FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Rappaport, SM Kim, S Lan, Q Li, GL Vermeulen, R Waidyanatha, S Zhang, LP Yin, SN Smith, MT Rothman, N AF Rappaport, Stephen M. Kim, Sungkyoon Lan, Qing Li, Guilan Vermeulen, Roel Waidyanatha, Suramya Zhang, Luoping Yin, Songnian Smith, Martyn T. Rothman, Nathaniel TI Human benzene metabolism following occupational and environmental exposures SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE Benzene; Metabolism; Toxicokinetics; Biomonitoring ID GENETIC POLYMORPHISMS; URINARY BIOMARKERS; UNEXPOSED SUBJECTS; LEUKEMIA; WORKERS; HYDROQUINONE; HYPOTHESIS; EXCRETION; ADDUCTS; PHENOL AB We previously reported evidence that humans metabolize benzene via two enzymes, including a hitherto unrecognized high-affinity enzyme that was responsible for an estimated 73% of total urinary metabolites [sum of phenol (PH), hydroquinone (HQ), catechol (CA), E,E-muconic acid (MA), and S-phenylmercapturic acid (SPMA)] in nonsmoking females exposed to benzene at sub-saturating (ppb) air concentrations. Here, we used the same Michaelis-Menten-like kinetic models to individually analyze urinary levels of PH, HQ CA and MA from 263 nonsmoking Chinese women (179 benzene-exposed workers and 84 control workers) with estimated benzene air concentrations ranging from less than 0.001-299 ppm. One model depicted benzene metabolism as a single enzymatic process (1-enzyme model) and the other as two enzymatic processes which competed for access to benzene (2-enzyme model). We evaluated model fits based upon the difference in values of Akaike's Information Criterion (Delta AIC), and we gauged the weights of evidence favoring the two models based upon the associated Akaike weights and Evidence Ratios. For each metabolite, the 2-enzyme model provided a better fit than the 1-enzyme model with Delta AIC values decreasing in the order 9.511 for MA, 7.379 for PH, 1.417 for CA, and 0.193 for HQ. The corresponding weights of evidence favoring the 2-enzyme model (Evidence Ratios) were: 116.2:1 for MA, 40.0:1 for PH, 2.0:1 for CA and 1.1:1 for HQ. These results indicate that our earlier findings from models of total metabolites were driven largely by MA, representing the ring-opening pathway, and by PH, representing the ring-hydroxylation pathway. The predicted percentage of benzene metabolized by the putative high-affinity enzyme at an air concentration of 0.001 ppm was 88% based upon urinary MA and was 80% based upon urinary PH. As benzene concentrations increased, the respective percentages of benzene metabolized to MA and PH by the high-affinity enzyme decreased successively to 66 and 77% at 0.1 ppm, 20 and 58% at 1 ppm, and 2.7 and 17% at 10 ppm. This indicates that the putative high-affinity enzyme was active primarily below 1 ppm and favored the ring-opening pathway. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Rappaport, Stephen M.; Zhang, Luoping; Smith, Martyn T.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Kim, Sungkyoon] Seoul Natl Univ, Sch Publ Hlth, Seoul, South Korea. [Lan, Qing] NCI, NIH, DHHS, Bethesda, MD 20892 USA. [Li, Guilan; Yin, Songnian] Chinese Ctr Dis Control & Prevent, Inst Occupat Hlth & Poison Control, Beijing, Peoples R China. [Vermeulen, Roel; Rothman, Nathaniel] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Waidyanatha, Suramya] Univ N Carolina, Gillings Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. RP Rappaport, SM (reprint author), Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. EM srappaport@berkeley.edu RI Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU American Petroleum Institute; American Chemistry Council; National Institute for Environmental Health Sciences [P42ES05948, P30ES10126, R01ES06721, P42ES04705]; NIH, National Cancer Institute FX S.M.R. has received consulting and expert testimony fees from law firms representing plaintiffs' cases involving exposure to benzene and has received research support from the American Petroleum Institute and the American Chemistry Council. G.L. has received funds from the American Petroleum Institute for consulting on benzene-related health research. M.T.S. has received consulting and expert testimony fees from law firms representing both plaintiffs and defendants in cases involving exposure to benzene.; Funding sources: This research was supported by the National Institute for Environmental Health Sciences through grants P42ES05948 and P30ES10126 (S.M.R.) and R01ES06721 and P42ES04705 (M.T.S.) and by funds from the intramural research program of the NIH, National Cancer Institute. NR 30 TC 19 Z9 21 U1 4 U2 15 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 MAR 19 PY 2010 VL 184 IS 1-2 SI SI BP 189 EP 195 DI 10.1016/j.cbi.2009.12.017 PG 7 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 586CD UT WOS:000276877800024 PM 20026321 ER PT J AU Zarbl, H Gallo, MA Glick, J Yeung, KY Vouros, P AF Zarbl, Helmut Gallo, Michael A. Glick, James Yeung, Ka Yee Vouros, Paul TI The vanishing zero revisited: Thresholds in the age of genomics SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article DE No observable transcriptional effect level; Low dose-response; Risk assessment; Toxicogenomics ID TRANSCRIPTIONAL-EFFECT-LEVEL; DOSE-RESPONSE RELATIONSHIPS; GENE-EXPRESSION; RISK-ASSESSMENT; BONE-MARROW; CHRONIC EXPOSURE; INHALED BENZENE; ETHYLENE-OXIDE; DNA-ADDUCTS; TOXICITY AB The concept of the vanishing zero, which was first discussed 50 years ago in relation to pesticide residues in foods and food crops, focused on the unintended regulatory consequences created by ever-increasing sensitivity and selectivity of analytical methods, in conjunction with the ambiguous wording of legislation meant to protect public health. In the interim, the ability to detect xenobiotics in most substrates has increased from tens of parts per million to parts per trillion or less, challenging our ability to interpret the biological significance of exposures at the lowest detectable levels. As a result the focus of risk assessment, especially for potential carcinogens, has shifted from defining an acceptable level, to extrapolating from the best available analytical results. Analysis of gene expression profiles in exposed target cells using genomic technologies can identify biological pathways induced or repressed by the exposure as a function of dose and time. This treatise explores how toxicogenomic responses at low doses may inform risk assessment and risk management by defining thresholds for cellular responses linked to modes or mechanisms of toxicity at the molecular level. (C) 2010 Elsevier Ireland Ltd. All rights reserved. C1 [Zarbl, Helmut] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Environm & Occupat Hlth Sci Inst, NIEHS Ctr Environm Exposures & Dis, Piscataway, NJ 08854 USA. [Glick, James; Vouros, Paul] Northeastern Univ, Dept Chem & Chem Biol, Boston, MA 02115 USA. [Glick, James; Vouros, Paul] Northeastern Univ, Barnett Inst, Boston, MA 02115 USA. [Yeung, Ka Yee] Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. RP Zarbl, H (reprint author), Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Environm & Occupat Hlth Sci Inst, NIEHS Ctr Environm Exposures & Dis, 170 Frelinghuysen Rd,Room 426, Piscataway, NJ 08854 USA. EM zarbl@eohsi.rutgers.edu OI Yeung, Ka Yee/0000-0002-1754-7577 FU NIH [RO1CA112231, U19ES011387, P30ES005022, 3R01GM084163, 5K25CA106988] FX This work was supported by Public Health Services Grants (NIH): RO1CA112231 (P. Vouros, P.I.), U19ES011387 (H. Zarbl, P.I), P30ES005022 (H. Zarbl, P.I.), 3R01GM084163 (K.A. Yeung, PI) and 5K25CA106988 (K.A. Yeung, P.I). NR 50 TC 8 Z9 8 U1 0 U2 6 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 MAR 19 PY 2010 VL 184 IS 1-2 SI SI BP 273 EP 278 DI 10.1016/j.cbi.2010.01.031 PG 6 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 586CD UT WOS:000276877800038 PM 20109442 ER PT J AU Patino-Lopez, G Aravind, L Dong, XY Kruhlak, MJ Ostap, EM Shaw, S AF Patino-Lopez, Genaro Aravind, L. Dong, Xiaoyun Kruhlak, Michael J. Ostap, E. Michael Shaw, Stephen TI Myosin 1G Is an Abundant Class I Myosin in Lymphocytes Whose Localization at the Plasma Membrane Depends on Its Ancient Divergent Pleckstrin Homology (PH) Domain (Myo1PH) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BRUSH-BORDER; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; TISSUE DISTRIBUTION; STRUCTURAL BASIS; L-SELECTIN; BINDING; TAIL; PROTEIN; CELLS; PHOSPHOINOSITIDES AB Class I myosins, which link F-actin to membrane, are largely undefined in lymphocytes. Mass spectrometric analysis of lymphocytes identified two short tail forms: (Myo1G and Myo1C) and one long tail (Myo1F). We investigated Myo1G, the most abundant in T-lymphocytes, and compared key findings with Myo1C and Myo1F. Myo1G localizes to the plasma membrane and associates in an ATP-releasable manner to the actin-containing insoluble pellet. The IQ + tail region of Myo1G (Myo1C and Myo1F) is sufficient for membrane localization, but membrane localization is augmented by the motor domain. The minimal region lacks IQ motifs but includes: 1) a PH-like domain; 2) a "Pre-PH" region; and 3) a "Post-PH" region. The Pre-PH predicted alpha helices may contribute electrostatically, because two conserved basic residues on one face are required for optimal membrane localization. Our sequence analysis characterizes the divergent PH domain family, Myo1PH, present also in long tail myosins, in eukaryotic proteins unrelated to myosins, and in a probable ancestral protein in prokaryotes. The Myo1GMyo1PH domain utilizes the classic lipid binding site for membrane association, because mutating either of two basic residues in the "signature motif" destroys membrane localization. Mutation of each basic residue of the Myo1G Myo1PH domain reveals another critical basic residue in the beta 3 strand, which is shared only by Myo1D. Myo1G differs from Myo1C in its phosphatidylinositol 4,5-bisphosphate dependence for membrane association, because membrane localization of phosphoinositide 5-phosphatase releases Myo1C from the membrane but not Myo1G. Thus Myo1PH domains likely play universal roles in myosin I membrane association, but different isoforms have diverged in their binding specificity. C1 [Patino-Lopez, Genaro; Dong, Xiaoyun; Kruhlak, Michael J.; Shaw, Stephen] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Ostap, E. Michael] Univ Penn, Sch Med, Penn Muscle Inst, Philadelphia, PA 19104 USA. [Ostap, E. Michael] Univ Penn, Sch Med, Dept Physiol, Philadelphia, PA 19104 USA. RP Shaw, S (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36,10 Ctr Dr,MSC 1360, Bethesda, MD 20892 USA. EM shaws@mail.nih.gov OI Patino-Lopez, Genaro/0000-0002-8716-722X FU National Institutes of Health [GM57247]; NCI; National Library of Medicine FX This work was supported, in whole or in part, by National Institutes of Health Grant GM57247 and the Intramural Research Program of the National Institutes of Health, NCI. This work was also supported by the National Library of Medicine. NR 44 TC 33 Z9 35 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 19 PY 2010 VL 285 IS 12 BP 8675 EP 8686 DI 10.1074/jbc.M109.086959 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 568VZ UT WOS:000275553700020 PM 20071333 ER PT J AU Zhang, M Wang, MN Tan, XH Li, TF Zhang, YE Chen, D AF Zhang, Ming Wang, Meina Tan, Xiaohong Li, Tian-Fang Zhang, Ying E. Chen, Di TI Smad3 Prevents beta-Catenin Degradation and Facilitates beta-Catenin Nuclear Translocation in Chondrocytes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GROWTH-FACTOR-BETA; MESENCHYMAL STEM-CELLS; F-BOX PROTEIN; SIGNALING CROSS-TALK; TGF-BETA; UBIQUITIN LIGASE; CARCINOMA CELLS; WNT PATHWAYS; DIFFERENTIATION; BONE AB Our previous study demonstrated that transforming growth factor (TGF)-beta activates beta-catenin signaling through Smad3 interaction with beta-catenin in chondrocytes. In the present studies, we further investigated the detailed molecular mechanism of the cross-talk between TGF-beta/Smad3 and Wnt/beta-catenin signaling pathways. We found that C-terminal Smad3 interacted with both the N-terminal region and the middle region of beta-catenin protein in a TGF-beta-dependent manner. Both Smad3 and Smad4 were required for the interaction with beta-catenin and protected beta-catenin from an ubiquitin-proteasome-dependent degradation. In addition, the formation of the Smad3-Smad4-beta-catenin protein complex also mediated beta-catenin nuclear translocation. This Smad3-mediated regulatory mechanism of beta-catenin protein stability enhanced the activity of beta-catenin to activate downstream target genes during chondrogenesis. Our findings demonstrate a novel mechanism between TGF-beta and Wnt/beta-catenin signaling pathways during chondrocyte development. C1 [Zhang, Ming; Wang, Meina; Tan, Xiaohong; Li, Tian-Fang; Chen, Di] Univ Rochester, Med Ctr, Ctr Musculoskeletal Res, Dept Orthopaed & Rehabil, Rochester, NY 14642 USA. [Zhang, Ying E.] NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Chen, D (reprint author), Univ Rochester, Med Ctr, Ctr Musculoskeletal Res, Dept Orthopaed & Rehabil, Rochester, NY 14642 USA. EM di_chen@urmc.rochester.edu RI Zhang, Ming/H-6467-2011; Wang, Meina/K-8915-2012; Zhang, Ying/G-3657-2015 OI Zhang, Ying/0000-0003-2753-7601 FU National Institutes of Health [R01 AR051189, R01 AR054465, K02 AR052411, R01 AR055915]; New York State Department of Health [N08G-070]; Empire State Stem Cell Board FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 AR051189, R01 AR054465, K02 AR052411, and R01 AR055915 (to D. C.). This work was also supported by Grant N08G-070 (to D. C.) from the New York State Department of Health and the Empire State Stem Cell Board. NR 42 TC 40 Z9 41 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 19 PY 2010 VL 285 IS 12 BP 8703 EP 8710 DI 10.1074/jbc.M109.093526 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 568VZ UT WOS:000275553700023 PM 20097766 ER PT J AU De Donatis, GM Singh, SK Viswanathan, S Maurizi, MR AF De Donatis, Gian Marco Singh, Satyendra K. Viswanathan, Sarada Maurizi, Michael R. TI A Single ClpS Monomer Is Sufficient to Direct the Activity of the ClpA Hexamer SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID N-END RULE; ADAPTER PROTEIN CLPS; SUBSTRATE-BINDING DOMAIN; ATP-DEPENDENT PROTEASES; SSRA-TAGGED PROTEINS; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; CHAPERONE CLPA; PORE LOOPS; DEGRADATION AB ClpS is an adaptor protein that interacts with ClpA and promotes degradation of proteins with N-end rule degradation motifs (N-degrons) by ClpAP while blocking degradation of substrates with other motifs. Although monomeric ClpS forms a 1: 1 complex with an isolated N-domain of ClpA, only one molecule of ClpS binds with high affinity to ClpA hexamers (ClpA(6)). One or two additional molecules per hexamer bind with lower affinity. Tightly bound ClpS dissociates slowly from ClpA(6) with a t(1/2) of similar to 3 min at 37 degrees C. Maximum activation of degradation of the N-end rule substrate, LR-GFP(Venus), occurs with a single ClpS bound per ClpA(6); one ClpS is also sufficient to inhibit degradation of proteins without N-degrons. ClpS competitively inhibits degradation of unfolded substrates that interact with ClpA N-domains and is a non-competitive inhibitor with substrates that depend on internal binding sites in ClpA. ClpS inhibition of substrate binding is dependent on the order of addition. When added first, ClpS blocks binding of both high and low affinity substrates; however, when substrates first form committed complexes with ClpA(6), ClpS cannot displace them or block their degradation by ClpP. We propose that the first molecule of ClpS binds to the N-domain and to an additional functional binding site, sterically blocking binding of non-N-end rule substrates as well as additional ClpS molecules to ClpA(6). Limiting ClpS-mediated substrate delivery to one per ClpA(6) avoids congestion at the axial channel and allows facile transfer of proteins to the unfolding and translocation apparatus. C1 [De Donatis, Gian Marco; Singh, Satyendra K.; Viswanathan, Sarada; Maurizi, Michael R.] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Maurizi, MR (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bldg 37 Rm 2128,37 Convent Dr MSC4256, Bethesda, MD 20892 USA. EM mmaurizi@helix.nih.gov FU National Institutes of Health, NCI, Center for Cancer Research FX This work was supported, in whole or in part, by the National Institutes of Health, NCI, Center for Cancer Research, Intramural Research Program. NR 47 TC 16 Z9 16 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 19 PY 2010 VL 285 IS 12 BP 8771 EP 8781 DI 10.1074/jbc.M109.053736 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 568VZ UT WOS:000275553700029 PM 20068042 ER PT J AU Yang, RQ Zhan, M Nalabothula, NR Yang, QY Indig, FE Carrier, F AF Yang, Ruiqing Zhan, Ming Nalabothula, Narasimha Rao Yang, Qingyuan Indig, Fred E. Carrier, France TI Functional Significance for a Heterogenous Ribonucleoprotein A18 Signature RNA Motif in the 3 '-Untranslated Region of Ataxia Telangiectasia Mutated and Rad3-related (ATR) Transcript SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DAMAGE-INDUCIBLE TRANSCRIPTS; TARGET MESSENGER-RNAS; BINDING PROTEIN; POSTTRANSCRIPTIONAL REGULATION; GENOME INTEGRITY; KINASE; IDENTIFICATION; THIOREDOXIN; TRANSLATION; INHIBITION AB The predominantly nuclear heterogenous ribonucleoprotein A18 (hnRNP A18) translocates to the cytosol in response to cellular stress and increases translation by specifically binding to the 3'-untranslated region (UTR) of several mRNA transcripts and the eukaryotic initiation factor 4G. Here, we identified a 51-nucleotide motif that is present 11.49 times more often in the 3'-UTR of hnRNP A18 mRNA targets than in the UniGene data base. This motif was identified by computational analysis of primary sequences and secondary structures of hnRNP A18 mRNA targets against the unaligned sequences. Band shift analyses indicate that the motif is sufficient to confer binding to hnRNP A18. A search of the entire UniGene data base indicates that the hnRNP A18 motif is also present in the 3'-UTR of the ataxia telangiectasia mutated and Rad3-related (ATR) mRNA. Validation of the predicted hnRNP A18 motif is provided by amplification of endogenous ATR transcript on polysomal fractions immunoprecipitated with hnRNP A18. Moreover, overexpression of hnRNP A18 results in increased ATR protein levels and increased phosphorylation of Chk1, a preferred ATR substrate, in response to UV radiation. In addition, our data indicate that inhibition of casein kinase II or GSK3 beta significantly reduced hnRNP A18 cytosolic translocation in response to UV radiation. To our knowledge, this constitutes the first demonstration of a post-transcriptional regulatory mechanism for ATR activity. hnRNP A18 could thus become a new target to trigger ATR activity as back-up stress response mechanisms to functionally compensate for absent or defective responders. C1 [Yang, Ruiqing; Nalabothula, Narasimha Rao; Yang, Qingyuan; Carrier, France] Univ Maryland, Dept Radiat Oncol, Marlene & Stewart Greenebaum Canc Ctr, Sch Med, Baltimore, MD 21201 USA. [Zhan, Ming] NIA, Res Resources Branch, Intramural Res Program, Baltimore, MD 21224 USA. [Indig, Fred E.] NIA, NIH, Baltimore, MD 21224 USA. RP Carrier, F (reprint author), 655 W Baltimore St, Baltimore, MD 21201 USA. EM fcarr001@umaryland.edu FU National Institutes of Health [RO1 GM57827, RO1 1CA116491-01]; University of Maryland, Baltimore FX This work was supported in part by National Institutes of Health Grants RO1 GM57827 and RO1 1CA116491-01 (to F. C.). This work was also supported by funds from the graduate program in biochemistry of the University of Maryland, Baltimore (to R. Y.). NR 33 TC 13 Z9 13 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 19 PY 2010 VL 285 IS 12 BP 8887 EP 8893 DI 10.1074/jbc.M109.013128 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 568VZ UT WOS:000275553700040 PM 20103595 ER PT J AU Navath, RS Wang, B Kannan, S Romero, R Kannan, RM AF Navath, Raghavendra S. Wang, Bing Kannan, Sujatha Romero, Roberto Kannan, Rangaramanujam M. TI Stimuli-responsive star poly(ethylene glycol) drug conjugates for improved intracellular delivery of the drug in neuroinflammation SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE PEG; Polyethylene glycol-drug conjugates; Intracellular delivery; N-acetyl cysteine; Neuroinflammation; Microglial cells ID POLYMERIC ANTICANCER DRUGS; PH-CONTROLLED ACTIVATION; N-ACETYLCYSTEINE; L-CYSTEINE; IN-VITRO; RELEASE; PRODRUGS; THERAPEUTICS; SYSTEMS; CANCER AB N-Acetyl cysteine (NAC) is a vital drug currently under clinical trials for the treatment of neuroinflammation in maternal-fetal applications. The free sulfhydryl groups in NAG lead to high plasma protein binding, resulting in low bioavailability. Preparation and activity of conjugates of NAC with thiol terminated multi-arm (6 and 8) poly(ethylene-glycol) (PEG) with disulfide linkages involving sulfhydryls of NAC are reported. Multiple copies (5 and 7) of NAC were conjugated on 6 and 8-arm-PEG respectively. Both the conjugates released 74% of NAG within 2 h by thiol exchange reactions in the redox environment provided by glutathione (GSH) intracellularly (2-10 mM). At physiological extracellular glutathione concentration (2 mu M) both the conjugates were stable and did not release NAC. MTT assay showed