Mazaki-Tovi, S Romero, R Vaisbuch, E Kim, SK Kusanovic, JP Chaiworapongsa, T Mittal, P Dong, Z Pacora, P Yeo, L Hassan, SS AF Mazaki-Tovi, Shali Romero, Roberto Vaisbuch, Edi Kim, Sun Kwon Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Mittal, Pooja Dong, Zhong Pacora, Percy Yeo, Lami Hassan, Sonia S. TI Evidence for differential regulation of the adipokine visfatin in the maternal and fetal compartments in normal spontaneous labor at term SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Mazaki-Tovi, Shali; Vaisbuch, Edi; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Mittal, Pooja; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Sch Med, Detroit, MI USA. [Romero, Roberto; Kim, Sun Kwon; Dong, Zhong; Pacora, Percy] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto; Kim, Sun Kwon; Dong, Zhong; Pacora, Percy] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 227 BP S95 EP S96 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500226 ER PT J AU Mercer, B AF Mercer, Brian TI Prediction of serious newborn complications after conservative management of PROM < 32 weeks SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Mercer, Brian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 497 BP S186 EP S186 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500493 ER PT J AU Mercer, B AF Mercer, Brian TI Prediction of failed conservative management of PROM remote from term SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Mercer, Brian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 496 BP S185 EP S186 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500492 ER PT J AU Mercer, B AF Mercer, Brian TI Impact of antenatal MgS04 on the relationships between thyroid function at birth and adverse neurologic outcomes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology C1 [Mercer, Brian] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 195 BP S85 EP S85 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500195 ER PT J AU Mittal, P Romero, R Soto, E Cordoba, M Nhan-Chang, CL Vaisbuch, E Bieda, J Chaiworapongsa, T Kusanovic, JP Yeo, L Yoon, BH Hassan, SS AF Mittal, Pooja Romero, Roberto Soto, Eleazar Cordoba, Marcos Nhan-Chang, Chia-Ling Vaisbuch, Edi Bieda, Janine Chaiworapongsa, Tinnakorn Kusanovic, Juan Pedro Yeo, Lami Yoon, Bo Hyun Hassan, Sonia S. TI A role for placental alpha-microglobulin-1 in the identification of women with a sonographic short cervix at risk for spontaneous rupture of membranes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Mittal, Pooja; Soto, Eleazar; Cordoba, Marcos; Nhan-Chang, Chia-Ling; Vaisbuch, Edi; Bieda, Janine; Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Sch Med, Detroit, MI USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Yoon, Bo Hyun] Seoul Natl Univ Hosp, Seoul 110744, South Korea. NR 0 TC 5 Z9 7 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 528 BP S196 EP S197 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500524 ER PT J AU Mittal, P Romero, R Tarca, AL Nhan-Chang, CL Chaiworapongsa, T Hotra, J Gomez, R Kusanovic, JP Kim, JS Kim, CJ Hassan, SS AF Mittal, Pooja Romero, Roberto Tarca, Adi L. Nhan-Chang, Chia-Ling Chaiworapongsa, Tinnakorn Hotra, John Gomez, Ricardo Kusanovic, Juan Pedro Kim, Jung-Sun Kim, Chong Jai Hassan, Sonia S. TI The molecular signature of an arrest of descent in human parturition SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Mittal, Pooja; Tarca, Adi L.; Nhan-Chang, Chia-Ling; Chaiworapongsa, Tinnakorn; Hotra, John; Kusanovic, Juan Pedro; Kim, Jung-Sun; Kim, Chong Jai; Hassan, Sonia S.] Wayne State Univ, Sch Med, Detroit, MI USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Gomez, Ricardo] Catholic Univ Chile, Sotero Rio Hosp, CEDIP, Puente Alto, Chile. [Gomez, Ricardo] Catholic Univ Chile, Sotero Rio Hosp, CEDIP, Santiago, Chile. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 325 BP S129 EP S129 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500323 ER PT J AU Myatt, L AF Myatt, Leslie TI Platelet count and mean platelet volume in prediction of preeclampsia in a low risk population SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Myatt, Leslie] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 784 BP S282 EP S282 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500777 ER PT J AU Myatt, L AF Myatt, Leslie TI Uterine artery Doppler velocimetry in screening for hypertensive disorders in a low risk population SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Myatt, Leslie] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 282 BP S115 EP S115 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500281 ER PT J AU Nhan-Chang, CL Romero, R Tarca, AL Mittal, P Kusanovic, JP Erez, O Mazaki-Tovi, S Chaiworapongsa, T Hotra, J Kim, JS Hassan, SS Kim, CJ AF Nhan-Chang, Chia-Ling Romero, Roberto Tarca, Adi L. Mittal, Pooja Kusanovic, Juan Pedro Erez, Offer Mazaki-Tovi, Shali Chaiworapongsa, Tinnakorn Hotra, John Kim, Jung-Sun Hassan, Sonia S. Kim, Chong Jai TI Identification of signature pathways at the site of rupture in chorionic membranes in spontaneous labor at term SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Nhan-Chang, Chia-Ling; Tarca, Adi L.; Mittal, Pooja; Kusanovic, Juan Pedro; Erez, Offer; Mazaki-Tovi, Shali; Chaiworapongsa, Tinnakorn; Hotra, John; Kim, Jung-Sun; Hassan, Sonia S.; Kim, Chong Jai] Wayne State Univ, Sch Med, Detroit, MI USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 1 BP S2 EP S2 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500002 ER PT J AU Ogge, G Romero, R Kusanovic, JP Chaiworapongsa, T Dong, Z Mittal, P Vaisbuch, E Mazaki-Tovi, S Gonzalez, J Yeo, L Hassan, SS AF Ogge, Giovanna Romero, Roberto Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Dong, Zhong Mittal, Pooja Vaisbuch, Edi Mazaki-Tovi, Shali Gonzalez, Juan Yeo, Lami Hassan, Sonia S. TI Serum and plasma determination of angiogenic and anti-angiogenic factors yield different results: the need for standardization in clinical practice SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Ogge, Giovanna; Romero, Roberto; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Ogge, Giovanna; Romero, Roberto; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Mittal, Pooja; Vaisbuch, Edi; Mazaki-Tovi, Shali; Gonzalez, Juan; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Sch Med, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 805 BP S288 EP S289 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500798 ER PT J AU Oh, KJ Yoon, BH Romero, R Park, CW Lee, SM Kim, SM AF Oh, Kyung Joon Yoon, Bo Hyun Romero, Roberto Park, Chan-Wook Lee, Seung Mi Kim, Sun Min TI The frequency and clinical significance of intra-amniotic inflammation in twin pregnancies with preterm labor and intact membranes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Oh, Kyung Joon; Yoon, Bo Hyun; Park, Chan-Wook; Lee, Seung Mi; Kim, Sun Min] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. RI Park, Chan-Wook/J-5498-2012 NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 434 BP S166 EP S166 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500431 ER PT J AU Oh, KJ Lee, KA Sohn, YK Park, CW Hong, JS Romero, R Yoon, BH AF Oh, Kyung Joon Lee, Kyung A. Sohn, Yoo-Kyung Park, Chan-Wook Hong, Joon-Seok Romero, Roberto Yoon, Bo Hyun TI Intra-amniotic infection with genital mycoplasmas is characterized by an intense inflammatory response in the amniotic cavity and in the maternal compartment SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology C1 [Oh, Kyung Joon; Lee, Kyung A.; Sohn, Yoo-Kyung; Park, Chan-Wook; Hong, Joon-Seok; Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Dept Obstet & Gynecol, Seoul, South Korea. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. RI Park, Chan-Wook/J-5498-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 433 BP S165 EP S166 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500430 ER PT J AU Roberson, R Incerti, M Nold, C Abebe, D Spong, C AF Roberson, Robin Incerti, Maddalena Nold, Christoper Abebe, Daniel Spong, Catherine TI Neuroprotective peptides NAP and SAL may alter KIF17 levels in TS65DN mice treated postnatally SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Roberson, Robin; Incerti, Maddalena; Spong, Catherine] NIH, Bethesda, MD 20892 USA. [Nold, Christoper] Univ Connecticut, Ctr Hlth, Farmington, CT USA. [Abebe, Daniel] NICHD, NIH, Unit Perinatal & Dev Neurobiol, NIAAA, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 229 BP S96 EP S96 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500228 ER PT J AU Romero, R Velez, DR Mazaki-Tovi, S Gomez, R Behnke, E Chaiworapongsa, T Anant, MK Salisbury, B Carr, J Vovis, G Kim, CJ Tromp, G Menon, R Williams, S AF Romero, Roberto Velez, Digna Rosa Mazaki-Tovi, Shali Gomez, Ricardo Behnke, Ernesto Chaiworapongsa, Tinnakorn Anant, Madan Kumar Salisbury, Benjamin Carr, Janet Vovis, Gerald Kim, Chong Jai Tromp, Gerard Menon, Ramkumar Williams, Scott TI Identification of fetal and maternal single nucleotide polymorphisms in candidate genes that predispose to spontaneous preterm labor with intact membranes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Velez, Digna Rosa] Univ Miami, Miami Inst Human Gen, Miami, FL USA. [Mazaki-Tovi, Shali; Chaiworapongsa, Tinnakorn; Kim, Chong Jai; Tromp, Gerard] Wayne State Univ, Sch Med, Detroit, MI USA. [Gomez, Ricardo; Behnke, Ernesto] Pontificia Univ Catolica Chile, Sotero Rio Hosp, Puente Alto, Chile. [Anant, Madan Kumar; Salisbury, Benjamin; Carr, Janet; Vovis, Gerald] Clin Data Inc, Genaissance Pharmaceut, New Haven, CT USA. [Menon, Ramkumar] Emory Univ, Dept Epidemiol, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Williams, Scott] Vanderbilt Univ, Dept Cardiovasc Med, Nashville, TN USA. [Williams, Scott] Vanderbilt Univ, Ctr Human Genet Res, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 14 BP S9 EP S9 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500015 ER PT J AU Saade, GR AF Saade, George R. TI Demographic and pre-pregnancy risk factors for stillbirth: a population-based study SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Saade, George R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, SCRN, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 27 BP S17 EP S17 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500028 ER PT J AU Savasan, ZA Romero, R Chaiworapongsa, T Kusanovic, JP Kim, SK Mazaki-Tovi, S Vaisbuch, E Mittal, P Ogge, G Madan, I Dong, Z Yeo, L Hassan, SS AF Savasan, Zeynep Alpay Romero, Roberto Chaiworapongsa, Tinnakorn Kusanovic, Juan Pedro Kim, Sun Kwon Mazaki-Tovi, Shali Vaisbuch, Edi Mittal, Pooja Ogge, Giovanna Madan, Ichchha Dong, Zhong Yeo, Lami Hassan, Sonia S. TI Evidence in support for a role of anti-angiogenic factors in preterm prelabor rupture of membranes (PPROM) SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Savasan, Zeynep Alpay; Chaiworapongsa, Tinnakorn; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Vaisbuch, Edi; Mittal, Pooja; Madan, Ichchha; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Sch Med, Detroit, MI USA. [Romero, Roberto; Kim, Sun Kwon; Ogge, Giovanna; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. [Romero, Roberto; Kim, Sun Kwon; Ogge, Giovanna; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. RI Ogge, Giovanna/G-6109-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 534 BP S198 EP S198 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500530 ER PT J AU Sean, B AF Sean, Blackwell TI Excess weight gain increases neonatal fat mass in women treated for mild gestational diabetes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Sean, Blackwell] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 244 BP S103 EP S103 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500243 ER PT J AU Sibai, B Koch, M Freire, S Silva, JLPE Rudge, MVC Martins-Costa, S Moore, J Santos, CD Cecatti, JG Costa, R Ramos, JG Moss, N Spinnato, J AF Sibai, Baha Koch, Matthew Freire, Salvio Silva, Joao Luiz Pinto E. Cunha Rudge, Marilza Vieira Martins-Costa, Sergio Moore, Janet Santos, Cleide De Barros Cecatti, Jose Guilherme Costa, Roberto Ramos, Jose Geraldo Moss, Nancy Spinnato, Joseph, II TI The impact of a history of previous preeclampsia (PE) on the risk of superimposed preeclampsia and adverse pregnancy outcome in patients with chronic hypertension (CHTN) SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Sibai, Baha; Spinnato, Joseph, II] Univ Cincinnati, Cincinnati, OH USA. [Koch, Matthew; Moore, Janet] RTI Int, Res Triangle Pk, NC 27709 USA. [Freire, Salvio; Santos, Cleide De Barros] Univ Fed Pernambuco, Recife, PE, Brazil. [Silva, Joao Luiz Pinto E.; Cecatti, Jose Guilherme] Univ Estadual Campinas, BR-13081970 Campinas, SP, Brazil. [Martins-Costa, Sergio; Ramos, Jose Geraldo] Univ Fed Rio Grande do Sul, BR-90046900 Porto Alegre, RS, Brazil. [Moss, Nancy] NICHHD, Rockville, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 752 BP S271 EP S271 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500745 ER PT J AU Silver, R AF Silver, Robert TI Stillbirth collaborative research network: proximate causes of death in a prospective, population based, multi-center, case-control study with a standardized protocol SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Silver, Robert] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, SCRN, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 5 BP S4 EP S4 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500006 ER PT J AU Soto, E Romero, R Vaisbuch, E Erez, O Mazaki-Tovi, S Kusanovic, JP Dong, Z Chaiworapongsa, T Yeo, L Mittal, P Hassan, S AF Soto, Eleazar Romero, Roberto Vaisbuch, Edi Erez, Offer Mazaki-Tovi, Shali Kusanovic, Juan Pedro Dong, Zhong Chaiworapongsa, Tinnakorn Yeo, Lami Mittal, Pooja Hassan, Sonia TI Fragment Bb: evidence for activation of the alternative pathway of the complement system in pregnant women with pyelonephritis SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Soto, Eleazar; Vaisbuch, Edi; Erez, Offer; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Dong, Zhong; Chaiworapongsa, Tinnakorn; Yeo, Lami; Mittal, Pooja; Hassan, Sonia] Wayne State Univ, Sch Med, Detroit, MI USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 653 BP S237 EP S237 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500647 ER PT J AU Tita, A AF Tita, Alan TI Timing of elective repeat cesarean delivery at term and maternal outcomes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Tita, Alan] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 683 BP S246 EP S247 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500676 ER PT J AU Vaisbuch, E Romero, R Erez, O Mazaki-Tovi, S Kusanovic, JP Soto, E Dong, Z Chaiworapongsa, T Kim, SK Ogge, G Pacora, P Yeo, L Hassan, SS AF Vaisbuch, Edi Romero, Roberto Erez, Offer Mazaki-Tovi, Shali Kusanovic, Juan Pedro Soto, Eleazar Dong, Zhong Chaiworapongsa, Tinnakorn Kim, Sun Kwon Ogge, Giovanna Pacora, Percy Yeo, Lami Hassan, Sonia S. TI Activation of the alternative pathway of complement is a feature of preterm parturition but not of spontaneous labor at term SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology C1 [Vaisbuch, Edi; Erez, Offer; Mazaki-Tovi, Shali; Kusanovic, Juan Pedro; Soto, Eleazar; Chaiworapongsa, Tinnakorn; Yeo, Lami; Hassan, Sonia S.] Wayne State Univ, Sch Med, Detroit, MI USA. [Romero, Roberto; Dong, Zhong; Kim, Sun Kwon; Ogge, Giovanna; Pacora, Percy] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto; Dong, Zhong; Kim, Sun Kwon; Ogge, Giovanna; Pacora, Percy] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 520 BP S194 EP S194 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500516 ER PT J AU Vaisbuch, E Romero, R Mazaki-Tovi, S Nhan-Chang, CL Kusanovic, JP Chaiworapongsa, T Dong, Z Yeo, L Mittal, P Hassan, SS AF Vaisbuch, Edi Romero, Roberto Mazaki-Tovi, Shali Nhan-Chang, Chia-Ling Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Dong, Zhong Yeo, Lami Mittal, Pooja Hassan, Sonia S. TI One of every four patients with an asymptomatic short cervix (15mm) has subclinical intra-amniotic inflammation: implications for patient counseling and management SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology C1 [Vaisbuch, Edi; Mazaki-Tovi, Shali; Nhan-Chang, Chia-Ling; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Yeo, Lami; Mittal, Pooja; Hassan, Sonia S.] Wayne State Univ, Sch Med, Detroit, MI USA. [Romero, Roberto; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto; Dong, Zhong] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 521 BP S194 EP S194 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500517 ER PT J AU Varner, M Marshall, N AF Varner, Michael Marshall, Nicole TI The association of cord serum cytokines with neurodevelopmental outcomes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Varner, Michael; Marshall, Nicole] Eunice Kennedy Shriver NICHD, Maternal Fetal Med Units Network, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 189 BP S82 EP S83 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500189 ER PT J AU Velez, DR Romero, R Mazaki-Tovi, S Gomez, R Behnke, E Chaiworapongsa, T Anant, MK Salisbury, B Carr, J Lee, MS Vovis, G Kim, CJ Tromp, G Menon, R Williams, S AF Velez, Digna Rosa Romero, Roberto Mazaki-Tovi, Shali Gomez, Ricardo Behnke, Ernesto Chaiworapongsa, Tinnakorn Anant, Madan Kumar Salisbury, Benjamin Carr, Janet Lee, Min Soeb Vovis, Gerald Kim, Chong Jai Tromp, Gerard Menon, Ramkumar Williams, Scott TI Polymorphisms in maternal and fetal genes encoding for proteins involved in extracellular matrix metabolism alter the risk for small for gestational age SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med, Univ Texas Med Branch, Dept Obstetrics & Gynecology C1 [Velez, Digna Rosa] Univ Miami, Miami Inst Human Genom, Miami, FL USA. [Romero, Roberto] NICHHD, Perinatol Res Branch, NIH, DHHA, Bethesda, MD USA. [Romero, Roberto] NICHHD, Perinatol Res Branch, NIH, DHHA, Detroit, MI USA. [Mazaki-Tovi, Shali] Wayne State Univ, Sch Med, Detroit, MI USA. [Gomez, Ricardo; Behnke, Ernesto] Hosp Dr Sotero del Rio, Ctr Perinatal Diag & Res, Puente Alto, Chile. [Chaiworapongsa, Tinnakorn] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Anant, Madan Kumar; Salisbury, Benjamin; Carr, Janet; Lee, Min Soeb; Vovis, Gerald] Genaissance Pharmaceut, New Haven, CT USA. [Kim, Chong Jai] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. [Tromp, Gerard] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Menon, Ramkumar] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Williams, Scott] Vanderbilt Univ, Dept Cardiovasc Med, Nashville, TN USA. [Williams, Scott] Ctr Human Genet Res, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 692 BP S251 EP S251 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500685 ER PT J AU Yang, HJ Romero, R Park, CW Oh, KJ Kim, SM Yoon, BH AF Yang, Hye Jin Romero, Roberto Park, Chan-Wook Oh, Kyung Joon Kim, Sun Min Yoon, Bo Hyun TI The relationship between the severity of histologic chorioamnionitis and the intensity of fetal inflammatory response SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Yang, Hye Jin; Park, Chan-Wook; Oh, Kyung Joon; Kim, Sun Min; Yoon, Bo Hyun] Seoul Natl Univ, Coll Med, Seoul, South Korea. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. [Romero, Roberto] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 513 BP S191 EP S191 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500509 ER PT J AU Zhang, J Kim, SD Albert, P Sundaram, R Klebanoff, M Grewal, J AF Zhang, Jun Kim, Sung Duk Albert, Paul Sundaram, Rajeshwari Klebanoff, Mark Grewal, Jagteshwar TI Predicting macrosomia by individualized fetal growth velocity and maternal characteristics SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Meeting Abstract CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med C1 [Zhang, Jun; Sundaram, Rajeshwari] NIH, Bethesda, MD 20892 USA. [Kim, Sung Duk; Grewal, Jagteshwar] NICHD, DESPR, NIH, Bethesda, MD USA. [Albert, Paul; Klebanoff, Mark] NICHD, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 SU 1 MA 575 BP S213 EP S213 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 621FA UT WOS:000279559500570 ER PT J AU Joy, SD Zhao, Y Mercer, BM Miodovnik, M Goldenberg, RL Iams, JD VanDorsten, JP AF Joy, Saju D. Zhao, Yuan Mercer, Brian M. Miodovnik, Menachem Goldenberg, Robert L. Iams, Jay D. VanDorsten, J. Peter TI Latency and infectious complications after preterm premature rupture of membranes: impact of body mass index SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 28-FEB 02, 2008 CL Dallas, TX SP Soc Maternal Fetal Med DE BMI; body mass index; obesity; premature rupture of membranes; PROM ID MATERNAL OBESITY; BIRTH; PREGNANCY; ASSOCIATION; MORBIDITY AB OBJECTIVE: Obesity has been associated with chronic inflammation. We hypothesized that body mass index may be inversely related to latency and directly related to infectious complications after preterm premature rupture of membranes. STUDY DESIGN: This secondary analysis of a randomized trial of antibiotics for preterm premature rupture of membranes had information available for 562 subjects. We analyzed the association between body mass index and latency, the occurrence of chorioamnionitis, endometritis, and maternal infectious morbidity after controlling for gestational age at rupture and treatment group. Survival analysis, regression, and test of proportions were used as appropriate. RESULTS: When evaluated as a categorical or continuous variable, body mass index did not reveal any significant associations. Latency to delivery was affected by gestational age at rupture of membrane and antibiotic therapy but not by body mass index group. CONCLUSION: Body mass index was not associated with latency or the occurrence of maternal infectious complications during conservative management of premature rupture of membranes before 32 weeks' gestation. C1 [Joy, Saju D.; Zhao, Yuan; Mercer, Brian M.; Miodovnik, Menachem; Goldenberg, Robert L.; Iams, Jay D.; VanDorsten, J. Peter] Eunice Kennedy Shriver Natl Inst, Child Hlth & Human Dev Maternal Fetal Med Units N, Bethesda, MD USA. RP Joy, SD (reprint author), Eunice Kennedy Shriver Natl Inst, Child Hlth & Human Dev Maternal Fetal Med Units N, Bethesda, MD USA. FU NICHD NIH HHS [U10 HD021410, HD21410, HD21414, HD21434, HD27860, HD27861, HD27869, HD27889, HD27915, HD27917, HD36801, U01 HD036801, U10 HD027860, U10 HD027869, U10 HD027883, U10 HD027905, U10 HD027915, U10 HD027917, U10 HD036801, U10 HD040544, U10 HD040544-09, UG1 HD027869, UG1 HD027915] NR 13 TC 0 Z9 0 U1 2 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD DEC PY 2009 VL 201 IS 6 AR 600.e1 DI 10.1016/j.ajog.2009.06.030 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 527AH UT WOS:000272337600027 PM 19761998 ER PT J AU Oh, HS Korn, EL Zhang, XY Liu, Y Xu, TM Boyd, R Baumrind, S AF Oh, Hee Soo Korn, Edward L. Zhang, Xiaoyun Liu, Yan Xu, Tianmin Boyd, Robert Baumrind, Sheldon TI Correlations between cephalometric and photographic measurements of facial attractiveness in Chinese and US patients after orthodontic treatment SO AMERICAN JOURNAL OF ORTHODONTICS AND DENTOFACIAL ORTHOPEDICS LA English DT Article ID PROFILE PREFERENCES; FACES; SMILE; AESTHETICS; AVERAGE; PROPORTION; DIAGNOSIS; DEFORMITY; AGE AB Introduction: Orthodontists rely on esthetic judgments from facial photographs. Concordance between estimates of facial attractiveness made from lateral cephalograms and those made from clinical photographs has not been determined. We conducted a preliminary examination to correlate clinicians' rankings of facial attractiveness from standardized end-of-treatment facial photographs (Photo Attractiveness Rank) with cephalometric measurements of facial attractiveness made for the same subjects at the same time. Methods: Forty-five Chinese and US orthodontic clinicians ranked end-of-treatment photographs of separate samples of 45 US and 48 Chinese adolescent patients for facial attractiveness. Separately for each sample, the photographic rankings were correlated with the values of 21 conventional hard- and soft-tissue measures from lateral cephalograms taken at the same visits as the photographs. Results: Among US patients, higher rank for facial attractiveness on