comparable cell viability for unmodified PEGs and both the PEG-S-S-NAG conjugates. The conjugates were readily endocytosed by cells, as confirmed by flow cytometry and confocal microscopy. Efficacy of 6 and 8-arm-PEG-S-S-NAC conjugates was evaluated on activated microglial cells (the target cells, ill vivo) by monitoring cytokine release in lipopolysaccharide (LPS) induced inflammatory response in microglial cells using the reactive oxygen species (ROS), free radical nitrile (NO), anti-inflammatory activity and GSH depletion. The conjugates showed significant increase in antioxidant activity (more than a factor of 2) compared to free drug as seen from the inhibition of LPS induced ROS, NO, GSH and tumor necrosis factor-alpha (TNF-alpha) release in microglial cells. (C) 2009 Elsevier B.V. All rights reserved. C1 [Navath, Raghavendra S.; Kannan, Rangaramanujam M.] Wayne State Univ, Dept Chem Engn & Mat Sci & Biomed Engn, Detroit, MI 48202 USA. [Navath, Raghavendra S.; Wang, Bing; Kannan, Sujatha; Romero, Roberto; Kannan, Rangaramanujam M.] NICHD, Perinatol Res Branch, Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH,DHHS, Bethesda, MD USA. [Wang, Bing; Kannan, Sujatha] Wayne State Univ, Childrens Hosp Michigan, Dept Pediat Crit Care Med, Detroit, MI 48202 USA. RP Kannan, RM (reprint author), Wayne State Univ, Dept Chem Engn & Mat Sci & Biomed Engn, Detroit, MI 48202 USA. EM rkannan@eng.wayne.edu FU National Institute of Child Health and Human Development, NIH, DHHS FX This study was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, NIH, DHHS. NR 34 TC 33 Z9 38 U1 2 U2 31 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 MAR 19 PY 2010 VL 142 IS 3 BP 447 EP 456 DI 10.1016/j.jconrel.2009.10.035 PG 10 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 582ER UT WOS:000276579500022 PM 19896998 ER PT J AU Xu, YM Lorieau, J McDermott, AE AF Xu, Yimin Lorieau, Justin McDermott, Ann E. TI Triosephosphate Isomerase: N-15 and C-13 Chemical Shift Assignments and Conformational Change upon Ligand Binding by Magic-Angle Spinning Solid-State NMR Spectroscopy SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE triosephosphate isomerase; solid-state NMR; sequential assignment; crystal packing; conformational change ID TRIOSE PHOSPHATE ISOMERASE; SITE LOOP MOTION; ACTIVE-SITE; CATALYTIC MECHANISM; PROTON-TRANSFER; MICROCRYSTALLINE UBIQUITIN; RESOLUTION ENHANCEMENT; COMPUTER-SIMULATION; CRYSTAL-STRUCTURES; SPECTRAL-ANALYSIS AB Microcrystalline uniformly C-13, N-15-enriched yeast triosephosphate isomerase (TIM) is sequentially assigned by high-resolution solid-state NMR (SSNMR). Assignments are based on intraresidue and interresidue correlations, using dipolar polarization transfer methods, and guided by solution NMR assignments of the same protein. We obtained information on most of the active-site residues involved in chemistry, including sonic that were not reported in a previous solution NMR study, such as the side-chain carbons of His95 Chemical shift differences comparing the microcrystalline environment to the aqueous environment appear to be mainly due to crystal packing interactions. Site-specific perturbations of the enzyme's chemical shifts upon ligand binding are studied by SSNMR for the first time. These changes monitor protemwide conformational adjustment upon ligand binding, including many of the sites probed by solution NMR and X-ray studies Changes in Gln119, Ala163, and Gly210 were observed in our SSNM.R studies, but were not reported in solution NMR studies (chicken or yeast). These studies identify a number of new sites with particularly clear markers for ligand binding, paving the way for future studies of triosephosphate isomerase dynamics and mechanism. (C) 2009 Published by Elsevier Ltd C1 [Xu, Yimin; McDermott, Ann E.] Columbia Univ, Dept Chem, New York, NY 10027 USA. [Lorieau, Justin] NIH, Bethesda, MD 20892 USA. RP McDermott, AE (reprint author), Columbia Univ, Dept Chem, New York, NY 10027 USA. EM aem5@columbia.edu FU New York State Office of Science, Technology, and Academic Research; National Institutes of Health FX We thank Ivan Sergeyev for his program ACCEPTN M R (http: //mcdermott.chem/software/) used for crystal contact calculations. We thank previous and current McDermott group members for technical assistance. A.E.M. is a member of the New York Structural Biology Center. The New York Structural Biology Center is a STAR center supported by the New York State Office of Science, Technology, and Academic Research. This work was supported by funds from the National Institutes of Health. NR 66 TC 11 Z9 11 U1 0 U2 10 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAR 19 PY 2010 VL 397 IS 1 BP 233 EP 248 DI 10.1016/j.jmb.2010.10.043 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 571WC UT WOS:000275785600016 PM 19854202 ER PT J AU Zeng, X Yin, BL Hu, Z Liao, CZ Liu, JL Li, S Li, Z Nicklaus, MC Zhou, GB Jiang, S AF Zeng, Xin Yin, Biaolin Hu, Zheng Liao, Chenzhong Liu, Jinglei Li, Shang Li, Zheng Nicklaus, Marc C. Zhou, Guangbiao Jiang, Sheng TI Total Synthesis and Biological Evaluation of Largazole and Derivatives with Promising Selectivity for Cancers Cells SO ORGANIC LETTERS LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; NATURAL-PRODUCTS; ANALOGS; DRUGS AB The efficient total synthesis of the natural substance largazole is described. Using this strategy, a small library of largazole analogs was developed. Structure-activity relationship studies suggested that the geometry of the alkene In the side chain is critical. While the largazole's analogues with trans-alkene are potent for the anti proliferative effect, those with cls-alkene are completely inactive. Most importantly, replacement of valine with tyrosine in largazole increased selectivity toward human cancer cells over human normal cells more than 100-fold. C1 [Zeng, Xin; Hu, Zheng; Liu, Jinglei; Li, Shang; Zhou, Guangbiao; Jiang, Sheng] CAS, Guangzhou Inst Biomed & Hlth, Guangzhou 510663, Guangdong, Peoples R China. [Hu, Zheng; Liu, Jinglei; Zhou, Guangbiao] CAS, Lab Mol Carcinogenesis & Targeted Therapy Canc, State Key Lab Biomembrane & Membrane Biotechnol, Inst Zool, Beijing 100101, Peoples R China. [Yin, Biaolin] S China Univ Technol, Guangzhou 510640, Peoples R China. [Liao, Chenzhong; Nicklaus, Marc C.] NCI, NIH, Frederick, MD 21702 USA. [Hu, Zheng; Liu, Jinglei; Zhou, Guangbiao] Univ Sci & Technol China, Hefei 230027, Peoples R China. [Li, Zheng] Methodist Hosp, Res Inst, Houston, TX 77030 USA. RP Zhou, GB (reprint author), CAS, Guangzhou Inst Biomed & Hlth, Guangzhou 510663, Guangdong, Peoples R China. EM gbzhou@ioz.ac.cn; jiang_sheng@gibh.ac.cn RI Nicklaus, Marc/N-4183-2014; OI Zhou, Guangbiao/0000-0001-6778-7133; Nicklaus, Marc/0000-0002-4775-7030 FU National Natural Science Foundation [20802078, 20972160, 30871110]; 973 Program [2009CB940900, 2010CB529201] FX This project was supported by the National Natural Science Foundation (20802078, 20972160, 30871110), and 973 Program (2009CB940900, 2010CB529201). Dr. Nadya I. Tarasova at NO is thanked for correcting the English. NR 25 TC 53 Z9 54 U1 1 U2 19 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD MAR 19 PY 2010 VL 12 IS 6 BP 1368 EP 1371 DI 10.1021/ol100308a PG 4 WC Chemistry, Organic SC Chemistry GA 566NL UT WOS:000275379100057 PM 20184338 ER PT J AU Ruiz, MO Chaves, LF Hamer, GL Sun, T Brown, WM Walker, ED Haramis, L Goldberg, TL Kitron, UD AF Ruiz, Marilyn O. Chaves, Luis F. Hamer, Gabriel L. Sun, Ting Brown, William M. Walker, Edward D. Haramis, Linn Goldberg, Tony L. Kitron, Uriel D. TI Local impact of temperature and precipitation on West Nile virus infection in Culex species mosquitoes in northeast Illinois, USA SO PARASITES & VECTORS LA English DT Article ID SPATIAL INTERPOLATION METHODS; DROUGHT-INDUCED AMPLIFICATION; PIPIENS DIPTERA; UNITED-STATES; TARSALIS DIPTERA; LAND-USE; SEASONAL ABUNDANCE; BRIDGE VECTOR; CULICIDAE; TRANSMISSION AB Background: Models of the effects of environmental factors on West Nile virus disease risk have yielded conflicting outcomes. The role of precipitation has been especially difficult to discern from existing studies, due in part to habitat and behavior characteristics of specific vector species and because of differences in the temporal and spatial scales of the published studies. We used spatial and statistical modeling techniques to analyze and forecast fine scale spatial (2000 m grid) and temporal (weekly) patterns of West Nile virus mosquito infection relative to changing weather conditions in the urban landscape of the greater Chicago, Illinois, region for the years from 2004 to 2008. Results: Increased air temperature was the strongest temporal predictor of increased infection in Culex pipiens and Culex restuans mosquitoes, with cumulative high temperature differences being a key factor distinguishing years with higher mosquito infection and higher human illness rates from those with lower rates. Drier conditions in the spring followed by wetter conditions just prior to an increase in infection were factors in some but not all years. Overall, 80% of the weekly variation in mosquito infection was explained by prior weather conditions. Spatially, lower precipitation was the most important variable predicting stronger mosquito infection; precipitation and temperature alone could explain the pattern of spatial variability better than could other environmental variables (79% explained in the best model). Variables related to impervious surfaces and elevation differences were of modest importance in the spatial model. Conclusion: Finely grained temporal and spatial patterns of precipitation and air temperature have a consistent and significant impact on the timing and location of increased mosquito infection in the northeastern Illinois study area. The use of local weather data at multiple monitoring locations and the integration of mosquito infection data from numerous sources across several years are important to the strength of the models presented. The other spatial environmental factors that tended to be important, including impervious surfaces and elevation measures, would mediate the effect of rainfall on soils and in urban catch basins. Changes in weather patterns with global climate change make it especially important to improve our ability to predict how inter-related local weather and environmental factors affect vectors and vector-borne disease risk. Local impact of temperature and precipitation on West Nile virus infection in Culex species mosquitoes in northeast Illinois, USA. C1 [Ruiz, Marilyn O.; Sun, Ting; Brown, William M.] Univ Illinois, Dept Pathol, Urbana, IL 61801 USA. [Chaves, Luis F.; Kitron, Uriel D.] Emory Univ, Dept Environm Studies, Atlanta, GA 30322 USA. [Hamer, Gabriel L.; Goldberg, Tony L.] Univ Wisconsin, Dept Pathol Sci, Madison, WI USA. [Walker, Edward D.] Michigan State Univ, Dept Microbiol & Mol Genet, Lansing, MI USA. [Haramis, Linn] Illinois Dept Publ Hlth, Vector Control Program, Springfield, IL 62761 USA. [Kitron, Uriel D.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Ruiz, MO (reprint author), Univ Illinois, Dept Pathol, Urbana, IL 61801 USA. EM moruiz@illinois.edu RI Chaves, Luis Fernando/F-3448-2010 OI Chaves, Luis Fernando/0000-0002-5301-2764 FU NSF [0429124, 0840403]; University of Illinois Adaptive Infrastructure Information Systems Initiative; Village of Oak Lawn FX This project was funded through NSF Ecology of Infectious Disease Grants 0429124 (West Nile Virus: Eco-Epidemiology of Disease Emergence in Urban Areas) and 0840403 (Eco-epidemiology of Disease Emergence in Urban Areas II) and through funding from the University of Illinois Adaptive Infrastructure Information Systems Initiative. We thank the Village of Oak Lawn for ongoing support of this project. Kenneth Kunkel contributed to early discussions on this topic. Jane Messina, Julie Clennon and Joanna Ganning helped with geocoding and organization of spatial mosquito data. LFC and UK also thank the Research and Policy for Infectious Disease Dynamics (RAPIDD) program of the Science and Technology Directorate and the Fogarty International Center, National Institutes of Health program on mosquito borne diseases, for helpful discussions in the context of this manuscript. We thank Tavis Anderson and two anonymous reviewers for helpful suggestions for revisions, which have greatly improved the paper. NR 73 TC 78 Z9 81 U1 3 U2 45 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1756-3305 J9 PARASITE VECTOR JI Parasites Vectors PD MAR 19 PY 2010 VL 3 AR 19 DI 10.1186/1756-3305-3-19 PG 16 WC Parasitology SC Parasitology GA 586DN UT WOS:000276882100001 PM 20302617 ER PT J AU Fauriat, C Long, EO Ljunggren, HG Bryceson, YT AF Fauriat, Cyril Long, Eric O. Ljunggren, Hans-Gustaf Bryceson, Yenan T. TI Regulation of human NK-cell cytokine and chemokine production by target cell recognition SO BLOOD LA English DT Article ID NATURAL-KILLER-CELLS; MHC CLASS-I; INTERFERON-GAMMA; INHIBITORY RECEPTORS; LYMPHOCYTE SUBSETS; GENE-EXPRESSION; CUTTING EDGE; ACTIVATION; CD56(BRIGHT); CYTOTOXICITY AB Natural killer (NK)-cell recognition of infected or neoplastic cells can induce cytotoxicity and cytokine secretion. So far, it has been difficult to assess the relative contribution of multiple NK-cell activation receptors to cytokine and chemokine production upon target cell recognition. Using Drosophila cells expressing ligands for the NK-cell receptors LFA-1, NKG2D, DNAM-1, 2B4, and CD16, we studied the minimal requirements for secretion by freshly isolated, human NK cells. Target cell stimulation induced secretion of predominately proinflammatory cytokines and chemokines. Release of chemokines MIP-1 alpha, MIP-1 beta, and RANTES was induced within 1 hour of stimulation, whereas release of TNF-alpha and IFN-gamma occurred later. Engagement of CD16, 2B4, or NKG2D sufficed for chemokine release, whereas induction of TNF-alpha and IFN-gamma required engagement of additional receptors. Remarkably, our results revealed that, upon target cell recognition, CD56(dim) NK cells were more prominent cytokine and chemokine producers than CD56(bright) NK cells. The present data demonstrate how specific target cell ligands dictate qualitative and temporal aspects of NK-cell cytokine and chemokine responses. Conceptually, the results point to CD56(dim) NK cells as an important source of cytokines and chemokines upon recognition of aberrant cells, producing graded responses depending on the multiplicity of activating receptors engaged. (Blood. 2010;115:2167-2176) C1 [Fauriat, Cyril; Ljunggren, Hans-Gustaf; Bryceson, Yenan T.] Karolinska Univ, Huddinge Hosp, Ctr Infect Med, Dept Med,Karolinska Inst, S-14186 Stockholm, Sweden. [Long, Eric O.] NIAID, Immunogenet Lab, NIH, Rockville, MD 20852 USA. RP Fauriat, C (reprint author), Karolinska Univ, Huddinge Hosp, Ctr Infect Med, Dept Med,Karolinska Inst, S-14186 Stockholm, Sweden. EM cfauriat@wanadoo.fr; yenan.bryceson@ki.se RI Long, Eric/G-5475-2011; Fauriat, Cyril/D-4285-2017; OI Long, Eric/0000-0002-7793-3728; Bryceson, Yenan/0000-0002-7783-9934 FU Swedish Foundation for Strategic Research; Research Council, and Cancer Society; Intramural Research Program at National Institutes of Health; National Institute of Allergy and Infectious Diseases; Mary Beve's Foundation; David & Astrid Hagelen's Foundation; Karolinska Institute Research Foundation FX This work was supported by grants from the Swedish Foundation for Strategic Research, Research Council, and Cancer Society (C.F., H.- G.L., and Y.T.B.), by the Intramural Research Program at National Institutes of Health, National Institute of Allergy and Infectious Diseases (E.O.L.), and Mary Beve's Foundation, David & Astrid Hagelen's Foundation, the Karolinska Institute Research Foundation, and Jonas Soderquist's Stipend (Y.T.B.). NR 57 TC 237 Z9 245 U1 1 U2 11 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 18 PY 2010 VL 115 IS 11 BP 2167 EP 2176 DI 10.1182/blood-2009-08-238469 PG 10 WC Hematology SC Hematology GA 571KT UT WOS:000275751400012 PM 19965656 ER PT J AU McDermott, DH Conway, SE Wang, T Ricklefs, SM Agovi, MA Porcella, SF Tran, HTB Milford, E Spellman, S Abdi, R AF McDermott, David H. Conway, Susan E. Wang, Tao Ricklefs, Stacy M. Agovi, Manza A. Porcella, Stephen F. Tran, Huong Thi Bich Milford, Edgar Spellman, Stephen Abdi, Reza TI Donor and recipient chemokine receptor CCR5 genotype is associated with survival after bone marrow transplantation SO BLOOD LA English DT Article ID VERSUS-HOST-DISEASE; STEM-CELL TRANSPLANTATION; ALLOGENEIC TRANSPLANTATION; PROMOTER POLYMORPHISM; CHRONIC GRAFT; T-CELLS; PROGRESSION; RISK; REACTIVATION; EXPRESSION AB Despite continual improvement, morbidity and mortality after hematopoietic stem cell transplantation (HSCT) remain high. The importance of chemokines in HSCT lies in their regulation of immune responses that determine transplantation outcomes. We investigated the role of recipient and donor chemokine system gene polymorphisms by using a candidate gene approach on the incidence of graft-versus-host disease and posttransplantation outcomes in 1370 extensively human leukocyte antigen-matched, unrelated donor-recipient pairs by using multivariate Cox regression models. Our analysis identified that recipients homozygous for a common CCR5 haplotype (H1/H1) had better disease-free survival (DFS; P = .005) and overall survival (P = .021). When the same genotype of both the donor and recipient were considered in the models, a highly significant association with DFS and overall survival was noted (P < .001 and P = .007, respectively) with absolute differences in survival of up to 20% seen between the groups at 3 years after transplantation (50% DFS for pairs with recipient CCR5 H1/H1 vs 30% for pairs with donor CCR5 H1/H1). This finding suggests that donor and/or recipient CCR5 genotypes may be associated with HSCT outcome and suggests new diagnostic and therapeutic strategies for optimizing therapy. (Blood. 2010; 115: 2311- 2318) C1 [Abdi, Reza] Harvard Univ, Sch Med, Brigham & Womens Hosp, Transplantat Res Ctr,Renal Div, Boston, MA 02115 USA. [Conway, Susan E.; Tran, Huong Thi Bich; Milford, Edgar; Abdi, Reza] Childrens Hosp, Boston, MA 02115 USA. [McDermott, David H.] NIAID, Mol Signaling Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Wang, Tao] Med Coll Wisconsin, Div Biostat, Milwaukee, WI 53226 USA. [Ricklefs, Stacy M.; Porcella, Stephen F.] NIAID, Genom Core Unit, Res Technol Sect, Res Technol Branch,NIH, Hamilton, MO USA. [Agovi, Manza A.] CIBMTR, Minneapolis, MN USA. [Spellman, Stephen] NMDP, Minneapolis, MN USA. RP Abdi, R (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Transplantat Res Ctr,Renal Div, 221 Longwood Ave, Boston, MA 02115 USA. EM rabdi@rics.bwh.harvard.edu OI McDermott, David/0000-0001-6978-0867 FU Intramural Division of the National Institute of Allergy and Infectious Diseases, National Institutes of Health; National Marrow Donor Program (NMDP); National Cancer Institute (NCI) [U24-CA76518]; National Heart, Lung, and Blood Institute (NHLBI) [5U01HL069294]; National Institute of Allergy and Infectious Diseases (NIAID); Health Resources and Services Administration (HRSA/DHHS) [HHSH234200637015C]; Office of Naval Research [N00014-06-1-0704, N00014-08-1-0058]; AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen Inc FX This work was supported by the Intramural Division of the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and a grant to R. A. by the National Marrow Donor Program (NMDP).; The CIBMTR is supported by Public Health Service Grant/Cooperative Agreement U24-CA76518 from the National Cancer Institute (NCI), the National Heart, Lung, and Blood Institute (NHLBI), and the National Institute of Allergy and Infectious Diseases (NIAID); a Grant/Cooperative Agreement 5U01HL069294 from NHLBI and NCI; a contract HHSH234200637015C with Health Resources and Services Administration (HRSA/DHHS); grants N00014-06-1-0704 and N00014-08-1-0058 from the Office of Naval Research; and grants from AABB; Aetna; American Society for Blood and Marrow Transplantation; Amgen Inc; anonymous donation to the Medical College of Wisconsin; Astellas Pharma US Inc; Baxter International Inc; Bayer HealthCare Pharmaceuticals; Be the Match Foundation; Biogen IDEC; BioMarin Pharmaceutical Inc; Biovitrum AB; BloodCenter ofWisconsin; Blue Cross and Blue Shield Association; Bone Marrow Foundation; Canadian Blood and Marrow Transplant Group; CaridianBCT; Celgene Corporation; CellGenix, GmbH; Centers for Disease Control and Prevention; Children's Leukemia Research Association; ClinImmune Labs; CTI Clinical Trial and Consulting Services; Cubist Pharmaceuticals; Cylex Inc; CytoTherm; DOR BioPharma Inc; Dynal Biotech, an Invitrogen Company; Eisai Inc; Enzon Pharmaceuticals Inc; European Group for Blood and NR 29 TC 13 Z9 13 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 MAR 18 PY 2010 VL 115 IS 11 BP 2311 EP 2318 DI 10.1182/blood-2009-08-237768 PG 8 WC Hematology SC Hematology GA 571KT UT WOS:000275751400028 PM 20068218 ER PT J AU Lee, K Ambrose, Z Martin, TD Oztop, I Mulky, A Julias, JG Vandegraaff, N Baumann, JG Wang, R Yuen, W Takemura, T Shelton, K Taniuchi, I Li, Y Sodroski, J Littman, DR Coffin, JM Hughes, SH Unutmaz, D Engelman, A KewalRamani, VN AF Lee, KyeongEun Ambrose, Zandrea Martin, Thomas D. Oztop, Ilker Mulky, Alok Julias, John G. Vandegraaff, Nick Baumann, Joerg G. Wang, Rui Yuen, Wendy Takemura, Taichiro Shelton, Kenneth Taniuchi, Ichiro Li, Yuan Sodroski, Joseph Littman, Dan R. Coffin, John M. Hughes, Stephen H. Unutmaz, Derya Engelman, Alan KewalRamani, Vineet N. TI Flexible Use of Nuclear Import Pathways by HIV-1 SO CELL HOST & MICROBE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CENTRAL DNA FLAP; FACTOR-I-M; NONDIVIDING CELLS; PREINTEGRATION COMPLEX; MATRIX PROTEIN; PORE COMPLEX; INFECTION; TYPE-1; LOCALIZATION AB HIV-1 replication requires transport of nascent viral DNA and associated virion proteins, the retroviral preintegration complex (PIG), into the nucleus. Too large for passive diffusion through nuclear pore complexes (NPCs), PICs use cellular nuclear transport mechanisms and nucleoporins (NUPs), the NPC components that permit selective nuclear-cytoplasmic exchange, but the details remain unclear. Here we identify a fragment of the cleavage and polyadenylation factor 6, CPSF6, as a potent inhibitor of HIV-1 infection. When enriched in the cytoplasm, CPSF6 prevents HIV-1 nuclear entry by targeting the viral capsid (CA). HIV-1 harboring the N74D mutation in CA fails to interact with CPSF6 and evades the nuclear import restriction. Interestingly, whereas wild-type HIV-1 requires NUP153, N74D HIV-1 mimics feline immunodeficiency virus nuclear import requirements and is more sensitive to NUP155 depletion. These findings reveal a remarkable flexibility in HIV-1 nuclear transport and highlight a single residue in CA as essential in regulating interactions with NUPs. C1 [Lee, KyeongEun; Ambrose, Zandrea; Martin, Thomas D.; Mulky, Alok; Baumann, Joerg G.; Yuen, Wendy; Takemura, Taichiro; Shelton, Kenneth; Hughes, Stephen H.; KewalRamani, Vineet N.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Oztop, Ilker; Vandegraaff, Nick; Li, Yuan; Sodroski, Joseph; Engelman, Alan] Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. [Julias, John G.] SAIC Frederick, Frederick, MD 21702 USA. [Wang, Rui; Unutmaz, Derya] NYU, Sch Med, Dept Pathol & Microbiol, New York, NY 10016 USA. [Littman, Dan R.] NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA. [Littman, Dan R.] NYU, Sch Med, Mol Pathogenesis Program, Skirball Inst Biomol Med, New York, NY 10016 USA. [Taniuchi, Ichiro] Riken Res Ctr Allergy & Immunol, Lab Transcript Regulat, Yokohama, Kanagawa 2300045, Japan. [Coffin, John M.] Tufts Univ, Dept Mol Biol & Microbiol, Sackler Sch Biomed Sci, Boston, MA 02111 USA. RP KewalRamani, VN (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM vineet@mail.nih.gov RI Li, Yuan/B-4098-2013; Taniuchi, Ichiro/N-6399-2015 OI Taniuchi, Ichiro/0000-0002-9853-9068 FU National Cancer Institute's intramural Center for Cancer Research; HIV Drug Resistance Program; National Institutes of Health [A152014, A1033303, A1033856, A149131, CA0894, A1063987, A107609441]; American Foundation for AIDS Research postdoctoral fellowship [106404-33-RFMC]; George Kirby Foundation FX We thank Eric Freed for manuscript comments; Paul Bieniasz, Michael Emerman, Eric Freed, and Masahiro Yamashita for discussions; Julie Tang for assistance; and Sabine Dettwiler, Michael Emerman, Eric Freed, John Kappes, Walter Keller, Ned Landau, Eric Poeschla, Wes Sundquist, and Uta von Schwedler for reagents. This work was supported by the National Cancer Institute's intramural Center for Cancer Research, which supports the HIV Drug Resistance Program (S.H.H., V.N.K.); National Institutes of Health (NH) grants to A.E. (A152014), D.R.L. (A1033303; A1033856), D.U. (A149131), J.M.C. (CA089441), and J.S. (A1063987; A1076094); and an American Foundation for AIDS Research postdoctoral fellowship to Z.A. (106404-33-RFMC). J.M.C. was a Research Professor of the American Cancer Society, with support from the George Kirby Foundation. 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 51 TC 167 Z9 169 U1 1 U2 14 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 MAR 18 PY 2010 VL 7 IS 3 BP 221 EP 233 DI 10.1016/j.chom.2010.02.007 PG 13 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 573XA UT WOS:000275947500007 PM 20227665 ER PT J AU Wacholder, S Hartge, P Prentice, R Garcia-Closas, M Feigelson, HS Diver, WR Thun, MJ Cox, DG Hankinson, SE Kraft, P Rosner, B Berg, CD Brinton, LA Lissowska, J Sherman, ME Chlebowski, R Kooperberg, C Jackson, RD Buckman, DW Hui, P Pfeiffer, R Jacobs, KB Thomas, GD Hoover, RN Gail, MH Chanock, SJ Hunter, DJ AF Wacholder, Sholom Hartge, Patricia Prentice, Ross Garcia-Closas, Montserrat Feigelson, Heather Spencer Diver, W. Ryan Thun, Michael J. Cox, David G. Hankinson, Susan E. Kraft, Peter Rosner, Bernard Berg, Christine D. Brinton, Louise A. Lissowska, Jolanta Sherman, Mark E. Chlebowski, Rowan Kooperberg, Charles Jackson, Rebecca D. Buckman, Dennis W. Hui, Peter Pfeiffer, Ruth Jacobs, Kevin B. Thomas, Gilles D. Hoover, Robert N. Gail, Mitchell H. Chanock, Stephen J. Hunter, David J. TI Performance of Common Genetic Variants in Breast-Cancer Risk Models. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID GENOME-WIDE ASSOCIATION; BASE-LINE CHARACTERISTICS; SUSCEPTIBILITY LOCI; POLYMORPHISMS; RECLASSIFICATION; PREVENTION; ALLELES; DISEASE; MARKER AB Background: Genomewide association studies have identified multiple genetic variants associated with breast cancer. The extent to which these variants add to existing risk-assessment models is unknown. Methods: We used information on traditional risk factors and 10 common genetic variants associated with breast cancer in 5590 case subjects and 5998 control subjects, 50 to 79 years of age, from four U.S. cohort studies and one case-control study from Poland to fit models of the absolute risk of breast cancer. With the use of receiver-operating-characteristic curve analysis, we calculated the area under the curve (AUC) as a measure of discrimination. By definition, random classification of case and control subjects provides an AUC of 50%; perfect classification provides an AUC of 100%. We calculated the fraction of case subjects in quintiles of estimated absolute risk after the addition of genetic variants to the traditional risk model. Results: The AUC for a risk model with age, study and entry year, and four traditional risk factors was 58.0%; with the addition of 10 genetic variants, the AUC was 61.8%. About half the case subjects (47.2%) were in the same quintile of risk as in a model without genetic variants; 32.5% were in a higher quintile, and 20.4% were in a lower quintile. Conclusions: The inclusion of newly discovered genetic factors modestly improved the performance of risk models for breast cancer. The level of predicted breast-cancer risk among most women changed little after the addition of currently available genetic information. N Engl J Med 2010;362:986-93. C1 [Wacholder, Sholom; Hartge, Patricia; Garcia-Closas, Montserrat; Brinton, Louise A.; Sherman, Mark E.; Pfeiffer, Ruth; Jacobs, Kevin B.; Thomas, Gilles D.; Hoover, Robert N.; Gail, Mitchell H.; Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Berg, Christine D.] NCI, Early Detect Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. [Prentice, Ross; Kooperberg, Charles] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Feigelson, Heather Spencer; Diver, W. Ryan; Thun, Michael J.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. [Feigelson, Heather Spencer] Kaiser Permanente, Inst Hlth Res, Denver, CO USA. [Cox, David G.] INSERM, F-69008 Lyon, France. [Cox, David G.; Hankinson, Susan E.; Kraft, Peter; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Rosner, Bernard] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Hankinson, Susan E.; Rosner, Bernard; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hankinson, Susan E.; Rosner, Bernard; Hunter, David J.] Harvard Univ, Sch Med, Boston, MA USA. [Lissowska, Jolanta] Maria Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Chlebowski, Rowan] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Div Hematol & Med Oncol, Torrance, CA 90509 USA. [Jackson, Rebecca D.] Ohio State Univ, Columbus, OH 43210 USA. [Buckman, Dennis W.; Hui, Peter] Informat Management Serv Inc, Silver Spring, MD USA. RP Wacholder, S (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 5050,MSC 7244, Bethesda, MD 20892 USA. EM wacholds@mail.nih.gov RI Cox, David/A-2023-2009; Pfeiffer, Ruth /F-4748-2011; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; OI Cox, David/0000-0002-2152-9259; Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Lissowska, Jolanta/0000-0003-2695-5799 FU Division of Cancer Epidemiology and Genetics of the National Cancer Institute; National Institutes of Health [N01WH22110, P01 CA87969, P01 CA53996, R01 CA49449, U01CA098233, U01CA098710] FX Supported in part by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics of the National Cancer Institute and by grants from the National Institutes of Health (N01WH22110, P01 CA87969, P01 CA53996, R01 CA49449, U01CA098233, and U01CA098710). NR 32 TC 251 Z9 258 U1 0 U2 20 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 18 PY 2010 VL 362 IS 11 BP 986 EP 993 DI 10.1056/NEJMoa0907727 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 570CY UT WOS:000275650400009 PM 20237344 ER PT J AU Komiya, T Coxon, A Park, Y Chen, WD Zajac-Kaye, M Meltzer, P Karpova, T Kaye, FJ AF Komiya, T. Coxon, A. Park, Y. Chen, W-D Zajac-Kaye, M. Meltzer, P. Karpova, T. Kaye, F. J. TI Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer SO ONCOGENE LA English DT Article DE Crtc1; LKB1; lung cancer; Mect1/Torc1; NR4A2 ID SENSITIVE COINCIDENCE DETECTOR; PEUTZ-JEGHERS-SYNDROME; MUCOEPIDERMOID CARCINOMA; SALIVARY-GLAND; MAMMALIAN-CELLS; WARTHINS TUMORS; GENE-EXPRESSION; RECEPTOR NR4A2; FUSION; ACTIVATION AB Activation of Crtc1 (also known as Mect1/Torc1) by a t(11; 19) chromosomal rearrangement underlies the etiology of malignant salivary gland tumors. As LKB1 is a target for mutational inactivation in lung cancer and was recently shown to regulate hepatic Crtc2/CREB transcriptional activity in mice, we now present evidence suggesting disruption of an LKB1/Crtc pathway in cancer. Although Crtc1 is preferentially expressed in adult brain tissues, we observed elevated levels of steady-state Crtc1 in thoracic tumors. In addition, we show that somatic loss of LKB1 is associated with underphosphorylation of endogenous Crtc1, enhanced Crtc1 nuclear localization and enhanced expression of the Crtc prototypic target gene, NR4A2/Nurr1. Inhibition of NR4A2 was associated with growth suppression of LKB1 null tumors, but showed little effect on LKB1-wildtype cells. These data strengthen the role of dysregulated Crtc as a bona. de cancer gene, present a new element to the complex LKB1 tumorigenic axis, and suggest that Crtc genes may be aberrantly activated in a wider range of common adult malignancies. Oncogene (2010) 29, 1672-1680; doi:10.1038/onc.2009.453; published online 14 December 2009 C1 [Komiya, T.; Coxon, A.; Park, Y.; Chen, W-D; Meltzer, P.; Kaye, F. J.] NCI, Genet Branch, Bethesda, MD 20892 USA. [Komiya, T.; Coxon, A.; Park, Y.; Chen, W-D; Zajac-Kaye, M.; Meltzer, P.; Karpova, T.; Kaye, F. J.] Natl Naval Med Ctr, Bethesda, MD USA. [Zajac-Kaye, M.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Karpova, T.] NCI, Lab Receptor Biol, Bethesda, MD 20892 USA. RP Kaye, FJ (reprint author), Univ Florida Coll, Canc Genet Res Ctr, Dept Med, Rm 364,1376 Mowry Rd, Gainesville, FL 32610 USA. EM fkaye@ufl.edu RI kaye, frederic/E-2437-2011; CHEN, WEI-DONG/F-4521-2014 OI CHEN, WEI-DONG/0000-0003-2264-5515 NR 48 TC 22 Z9 23 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 18 PY 2010 VL 29 IS 11 BP 1672 EP 1680 DI 10.1038/onc.2009.453 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 570RC UT WOS:000275694700012 PM 20010869 ER PT J AU Ryan, BC Young, NB Crawley, JN Bodfish, JW Moy, SS AF Ryan, Bryce C. Young, Nancy B. Crawley, Jacqueline N. Bodfish, James W. Moy, Sheryl S. TI Social deficits, stereotypy and early emergence of repetitive behavior in the C58/J inbred mouse strain SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Autism; Social transmission of food preference; Maternal behavior; Neonatal development; Olfaction; Repetitive behavior; Social approach; Stereotypy ID AUTISM SPECTRUM DISORDERS; KNOCKOUT MICE; CORPUS-CALLOSUM; OLFACTORY FINGERPRINTS; FOOD PREFERENCE; LOW SOCIABILITY; MUTANT MICE; BODY ODORS; RELEVANT; TRANSMISSION AB Mouse lines with behavioral phenotypes relevant to symptoms in neurodevelopmental disorders may provide models to test hypotheses about disease etiology and to evaluate potential treatments. The present studies were designed to confirm and expand earlier work on the intriguing behavioral profile of the C58/J inbred strain, including low social approach and aberrant repetitive movements. Additional tests were selected to reflect aspects of autism, a severe neurodevelopmental disorder characterized by emergence of symptoms early in life, higher prevalence in males, social deficits and abnormal repetitive behavior. Mice from the C57BL/6J inbred strain, which has a similar genetic lineage and physical appearance to C58/J, served as a comparison group. Our results revealed that C58/J mice display elevated activity levels by postnatal day 6, which persist into adulthood. Despite normal olfactory ability, young adult male C58/J mice showed deficits in social approach in the three-chambered choice assay and failed to demonstrate social transmission of food preference. In contrast, female C58/J mice performed similarly to female C57BL/6J mice in both social tests. C58/J mice of both sexes demonstrated abnormal repetitive behaviors, displaying excessive Jumping and back flipping in both social and non-social situations. These stereotypies were clearly evident in C58/J pups by postnatal days 20-21, and were also observed in C58/J dams during a test for maternal behavior. Overall, the strain profile for C58/J, including spontaneously developing motor stereotypies emerging early in the developmental trajectory, and social deficits primarily in males, models multiple components of the autism phenotype. (C) 2009 ElsevierB.V. All rights reserved. C1 [Ryan, Bryce C.] Univ Redlands, Dept Biol, Redlands, CA 92373 USA. [Ryan, Bryce C.; Young, Nancy B.; Crawley, Jacqueline N.; Bodfish, James W.; Moy, Sheryl S.] Univ N Carolina, Sch Med, Neurodev Disorders Res Ctr, Chapel Hill, NC 27599 USA. [Crawley, Jacqueline N.] NIMH, Lab Behav Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. [Bodfish, James W.] Univ N Carolina, Sch Med, Clin Ctr Study Dev & Learning, Chapel Hill, NC 27599 USA. [Bodfish, James W.; Moy, Sheryl S.] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC 27599 USA. RP Ryan, BC (reprint author), 1200 E Colton Ave,POB 3080, Redlands, CA 92373 USA. EM bryce_ryan@redlands.edu FU NIMH [R21 MH084132, R01 MH73402]; NICHD [T32 HD40127, P30 HD03110]; National Institute of Mental Health Intrarmural Research Program FX The authors would like to thank Randal Nonneman, Joe Piven and Steve Reznick for their valuable assistance and insight throughout this project. This work was supported by NIMH grants R21 MH084132 and R01 MH73402, and NICHD grants T32 HD40127 and P30 HD03110 and the National Institute of Mental Health Intrarmural Research Program. NR 57 TC 53 Z9 54 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 17 PY 2010 VL 208 IS 1 BP 178 EP 188 DI 10.1016/j.bbr.2009.11.031 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 569TQ UT WOS:000275625100025 PM 19941908 ER PT J AU Ren, XF Hurley, JH AF Ren, Xuefeng Hurley, James H. TI VHS domains of ESCRT-0 cooperate in high-avidity binding to polyubiquitinated cargo SO EMBO JOURNAL LA English DT Article DE Cps1; crystal structure; protein structure; vacuole; yeast genetics ID MULTIVESICULAR BODY PATHWAY; UBIQUITIN-INTERACTING MOTIF; TRANS-GOLGI NETWORK; EARLY ENDOSOMES; GGA PROTEINS; MEMBRANE TRAFFICKING; SORTING MACHINERY; STRUCTURAL BASIS; EGF RECEPTOR; COMPLEX AB VHS (Vps27, Hrs, and STAM) domains occur in ESCRT-0 subunits Hrs and STAM, GGA adapters, and other trafficking proteins. The structure of the STAM VHS domain-ubiquitin complex was solved at 2.6 angstrom resolution, revealing that determinants for ubiquitin recognition are conserved in nearly all VHS domains. VHS domains from all classes of VHS-domain containing proteins in yeast and humans, including both subunits of ESCRT-0, bound ubiquitin in vitro. ESCRTs have been implicated in the sorting of Lys63-linked polyubiquitinated cargo. Intact human ESCRT-0 binds Lys63-linked tetraubiquitin 50-fold more tightly than monoubiquitin, though only 2-fold more tightly than Lys48-linked tetraubiquitin. The gain in affinity is attributed to the cooperation of flexibly connected VHS and UIM motifs of ESCRT-0 in avid binding to the polyubiquitin chain. Mutational analysis of all the five ubiquitin-binding sites in yeast ESCRT-0 shows that cooperation between them is required for the sorting of the Lys63-linked polyubiquitinated cargo Cps1 to the vacuole. The EMBO Journal (2010) 29, 1045-1054. doi: 10.1038/emboj.2010.6; Published online 11 February 2010 C1 [Ren, Xuefeng; Hurley, James H.] NIDDKD, Mol Biol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, US Dept HHS, Bldg 50 Rm 4517, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov FU US DOE, Basic Energy Sciences, Office of Science [W-31-109-Eng-38]; NIH FX We thank D Kloer for assistance with crystallographic analysis, B Baibokov and Y Im for assistance with microscopy, L Saidi for cell culture support, J Dean for microscope access, K Iwai, C Wolberger, S Misra, Y Ye, and A Weissman for reagents and advice on polyUb chain synthesis, C Philpott, J Bonifacino, and R Puertollano for cDNAs, and W Prinz for yeast strains. Use of the APS was supported by the US DOE, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38. This work was supported by the NIDDK and IATAP programs of the NIH intramural research program. Crystallographic coordinates have been deposited in the Protein Data Bank with the accession code 3LDZ. NR 51 TC 76 Z9 78 U1 1 U2 8 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 MAR 17 PY 2010 VL 29 IS 6 BP 1045 EP 1054 DI 10.1038/emboj.2010.6 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 570NP UT WOS:000275685300004 PM 20150893 ER PT J AU Schiffman, M Solomon, D AF Schiffman, Mark Solomon, Diane TI Liquid-Based Cytology vs Conventional Cytology in Detecting Cervical Cancer Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Solomon, Diane] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Schiffman, M (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM schiffman@mail.