the photographs was strongly associated with higher values for profile angle, chin prominence, lower lip prominence, and Z-angle, and also with lower values for angle of convexity, H-angle, and ANB. Among Chinese patients, higher rank for facial attractiveness on the photographs was strongly associated with higher values for Z-angle and chin prominence, and also with lower values for angle of convexity, H-angle, B-line to upper lip, and mandibular plane angle. Chinese patients whose % lower face height values approximated the ethnic "ideal'' (54%) tended to rank higher for facial attractiveness than patients with either higher or lower values for % lower face height. The absolute values of the correlations for the 7 US measures noted above ranged from 0.41 to 0.59; those of the 7 Chinese measures ranged from 0.39 to 0.49. The P value of the least statistically significant of these 14 correlations was 0.006, unadjusted for multiple comparisons. On the other hand, many cephalometric measures believed by clinicians to be indicators of facial attractiveness failed to correlate with facial attractiveness rank for either ethnicity at even the P<0.05 level, including SN-pogonion angle, lower incisor to mandibular plane angle, and Wits appraisal. Conclusions: In general, there was less association than expected or desired between objective measurements on the lateral cephalograms and clinicians' rankings of facial attractiveness on sets of clinical photographs. (Am J Orthod Dentofacial Orthop 2009;136:762.e1-762.e14) C1 [Oh, Hee Soo; Boyd, Robert; Baumrind, Sheldon] Univ Pacific, Arthur A Dugoni Sch Dent, Dept Orthodont, San Francisco, CA USA. [Korn, Edward L.] NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. [Zhang, Xiaoyun; Liu, Yan; Xu, Tianmin] Peking Univ, Sch Stomatol, Dept Orthodont, Beijing 100871, Peoples R China. [Zhang, Xiaoyun; Liu, Yan; Xu, Tianmin] Peking Univ, Hosp Stomatol, Dept Orthodont, Beijing 100871, Peoples R China. Peking Univ, Hosp Stomatol, Dept Orthodont, Beijing 100871, Peoples R China. [Baumrind, Sheldon] Univ Pacific, Arthur A Dugoni Sch Dent, Craniofacial Res Instrumentat Lab, San Francisco, CA USA. RP Baumrind, S (reprint author), 1525 Walnut St, Berkeley, CA 94709 USA. EM sbaumrind@pacific.edu FU American Association of Orthodontists Foundation; NIH-NIDR [DE07332, DE08713] FX Supported by a grant of Orthodontic Faculty Development Fellowship Award from the American Association of Orthodontists Foundation and in part by NIH-NIDR Grants DE07332 and DE08713. NR 61 TC 2 Z9 4 U1 0 U2 9 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0889-5406 J9 AM J ORTHOD DENTOFAC JI Am. J. Orthod. Dentofac. Orthop. PD DEC PY 2009 VL 136 IS 6 AR 762.e1 DI 10.1016/j.ajodo.2009.04.020 PG 14 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 528FJ UT WOS:000272427200010 PM 19962590 ER PT J AU Mukherjee, S Richardson, AM Rodriguez-Canales, J Ylaya, K Erickson, HS Player, A Kawasaki, ES Pinto, PA Choyke, PL Merino, MJ Albert, PS Chuaqui, RF Emmert-Buck, MR AF Mukherjee, Sumana Richardson, Annely M. Rodriguez-Canales, Jaime Ylaya, Kris Erickson, Heidi S. Player, Audrey Kawasaki, Ernest S. Pinto, Peter A. Choyke, Peter L. Merino, Maria J. Albert, Paul S. Chuaqui, Rodrigo F. Emmert-Buck, Michael R. TI Identification of EpCAM as a Molecular Target of Prostate Cancer Stroma SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID TUMOR-STROMA; EPITHELIAL INTERACTIONS; JUVENILE POLYPOSIS; EP-CAM; EXPRESSION; CARCINOMA; MICROENVIRONMENT; THERAPY; CELLS; CARCINOGENESIS AB To delineate the molecular changes that occur in the tumor microenvironment, we previously performed global transcript analysis of human prostate cancer specimens using tissue microdissection and expression microarrays. Epithelial and stromal compartments; were individually studied in both tumor and normal fields. Tumor-associated stroma showed a distinctly different expression pattern compared with normal stroma, having 44 differentially expressed transcripts, the majority of which were up-regulated. In the present study, one of the up-regulated transcripts, epithelial cell adhesion activating molecule, was further evaluated at the protein level in 20 prostate cancer cases using immunohistochemistry and a histomathematical analysis strategy. The epithelial cell adhesion activating molecule showed a 76-fold expression increase in the tumor-associated stroma, as compared with matched normal stroma. Moreover, Gleason 4 or 5 tumor stroma was increased 170-fold relative to matched normal stroma, whereas the Gleason 3 tumor area showed only a 36-fold increase, indicating a positive correlation with Gleason tumor grade. Since the stromal compartment may be particularly accessible to vascular-defivered agents, epithelial cell adhesion activating molecule could become a valuable molecular target for imaging or treatment of prostate cancer. (Am J Patbol 2009, 175.-2277-2287; DOI: 10.2353/ajpath.2009.090013) C1 [Emmert-Buck, Michael R.] NCI, Pathogenet Unit, Adv Technol Ctr, Pathol Lab,NIH, Bethesda, MD 20892 USA. [Ylaya, Kris] NCI, Urol Oncol Branch, TARP Lab, NIH, Bethesda, MD 20892 USA. [Player, Audrey; Kawasaki, Ernest S.] NCI, Microarray Facil, NIH, Bethesda, MD 20892 USA. [Pinto, Peter A.] NCI, Methylat Lab, Ctr Canc Res, Urol Oncol Branch,NIH, Bethesda, MD 20892 USA. [Choyke, Peter L.] NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. [Albert, Paul S.] NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Emmert-Buck, MR (reprint author), NCI, Pathogenet Unit, Adv Technol Ctr, Pathol Lab,NIH, 8717 Grovemt Circle, Bethesda, MD 20892 USA. EM buckm@mail.nih.gov OI Rodriguez-Canales, Jaime/0000-0002-0885-2377 FU Intramural NIH HHS NR 50 TC 19 Z9 19 U1 0 U2 2 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2009 VL 175 IS 6 BP 2277 EP 2287 DI 10.2353/ajpath.2009.090013 PG 11 WC Pathology SC Pathology GA 530NW UT WOS:000272600600005 PM 19850885 ER PT J AU Wangsa, D Heselmeyer-Haddad, K Ried, P Eriksson, E Schaffer, AA Morrison, LE Luo, JH Auer, G Munck-Wikland, E Ried, T Lundqvist, EA AF Wangsa, Darawalee Heselmeyer-Haddad, Kerstin Ried, Patricia Eriksson, Elina Schaeffer, Alejandro A. Morrison, Larry E. Luo, Juhua Auer, Gert Munck-Wikland, Eva Ried, Thomas Lundqvist, Elisabeth Avall TI Fluorescence in Situ Hybridization Markers for Prediction of Cervical Lymph Node Metastases SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID SQUAMOUS-CELL CARCINOMA; COMPARATIVE GENOMIC HYBRIDIZATION; TELOMERASE GENE TERC; CHROMOSOMAL-ABERRATIONS; RECURRENT PATTERN; UTERINE CERVIX; CANCER; EXPRESSION; SYSTEM; GAIN AB The presence of lymph node metastases is associated with poor prognosis in early stage cervical cancer. As of yet, no molecular markers predicting lymph node metastases have been identified. We examined single genetic markers and a composite marker, comprised of three fluorescence in situ hybridization (FISH) probes targeting the genes LAMP3, PROX1, and PRKAA1, in pretreatment cervical biopsies from 16 lymph node positive cases and 15 lymph node negative controls from women with stage IB and IIA cervical cancer. in addition, we determined clonal patterns by including CCND1 to compare the clonal constitution of primary tumors and associated lymph node metastases. The composite FISH marker allowed for classification of patients into those with and without lymph node metastases with a sensitivity and specificity of 75% and 87%, respectively (P = 0.001). The positive predictive value and negative predictive value were 86% and 76%, respectively. Clonal patterns varied among the tumors. In many cases, changes between the primary tumor and lymph node metastases in the most common clones may indicate that certain clones have a growth advantage for establishing metastases in lymph nodes. We conclude that the composite FISH marker may be useful for determining risk for subsequent development of lymph node metastases in patients with cervical cancer. (Am J Pathol 2009, 175:2637-2645; DOI: 10.2353/ajpath.2009.090289) C1 [Wangsa, Darawalee; Heselmeyer-Haddad, Kerstin; Ried, Thomas] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Wangsa, Darawalee; Ried, Patricia; Eriksson, Elina; Auer, Gert] Karolinska Inst, Dept Oncol Pathol, Karolinska Univ Hosp, Stockholm, Sweden. [Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. [Morrison, Larry E.] Abbott Mol Inc, Des Plaines, IL USA. [Luo, Juhua] Beijing Normal Univ, Sch Social Dev & Publ Policy, Beijing 100875, Peoples R China. [Munck-Wikland, Eva] Karolinska Univ Hosp, Radiumhemmet, Dept Otorhinolaryngol Head & Neck Surg, Stockholm, Sweden. [Lundqvist, Elisabeth Avall] Karolinska Univ Hosp, Radiumhemmet, Dept Gynaecol Oncol, Stockholm, Sweden. RP Ried, T (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, 50 S Dr,Room 1306, Bethesda, MD 20892 USA. EM riedt@mail.nih.gov RI Schaffer, Alejandro/F-2902-2012 FU Swedish Cancer Society (Cancerfonden); Cancer Society of Stockholm (Cancerforeningen); Karolinska Institutet; National Institutes of Health; National Cancer Institute; National Library of Medicine FX Supported by the Swedish Cancer Society (Cancerfonden), the Cancer Society of Stockholm (Cancerforeningen), Karolinska Institutet, the Intramural Research Program of the National Institutes of Health, National Cancer Institute, and the National Library of Medicine. NR 40 TC 17 Z9 18 U1 0 U2 3 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD DEC PY 2009 VL 175 IS 6 BP 2637 EP 2645 DI 10.2353/ajpath.2009.090289 PG 9 WC Pathology SC Pathology GA 530NW UT WOS:000272600600038 PM 19893027 ER PT J AU Shoemaker, LL Lenker, JA Fuhrer, MJ Jutai, JW Demers, L DeRuyter, F AF Shoemaker, Laura L. Lenker, James A. Fuhrer, Marcus J. Jutai, Jeffrey W. Demers, Louise DeRuyter, Frank TI Mobility-Related Assistive Technology Device Classifications Implications for Outcomes Research SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE Classification; Wheelchairs; Dependent Ambulation; Assistive Technology ID ELECTRIC-POWERED WHEELCHAIRS; SPINAL-CORD-INJURY; MEDICAL REHABILITATION; ANSI/RESNA STANDARDS; MANUAL WHEELCHAIRS; TREATMENT FIDELITY; CLINICAL-TRIALS; BLACK-BOX; TAXONOMY; STROKE AB This article evaluates six mobility-related device classifications for their ability to support assistive technology outcomes research. Our evaluation considered classifications that had been created for various purposes, including those created to support third-party reimbursement decisions, consumer education and safety, and research. Classifications were excluded if their scope was limited to a single mobility device domain. The six classifications were analyzed according to a common framework: (1) purpose, (2) completeness, (3) granularity, and (4) research applications. Although each classification addresses three principal mobility device domains (ambulation aids, manual wheelchairs, and powered mobility devices), the analysis revealed a range of detail with which each domain is described. Some classifications were hampered by their use of unclear idiosyncratic terminology, whereas others conflated multiple device features within device categories. The analysis suggests that existing classifications do not fully meet the needs of assistive technology outcomes researchers. Creation of a common taxonomy of mobility devices is needed to serve the needs of the assistive technology outcomes research field. C1 [Shoemaker, Laura L.; Lenker, James A.] SUNY Buffalo, Dept Rehabil Sci, Sch Publ Hlth & Hlth Profess, Buffalo, NY 14214 USA. [Fuhrer, Marcus J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD USA. [Jutai, Jeffrey W.] Univ Ottawa, Fac Hlth Sci, Bachelors Program Hlth Sci, Ottawa, ON, Canada. [Demers, Louise] Montreal Geriatr Univ Inst, Res Ctr, Montreal, PQ, Canada. [Demers, Louise] Univ Montreal, Fac Med, Sch Rehabil, Montreal, PQ H3C 3J7, Canada. [DeRuyter, Frank] Duke Univ, Med Ctr, Div Speech Pathol & Audiol, Durham, NC USA. RP Lenker, JA (reprint author), SUNY Buffalo, Dept Rehabil Sci, Sch Publ Hlth & Hlth Profess, 515 Kimball Tower,3435 Main St, Buffalo, NY 14214 USA. OI Jutai, Jeffrey/0000-0002-7294-1323 FU National Institute on Disability and Rehabilitation Research (NIDRR) [H133AO60062] FX This work has been supported in part by the National Institute on Disability and Rehabilitation Research (NIDRR) under Grant H133AO60062. The authors received no financial benefit from this activity. A portion of this material was presented at the 2008 ACRM-ASNR Joint Conference, October 15-19, 2008, Toronto, ON. NR 79 TC 2 Z9 2 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD DEC PY 2009 VL 88 IS 12 BP 1020 EP 1032 DI 10.1097/PHM.0b013e3181bc0d55 PG 13 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 527XV UT WOS:000272405400009 PM 19789430 ER PT J AU Baum, BJ AF Baum, Bruce J. TI In vivo veritas: the power of in situ manipulation of cells in a living animal. Focus on "Expression of plasmid DNA in the salivary gland epithelium: novel approaches to study dynamic cellular processes in live animals" SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article ID MICROSCOPY; SECRETION; PATHWAYS; HORMONE C1 NIDCR, MPTB, NIH, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), NIDCR, MPTB, NIH, Bldg 10,Rm 1N113,MSC 1190,10 Ctr Dr, Bethesda, MD 20892 USA. EM bbaum@dir.nidcr.nih.gov FU Intramural NIH HHS NR 17 TC 1 Z9 1 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD DEC PY 2009 VL 297 IS 6 BP C1333 EP C1335 DI 10.1152/ajpcell.00437.2009 PG 3 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 524PV UT WOS:000272156100002 PM 19812369 ER PT J AU Li, R Maminishkis, A Banzon, T Wan, Q Jalickee, S Chen, S Miller, SS AF Li, Rong Maminishkis, Arvydas Banzon, Tina Wan, Qin Jalickee, Stephen Chen, Shan Miller, Sheldon S. TI IFN gamma regulates retinal pigment epithelial fluid transport SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE interferon; inflammation; CFTR; JAK-STAT; cAMP; cGMP; proliferation ID CFTR GENE-EXPRESSION; TRANSMEMBRANE CONDUCTANCE REGULATOR; PROTEIN-KINASE PATHWAY; INTERFERON-GAMMA; MACULAR DEGENERATION; CYSTIC-FIBROSIS; NITRIC-OXIDE; ION-TRANSPORT; (R)-ALPHA-LIPOIC ACID; TRANSCRIPTION FACTORS AB Li R, Maminishkis A, Banzon T, Wan Q, Jalickee S, Chen S, Miller SS. IFN gamma regulates retinal pigment epithelial fluid transport. Am J Physiol Cell Physiol 297: C1452-C1465, 2009. First published September 30, 2009; doi:10.1152/ajpcell.00255.2009.-The present experiments show that IFN gamma receptors are mainly localized to the basolateral membrane of human retinal pigment epithelium (RPE). Activation of these receptors in primary cultures of human fetal RPE inhibited cell proliferation and migration, decreased RPE mitochondrial membrane potential, altered transepithelial potential and resistance, and significantly increased transepithelial fluid absorption. These effects are mediated through JAK-STAT and p38 MAPK signaling pathways. Second messenger signaling through cAMP-PKA pathway- and interferon regulatory factor-1-dependent production of nitric oxide/cGMP stimulated the CFTR at the basolateral membrane and increased transepithelial fluid absorption. In vivo experiments using a rat model of retinal reattachment showed that IFN gamma applied to the anterior surface of the eye can remove extra fluid deposited in the extracellular or subretinal space between the retinal photoreceptors and RPE. Removal of this extra fluid was blocked by a combination of PKA and JAK-STAT pathway inhibitors injected into the subretinal space. These results demonstrate a protective role for IFN gamma in regulating retinal hydration across the outer blood-retinal barrier in inflammatory disease processes and provide the basis for possible therapeutic interventions. C1 [Li, Rong; Maminishkis, Arvydas; Banzon, Tina; Wan, Qin; Jalickee, Stephen; Chen, Shan; Miller, Sheldon S.] NIH, Bethesda, MD 20892 USA. RP Miller, SS (reprint author), NIH, 31 Ctr Dr,Rm 31-6A22,MSC 2510, Bethesda, MD 20892 USA. EM Millers@nei.nih.gov FU National Institutes of Health Intramural Research Program FX This work was supported by the National Institutes of Health Intramural Research Program. NR 76 TC 17 Z9 17 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD DEC PY 2009 VL 297 IS 6 BP C1452 EP C1465 DI 10.1152/ajpcell.00255.2009 PG 14 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 524PV UT WOS:000272156100015 PM 19794146 ER PT J AU Sramkova, M Masedunskas, A Parente, L Molinolo, A Weigert, R AF Sramkova, Monika Masedunskas, Andrius Parente, Laura Molinolo, Alfredo Weigert, Roberto TI Expression of plasmid DNA in the salivary gland epithelium: novel approaches to study dynamic cellular processes in live animals SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE intravital two-photon microscopy; compensatory endocytosis; membrane traffic ID MEDIATED GENE-TRANSFER; INTRAVITAL 2-PHOTON MICROSCOPY; PAROTID ACINAR-CELLS; IN-VIVO; COMPENSATORY ENDOCYTOSIS; TRANSGENE EXPRESSION; FLUORESCENT PROTEIN; ELECTRON-MICROSCOPY; SECRETORY GRANULES; GROWTH-HORMONE AB Sramkova M, Masedunskas A, Parente L, Molinolo A, Weigert R. Expression of plasmid DNA in the salivary gland epithelium: novel approaches to study dynamic cellular processes in live animals. Am J Physiol Cell Physiol 297: C1347-C1357, 2009. First published September 30, 2009; doi:10.1152/ajpcell.00262.2009.-The ability to dynamically image cellular and subcellular structures in a live animal and to target genes to a specific cell population in a living tissue provides a unique tool to address many biological questions in the proper physiological context. Here, we describe a powerful approach that is based on the use of rat submandibular salivary glands, which offer the possibility to easily perform intravital imaging and deliver molecules from the oral cavity, and plasmid DNA, which offers the advantage of rapid manipulations. We show that, under different experimental conditions, a reporter molecule can be rapidly expressed in specific compartments of the glands: 1) in the intercalated ducts, when plasmid DNA is administered alone, and 2) in granular ducts, striated ducts, and, to a lesser extent, acini, when plasmid DNA is mixed with replication-deficient adenovirus subtype 5 particles. Remarkably, we also found that gene expression can be directed to acinar cells when plasmid DNA is administered during isoproterenol-stimulated exocytosis, suggesting a novel mechanism of plasmid internalization regulated by compensatory endocytosis. Finally, as a practical application of these strategies, we show how the expression of fluorescently tagged molecules enables the study of the dynamics of various organelles in live animals at a resolution comparable to that achieved in cell cultures. C1 [Weigert, Roberto] Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, OPCB, NIH, Bethesda, MD 20892 USA. RP Weigert, R (reprint author), Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, OPCB, NIH, 30 Convent Dr,Rm 303A, Bethesda, MD 20892 USA. EM weigertr@mail.nih.gov OI Masedunskas, Andrius/0000-0002-4533-5467 FU National Institute of Dental and Craniofacial Research Intramural Research Program FX This research was supported by the National Institute of Dental and Craniofacial Research Intramural Research Program. NR 44 TC 16 Z9 16 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD DEC PY 2009 VL 297 IS 6 BP C1347 EP C1357 DI 10.1152/ajpcell.00262.2009 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 524PV UT WOS:000272156100005 PM 19794147 ER PT J AU Kilimnik, G Kim, A Jo, J Miller, K Hara, M AF Kilimnik, German Kim, Abraham Jo, Junghyo Miller, Kevin Hara, Manami TI Quantification of pancreatic islet distribution in situ in mice SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE pancreatic beta-cells; islets; beta-cell area; insulinoma; diabetes ID BETA-CELL MASS; DIABETES-MELLITUS; TRANSGENIC MICE; PREGNANCY; ONSET; PROLIFERATION AB Kilimnik G, Kim A, Jo J, Miller K, Hara M. Quantification of pancreatic islet distribution in situ in mice. Am J Physiol Endocrinol Metab 297: E1331-E1338, 2009. First published October 6, 2009; doi:10.1152/ajpendo.00479.2009.-Tracing changes of specific cell populations in health and disease is an important goal of biomedical research. Precisely monitoring pancreatic beta-cell proliferation and islet growth is a challenging area of research. We have developed a method to capture the distribution of beta-cells in the intact pancreas of transgenic mice with fluorescence-tagged beta-cells with a macro written for ImageJ (rsb.info.nih.gov/ij/). Total beta-cell area and islet number and size distribution are quantified with reference to specific parameters and location for each islet and for small clusters of beta-cells. The entire distribution of islets can now be plotted in three dimensions, and the information from the distribution on the size and shape of each islet allows a quantitative and a qualitative comparison of changes in overall beta-cell area at a glance. C1 [Kilimnik, German; Kim, Abraham; Miller, Kevin; Hara, Manami] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Jo, Junghyo] NIDDKD, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Hara, M (reprint author), Univ Chicago, Dept Med, 5841 S Maryland Ave,MC1027, Chicago, IL 60637 USA. EM mhara@midway.uchicago.edu FU US Public Health Service [DK-081527, DK-072473, DK-20595] FX This study is supported by US Public Health Service Grants DK-081527, DK-072473, and DK-20595 to the University of Chicago Diabetes Research and Training Center (Animal Models Core) and by a gift from the Kovler Family Foundation. NR 17 TC 17 Z9 17 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD DEC PY 2009 VL 297 IS 6 BP E1331 EP E1338 DI 10.1152/ajpendo.00479.2009 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 523BX UT WOS:000272047400013 PM 19808908 ER PT J AU Baragatti, B Schwartzman, ML Angeloni, D Scebba, F Ciofini, E Sodini, D Ottaviano, V Nencioni, S Paolicchi, A Graves, JP Zeldin, DC Gotlinger, K Luin, S Coceani, F AF Baragatti, Barbara Schwartzman, Michal Laniado Angeloni, Debora Scebba, Francesca Ciofini, Enrica Sodini, Daria Ottaviano, Virginia Nencioni, Simona Paolicchi, Aldo Graves, Joan P. Zeldin, Darryl C. Gotlinger, Katherine Luin, Stefano Coceani, Flavio TI EDHF function in the ductus arteriosus: evidence against involvement of epoxyeicosatrienoic acids and 12S-hydroxyeicosatetraenoic acid SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE bradykinin; arachidonic acid epoxygenase; arachidonic acid monooxygenase; fetal and neonatal physiology ID NITRIC-OXIDE SYNTHASE; MOLECULAR-CLONING; HYDROGEN-SULFIDE; VITAMIN-A; MOUSE; RAT; CYTOCHROME-P450; INHIBITORS; 12R-LIPOXYGENASE; 12-LIPOXYGENASE AB Baragatti B, Schwartzman ML, Angeloni D, Scebba F, Ciofini E, Sodini D, Ottaviano V, Nencioni S, Paolicchi A, Graves JP, Zeldin DC, Gotlinger K, Luin S, Coceani F. EDHF function in the ductus arteriosus: evidence against involvement of epoxyeicosatrienoic acids and 12S-hydroxyeicosatetraenoic acid. Am J Physiol Heart Circ Physiol 297: H2161-H2168, 2009. First published October 2, 2009; doi: 10.1152/ajpheart.00576.2009.-We have previously shown (Ref. 2) that endothelium-derived hyperpolarizing factor (EDHF) becomes functional in the fetal ductus arteriosus on removal of nitric oxide and carbon monoxide. From this, it was proposed that EDHF originates from a cytochrome P-450 (CYP450)-catalyzed reaction being inhibited by the two agents. Here, we have examined in the mouse ductus whether EDHF can be identified as an arachidonic acid product of a CYP450 epoxygenase and allied pathways. We did not detect transcripts of the mouse CYP2C subfamily in vessel, while CYP2J subfamily transcripts were expressed with CYP2J6 and CYP2J9. These CYP2J hemoproteins were also detected in the ductus by immunofluorescence microscopy, being colocalized with the endoplasmic reticulum in both endothelial and muscle cells. Distinct CYP450 transcripts were also detected and were responsible for omega-hydroxylation (CYP4A31) and 12R-hydroxylation (CYP4B1). Mass spectrometric analysis showed formation of epoxyeicosatrienoic acids (EETs) in the intact ductus, with 11,12- and 14,15-EETs being more prominent than 5,6- and 8,9-EETs. However, their yield did not increase with nitric oxide/carbon monoxide suppression, nor did it abate with endothelium removal. No evidence was obtained for formation of 12R-hydroxyeicosatrienoic acid and omega-hydroxylation products. 2S-hydroxyeicosatetraenoic acid was instead detected, and, contrary to data implicating this compound as an alternative EDHF, its suppression with baicalein did not modify the EDHF-mediated relaxation to bradykinin. We conclude that none of the more common CYP450-linked arachidonic acid metabolites appears to qualify as EDHF in mouse ductus. We speculate that some novel eicosanoid or a totally unrelated compound requiring CYP450 for its synthesis accounts for EDHF in this vessel. C1 [Baragatti, Barbara; Angeloni, Debora; Scebba, Francesca; Ciofini, Enrica; Sodini, Daria; Nencioni, Simona; Coceani, Flavio] Scuola Super Sant Anna, I-56127 Pisa, Italy. [Baragatti, Barbara; Angeloni, Debora; Coceani, Flavio] CNR, Inst Clin Physiol, I-56100 Pisa, Italy. [Schwartzman, Michal Laniado; Gotlinger, Katherine] New York Med Coll, Dept Pharmacol, Valhalla, NY 10595 USA. [Ottaviano, Virginia; Paolicchi, Aldo] Univ Pisa, Dept Expt Pathol, Pisa, Italy. [Graves, Joan P.; Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Luin, Stefano] Scuola Normale Super Pisa, Natl Enterprise NanoSci & NanoTechnol, CNR, Ist Nazl Fis Mat, Pisa, Italy. RP Coceani, F (reprint author), Scuola Super Sant Anna, Piazza Martiri Liberta 33, I-56127 Pisa, Italy. EM coceani@sssup.it RI Luin, Stefano/B-5532-2012 OI Luin, Stefano/0000-0003-2673-366X FU Italian Ministry of Education and Research [PRIN 2007E7Y7R]; National Institutes of Health (NIH) [HL34300]; NIH, National Institute of Environmental Health Sciences [Z01 ES025034]; Scuola Superiore Sant' Anna FX This work was supported by grants of the Italian Ministry of Education and Research (PRIN 2007E7Y7R to F. Coceani) and the National Institutes of Health (NIH) (Grant HL34300 to M. L. Schwartzman). Portions of this work were also supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES025034). S. Nencioni and D. Sodini are recipient of, respectively, a graduate studentship and a postdoctoral fellowship from the Scuola Superiore Sant' Anna. NR 36 TC 6 Z9 6 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD DEC PY 2009 VL 297 IS 6 BP H2161 EP H2168 DI 10.1152/ajpheart.00576.2009 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 523LQ UT WOS:000272075300025 PM 19801493 ER PT J AU Lutken, SC Kim, SW Jonassen, T Marples, D Knepper, MA Kwon, TH Frokiaer, J Nielsen, S AF Lutken, Sophie C. Kim, Soo Wan Jonassen, Thomas Marples, David Knepper, Mark A. Kwon, Tae-Hwan Frokiaer, Jorgen Nielsen, Soren TI Changes of renal AQP2, ENaC, and NHE3 in experimentally induced heart failure: response to angiotensin II AT(1) receptor blockade SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE collecting duct; aquaporin; type 3 Na+/H+ exchanger; Na+-K+-2Cl(-) cotransporter; epithelial sodium channel ID THICK ASCENDING LIMB; IMMUNOELECTRON MICROSCOPIC LOCALIZATION; PROXIMAL CONVOLUTED TUBULE; AQUAPORIN-2 WATER CHANNEL; KIDNEY COLLECTING DUCT; RAT-KIDNEY; 11-BETA-HYDROXYSTEROID DEHYDROGENASE; DECREASED EXPRESSION; APICAL MEMBRANE; SODIUM TRANSPORTERS AB Lutken SC, Kim SW, Jonassen T, Marples D, Knepper MA, Kwon TH, Frokiaer, Nielsen S. Changes of renal AQP2, ENaC, and NHE3 in experimentally induced heart failure: response to angiotensin II AT(1) receptor blockade. Am J Physiol Renal Physiol 297: F1678-F1688, 2009. First published September 23, 2009; doi: 10.1152/ajprenal.00010.2009.-Heart failure (HF) was induced by ligation of the left anterior descending artery (LAD). Left ventricular end-diastolic pressure (LVEDP) >25 mmHg (at day 23 after LAD ligation) was the inclusion criterion. The rats were divided into three groups: sham-operated (Sham, n = 23, LVEDP: 5.6 +/- 0.6 mmHg), HF (n = 14, LVEDP: 29.4 +/- 1.4 mmHg), and candesartan (1 mg.kg(-1).day(-1) sc)-treated HF (HF + Can, n = 9, LVEDP: 29.2 +/- 1.2 mmHg). After 7 days (i.e., 29 days after LAD ligation) semiquantitative immunoblotting revealed increased abundance of inner medulla aquaporin-2 (AQP2) and AQP2 phosphorylated at Ser(256) (p-AQP2) in HF. There was also markedly enhanced apical targeting of AQP2 and p-AQP2 in inner medullary collecting duct (IMCD) in HF compared with Sham rats, shown by immunocytochemistry. Candesartan treatment significantly reversed the increases in both AQP2 and p-AQP2 expression and targeting. In contrast, there were only modest changes in other collecting duct segments. Semi-quantitative immunoblots revealed increased expression of type 3 Na+/H+ exchanger (NHE3) and Na+-K+-2Cl(-) cotransporter (NKCC2) in kidneys from HF compared with Sham rats: both effects were reversed or prevented by candesartan treatment. The protein abundance of alpha-epithelial sodium channel (alpha-ENaC) was increased while beta-ENaC and gamma-ENaC expression was decreased in the cortex and outer stripe of the outer medulla in HF compared with Sham rats, which was partially reversed by candesartan treatment. These findings strongly support an important role of angiotensin II in the pathophysiology of renal water and sodium retention associated with HF. C1 [Lutken, Sophie C.; Kim, Soo Wan; Kwon, Tae-Hwan; Frokiaer, Jorgen; Nielsen, Soren] Univ Aarhus, Water & Salt Res Ctr, Aarhus C, Denmark. [Lutken, Sophie C.; Nielsen, Soren] Univ Aarhus, Inst Anat, Aarhus C, Denmark. [Kim, Soo Wan] Chonnam Natl Univ, Sch Med, Dept Internal Med, Kwangju, South Korea. [Jonassen, Thomas] Univ Copenhagen, Panum Inst, Dept Pharmacol, DK-1168 Copenhagen, Denmark. [Marples, David] Univ Leeds, Inst Membrane & Syst Biol, Leeds, W Yorkshire, England. [Knepper, Mark A.] NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. [Kwon, Tae-Hwan] Kyungpook Natl Univ, Sch Med, Dept Biochem & Cell Biol, Taegu 702701, South Korea. [Frokiaer, Jorgen] Aarhus Univ Hosp, Inst Clin Med, Aarhus N, Denmark. RP Frokiaer, J (reprint author), Univ Aarhus, Inst Clin Med, Water & Salt Res Ctr, DK-8200 Aarhus N, Denmark. EM jf@ki.au.dk OI Frokiaer, Jorgen/0000-0002-6206-8065 FU Karen Elise Jensen Foundation; European Commission [QRLT 2000 00778, QRLT 2000 00987]; National Research Foundation; Ministry of Education, Science and Technology, Korea [R01-2007-000-20441-0] FX The Water and Salt Research Center at the University of Aarhus is established and supported by the Danish National Research Foundation (Danmarks Grundforskningsfond). Support for this study was provided by the Karen Elise Jensen Foundation, Human Frontier Science Program; the European Commission (QRLT 2000 00778 and QRLT 2000 00987); National Research Foundation funded by the Ministry of Education, Science and Technology, Korea (R01-2007-000-20441-0), and the intramural budget of the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 62 TC 18 Z9 18 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 2009 VL 297 IS 6 BP F1678 EP F1688 DI 10.1152/ajprenal.00010.2009 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 539VY UT WOS:000273288100021 PM 19776175 ER PT J AU Wang, XX Jiang, T Shen, Y Adorini, L Pruzanski, M Gonzalez, FJ Scherzer, P Lewis, L Miyazaki-Anzai, S Levi, M AF Wang, Xiaoxin X. Jiang, Tao Shen, Yan Adorini, Luciano Pruzanski, Mark Gonzalez, Frank J. Scherzer, Pnina Lewis, Linda Miyazaki-Anzai, Shinobu Levi, Moshe TI The farnesoid X receptor modulates renal lipid metabolism and diet-induced renal inflammation, fibrosis, and proteinuria SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE nuclear receptor; diet-induced obesity; obesity-related renal disease ID CHRONIC KIDNEY-DISEASE; OBESITY-RELATED GLOMERULOPATHY; ELEMENT-BINDING PROTEINS; GROWTH-FACTOR-BETA; NUCLEAR RECEPTOR; DIABETIC-NEPHROPATHY; BILE-ACIDS; MICE; FXR; GLOMERULOSCLEROSIS AB Wang XX, Jiang T, Shen Y, Adorini L, Pruzanski M, Gonzalez FJ, Scherzer P, Lewis L, Miyazaki-Anzai S, Levi M. The farnesoid X receptor modulates renal lipid metabolism and diet-induced renal inflammation, fibrosis, and proteinuria. Am J Physiol Renal Physiol 297: F1587-F1596, 2009. First published September 23, 2009; doi:10.1152/ajprenal.00404.2009.-Diet-induced obesity is associated with proteinuria and glomerular disease in humans and rodents. We have shown that in mice fed a high-fat diet, increased renal expression of the transcriptional factor sterol-regulatory element binding protein-1 (SREBP-1) plays a critical role in renal lipid accumulation and increases the activity of proinflammatory cytokines and profibrotic growth factors. In the current study, we have determined a key role of the farnesoid X receptor (FXR) in modulating renal SREBP-1 activity, glomerular lesions, and proteinuria. We found that feeding a Western-style diet to DBA/2J mice results in proteinuria, podocyte loss, mesangial expansion, renal lipid accumulation, and increased expression of proinflammatory factors, oxidative stress, and profibrotic growth factors. Treatment of these mice with the highly selective and potent FXR-activating ligand 6-alpha-ethyl-chenodeoxycholic acid (INT-747) ameliorates triglyceride accumulation by modulating fatty acid synthesis and oxidation, improves proteinuria, prevents podocyte loss, mesangial expansion, accumulation of extracellular matrix proteins, and increased expression of profibrotic growth factors and fibrosis markers, and modulates inflammation and oxidative stress. Our results therefore indicate that FXR activation could represent an effective therapy for treatment of abnormal renal lipid metabolism with associated inflammation, oxidative stress, and kidney pathology in patients affected by obesity. C1 [Wang, Xiaoxin X.; Jiang, Tao; Shen, Yan; Lewis, Linda; Miyazaki-Anzai, Shinobu; Levi, Moshe] Univ Colorado Denver, Div Renal Dis & Hypertens, Dept Med, Aurora, CO 80045 USA. [Wang, Xiaoxin X.; Jiang, Tao; Shen, Yan; Lewis, Linda; Miyazaki-Anzai, Shinobu; Levi, Moshe] Vet Affairs Med Ctr, Aurora, CO USA. [Pruzanski, Mark] Intercept Pharmaceut, New York, NY USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Scherzer, Pnina] Hadassah Univ Hosp, Serv Nephrol, IL-91120 Jerusalem, Israel. [Scherzer, Pnina] Hadassah Univ Hosp, Hypertens Serv, IL-91120 Jerusalem, Israel. RP Levi, M (reprint author), Univ Colorado Denver, Div Renal Dis & Hypertens, Dept Med, 12700 E 19th Ave,Res 2,Rm 7002, Aurora, CO 80045 USA. EM Moshe.Levi@ucdenver.edu OI Levi, Moshe/0000-0002-6225-946X FU National Institutes of Health [U01 DK076134, R01 AG026529]; Juvenile Diabetes Research Foundation FX The work was supported by National Institutes of Health Grants U01 DK076134 and R01 AG026529, the Juvenile Diabetes Research Foundation, and a Veterans Affairs Merit Review. NR 55 TC 57 Z9 59 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD DEC PY 2009 VL 297 IS 6 BP F1587 EP F1596 DI 10.1152/ajprenal.00404.2009 PG 10 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 539VY UT WOS:000273288100012 PM 19776172 ER PT J AU Storti, KL Arena, VC Barmada, M Bunker, CH Hanson, RL Laston, SL Yeh, JL Zmuda, JM Howard, BV Kriska, AM AF Storti, Kristi L. Arena, Vincent C. Barmada, Michael Bunker, Clareann H. Hanson, Robert L. Laston, Sandra L. Yeh, Jeun-Liang Zmuda, Joseph M. Howard, Barbara V. Kriska, Andrea M. TI Physical Activity Levels in American-Indian Adults The Strong Heart Family Study SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID BODY-MASS INDEX; CARDIOVASCULAR-DISEASE; ELECTRONIC PEDOMETERS; ACTIVITY PATTERNS; MEASURING STEPS; PUBLIC-HEALTH; ACCURACY; MORTALITY; EXERCISE; DISTANCE AB Background: A limited body of evidence, mostly based on self-report, is available regarding physical activity levels among American-Indian adults. Purpose: This study aims to examine physical activity levels objectively using pedometers among a large cohort of American-Indian adult participants in the Strong Heart Family Study (SHFS). Methods: Physical activity levels in 2604 American-Indian adults, aged 18-91 years, from 13 American-Indian communities were assessed using Accusplit AE120 pedometers over a period of 7 days during 2001-2003. Anthropometric measurements were also assessed. All data analyses were conducted in 2008. Age-adjusted Pearson correlations were used to examine the relationship between average steps per day and age and anthropometric variables. Subjects were placed in age and BMI categories (according to National Heart, Lung, and Blood Institute cut points) to examine trends in physical activity with increasing age and BMI. Results: Daily pedometer steps ranged from 1001 to 38,755. Mean step counts by age group for men were 5384 (aged 18-29 years); 5120 (aged 30-39 years); 5040 (aged 40-49 years); 4561 (aged 50-59 years); 4321 (aged 60-69 years); and 3768 (aged >= 70 years) and for women, 5038 (aged 18-29 years); 5112 (aged 30-39 years); 5054 (aged 40-49 years); 4582 (aged 50-59 years); 3653 (aged 60-69 years); and 3770 (aged >= 70 years). A significant linear trend in physical activity was noted with increasing age (p=0.002 for men, p<0.0001 for women) and with increasing BMI (p=0.05 for men, p=0.04 for women). Conclusions: Objectively measured data suggest that inactivity is a problem among American-Indian adults and that a majority of American-Indian adults in the SHFS may not be meeting the minimum physical activity public health recommendations. Efforts to increase physical activity levels in this population are warranted. (Am J Prev Med 2009;37(6):481-487) (C) 2009 American Journal of Preventive Medicine C1 [Storti, Kristi L.; Bunker, Clareann H.; Zmuda, Joseph M.; Kriska, Andrea M.] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Arena, Vincent C.] Univ Pittsburgh, Dept Biostat, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Barmada, Michael] Univ Pittsburgh, Dept Genet, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Hanson, Robert L.] NIDDK, DECRS, NIH, Phoenix, AZ USA. [Laston, Sandra L.] SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. [Yeh, Jeun-Liang] Univ Oklahoma, Hlth Sci Ctr, Ctr Amer Indian Hlth Res, Oklahoma City, OK USA. [Howard, Barbara V.] MedStar Res Inst, Hyattsville, MD USA. [Howard, Barbara V.] Georgetown Univ, Dept Med, Washington, DC USA. RP Storti, KL (reprint author), Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, 515 Parran Hall GSPH,130 Soto St, Pittsburgh, PA 15261 USA. EM stortik@edc.pitt.edu RI Hanson, Robert/O-3238-2015; OI Hanson, Robert/0000-0002-4252-7068; Arena, Vincent/0000-0002-1634-7207; Kriska, Andrea/0000-0002-3522-0869; Barmada, M Michael/0000-0002-3604-6460 FU National Institute of Diabetes and Digestive and Kidney Diseases [U01 HL41642, U01 H141652, U01 HL4164, MD-000-207-03] FX SHS is conducted as a collaborative agreement supported by Grants U01 HL41642, U01 H141652, U01 HL4164, and MD-000-207-03. In addition, this research was supported in part by the intramural research program of the National Institute of Diabetes and Digestive and Kidney Diseases. NR 44 TC 19 Z9 19 U1 0 U2 3 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 2009 VL 37 IS 6 BP 481 EP 487 DI 10.1016/j.amepre.2009.07.019 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 532SJ UT WOS:000272769700002 PM 19944912 ER PT J AU Koehly, LM Peters, JA Kenen, R Hoskins, LM Ersig, AL Kuhn, NR Loud, JT Greene, MH AF Koehly, Laura M. Peters, June A. Kenen, Regina Hoskins, Lindsey M. Ersig, Anne L. Kuhn, Natalia R. Loud, Jennifer T. Greene, Mark H. TI Characteristics of Health Information Gatherers, Disseminators, and Blockers Within Families at Risk of Hereditary Cancer: Implications for Family Health Communication Interventions SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID GENETIC RELATIONSHIP MAP; COLORECTAL-CANCER; SOCIAL NETWORKS; OVARIAN-CANCER; BREAST-CANCER; LOGIT-MODELS; MEDICINE USE; BRCA1; WOMEN; PREVENTION AB Objectives. Given the importance of the dissemination of accurate family history to assess disease risk, we characterized the gatherers, disseminators, and blockers of health information within families at high genetic risk of cancer. Methods. A total of 5466 personal network members of 183 female participants of the Breast Imaging Study from 124 families with known mutations in the BRCA1/2 genes (associated with high risk of breast, ovarian, and other types of cancer) were identified by using the Colored Eco-Genetic Relationship Map (CEGRM). Hierarchical nonlinear models were fitted to characterize information gatherers, disseminators, and blockers. Results. Gatherers of information were more often female (P<.001), parents (P<.001), and emotional support providers (P<.001). Disseminators were more likely female first- and second- degree relatives (both P<.001), family members in the older or same generation as the participant (P<.001), those with a cancer history (P<.001), and providers of emotional (P<.001) or tangible support (P<.001). Blockers tended to be spouses or partners (P<.001) and male, first-degree relatives (P<.001). Conclusions. Our results provide insight into which family members may, within a family-based intervention, effectively gather family risk information, disseminate information, and encourage discussions regarding shared family risk. (Am J Public Health. 2009;99:2203-2209. doi:10.2105/AJPH.2008.154096) C1 [Koehly, Laura M.; Ersig, Anne L.; Kuhn, Natalia R.] NHGRI, Social & Behav Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Peters, June A.; Hoskins, Lindsey M.; Loud, Jennifer T.; Greene, Mark H.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Kenen, Regina] Coll New Jersey, Dept Sociol & Anthropol, Ewing, NJ USA. [Ersig, Anne L.] Univ Iowa, Coll Nursing, Iowa City, IA 52242 USA. RP Koehly, LM (reprint author), Bldg 31,Room B1B37D,31 Ctr Dr,MSC 2073, Bethesda, MD 20892 USA. EM koehlyl@mail.nih.gov FU Intramural NIH HHS [Z01 HG200335-02, Z99 CA999999]; NCI NIH HHS [N02CP11019, N02CP65504]; NHGRI NIH HHS [Z01 HG200335]; NIEHS NIH HHS [27307C0009] NR 59 TC 56 Z9 56 U1 1 U2 8 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD DEC PY 2009 VL 99 IS 12 BP 2203 EP 2209 DI 10.2105/AJPH.2008.154096 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 529GI UT WOS:000272503700020 PM 19833996 ER PT J AU Rouhani, FN Brantly, ML Markello, TC Helip-Wooley, A O'Brien, K Hess, R Huizing, M Gahl, WA Gochuico, BR AF Rouhani, Farshid N. Brantly, Mark L. Markello, Thomas C. Helip-Wooley, Amanda O'Brien, Kevin Hess, Richard Huizing, Marjan Gahl, William A. Gochuico, Bernadette R. TI Alveolar Macrophage Dysregulation in Hermansky-Pudiak Syndrome Type 1 SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE inflammation; cytokines; chemokines; bronchoalveolar lavage; pirfenidone ID IDIOPATHIC PULMONARY-FIBROSIS; BLEOMYCIN-HAMSTER MODEL; LAMELLAR BODY DEGENERATION; INTERSTITIAL LUNG-DISEASE; PUDLAK-SYNDROME TYPE-4; BETA-3A SUBUNIT; MOUSE MODEL; PIRFENIDONE; GENE; MUTATIONS AB Rationale Individuals with Hermansky-Pudlak syndrome type 1 (HPS-1), an autosomal recessive disorder characterized by defective biogenesis of lysosome-related organelles, develop an accelerated form of progressive fibrotic lung disease. The etiology of pulmonary fibrosis associated with HPS-1 is unknown. Objectives: To investigate the potential pathogenesis of pulmonary fibrosis in HPS-1, lung cells and proteins from individuals with HPS-1 were studied. Methods: Forty-one subjects with HPS-1 with and without pulmonary fibrosis were evaluated with pulmonary function tests, high-resolution computed tomography scan, and bronchoscopy. Bronchoalveolar lavage cells and analytes were analyzed. Measurements and Main Results: Concentrations of total bronchoalveolar lavage cells and alveolar macrophages were significantly higher in epithelial lining fluid from subjects with HIPS-1 with and without pulmonary fibrosis compared with healthy research volunteers. Concentrations of cytokines and chemokines (i.e., monocyte chemoattractant protein-1, macrophage inflammatory protein-1 alpha, and granulocyte-macrophage colony-stimulating factor) in alveolar epithelial lining fluid were significantly higher in subjects with HPS-1 with and without pulmonary fibrosis compared with healthy research volunteers (P < 0.001). In vitro, HIPS-1 pulmonary fibrosis alveolar macrophages, which did not express HPS1 mRNA, secreted significantly higher concentrations of monocyte chemoattractantprotein-1, macrophage inflammatory protein-1 alpha, and regulated upon activation, normal T cell expressed and secreted (RANTES) protein compared with normal cells (P = 0.001, P = 0.014, and P = 0.011, respectively). Pirfenidone suppressed HPS-1 alveolar macrophage cytokine and chemokine secretion in vitro in a dose-dependent manner. Conclusions: In HPS-1, alveolar inflammation predominantly involves macrophages and is associated with high lung concentrations of cytokines and chemokines. HPS-1 alveolar macrophages provide a model system in which to study the pathogenesis and treatment of HPS pulmonary fibrosis. C1 [Rouhani, Farshid N.; Brantly, Mark L.] NHLBI, Pulm Crit Care Med Branch, Bethesda, MD 20892 USA. [Markello, Thomas C.; Helip-Wooley, Amanda; O'Brien, Kevin; Hess, Richard; Huizing, Marjan; Gahl, William A.; Gochuico, Bernadette R.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Gochuico, BR (reprint author), 10 Ctr Dr,MSC 1851, Bethesda, MD 20892 USA. EM gochuicb@mail.nih.gov FU National Human Genome Research Institute; National Heart, Lung, and Blood Institute; National Institute of Child Health and Human Development; National Institutes of Health FX Supported by the Intramural Research Program of the National Human Genome Research Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Child Health and Human Development, National Institutes of Health. NR 51 TC 24 Z9 24 U1 0 U2 0 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD DEC 1 PY 2009 VL 180 IS 11 BP 1114 EP 1121 DI 10.1164/rccm.200901-0023OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 523WA UT WOS:000272104100013 PM 19729668 ER PT J AU Hoshino, T Okamoto, M Sakazaki, Y Kato, S Young, HA Aizawal, H AF Hoshino, Tomoaki Okamoto, Masaki Sakazaki, Yuki Kato, Seiya Young, Howard A. Aizawal, Hisamichi TI Role of Proinflammatory Cytokines IL-18 and IL-1 beta in Bleomycin-Induced Lung Injury in Humans and Mice SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE bleomycin; lung injury; cytokine; mouse model ID INDUCED PULMONARY-FIBROSIS; RECEPTOR-RELATED PROTEIN; CD4(+) T-CELLS; IN-VIVO; INTERSTITIAL PNEUMONIA; POTENTIAL ROLE; UP-REGULATION; CUTTING EDGE; INTERLEUKIN-18; EXPRESSION AB Administration of several chemotherapeutic drugs, such as bleomycin, busulfan, and gefitinib, often induces lethal lung injury. However, the precise mechanisms responsible for this drug-induced lung injury are still unclear. In the present study, we examined the role of the proinflammatory cytokines IL-18 and IL-1 beta in the mechanism of bleomycin-induced lung injury. We performed immunohistochemical analysis of IL-18 and IL-18 receptor (R) alpha chain expression in the lungs of five patients with bleomycin-induced lethal lung injury. Enhanced expression of both IL-18 and IL-118R alpha was observed in the lungs of all five patients with bleomycin-induced lung injury. To support the data obtained from patient samples, the levels of IL-1 beta and IL-18 mRNA and protein, pulmonary inflammation, and lung fibrosis were examined in mouse models of bleomycin-induced lung injury. Intravenous administration of bleomycin induced the expression of IL-1 beta and IL-18 in the serum and lungs of wild-type C57BL/6 mice. IL-18-producing F4/80(+) neutrophils, but not CD3(+) T cells, were greatly increased in the lungs of treated mice. Moreover, bleomycin-induced lung injury was significantly attenuated in caspase-1(-/-), IL-18(-/-), and IL-18R alpha(-/-) mice in comparison with control mice. Thus, our results provide evidence for an important role of IL-1 beta and IL-18 in chemotherapy-induced lung injury. C1 [Hoshino, Tomoaki; Okamoto, Masaki; Sakazaki, Yuki; Aizawal, Hisamichi] Kurume Univ, Sch Med, Dept Med, Div Respirol Neurol & Rheumatol, Kurume, Fukuoka 8300011, Japan. [Kato, Seiya] Univ Ryukyus, Div Pathol & Cell Biol, Grad Sch, Okinawa, Japan. [Kato, Seiya] Univ Ryukyus, Fac Med, Okinawa, Japan. [Hoshino, Tomoaki; Young, Howard A.] NCI, Expt Immunol Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Hoshino, T (reprint author), Kurume Univ, Sch Med, Dept Internal Med, Div Respirol Neurol & Rheumatol, Kurume, Fukuoka 8300011, Japan. EM hoshino@med.kurume-u.ac.jp FU Ministry of Education, Science, Sports, and Culture of Japan [17390244, 18659244]; Kakihara Foundation (Fukuoka, Japan); Takeda Science Foundation (Osaka, Japan) [18390244] FX This work was supported by a Grant-in-Aid for Scientific Research (B) (no. 17390244) and a Grant-in-Aid for Exploratory Research (no. 18659244) from the Ministry of Education, Science, Sports, and Culture of Japan, a grant from the Kakihara Foundation (Fukuoka, Japan), a grant from the Takeda Science Foundation (Osaka, Japan) (T.H.), and a Grant-in-Aid for Scientific Research (B) (no. 18390244) to H.A. NR 42 TC 69 Z9 70 U1 1 U2 8 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD DEC PY 2009 VL 41 IS 6 BP 661 EP 670 DI 10.1165/rcmb.2008-0182OC PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 523YV UT WOS:000272111900004 PM 19265174 ER PT J AU Mollura, DJ Asnis, DS Crupi, RS Conetta, R Feigin, DS Bray, M Taubenberger, JK Bluemke, DA AF Mollura, Daniel J. Asnis, Deborah S. Crupi, Robert S. Conetta, Rick Feigin, David S. Bray, Mike Taubenberger, Jeffery K. Bluemke, David A. TI Imaging Findings in a Fatal Case of Pandemic Swine-Origin Influenza A (H1N1) SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE chest CT; emergency medicine; H1N1; infectious diseases; multifocal ground-glass opacities; swine-origin influenza A ID VIRUS; PNEUMONIA; DISEASE AB OBJECTIVE. Although most cases of swine-origin influenza A (H1N1) virus (S-OIV) have been self-limited, fatal cases raise questions about virulence and radiology's role in early detection. We describe the radiographic and CT findings in a fatal S-OIV infection. CONCLUSION. Radiography showed peripheral lung opacities. CT revealed peripheral ground-glass opacities suggesting peribronchial injury. These imaging findings raised suspicion of S-OIV despite negative H1N1 influenza rapid antigen test results from two nasopharyngeal swabs; subsequently, those results were proven to be false-negatives by reverse transcriptase polymerase chain reaction. This case suggests a role for CT in the early recognition of severe S-OIV. C1 [Feigin, David S.; Bluemke, David A.] Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. [Mollura, Daniel J.; Bluemke, David A.] NIH, Dept Radiol & Imaging Sci, Ctr Clin, Bethesda, MD 20892 USA. [Asnis, Deborah S.] Flushing Hosp & Med Ctr, Med Ctr, Dept Infect Dis, Flushing, NY USA. [Asnis, Deborah S.] Weill Cornell Med Coll, Dept Med, New York, NY USA. [Crupi, Robert S.] Flushing Hosp & Med Ctr, Med Ctr, Dept Emergency Med, Flushing, NY USA. [Conetta, Rick] Flushing Hosp & Med Ctr, Med Ctr, Dept Crit Care Med, Flushing, NY USA. [Bray, Mike] NIAID, Integrated Res Facil, NIH, Bethesda, MD 20892 USA. [Taubenberger, Jeffery K.] NIAID, Viral Pathogenesis & Evolut Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), Johns Hopkins Univ, Russell H Morgan Dept Radiol & Radiol Sci, 600 N Wolfe St, Baltimore, MD 21287 USA. EM David.Bluemke@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU Intramural NIH HHS [ZIA CL090019-01, ZIA EB000072-01, Z99 CL999999] NR 22 TC 48 Z9 63 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2009 VL 193 IS 6 BP 1500 EP 1503 DI 10.2214/AJR.09.3365 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 523AT UT WOS:000272043200007 PM 19933640 ER PT J AU Gharib, AM Pettigrew, RI Elagha, A Hsu, A Welch, P Holland, SM Freeman, AF AF Gharib, Ahmed M. Pettigrew, Roderic I. Elagha, Abdalla Hsu, Amy Welch, Pam Holland, Steven M. Freeman, Alexandra F. TI Coronary Abnormalities in Hyper-IgE Recurrent Infection Syndrome: Depiction at Coronary MDCT Angiography SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE coronary abnormalities; coronary aneurysms; ectatic coronaries; hyper-IgE recurrent infection syndrome (HIES or Job's syndrome); coronary MDCT angiography ID ARTERY ANEURYSMS; MUTATIONS; CT AB OBJECTIVE. Hyper-IgE recurrent infection syndrome (HIES or Job's syndrome) is a rare disorder affecting the immune system and connective tissues. The purpose of this study is to describe the coronary abnormalities in genetically confirmed HIES patients as depicted by coronary MDCT angiography (MDCTA). CONCLUSION. Coronary MDCTA has provided an opportunity for noninvasive evaluation of the coronary arteries in patients with HIES. These coronary abnormalities vary from tortuosity to ectatic dilation and focal aneurysms of the coronary arteries. Such an evaluation has potential value in identifying new aspects of this disease and thereby providing better understanding of the pathophysiology of the disorder. C1 [Gharib, Ahmed M.; Elagha, Abdalla] NIDDKD, Dept Radiol, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. [Pettigrew, Roderic I.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. [Hsu, Amy; Holland, Steven M.; Freeman, Alexandra F.] NIAID, NIH, Bethesda, MD 20892 USA. [Welch, Pam] NCI, SAIC Frederick, Frederick, MD 21701 USA. RP Gharib, AM (reprint author), NIDDKD, Dept Radiol, NIH, Clin Res Ctr, Bldg 10,Rm 3-5340,MSC 1263,10 Ctr Dr, Bethesda, MD 20892 USA. EM agharib@mail.nih.gov RI Gharib, Ahmed/O-2629-2016; OI Gharib, Ahmed/0000-0002-2476-481X; Elagha, Abdalla/0000-0003-3136-2293 FU National Cancer Institute, National Institutes of Health [N01-C0-12400, HHSN26120080000]; National Institute of Allergy and Infectious Diseases; National Institute of Diabetes and Digestive and Kidney Diseases FX This project was funded in part by the National Cancer Institute, National Institutes of Health, under contracts N01-C0-12400 and HHSN26120080000. The project was also supported in part by the National Institute of Allergy and Infectious Diseases and the National Institute of Diabetes and Digestive and Kidney Diseases. NR 14 TC 10 Z9 10 U1 1 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD DEC PY 2009 VL 193 IS 6 BP W478 EP W481 DI 10.2214/AJR.09.2623 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 523AT UT WOS:000272043200042 PM 19933621 ER PT J AU Gualco, G Weiss, LM Harrington, WJ Bacchi, CE AF Gualco, Gabriela Weiss, Lawrence M. Harrington, William J., Jr. Bacchi, Carlos E. TI Nodal Diffuse Large B-cell Lymphomas in Children and Adolescents: Immunohistochemical Expression Patterns and c-MYC Translocation in Relation to Clinical Outcome SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE pediatric non-Hodgkin lymphoma; diffuse large B-cell lymphoma; TCL1; germinal center-like DLBCL (GCB); nongerminal center-like DLBCL; c-MYC and BCL2 ID HIGH PROLIFERATION INDEX; NON-HODGKIN-LYMPHOMA; EPSTEIN-BARR-VIRUS; GERMINAL-CENTER; BURKITT-LYMPHOMA; TCL1; ACTIVATION; PROTEIN; GENE; DIFFERENTIATION AB Diffuse large B-cell lymphoma (DLBCL) is a very infrequent neoplasm in the pediatric age group; therefore there are very few studies on the immunophenotype or genetics of these cases. We Studied a series of 16 patients with nodal DLBCL Occurring in patients between 10 and 18 years of age. The cases were classified according to the 2008 World Health Organization classification criteria, with application of immunohistochemistry for the detection of CD10, BCL-6, and MUM1 proteins to divide the lymphomas into germinal center and nongerminal center types. In addition, TCL1, BCL-2 expression, and the Ki-67 proliferation index were evaluated by immunohistochemistry, and c-MYC and BCL2 translocations were evaluated by fluorescence in situ hybridization. All these parameters were correlated with clinical features and Outcome. Our study revealed that centroblastic morphology and the germinal center type of DLBCL are more prevalent in these young patients (63%), with 37% containing a c-MYC translocation. Only 1 case showed a BCL2 translocation, reflecting a double-hit case with features intermediate between DLBCL and Burkitt lymphoma. We found a higher frequency of BCL-2 expression than previously reported, with no direct influence on the outcome of the disease in univariate or multivariate analysis. The expression of TCL1 has not been specifically studied in nodal pediatric DLBCL before; we found a 31% incidence of TCL1 expression. MUM1 expression was observed in 44% of the cases and these positive cases showed a significant negative impact on clinical Outcome. TCL1 is directly and significantly associated with the presence of c-MYC and a high proliferative index. The germinal center and nongerminal center subtypes showed significant differences for both overall survival and disease-free interval. c-MYC translocation was found in 37% of patients, and had a favorable impact on clinical outcome. We conclude that nodal pediatric and adolescent DLBCL are mainly of the germinal center type, with a generally good Outcome despite the frequent expression of BCL-2 and the presence of c-MYC translocation. TCL1 expression seems to be associated with a good clinical outcome, whereas MUM1 expression predicts a poor clinical outcome. C1 [Gualco, Gabriela; Bacchi, Carlos E.] Consultoria Patol, BR-18602010 Botucatu, SP, Brazil. [Weiss, Lawrence M.] City Hope Natl Med Ctr, Div Pathol, Duarte, CA 91010 USA. [Harrington, William J., Jr.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Harrington, William J., Jr.] Fogarty Int Ctr, Sylvester Canc Ctr, Miami, FL USA. RP Bacchi, CE (reprint author), Consultoria Patol, Rua Major Leonides Cardoso 739, BR-18602010 Botucatu, SP, Brazil. EM bacchi@conspat.com.br FU NIH [R01CA1219-09] FX This study was partially supported by NIH R01CA1219-09 (W.H.). NR 38 TC 18 Z9 25 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD DEC PY 2009 VL 33 IS 12 BP 1815 EP 1822 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 527XG UT WOS:000272403900011 PM 19816150 ER PT J AU Shakleya, DM Huestis, MA AF Shakleya, Diaa M. Huestis, Marilyn A. TI Optimization and validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of nicotine, cotinine, trans-3'-hydroxycotinine and norcotinine in human oral fluid SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE Nicotine; Cotinine; trans-3 '-Hydroxycotinine; Norcotinine; Oral fluid; Tobacco biomarkers; LCMSMS; Saliva ID SOLID-PHASE EXTRACTION; HUMAN URINE; SALIVA; METABOLITES; TRANS-3'-HYDROXYCOTININE; SMOKERS; SERUM; NONSMOKERS; ANABASINE; ALKALOIDS AB An analytical procedure was developed and validated for the simultaneous identification and quantification of nicotine, cotinine, trans-3'-hydroxycotinine, and norcotinine in 0.5 mL of human oral fluid collected with the Quantisal (TM) oral fluid collection device. Solid phase extraction and liquid chromatography-tandem mass spectrometry with multiple reaction monitoring were utilized. Endogenous and exogenous interferences were extensively evaluated. Limits of quantification were empirically identified by decreasing analyte concentrations. Linearity was from 1 to 2,000 ng/mL for nicotine and norcotinine, 0.5 to 2,000 ng/mL for trans-3'-hydroxycotinine, and 0.2 to 2,000 ng/mL for cotinine. Correlation coefficients for calibration curves were > 0.99 and analytes quantified within +/- 13% of target at all calibrator concentrations. Suitable analytical recovery (> 91%) was achieved with extraction efficiencies > 56% and matrix effects < 29%. This assay will be applied to the quantification of nicotine and metabolites in oral fluid in a clinical study determining the most appropriate nicotine biomarker concentrations differentiating active, passive, and environmental nicotine exposure. C1 [Shakleya, Diaa M.; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, Biomed Res Ctr, 251 Bayview Blvd Suite 200,Room 05A-721, Baltimore, MD 21224 USA. EM shakleyad@intra.nida.nih.gov; mhuestis@intra.nida.nih.gov FU National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health. NR 26 TC 23 Z9 23 U1 0 U2 10 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD DEC PY 2009 VL 395 IS 7 BP 2349 EP 2357 DI 10.1007/s00216-009-3157-2 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 522RV UT WOS:000272017000042 PM 19838828 ER PT J AU Delvolve, A Woods, AS AF Delvolve, Alice Woods, Arnina S. TI Ammonium Sulfate and MALDI In-Source Decay: A Winning Combination for Sequencing Peptides SO ANALYTICAL CHEMISTRY LA English DT Article ID ASSISTED LASER-DESORPTION; FLIGHT MASS-SPECTROMETER; SOURCE FRAGMENTATION; PROTEIN SEQUENATOR; IONIZATION; EXTRACTION; IONS; TOF; IDENTIFICATION; INFORMATION AB In previous papers, we highlighted the role of ammonium sulfate in increasing peptide fragmentation by in-source decay (ISD). The current work systematically investigated effects of matrix assisted laser desorption ionization (MALDI) extraction delay, peptide amino acid composition, matrix, and ammonium sulfate concentration on peptide ISD fragmentation. The data confirmed that ammonium sulfate increased peptides signal-to-noise ratio as well as their in-source fragmentation, resulting in complete sequence coverage regardless of the amino acid composition. This method is easy, inexpensive, and generates the peptides sequence instantly. C1 [Delvolve, Alice; Woods, Arnina S.] NIDA, IRP, NIH, Baltimore, MD 21224 USA. RP Woods, AS (reprint author), NIDA, IRP, NIH, 333 Cassell Dr,Rm 1120, Baltimore, MD 21224 USA. EM awoods@mail.nih.gov FU National Institute on Drug Abuse, NIH; Office of National Drug Control Policy (ONDCP) FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, NIH. We thank the Office of National Drug Control Policy (ONDCP) for instrumentation funding, without which this and other projects could not have been accomplished. NR 30 TC 7 Z9 7 U1 0 U2 3 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 1 PY 2009 VL 81 IS 23 BP 9585 EP 9589 DI 10.1021/ac901518a PG 5 WC Chemistry, Analytical SC Chemistry GA 523OX UT WOS:000272084700014 PM 19877641 ER PT J AU Schultz, ZD Stranick, SJ Levin, IW AF Schultz, Zachary D. Stranick, Stephan J. Levin, Ira W. TI Advantages and Artifacts of Higher Order Modes in Nanoparticle-Enhanced Backscattering Raman Imaging SO ANALYTICAL CHEMISTRY LA English DT Article ID CHEMICAL-ANALYSIS; CARBON NANOTUBES; SPECTROSCOPY; MICROSCOPY; FIELD; SCATTERING; SILVER; RECOGNITION; NANOSCALE; MOLECULES AB In order to facilitate nanoparticle-enhanced Raman imaging of complicated biological specimens, we have examined the use of higher order modes with radial and azimuthal polarizations focused onto a Au nanoparticle atomic force microscope (AFM) tip utilizing a backscattering reflection configuration. When comparing the Raman intensity profiles with the observed sample topography, the radial-polarized configuration demonstrates enhanced spatial resolution. This enhanced resolution results from the direction of the induced electron oscillation in the metal nanoparticle oriented by the electromagnetic field at the laser focus. The electric field component along the direction of laser propagation, attendant to the radial polarization, creates an enhanced field along the z-axis and normal to the sample. Substantial enhancement is observed utilizing an intermediate numerical aperture objective (NA = 0.7), necessary for backscattering measurements. The azimuthal polarization, similar to linear polarization, results in an enhanced field predominantly parallel to the sample, resulting in imaging artifacts. The Raman intensity profiles observed as the exciting laser polarization is switched between either a radially polarized or an azimuthally polarized state illustrate these imaging artifacts. Because azimuthal polarization arises readily from changes in the incident polarization onto the mode converter, the results presented here aid in identifying such artifacts when analyzing nanoparticle-enhanced Raman spectroscopic images. Due to the power law decay of the enhanced field, an enhancement orientation normal to the sample enables contrast between structures smaller than the tip dimensions as the apex of the nanoparticle tip, where the enhancement is strongest, passes over the sample. These effects are demonstrated using both carbon nanotube and fixed biological samples. C1 [Schultz, Zachary D.; Stranick, Stephan J.; Levin, Ira W.] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Levin, IW (reprint author), NIDDKD, Chem Phys Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM iwi@helix.nih.gov RI Schultz, Zachary/L-5724-2013 OI Schultz, Zachary/0000-0003-1741-8801 FU NIH [K99RR024367] FX The authors thank Shuko Yoshikami for assistance isolating rod photoreceptor cells. This work was funded through the NIDDK intramural research program. Z.D.S. acknowledges support from NIH K99RR024367. NR 52 TC 13 Z9 13 U1 2 U2 12 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 1 PY 2009 VL 81 IS 23 BP 9657 EP 9663 DI 10.1021/ac901789w PG 7 WC Chemistry, Analytical SC Chemistry GA 523OX UT WOS:000272084700023 PM 19947663 ER PT J AU Dunton, GF Atienza, AA Castro, CM King, AC AF Dunton, Genevieve Fridlund Atienza, Audie A. Castro, Cynthia M. King, Abby C. TI Using Ecological Momentary Assessment to Examine Antecedents and Correlates of Physical Activity Bouts in Adults Age 50+Years: A Pilot Study SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Physical activity; Ecological momentary assessment; Psychosocial factors; Middle-aged and older adults ID AMBULATORY BLOOD-PRESSURE; OLDER-ADULTS; SELF-EFFICACY; NATURAL ENVIRONMENTS; FEELING STATES; ACUTE EXERCISE; HEALTH; WOMEN; BEHAVIOR; LIFE AB Background National recommendations supporting the promotion of multiple short (10+ minute) physical activity bouts each day to increase overall physical activity levels in middle-aged and older adults underscore the need to identify antecedents and correlates of such daily physical activity episodes. Purpose This pilot study used Ecological Momentary Assessment to examine the time-lagged and concurrent effects of empirically supported social, cognitive, affective, and physiological factors on physical activity among adults age 50+ years. Methods Participants (N=23) responded to diary prompts on a handheld computer four times per day across a 2-week period. Moderate-to-vigorous physical activity (MVPA), self-efficacy, positive and negative affect, control, demand, fatigue, energy, social interactions, and stressful events were assessed during each sequence. Results Multivariate results showed that greater self-efficacy and control predicted greater MVPA at each subsequent assessment throughout the day (p<0.05). Also, having a positive social interaction was concurrently related to higher levels of MVPA (p=0.052). Conclusion Time-varying multidimensional individual processes predict within daily physical activity levels. C1 [Dunton, Genevieve Fridlund] Univ So Calif, Inst Hlth Promot & Dis Prevent Res, Alhambra, CA 91803 USA. [Dunton, Genevieve Fridlund; Atienza, Audie A.] NCI, Hlth Promot Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Castro, Cynthia M.] Stanford Univ, Sch Med, Dept Med, Stanford Prevent Res Ctr, Palo Alto, CA 94304 USA. [King, Abby C.] Stanford Univ, Sch Med, Dept Med, Dept Hlth Res & Policy,Div Epidemiol, Palo Alto, CA 94304 USA. [King, Abby C.] Stanford Univ, Sch Med, Dept Med, Stanford Prevent Res Ctr, Palo Alto, CA 94304 USA. RP Dunton, GF (reprint author), Univ So Calif, Inst Hlth Promot & Dis Prevent Res, 1000 S Fremont Ave,Unit 8,Bldg 5,Rm 5229, Alhambra, CA 91803 USA. EM dunton@usc.edu FU NIA NIH HHS [AG-12358] NR 48 TC 36 Z9 36 U1 0 U2 18 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD DEC PY 2009 VL 38 IS 3 BP 249 EP 255 DI 10.1007/s12160-009-9141-4 PG 7 WC Psychology, Multidisciplinary SC Psychology GA 567ED UT WOS:000275425100008 PM 20052568 ER PT J AU Klein, WMP Zajac, LE Monin, MM AF Klein, William M. P. Zajac, Laura E. Monin, Matthew M. TI Worry as a Moderator of the Association Between Risk Perceptions and Quitting Intentions in Young Adult and Adult Smokers SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Worry; Risk perception; Quitting intentions; Smoking ID BREAST-CANCER WORRY; INFLUENZA VACCINATION; PLANNED BEHAVIOR; HEALTH BEHAVIOR; ALCOHOL; METAANALYSIS; FEELINGS AB Background Although much work addresses the association between risk perceptions and behavior, much less attention has been devoted to identifying psychosocial and sociodemographic moderators of this relationship. Purpose We explored whether worry moderates the relationship between risk perceptions and behavioral intentions in an adult sample (where the relationship is typically positive) and a young adult sample (where we have found that the relationship can be negative). Method Two samples of smokers (adults and college students) were asked to report worry, risk perceptions, and quitting intentions as part of two cessation interventions. Results Among low-worry individuals, the risk perception/intentions relationship was positive in the adult sample and negative in the young adult sample. However, among high-worry individuals, the relationship was negative in the adult sample (and nonsignificant in the young adult sample). Conclusions These findings suggest that worry can moderate the extent to which risk perceptions motivate risk-related intentions and that the nature of such moderation may depend on other factors such as age. C1 [Klein, William M. P.] NCI, Behav Res Program, Bethesda, MD 20892 USA. [Klein, William M. P.; Zajac, Laura E.; Monin, Matthew M.] Univ Pittsburgh, Pittsburgh, PA USA. RP Klein, WMP (reprint author), NCI, Behav Res Program, 6130 Execut Blvd,MSC 7326,Execut Plaza N,Room 406, Bethesda, MD 20892 USA. EM kleinwm@mail.nih.gov NR 33 TC 28 Z9 28 U1 3 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD DEC PY 2009 VL 38 IS 3 BP 256 EP 261 DI 10.1007/s12160-009-9143-2 PG 6 WC Psychology, Multidisciplinary SC Psychology GA 567ED UT WOS:000275425100009 PM 20049660 ER PT J AU Gillespie, AMH Johnson-Askew, WL AF Gillespie, Ardyth M. H. Johnson-Askew, Wendy L. TI Changing Family Food and Eating Practices: The Family Food Decision-Making System SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Food decision-making; Family; Changing food practices; Behavior change AB Background Food decision-making processes interact with family and community environments to shape families' thinking (i.e., their constructed reality) about food, eating, health, and well-being as discussed by Gillespie and Gillespie (J Fam Consum Sci 99(2): 22-28 2007). Purpose To understand the processes and impetuses for changing family food and eating routines and policies and to develop a framework for the family food decision-making system (FFDS). Methods Interviews and observations with parents and change agents were used to generate grounded theory in the form of propositions which provided the basis for the FFDS framework. Results The propositions elucidate the processes of and influences on family food decision-making systems. The framework illustrates the family food decision-making system and processes of changing family food and eating routines and policies. Conclusion The FDMS framework begins to address the complexity of food decision-making to guide intervention planning and further research. C1 [Gillespie, Ardyth M. H.] Cornell Univ, Ithaca, NY 14850 USA. [Johnson-Askew, Wendy L.] NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. RP Gillespie, AMH (reprint author), Cornell Univ, Ithaca, NY 14850 USA. EM ahg2@cornell.edu NR 4 TC 9 Z9 10 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD DEC PY 2009 VL 38 SU 1 BP S31 EP S36 DI 10.1007/s12160-009-9122-7 PG 6 WC Psychology, Multidisciplinary SC Psychology GA V16HW UT WOS:000207861700005 PM 19885714 ER PT J AU Johnson-Askew, WL Fisher, RA Yaroch, AL AF Johnson-Askew, Wendy L. Fisher, Rachel A. Yaroch, Amy L. TI Decision Making in Eating Behavior: State of the Science and Recommendations for Future Research SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Decision making; Eating behavior; Food-related decisions ID EDUCATIONAL-ATTAINMENT; PUBLIC-HEALTH; OBESITY; WEIGHT; LITERACY; GENETICS; MODEL AB Background The National Institutes of Health Division of Nutrition Research Coordination, the National Cancer Institute, the National Health Lung and Blood Institute, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Diabetes, Digestive and Kidney Diseases convened a scientific workshop entitled "Decision Making in Eating Behavior: Integrating