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 17 PY 2010 VL 303 IS 11 BP 1034 EP 1035 DI 10.1001/jama.2010.278 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 569KC UT WOS:000275594100012 ER PT J AU Hui, D Elsayem, A De La Cruz, M Berger, A Zhukovsky, DS Palla, S Evans, A Fadul, N Palmer, JL Bruera, E AF Hui, David Elsayem, Ahmed De La Cruz, Maxine Berger, Ann Zhukovsky, Donna S. Palla, Shana Evans, Avery Fadul, Nada Palmer, J. Lynn Bruera, Eduardo TI Availability and Integration of Palliative Care at US Cancer Centers SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID UNITED-STATES; SUPPORTIVE CARE; MEDICAL-CARE; DATA-BASE; LIFE; ONCOLOGY; QUALITY; END; HOSPITALS; SOCIETY AB Context The current state of palliative care in cancer centers is not known. Objectives To determine the availability and degree of integration of palliative care services and to compare between National Cancer Institute (NCI) and non-NCI cancer centers in the United States. Design, Setting, and Participants A survey of 71 NCI-designated cancer centers and a random sample of 71 non-NCI cancer centers of both executives and palliative care clinical program leaders, where applicable, regarding their palliative care services between June and October 2009. Survey questions were generated after a comprehensive literature search, review of guidelines from the National Quality Forum, and discussions among 7 physicians with research interest in palliative oncology. Executives were also asked about their attitudes toward palliative care. Main Outcome Measure Availability of palliative care services in the cancer center, defined as the presence of at least 1 palliative care physician. Results A total of 142 and 120 surveys were sent to executives and program leaders, with response rates of 71% and 82%, respectively. National Cancer Institute cancer centers were significantly more likely to have a palliative care program (50/51 [98%] vs 39/50 [78%]; P=.002), at least 1 palliative care physician (46/50 [92%] vs 28/38 [74%]; P=.04), an inpatient palliative care consultation team (47/51 [92%] vs 28/50 [56%]; P<.001), and an outpatient palliative care clinic (30/51 [59%] vs 11/50 [22%]; P<.001). Few centers had dedicated palliative care beds (23/101 [23%]) or an institution-operated hospice (37/101 [37%]). The median (interquartile range) reported durations from referral to death were 7 (4-16), 7 (5-10), and 90 (30-120) days for inpatient consultation teams, inpatient units, and outpatient clinics, respectively. Research programs, palliative care fellowships, and mandatory rotations for oncology fellows were uncommon. Executives were supportive of stronger integration and increasing palliative care resources. Conclusion Most cancer centers reported a palliative care program, although the scope of services and the degree of integration varied widely. JAMA. 2010; 303(11): 1054-1061 C1 [Hui, David; Elsayem, Ahmed; De La Cruz, Maxine; Zhukovsky, Donna S.; Evans, Avery; Fadul, Nada; Bruera, Eduardo] Univ Texas MD Anderson Canc Ctr, Dept Palliat Care & Rehabil Med, Houston, TX 77030 USA. [Palla, Shana; Palmer, J. Lynn] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. [Berger, Ann] NCI, Dept Palliat Care, Ctr Clin Canc, Bethesda, MD 20892 USA. RP Elsayem, A (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Palliat Care & Rehabil Med, Unit 1414,1515 Holcombe Blvd, Houston, TX 77030 USA. EM aelsayem@mdanderson.org FU National Institutes of Health [RO1NR010162-01A1, RO1CA122292-01, RO1CA124481-01]; National Cancer Institute [CA16672]; Royal College of Physicians and Surgeons of Canada FX Funding/Support: This work was supported in part by grants RO1NR010162-01A1, RO1CA122292-01, and RO1CA124481-01 from the National Institutes of Health (Dr Bruera); grant CA16672 from the National Cancer Institute (Patient- Reported Outcomes, Survey and Population Research Shared Resources); and the Clinician Investigator Program, Royal College of Physicians and Surgeons of Canada (Dr Hui). NR 33 TC 171 Z9 173 U1 1 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 17 PY 2010 VL 303 IS 11 BP 1054 EP 1061 DI 10.1001/jama.2010.258 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 569KC UT WOS:000275594100018 PM 20233823 ER PT J AU Niederhuber, JE AF Niederhuber, John E. TI Translating Discovery to Patient Care SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID TUMOR MICROENVIRONMENT; CANCER C1 NCI, Bethesda, MD 20892 USA. RP Niederhuber, JE (reprint author), NCI, 31 Ctr Dr,Room 11A48, Bethesda, MD 20892 USA. EM niederj@mail.nih.gov NR 9 TC 6 Z9 6 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD MAR 17 PY 2010 VL 303 IS 11 BP 1088 EP 1089 DI 10.1001/jama.2010.281 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 569KC UT WOS:000275594100024 PM 20233829 ER PT J AU Conant, K Wang, Y Szklarczyk, A Dudak, A Mattson, MP Lim, ST AF Conant, K. Wang, Y. Szklarczyk, A. Dudak, A. Mattson, M. P. Lim, S. T. TI MATRIX METALLOPROTEINASE-DEPENDENT SHEDDING OF INTERCELLULAR ADHESION MOLECULE-5 OCCURS WITH LONG-TERM POTENTIATION SO NEUROSCIENCE LA English DT Article DE telencephalin; NMDA; MMPs; dendrite; plasticity; shedding ID SYNAPTIC PLASTICITY; EXTRACELLULAR-MATRIX; HIPPOCAMPAL-NEURONS; DENDRITIC SPINES; TISSUE INHIBITOR; ERM PROTEINS; MATRIX-METALLOPROTEINASE-9; TELENCEPHALIN; INVOLVEMENT; ACTIVATION AB Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases that can be released or activated in a neuronal activity dependent manner. Although pathologically elevated levels of MMPs may be synaptotoxic, physiologically appropriate levels of MMPs may instead enhance synaptic transmission. MMP inhibitors can block long term potentiation (LTP), and at least one family member can affect an increase in the volume of dendritic spines. While the mechanism by which MMPs affect these changes is not completely understood, one possibility is that the cleavage of specific synaptic cell adhesion molecules plays a role. In the present study, we have examined the ability of neuronal activity to stimulate rapid MMP dependent shedding of the intercellular adhesion molecule-5 (ICAM-5), a synaptic adhesion molecule that is thought to inhibit the maturation and enlargement of dendritic spines. Since such cleavage would likely occur within minutes if it were relevant to a process such as LTP, we focused on post stimulus time points of 30 min or less. We show that NMDA can stimulate rapid shedding of ICAM-5 from cortical neurons in dissociated cell cultures and that such shedding is diminished by pretreatment of cultures with inhibitors that target MMP-3 and -9, proteases thought to influence synaptic plasticity. Additional studies suggest that MMP mediated cleavage of ICAM-5 occurs at amino acid 780, so that the major portion of the ectodomain is released. Since reductions in ICAM-5 have been linked to changes in dendritic spine morphology that are associated with LTP, we also examined the possibility that MMP dependent ICAM-5 shedding occurs following high frequency tetanic stimulation of murine hippocampal slices. Results show that the shedding of ICAM-5 occurs in association with LTP, and that both LTP and the associated ICAM-5 shedding are reduced when slices are pretreated with an MMP inhibitor. Together, these findings suggest that neuronal activity is linked to the shedding of a molecule that may inhibit dendritic spine enlargement and that MMPs can affect this change. While further studies will be necessary to determine the extent to which cleavage of ICAM-5 in particular contributes to MMP dependent LTP, our data support an emerging body of literature suggesting that MMPs are critical mediators of synaptic plasticity. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Conant, K.; Szklarczyk, A.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. [Conant, K.; Dudak, A.; Lim, S. T.] Georgetown Univ, Dept Neurosci, Washington, DC USA. [Wang, Y.; Mattson, M. P.] NIA, Neurosci Lab, Baltimore, MD 21224 USA. RP Conant, K (reprint author), Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. EM kec84@georgetown.edu; ls379@georgetown.edu RI Mattson, Mark/F-6038-2012 FU Alzheimer's Association; National Institutes of Drug Abuse [DA024447]; National Multiple Sclerosis Society; National Institutes of Aging [AG029806] FX This work was supported in part by the Alzheimer's Association, the National Institutes of Drug Abuse (DA024447), the National Multiple Sclerosis Society, and the National Institutes of Aging (Intramural Program and AG029806). NR 59 TC 53 Z9 55 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD MAR 17 PY 2010 VL 166 IS 2 BP 508 EP 521 DI 10.1016/j.neuroscience.2009.12.061 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 560PJ UT WOS:000274914300019 PM 20045450 ER PT J AU Jett, DA AF Jett, David A. TI Finding New Cures for Neurological Disorders: A Possible Fringe Benefit of Biodefense Research? SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID STATUS EPILEPTICUS; ENZYME EVOLUTION; X-RAY; SARIN; ACETYLCHOLINESTERASE; RECOGNITION; MECHANISMS; ZEBRAFISH; RECEPTORS; DYNAMICS AB The National Institutes of Health (NIH) supports research about and the development of better therapies for treating exposure to toxic chemicals that could be used in a terrorist attack or released during an industrial accident. A review of recent research published by NIH investigators working in this field indicates that scientific advances in this area also have implications for reducing the burden of other neurological diseases and disorders. Some key examples discussed include studies on the development of therapeutic drugs to treat seizures and the neuropathology caused by chemical nerve agents, which may help find better cures for epilepsy, stroke, and neurodegenerative diseases. C1 NINDS, NIH CounterACT Res, NIH, Bethesda, MD 20892 USA. RP Jett, DA (reprint author), NINDS, NIH CounterACT Res, NIH, Bethesda, MD 20892 USA. EM jettd@ninds.nih.gov NR 35 TC 3 Z9 3 U1 0 U2 6 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 MAR 17 PY 2010 VL 2 IS 23 AR 23ps12 DI 10.1126/scitranslmed.3000752 PG 4 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 591ME UT WOS:000277304000002 PM 20375001 ER PT J AU Goldfine, AB Fonseca, V Jablonski, KA Pyle, L Staten, MA Shoelson, SE AF Goldfine, Allison B. Fonseca, Vivian Jablonski, Kathleen A. Pyle, Laura Staten, Myrlene A. Shoelson, Steven E. CA TINSAL-T2D Targeting Inflammation TI The Effects of Salsalate on Glycemic Control in Patients With Type 2 Diabetes A Randomized Trial SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID NF-KAPPA-B; GLOMERULAR-FILTRATION-RATE; INDUCED INSULIN-RESISTANCE; SODIUM-SALICYLATE; IKK-BETA; NONACETYLATED SALICYLATE; CYSTATIN-C; URIC-ACID; ASPIRIN; INFLAMMATION AB Background: Salsalate, a nonacetylated prodrug of salicylate, has been shown to decrease blood glucose concentration in small studies. Objective: To compare the efficacy and safety of salsalate at different doses in patients with type 2 diabetes. Design: Parallel randomized trial with computer-generated randomization and centralized allocation. Patients and investigators, including those assessing outcomes and performing analyses, were masked to group assignment. (ClinicalTrials.gov registration number: NCT00392678) Setting: 3 private practices and 14 universities in the United States. Patients: Persons aged 18 to 75 years with fasting plasma glucose concentrations of 12.5 mmol/L or less (<= 225 mg/dL) and hemoglobin A(1c) (HbA(1c)) levels of 7.0% to 9.5% treated by diet, exercise, and oral medication at stable doses for at least 8 weeks. Intervention: After a 4-week, single-masked run-in period, patients were randomly assigned to receive placebo or salsalate in dosages of 3.0, 3.5, or 4.0 g/d for 14 weeks (27 patients each) in addition to their current therapy. Measurements: Change in HbA(1c) was the primary outcome. Adverse effects and changes in measures of coronary risk and renal function were secondary outcomes. Results: Higher proportions of patients in the 3 salsalate treatment groups experienced decreases in HbA(1c) levels of 0.5% or more from baseline (P = 0.009). Mean HbA(1c) changes were -0.36% (P = 0.02) at 3.0 g/d, -0.34% (P = 0.02) at 3.5 g/d, and -0.49% (P = 0.001) at 4.0 g/d compared with placebo. Other markers of glycemic control also improved in the 3 salsalate groups, as did circulating triglyceride and adiponectin concentrations. Mild hypoglycemia was more common with salsalate; documented events occurred only in patients taking sulfonylureas. Urine albumin concentrations increased in all salsalate groups compared with placebo. The drug was otherwise well tolerated. Limitation: The number of patients studied and the trial duration were insufficient to warrant recommending the use of salsalate for type 2 diabetes at this time. Conclusion: Salsalate lowers HbA(1c) levels and improves other markers of glycemic control in patients with type 2 diabetes and may therefore provide a new avenue for treatment. Renal and cardiac safety of the drug require further evaluation. C1 [Shoelson, Steven E.] Joslin Diabet Ctr, Boston, MA 02215 USA. Tulane Univ, New Orleans, LA 70118 USA. George Washington Univ, Rockville, MD USA. NIDDKD, Washington, DC USA. RP Shoelson, SE (reprint author), Joslin Diabet Ctr, 1 Joslin Pl, Boston, MA 02215 USA. EM steven.shoelson@joslin.harvard.edu FU National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; National Institutes of Health [U01 DK74556, P50 HL83813]; National Institutes of Health General Clinical Research Center; Clinical and Translational Science FX National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health.; By National Institutes of Health grants U01 DK74556 and P50 HL83813, National Institutes of Health General Clinical Research Center and Clinical and Translational Science Award grants at multiple sites, and the Tullis-Tulane (Dr. Fonseca) and Helen and Morton Adler (Dr. Shoelson) Chairs. Caraco Pharmaceuticals (Detroit, Michigan) supplied drug and placebo, Lifescan (Miltipas, California; a division of Johnson & Johnson) supplied home glucose-monitoring kits, and Mercodia (Uppsala, Sweden) supplied insulin assay kits. NR 37 TC 198 Z9 201 U1 0 U2 13 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 EI 1539-3704 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAR 16 PY 2010 VL 152 IS 6 BP 346 EP + DI 10.7326/0003-4819-152-6-201003160-00004 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 573IF UT WOS:000275905200002 PM 20231565 ER PT J AU Polgar, O Ierano, C Tamaki, A Stanley, B Ward, Y Xia, D Tarasova, N Robey, RW Bates, SE AF Polgar, Orsolya Ierano, Caterina Tamaki, Akina Stanley, Bradford Ward, Yvona Xia, Di Tarasova, Nadya Robey, Robert W. Bates, Susan E. TI Mutational Analysis of Threonine 402 Adjacent to the GXXXG Dimerization Motif in Transmembrane Segment 1 of ABCG2 SO BIOCHEMISTRY LA English DT Article ID MULTIDRUG-RESISTANCE TRANSPORTER; BREAST-CANCER CELLS; GLYCOPHORIN-A; PHARMACOLOGICAL CHAPERONES; BIOLOGICAL MEMBRANE; ACQUIRED MUTATIONS; HELIX INTERACTIONS; CYSTIC-FIBROSIS; DIMER; GENE AB ABCG2 is an ATP-binding cassette half-transporter important in normal tissue protection, drug distribution, and excretion. ABCG2 requires homodimerization for function, though the mechanism for dimerization has not been elucidated. We conducted mutational analysis of threonine 402, three residues from the GXXXG motif in TM1, to study its potential role in ABCG2 dimerization (TXXXGXXXG). Single Mutations to leucine (T402L) or arginine (T402R) did not have a significant impact oil the ABCG2 protein. On the other hand, combining the T402 Mutations with the GXXXG glycine to leucine mutations (T402L/G406L/G410L and T402R/G406L/G410L) resulted in a substantially reduced level of expression, altered glycosylation, degradation by it proteosome-independent pathway, and partial retention in the endoplasmic reticulum as suggested by immunostaining, Endo H sensitivity, and MG132 and bafilomycin failed effect. The T402L/G406L/G410L Mutant when incubated with the ABCG2 substrate NIX showed it shift oil immunoblot analysis to the band representing the fully Mature glycoprotein. The T402R/G406L/G410L mutant carrying the more drastic substitution Was found to primarily localize intracellularly. The same set of mutations also displayed impaired dimerization in the TOXCAT assay for TM1 compared to that of the wild type. Homology modeling of ABCG2 places the TXXXGXXXG motif at the dimer interface. These Studies are consistent with a role for the extended TXXXGXXXG motif in ABCG2 folding, processing, and/or dimerization. C1 [Polgar, Orsolya; Ierano, Caterina; Tamaki, Akina; Robey, Robert W.; Bates, Susan E.] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Xia, Di] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Stanley, Bradford] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT 06520 USA. [Tarasova, Nadya] NCI, Mol Aspects Drug Design Sect, Struct Biophys Lab, Frederick, MD 21702 USA. [Ward, Yvona] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Med Oncol Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 13N240, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov RI Ierano, Caterina/K-1676-2016 OI Ierano, Caterina/0000-0003-3138-1873 FU National institutes of Health, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the National institutes of Health, National Cancer Institute, Center for Cancer Research. NR 54 TC 26 Z9 26 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 16 PY 2010 VL 49 IS 10 BP 2235 EP 2245 DI 10.1021/bi902085q PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564PH UT WOS:000275227000016 PM 20088606 ER PT J AU McCormack, T Petrovich, RM Mercier, KA DeRose, EF Cuneo, MJ Williams, J Johnson, KL Lamb, PW London, RE Yakel, JL AF McCormack, Thomas Petrovich, Robert M. Mercier, Kelly A. DeRose, Eugene F. Cuneo, Matthew J. Williams, Jason Johnson, Katina L. Lamb, Patricia W. London, Robert E. Yakel, Jerrel L. TI Identification and Functional Characterization of a Novel Acetylcholine-Binding Protein from the Marine Annelid Capitella teleta SO BIOCHEMISTRY LA English DT Article ID RAY SOLUTION SCATTERING; CRYSTAL-STRUCTURE; NICOTINIC RECEPTORS; ESCHERICHIA-COLI; HIGH-RESOLUTION; LIGAND-BINDING; DOMAIN; NMR; TRANSITIONS; REVEALS AB We identified it homologue of the molluscan acetylcholine-binding protein (AChBP) in the marine polychaete Capitella teleta, from the annelid phylum. The amino acid sequence of C. teleta AChBP (ct-AChBP) is 21-30% identical with those of known molluscan AMPS. Sequence alignments Indicate that ct-AChBP has a shortened Cys loop compared to other Cys loop receptors, and a variation on a conserved Cys loop triad, which is associated with ligand binding in other AChBPs and nicotinic ACh receptor (nAChR) alpha subunits. Within the D loop of ct-AChBP, a conserved aromatic residue (Tyr or Trp) in nAChRs and molluscan AChBPs. which has been implicated directly in ligand binding, is substituted with an isoleucine. Mass spectrometry results that Asn 122 and Asn216 of ct-AChBP are glycosylated expressed using HEK293 cells. Small-angle X-ray scattering data suggest that the overall shape of ct-AChBP in the apo of unliganded state is similar to that of homologous with known pentameric crystal Structures. NMR experiments show that acetylcholine, nicotine, and alpha-bungarotoxin bind to ct-AChBP with high affinity, with K(D) values of 28.7 mu M, 209 nM, and 110 nM, respectively. Choline bound with a lower affinity (K(D) = 163 mu M). Our finding of a functional AChBP in it marine annelid demonstrates that AChBPs may exhibit variations in hallmark motifs such its ligand-binding residues and Cys loop length and shows conclusively that this neurotransmitter binding, protein is not limited to the phyllum Mollusca. C1 [McCormack, Thomas; Lamb, Patricia W.; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Petrovich, Robert M.; Mercier, Kelly A.; DeRose, Eugene F.; Cuneo, Matthew J.; Williams, Jason; Johnson, Katina L.; London, Robert E.] NIEHS, Struct Biol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yakel, JL (reprint author), NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, F2-08,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM yakel@niehs.nih.gov OI Cuneo, Matthew/0000-0002-1475-6656 FU National Institutes of Health, National Institute of Environmental Health Sciences [HHSN273200700046U] FX Supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. E.F.D's contribution was funded in whole with federal funds from the National Institutes of Health, National Institute of Environmental Health Sciences, under Delivery Order HHSN273200700046U to SRA International, Inc. NR 27 TC 14 Z9 14 U1 0 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 16 PY 2010 VL 49 IS 10 BP 2279 EP 2287 DI 10.1021/bi902023y PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 564PH UT WOS:000275227000020 PM 20136097 ER PT J AU Huang, J Chen, K Chen, J Gong, W Dunlop, NM Howard, OMZ Gao, Y Bian, XW Wang, JM AF Huang, J. Chen, K. Chen, J. Gong, W. Dunlop, N. M. Howard, O. M. Z. Gao, Y. Bian, X-W Wang, J. M. TI The G-protein-coupled formylpeptide receptor FPR confers a more invasive phenotype on human glioblastoma cells SO BRITISH JOURNAL OF CANCER LA English DT Article DE formylpeptide receptor; invasion; glioblastoma; cancer ID FORMYL PEPTIDE-RECEPTOR; METHIONYL-LEUCYL-PHENYLALANINE; ENDOTHELIAL GROWTH-FACTOR; MALIGNANT GLIOMA-CELLS; LISTERIA-MONOCYTOGENES; N-FORMYLPEPTIDE; CYCLOSPORINE-H; ANNEXIN-I; ACTIVATION; IDENTIFICATION AB BACKGROUND: The G-protein-coupled formylpeptide receptor (FPR) that mediates chemotaxis of phagocytic leucocytes induced by bacterial and host-derived chemotactic peptides is selectively expressed by highly malignant human gliomas and contributes to tumour growth and angiogenesis. As invasion of surrounding normal tissues is one of the important features of tumour malignancy, we investigated the function of FPR in the invasive behaviour of human glioblastoma cells. METHODS: Cells (FPR(+) and FPR(-)) were isolated by single-cell cloning from a human glioblastoma cell line U-87MG. The FPR expression was assayed by flow cytometry and reverse transcription PCR. The function of FPR was investigated by chemotaxis and calcium flux induced by FPR agonist fMLF. Tumour cell motility was assayed by a wound-healing model in vitro. The growth and invasive phenotype were observed with subcutaneous implantation of tumour cells in nude mice. Over-expression of FPR in FPR(-) cells was performed by transfection of a plasmid vector-containing human FPR gene. RESULTS: One of the glioma clones F9 that expressed high level of FPR showed a more 'motile' phenotype in vitro as compared with a clone G3 without FPR expression. Although F9 and G3 clones both formed subcutaneous tumours in nude mice, only F9 tumours invaded surrounding mouse connective tissues. Over-expression of FPR in G3 clone (G3F) increased the cell motility in vitro and the capacity of the cells to form more rapidly growing and invasive tumours in nude mice. We further found that, in addition to supernatant of necrotic tumour cells, foetal calf serum and human serum used in culture media contained FPR agonist activity and increased the motility of FPR-expressing glioblastoma cells. CONCLUSION: The expression of FPR is responsible for increased motility of human glioblastoma cells and their formation of highly invasive tumours. British Journal of Cancer (2010) 102, 1052-1060. doi:10.1038/sj.bjc.6605591 www.bjcancer.com Published online 2 March 2010 (C) 2010 Cancer Research UK C1 [Huang, J.; Gao, Y.] Third Mil Med Univ, Coll High Altitude Mil Med, Dept Pathophysiol, Chongqing 400038, Peoples R China. [Huang, J.; Chen, K.; Dunlop, N. M.; Howard, O. M. Z.; Wang, J. M.] NCI Frederick, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Chen, J.; Bian, X-W] Third Mil Med Univ, Inst Pathol, Chongqing 400038, Peoples R China. [Chen, J.; Bian, X-W] Third Mil Med Univ, SW Canc Ctr, Southwest Hosp, Chongqing 400038, Peoples R China. [Gong, W.] NCI Frederick, Basic Res Program, SAIC Frederick, Frederick, MD 21702 USA. RP Huang, J (reprint author), Third Mil Med Univ, Coll High Altitude Mil Med, Dept Pathophysiol, Chongqing 400038, Peoples R China. EM hj3red@gmail.com; wangji@mail.nih.gov RI Bian, Xiuwu/F-1569-2011; Howard, O M Zack/B-6117-2012; Bian, Xiu-wu/D-4736-2017 OI Howard, O M Zack/0000-0002-0505-7052; Bian, Xiu-wu/0000-0003-4383-0197 FU National Cancer Institutes, National Institutes of Health [NO1-CO-12400]; National Natural Science foundation of China [30973446] FX We thank Dr Joost J Oppenheim for reviewing the manuscript and Ms Cheryl N Magers and Ms Cheryl F Lamb for secretarial assistance. 