Perspectives from the Individual, Family, and Environment" in April 2008 Purpose/Methods The purpose of this paper is to provide a synthesis of the workshop. Results The common themes that ran throughout the conference were as follows: (1) Initiating behavior differs conceptually from sustaining behaviors; (2) The intersection of biology, genetics, and environment (physical, political, economic, and social) is where eating behavior occurs; (3) Marketing and advertising influence eating behavior influence; and (4) sometimes, seemingly unrelated policies influence eating behavior. Conclusions Additional research is needed. C1 [Johnson-Askew, Wendy L.; Fisher, Rachel A.] NIH, Bethesda, MD 20892 USA. [Yaroch, Amy L.] Ctr Human Nutr, Omaha, NE USA. RP Johnson-Askew, WL (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM wendyjt@mail.nih.gov NR 44 TC 3 Z9 3 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD DEC PY 2009 VL 38 SU 1 BP S88 EP S92 DI 10.1007/s12160-009-9125-4 PG 5 WC Psychology, Multidisciplinary SC Psychology GA V16HW UT WOS:000207861700011 PM 19898913 ER PT J AU Rothman, AJ Gillespie, AH Johnson-Askew, WL AF Rothman, Alexander J. Gillespie, Ardyth H. Johnson-Askew, Wendy L. TI Decision Making in Eating Behavior: Interacting Perspectives from the Individual, Family, and Environment: An Introduction SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Editorial Material C1 [Rothman, Alexander J.] Univ Minnesota, Dept Psychol, Minneapolis, MN 55455 USA. [Gillespie, Ardyth H.] Cornell Univ, Div Nutr Sci, Coll Human Ecol, Ithaca, NY 14850 USA. [Johnson-Askew, Wendy L.] NIH, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. RP Rothman, AJ (reprint author), Univ Minnesota, Dept Psychol, 75 E River Rd, Minneapolis, MN 55455 USA. EM rothm001@umn.edu; ahg2@cornell.edu; wj50v@nih.gov NR 3 TC 6 Z9 6 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD DEC PY 2009 VL 38 SU 1 BP S1 EP S3 DI 10.1007/s12160-009-9128-1 PG 3 WC Psychology, Multidisciplinary SC Psychology GA V16HW UT WOS:000207861700001 PM 19898912 ER PT J AU Wethington, E Johnson-Askew, WL AF Wethington, Elaine Johnson-Askew, Wendy L. TI Contributions of the Life Course Perspective to Research on Food Decision Making SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE Life course perspective; Food decision making; Work-family stress AB Background The life course perspective (LCP) has emerged as a powerful organizing framework for the study of health, illness, and mortality. LCP represents a "whole life" analysis perspective which originated in the field of sociology. Methods Its concepts are increasingly applied to understanding the development of chronic disease over long periods of time in the human life span. A missing link, however, in the adaptation of the LCP to health research, is the insight the LCP may offer into understanding the societal, social network, and family contexts that frame stability and change in dietary behavior. Results This paper reviews key concepts that comprise the LCP but primarily focuses on applications that have relevance to food decision making in social context. A case study of chronic work-family stress and perceived time scarcity as barriers to dietary improvement is included. Conclusion Illustrative findings are presented on dietary behavior in a diverse sample of lower-income working parents. This paper also offers ideas on increasing the contributions of the LCP to nutritional research. C1 [Wethington, Elaine] Cornell Univ, Dept Human Dev, Ithaca, NY 14853 USA. [Wethington, Elaine] Cornell Univ, Dept Sociol, Ithaca, NY 14853 USA. [Johnson-Askew, Wendy L.] NIH, Div Nutr & Res Coordinat, Bethesda, MD 20892 USA. RP Wethington, E (reprint author), Cornell Univ, Dept Human Dev, MVR Hall, Ithaca, NY 14853 USA. EM ew20@cornell.edu; wj50v@nih.gov FU NCI NIH HHS [1 R01 CA 102684, R01 CA102684]; NIA NIH HHS [P30 AG022845, 1 P30 AG022845]; NICHD NIH HHS [R24 HD058488] NR 62 TC 12 Z9 12 U1 7 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD DEC PY 2009 VL 38 SU 1 BP S74 EP S80 DI 10.1007/s12160-009-9123-6 PG 7 WC Psychology, Multidisciplinary SC Psychology GA V16HW UT WOS:000207861700009 PM 19890684 ER PT J AU Faupel-Badger, JM Berrigan, D Ballard-Barbash, R Potischman, N AF Faupel-Badger, Jessica M. Berrigan, David Ballard-Barbash, Rachel Potischman, Nancy TI Anthropometric Correlates of Insulin-Like Growth Factor 1 (IGF-1) and IGF Binding Protein-3 (IGFBP-3) Levels by Race/Ethnicity and Gender SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE BMI; Obesity; Cancer; IGF ID PROSTATE-CANCER RISK; BODY-MASS INDEX; FACTOR-I; FACTOR (IGF)-I; LIFE-STYLE; COLORECTAL-CANCER; EPIDEMIOLOGIC EVIDENCE; POSTMENOPAUSAL WOMEN; CIRCULATING LEVELS; ENERGY-BALANCE AB PURPOSE: Insulin-like growth factor 1 (IGF-1) levels are positively related to some cancers and negatively related to cardiovascular disease. These conditions are also related to insulin resistance and high body weight, leading to the hypothesis that IGF-1 levels may, in part, mediate the association of high body weight with these health outcomes. Using the National Health and Nutrition Examination Survey (NHANES) Ill population, we examined the associations between IGF-1, IGF binding protein-3 (IGFBP-3), and the IGF-1/IGFBP-3 molar ratio with anthropometric measures in a large, U.S. population-based study where these associations could also be stratified by race/ethnicity and gender. METHODS: The study population consisted of 3,168 women and 2,635 men (44% non-Hispanic white, 28.2% non-Hispanic black, and 27.7% Mexican-American). Anthropometric measures were obtained by trained personnel in the NHANES mobile examination centers. IGF-1 and IGFBP-3 were measured using immunoassays by staff at Diagnostic System Laboratories (DSL) Inc. (Webster, TX). Associations of IGF-1, IGFBP-3, and IGF-1/IGFBP-3 molar ratio with anthropometric variables across race/ethnicity and gender were evaluated by using linear regression modeling. RESULTS: Body mass index (BMI) was inversely associated with IGF-1 levels across all of the race/ethnicity and gender subgroups. In contrast, BMI, waist to hip ratio (WHR), and waist circumference were positively associated with IGFBP-3 levels only in non-Hispanic black men and non-Hispanic white women. The IGF-1/IGFBP-3 molar ratio was inversely associated with all anthropometric measures, except height, in all subgroups of the population. CONCLUSION: The significant inverse associations of BMI with IGF-1 levels and of all anthropometric variables, except height, with the IGF-1:IGFBP-3 molar ratio in all subgroups do not support existing hypotheses that associations of excess weight with negative health outcomes, such as specific cancer diagnoses, are mediated through high IGF-1 levels. Ann Epidemiol 2009;19:841-849. (C) Published by Elsevier Inc. C1 [Faupel-Badger, Jessica M.] NCI, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. [Berrigan, David; Ballard-Barbash, Rachel; Potischman, Nancy] NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Faupel-Badger, JM (reprint author), NCI, Canc Prevent Fellowship Program, NIH, 6120 Execut Blvd EPS,Suite 150E,MSC 7105, Bethesda, MD 20892 USA. EM badgerje@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 52 TC 22 Z9 22 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD DEC PY 2009 VL 19 IS 12 BP 841 EP 849 DI 10.1016/j.annepidem.2009.08.005 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 574NR UT WOS:000275997500001 PM 19944347 ER PT J AU Yanez, ND Burke, GL Manolio, T Gardin, JM Polak, J AF Yanez, N. David Burke, Gregory L. Manolio, Teri Gardin, Julius M. Polak, Joseph CA CHS Collaborative Res Grp TI Sibling History of Myocardial Infarction or Stroke and Risk of Cardiovascular Disease in the Elderly: The Cardiovascular Health Study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Epidemiology; Cardiovascular Diseases; Risk Factors; Atherosclerosis; Lifestyle ID CORONARY-HEART-DISEASE; TRANSIENT ISCHEMIC ATTACK; 1ST DEGREE RELATIVES; FAMILY-HISTORY; PARENTAL HISTORY; BLOOD-PRESSURE; CHILDREN; AGGREGATION; HYPERTENSION; GENETICS AB PURPOSE: To assess the relationship between sibling history of myocardial infarction (MI) or stroke with cardiovascular disease (CVD) and risk factors in older adults. METHODS: Prospective cohort study of 5,888 older adults participating in the Cardiovascular Health Study (CHS). History of MI and stroke in siblings was obtained by self-report. Participants with positive sibling histories were compared to those with negative histories to determine if prevalent or incident disease (coronary heart disease [CHD], MI, stroke, angina), subclinical CVD (carotid wall thickness, left ventricular mass, hypertension, diabetes, ankle-brachial index), CVD risk factors differed between groups. RESULTS: More than 91% (n = 5,383) of CHS participants reported at least one sibling. Sibling history of MI was associated with increased disease prevalence (CHD, MI, angina) and incidence (CHD, angina). Sibling history of stroke was associated with increased disease prevalence (CHD, angina). Sibling history of either MI or stroke was associated with increased disease prevalence and incidence for CHD, MI and angina, more subclinical disease, and a higher CVD risk profile. CONCLUSIONS: Sibling history of Nil and stroke were markers of higher CVD risk status even in older adults. Of clinical importance, participants with positive sibling history have numerous risk factors amenable to intervention. Ann Epidemiol 2009;19:858-866. (C) 2009 Elsevier Inc. All rights reserved. C1 [Yanez, N. David] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Burke, Gregory L.] Wake Forest Univ, Bowman Gray Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27103 USA. [Manolio, Teri] NHGRI, NIH, Bethesda, MD 20892 USA. [Gardin, Julius M.] St John Hosp & Med Ctr, Div Cardiol, Detroit, MI USA. [Polak, Joseph] Tufts Univ, Dept Radiol, Boston, MA 02111 USA. RP Yanez, ND (reprint author), Univ Washington, Dept Biostat, Box 357232,1959 NE Pacific St, Seattle, WA 98195 USA. EM yanez@u.washington.edu FU National Heart, Lung, and Blood Institute [N01-HC-85079, N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, U01 HL080295, R01 HL-075366]; National Institute on Aging [R01 AG-15928, R01 AG-20098, AG-027058]; University of Pittsburgh Claude. D. Pepper Older Americans Independence Center [P30-AG-024827] FX The research reported in this article was supported by contract numbers N01-HC-85079 through N01-HC-85086, N01-HC-35129, N01 HC-15103, N01 HC-55222, N01-HC-75150, N01-HC-45133, grant number U01 HL080295 from the National Heart, Lung, and Blood Institute, with additional contribution from the National Institute of Neurological Disorders and Stroke. Additional support was provided through R01 AG-15928, R01 AG-20098, and AG-027058 from the National Institute on Aging; R01 HL-075366 from the National Heart, Lung and Blood Institute; and the University of Pittsburgh Claude. D. Pepper Older Americans Independence Center P30-AG-024827. NR 40 TC 8 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD DEC PY 2009 VL 19 IS 12 BP 858 EP 866 DI 10.1016/j.annepidem.2009.07.095 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 574NR UT WOS:000275997500003 PM 19944349 ER PT J AU Park, Y Sheetlin, S Spouge, JL AF Park, Yonil Sheetlin, Sergey Spouge, John L. TI ESTIMATING THE GUMBEL SCALE PARAMETER FOR LOCAL ALIGNMENT OF RANDOM SEQUENCES BY IMPORTANCE SAMPLING WITH STOPPING TIMES SO ANNALS OF STATISTICS LA English DT Article DE Gumbel scale parameter estimation; gapped sequence alignment; importance sampling; stopping time; Markov renewal process; Markov additive process ID ACID SUBSTITUTION MATRICES; APPROXIMATE P-VALUES; STATISTICAL SIGNIFICANCE AB The gapped local alignment score of two random sequences follows a Gumbel distribution. If computers could estimate the parameters of the Gumbel distribution within one second, the use of arbitrary alignment scoring schemes could increase the sensitivity of searching biological sequence databases over the web. Accordingly, this article gives a novel equation for the scale parameter of the relevant Gumbel distribution. We speculate that the equation is exact, although present numerical evidence is limited. The equation involves ascending ladder variates in the global alignment of random sequences. In global alignment simulations, the ladder variates yield stopping times specifying random sequence lengths. Because of the random lengths. and because our trial distribution for importance sampling occurs on a different sample space from our target distribution, our study led to a mapping theorem, which led naturally in turn to an efficient dynamic programming algorithm for the importance sampling weights. Numerical studies using several popular alignment scoring schemes then examined the efficiency and accuracy of the resulting simulations. C1 [Park, Yonil; Sheetlin, Sergey; Spouge, John L.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Park, Y (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM park@ncbi.nlm.nih.gov; sheetlin@ncbi.nlm.nih.gov; spouge@ncbi.nlm.nih.gov RI Park, Yonil/E-6075-2010 FU NIH, National Library of Medicine FX The authors Y. Park and S. Sheetlin contributed equally to the article. All authors would like to acknowledge helpful discussion with Dr. Nak-Kyeong Kim. This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 35 TC 4 Z9 4 U1 2 U2 3 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 0090-5364 J9 ANN STAT JI Ann. Stat. PD DEC PY 2009 VL 37 IS 6A BP 3697 EP 3714 DI 10.1214/08-AOS663 PG 18 WC Statistics & Probability SC Mathematics GA 518EO UT WOS:000271673500022 PM 20148197 ER PT J AU Suh, I Shibru, D Eisenhofer, G Pacak, K Duh, QY Clark, OH Kebebew, E AF Suh, Insoo Shibru, Daniel Eisenhofer, Graeme Pacak, Karel Duh, Quan-Yang Clark, Orlo H. Kebebew, Electron TI Candidate Genes Associated With Malignant Pheochromocytomas by Genome-Wide Expression Profiling SO ANNALS OF SURGERY LA English DT Article ID SET ENRICHMENT ANALYSIS; UP-REGULATE NOTCH-1; PC12 CELLS; INHIBIT GROWTH; C-MYC; DIFFERENTIATION; PARAGANGLIOMA; DIAGNOSIS; PROTEIN; BENIGN AB Objective: To improve our understanding of the molecular mechanisms involved in malignant pheochromocytoma by examining differences in the gene expression profile between benign and malignant tumors. Background: The molecular events involved in the malignant transformation of pheochromocytoma are poorly understood. There are also no reliable and uniformly accepted histopathologic criteria to distinguish benign from malignant pheochromocytoma. Methods: We performed genome-wide expression profiling of 58 pheochromocytomas (29 benign and sporadic, 16 benign and hereditary, 13 malignant) with technical and biologic replication. Results: Unsupervised cluster analysis showed 3 main clusters of tumors that did not have complete concordance with the clinical and pathologic groupings of pheochromocytomas. Supervised cluster analysis showed almost completely separate clustering between benign and malignant tumors. The differentially expressed genes with known function belonged to 8 biologic process categories; signal transduction, transcription, protein transport, protein synthesis, smooth muscle contraction, ion transport, chemotaxis, and electron transport. Gene set enrichment analysis revealed significant correlation between the microarray profiles of malignant pheochromocytomas and several known molecular pathways associated with carcinogenesis and dedifferentiation. Ten differentially expressed genes had high diagnostic accuracy, and 5 of these genes (CFC1, FAM62B, HOMER1, LRRN3, TBX3, ADAMTS) in combination had an area under the receiver operating characteristic (ROC) curve of 0.96 for distinguishing benign versus malignant tumors. Conclusions: Differentially expressed genes between benign and malignant pheochromocytomas distinguish between these tumors with high diagnostic accuracy. Our findings provide new insight into the genes and molecular pathways that may be involved in malignant pheochromocytomas. C1 [Kebebew, Electron] Univ Calif San Francisco, Dept Surg, UCSF Comprehens Canc Ctr, San Francisco, CA 94143 USA. [Eisenhofer, Graeme] Univ Dresden, Dept Internal Med 3, Inst Clin Chem & Lab Med, Dresden, Germany. [Pacak, Karel] NIH, Reprod & Adult Endocrinol Program, Bethesda, MD 20892 USA. RP Kebebew, E (reprint author), Univ Calif San Francisco, Dept Surg, UCSF Comprehens Canc Ctr, Box 1674, San Francisco, CA 94143 USA. EM kebebewe@surgery.ucsf.edu NR 34 TC 12 Z9 14 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD DEC PY 2009 VL 250 IS 6 BP 983 EP 990 DI 10.1097/SLA.0b013e3181b248bb PG 8 WC Surgery SC Surgery GA 526SM UT WOS:000272313700020 PM 19661783 ER PT J AU Huang, T Sun, LG Wang, YH Liu, XD Zhu, RB AF Huang, Tao Sun, Liguang Wang, Yuhong Liu, Xiaodong Zhu, Renbin TI Penguin population dynamics for the past 8500 years at Gardner Island, Vestfold Hills SO ANTARCTIC SCIENCE LA English DT Article DE Antarctic climate; bio-element; guano; late Holocene; penguin optimum; sedimentation rate ID HISTORICAL SEABIRD POPULATION; EAST ANTARCTICA; LAKE-SEDIMENTS; CLIMATE-CHANGE; LATE-HOLOCENE; DIATOM ASSEMBLAGES; SEAL POPULATIONS; WINDMILL ISLANDS; LARSEMANN HILLS; SALINE LAKES AB In order to reconstruct past changes in penguin populations we performed geochemical analyses on a penguin ornithogenic sediment core DG4 retrieved from a lake catchment on Gardner Island, Vestfold Hills. P, Se, F, S, As, Sr and Cu in DG4 were identified as the bio-element assemblage by R-clustering analyses on the elemental concentrations and comparisons with those in bedrock and fresh penguin guano. Factor analysis on the levels of these bio-elements in the core permitted a reconstruction of variations in historical penguin populations at Gardner Island spanning the past 8500 years. The penguin population showed significant fluctuations, reaching its highest density between 4700-2400 calibrated years before present. This coincides with evidence for a late Holocene warm period in the Vestfold Hills, similar to that associated with the late Holocene penguin optimum recorded in the Ross Sea and Antarctic Peninsula regions. C1 [Huang, Tao; Sun, Liguang; Wang, Yuhong; Liu, Xiaodong; Zhu, Renbin] Univ Sci & Technol China, Inst Polar Environm, Hefei 230026, Peoples R China. [Wang, Yuhong] NIH, Bethesda, MD 20892 USA. RP Huang, T (reprint author), Univ Sci & Technol China, Inst Polar Environm, Hefei 230026, Peoples R China. EM slg@ustc.edu.cn RI Huang, Tao/B-5915-2009 FU National Natural Science Foundation of China [40730107]; National Science and Technology Supporting Program [2006BAB18B07]; IPY 2007-2008 China Programme [1PY2008-P05040015-05]; Australia Antarctic Division [AAD2873] FX We thank the Chinese Arctic and Antarctic Administration, Polar Research Institute of China, Australian Antarctic Division, the CHINARE22 team in Zhong Shan Station and the members of Davis Station for their support and assistance in field. We especially thank the reviewers for their valuable comments and careful corrections on this manuscript and its earlier version. This study was funded by the National Natural Science Foundation of China (No.40730107), the National Science and Technology Supporting Program (2006BAB18B07), the IPY 2007-2008 China Programme (1PY2008-P05040015-05) and the Australia Antarctic Division Science Project (AAD2873). NR 33 TC 27 Z9 31 U1 1 U2 7 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0954-1020 J9 ANTARCT SCI JI Antarct. Sci. PD DEC PY 2009 VL 21 IS 6 BP 571 EP 578 DI 10.1017/S0954102009990332 PG 8 WC Environmental Sciences; Geography, Physical; Geosciences, Multidisciplinary SC Environmental Sciences & Ecology; Physical Geography; Geology GA 536XT UT WOS:000273077900004 ER PT J AU Arlen, PM Gulley, JL AF Arlen, Philip M. Gulley, James L. TI Current Perspectives in Prostate Cancer Vaccines SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Article DE Prostate cancer; immunotherapy; vaccine; cancer vaccine; clinical protocols; tumor-associated antigens ID COLONY-STIMULATING FACTOR; REGULATORY T-CELLS; ANDROGEN-DEPRIVATION THERAPY; IMMUNE-RESPONSES; COMBINATION THERAPY; CELLULAR IMMUNOTHERAPY; IMMUNOLOGICAL RESPONSE; DOSE CYCLOPHOSPHAMIDE; ANTITUMOR IMMUNITY; RADIATION-THERAPY AB The use of vaccines as a potential therapeutic modality for the treatment of cancer has been extensively studied. Recent advances include identification and characterization of tumor-associated antigens, novel vaccine delivery systems, and the combination of vaccines with immune stimulants and other therapeutic modalities. Immunotherapy as a modality for treatment of prostate cancer has received significant attention. There are several characteristics of prostate cancer that make it an ideal target for immunotherapy. Prostate cancer's relative indolence allows sufficient time to generate immune responses, which may take weeks or months to mount. In addition, prostate cancer-associated antigens direct the immune response to prostate cancer cells, thus sparing normal vital tissue. This review focuses on promising new vaccines and novel perspectives in the treatment of prostate cancer. C1 [Arlen, Philip M.; Gulley, James L.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gulley, JL (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Room 8B09,MSC 1750, Bethesda, MD 20892 USA. EM gulleyj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS [Z01 BC010666-03] NR 71 TC 1 Z9 1 U1 0 U2 1 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD DEC PY 2009 VL 9 IS 10 BP 1052 EP 1057 PG 6 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 513RO UT WOS:000271341100004 PM 19719454 ER PT J AU Sissung, TM Thordardottir, S Gardner, ER Figg, WD AF Sissung, Tristan M. Thordardottir, Silja Gardner, Erin R. Figg, William D. TI Current Status of Thalidomide and CC-5013 in the Treatment of Metastatic Prostate Cancer SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Article DE Prostate cancer; thalidomide; lenalidomide; CC-5013; angiogenesis inhibition ID NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; PHASE-II TRIAL; TNF-ALPHA; ANGIOGENESIS INHIBITORS; ENDOTHELIAL-CELLS; MULTIPLE-MYELOMA; IMMUNOMODULATORY DRUGS; UP-REGULATION; EXPRESSION AB Thalidomide is emerging as a potentially important therapeutic option in the treatment of metastatic prostate cancer. Although the mechanism of action of this agent remains elusive in malignancies of the prostate, recent data has indicated that thalidomide may play a role in inflammation, immunomodulation, and anti-angiogenesis. Lenalidomide (CC-5013), a thalidomide analogue with improved activity and safety profile in certain disease contexts, is in the early stages of development in prostate cancer. This review will provide the current status of the history, mechanism, metabolism, and clinical use of thalidomide in metastatic prostate cancer. It will also describe the mechanism and clinical use of lenalidomide as it pertains to malignancies of the prostate. C1 [Figg, William D.] NCI, Clin Pharmacol Program, Med Oncol Clin Res Unit, Med Oncol Branch,Ctr Canc Res, Bethesda, MD 20892 USA. [Thordardottir, Silja] Univ Iceland, Fac Pharmaceut Sci, Reykjavik, Iceland. [Gardner, Erin R.] SAIC Frederick Inc, Clin Pharmacol Program, NCI Frederick, Frederick, MD 21702 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, Med Oncol Clin Res Unit, Med Oncol Branch,Ctr Canc Res, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU Intramural NIH HHS; PHS HHS [HHSN261200800001E] NR 96 TC 7 Z9 8 U1 3 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD DEC PY 2009 VL 9 IS 10 BP 1058 EP 1069 PG 12 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 513RO UT WOS:000271341100005 PM 19719457 ER PT J AU Madan, RA Dahut, WL AF Madan, Ravi A. Dahut, William L. TI Angiogenesis Inhibition in the Treatment of Prostate Cancer SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Review DE Antiangiogenesis; prostate cancer; bevacizumab; multikinase inhibitors; fusion proteins ID ENDOTHELIAL GROWTH-FACTOR; PHASE-II TRIAL; METASTATIC COLORECTAL-CANCER; TYROSINE KINASE INHIBITOR; RENAL-CELL CARCINOMA; IN-VIVO; RADICAL PROSTATECTOMY; RADIATION-THERAPY; DOCETAXEL TAXOTERE; FACTOR RECEPTOR-2 AB For many men, prostate cancer is an indolent disease that, even without definitive therapy, may have no impact on their quality of life or overall survival. However for those men who are either diagnosed with or eventually develop metastatic disease, prostate cancer is a painful and universally fatal disease. Testosterone-lowering hormonal therapy may control the disease for some time, but patients eventually develop resistance and progress clinically. At this point, only docetaxel has been shown to improve survival, so clearly additional therapeutic options are needed. Angiogenesis inhibition is an active area of clinical research in prostate cancer. Without angiogenesis, tumors have insufficient nutrients and oxygen to grow larger than a few millimeters and are potentially less likely to metastasize. In prostate cancer in particular, angiogenesis plays a significant role in tumor proliferation, and markers of angiogenesis appear to have prognostic significance. Several different compounds have been developed to inhibit angiogenesis, including monoclonal antibodies, multitargeted kinase inhibitors, and fusion proteins. In addition, more traditional agents may also have an impact on angiogenesis. Trials studying antiangiogenic agents have been conducted in localized and advanced prostate cancer. There are several large, ongoing phase III trials in metastatic castration-resistant prostate cancer. The findings of these and future studies will ultimately determine the role of angiogenesis inhibitors in the treatment of prostate cancer. C1 [Madan, Ravi A.; Dahut, William L.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Madan, Ravi A.] NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Dahut, WL (reprint author), NCI, Med Oncol Branch, NIH, Bldg 10,Rm 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dahutw@mail.nih.gov NR 112 TC 4 Z9 4 U1 0 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD DEC PY 2009 VL 9 IS 10 BP 1070 EP 1078 PG 9 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 513RO UT WOS:000271341100006 PM 19719453 ER PT J AU Crea, F Mathews, LA Farrar, WL Hurt, EM AF Crea, Francesco Mathews, Lesley A. Farrar, William L. Hurt, Elaine M. TI Targeting Prostate Cancer Stem Cells SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Review DE Prostate; cancer stem cells; tumor-initiating cells; molecular therapies; transforming growth factor beta; hedgehog; notch; beta-catenin ID FAMILIAL ADENOMATOUS POLYPOSIS; TUMOR-INITIATING CELLS; GROWTH-FACTOR-BETA; SMALL-MOLECULE ANTAGONISTS; ACUTE MYELOID-LEUKEMIA; TGF-BETA; IN-VIVO; DRUG-RESISTANCE; TELOMERASE ACTIVITY; HEDGEHOG PATHWAY AB Cancer stem cells are the sub-population of cells present within tumors responsible for tumorigenesis. These cells have unique biological properties including self-renewal and the ability to differentiate. Furthermore, it is thought that these cells are more resistant to conventional chemotherapy and, as a result, are responsible for patient relapse. We will discuss the identification of prostate cancer stem cells, their unique properties and how these cells may be targeted for more efficacious therapies. C1 [Crea, Francesco; Mathews, Lesley A.; Farrar, William L.; Hurt, Elaine M.] NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Frederick, MD 21701 USA. RP Hurt, EM (reprint author), NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, 1050 Boyles St,Bldg 560,Room 21-81, Frederick, MD 21701 USA. EM hurte@ncifcrf.gov RI Crea, Francesco /I-8383-2015 FU National Cancer Institute, National Institutes of Health [N01-]; Intramural Research Program of the NIH, National Cancer Institut FX This publication has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract No. N01-CO-12400. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute. 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 122 TC 18 Z9 19 U1 0 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD DEC PY 2009 VL 9 IS 10 BP 1105 EP 1113 PG 9 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 513RO UT WOS:000271341100009 PM 19925394 ER PT J AU Miyashita, K Nakada, M Shakoori, A Ishigaki, Y Shimasaki, T Motoo, Y Kawakami, K Minamoto, T AF Miyashita, Katsuyoshi Nakada, Mitsutoshi Shakoori, Abbas Ishigaki, Yasuhito Shimasaki, Takeo Motoo, Yoshiharu Kawakami, Kazuyuki Minamoto, Toshinari TI An Emerging Strategy for Cancer Treatment Targeting Aberrant Glycogen Synthase Kinase 3 beta SO ANTI-CANCER AGENTS IN MEDICINAL CHEMISTRY LA English DT Review DE Glycogen synthase kinase 3 beta; molecular target; cancer ID FACTOR-KAPPA-B; EPITHELIAL-MESENCHYMAL TRANSITION; CHEMOTHERAPY-INDUCED APOPTOSIS; UBIQUITIN LIGASE RECEPTOR; ONCOGENIC BETA-CATENIN; ACUTE MYELOID-LEUKEMIA; HUMAN BREAST-CANCER; HUMAN COLON-CANCER; VALPROIC ACID; COLORECTAL-CANCER AB Improvement in the outcome of cancer patients who are refractory to currently available treatments relies on the development of target-directed therapies. One group of molecular targets with potential clinical relevance is a set of protein tyrosine kinases encoded mostly by proto-oncogenes and that are frequently deregulated in cancer. Glycogen synthase kinase 3 beta (GSK3 beta), a serine/threonine protein kinase, has emerged as a therapeutic target for common chronic diseases including type 2 diabetes mellitus, neurodegenerative disorders, inflammation and osteoporosis. This is based on its currently known functions and primary pathologic causalities. GSK3 beta has well characterized roles in the regulation of gene transcription and in oncogenic signaling. We have shown that deregulated GSK3 beta promotes gastrointestinal, pancreatic and liver cancers and glioblastomas. Furthermore, we have demonstrated that inhibition of GSK3 beta attenuates cancer cells survival and proliferation, induces cell senescence and apoptosis and sensitizes tumor cells to chemotherapeutic agents and ionizing radiation. This has led us to propose GSK3 beta as a potential therapeutic target in cancer. The anti-tumor effects of GSK3 beta inhibition are mediated by changes in the expression and phosphorylation of molecules critical to the regulation of cell cycling, proliferation and apoptosis and underlie the pathological role for GSK3 beta in cancer. Investigation of the mechanisms responsible for deregulation of GSK3 beta and the consequent downstream pathologic effects in cancer cells has shed light on the molecular pathways leading to tumorigenesis. This will allow exploration of novel therapeutic strategies for cancer that target aberrant GSK3 beta. C1 [Miyashita, Katsuyoshi; Shakoori, Abbas; Kawakami, Kazuyuki; Minamoto, Toshinari] Kanazawa Univ, Div Translat & Clin Oncol, Canc Res Inst, Kanazawa, Ishikawa 9200934, Japan. [Minamoto, Toshinari] Kanazawa Univ, Div Surg Oncol, Canc Res Inst, Kanazawa, Ishikawa 9200934, Japan. [Miyashita, Katsuyoshi; Nakada, Mitsutoshi] Kanazawa Univ, Grad Sch Med Sci, Dept Neurosurg, Kanazawa, Ishikawa 9200934, Japan. [Shakoori, Abbas] NCI, Sect Canc Genom, Genet Branch, NIH, Bethesda, MD 20892 USA. [Ishigaki, Yasuhito] Kanazawa Med Univ, Med Res Inst, Uchinada, Ishikawa 92002, Japan. [Shimasaki, Takeo; Motoo, Yoshiharu] Kanazawa Med Univ, Dept Med Oncol, Uchinada, Ishikawa 92002, Japan. RP Minamoto, T (reprint author), Kanazawa Univ, Div Translat & Clin Oncol, Canc Res Inst, 13-1 Takara Machi, Kanazawa, Ishikawa 9200934, Japan. EM minamoto@staff.kanazawa-u.ac.jp FU Japanese Ministry of Education, Science, Sports, Technology and Culture; Ministry of Health, Labour and Welfare; Japan Society for the Promotion of Science FX The authors dedicate this article to the late Dr. Masayoshi Mai whose continuous support and encouragement was instrumental for the works carried out in our laboratory. We thank Dr. Barry Iacopetta (School of Surgery, University of Western Australia) for critical reading of the manuscript. This work was funded in part by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Science, Sports, Technology and Culture, from the Ministry of Health, Labour and Welfare, and from the Japan Society for the Promotion of Science. NR 134 TC 30 Z9 33 U1 0 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1871-5206 J9 ANTI-CANCER AGENT ME JI Anti-Cancer Agents Med. Chem. PD DEC PY 2009 VL 9 IS 10 BP 1114 EP 1122 PG 9 WC Oncology; Chemistry, Medicinal SC Oncology; Pharmacology & Pharmacy GA 513RO UT WOS:000271341100010 PM 19925395 ER PT J AU Zheng, XH Mueller, GA DeRose, EF London, RE AF Zheng, Xunhai Mueller, Geoffrey A. DeRose, Eugene F. London, Robert E. TI Solution characterization of [methyl-C-13]methionine HIV-1 reverse transcriptase by NMR spectroscopy SO ANTIVIRAL RESEARCH LA English DT Article DE HIV-1 reverse transcriptase; Solution behavior; [Methyl-C-13]methionine labeled; NMR spectroscopy ID IMMUNODEFICIENCY-VIRUS TYPE-1; NONNUCLEOSIDE INHIBITORS; PRIMER GRIP; CONFORMATIONAL-CHANGES; ANGSTROM RESOLUTION; CRYSTAL-STRUCTURES; ESCHERICHIA-COLI; TEMPLATE-PRIMER; MECHANISM; PROTEINS AB HIV reverse transcriptase (RT) is a primary target for drug intervention in the treatment of AIDS. We report the first solution NMR studies of [methyl-C-13]methionine HIV-1 RT, aimed at better understanding the conformational and dynamic characteristics of RT,both in the presence and absence of the non-nucleoside RT inhibitor (NNRTI) nevirapine. The selection of methionine as a structural probe was based both on its favorable NMR characteristics, and on the presence of two important active site methionine residues, M184(66) and M230(66). Observation of the M184 resonance is subunit dependent; in the p66 subunit the solvent-exposed residue produces a readily observed signal with a characteristic resonance shift, while in the globular p51 subunit, the M184(51) resonance is shifted and broadened as M184 becomes buried in the protein interior. In contrast, although structural data indicates that the environment of M230 is also strongly subunit dependent, the M230 resonances from both subunits have very similar shift and relaxation characteristics. A comparison of chemical shift and intensity data with model-based predictions gives reasonable agreement for M184(66), While M230(66), located on the beta-hairpin "primer grip", is more mobile and solvent-exposed than suggested by crystal structures of the apo enzyme which have a "closed" fingers-thumb conformation. This mobility of the primer grip is presumably important for binding of non-nucleoside RT inhibitors (NNRTIs), since the NNRTI binding pocket is not observed in the absence of the inhibitors, requiring instead that the binding pocket be dynamically accessible. In the presence of the nevirapine, both the M184(66) and M230(66) resonances are significantly perturbed, while none of the methionine resonances in the p51 subunit is sensitive to this inhibitor. Site-directed mutagenesis indicates that both M16 and M357 produce two resonances in each subunit, and for both residues, the intensity ratio of the component peaks is strongly subunit dependent. Conformational features that might explain the multiple peaks are discussed. Published by Elsevier B.V. C1 [Zheng, Xunhai; Mueller, Geoffrey A.; DeRose, Eugene F.; London, Robert E.] NIEHS, Mol Biophys Lab, NIH, Res Triangle Pk, NC 27709 USA. RP London, RE (reprint author), NIEHS, Mol Biophys Lab, NIH, 111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov RI Zheng, Xunhai/G-1187-2015 OI Zheng, Xunhai/0000-0003-0390-2491 FU National Institutes of Health [Z01-ES050147] FX This research was supported by Research Project number Z01-ES050147 to REL in the Intramural Research Program of the National Institutes of Health. NR 46 TC 14 Z9 14 U1 0 U2 7 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 2009 VL 84 IS 3 BP 205 EP 214 DI 10.1016/j.antiviral.2009.07.021 PG 10 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 527YF UT WOS:000272406500001 PM 19665484 ER PT J AU Yutin, N Suzuki, MT Rosenberg, M Rotem, D Madigan, MT Suling, J Imhoff, JF Beja, O AF Yutin, Natalya Suzuki, Marcelino T. Rosenberg, Mira Rotem, Denisse Madigan, Michael T. Sueling, Joerg Imhoff, Johannes F. Beja, Oded TI BchY-Based Degenerate Primers Target All Types of Anoxygenic Photosynthetic Bacteria in a Single PCR SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID MATTHEWS-OLSON PROTEIN; GREEN SULFUR BACTERIA; 16S RIBOSOMAL-RNA; GENE-SEQUENCES; LAKE KINNERET; SP-NOV.; MARINE; DIVERSITY; PHOTOTROPHS; BIOGEOGRAPHY AB To detect anoxygenic bacteria containing either type 1 or type 2 photosynthetic reaction centers in a single PCR, we designed a degenerate primer set based on the bchY gene. The new primers were validated in silico using the GenBank nucleotide database as well as by PCR on pure strains and environmental DNA. C1 [Yutin, Natalya] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Yutin, Natalya; Rosenberg, Mira; Beja, Oded] Technion Israel Inst Technol, Fac Biol, IL-32000 Haifa, Israel. [Suzuki, Marcelino T.] Univ Maryland, Chesapeake Biol Lab, Ctr Environm Sci, Solomons, MD 20688 USA. [Rotem, Denisse] Ort Braude Coll, Biotechnol Engn Unit, IL-21982 Karmiel, Israel. [Madigan, Michael T.] So Illinois Univ, Dept Microbiol, Carbondale, IL 62901 USA. [Sueling, Joerg; Imhoff, Johannes F.] Leibniz Inst Meereswissensch IFM GEOMAR, D-24105 Kiel, Germany. RP Yutin, N (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM yutin@ncbi.nlm.nih.gov RI Imhoff, Johannes/D-2515-2010; Suling, Jorg/H-1042-2011; Suling, Jorg/A-7384-2014; Suzuki, Marcelino/D-3329-2009 OI Suzuki, Marcelino/0000-0003-3868-6362 FU National Institutes of Health; National Library of Medicine; Israel Science Foundation [434/02]; Israeli Ministry of Science and Technology; EMBO YIP award; U.S. National Science Foundation [NSF-0950550, OCE-0550547] FX This work was supported in part by the Department of Health and Human Services intramural program of the National Institutes of Health, National Library of Medicine (N. Y.); grant 434/02 from the Israel Science Foundation (O. B.); a grant from the Israeli Ministry of Science and Technology; an EMBO YIP award (O. B.); and grants NSF-0950550 (M. T. M.) and OCE-0550547 (M. T. S.) from the U.S. National Science Foundation. NR 20 TC 8 Z9 10 U1 0 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD DEC 1 PY 2009 VL 75 IS 23 BP 7556 EP 7559 DI 10.1128/AEM.01014-09 PG 4 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 521SR UT WOS:000271944800032 PM 19801482 ER PT J AU Duncan, WC Barbato, G Fagioli, I Garcia-Borreguero, D Wehr, TA AF Duncan, W. C. Barbato, G. Fagioli, I. Garcia-Borreguero, D. Wehr, T. A. TI A biphasic daily pattern of Slow Wave Activity during a two-day 90-minute sleep wake schedule SO ARCHIVES ITALIENNES DE BIOLOGIE LA English DT Article DE SWA; SWS; Rate of Synchronisation; Circadian rhythm; 30:60 sleep-wake schedule ID EXTENDED SLEEP; REM-SLEEP; CIRCADIAN MODULATION; BODY-TEMPERATURE; HUMANS; EEG; DYNAMICS; DEPRIVATION; HOMEOSTASIS; RHYTHMS AB Twenty-four hour sleep patterns were measured in six healthy male volunteers during a 90-minute short sleep-wake (SW 30:60) cycle protocol for 48 hours. Sleep pressure estimates (amount of Slow Wave Sleep [SWS]. SWA, and Rate of Synchronization [RoS: the rate of SWA build-up at the beginning of the NREM period]) were compared with the 24-hour patterns of body temperature (Tb(24)) and sleep propensity. A moderate sleep debt was incurred over the 48 hour study as indicated by decreased levels of 24 hour sleep. On day 1, ultradian patterns of REM and SWS sleep were prominent; on day 2, more prominent were circadian patterns of REM sleep, SWS, Sleep Latency, TST and Tb(24). Also on Day 2, biphasic patterns of SWA and RoS were expressed, with peaks occuring during the falling and rising limbs of Tb(24). The biphasic peaks in SWA and RoS may be associated with phase-specific interactions of the circadian pacemaker with the sleep homeostat during conditions of moderate sleep prerssure. Further research is needed to replicate the finding and to identify biological factors that may underlie the twelve hour pattern in SWA. C1 [Duncan, W. C.] NIMH, Mood & Anxiety Disorders Program, NIH, IRP, Bethesda, MD 20892 USA. [Barbato, G.] Univ Naples 2, Dept Psychol, Naples, Italy. [Fagioli, I.] Univ Florence, Dept Psychol, I-50121 Florence, Italy. [Garcia-Borreguero, D.] Fdn Jimenez Diaz, Dept Neurol, E-28040 Madrid, Spain. RP Duncan, WC (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, IRP, Bethesda, MD 20892 USA. EM wduncan@mail.nih.gov RI Barbato, Giuseppe/Q-9774-2016 OI Barbato, Giuseppe/0000-0001-6523-5327 FU Intramural Program of the NIH; National Institute of Mental Health FX This research was supported by the Intramural Program of the NIH, and the National Institute of Mental Health. NR 50 TC 1 Z9 1 U1 0 U2 3 PU UNIV PISA PI PISA PA LUNGARNO A PACINOTTI 43, 56100 PISA, ITALY SN 0003-9829 J9 ARCH ITAL BIOL JI Arch. Ital. Biol. PD DEC PY 2009 VL 147 IS 4 BP 117 EP 130 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 548XR UT WOS:000274003800002 PM 20162861 ER PT J AU Levin, SW Baker, EH Gropman, A Quezado, Z Miao, N Zhang, ZJ Jollands, A Di Capua, M Caruso, R Mukherjee, AB AF Levin, Sondra W. Baker, Eva H. Gropman, Andrea Quezado, Zenaide Miao, Ning Zhang, Zhongjian Jollands, Alice Di Capua, Matteo Caruso, Rafael Mukherjee, Anil B. TI Subdural Fluid Collections in Patients With Infantile Neuronal Ceroid Lipofuscinosis SO ARCHIVES OF NEUROLOGY LA English DT Article ID PALMITOYL-PROTEIN THIOESTERASE; TRAUMATIC BRAIN-INJURY; NEURODEGENERATIVE DISEASE; YOUNG-CHILDREN; MRI EVALUATION; HEMATOMAS; CHILDHOOD; DRUGS AB Objective: To describe subdural fluid collections on magnetic resonance imaging as part of the natural history of infantile neuronal ceroid lipofuscinosis. Design: Case series. Setting: Program on Developmental Endocrinology and Genetics, The Clinical Center, National Institutes of Health, Bethesda, Maryland. Patients: Patients with infantile neuronal ceroid lipofuscinosis with subdural fluid collections. Main Outcome Measure: Neurodegeneration on magnetic resonance imaging. Results: During an ongoing bench-to-bedside clinical investigation, magnetic resonance imaging examinations led to the incidental discovery of subdural fluid collections in 4 of 9 patients with infantile neuronal ceroid lipofuscinosis. No particular event (such as trauma) or change in symptoms was linked to this finding, which was already in the chronic phase when discovered. Of the 4 patients, I was followed up for 7 years, 2 for 4 years, and 1 for 2.5 years. Over time, these collections remained stable or decreased in size. Conclusion: Recognition that subdural fluid collections are part of the infantile neuronal ceroid lipofuscinosis disease process may obviate the necessity of additional workup as well as therapeutic interventions in these chronically sick children. C1 [Levin, Sondra W.] Walter Reed Army Med Ctr, Dept Pediat, Washington, DC 20307 USA. [Baker, Eva H.; Mukherjee, Anil B.] NIH, Mark O Hatfield Clin Res Ctr, Dept Radiol, Bethesda, MD 20892 USA. [Quezado, Zenaide; Miao, Ning] NIH, Dept Anesthesia & Surg Serv, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. [Gropman, Andrea] Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. [Jollands, Alice] Ninewells Hosp, Dept Pediat Neurol, Dundee DD1 9SY, Scotland. [Di Capua, Matteo] Bambino Gesu Pediat Hosp, Div Child Neurol, Rome, Italy. [Caruso, Rafael] NEI, Bethesda, MD 20892 USA. RP Mukherjee, AB (reprint author), NIH, Mark O Hatfield Clin Res Ctr, Dept Radiol, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 FU National Institute of Child Health and Human Development; National Institutes of Health FX This research was supported in full by the intramural program of the National Institute of Child Health and Human Development, National Institutes of Health. NR 22 TC 3 Z9 3 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD DEC PY 2009 VL 66 IS 12 BP 1567 EP 1571 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 529YB UT WOS:000272554200021 PM 20008666 ER PT J AU Vitale, S Sperduto, RD Ferris, FL AF Vitale, Susan Sperduto, Robert D. Ferris, Frederick L., III TI Increased Prevalence of Myopia in the United States Between 1971-1972 and 1999-2004 SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID REFRACTIVE ERROR; AUSTRALIA; ADULTS; EPIDEMIOLOGY; OVERWEIGHT; RISK AB Objective: To compare US population prevalence estimates for myopia in 1971-1972 and 1999-2004. Methods: The 1971-1972 National Health and Nutrition Examination Survey provided the earliest nationally representative estimates for US myopia prevalence; myopia was diagnosed by an algorithm using either lensometry, pinhole visual acuity, and presenting visual acuity (for presenting visual acuity >= 20/40) or retinoscopy (for presenting visual acuity <= 20/50). Using a similar method for diagnosing myopia, we examined data from the 1999-2004 National Health and Nutrition Examination Survey to determine whether myopia prevalence had changed during the 30 years between the 2 surveys. Results: Using the 1971-1972 method, the estimated prevalence of myopia in persons aged 12 to 54 years was significantly higher in 1999-2004 than in 1971-1972 (41.6% vs 25.0%, respectively; P < .001). Prevalence estimates were higher in 1999-2004 than in 1971-1972 for black individuals (33.5% vs 13.0%, respectively; P < .001) and white individuals (43.0% vs 26.3%, respectively; P < .001.) and for all levels of myopia severity (>-2.0 diopters [D]: 17.5% vs 13.4%, respectively [P < .001]; <=-2.0 to >-7.9 D: 22.4% vs 11.4%, respectively [P < .001]; <=-7.9 D: 1.6% vs 0.2%, respectively [P<.001]). Conclusions: When using similar methods for each period, the prevalence of myopia in the United States appears to be substantially higher in 1999-2004 than 30 years earlier. Identifying modifiable risk factors for myopia could lead to the development of cost-effective interventional strategies. C1 [Vitale, Susan; Sperduto, Robert D.; Ferris, Frederick L., III] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. RP Vitale, S (reprint author), NEI, Div Epidemiol & Clin Applicat, NIH, 10 Ctr Dr,Room 10D45,Mail Stop 1863, Bethesda, MD 20892 USA. EM sev@nei.nih.gov FU National Center for Health Statistics; Centers for Disease Control and Prevention; NHANES Vision Component [Z01EY000402]; National Eye Institute; National Institutes of Health FX The NHANES is sponsored by the National Center for Health Statistics, Centers for Disease Control and Prevention. Additional funding for the NHANES Vision Component was provided by Intramural Research Program Z01EY000402 of the National Eye Institute, National Institutes of Health. NR 31 TC 261 Z9 270 U1 16 U2 35 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2009 VL 127 IS 12 BP 1632 EP 1639 PG 8 WC Ophthalmology SC Ophthalmology GA 529YC UT WOS:000272554300013 PM 20008719 ER PT J AU Chew, EY Lindblad, AS Clemons, T AF Chew, Emily Y. Lindblad, Anne S. Clemons, Traci CA Age Related Eye Dis Study Res Grp TI Summary Results and Recommendations From the Age-Related Eye Disease Study SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID HIGH-DOSE SUPPLEMENTATION; BETA-CAROTENE; MACULAR DEGENERATION; VITAMIN-E; CLINICAL-TRIAL; UNITED-STATES; LUNG-CANCER; VISION LOSS; ZINC; ANTIOXIDANTS C1 [Chew, Emily Y.] NEI, NIH, Div Epidemiol & Clin Applicat, Clin Res Ctr, Bethesda, MD 20892 USA. [Lindblad, Anne S.; Clemons, Traci] EMMES Corp, Rockville, MD USA. RP Chew, EY (reprint author), NEI, NIH, Div Epidemiol & Clin Applicat, Clin Res Ctr, 10 Ctr Dr,Bldg 10,Room 3-2531,Mail Stop Ctr 1204, Bethesda, MD 20892 USA. EM echew@nei.nih.gov FU Intramural NIH HHS [Z99 EY999999, ZIA EY000489-01] NR 11 TC 21 Z9 21 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD DEC PY 2009 VL 127 IS 12 BP 1678 EP 1679 PG 2 WC Ophthalmology SC Ophthalmology GA 529YC UT WOS:000272554300023 PM 20008727 ER PT J AU Vosters, JL Landek-Salgado, MA Yin, HG Swaim, WD Kimura, H Tak, PP Caturegli, P Chiorini, JA AF Vosters, Jelle L. Landek-Salgado, Melissa A. Yin, Hongen Swaim, William D. Kimura, Hiroaki Tak, Paul P. Caturegli, Patrizio Chiorini, John A. TI Interleukin-12 Induces Salivary Gland Dysfunction in Transgenic Mice, Providing a New Model of Sjogren's Syndrome SO ARTHRITIS AND RHEUMATISM LA English DT Article ID SPONTANEOUS AUTOIMMUNE-DISEASE; MRL/MP-LPR/LPR