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 organisations implies endorsement by the US Government. This project has been funded in part with federal funds from the National Cancer Institutes, National Institutes of Health, under Contract No. NO1-CO-12400. The research was also supported in part by the Intramural Research Program of the NCI, NIH and National Natural Science foundation of China (NSFC, No. 30973446). Animal care was provided in accordance with the procedures outlined in the 'Guide for Care and Use of Laboratory Animals' (National Research Council; 1996; National Academy Press; Washington, D. C.). NR 32 TC 31 Z9 34 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAR 16 PY 2010 VL 102 IS 6 BP 1052 EP 1060 DI 10.1038/sj.bjc.6605591 PG 9 WC Oncology SC Oncology GA 569XK UT WOS:000275635900017 PM 20197768 ER PT J AU Burgos, PV Mardones, GA Rojas, AL daSilva, LLP Prabhu, Y Hurley, JH Bonifacino, JS AF Burgos, Patricia V. Mardones, Gonzalo A. Rojas, Adriana L. daSilva, Luis L. P. Prabhu, Yogikala Hurley, James H. Bonifacino, Juan S. TI Sorting of the Alzheimer's Disease Amyloid Precursor Protein Mediated by the AP-4 Complex SO DEVELOPMENTAL CELL LA English DT Article ID TRANS-GOLGI NETWORK; BETA-PROTEIN; AP2 COMPLEX; STRUCTURAL EXPLANATION; SECRETASE CLEAVAGE; MEDIUM CHAINS; CELL-SURFACE; SIGNALS; ADAPTER; GENERATION AB Adaptor protein 4 (AP-4) is the most recently discovered and least well-characterized member of the family of heterotetrameric adaptor protein (AP) complexes that mediate sorting of transmembrane cargo in post-Golgi compartments. Herein, we report the interaction of an YKFFE sequence from the cytosolic tail of the Alzheimer's disease amyloid precursor protein (APP) with the mu 4 subunit of AP-4. Biochemical and X-ray crystallographic analyses reveal that the properties of the APP sequence and the location of the binding site on mu 4 are distinct from those of other signal-adaptor interactions. Disruption of the APP-AP-4 interaction decreases localization of APP to endosomes and enhances gamma-secretase-catalyzed cleavage of APP to the pathogenic amyloid-beta peptide. These findings demonstrate that APP and AP-4 engage in a distinct type of signal-adaptor interaction that mediates transport of APP from the trans-Golgi network (TGN) to endosomes, thereby reducing amyloidogenic processing of the protein. C1 [Burgos, Patricia V.; Mardones, Gonzalo A.; daSilva, Luis L. P.; Prabhu, Yogikala; Bonifacino, Juan S.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Rojas, Adriana L.; Hurley, James H.] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM juan@helix.nih.gov RI LP daSilva, Luis/A-9949-2010; Rojas, Adriana/G-2403-2011; OI LP daSilva, Luis/0000-0003-3558-0087; Rojas, Adriana/0000-0002-7358-3505; Bonifacino, Juan S./0000-0002-5673-6370 FU National Cancer Institute [Y1-C0-1020]; National Institute of General Medical Science [Y1-GM-1104]; U.S. Department of Energy, Basic Energy Sciences, Office of Science [DE-AC02-06CH11357]; NICHD; NIDDK; NIH FX We thank X. Zhu, and N. Tsai for excellent technical assistance; R. Doms, C. Dotti, A. Gonzalez, C. Haass, R. Hegde, M. S. Robinson, and W. Smith for gifts of reagents; J. Sayer, J. Louis, and G. M. Clore for use of the iTC200 microcalorimeter; N. Noinaj for collecting the native data set; and the staffs of the SER-CAT and GM/CA-CAT beamlines at the APS, Argonne National Laboratory, for assistance with X-ray data collection. GM/CA-CAT has been funded in whole or in part with funds from the National Cancer Institute (Y1-C0-1020) and the National Institute of General Medical Science (Y1-GM-1104). Use of the APS was supported by the U.S. Department of Energy, Basic Energy Sciences, Office of Science, under contract no. DE-AC02-06CH11357. This work was funded by the Intramural Programs of NICHD and NIDDK, NIH. NR 46 TC 115 Z9 119 U1 1 U2 11 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD MAR 16 PY 2010 VL 18 IS 3 BP 425 EP 436 DI 10.1016/j.devcel.2010.01.015 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 575HP UT WOS:000276058400013 PM 20230749 ER PT J AU Chen, H Huang, X Guo, X Mailman, RB Park, Y Kamel, F Umbach, DM Xu, Q Hollenbeck, A Schatzkin, A Blair, A AF Chen, H. Huang, X. Guo, X. Mailman, R. B. Park, Y. Kamel, F. Umbach, D. M. Xu, Q. Hollenbeck, A. Schatzkin, A. Blair, A. TI Smoking duration, intensity, and risk of Parkinson disease SO NEUROLOGY LA English DT Article ID CIGARETTE-SMOKING; TRANSDERMAL NICOTINE; PROGRESSION; SURVIVAL; COHORT; HEALTH; MOTOR; TWINS; DIET AB Objective: To evaluate the relative importance of smoking duration vs intensity in reducing the risk of Parkinson disease (PD). Methods: The study included 305,468 participants of the NIH-AARP Diet and Health cohort, of whom 1,662 had a PD diagnosis after 1995. We estimated odds ratios (OR) and 95% confidence intervals from multivariate logistic regression models. Results: Compared with never smokers, the multivariate ORs were 0.78 for past smokers and 0.56 for current smokers. Among past smokers, a monotonic trend toward lower PD risk was observed for all indicators of more smoking. Stratified analyses indicated that smoking duration was associated with lower PD risk within fixed intensities of smoking. For example, compared with never smokers, the ORs among past smokers who smoked >20 cigarettes/day were 0.96 for 1-9 years of smoking, 0.78 for 10-19 years, 0.64 for 20-29 years, and 0.59 for 30 years or more (p for trend = 0.001). In contrast, at fixed duration, the typical number of cigarettes smoked per day in general was not related to PD risk. Close examination of smoking behaviors in early life showed that patients with PD were less likely to be smokers at each age period, but if they smoked, they smoked similar numbers of cigarettes per day as individuals without PD. Conclusions: This large study suggests that long-term smoking is more important than smoking intensity in the smoking-Parkinson disease relationship. Neurology (R) 2010; 74: 878-884 C1 [Chen, H.; Kamel, F.; Xu, Q.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Umbach, D. M.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Huang, X.; Mailman, R. B.] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurol, Hershey, PA 17033 USA. [Huang, X.] Penn State Univ, Milton S Hershey Med Ctr, Dept Radiol, Hershey, PA 17033 USA. [Huang, X.] Penn State Univ, Milton S Hershey Med Ctr, Dept Neurosurg, Hershey, PA 17033 USA. [Huang, X.; Mailman, R. B.] Penn State Univ, Milton S Hershey Med Ctr, Dept Pharmacol, Hershey, PA 17033 USA. [Huang, X.] Penn State Univ, Milton S Hershey Med Ctr, Dept Kinesiol, Hershey, PA 17033 USA. [Huang, X.] Penn State Univ, Milton S Hershey Med Ctr, Dept Bioengn, Hershey, PA 17033 USA. [Guo, X.] Westat Corp, Res Triangle Pk, NC USA. [Park, Y.; Schatzkin, A.] NCI, Nutr Epidemiol Branch, Rockville, MD USA. [Blair, A.] NCI, Occupat & Environm Epidemiol Branch, Rockville, MD USA. [Hollenbeck, A.] AARP, Washington, DC USA. RP Chen, H (reprint author), NIEHS, Epidemiol Branch, 111 TW Alexander Dr,POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM chenh2@niehs.nih.gov OI Kamel, Freya/0000-0001-5052-6615; Mailman, Richard/0000-0003-1353-2738; Chen, Honglei/0000-0003-3446-7779; Park, Yikyung/0000-0002-6281-489X FU Intramural NIH HHS; NCI NIH HHS [Z01 CP010196-02]; NIEHS NIH HHS [Z01-ES-101986] NR 27 TC 86 Z9 89 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 16 PY 2010 VL 74 IS 11 BP 878 EP 884 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 569LO UT WOS:000275598700005 PM 20220126 ER PT J AU Segal, BH Han, W Bushey, JJ Joo, M Bhatti, Z Feminella, J Dennis, CG Vethanayagam, RR Yull, FE Capitano, M Wallace, PK Minderman, H Christman, JW Sporn, MB Chan, J Vinh, DC Holland, SM Romani, LR Gaffen, SL Freeman, ML Blackwell, TS AF Segal, Brahm H. Han, Wei Bushey, Jennifer J. Joo, Myungsoo Bhatti, Zahida Feminella, Joy Dennis, Carly G. Vethanayagam, R. Robert Yull, Fiona E. Capitano, Maegan Wallace, Paul K. Minderman, Hans Christman, John W. Sporn, Michael B. Chan, Jefferson Vinh, Donald C. Holland, Steven M. Romani, Luigina R. Gaffen, Sarah L. Freeman, Michael L. Blackwell, Timothy S. TI NADPH Oxidase Limits Innate Immune Responses in the Lungs in Mice SO PLOS ONE LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; NF-KAPPA-B; SMOKE-INDUCED EMPHYSEMA; CUL3-BASED E3 LIGASE; CDDO-IMIDAZOLIDE; HOST-DEFENSE; DEFICIENT MICE; ENHANCES SUSCEPTIBILITY; SYNTHETIC TRITERPENOIDS; INFLAMMATORY RESPONSES AB Background: Chronic granulomatous disease (CGD), an inherited disorder of the NADPH oxidase in which phagocytes are defective in generating superoxide anion and downstream reactive oxidant intermediates (ROIs), is characterized by recurrent bacterial and fungal infections and by excessive inflammation (e. g., inflammatory bowel disease). The mechanisms by which NADPH oxidase regulates inflammation are not well understood. Methodology/Principal Findings: We found that NADPH oxidase restrains inflammation by modulating redox-sensitive innate immune pathways. When challenged with either intratracheal zymosan or LPS, NADPH oxidase-deficient p47(phox-/-) mice and gp91(phox)-deficient mice developed exaggerated and progressive lung inflammation, augmented NF-kappa B activation, and elevated downstream pro-inflammatory cytokines (TNF-alpha, IL-17, and G-CSF) compared to wildtype mice. Replacement of functional NADPH oxidase in bone marrow-derived cells restored the normal lung inflammatory response. Studies in vivo and in isolated macrophages demonstrated that in the absence of functional NADPH oxidase, zymosan failed to activate Nrf2, a key redox-sensitive anti-inflammatory regulator. The triterpenoid, CDDO-Im, activated Nrf2 independently of NADPH oxidase and reduced zymosan-induced lung inflammation in CGD mice. Consistent with these findings, zymosan-treated peripheral blood mononuclear cells from X-linked CGD patients showed impaired Nrf2 activity and increased NF-kB activation. Conclusions/Significance: These studies support a model in which NADPH oxidase-dependent, redox-mediated signaling is critical for termination of lung inflammation and suggest new potential therapeutic targets for CGD. C1 [Segal, Brahm H.; Bushey, Jennifer J.; Feminella, Joy; Dennis, Carly G.; Vethanayagam, R. Robert; Minderman, Hans] Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. [Segal, Brahm H.; Capitano, Maegan] Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14263 USA. [Segal, Brahm H.; Bhatti, Zahida] Univ Buffalo, Sch Med & Biomed Sci, Buffalo, NY USA. [Han, Wei; Blackwell, Timothy S.] Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. [Joo, Myungsoo] Pusan Natl Univ, Sch Oriental Med, Div Appl Med, Yangsan, South Korea. [Yull, Fiona E.; Blackwell, Timothy S.] Vanderbilt Univ, Sch Med, Dept Canc Biol, Nashville, TN 37212 USA. [Wallace, Paul K.; Minderman, Hans] Roswell Pk Canc Inst, Dept Pathol, Buffalo, NY 14263 USA. [Christman, John W.] Univ Illinois, Sect Pulm Crit Care & Sleep Med, Chicago, IL USA. [Sporn, Michael B.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Pharmacol & Toxicol, Hanover, NH 03756 USA. [Chan, Jefferson] Univ So Calif, Sch Med, Dept Pathol, Irvine, CA USA. [Vinh, Donald C.; Holland, Steven M.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Romani, Luigina R.] Univ Perugia, Dept Expt Med, I-06100 Perugia, Italy. [Gaffen, Sarah L.] Univ Pittsburgh, Div Rheumatol & Clin Immunol, Pittsburgh, PA USA. [Freeman, Michael L.] Vanderbilt Univ, Sch Med, Dept Radiat Oncol, Nashville, TN 37212 USA. [Blackwell, Timothy S.] Vanderbilt Univ, Sch Med, Dept Cell & Dev Biol, Nashville, TN 37212 USA. [Blackwell, Timothy S.] Dept Vet Affairs, Nashville, TN USA. RP Segal, BH (reprint author), Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. EM brahm.segal@roswellpark.org OI VINH, DONALD/0000-0003-1347-7767; Freeman, Michael/0000-0003-1881-366X; Romani, Luigina/0000-0002-1356-525X FU Chronic Granulomatous Disorder Research Trust; NIH/NIAID [R01AI079253]; NIH/NCI [CA115556]; NIH [HL61419]; U.S. Department of Veterans Affairs (TSB); Korea Healthcare Technology RD [A084891]; NCI Cancer Center [CA016056] FX This work was supported by Chronic Granulomatous Disorder Research Trust and NIH/NIAID R01AI079253 (BHS), NIH/NCI CA115556 (MLF), NIH HL61419 (TSB), the U.S. Department of Veterans Affairs (TSB), and Korea Healthcare Technology R&D Project A084891 (MJ). This research was supported, in part, by the NCI Cancer Center Support Grant to Roswell Park Cancer Institute (CA016056). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 65 TC 83 Z9 84 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 MAR 16 PY 2010 VL 5 IS 3 AR e9631 DI 10.1371/journal.pone.0009631 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 570ZC UT WOS:000275716400001 PM 20300512 ER PT J AU Auld, DS Lovell, S Thorne, N Lea, WA Maloney, DJ Shen, M Rai, G Battaile, KP Thomas, CJ Simeonov, A Hanzlik, RP Inglese, J AF Auld, Douglas S. Lovell, Scott Thorne, Natasha Lea, Wendy A. Maloney, David J. Shen, Min Rai, Ganesha Battaile, Kevin P. Thomas, Craig J. Simeonov, Anton Hanzlik, Robert P. Inglese, James TI Molecular basis for the high-affinity binding and stabilization of firefly luciferase by PTC124 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Ataluren; multisubstrate adduct inhibitor; protein stability; reporter gene assay; X-ray crystallography ID MULTISUBSTRATE ADDUCT INHIBITOR; CRYSTAL-STRUCTURE; BIOLUMINESCENCE; MECHANISM; REPORTER; ENZYME; ASSAYS; TRANSFORMYLASE; IDENTIFICATION; SPECIFICITY AB Firefly luciferase (FLuc), an ATP-dependent bioluminescent reporter enzyme, is broadly used in chemical biology and drug discovery assays. PTC124 (Ataluren; (3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl] benzoic acid) discovered in an FLuc-based assay targeting nonsense codon suppression, is an unusually potent FLuc-inhibitor. Paradoxically, PTC124 and related analogs increase cellular FLuc activity levels by posttranslational stabilization. In this study, we show that FLuc inhibition and stabilization is the result of an inhibitory product formed during the FLuc-catalyzed reaction between its natural substrate, ATP, and PTC124. A 2.0 angstrom cocrystal structure revealed the inhibitor to be the acyl-AMP mixed-anhydride adduct PTC124-AMP, which was subsequently synthesized and shown to be a high-affinity multisubstrate adduct inhibitor (MAI; K(D) = 120 pM) of FLuc. Biochemical assays, liquid chromatography/mass spectrometry, and near-attack conformer modeling demonstrate that formation of this novel MAI is absolutely dependent upon the precise positioning and reactivity of a key meta-carboxylate of PTC124 within the FLuc active site. We also demonstrate that the inhibitory activity of PTC124-AMP is relieved by free coenzyme A, a component present at high concentrations in luciferase detection reagents used for cell-based assays. This explains why PTC124 can appear to increase, instead of inhibit, FLuc activity in cell-based reporter gene assays. To our knowledge, this is an unusual example in which the "off-target" effect of a small molecule is mediated by an MAI mechanism. C1 [Auld, Douglas S.; Thorne, Natasha; Lea, Wendy A.; Maloney, David J.; Shen, Min; Rai, Ganesha; Thomas, Craig J.; Simeonov, Anton; Inglese, James] NIH, Chem Genom Ctr, Bethesda, MD 20892 USA. [Lovell, Scott; Hanzlik, Robert P.] Univ Kansas, Struct Biol Ctr, Lawrence, KS 66047 USA. [Battaile, Kevin P.] Argonne Natl Lab, Adv Photon Source, Ind Macromol Crystallog Assoc Collaborat Access T, Argonne, IL 60439 USA. RP Inglese, J (reprint author), NIH, Chem Genom Ctr, Bldg 10, Bethesda, MD 20892 USA. EM jinglese@mail.nih.gov OI Battaile, Kevin/0000-0003-0833-3259 FU Molecular Libraries Initiative of the National Institutes of Health (NIH) Roadmap for Medical Research; NIH Center of Biomedical Research [5P20 RR17708] FX This research was supported by the Molecular Libraries Initiative of the National Institutes of Health (NIH) Roadmap for Medical Research, and an NIH Center of Biomedical Research Excellence Award (5P20 RR17708) to the University of Kansas (KU). We thank Nadya Galeva from the KU Mass Spectrometry Laboratory for her assistance with the Matrix Assisted Laser Desorption-Ionization-Mass Spectrometry analysis, and Bill Leister of the NIH Chemical Genomics Center for analytical chemistry support. NR 31 TC 89 Z9 93 U1 0 U2 24 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 16 PY 2010 VL 107 IS 11 BP 4878 EP 4883 DI 10.1073/pnas.0909141107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 570YI UT WOS:000275714300017 PM 20194791 ER PT J AU McElhinny, SAN Watts, BE Kumar, D Watt, DL Lundstrom, EB Burgers, PMJ Johansson, E Chabes, A Kunkel, TA AF McElhinny, Stephanie A. Nick Watts, Brian E. Kumar, Dinesh Watt, Danielle L. Lundstrom, Else-Britt Burgers, Peter M. J. Johansson, Erik Chabes, Andrei Kunkel, Thomas A. TI Abundant ribonucleotide incorporation into DNA by yeast replicative polymerases SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DNA replication; nucleotide precursors; nucleotide selectivity ID SACCHAROMYCES-CEREVISIAE; SUBSTRATE-SPECIFICITY; REVERSE-TRANSCRIPTASE; CRYSTAL-STRUCTURE; RESIDUE; EPSILON; REPAIR; FIDELITY; DAMAGE; SUGAR AB Measurements of nucleoside triphosphate levels in Saccharomyces cerevisiae reveal that the four rNTPs are in 36- to 190-fold molar excess over their corresponding dNTPs. During DNA synthesis in vitro using the physiological nucleoside triphosphate concentrations, yeast DNA polymerase epsilon, which is implicated in leading strand replication, incorporates one rNMP for every 1,250 dNMPs. Pol delta and Pol alpha, which conduct lagging strand replication, incorporate one rNMP for every 5,000 or 625 dNMPs, respectively. Discrimination against rNMP incorporation varies widely, in some cases by more than 100-fold, depending on the identity of the base and the template sequence context in which it is located. Given estimates of the amount of replication catalyzed by Pols alpha, delta, and epsilon, the results are consistent with the possibility that more than 10,000 rNMPs may be incorporated into the nuclear genome during each round of replication in yeast. Thus, rNMPs may be the most common noncanonical nucleotides introduced into the eukaryotic genome. Potential beneficial and negative consequences of abundant ribonucleotide incorporation into DNA are discussed, including the possibility that unrepaired rNMPs in DNA could be problematic because yeast DNA polymerase epsilon has difficulty bypassing a single rNMP present within a DNA template. C1 [McElhinny, Stephanie A. Nick; Watts, Brian E.; Watt, Danielle L.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [McElhinny, Stephanie A. Nick; Watts, Brian E.; Watt, Danielle L.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Kumar, Dinesh; Lundstrom, Else-Britt; Johansson, Erik; Chabes, Andrei] Umea Univ, Dept Med Biochem & Biophys, SE-90187 Umea, Sweden. [Burgers, Peter M. J.] Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. [Chabes, Andrei] Umea Univ, Lab Mol Infect Med Sweden MIMS, SE-90187 Umea, Sweden. RP Kunkel, TA (reprint author), NIEHS, Mol Genet Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov OI Chabes, Andrei/0000-0003-1708-8259 FU National Institutes of Health, National Institute on Environmental Health Sciences [Z01 ES065070]; Swedish Foundation for Strategic Research; Swedish Research Council; Swedish Cancer Society; Swedish Cancer Society, Smartafonden; Basic Science-oriented Biotechnology, Medical Faculty of Umea University; National Institutes of Health [GM032431] FX We thank A. Clark and M. Murray for helpful comments on the manuscript. This work was supported in part by Project Z01 ES065070 ( to T. A. K.) from the Division of Intramural Research of the National Institutes of Health, National Institute on Environmental Health Sciences; by the Swedish Foundation for Strategic Research, the Swedish Research Council and the Swedish Cancer Society ( to A. C.); by the Swedish Research Council, the Swedish Cancer Society, Smartafonden and the fund for Basic Science-oriented Biotechnology, Medical Faculty of Umea University ( to E.J.); and by National Institutes of Health Grant GM032431 ( to P. M. B.). NR 50 TC 154 Z9 155 U1 1 U2 15 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 16 PY 2010 VL 107 IS 11 BP 4949 EP 4954 DI 10.1073/pnas.0914857107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 570YI UT WOS:000275714300029 ER PT J AU Dail, M Li, Q McDaniel, A Wong, J Akagi, K Huang, B Kang, HC Kogan, SC Shokat, K Wolff, L Braun, BS Shannon, K AF Dail, Monique Li, Qing McDaniel, Andrew Wong, Jason Akagi, Keiko Huang, Ben Kang, Hio Chung Kogan, Scott C. Shokat, Kevan Wolff, Linda Braun, Benjamin S. Shannon, Kevin TI Mutant Ikzf1, Kras(G12D), and Notch1 cooperate in T lineage leukemogenesis and modulate responses to targeted agents SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE K-ras; retroviral insertional mutagenesis; T cell leukemia; targeted therapeutics; Ikaros ID ACUTE LYMPHOBLASTIC-LEUKEMIA; PROVIRUS INSERTIONAL MUTAGENESIS; K-RAS; CELL LEUKEMOGENESIS; MOLECULAR-GENETICS; SOMATIC ACTIVATION; TRANSGENIC MICE; ONCOGENIC KRAS; C-MYC; MUTATIONS AB Mice that accurately model the genetic diversity found in human cancer are valuable tools for interrogating disease mechanisms and investigating novel therapeutic strategies. We performed insertional mutagenesis with the MOL4070LTR retrovirus in Mx1-Cre, Kras(G12D) mice and generated a large cohort of T lineage acute lymphoblastic leukemias (T-ALLs). Molecular analysis infers that retroviral integration within Ikzf1 is an early event in leukemogenesis that precedes KrasG12D expression and later acquisition of somatic Notch1 mutations. Importantly, biochemical analysis uncovered unexpected heterogeneity, which suggests that Ras signaling networks are remodeled during multistep tumorigenesis. We tested tumor-derived cell lines to identify biomarkers of therapeutic response to targeted inhibitors. Whereas all T-ALLs tested were sensitive to a dual-specificity phosphoinosityl 3-kinase/mammalian target of rapamycin inhibitor, biochemical evidence of Notch1 activation correlated with sensitivity to gamma-secretase inhibition. In addition, Kras(G12D) T-ALLs were more responsive to a MAP/ERK kinase inhibitor in vitro and in vivo. Together, these studies identify a genetic pathway involving Ikzf1, Kras(G12D), and Notch1 in T lineage leukemogenesis, reveal unexpected diversity in Ras-regulated signaling networks, and define biomarkers of drug responses that may inform treatment strategies. C1 [Dail, Monique; McDaniel, Andrew; Wong, Jason; Huang, Ben; Kang, Hio Chung; Braun, Benjamin S.; Shannon, Kevin] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. [Li, Qing] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Kogan, Scott C.] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA. [Shokat, Kevan] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. [Akagi, Keiko] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Wolff, Linda] NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. RP Shannon, K (reprint author), Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. EM shannonk@peds.ucsf.edu FU National Institutes of Health [U01 CA84221, R37 CA72614, K08 CA119105]; Leukemia and Lymphoma Society of America [7019-04]; William Lawrence and Blanche Hughes Foundation; Jeffrey and Karen Peterson Family Foundation; Frank A. Campini Foundation; LLSA FX We thank Judith Leopold (Pfizer) for providing PD0325901 and David Tuveson and Tyler Jacks for providing KrasG12D mice; Charles Mullighan for the Murine Stem Cell Virus Ik6 construct and for helpful comments and suggestions; Jon Aster and Michelle Hermison for insightful comments; and Michelle Kang for technical guidance. This work was supported by National Institutes of Health Grants U01 CA84221, R37 CA72614, and K08 CA119105, by a Specialized Center of Research award from the Leukemia and Lymphoma Society of America (LLSA 7019-04), by the William Lawrence and Blanche Hughes Foundation, the Jeffrey and Karen Peterson Family Foundation, and by the Frank A. Campini Foundation. S. C. K. is an LLSA Scholar, and M. D. is a supported by an LLSA Fellowship. The Intramural Research Program of the National Cancer Institute Center for Cancer Research supports research in the laboratory of L. W. at the National Institutes of Health. NR 41 TC 30 Z9 32 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 16 PY 2010 VL 107 IS 11 BP 5106 EP 5111 DI 10.1073/pnas.1001064107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 570YI UT WOS:000275714300056 PM 20194733 ER PT J AU Lee, J Shmueli, K Fukunaga, M van Gelderen, P Merkle, H Silva, AC Duyn, JH AF Lee, Jongho Shmueli, Karin Fukunaga, Masaki van Gelderen, Peter Merkle, Hellmut Silva, Afonso C. Duyn, Jeff H. TI Sensitivity of MRI resonance frequency to the orientation of brain tissue microstructure SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE MRI phase contrast; resonance frequency shift; anisotropic susceptibility; magnetic susceptibility tensor; white matter fiber tracking ID HIGH-FIELD MRI; IN-VIVO; MAGNETIC-SUSCEPTIBILITY; WHITE-MATTER; LECITHIN MEMBRANES; PHASE-CONTRAST; ANISOTROPY; RELAXATION; PROTEINS; BILAYERS AB Recent advances in high-field (>= 7 T) MRI have made it possible to study the fine structure of the human brain at the level of fiber bundles and cortical layers. In particular, techniques aimed at detecting MRI resonance frequency shifts originating from local variation in magnetic susceptibility and other sources have greatly improved the visualization of these structures. A recent theoretical study [He X, Yablonskiy DA (2009) Proc Natl Acad Sci USA 106:13558-13563] suggests that MRI resonance frequency may report not only on tissue composition, but also on microscopic compartmentalization of susceptibility inclusions and their orientation relative to the magnetic field. The proposed sensitivity to tissue structure may greatly expand the information available with conventional MRI techniques. To investigate this possibility, we studied postmortem tissue samples from human corpus callosum with an experimental design that allowed separation of microstructural effects from confounding macrostructural effects. The results show that MRI resonance frequency does depend on microstructural orientation. Furthermore, the spatial distribution of the resonance frequency shift suggests an origin related to anisotropic susceptibility effects rather than microscopic compartmentalization. This anisotropy, which has been shown to depend on molecular ordering, may provide valuable information about tissue molecular structure. C1 [Lee, Jongho; Shmueli, Karin; Fukunaga, Masaki; van Gelderen, Peter; Merkle, Hellmut; Duyn, Jeff H.] NINDS, Adv MRI Sect, NIH, Bethesda, MD 20892 USA. [Silva, Afonso C.] NINDS, Cerebral Microcirculat Unit, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Lee, J (reprint author), NINDS, Adv MRI Sect, NIH, Bethesda, MD 20892 USA. EM jonghoyi@mail.nih.gov RI Duyn, Jozef/F-2483-2010; Silva, Afonso/A-7129-2009; Fukunaga, Masaki/F-6441-2013; Shmueli, Karin/B-9432-2017 OI Fukunaga, Masaki/0000-0003-1010-2644; FU National Institutes of Health; National Institute of Neurological Disorders and Stroke FX We thank Dr. Ara Kocharyan and Dr. Kant M. Matsuda for tissue preparation. This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke. NR 40 TC 108 Z9 110 U1 0 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 16 PY 2010 VL 107 IS 11 BP 5130 EP 5135 DI 10.1073/pnas.0910222107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 570YI UT WOS:000275714300060 PM 20202922 ER PT J AU Reimann, F Cox, JJ Belfer, I Diatchenko, L Zaykin, DV McHale, DP Drenth, JPH Dai, F Wheeler, J Sanders, F Wood, L Wu, TX Karppinen, J Nikolajsen, L Mannikko, M Max, MB Kiselycznyk, C Poddar, M Morsche, RHMT Smith, S Gibson, D Kelempisioti, A Maixner, W Gribble, FM Woods, CG AF Reimann, Frank Cox, James J. Belfer, Inna Diatchenko, Luda Zaykin, Dmitri V. McHale, Duncan P. Drenth, Joost P. H. Dai, Feng Wheeler, Jerry Sanders, Frances Wood, Linda Wu, Tian-Xia Karppinen, Jaro Nikolajsen, Lone Mannikko, Minna Max, Mitchell B. Kiselycznyk, Carly Poddar, Minakshi Morsche, Rene H. M. Te Smith, Shad Gibson, Dustin Kelempisioti, Anthi Maixner, William Gribble, Fiona M. Woods, C. Geoffrey TI Pain perception is altered by a nucleotide polymorphism in SCN9A SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Na(v)1.7; nociception; pain; SCN9A; single nucleotide polymorphisms ID CHANNEL ALPHA-SUBUNIT; OF-FUNCTION MUTATIONS; SODIUM-CHANNEL; PRIMARY ERYTHERMALGIA; ERYTHROMELALGIA; DISORDER; SENSITIVITY; NOCICEPTION; MANAGEMENT AB The gene SCN9A is responsible for three human pain disorders. Nonsense mutations cause a complete absence of pain, whereas activating mutations cause severe episodic pain in paroxysmal extreme pain disorder and primary erythermalgia. This led us to investigate whether single nucleotide polymorphisms (SNPs) in SCN9A were associated with differing pain perception in the general population. We first genotyped 27 SCN9A SNPs in 578 individuals with a radiographic diagnosis of osteoarthritis and a pain score assessment. A significant association was found between pain score and SNP rs6746030; the rarer A allele was associated with increased pain scores compared to the commoner G allele (P = 0.016). This SNP was then further genotyped in 195 pain-assessed people with sciatica, 100 amputees with phantom pain, 179 individuals after lumbar discectomy, and 205 individuals with pancreatitis. The combined P value for increased A allele pain was 0.0001 in the five cohorts tested (1277 people in total). The two alleles of the SNP rs6746030 alter the coding sequence of the sodium channel Nav1.7. Each was separately transfected into HEK293 cells and electrophysiologically assessed by patch-clamping. The two alleles showed a difference in the voltage-dependent slow inactivation (P = 0.042) where the Aallele would be predicted to increase Nav1.7 activity. Finally, we genotyped 186 healthy females characterized by their responses to a diverse set of noxious stimuli. The A allele of rs6746030 was associated with an altered pain threshold and the effect mediated through C-fiber activation. We conclude that individuals experience differing amounts of pain, per nociceptive stimulus, on the basis of their SCN9A rs6746030 genotype. C1 [Reimann, Frank; Gribble, Fiona M.] Addenbrookes Hosp, Cambridge Inst Med Res, Dept Clin Biochem, Cambridge CB2 0XY, England. [Cox, James J.; Woods, C. Geoffrey] Addenbrookes Hosp, Cambridge Inst Med Res, Dept Med Genet, Cambridge CB2 0XY, England. [Belfer, Inna; Dai, Feng; Max, Mitchell B.; Poddar, Minakshi] Univ Pittsburgh, Dept Anaesthesiol, Mol Epidemiol Pain Program, Pittsburgh, PA 15261 USA. [Diatchenko, Luda; Smith, Shad; Gibson, Dustin; Maixner, William] Univ N Carolina, Sch Dent, Ctr Neurosensory Disorders, Chapel Hill, NC 27599 USA. [Zaykin, Dmitri V.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [McHale, Duncan P.; Wheeler, Jerry; Sanders, Frances] Pfizer Global Res & Dev, Sandwich Labs, Sandwich CT13 9NJ, Kent, England. [Drenth, Joost P. H.; Morsche, Rene H. M. Te] Radboud Univ Nijmegen, Ctr Med, Dept Gastroenterol & Hepatol, NL-6500 HB Nijmegen, Netherlands. [Dai, Feng] Univ Pittsburgh, Sch Med, Dept Anesthesiol, Pittsburgh, PA 15261 USA. [Dai, Feng] Univ Pittsburgh, Sch Med, Dept Biostat & Human Genet, Pittsburgh, PA 15261 USA. [Wood, Linda] Pfizer Global Res & Dev, Groton Labs, Groton, CT 06340 USA. [Wu, Tian-Xia; Kiselycznyk, Carly] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. [Karppinen, Jaro; Mannikko, Minna; Kelempisioti, Anthi] Univ Oulu, Oulu Ctr Cell Matrix Res, Bioctr, FIN-90014 Oulu, Finland. [Karppinen, Jaro; Mannikko, Minna; Kelempisioti, Anthi] Univ Oulu, Dept Med Biochem & Mol Biol, FIN-90014 Oulu, Finland. [Nikolajsen, Lone] Univ Oulu, Finnish Inst Occupat Hlth, Musculoskeletal Ctr, FI-90220 Oulu, Finland. [Nikolajsen, Lone] Univ Oulu, Dept Phys Med & Rehabil, Inst Clin Sci, FI-90220 Oulu, Finland. RP Gribble, FM (reprint author), Addenbrookes Hosp, Cambridge Inst Med Res, Dept Clin Biochem, Cambridge CB2 0XY, England. EM fmg23@cam.ac.uk; cw347@cam.ac.uk RI woods, christopher/A-1361-2010; Drenth, J.P.H./H-8025-2014; te Morsche, Rene/P-9143-2015; Cox, James/R-1910-2016; OI Gibson, Dustin/0000-0002-9073-3376 FU National Institutes of Health; National Institute of Environmental Health Sciences; Wellcome Trust; Pfizer FX We thank Adeline Nicholas, Gemma Thornton, Baljinder Matharu, and John Yates for help in preparing this manuscript. We also thank Steven J. Atlas and Robert B. Keller, the principal clinical investigators of the Maine Lumbar Spine Study, for allowing us to investigate their patients; and Monique H. M. Derikx for clinical data collection. St John's College in Cambridge, United Kingdom, the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences, the Wellcome Trust, and Pfizer contributed to the funding of this project. NR 34 TC 132 Z9 137 U1 2 U2 28 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 16 PY 2010 VL 107 IS 11 BP 5148 EP 5153 DI 10.1073/pnas.0913181107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 570YI UT WOS:000275714300062 PM 20212137 ER PT J AU Anstrom, KJ Kaner, RJ Loyd, JE Roman, J Brown, KK King, TE Lasky, JA Martinez, FJ Noth, I Deandrade, J Raghu, G Ryu, JH Lynch, JP Hunninghake, GW Reynolds, HY AF Anstrom, Kevin J. Kaner, Robert J. Loyd, James E. Roman, Jesse Brown, Kevin K. King, Talmadge E., Jr. Lasky, Joseph A. Martinez, Fernando J. Noth, Imre Deandrade, Joao Raghu, Ganesh Ryu, Jay H. Lynch, Joseph P., III Hunninghake, Gary W. Reynolds, Herbert Y. CA IPFnet Investigators TI The IPFnet Strategy Creating a Comprehensive Approach in the Treatment of Idiopathic Pulmonary Fibrosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID LUNG; TELOMERASE; MUTATIONS; ORIGIN; CELLS C1 [Anstrom, Kevin J.] Duke Univ, Durham, NC 27706 USA. [Kaner, Robert J.] Weill Cornell Med Coll, New York, NY USA. [Loyd, James E.] Vanderbilt Univ, Nashville, TN USA. [Roman, Jesse] Univ Louisville, Louisville, KY 40292 USA. [Brown, Kevin K.] Natl Jewish Med & Res Ctr, Denver, CO USA. [King, Talmadge E., Jr.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lasky, Joseph A.] Tulane Univ, New Orleans, LA 70118 USA. [Martinez, Fernando J.] Univ Michigan, Ann Arbor, MI 48109 USA. [Noth, Imre] Univ Chicago, Chicago, IL 60637 USA. [Deandrade, Joao] Univ Alabama, Birmingham, AL USA. [Raghu, Ganesh] Univ Washington, Seattle, WA 98195 USA. [Ryu, Jay H.] Mayo Clin, Rochester, MN USA. [Lynch, Joseph P., III] Univ Calif Los Angeles, Los Angeles, CA 90024 USA. [Hunninghake, Gary W.] Univ Iowa, Iowa City, IA USA. [Reynolds, Herbert Y.] NHLBI, Bethesda, MD 20892 USA. RP Anstrom, KJ (reprint author), Duke Univ, Durham, NC 27706 USA. NR 14 TC 5 Z9 5 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 MAR 15 PY 2010 VL 181 IS 6 BP 527 EP 528 DI 10.1164/rccm.200903-0483ED PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 632RX UT WOS:000280446500001 ER PT J AU Mularski, RA Campbell, ML Asch, SM Reeve, BB Basch, E Maxwell, TL Hoverman, JR Cuny, J Clauser, SB Snyder, C Seow, H Wu, AW Dy, S AF Mularski, Richard A. Campbell, Margaret L. Asch, Steven M. Reeve, Bryce B. Basch, Ethan Maxwell, Terri L. Hoverman, J. Russell Cuny, Joanne Clauser, Steve B. Snyder, Claire Seow, Hsien Wu, Albert W. Dy, Sydney TI A Review of Quality of Care Evaluation for the Palliation of Dyspnea SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE dyspnea; quality of health care; quality indicators; health care; assessment ID CLINICAL METHODS; LIFE CARE; DISEASE; BREATHLESSNESS; QUESTIONNAIRE; END; INDICATORS; CANCER; DESCRIPTORS; SHORTNESS AB Assessment and management of dyspnea has emerged as a priority topic for quality evaluation and improvement. Evaluating dyspnea quality of care requires valid, reliable, and responsive measures of the care provided to patients across settings and diseases. As part of an Agency for Healthcare Research and Quality Symposium, we reviewed quality of care measures for dyspnea by compiling quality measures identified in systematic searches and reviews. Systematic reviews identified only three existing quality measurement sets that included quality measures for dyspnea care. The existing dyspnea quality measures reported by retrospective evaluations of care assess only four aspects: dyspnea assessment within 48 hours of hospital admission, use of objective scales to rate dyspnea severity, identification of management plans, and evidence of dyspnea reduction. To begin to improve care, clinicians need to assess and regularly document patient's experiences of dyspnea. There is no consensus on how dyspnea should be characterized for quality measurement, and although over 40 tools exist to assess dyspnea, no rating scale or instrument is ideal for palliative care. The panel recommended that dyspnea assessment should include a measure of intensity and some inquiry into the associated bother or distress experienced by the patient. A simple question into the presence or absence of dyspnea would be unlikely to help guide therapy, as complete relief of dyspnea in advanced disease would not be anticipated. Additional knowledge gaps include standards for clinical dyspnea care, assessment in the cognitively impaired, and evaluation of effectiveness of dyspnea care for patients with advanced disease. C1 [Mularski, Richard A.] Oregon Hlth & Sci Univ, Ctr Hlth Res, Portland, OR 97227 USA. [Campbell, Margaret L.] Wayne State Univ, Detroit Receiving Hosp Ctr Hlth Res, Detroit, MI USA. [Asch, Steven M.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, VA Greater Los Angeles Healthcare Syst, Los Angeles, CA 90095 USA. [Reeve, Bryce B.; Clauser, Steve B.] NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Basch, Ethan] Mem Sloan Kettering Canc Ctr, Hlth Outcomes Grp, New York, NY 10021 USA. [Maxwell, Terri L.] ExcelleRx Inc, Philadelphia, PA USA. [Hoverman, J. Russell] Texas Oncol, Dallas, TX USA. [Cuny, Joanne] Univ HealthSyst Consortium, Oak Brook, IL USA. [Snyder, Claire; Dy, Sydney] Johns Hopkins Sch Publ Hlth, Dept Hlth Policy & Management, Johns Hopkins Sch Med, Div Gen Internal Med, Baltimore, MD USA. [Seow, Hsien] McMaster Univ, Dept Oncol, Hamilton, ON, Canada. RP Mularski, RA (reprint author), Oregon Hlth & Sci Univ, Ctr Hlth Res, 3800 N Interstate,WIN 1060, Portland, OR 97227 USA. EM Richard.A.Mularski@kpchr.org OI Campbell, Margaret/0000-0003-4517-690X FU Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services [290-2005-00341]; Spiration, Inc.; Novartis; Amgen; Wyeth Pharmaceuticals; United Healthcare FX Supported by Contract No. 290-2005-00341 from the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services as part of the Developing Evidence to Inform Decisions about Effectiveness (DEcIDE) program. The Symposium on Developing a Framework to Assess Cancer Quality Indicators for End-of-Life Care was held in Baltimore, MD on April 28, 2008. The authors of this manuscript are responsible for its content. Statements in the manuscript should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.; R.A.M. received 850,001-$100,000 from Spiration, Inc., and 850,001-8100,001 from Novartis in industry-sponsored grants. M.L.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.M.A. received more than 8100,001 from Amgen in grants. B.B.R. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. E.B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. T.L.M. is a full-time employee of excelleRx, Inc., and received S10,001-850,000 from Wyeth Pharmaceuticals in industry-sponsored grants for database analysis related to constipation prevalence at the end of life. J.R.H. received $1,001-85,000 from United Healthcare in advisory board fees. j.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.B.C. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. C.S. does not have a financial relationship with a commercial I. entity that has an interest in the subject of this manuscript. H.S. does not NR 50 TC 20 Z9 20 U1 1 U2 3 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAR 15 PY 2010 VL 181 IS 6 BP 534 EP 538 DI 10.1164/rccm.200903-0462PP PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 632RX UT WOS:000280446500005 PM 20056904 ER PT J AU Wang, PY Rao, JN Zou, TT Liu, L Xiao, L Yu, TX Turner, DJ Gorospe, M Wang, JY AF Wang, Peng-Yuan Rao, Jaladanki N. Zou, Tongtong Liu, Lan Xiao, Lan Yu, Ting-Xi Turner, Douglas J. Gorospe, Myriam Wang, Jian-Ying TI Post-transcriptional regulation of MEK-1 by polyamines through the RNA-binding protein HuR modulating intestinal epithelial apoptosis SO BIOCHEMICAL JOURNAL LA English DT Article DE mitogen-activated protein kinase kinase-1 (MEK-1); mRNA stability; ornithine decarboxylase; polyamine; ribonucleoprotein; translational regulation; 3 '-untranslated region (3 '-UTR) ID AU-RICH ELEMENTS; MESSENGER-RNA; BARRIER FUNCTION; GENE-EXPRESSION; HEAT-SHOCK; CELLS; KINASE; PHOSPHORYLATION; DEPLETION; STABILIZATION AB MEK-1 [MAPK (mitogen-activated protein kinase) kinase-1] is all important signal transducing enzyme that is implicated ill many aspects Of Cellular functions. In the present paper, we report that cellular polyamines regulate MEK-1 expression at the post-transcriptional level through the RNA-binding protein HuR (Hu-antigen R) in IECs (intestinal epithelial cells). Decreasing the levels of cellular polyamines by inhibiting ODC (ornithine decarboxylase) stabilized MEK-1 mRNA and promoted its translation through enhancement of the interaction between HuR and the 3'-untranslated region of MEK-1 mRNA, whereas increasing polyamine levels by ectopic ODC overexpression destabilized the MEK-1 transcript and repressed its translation by reducing the abundance of HuR-MEK-1 mRNA complex, neither intervention changed MEK-1 gene transcription via its promoter. HuR silencing rendered the MEK-1 mRNA unstable and inhibited its translation, thus preventing increases in MEK-1 mRNA and protein in polyamine-deficient cells. Conversely, HuR overexpression increased MEK-1 mRNA stability and promoted its translation. Inhibition of Mill expression by MEK-1 silencing or HuR silencing prevented the increased resistance of polyamine-deficient cells to apoptosis. Moreover. HuR overexpression did not protect against apoptosis if MEK-1 expression vas silenced. These results indicate that polyamines destabilize the Mill mRNA and repress its translation by inhibiting the association between HuR and the MEK-1 transcript. Our findings indicate that MEK-1 is a key effector of the HuR-elicited anti-apoptotic programme in IECs. C1 [Wang, Peng-Yuan; Rao, Jaladanki N.; Zou, Tongtong; Liu, Lan; Xiao, Lan; Yu, Ting-Xi; Turner, Douglas J.; Wang, Jian-Ying] Univ Maryland, Sch Med, Cell Biol Grp, Dept Surg, Baltimore, MD 21201 USA. [Wang, Peng-Yuan; Rao, Jaladanki N.; Zou, Tongtong; Liu, Lan; Yu, Ting-Xi; Turner, Douglas J.] Baltimore Vet Affairs Med Ctr, Baltimore, MD 21201 USA. [Xiao, Lan; Wang, Jian-Ying] Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. [Gorospe, Myriam] NIA, Cellular & Mol Biol Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Wang, JY (reprint author), Univ Maryland, Sch Med, Cell Biol Grp, Dept Surg, Baltimore, MD 21201 USA. EM jwang@smail.umaryland.edu FU Department of Veterans Affairs, U.S.A.; National Institutes of Health [DK-57819, DK-61972, DK-68461]; National Institute on Aging FX This work was supported by the Department of Veterans Affairs, U.S.A. [Merit Review Grant (to J.