MICE; GENE-TRANSFER; MURINE MODEL; NOD MICE; CYTOKINE; IL-12; ANTIBODIES; INDUCTION; ARTHRITIS AB Objective. Interleukin-12 (IL-12) is a pleiotropic cytokine that is elevated in the affected organs of patients with Sjogren's syndrome (SS). We have previously reported that overexpression of IL-12 in CBA mice leads to mononuclear infiltration of salivary and lacrimal glands, as well as to expansion of bronchial lymphoid tissue and decreased mucociliary clearance. Because xerostomia is one of the most important clinical features in SS patients, our main objective in the current study was to evaluate salivary gland function in IL-12-transgenic mice. Our secondary objective was to further characterize this animal model and to determine if the changes observed in these mice are representative of those observed in patients with SS overall. Methods. Pilocarpine-stimulated salivary flow was used to address salivary gland function in a large group of IL-12-transgenic mice bred onto the autoimmune-prone SJL background. Furthermore, salivary glands were removed to assess the formation of infiltrates in the glands and gland morphology. Serum was also collected from these animals to investigate the formation of autoantibodies. Results. Pilocarpine-stimulated salivary flow was significantly lower in IL-12-transgenic mice than in wild-type controls. Salivary glands from transgenic mice exhibited an increase in both the number and the size of lymphocytic foci, versus glands from age-matched controls. Furthermore, the acini in transgenic mice were fewer in number and larger in size compared with acini in controls. An age-dependent increase in anti-SSB/La antibodies was observed in IL-12-transgenic mice and was accompanied by an increase in antinuclear antibodies. Conclusion. Our findings indicate that a number of conditions associated with SS are exhibited by IL-12-transgenic SJL mice and that this model might be useful in researching multiple aspects of the disease. C1 [Vosters, Jelle L.; Yin, Hongen; Swaim, William D.; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Vosters, Jelle L.; Tak, Paul P.] Univ Amsterdam, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Landek-Salgado, Melissa A.; Kimura, Hiroaki; Caturegli, Patrizio] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Caturegli, Patrizio] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Chiorini, JA (reprint author), Natl Inst Dent & Craniofacial Res, NIH, 10-1N113,10 Ctr Dr,MSC1190, Bethesda, MD 20892 USA. EM pcat@jhmi.edu; jchiorini@dir.nider.nih.gov OI Landek-Salgado, Melissa/0000-0002-4707-2066 FU Dutch Arthritis Association [NR 07-1-406]; Sjogren's Syndrome Foundation; National Institute of Dental and Craniofacial Research, NIH FX Dr. Vosters' work was supported by a grant from the Dutch Arthritis Association (NR 07-1-406). Dr. Caturegli's work was supported by a grant from the Sjogren's Syndrome Foundation. Dr. Chiorini's work was supported by an intramural research grant from the National Institute of Dental and Craniofacial Research, NIH. NR 24 TC 25 Z9 25 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD DEC PY 2009 VL 60 IS 12 BP 3633 EP 3641 DI 10.1002/art.24980 PG 9 WC Rheumatology SC Rheumatology GA 531BC UT WOS:000272636700015 PM 19950301 ER PT J AU Tanega, C Shen, M Mott, BT Thomas, CJ MacArthur, R Inglese, J Auld, DS AF Tanega, Cordelle Shen, Min Mott, Bryan T. Thomas, Craig J. MacArthur, Ryan Inglese, James Auld, Douglas S. TI Comparison of Bioluminescent Kinase Assays Using Substrate Depletion and Product Formation SO ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES LA English DT Article ID FLUORESCENCE POLARIZATION DETECTION; THROUGHPUT SCREENING ASSAYS; RESONANCE ENERGY-TRANSFER; CHEMICAL LIBRARIES; PYRUVATE-KINASE; PROTEIN-KINASES; IDENTIFICATION; LUCIFERASE; INHIBITORS; SERINE/THREONINE AB Assays for ATPases have been enabled for high-throughput screening (HTS) by employing firefly luciferase to detect the remaining ATP in the assay. However, for any enzyme assay, measurement of product formation is a more sensitive assay design. Recently, technologies that allow detection of the ADP product from ATPase reactions have been described using fluorescent methods of detection. We describe here the characterization of a bioluminescent assay that employs firefly luciferase in a coupled-enzyme assay format to enable detection of ADP levels from ATPase assays (ADP-Glo (R), Promega Corp.). We determined the performance of the ADP-Glo assay in 1,536-well microtiter plates using the protein kinase Clk4 and a 1,352 member kinase focused combinatorial library. The ADP-Glo assay was compared to the Clk4 assay performed using a bioluminescence ATP-depletion format (Kinase-Glo (TM), Promega Corp). We performed this analysis using quantitative HTS (qHTS) where we determined potency values for all library members and identified similar to 300 compounds with potencies ranging from as low as 50 nM to >10 mu M, yielding a robust dataset for the comparison. Both assay formats showed high performance (Z'-factors similar to 0.9) and showed a similar potency distribution for the actives. We conclude that the bioluminescence ADP detection assay system is a viable generic alternative to the widely used ATP-depletion assay for ATPases and discuss the advantages and disadvantages of both approaches. C1 [Tanega, Cordelle; Shen, Min; Mott, Bryan T.; Thomas, Craig J.; MacArthur, Ryan; Inglese, James; Auld, Douglas S.] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. RP Auld, DS (reprint author), NIH, Chem Genom Ctr, 9800 Med Ctr Dr, Rockville, MD 20850 USA. EM dauld@mail.nih.gov FU NIH Roadmap for Medical Research; National Human Genome Research Institute; National Institutes of Health FX This research was supported by the Molecular Libraries Initiative of the NIH Roadmap for Medical Research and the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The authors wish to acknowledge Paul Shinn for help with compound management. NR 33 TC 12 Z9 13 U1 1 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-658X J9 ASSAY DRUG DEV TECHN JI ASSAY DRUG DEV. TECHNOL. PD DEC PY 2009 VL 7 IS 6 BP 606 EP 614 DI 10.1089/adt.2009.0230 PG 9 WC Biochemical Research Methods; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 549BC UT WOS:000274014800006 PM 20059377 ER PT J AU Reis, JP von Muhlen, D Michos, ED Miller, ER Appel, LJ Araneta, MR Barrett-Connor, E AF Reis, Jared P. von Muehlen, Denise Michos, Erin D. Miller, Edgar R., III Appel, Lawrence J. Araneta, Maria R. Barrett-Connor, Elizabeth TI Serum vitamin D, parathyroid hormone levels, and carotid atherosclerosis SO ATHEROSCLEROSIS LA English DT Article DE Atherosclerosis; Vitamin D; Parathyroid hormone; Cardiovascular diseases ID INTIMA-MEDIA THICKNESS; SMOOTH-MUSCLE-CELLS; BEAM COMPUTED-TOMOGRAPHY; 25-HYDROXYVITAMIN-D LEVELS; CARDIOVASCULAR-DISEASE; HEART-DISEASE; PRIMARY HYPERPARATHYROIDISM; 1,25-DIHYDROXYVITAMIN D-3; CIRCULATING CONCENTRATION; MYOCARDIAL-INFARCTION AB Evidence suggests low vitamin D and elevated parathyroid hormone (PTH) concentrations may increase risk for cardiovascular disease. However, little is known about the association between vitamin D or PTH and subclinical atherosclerosis. This cross-sectional study included 654 community-dwelling older adults aged 55-96 years (mean age, 75.5 years) without a history of coronary heart disease, revascularization, or stroke enrolled in the Rancho Bernardo Study who completed a clinic examination in 1997-1999 and provided a blood sample for determination of serum 25-hydroxyvitamin D[25(OH) D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and PTH concentrations. Carotid artery intima-media wall thickness (IMT) was measured as an indicator of atherosclerosis at two sites with B-mode ultrasound. After adjusting for age, sex, smoking, alcohol intake, waist-to-hip ratio, exercise, season of blood draw, diabetes, and hypertension, geometric mean internal carotid IMT (p(trend) 0.022), but not common carotid IMT (p(trend) 0.834) decreased in a dose-dependent fashion with increasing concentration of 25(OH) D. There was no association of 1,25(OH)(2)D or PTH with either measure of carotid IMT. In subgroup analyses, 1,25(OH)(2)D was inversely associated with internal carotid IMT among those with hypertension (p for interaction 0.036). These findings from a population-based cohort of older adults suggest a potential role for vitamin D in the development of subclinical atherosclerosis. Additional research is needed to determine whether vitamin D may influence the progression of atherosclerosis, including the effects of supplementation on the atherosclerotic process. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Reis, Jared P.; Miller, Edgar R., III; Appel, Lawrence J.] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. [von Muehlen, Denise; Araneta, Maria R.; Barrett-Connor, Elizabeth] Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. [Michos, Erin D.] Johns Hopkins Sch Med, Div Cardiol, Baltimore, MD USA. RP Reis, JP (reprint author), NHLBI, Div Prevent & Populat Sci, 6701 Rockledge Dr,Suite 10197, Bethesda, MD 20892 USA. EM reisjp@nhlbi.nih.gov FU National Institute of Diabetes and Digestive and Kidney Diseases [DK31801]; National Institute on Aging [AG07181]; National Heart, Lung, and Blood Institute [T32 HL07024] FX The Rancho Bernardo Study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK31801) and by the National Institute on Aging (AG07181). JPR was supported by a grant from the National Heart, Lung, and Blood Institute (T32 HL07024). None of the other authors have any personal or professional conflict of interest. NR 44 TC 83 Z9 88 U1 0 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD DEC PY 2009 VL 207 IS 2 BP 585 EP 590 DI 10.1016/j.atherosclerosis.2009.05.030 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 543IB UT WOS:000273566700048 PM 19539290 ER PT J AU Yerys, BE Wallace, GL Sokoloff, JL Shook, DA James, JD Kenworthy, L AF Yerys, Benjamin E. Wallace, Gregory L. Sokoloff, Jennifer L. Shook, Devon A. James, Joette D. Kenworthy, Lauren TI Attention Deficit/Hyperactivity Disorder Symptoms Moderate Cognition and Behavior in Children With Autism Spectrum Disorders SO AUTISM RESEARCH LA English DT Article DE clinical psychology; neuropsychology; school age < pediatrics; psychopathology ID DEFICIT-HYPERACTIVITY DISORDER; PERVASIVE DEVELOPMENTAL DISORDERS; DIAGNOSTIC OBSERVATION SCHEDULE; HIGHER FUNCTIONING INDIVIDUALS; RECIPROCAL SOCIAL-BEHAVIOR; EXECUTIVE FUNCTION; COMMUNICATION ABILITIES; ADAPTIVE SKILLS; TWIN SAMPLE; ADHD AB Recent estimates suggest that 31% of children with autism spectrum disorders (ASD) meet diagnostic criteria for attention deficit/hyperactivity disorder (ADHD), and another 24% of children with ASD exhibit subthreshold clinical ADHD symptoms. Presence of ADHD symptoms in the context of ASD could have a variety of effects on cognition, autistic traits, and adaptive/maladaptive behaviors including: exacerbating core ASD impairments; adding unique impairments specific to ADHD; producing new problems unreported in ASD or ADHD; having no clear impact; or producing some combination of these scenarios. Children with ASD and co-morbid ADHD symptoms (ASD+ADHD; n = 21), children with ASD without ADHD (ASD; n = 28), and a typically developing control group (n = 21) were included in the study; all groups were matched on age, gender-ratio, 10, and socioeconomic status. Data were collected on verbal and spatial working memory, response inhibition, global executive control (EC), autistic traits, adaptive functioning, and maladaptive behavior problems. In this sample, the presence of ADHD symptoms in ASD exacerbated impairments in EC and adaptive behavior and resulted in higher autistic trait, and externalizing behavior ratings. ADHD symptoms were also associated with greater impairments on a lab measure of verbal working memory. These findings suggest that children with ASD+ADHD symptoms present with exacerbated impairments in some but not all domains of functioning relative to children with ASD, most notably in adaptive behavior and working memory. Therefore, ADHD may moderate the expression of components of the ASD cognitive and behavioral phenotype, but ASD+ADHD may not represent an etiologically distinct phenotype from ASD alone. C1 [Yerys, Benjamin E.; Sokoloff, Jennifer L.; James, Joette D.; Kenworthy, Lauren] Childrens Natl Med Ctr, Childrens Res Inst Neurosci, Washington, DC 20010 USA. [Yerys, Benjamin E.; Sokoloff, Jennifer L.; James, Joette D.; Kenworthy, Lauren] Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Washington, DC 20010 USA. [Wallace, Gregory L.] NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. [Shook, Devon A.] Georgetown Univ, Dept Psychol, Washington, DC 20057 USA. RP Yerys, BE (reprint author), Childrens Natl Med Ctr, Childrens Res Inst Neurosci, 111 Michigan Ave NW, Washington, DC 20010 USA. EM byers@cnmc.org OI Wallace, Gregory/0000-0003-0329-5054 FU Frederick and Elizabeth Singer Foundation; NIH [IDDRC P30HD40677, NIH T32HD046388]; National Institute of Mental Health Intramural Research Program [U54 MH066417]; Studies for the Advancement of Autism Research and Treatment; Intellectual and Developmental Disabilities Research Center at Children's National Medical Center; General Clinic Research Center [NIH GCRC M01-RR13297] FX Grant sponsors: Frederick and Elizabeth Singer Foundation; NIH; National Institute of Mental Health Intramural Research Program; Studies for the Advancement of Autism Research and Treatment; Grant number: NIMH U54 MH066417; Grant sponsor: Intellectual and Developmental Disabilities Research Center at Children's National Medical Center; Grant numbers: NIH IDDRC P30HD40677; NIH T32HD046388; Grant sponsor: General Clinic Research Center; Grant number: NIH GCRC M01-RR13297. NR 75 TC 86 Z9 89 U1 13 U2 24 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1939-3792 J9 AUTISM RES JI Autism Res. PD DEC PY 2009 VL 2 IS 6 BP 322 EP 333 DI 10.1002/aur.103 PG 12 WC Behavioral Sciences; Psychology, Developmental SC Behavioral Sciences; Psychology GA 546II UT WOS:000273804100003 PM 19998356 ER PT J AU Mosack, KE Weinhardt, LS Kelly, JA Gore-Felton, C McAuliffe, TL Johnson, MO Remien, RH Rotheram-Borus, MJ Ehrhardt, AA Chesney, MA Morin, SF AF Mosack, Katie E. Weinhardt, Lance S. Kelly, Jeffrey A. Gore-Felton, Cheryl McAuliffe, Timothy L. Johnson, Mallory O. Remien, Robert H. Rotheram-Borus, Mary Jane Ehrhardt, Anke A. Chesney, Margaret A. Morin, Stephen F. TI Influenced Coping, Social Support, and Depression on Subjective Health Status Among HIV-Positive Adults With Different Sexual Identities SO BEHAVIORAL MEDICINE LA English DT Article DE coping; depression; HIV; sexual identity; symptoms; social support ID QUALITY-OF-LIFE; HUMAN-IMMUNODEFICIENCY-VIRUS; GAY MEN; REPRESENTATIVE SURVEY; HOMOSEXUAL IDENTITY; SYMPTOM PREVALENCE; EMOTIONAL DISTRESS; TRANSMISSION RISK; INFECTED MEN; WOMEN AB The authors examined associations between psychosocial variables (coping self-efficacy, social support, and cognitive depression) and subjective health status among a large national sample (N = 3,670) of human immunodeficiency virus (HIV)-positive persons with different sexual identities. After controlling for ethnicity, heterosexual men reported fewer symptoms than did either bisexual or gay men and heterosexual women reported fewer symptoms than did bisexual women. Heterosexual and bisexual women reported greater symptom intrusiveness than did heterosexual or gay men. Coping self-efficacy and cognitive depression independently explained symptom reports and Symptom intrusiveness for heterosexual, gay, and bisexual men. Coping self-efficacy and cognitive depression explained symptom intrusiveness among heterosexual women. Cognitive depression significantly contributed to the number of symptom reports for heterosexual and bisexual women and to symptom intrusiveness for lesbian and bisexual women. Individuals likely experience HIV differently on the basis of sociocultural realities associated with sexual identity. Further symptom intrusiveness may be a more sensitive measure of subjective health status for these groups. C1 [Mosack, Katie E.] Univ Wisconsin, Dept Psychol, Milwaukee, WI 53201 USA. [Weinhardt, Lance S.; McAuliffe, Timothy L.] Med Coll Wisconsin, Dept Psychiat & Behav Med, Milwaukee, WI 53226 USA. [Gore-Felton, Cheryl] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. [Johnson, Mallory O.; Morin, Stephen F.] Univ Calif San Francisco, Ctr AIDS Prevent Studies, San Francisco, CA 94143 USA. [Rotheram-Borus, Mary Jane] Univ Calif Los Angeles, HIV Identificat Prevent & Treatment Serv, Los Angeles, CA USA. [Remien, Robert H.; Ehrhardt, Anke A.] New York State Psychiat Inst & Hosp, HIV Ctr Clin & Behav Studies, New York, NY 10032 USA. [Ehrhardt, Anke A.] Columbia Univ, New York, NY USA. [Chesney, Margaret A.] Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. RP Mosack, KE (reprint author), Univ Wisconsin, Dept Psychol, POB 413, Milwaukee, WI 53201 USA. EM kemosack@uwm.edu FU NIMH NIH HHS [U10MH057615, P30 MH043520, R01 MH057631, R01 MH057631-01A1, U10 MH057615, U10 MH057616, U10 MH057631, U10 MH057636, U10MH057616, U10MH057631, U10MH057636] NR 55 TC 17 Z9 18 U1 4 U2 12 PU HELDREF PUBLICATIONS PI WASHINGTON PA 1319 EIGHTEENTH ST NW, WASHINGTON, DC 20036-1802 USA SN 0896-4289 J9 BEHAV MED JI Behav. Med. PD WIN PY 2009 VL 34 IS 4 BP 133 EP 144 DI 10.3200/BMED.34.4.133-144 PG 12 WC Behavioral Sciences; Psychiatry SC Behavioral Sciences; Psychiatry GA 383CW UT WOS:000261652700002 PM 19064372 ER PT J AU Fedorova, I Alvheim, AR Hussein, N Salem, N AF Fedorova, Irina Alvheim, Anita R. Hussein, Nahed Salem, Norman, Jr. TI Deficit in Prepulse Inhibition in Mice Caused by Dietary n-3 Fatty Acid Deficiency SO BEHAVIORAL NEUROSCIENCE LA English DT Article DE prepulse inhibition; PPI; DHA; n-3 fatty acid deficiency ID MAGNETIC-RESONANCE-SPECTROSCOPY; MEMBRANE PHOSPHOLIPID-METABOLISM; SCHIZOPHRENIC-PATIENTS; DOCOSAHEXAENOIC ACID; EICOSAPENTAENOIC ACID; PREFRONTAL CORTEX; ACOUSTIC STARTLE; SYMPTOMS; REFLEX; OMEGA-3-FATTY-ACIDS AB Docosahexatenoic acid (DHA) and eicosapentaenoic acid (EPA) may be biosynthesized from a precursor alpha-linolenic acid (LNA) or obtained preformed in the diet. Dams were fed four diets with different level, of the various n-3 fatty acids during pregnancy and lactation, and their offspring were weaned to the same diet,. "n-3 Deficient." containing (as % total fatty acids) 0.07% of LNA; "Low LNA" (0.4%): "High LNA" (4.8%), and a "DHA + EPA(-) diet, containing 0.4% of LNA. 2%. DHA. ani 2%. EPA. Sensorimotor gating was measured by prepulse inhibition (PPI) or the acoustic startle response in C57B16 mice The n-3 Deficient and Low LNA diets caused a substantial deficit in PPI compared to the DHA + EPA diet, whereas the High LNA diet induced a less pronounced, bill significant reduction of PPI. These are the first data that demonstrate a deficit in sensorimotor gating in rodents caused by an inadequate amount of the n-3 fatty acids in the diet Our results differentiate the effects of a High LNA diet from one with added EPA and DHA even though the difference in brain DHA content is only 12% between these dietary groups C1 [Fedorova, Irina; Hussein, Nahed; Salem, Norman, Jr.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD USA. [Alvheim, Anita R.] Natl Inst Nutr & Seafood Res, Natl Inst Hlth, Natl Inst Alcohol Abuse & Alcoholism, Lab Membrane Biochem & Biophys, Bergen, Norway. RP Fedorova, I (reprint author), Martek Biosci Corp, 6480 Dobbin Rd, Columbia, MD 21045 USA. EM idahms@martek.com FU Intramural NIH HHS [Z01 AA000235-25] NR 49 TC 15 Z9 15 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0735-7044 J9 BEHAV NEUROSCI JI Behav. Neurosci. PD DEC PY 2009 VL 123 IS 6 BP 1218 EP 1225 DI 10.1037/a0017446 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 532HP UT WOS:000272738100007 PM 20001105 ER PT J AU Soto, PL Hiranita, T Katz, JL AF Soto, Paul L. Hiranita, Takato Katz, Jonathan L. TI Citalopram enhances cocaine's subjective effects in rats SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE citalopram; cocaine; drug discrimination; rats ID SEROTONIN REUPTAKE INHIBITORS; DISCRIMINATIVE STIMULUS PROPERTIES; INDUCED LOCOMOTOR-ACTIVITY; SELECTIVE SEROTONIN; NUCLEUS-ACCUMBENS; SQUIRREL-MONKEYS; N-DEMETHYLATION; MODULATION; DOPAMINE; FLUOXETINE AB Serotonin-selective reuptake inhibitors (SSRIs) have been shown to enhance the locomotor stimulatory, discriminative-stimulus, and convulsive effects of cocaine in rodents. A pharmacokinetic mechanism for the interaction is supported by increases in the brain levels of cocaine by fluoxetine treatment Furthermore, the locomotor-stimulant effects of cocaine in rodents are enhanced by fluoxetine and fluvoxamine, SSRIs known to inhibit cocaine-metabolizing cytochrome P450 enzymes, whereas citalopram, an SSRI that does not inhibit P450 enzymes, does not enhance cocaine's locomotor-stimulant effects. Citalopram, however, attenuated the discriminative-stimulus effects of cocaine in squirrel monkeys trained to discriminate cocaine from saline, though it enhanced the discriminative-stimulus effects of a low dose of cocaine in rats trained to discriminate high and low doses of the drug. This study investigated the effects of citalopram on cocaine's discriminative-stimulus effects in rats trained more simply to discriminate cocaine from saline. Citalopram alone produced predominantly saline-appropriate responding, but when administered before cocaine, citalopram dose-dependently shifted the cocaine dose-response curve leftward. The present findings suggest that enhancement of cocaine's discriminative-stimulus effects may occur through a mechanism different from that underlying enhancement of cocaine's locomotor effects or that another action of citalopram selectively blocks locomotor enhancement. Behavioural Pharmacology 20:759-762 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins. C1 [Soto, Paul L.] Johns Hopkins Univ, Behav Biol Res Ctr, Baltimore, MD 21224 USA. [Soto, Paul L.; Hiranita, Takato; Katz, Jonathan L.] NIDA, Baltimore, MD USA. RP Soto, PL (reprint author), Johns Hopkins Univ, Behav Biol Res Ctr, 5510 Nathan Shock Dr,Suite 3000, Baltimore, MD 21224 USA. EM psoto@jhmi.edu RI Hiranita, Takato/G-6567-2011; OI Katz, Jonathan/0000-0002-1068-1159 FU Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse FX These studies were supported by the Intramural Research Program of the Department of Health and Human Services, National Institutes of Health, National Institute on Drug Abuse. NR 23 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD DEC PY 2009 VL 20 IS 8 BP 759 EP 762 DI 10.1097/FBP.0b013e328333a267 PG 4 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 526UR UT WOS:000272320600010 PM 20195220 ER PT J AU Pilotto, A Addante, F D'Onofrio, G Sancarlo, D Ferrucci, L AF Pilotto, Alberto Addante, Filomena D'Onofrio, Grazia Sancarlo, Daniele Ferrucci, Luigi TI The Comprehensive Geriatric Assessment and the multidimensional approach. A new look at the older patient with gastroenterological disorders SO BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY LA English DT Article DE Comprehensive Geriatric Assessment; Mortality; Multidimensional-Prognostic Index ID UPPER-GASTROINTESTINAL HEMORRHAGE; RISK SCORING SYSTEM; OUTPATIENT MANAGEMENT; PROGNOSTIC INDEX; ELDERLY PATIENTS; VALIDATION; MORTALITY; VARICES; PEOPLE; SCALE AB The Comprehensive Geriatric Assessment (CGA) is a multidimensional, usually interdisciplinary, diagnostic process intended to determine an elderly person's medical, psychosocial, and functional capacity and problems with the objective of developing an overall plan for treatment and short- and long-term follow-up. The potential usefulness of the CGA in evaluating treatment and follow-up of older patients with gastroenterological disorders is unknown. In the paper we reported the efficacy of a Multidimensional-Prognostic Index (MPI), calculated from information collected by a standardized CGA, in predicting mortality risk in older patients hospitalized with upper gastrointestinal bleeding and liver cirrhosis. Patients underwent a CGA that included six standardized scales, i.e. Activities of Daily Living (ADL), Instrumental Activities of Daily Living (IADL), Short-Portable Mental Status Questionnaire (SPMSQ), Mini-Nutritional Assessment (MNA), Exton-Smith Score (ESS) and Comorbity Index Rating Scale (CIRS), as well as information on medication history and cohabitation, for a total of 63 items. The MPI was calculated from the integrated total scores and expressed as MPI 1 = low risk, MPI 2 = moderate risk and MPI 3 = severe risk of mortality. Higher MPI values were significantly associated with higher short- and long-term mortality in older patients with both upper gastrointestinal bleeding and liver cirrhosis. A close agreement was found between the estimated mortality by MPI and the observed mortality. Moreover, MPI seems to have a greater discriminatory power than organ-specific prognostic indices such as Rockall and Blatchford scores (in upper gastrointestinal bleeding patients) and Child-Plugh score (in liver cirrhosis patients). All these findings support the concept that a multidimensional approach may be appropriate for the evaluation of older patients with gastroenterological disorders, like it has been reported for patients with other pathological conditions. (C) 2009 Elservier Ltd. All rights reserved. C1 [Pilotto, Alberto; Addante, Filomena; D'Onofrio, Grazia; Sancarlo, Daniele] IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Geriatr Unit, I-71013 San Giovanni Rotondo, FG, Italy. [Pilotto, Alberto; Addante, Filomena; D'Onofrio, Grazia; Sancarlo, Daniele] IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Gerontol Geriatr Res Lab, I-71013 San Giovanni Rotondo, FG, Italy. [Ferrucci, Luigi] Harbor Hosp Ctr, NIA, Longitudinal Studies Sect, Baltimore, MD USA. RP Pilotto, A (reprint author), IRCCS Casa Sollievo Sofferenza, Dept Med Sci, Geriatr Unit, Viale Cappuccini 1, I-71013 San Giovanni Rotondo, FG, Italy. EM alberto.pilotto@operapadrepio.it RI D'Onofrio, Grazia/K-9740-2016; Sancarlo, Daniele/C-1056-2017 OI D'Onofrio, Grazia/0000-0002-5905-6063; Sancarlo, Daniele/0000-0001-9541-6364 FU Ministero della Salute; IRCCS Research Program; NIH; National Institute on Aging FX This work was supported by grants from Ministero della Salute, IRCCS Research Program 2006-2008, Line 2: 'Malattie di rilevanza sociale' and in part by the Intramural Research Program of the NIH, National Institute on Aging. NR 35 TC 22 Z9 23 U1 2 U2 3 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1521-6918 J9 BEST PRACT RES CL GA JI Best Pract. Res. Clin. Gastroenterol. PD DEC PY 2009 VL 23 IS 6 BP 829 EP 837 DI 10.1016/j.bpg.2009.10.001 PG 9 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 537NZ UT WOS:000273121000005 PM 19942161 ER PT J AU Gaynutdinov, TI Brown, P Neumann, RD Panyutin, IG AF Gaynutdinov, Timur I. Brown, Patrick Neumann, Ronald D. Panyutin, Igor G. TI Duplex Formation at the 5 ' End Affects the Quadruplex Conformation of the Human Telomeric Repeat Overhang in Sodium but Not in Potassium SO BIOCHEMISTRY LA English DT Article ID INTRAMOLECULAR G-QUADRUPLEX; K+ SOLUTION; CIRCULAR-DICHROISM; HUMAN-CHROMOSOMES; DNA; POLYMORPHISM; FORMS; SEQUENCE; TETRAPLEX AB Human telomeres contain numerous copies of the (TTAGGG)(n).(AATCCC)(n) repeated sequence With multiple TTAGGG repeats in 3' single-stranded overhangs. Single-stranded oligonucleotides consisting of four TTAGGG repeats can fold into various intramolecular quadruplex structures stabilized by quartets of guanines. The quadruplex Structures are believed to play a role in telomere functions and considered as targets for anticancer drug design. In an effort to create a more realistic model of telomeric DNA, we designed oligonucleotides containing a duplex region at the 5' end and four telomeric repeats in the 3' overhang. We applied CD spectroscopy and (125)I radioprobing to determine the conformation of the quadruplexes formed in the 3' overhangs. We found that in the presence of NaCl the conformation of the quadruplex changes with formation of the 5' duplex and depends on the position of the interface between the duplex and the 3' telomeric sequence. When the duplex region extended to the first T of the first TTAGGG repeat, both CD and radioprobing data are consistent with the parallel propeller conformation of the overhang. In the presence of KCl, formation of the duplex at the 5' end of DNA molecules did not change the fold of the quadruplex in the overhang which was interpreted as a mixture of two isomers of 3+1 conformation regardless of the duplex-overhang interface position. Our results demonstrate that the interface between the duplex and single-stranded overhang can affect the conformation of the telomeric quadruplex. C1 [Gaynutdinov, Timur I.; Neumann, Ronald D.; Panyutin, Igor G.] NIH, CC, RAD&IS, Bethesda, MD 20892 USA. [Brown, Patrick] Natl Inst Biomed Imaging & Bioengn, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Panyutin, IG (reprint author), NIH, CC, RAD&IS, Bldg 10,Rm 1C401, Bethesda, MD 20892 USA. EM igorp@helix.nih.gov FU National Institutes of Health; Clinical Center; National Institute of Biomedical Imaging and Bioengineering FX This research was supported by the Intramural Research Program of the National Institutes of Health, Clinical Center, and the National Institute of Biomedical Imaging and Bioengineering. NR 31 TC 8 Z9 8 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD DEC 1 PY 2009 VL 48 IS 47 BP 11169 EP 11177 DI 10.1021/bi901063g PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 521UV UT WOS:000271950900006 PM 19856972 ER PT J AU Sengupta, A Carlson, BA Labunskyy, VM Gladyshev, VN Hatfield, DL AF Sengupta, Aniruddha Carlson, Bradley A. Labunskyy, Vyacheslav M. Gladyshev, Vadim N. Hatfield, Dolph L. TI Selenoprotein T deficiency alters cell adhesion and elevates selenoprotein W expression in murine fibroblast cells SO BIOCHEMISTRY AND CELL BIOLOGY-BIOCHIMIE ET BIOLOGIE CELLULAIRE LA English DT Article DE carbonyl reductase 3; oxidoreductase; selenoprotein T; selenoprotein T deficiency; selenoprotein W ID HUMAN CARBONYL REDUCTASE; CONTAINING PROTEINS; SELENIUM; IDENTIFICATION AB Mammalian selenoproteins have diverse functions, cellular locations, and evolutionary histories, but all use the amino acid selenocysteine ( Sec), often present in the enzyme's active site. Only about half of mammalian selenoproteins have been functionally characterized, with most being oxidoreductases. The cellular role of selenoprotein T ( SelT), manifesting a CxxU motif in a thioredoxin-like fold and localized to Golgi and the endoplasmic reticulum, is not known. To examine its biological function, we knocked down SelT expression in mouse fibroblast cells and found that SelT deficiency alters cell adhesion and enhances the expression of several oxidoreductase genes, while decreasing the expression of genes involved in cell structure organization, suggesting the involvement of SelT in redox regulation and cell anchorage. Furthermore, we found that the loss of SelT elevates expression of another selenoprotein, selenoprotein W (SepW1). SelT and SepW1 belong to the same protein family, suggesting that SepW1 may functionally compensate for SelT. C1 [Sengupta, Aniruddha; Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Labunskyy, Vyacheslav M.; Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. [Labunskyy, Vyacheslav M.; Gladyshev, Vadim N.] Univ Nebraska, Redox Biol Ctr, Lincoln, NE 68588 USA. RP Hatfield, DL (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov RI Gladyshev, Vadim/A-9894-2013 FU NIH; NCI; CCR FX This research was supported by the Intramural Research Program of NIH, NCI, CCR, to D. L. H. and by NIH grants to V.N.G. NR 22 TC 24 Z9 26 U1 0 U2 5 PU NATL RESEARCH COUNCIL CANADA-N R C RESEARCH PRESS PI OTTAWA PA BUILDING M 55, OTTAWA, ON K1A 0R6, CANADA SN 0829-8211 J9 BIOCHEM CELL BIOL JI Biochem. Cell Biol. PD DEC PY 2009 VL 87 IS 6 BP 953 EP 961 DI 10.1139/O09-064 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 525GG UT WOS:000272202200014 PM 19935881 ER PT J AU Li, YC Dunn, L Greggio, E Krumm, B Jackson, GS Cookson, MR Lewis, PA Deng, JP AF Li, Yongchao Dunn, Laura Greggio, Elisa Krumm, Brian Jackson, Graham S. Cookson, Mark R. Lewis, Patrick A. Deng, Junpeng TI The R1441C mutation alters the folding properties of the ROC domain of LRRK2 SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE LRRK2; ROCO protein; GTPase; Parkinson's disease; Differential scanning fluorimetry; Circular dichroism ID DISEASE-ASSOCIATED MUTATIONS; FAMILIAL PARKINSONS-DISEASE; PROTEIN-KINASE ACTIVITY; LEUCINE-RICH-REPEAT-KINASE-2 LRRK2; NEURONAL TOXICITY; GTP-BINDING; GENE; MUTANTS AB LRRK2 is a 250 kDa multidomain protein, mutations in which cause familial Parkinson's disease. Previously, we have demonstrated that the R1441C mutation in the ROC domain decreases GTPase activity. Here we show that the R1441C alters the folding properties of the ROC domain, lowering its thermodynamic stability. Similar to small GTPases, binding of different guanosine nucleotides alters the stability of the ROC domain, suggesting that there is an alteration in conformation dependent on GDP or GTP occupying the active site. GTP/GDP bound state also alters the self-interaction of the ROC domain, accentuating the impact of the R1441C mutation on this property. These data suggest a mechanism whereby the R1441C mutation can reduce the GTPase activity of LRRK2, and highlights the possibility of targeting the stability of the ROC domain as a therapeutic avenue in LRRK2 disease. (C) 2009 Elsevier B.V. All rights reserved. C1 [Dunn, Laura; Lewis, Patrick A.] UCL, Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Dunn, Laura; Lewis, Patrick A.] UCL, Inst Neurol, Reta Lila Weston Labs, London WC1N 3BG, England. [Li, Yongchao; Krumm, Brian; Deng, Junpeng] Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA. [Greggio, Elisa; Cookson, Mark R.] NIH, Cell Biol & Gene Express Unit, Neurogenet Lab, Bethesda, MD 20892 USA. [Jackson, Graham S.] UCL, Inst Neurol, MRC Pr Unit, UCL Dept Neurodegenerat Dis, London WC1N 3BG, England. RP Lewis, PA (reprint author), UCL, Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. EM p.lewis@ion.ucl.ac.uk; junpeng.deng@okstate.edu RI Lewis , Patrick/C-3674-2009; Greggio, Elisa/H-6119-2013; OI Greggio, Elisa/0000-0002-8172-3598; Jackson, Graham/0000-0002-3125-2011; Lewis, Patrick/0000-0003-4537-0489 FU National Institute on Aging (M.R.C.), NIH [NS062287]; Oklahoma Agricultural Experiment Station; Parkinson's Disease Society [K-0812]; Medical Research Council; Brain Research Trust; RT-PCR instrumentation FX This work was funded in part by the Intramural Research Program of the National Institute on Aging (M.R.C.), NIH (NS062287, J.D.), Oklahoma Agricultural Experiment Station at Oklahoma State University (J.D.), the Parkinson's Disease Society (grant #K-0812, P.A.L.) and the Medical Research Council. P.A.L is funded by a senior research fellowship from the Brain Research Trust. The authors would like to thank Dr. Udaya Desilva for his kind support with RT-PCR instrumentation, and declare no competing interest. NR 24 TC 27 Z9 27 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD DEC PY 2009 VL 1792 IS 12 BP 1194 EP 1197 DI 10.1016/j.bbadis.2009.09.010 PG 4 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 530HG UT WOS:000272579400014 PM 19781641 ER PT J AU Peters, JM Gonzalez, FJ AF Peters, Jeffrey M. Gonzalez, Frank J. TI Sorting out the functional role(s) of peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) in cell proliferation and cancer SO BIOCHIMICA ET BIOPHYSICA ACTA-REVIEWS ON CANCER LA English DT Review DE Peroxisome proliferator-activated receptor-beta/delta; Cell proliferation; Apoptosis; Differentiation; Cancer ID SMOOTH-MUSCLE-CELLS; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; HEPATOCELLULAR-CARCINOMA CELLS; E-2 SIGNALING PATHWAYS; DIETARY RETINOIC ACID; SKIN TUMOR PROMOTION; FEMALE SENCAR MICE; LIGAND ACTIVATION; DELTA AGONIST; COLON CARCINOGENESIS AB Peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) has many beneficial physiological functions ranging from enhancing fatty acid catabolism, improving insulin sensitivity, inhibiting inflammation and increasing oxidative myofibers allowing for improved athletic performance. Thus, given the potential for targeting PPAR beta/delta for the prevention and/or treatment of diseases including diabetes, dyslipidemias, metabolic syndrome and cancer, it is critical to clarify the functional role of PPAR beta/delta in cell proliferation and associated disorders such as cancer. However, there is considerable controversy whether PPAR beta/delta stimulates or inhibits cell proliferation. This review summarizes the literature describing the influence of PPAR beta/delta on cell proliferation, with an emphasis toward dissecting the data that give rise to opposing hypotheses. Suggestions are offered to standardize measurements associated with these studies so that interlaboratory comparisons can be accurately assessed. (C) 2009 Elsevier B.V. All rights reserved. C1 [Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. [Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, University Pk, PA 16802 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, University Pk, PA 16802 USA. EM jmp21@psu.edu RI Peters, Jeffrey/D-8847-2011 FU National Institutes of Health FX Work in our laboratories is supported by the National Institutes of Health. NR 119 TC 78 Z9 78 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-419X J9 BBA-REV CANCER JI Biochim. Biophys. Acta-Rev. Cancer PD DEC PY 2009 VL 1796 IS 2 BP 230 EP 241 DI 10.1016/j.bbcan.2009.06.002 PG 12 WC Biochemistry & Molecular Biology; Biophysics; Oncology SC Biochemistry & Molecular Biology; Biophysics; Oncology GA 506ID UT WOS:000270767600014 PM 19505534 ER PT J AU Shamir, L Wolkow, CA Goldberg, IG AF Shamir, Lior Wolkow, Catherine A. Goldberg, Ilya G. TI Quantitative measurement of aging using image texture entropy SO BIOINFORMATICS LA English DT Article ID CAENORHABDITIS-ELEGANS; C-ELEGANS; TRANSCRIPTIONAL PROFILE; SENESCENCE; EVOLUTION AB Motivation: A key element in understanding the aging of Caenorhabditis elegans is objective quanti. cation of the morphological differences between younger and older animals. Here we propose to use the image texture entropy as an objective measurement that reflects the structural deterioration of the C. elegans muscle tissues during aging. Results: The texture entropy and directionality of the muscle microscopy images were measured using 50 animals on Days 0, 2, 4, 6, 8, 10 and 12 of adulthood. Results show that the entropy of the C.elegans pharynx tissues increases as the animal ages, but a sharper increase was measured between Days 2 and 4, and between Days 8 and 10. These results are in agreement with gene expression findings, and support the contention that the process of C.elegans aging has several distinct stages. This can indicate that C.elegans aging is driven by developmental pathways, rather than stochastic accumulation of damage. C1 [Shamir, Lior; Wolkow, Catherine A.; Goldberg, Ilya G.] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Shamir, L (reprint author), NIA, Genet Lab, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. RI Goldberg, Ilya/H-5307-2011 OI Goldberg, Ilya/0000-0001-8514-6110 FU National Institutes of Health, National Institute on Aging FX Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 28 TC 31 Z9 32 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD DEC 1 PY 2009 VL 25 IS 23 BP 3060 EP 3063 DI 10.1093/bioinformatics/btp571 PG 4 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 523NL UT WOS:000272080800003 PM 19808878 ER PT J AU Insel, TR Cuthbert, BN AF Insel, Thomas R. Cuthbert, Bruce N. TI Endophenotypes: Bridging Genomic Complexity and Disorder Heterogeneity SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID SCHIZOPHRENIA; GENETICS C1 [Insel, Thomas R.; Cuthbert, Bruce N.] NIMH, Bethesda, MD 20892 USA. RP Cuthbert, BN (reprint author), NIMH, 6001 Execut Blvd,MSC 9632, Bethesda, MD 20892 USA. EM bcuthber@mail.nih.gov NR 12 TC 124 Z9 125 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 1 PY 2009 VL 66 IS 11 BP 988 EP 989 DI 10.1016/j.biopsych.2009.10.008 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 521JL UT WOS:000271917100001 PM 19900610 ER PT J AU Meyer, JM McEvoy, JP Davis, VG Goff, DC Nasrallah, HA Davis, SM Hsiao, JK Swartz, MS Stroup, TS Lieberman, JA AF Meyer, Jonathan M. McEvoy, Joseph P. Davis, Vicki G. Goff, Donald C. Nasrallah, Henry A. Davis, Sonia M. Hsiao, John K. Swartz, Marvin S. Stroup, T. Scott Lieberman, Jeffrey A. TI Inflammatory Markers in Schizophrenia: Comparing Antipsychotic Effects in Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness Study SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Antipsychotic; cardiovascular risk; C-reactive protein; E-selectin; ICAM-1; inflammation; schizophrenia; VCAM-1 ID C-REACTIVE PROTEIN; INDUCED WEIGHT-GAIN; PLACEBO-CONTROLLED TRIAL; CORONARY-ARTERY-DISEASE; LOW-DENSITY-LIPOPROTEIN; ADHESION MOLECULES; METABOLIC SYNDROME; E-SELECTIN; CARDIOVASCULAR-DISEASE; SEVERE DYSLIPIDEMIA AB Background: C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin are systemic inflammatory markers (IM) that positively correlate with cardiovascular (CV) risk. Despite the known CV effects of atypical antipsychotics, there is limited prospective data on IM changes during treatment. Methods: The IM outcomes were compared between antipsychotic treatment groups in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) schizophrenia trial phase 1 with subjects with laboratory assessments at baseline and 3 months (n = 789). Results: There were significant treatment differences in CRP, E-selectin, and ICAM-1 at 3 months, with a differential impact of baseline values on the CRP and ICAM-1 results. In overall comparisons, quetiapine and olanzapine had the highest median levels for CRP, and olanzapine for E-selectin and ICAM-1. Olanzapine was significantly different after baseline adjustment than perphenazine (p =.001) for E-selectin, and in those with low baseline CRP (<1 mg/L), olanzapine was significantly different than perphenazine (p <.001), risperidone (p <.001), and ziprasidone (p =.002) for CRP. Perphenazine had the lowest 3-month ICAM-1 levels in subjects with baseline ICAM-1 above the median, but the differences were not statistically significant versus olanzapine (p =.010), quetiapine (p =.010), and risperidone (p =.006) after controlling for multiple comparisons. The 18-month repeated measures CRP analysis confirmed the significantly higher values for olanzapine in those with low baseline CRP. Conclusions: This analysis provides further evidence for differential antipsychotic metabolic liabilities as measured by changes in systemic inflammation. C-reactive protein might emerge as a useful target for CV risk outcomes in schizophrenia patients. C1 [Meyer, Jonathan M.] VA San Diego Healthcare Syst, La Jolla, CA 92161 USA. [Meyer, Jonathan M.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [McEvoy, Joseph P.] Duke Univ, John Umstead Hosp, Dept Psychiat, Butner, NC USA. [Davis, Vicki G.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Stroup, T. Scott] Univ N Carolina, Dept Psychiat, Chapel Hill, NC USA. [Swartz, Marvin S.] Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. [Davis, Sonia M.] Quintiles, Morrisville, NC USA. [Goff, Donald C.] Harvard Univ, Dept Psychiat, Schizophrenia Program, Boston, MA 02115 USA. [Goff, Donald C.] Mental Hlth Ctr, Gen Hosp, Freedom Trail Clin Lindemann, Boston, MA USA. [Nasrallah, Henry A.] Univ Cincinnati, Cincinnati, OH USA. [Hsiao, John K.] NIMH, Adult Psychopharmacol Program, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Lieberman, Jeffrey A.] Columbia Univ, Dept Psychiat, Inst Psychiat, New York, NY USA. RP Meyer, JM (reprint author), VA San Diego Healthcare Syst, 3350 La Jolla Village Dr 116A, La Jolla, CA 92161 USA. EM jmmeyer@ucsd.edu RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU NCRR NIH HHS [UL1 RR024128]; NIAID NIH HHS [AI51445, P30 AI051445]; NIMH NIH HHS [K24 MH002025, N01 MH90001, N01MH90001] NR 52 TC 48 Z9 49 U1 1 U2 5 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 1 PY 2009 VL 66 IS 11 BP 1013 EP 1022 DI 10.1016/j.biopsych.2009.06.005 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 521JL UT WOS:000271917100005 PM 19640511 ER PT J AU Bacigalupo, A Ballen, K Rizzo, D Giralt, S Lazarus, H Ho, V Apperley, J Slavin, S Pasquini, M Sandmaier, BM Barrett, J Blaise, D Lowski, R Horowitz, M AF Bacigalupo, Andrea Ballen, Karen Rizzo, Doug Giralt, Sergio Lazarus, Hillard Ho, Vincent Apperley, Jane Slavin, Shimon Pasquini, Marcelo Sandmaier, Brenda M. Barrett, John Blaise, Didier Lowski, Robert Horowitz, Mary TI Defining the Intensity of Conditioning Regimens: Working Definitions SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Allogeneic transplantation; Conditioning regimens; Reduced intensity; Myeloablative conditioning ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; TOTAL-BODY IRRADIATION; ACUTE MYELOID-LEUKEMIA; ACUTE MYELOBLASTIC-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; VERSUS-HOST-DISEASE; TERM-FOLLOW-UP; REDUCED-INTENSITY; HEMATOLOGIC MALIGNANCIES AB Defining conditioning regimen intensity has become a critical issue for the hemopoietic stem cell transplant (HSCT) community. In the present report we propose to define conditioning regimens in 3 categories: (1) myeloablative (MA) conditioning, (2) reduced-intensity conditioning (RIC), and (3) nonmyeloablative (NMA) conditioning. Assignment to these categories is based on the duration of cytopenia and on the requirement for stem cell (SC) support: MA regimens cause irreversible cytopenia and SC support is mandatory. NMA regimens cause minimal cytopenia, and can be given also without SC support. RIC regimens do not fit criteria for MA or NMA regimens: they cause cytopenia of variable duration, and should be given with stem cell support, although cytopenia may not be irreversible. This report also assigns commonly used regimens to one of these categories, based upon the agents, dose, or combinations. Standardized classification of conditioning regimen intensities will allow comparison across studies and interpretation of study results. Biol Blood Marrow Transplant 15: 1628-1633 (2009) (C) 2009 American Society for Blood and Marrow Transplantation C1 [Bacigalupo, Andrea] San Martino Hosp, I-16132 Genoa, Italy. [Ballen, Karen] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Rizzo, Doug; Pasquini, Marcelo; Horowitz, Mary] Med Coll Wisconsin, CIBMTR, Milwaukee, WI 53226 USA. [Giralt, Sergio] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Lazarus, Hillard] Univ Hosp Cleveland, Cleveland, OH 44106 USA. [Ho, Vincent] Dana Farber Canc Inst, Boston, MA 02115 USA. [Apperley, Jane] Hammersmith Hosp, London, England. [Slavin, Shimon] Tel Aviv Med Ctr & Sch Med, Tel Aviv, Israel. [Sandmaier, Brenda M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Barrett, John] NIH, Bethesda, MD 20892 USA. [Blaise, Didier] Inst J Paoli I Calmettes, F-13009 Marseille, France. [Lowski, Robert] Stanford Univ, Sch Med, Stanford, CA 94305 USA. RP Bacigalupo, A (reprint author), San Martino Hosp, Lgo R Benzi 10, I-16132 Genoa, Italy. EM andrea.bacigalupo@hsanmartino.it FU NCI NIH HHS [P01 CA018029, P01 CA078902, P01 CA078902-11, P01 CA018029-34]; NHLBI NIH HHS [P01 HL036444, P01 HL036444-29] NR 50 TC 365 Z9 368 U1 3 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD DEC PY 2009 VL 15 IS 12 BP 1628 EP 1633 DI 10.1016/j.bbmt.2009.07.004 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 523UP UT WOS:000272100400017 PM 19896087 ER PT J AU Murphy, WJ Artz, AS Champlin, RE Koreth, J Longo, DL AF Murphy, William J. Artz, Andrew S. Champlin, Richard E. Koreth, John Longo, Dan L. TI Blood Stem Cell Transplantation in Older Patients SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article AB A serious dichotomy currently exists in hematopoietic stem cell transplantation (HSCT) and cancer research. Cancer is a disease that predominantly affects older people, yet there is a paucity of cancer research addressing the very unique needs of this population