-Y W.)] the National Institutes of Health [grant numbers DK-57819, DK-61972 and DK-68461 (to J.-Y. W.)]. P.-YW. is a visiting scientist from Peking University First Hospital, Beijing, China J.-Y. W. is a Research Career Scientist, Medical Research Service, Department of Veterans Affairs. M. G. is supported by the National Institute on Aging Intramural Research Program. NR 59 TC 28 Z9 29 U1 0 U2 0 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 MAR 15 PY 2010 VL 426 BP 293 EP 306 DI 10.1042/BJ20091459 PN 3 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 572OU UT WOS:000275843300005 PM 20001965 ER PT J AU Gao, ZG Ding, Y Jacobson, KA AF Gao, Zhan-Guo Ding, Yi Jacobson, Kenneth A. TI UDP-glucose acting at P2Y(14) receptors is a mediator of mast cell degranulation SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Nucleotide; P2Y receptor; Mast cell; Allergy; Inflammation; G protein-coupled receptor ID PROTEIN-COUPLED RECEPTOR; A(3) ADENOSINE RECEPTOR; FUNCTIONAL EXPRESSION; DENDRITIC CELLS; LEUKEMIA-CELLS; P2Y14 RECEPTOR; ACTIVATION; RELEASE; MECHANISMS; ENHANCEMENT AB UDP-glucose (UDPG), a glycosyl donor in the biosynthesis of carbohydrates, is an endogenous agonist of the G protein-coupled P2Y(14) receptor. RBL-2H3 mast cells endogenously express a P2Y(14) receptor at which UDPG mediates degranulation as indicated by beta-hexosaminidase (HEX) release. Both UDPG and a more potent, selective 2-thio-modified UDPG analog, MRS2690 (diphosphoric acid 1-alpha-D-glucopyranosyl ester 2-[(2-thio)uridin-5 ''-yl] ester), caused a substantial calcium transient in RBL-2H3 cells, which was blocked by pertussis toxin, indicating the presence of the G(i)-coupled P2Y(14) receptor, supported also by quantitative detection of abundant mRNA. Expression of the closely related P2Y(6) receptor was over 100 times lower than the P2Y(14) receptor, and the P2Y(6) agonist 3-phenacyl-UDP was inactive in RBL-2H3 cells. P2Y(14) receptor agonists also induced [S-35]GTP gamma S binding to RBL-2H3 cell membranes, and phosphorylation of ERK1/2, P38 and JNK. UDPG and MRS2690 concentration-dependently enhanced HEX release with EC50 values of 1150 +/- 320 and 103 +/- 18 nM, respectively. The enhancement was completely blocked by pertussis toxin and significantly diminished by P2Y(14) receptor-specific siRNA. Thus, mast cells express an endogenous P2Y(14) receptor, which mediates G(i)-dependent degranulation and is therefore a potential novel therapeutic target for allergic conditions. Published by Elsevier Inc. C1 [Gao, Zhan-Guo; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. [Ding, Yi] NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Gao, ZG (reprint author), NIDDK, Mol Recognit Sect, NIH, LBC, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM ZhanguoG@niddk.nih.gov; kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Institutes of Health FX Supported by the NIDDK Intramural Research Program, National Institutes of Health. NR 33 TC 28 Z9 28 U1 1 U2 6 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 MAR 15 PY 2010 VL 79 IS 6 BP 873 EP 879 DI 10.1016/j.bcp.2009.10.024 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 550WZ UT WOS:000274165500008 PM 19896471 ER PT J AU Das, U Doroudi, A Gul, HI Pati, HN Kawase, M Sakagami, H Chu, Q Stables, JP Dimmock, JR AF Das, Umashankar Doroudi, Alireza Gul, H. Inci Pati, Hari N. Kawase, Masami Sakagami, Hiroshi Chu, Qing Stables, James P. Dimmock, Jonathan R. TI Cytotoxic 2-benzylidene-6-(nitrobenzylidene)cyclohexanones which display substantially greater toxicity for neoplasms than non-malignant cells SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE Unsaturated ketones; Selective cytotoxicity; Structure-activity relationships; Murine toxicity ID MANNICH-BASES; MULTIDRUG-RESISTANCE; SELECTIVE TOXICITY; STYRYL KETONES; REVERSAL; GLUTATHIONE; ANTITUMOR AB Various 2-benzylidene-6-(nitrobenzylidene)cyclohexanones were prepared as candidate cytotoxins in which the nitro group was located in the ortho, meta and para positions leading to series 1-3, respectively. The CC(50) values towards human HSC-2 and HSC-4 oral squamous cell carcinomas as well as human HL-60 promyelocytic leukemic cells are in the low micromolar range in general. On the other hand, most of the compounds afforded clear evidence of being far less toxic towards human HGF gingival fibroblasts, HPC pulp cells and HPLF periodontal ligament. broblasts which are non-malignant cells. Selectivity index (SI) figures were generated which are the ratios of the average CC(50) values towards normal cells and the CC(50) figure towards a malignant cell line. Huge SI values were obtained for many of the compounds. In particular 1c, 2f, 3c and 3g which have average SI values of >76, >38, 124 and 341, respectively, are clearly lead molecules affording direction for amplification of this area of study. A lead compound 1c caused internucleosomal DNA fragmentation and activation of caspase-3 in HL-60 cells but not in HSC-2 carcinomas. In a short-term toxicity study, doses up to and including 300 mg/kg of the majority of the compounds prepared in this study did not cause any mortalities to mice. Some guidelines for development of these tumor-selective cytotoxins are presented. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Das, Umashankar; Doroudi, Alireza; Gul, H. Inci; Pati, Hari N.; Dimmock, Jonathan R.] Univ Saskatchewan, Drug Design & Discovery Res Grp, Coll Pharm & Nutr, Saskatoon, SK S7N 5C9, Canada. [Kawase, Masami] Matsuyama Univ, Fac Pharmaceut Sci, Maysuyama, Ehime 7908578, Japan. [Sakagami, Hiroshi; Chu, Qing] Meikai Univ, Sch Dent, Div Pharmacol, Dept Diagnost & Therapeut Sci, Saitama 3500238, Japan. [Stables, James P.] Natl Inst Neurol Disorders & Stroke, Rockville, MD 20852 USA. RP Dimmock, JR (reprint author), Univ Saskatchewan, Drug Design & Discovery Res Grp, Coll Pharm & Nutr, 110 Sci Pl, Saskatoon, SK S7N 5C9, Canada. EM jr.dimmock@usask.ca FU Canadian Institutes of Health Research; Ministry of Education, Science, Sports and Culture of Japan [19592156]; National Institute of Neurological Disorders and Stroke, USA; Iranian Ministry of Health and Medical Education; Scientific and Technical Research Council of Turkey (TUBITAK) [NATO-B2] FX The authors thank the Canadian Institutes of Health Research for an operating grant to J. R. Dimmock and the Ministry of Education, Science, Sports and Culture of Japan for a Grant-in-Aid (No. 19592156) to H. Sakagami. The National Institute of Neurological Disorders and Stroke, USA undertook the in vivo experimentation with mice which is recorded with gratitude. Our appreciation is extended to the Iranian Ministry of Health and Medical Education who provided financial support for A. Doroudi while H. I. Gul was supported by a visiting scholar grant (NATO-B2) distributed by the Scientific and Technical Research Council of Turkey (TUBITAK). NR 27 TC 9 Z9 9 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAR 15 PY 2010 VL 18 IS 6 BP 2219 EP 2224 DI 10.1016/j.bmc.2010.01.069 PG 6 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 568HR UT WOS:000275513700018 PM 20189402 ER PT J AU Weidlich, IE Dexheimer, T Marchand, C Antony, S Pommier, Y Nicklaus, MC AF Weidlich, Iwona E. Dexheimer, Thomas Marchand, Christophe Antony, Smitha Pommier, Yves Nicklaus, Marc C. TI Inhibitors of human tyrosyl-DNA phospodiesterase (hTdp1) developed by virtual screening using ligand-based pharmacophores (vol 18, pg 182, 2010) SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Correction C1 [Weidlich, Iwona E.; Nicklaus, Marc C.] NCI, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. [Dexheimer, Thomas; Marchand, Christophe; Antony, Smitha; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. RP Nicklaus, MC (reprint author), NCI, Biol Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. EM iweidlic@helix.nih.gov; mn1@helix.nih.gov RI Nicklaus, Marc/N-4183-2014 NR 1 TC 2 Z9 2 U1 1 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAR 15 PY 2010 VL 18 IS 6 BP 2346 EP 2346 DI 10.1016/j.bmc.2010.02.008 PG 1 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 568HR UT WOS:000275513700031 ER PT J AU Jagadeeswaran, P Lin, S Weinstein, B Hutson, A Kim, S AF Jagadeeswaran, Pudur Lin, Shuo Weinstein, Brant Hutson, Angela Kim, Seongcheol TI Loss of GATA1 and gain of FLI1 expression during thrombocyte maturation SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article DE Zebrafish; Thrombocyte; Transcription; Maturation; GFP; FLI1; GATA1 ID ZEBRAFISH THROMBOCYTES; TRANSGENIC ZEBRAFISH; FAMILY; GENE AB In this paper, we characterized expression of GATA1 and FLI1 gene promoters in thrombocytes of zebrafish transgenic lines, G1-GM2 and TG(fli1:EGFP)y1 that carry transgenes of GATA1 and FLI1 gene promoters driving GFR We found two discrete populations of thrombocytes verified by morphology, labeled with GFP in both G1-GM2 and TG(fli1:EGFP)y1 lines: (1) the more intensely labeled GFP+ thrombocyte. and (2) the less intensely labeled GFP+ thrombocytes. The more intensely labeled GFP+ thrombocyte in G1-GM2 line and the less intensely labeled GFP+ thrombocytes in the TG(fli1:EGFP)y1 line corresponded to young thrombocytes. These results showed that young thrombocytes have higher GATA1 promoter activity, while mature thrombocytes have more FLI1 gene promoter transcription. This finding suggests that there is a gradual loss of GATA1 and gain of FLI1 expression as the thrombocytes mature, and this overexpression of FLI1 may help maintain the thrombocyte lineage. Furthermore, the presence of transcriptional factors similar to those found in megakaryocytes raises the possibility that vertebrate thrombocytes may be the forerunners of mammalian megakaryocytes and, therefore, could serve as a model to study megakaryocyte maturation. (C) 2009 Elsevier Inc. All rights reserved. C1 [Jagadeeswaran, Pudur; Hutson, Angela; Kim, Seongcheol] Univ N Texas, Dept Biol Sci, Denton, TX 76203 USA. [Lin, Shuo] Univ Calif Los Angeles, Dept Mol Cellular & Dev Biol, Los Angeles, CA 90095 USA. [Weinstein, Brant] NICD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Jagadeeswaran, P (reprint author), Univ N Texas, Dept Biol Sci, 1510 Chestnut Ave, Denton, TX 76203 USA. EM jag@unt.edu FU National Institutes of Health [HL077910] FX This research was supported by a grant from the National Institutes of Health, HL077910 (to P.J.). NR 11 TC 12 Z9 12 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR 15 PY 2010 VL 44 IS 3 BP 175 EP 180 DI 10.1016/j.bcmd.2009.12.012 PG 6 WC Hematology SC Hematology GA 564MC UT WOS:000275217800010 PM 20110178 ER PT J AU Sarosy, GA Hussain, MM Seiden, MV Fuller, AF Nikrui, N Goodman, A Minasian, L Reed, E Steinberg, SM Kohn, EC AF Sarosy, Gisele A. Hussain, Mahrukh M. Seiden, Michael V. Fuller, Arlan F. Nikrui, Najmosama Goodman, Annekathryn Minasian, Lori Reed, Eddie Steinberg, Seth M. Kohn, Elise C. TI Ten-Year Follow-Up of a Phase 2 Study of Dose-Intense Paclitaxel With Cisplatin and Cyclophosphamide as Initial Therapy for Poor-Prognosis, Advanced-Stage Epithelial Ovarian Cancer SO CANCER LA English DT Article DE ovarian neoplasms; paclitaxel; cyclophosphamide; cisplatin; antineoplastic combined chemotherapy protocols; filgrastim; drug dose-response relation ID GYNECOLOGIC-ONCOLOGY-GROUP; CARCINOMA CELL-LINES; 1ST-LINE TREATMENT; IV; PACLITAXEL/CARBOPLATIN; CYTOTOXICITY AB BACKGROUND: The objective of this study was to assess activity and toxicity in patients with newly diagnosed, advanced-stage epithelial ovarian cancer (EOC) who were receiving dose-intense paclitaxel, cyclophosphamide, cisplatin, and filgrastim delivered with a flexible dosing schedule. METHODS: Patients with stage III/IV EOC received cyclophosphamide 750 mg/m(2), followed by a 24-hour infusion of paclitaxel 250 mg/m(2) and cisplatin 75 mg/m(2) on Day 2. Filgrastim began on Day 3 at 10 mu g/kg daily for 9 days. Patients received 6 cycles of all drugs. Those who achieved a pathologic complete response or had microscopic residual disease at the conclusion of 6 cycles of therapy received an additional 2 to 4 cycles of paclitaxel with cyclophosphamide. Patients who had an objective response continued on cyclophosphamide and paclitaxel. RESULTS: Sixty-two patients were enrolled. Thirty-two of 62 patients had stage IIIC disease, and 26 of 62 patients had stage IV disease. According to an intent-to-treat analysis, 55 patients (89%) experienced a clinical complete remission. At a median potential follow-up of 11.4 years, the median progression-free survival was 18.9 months, and the median survival was 5.4 years. The most serious toxicity was grade 3/4 neutropenic fever (35%). Although all participants developed peripheral neuropathy, improvement in neuropathic symptoms began with the decrease or cessation of paclitaxel. CONCLUSIONS: The studied regimen yielded a high response rate and encouraging overall survival. The current data and those reported by the Japanese Gynecologic Cincology Group suggest that further study is warranted of dose-dense or dose-intense paclitaxel regimens in women with newly diagnosed, advanced-stage EOC. Cancer 2010;116:1476-84. (C) 2070 American Cancer Society. C1 [Sarosy, Gisele A.; Hussain, Mahrukh M.; Minasian, Lori; Reed, Eddie; Kohn, Elise C.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Seiden, Michael V.] Massachusetts Gen Hosp, Div Canc Biol, Boston, MA 02114 USA. [Fuller, Arlan F.; Nikrui, Najmosama; Goodman, Annekathryn] Massachusetts Gen Hosp, Div Gynecol Oncol, Boston, MA 02114 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kohn, EC (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, 10 Ctr Dr,MSC 1906, Bethesda, MD 20892 USA. EM kohne@mail.nih.gov FU National Institutes of Health; National Cancer Institute, Center for Cancer Research; Amgen Corporation FX Supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. Patient care Support was provided to the Massachusetts General Hospital investigators from Amgen Corporation. NR 24 TC 13 Z9 13 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD MAR 15 PY 2010 VL 116 IS 6 BP 1476 EP 1484 DI 10.1002/cncr.24861 PG 9 WC Oncology SC Oncology GA 564SY UT WOS:000275238800015 PM 20091841 ER PT J AU Freedman, ND Lacey, JV Hollenbeck, AR Leitzmann, MF Schatzkin, A Abnet, CC AF Freedman, Neal D. Lacey, James V., Jr. Hollenbeck, Albert R. Leitzmann, Michael F. Schatzkin, Arthur Abnet, Christian C. TI The Association of Menstrual and Reproductive Factors With Upper Gastrointestinal Tract Cancers in the NIH-AARP Cohort SO CANCER LA English DT Article DE head and neck neoplasms; stomach neoplasms; esophageal neoplasms; estrogen replacement therapy ID HORMONE-REPLACEMENT THERAPY; CONJUGATED EQUINE ESTROGENS; GASTRIC-CANCER; POSTMENOPAUSAL WOMEN; RISK-FACTORS; NECK-CANCER; NATIONAL-INSTITUTES; ENDOMETRIAL CANCER; COLORECTAL-CANCER; ESOPHAGEAL CANCER AB BACKGROUND: In most populations, incidence rates of upper gastrointestinal (UGI) tract cancers (head and neck, esophagus, and stomach) are higher among men than among women. Established risk factors do not appear to explain these differences, suggesting a possible role for sex hormones. METHODS: 201,506 women of the NIH-AARP Diet and Health cohort completed a questionnaire in 1995-1996. Hazard ratios and 95% confidence intervals were estimated from Cox proportional hazards models. RESULTS: During follow-up through 2003, 162 incident adenocarcinomas (ACs; esophagus, N = 25, and stomach, N = 137) and 353 incident squamous cell carcinomas (SCCs; head and neck, n = 297, and esophagus, N = 56) occurred. Among examined exposures, older age at menopause was associated inversely with SCC (P(trend) across categories = .013) but not AC (P(trend) = .501). Use of menopausal hormone therapy (MHT) was significantly associated with lower risk of SCC (hazard ratio [HR] = 0.77, 0.62-0.96) and nonsignificantly associated with lower risk of AC (HR = 0.81, 0.59-1.12). A subset (N = 127,386) of the cohort completed a more detailed MHT questionnaire a year after baseline. In 74,372 women with intact uteri, ever use of estrogen-progestin MHT conferred 0.47 (0.30-0.75) times the risk for SCC and 0.52 (0.26-1.07) times the risk for ACC. In 51,515 women with a hysterectomy before baseline, we found no associations between use of estrogen MHT and AC or SCC. CONCLUSIONS: Higher estrogen and progesterone levels may be related inversely to UGI cancers and in this way help explain lower incidence rates in women compared with men. Cancer 2010;116:1572-81. (C) 2070 American Cancer Society. C1 [Freedman, Neal D.] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. [Leitzmann, Michael F.] Univ Regensburg, Inst Epidemiol & Prevent Med, Regensburg, Germany. RP Freedman, ND (reprint author), NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS-320,MSC 7232, Rockville, MD 20852 USA. EM freedmanne@mail.nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098 FU National Institutes of Health, National Cancer Institute FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 34 TC 31 Z9 32 U1 3 U2 7 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD MAR 15 PY 2010 VL 116 IS 6 BP 1572 EP 1581 DI 10.1002/cncr.24880 PG 10 WC Oncology SC Oncology GA 564SY UT WOS:000275238800026 PM 20186831 ER PT J AU Maity, A Bernhard, EJ AF Maity, Amit Bernhard, Eric J. TI Modulating Tumor Vasculature through Signaling Inhibition to Improve Cytotoxic Therapy SO CANCER RESEARCH LA English DT Review ID IONIZING-RADIATION; ENDOTHELIAL-CELLS; FLUID PRESSURE; UP-REGULATION; GROWTH; HYPOXIA; ANGIOGENESIS; NORMALIZATION; CANCER; RAS AB The tumor microenvironment is a key factor in cancer treatment response. Recent work has shown that changes in the tumor vasculature can be achieved by inhibiting tumor cell signaling, resulting in enhanced tumor oxygenation. These changes could promote responses to both chemo- and radiation therapy. Cancer Res; 70( 6); 2141-5. (C) 2010 AACR. C1 [Bernhard, Eric J.] NCI, Radiotherapy Dev Branch, Radiat Res Program, Div Canc Treatment & Diag,NIH, Rockville, MD 20892 USA. [Maity, Amit] Univ Penn, Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA. RP Bernhard, EJ (reprint author), NCI, Radiotherapy Dev Branch, Radiat Res Program, Div Canc Treatment & Diag,NIH, 6130 Execut Blvd,Rm 6010,MSC 7440, Rockville, MD 20892 USA. EM bernhardej@mail.nih.gov FU National Institutes of Health (NIH) [CA093638, CA73820]; MRC FX Grant Support; Grants from the National Institutes of Health (NIH): CA093638 (A. Maity), CA73820 (E.J. Bernhard), and MRC (E.J. Bernhard) during the studies described in this report. NR 36 TC 23 Z9 24 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 MAR 15 PY 2010 VL 70 IS 6 BP 2141 EP 2145 DI 10.1158/0008-5472.CAN-09-3615 PG 5 WC Oncology SC Oncology GA 607GA UT WOS:000278485900001 PM 20179191 ER PT J AU Reinhold, WC Mergny, JL Liu, HF Ryan, M Pfister, TD Kinders, R Parchment, R Doroshow, J Weinstein, JN Pommier, Y AF Reinhold, William C. Mergny, Jean-Louis Liu, Hongfang Ryan, Michael Pfister, Thomas D. Kinders, Robert Parchment, Ralph Doroshow, James Weinstein, John N. Pommier, Yves TI Exon Array Analyses across the NCI-60 Reveal Potential Regulation of TOP1 by Transcription Pausing at Guanosine Quartets in the First Intron SO CANCER RESEARCH LA English DT Article ID CANCER-CELL LINES; TOPOISOMERASE-I INHIBITORS; RNA-POLYMERASE-II; DNA TOPOISOMERASES; PROMOTER; EXPRESSION; GENE; MICROARRAY; PANEL; CAMPTOTHECIN AB Because topoisomerase 1 (TOP1) is critical for the relaxation of DNA supercoils and because it is the target for the anticancer activity of camptothecins, we assessed TOP1 transcript levels in the 60 cell line panel (the NCI-60) of the National Cancer Institute's anticancer drug screen. TOP1 expression levels varied over a 5.7-fold range across the NCI-60. HCT116 colon and MCF-7 breast cancer cells were the highest expressers; SK-MEL-28 melanoma and HS578T breast carcinoma cells were the lowest. TOP1 mRNA expression was highly correlated with Top1 protein levels, indicating that TOP1 transcripts could be conveniently used to monitor Top1 protein levels and activity in tissues. Assessment of the TOP1 locus by array comparative genomic hybridization across the NCI-60 showed copy numbers ranging from 1.71 to 4.13 and a statistically significant correlation with TOP1 transcript levels (P < 0.01). Further analyses of TOP1 expression on an exon-specific basis revealed that exon 1 expression was generally higher and less variable than expression of the other exons, suggesting some form of transcriptional pausing regulation between exons 1 and 2. Accordingly, we found the presence of multiple evolutionarily conserved potential G-quadruplex-forming sequences in the first TOP1 intron. Physicochemical tests for actual quadruplex formation by several of those sequences yielded quadruplex formation for two of them and duplex formation for one. The observations reported here suggest the hypothesis that there is a conserved negative transcription regulator within intron 1 of the TOP1 gene associated with a quadruplex-prone region. Cancer Res; 70(6); 2191-203. (C) 2010 AACR. C1 [Reinhold, William C.; Liu, Hongfang; Doroshow, James; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20894 USA. [Doroshow, James] NCI, Dev Therapeut Program, Ctr Canc Res, NIH, Bethesda, MD 20894 USA. [Mergny, Jean-Louis] Museum Natl Hist Nat USM 503, Inst Natl Sante & Rech Med U565, Regulat & Dynam Genomes Lab Biophys, Paris, France. [Liu, Hongfang] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. [Ryan, Michael] Tiger Team Consulting, Fairfax, VA USA. [Pfister, Thomas D.; Kinders, Robert; Parchment, Ralph] NCI, Lab Human Toxicol & Pharmacol, Appl Dev Res Support Directorate, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. [Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA. [Weinstein, John N.] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA. RP Reinhold, WC (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 37,Room 5056, Bethesda, MD 20894 USA. EM wcr@mail.nih.gov RI Mergny, Jean-Louis/E-2860-2013 OI Mergny, Jean-Louis/0000-0003-3043-8401 FU National Cancer Institute, Center for Cancer Research FX Grant Support; Intramural Program of National Cancer Institute, Center for Cancer Research. NR 42 TC 39 Z9 39 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2010 VL 70 IS 6 BP 2191 EP 2203 DI 10.1158/0008-5472.CAN-09-3528 PG 13 WC Oncology SC Oncology GA 607GA UT WOS:000278485900007 PM 20215517 ER PT J AU Amos, CI Pinney, SM Li, YF Kupert, E Lee, J de Andrade, MA Yang, P Schwartz, AG Fain, PR Gazdar, A Minna, J Wiest, JS Zeng, D Rothschild, H Mandal, D You, M Coons, T Gaba, C Bailey-Wilson, JE Anderson, MW AF Amos, Christopher I. Pinney, Susan M. Li, Yafang Kupert, Elena Lee, Juwon de Andrade, Mariza A. Yang, Ping Schwartz, Ann G. Fain, Pam R. Gazdar, Adi Minna, John Wiest, Jonathan S. Zeng, Dong Rothschild, Henry Mandal, Diptasri You, Ming Coons, Teresa Gaba, Colette Bailey-Wilson, Joan E. Anderson, Marshall W. TI A Susceptibility Locus on Chromosome 6q Greatly Increases Lung Cancer Risk among Light and Never Smokers SO CANCER RESEARCH LA English DT Article ID FAMILIAL RISK; RELATIVES; GENE; POPULATION; VALIDITY; 6Q23-25 AB Cigarette smoking is the major cause for lung cancer, but genetic factors also affect susceptibility. We studied families that included multiple relatives affected by lung cancer. Results from linkage analysis showed strong evidence that a region of chromosome 6q affects lung cancer risk. To characterize the effects that this region of chromosome 6q region has on lung cancer risk, we identified a haplotype that segregated with lung cancer. We then performed Cox regression analysis to estimate the differential effects that smoking behaviors have on lung cancer risk according to whether each individual carried a risk-associated haplotype or could not be classified and was assigned unknown haplotypic status. We divided smoking exposures into never smokers, light smokers (<20 pack-years), moderate smokers (20 to <40 pack-years), and heavy smokers (>= 40 pack-years). Comparing results according to smoking behavior stratified by carrier status, compared with never smokers, there was weakly increasing risk for increasing smoking behaviors, with the hazards ratios being 3.44, 4.91, and 5.18, respectively, for light, moderate, or heavy smokers, whereas among the individuals from families without the risk haplotype, the risks associated with smoking increased strongly with exposure, the hazards ratios being, respectively, 4.25, 9.17, and 11.89 for light, moderate, and heavy smokers. The never smoking carriers had a 4.71-fold higher risk than the never smoking individuals without known risk haplotypes. These results identify a region of chromosome 6q that increases risk for lung cancer and that confers particularly higher risks to never and light smokers. Cancer Res; 70(6); 2359-67. (C) 2010 AACR. C1 [Amos, Christopher I.; Li, Yafang; Zeng, Dong] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77005 USA. [Pinney, Susan M.; Kupert, Elena; Lee, Juwon; Anderson, Marshall W.] Univ Cincinnati, Cincinnati, OH USA. [de Andrade, Mariza A.; Yang, Ping] Mayo Clin, Coll Med, Rochester, MN USA. [Schwartz, Ann G.] Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. [Fain, Pam R.] Univ Colorado, Denver, CO 80202 USA. [Gazdar, Adi; Minna, John] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Wiest, Jonathan S.] NCI, NIH, Bethesda, MD 20892 USA. [Rothschild, Henry; Mandal, Diptasri] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [You, Ming] Washington Univ, St Louis, MO USA. [Coons, Teresa] Saccomanno Res Inst, Grand Junction, CO USA. [Gaba, Colette] Med Coll Ohio, Toledo, OH 43699 USA. [Bailey-Wilson, Joan E.] NHGRI, Baltimore, MD USA. RP Amos, CI (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, 1155 Pressler St,Unit 1340, Houston, TX 77005 USA. EM camos@mdanderson.org OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU NIH [UO1CA076293, P30ES06096, P30CA016772, R01CA133996, RO1CA060691, RO1CA87895, P30ES007789, P50CA70907, NO1PC35145]; National Cancer Institute; National Human Genome Research Institute, NIH FX Grant Support; NIH grants UO1CA076293, P30ES06096, P30CA016772, R01CA133996, RO1CA060691, RO1CA87895, P30ES007789, P50CA70907, and NO1PC35145 and the intramural programs of the National Cancer Institute and the National Human Genome Research Institute, NIH. NR 30 TC 24 Z9 24 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2010 VL 70 IS 6 BP 2359 EP 2367 DI 10.1158/0008-5472.CAN-09-3096 PG 9 WC Oncology SC Oncology GA 607GA UT WOS:000278485900023 PM 20215501 ER PT J AU Koutros, S Schumacher, FR Hayes, RB Ma, J Huang, WY Albanes, D Canzian, F Chanock, SJ Crawford, ED Diver, WR Feigelson, HS Giovanucci, E Haiman, CA Henderson, BE Hunter, DJ Kaaks, R Kolonel, LN Kraft, P Le Marchand, L Riboli, E Siddiq, A Stampfer, MJ Stram, DO Thomas, G Travis, RC Thun, MJ Yeager, M Berndt, SI AF Koutros, Stella Schumacher, Fredrick R. Hayes, Richard B. Ma, Jing Huang, Wen-Yi Albanes, Demetrius Canzian, Federico Chanock, Stephen J. Crawford, E. David Diver, W. Ryan Feigelson, Heather Spencer Giovanucci, Edward Haiman, Christopher A. Henderson, Brian E. Hunter, David J. Kaaks, Rudolf Kolonel, Laurence N. Kraft, Peter Le Marchand, Loic Riboli, Elio Siddiq, Afshan Stampfer, Mier J. Stram, Daniel O. Thomas, Gilles Travis, Ruth C. Thun, Michael J. Yeager, Meredith Berndt, Sonja I. TI Pooled Analysis of Phosphatidylinositol 3-Kinase Pathway Variants and Risk of Prostate Cancer SO CANCER RESEARCH LA English DT Article ID SINGLE-NUCLEOTIDE POLYMORPHISMS; GROWTH-FACTOR-I; PHOSPHOINOSITIDE 3-KINASE; FAMILY-HISTORY; GENETIC ASSOCIATION; REGULATORY SUBUNIT; BINDING PROTEIN-3; CELL-MIGRATION; OVARIAN-CANCER; FACTOR (IGF)-I AB The phosphatidylinositol 3-kinase (PI3K) pathway regulates various cellular processes, including cellular proliferation and intracellular trafficking, and may affect prostate carcinogenesis. Thus, we explored the association between single-nucleotide polymorphisms (SNP) in PI3K genes and prostate cancer. Pooled data from the National Cancer Institute Breast and Prostate Cancer Cohort Consortium were examined for associations between 89 SNPs in PI3K genes (PIK3C2B, PIK3AP1, PIK3C2A, PIK3CD, and PIK3R3) and prostate cancer risk in 8,309 cases and 9,286 controls. Odds ratios (OR) and 95% confidence intervals (95% CI) were estimated using logistic regression. SNP rs7556371 in PIK3C2B was significantly associated with prostate cancer risk [OR(per) (allele), 1.08 (95% CI, 1.03-1.14); P(trend) = 0.0017] after adjustment for multiple testing (P(adj) = 0.024). Simultaneous adjustment of rs7556371 for nearby SNPs strengthened the association [OR(per) (allele), 1.21 (95% CI, 1.09-1.34); P(trend) = 0.0003]. The adjusted association was stronger for men who were diagnosed before the age of 65 years [OR(per) (allele), 1.47 (95% CI, 1.20-1.79); P(trend) = 0.0001] or had a family history [OR(per) (allele) = 1.57 (95% CI, 1.11-2.23); P(trend) = 0.0114], and was strongest in those with both characteristics [OR(per) (allele) = 2.31 (95% CI, 1.07-5.07), P-interaction = 0.005]. Increased risks were observed among men in the top tertile of circulating insulin-like growth factor-I (IGF-I) levels [OR(per) (allele) = 1.46 (95% CI, 1.04-2.06); P(trend) = 0.075]. No differences were observed with disease aggressiveness (Gleason grade = 8 or stage T(3)/T(4) or fatal). In conclusion, we observed a significant association between PIK3C2B and prostate cancer risk, especially for familial, early-onset disease, which may be attributable to IGF-dependent PI3K signaling. Cancer Res; 70(6); 2389-96. (C)2010 AACR. C1 [Koutros, Stella] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Schumacher, Fredrick R.; Haiman, Christopher A.; Henderson, Brian E.; Stram, Daniel O.] Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. [Hayes, Richard B.] NYU, Sch Med, New York, NY USA. [Ma, Jing; Stampfer, Mier J.] Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. [Ma, Jing; Stampfer, Mier J.] Harvard Univ, Sch Med, Cambridge, MA 02138 USA. [Giovanucci, Edward; Kraft, Peter; Stampfer, Mier J.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Canzian, Federico; Kaaks, Rudolf] German Canc Res Ctr, Heidelberg, Germany. [Crawford, E. David] Univ Colorado, Hlth Sci Ctr, Dept Urol, Aurora, CO USA. [Diver, W. Ryan; Feigelson, Heather Spencer; Thun, Michael J.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30329 USA. [Feigelson, Heather Spencer; Hunter, David J.] Kaiser Permanente, Denver, CO USA. [Kolonel, Laurence N.; Le Marchand, Loic] Univ Hawaii, Canc Res Ctr, Honolulu, HI 96813 USA. [Riboli, Elio; Siddiq, Afshan] Univ London Imperial Coll Sci Technol & Med, London, England. [Travis, Ruth C.] Univ Oxford, Nuffield Dept Clin Med, Canc Epidemiol Unit, Oxford, England. RP Koutros, S (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8115,MSC 7240, Rockville, MD 20852 USA. EM KoutrosS@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; OI Hayes, Richard/0000-0002-0918-661X FU National Cancer Institute [CA98233, CA98710, CA98216, CA98758]; National Cancer Institute, NIH FX Grant Support; National Cancer Institute under UO1 grants CA98233, CA98710, CA98216, and CA98758 and the Intramural Research Program of the National Cancer Institute, NIH. NR 45 TC 28 Z9 29 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 MAR 15 PY 2010 VL 70 IS 6 BP 2389 EP 2396 DI 10.1158/0008-5472.CAN-09-3575 PG 8 WC Oncology SC Oncology GA 607GA UT WOS:000278485900026 PM 20197460 ER PT J AU Cross, AJ Ferrucci, LM Risch, A Graubard, BI Ward, MH Park, Y Hollenbeck, AR Schatzkin, A Sinha, R AF Cross, Amanda J. Ferrucci, Leah M. Risch, Adam Graubard, Barry I. Ward, Mary H. Park, Yikyung Hollenbeck, Albert R. Schatzkin, Arthur Sinha, Rashmi TI A Large Prospective Study of Meat Consumption and Colorectal Cancer Risk: An Investigation of Potential Mechanisms Underlying this Association SO CANCER RESEARCH LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRES; HETEROCYCLIC AMINE CONTENT; PUBLIC WATER-SUPPLIES; RED MEAT; COLON-CANCER; GENETIC POLYMORPHISMS; VARYING DEGREES; DIETARY HEME; EXPOSURE; ADENOMA AB Although the relation between red and processed meat intake and colorectal cancer has been reported in several epidemiologic studies, very few investigated the potential mechanisms. This study examined multiple potential mechanisms in a large U. S. prospective cohort with a detailed questionnaire on meat type and meat cooking methods linked to databases for estimating intake of mutagens formed in meats cooked at high temperatures (heterocyclic amines, polycyclic aromatic hydrocarbons), heme iron, nitrate, and nitrite. During 7 years of follow-up, 2,719 colorectal cancer cases were ascertained from a cohort of 300,948 men and women. The hazard ratios (HR) and 95% confidence intervals (95% CI) comparing the fifth to the first quintile for both red (HR, 1.24; 95% CI, 1.09-1.42; P-trend < 0.001) and processed meat (HR, 1.16; 95% CI, 1.01-1.32; P-trend = 0.017) intakes indicated an elevated risk for colorectal cancer. The potential mechanisms for this relation include heme iron (HR, 1.13; 95% CI, 0.99-1.29; P-trend = 0.022), nitrate from processed meats (HR, 1.16; 95% CI, 1.02-1.32; P-trend = 0.001), and heterocyclic amine intake [HR, 1.19; 95% CI, 1.05-1.34; P-trend < 0.001 for 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) and HR, 1.17; 95% CI, 1.05-1.29; P-trend < 0.001 for 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline (DiMeIQx)]. In general, the elevated risks were higher for rectal cancer than for colon cancer, with the exception of MeIQx and DiMeIQx, which were only associated with colon cancer. In conclusion, we found a positive association for red and processed meat intake and colorectal cancer; heme iron, nitrate/nitrite, and heterocyclic amines from meat may explain these associations. Cancer Res; 70(6); 2406-14. (C)2010 AACR. C1 [Cross, Amanda J.; Ferrucci, Leah M.; Park, Yikyung; Schatzkin, Arthur; Sinha, Rashmi] NCI, Nutr Epidemiol Branch, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Graubard, Barry I.] NCI, Biostat Branch, NIH, Dept Hlth & Human Serv, Rockville, MD USA. [Ward, Mary H.] NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD USA. [Risch, Adam] Informat Management Serv Inc, Silver Spring, MD USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Cross, AJ (reprint author), 6120 Execut Blvd, Rockville, MD 20852 USA. EM crossa@mail.nih.gov RI Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Park, Yikyung/0000-0002-6281-489X FU National Cancer Institute, NIH FX Grant Support; Intramural Research Program of National Cancer Institute, NIH. NR 42 TC 134 Z9 142 U1 5 U2 57 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2010 VL 70 IS 6 BP 2406 EP 2414 DI 10.1158/0008-5472.CAN-09-3929 PG 9 WC Oncology SC Oncology GA 607GA UT WOS:000278485900028 PM 20215514 ER PT J AU Ivy, SP Siu, LL Garrett-Mayer, E Rubinstein, L AF Ivy, S. Percy Siu, Lillian L. Garrett-Mayer, Elizabeth Rubinstein, Larry TI Approaches to Phase 1 Clinical Trial Design Focused on Safety, Efficiency, and Selected Patient Populations: A Report from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee SO CLINICAL CANCER RESEARCH LA English DT Article ID CONTINUAL REASSESSMENT METHOD; LATE-ONSET TOXICITIES; ONCOLOGY TRIALS; I TRIALS; BIOMARKERS; BENEFITS; AGENTS; RISKS; RATES; CRM AB The goals and objectives of phase 1 clinical trials are changing to include further evaluation of end-points such as molecular targeted effects, in addition to dose-toxicity profile of the investigational agent. Because of these changes in focus, the National Cancer Institute and Investigational Drug Steering Committee's Task Force on Clinical Trial Design met to evaluate the most efficient ways to design and implement early clinical trials with novel therapeutics. Clinical approaches discussed included the conventional 3 + 3 cohort expansion phase 1 design, multi-institutional phase 1 studies, accelerated titration designs, continual reassessment methods, the study of specific target patient populations, and phase 0 studies. Each of these approaches uniquely contributes to some aspect of the phase 1 study, with all focused on dose and schedule determination, patient safety, and limited patient exposure to ineffective doses of investigational agent. The benefit of labor-intensive generation of preliminary biomarker evidence of target inhibition, as well as the value of molecular profiling of the study population, is considered. New drug development is expensive and the failure rate remains high. By identifying patient populations expected to respond to the study agent and tailoring the treatment with a novel drug, investigators will be one step closer to personalizing cancer treatment. The "fail early and fast" approach is acceptable if the appropriate patient population is evaluated in the phase 1 trial. The approaches outlined in this overview address the merits, advantages, disadvantages, and obstacles encountered during first in human studies. Clin Cancer Res; 16(6); 1726-36. (C) 2010 AACR. C1 [Ivy, S. Percy; Rubinstein, Larry] NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD 20852 USA. [Ivy, S. Percy; Rubinstein, Larry] NCI, Biometr Res Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Rockville, MD 20852 USA. [Siu, Lillian L.] Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. [Garrett-Mayer, Elizabeth] Med Univ S Carolina, Charleston, SC 29425 USA. RP Ivy, SP (reprint author), NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, 6130 Execut Blvd,Suite 7131, Rockville, MD 20852 USA. EM ivyp@ctep.nci.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 46 TC 56 Z9 58 U1 1 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2010 VL 16 IS 6 BP 1726 EP 1736 DI 10.1158/1078-0432.CCR-09-1961 PG 11 WC Oncology SC Oncology GA 608OT UT WOS:000278595600006 PM 20215542 ER PT J AU Dancey, JE Dobbin, KK Groshen, S Jessup, JM Hruszkewycz, AH Koehler, M Parchment, R Ratain, MJ Shankar, LK Stadler, WM True, LD Gravell, A Grever, MR AF Dancey, Janet E. Dobbin, Kevin K. Groshen, Susan Jessup, J. Milburn Hruszkewycz, Andrew H. Koehler, Maria Parchment, Ralph Ratain, Mark J. Shankar, Lalitha K. Stadler, Walter M. True, Lawrence D. Gravell, Amy Grever, Michael R. CA Biomarkers Task Force NCI Invest TI Guidelines for the Development and Incorporation of Biomarker Studies in Early Clinical Trials of Novel Agents SO CLINICAL CANCER RESEARCH LA English DT Article ID SURROGATE END-POINTS; DRUG DEVELOPMENT; ASSESSMENT MODALITIES; DIAGNOSTIC-ACCURACY; VALIDATION; RECOMMENDATIONS; PATHWAY; TUMOR AB The National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) charged the Biomarker Task Force to develop recommendations to improve the decisions about incorporation of biomarker studies in early investigational drug trials. The Task Force members reviewed biomarker trials, the peer-reviewed literature, NCI and U. S. Food and Drug Administration (FDA) guidance documents, and conducted a survey of investigators to determine practices and challenges to executing biomarker studies in clinical trials of new drugs in early development. This document provides standard definitions and categories of biomarkers, and lists recommendations to sponsors and investigators for biomarker incorporation into such trials. Our recommendations for sponsors focus on the identification and prioritization of biomarkers and assays, the coordination of activities for the development and use of assays, and for operational activities. We also provide recommendations for investigators developing clinical trials with biomarker studies for scientific rationale, assay criteria, trial design, and analysis. The incorporation of biomarker studies into early drug trials is complex. Thus the decision to proceed with studies of biomarkers should be based on balancing the strength of science, assay robustness, feasibility, and resources with the burden of proper sample collection on the patient and potential impact of the results on drug development. The Task Force provides these guidelines in the hopes that improvements in biomarker studies will enhance the efficiency of investigational drug development. Clin Cancer Res; 16(6); 1745-55. (C) 2010 AACR. C1 [Grever, Michael R.] Ohio State Univ, Columbus, OH 43210 USA. [Groshen, Susan] Univ So Calif, Los Angeles, CA USA. [Dancey, Janet E.; Dobbin, Kevin K.; Jessup, J. Milburn; Hruszkewycz, Andrew H.; Shankar, Lalitha K.] NCI, Bethesda, MD 20892 USA. [Koehler, Maria] GlaxoSmithKline Inc, Narberth, PA USA. [Parchment, Ralph] NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. [Ratain, Mark J.; Stadler, Walter M.] Univ Chicago, Chicago, IL 60637 USA. [True, Lawrence D.] Univ Washington, Seattle, WA 98195 USA. [Gravell, Amy] Emmes Corp, Rockville, MD USA. RP Dancey, JE (reprint author), MaRS Ctr, Ontario Inst Canc Res, S Tower,101 Coll St,Suite 800, Toronto, ON M5G 0A3, Canada. EM janet.dancey@oicr.on.ca FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part by federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. NR 30 TC 128 Z9 128 U1 1 U2 9 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2010 VL 16 IS 6 BP 1745 EP 1755 DI 10.1158/1078-0432.CCR-09-2167 PG 11 WC Oncology SC Oncology GA 608OT UT WOS:000278595600008 PM 20215558 ER PT J AU Seymour, L Ivy, SP Sargent, D Spriggs, D Baker, L Rubinstein, L Ratain, MJ Le Blanc, M Stewart, D Crowley, J Groshen, S Humphrey, JS West, P Berry, D AF Seymour, Lesley Ivy, S. Percy Sargent, Daniel Spriggs, David Baker, Laurence Rubinstein, Larry Ratain, Mark J. Le Blanc, Michael Stewart, David Crowley, John Groshen, Susan Humphrey, Jeffrey S. West, Pamela Berry, Donald TI The Design of Phase II Clinical Trials Testing Cancer Therapeutics: Consensus Recommendations from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee SO CLINICAL CANCER RESEARCH LA English DT Article ID PROGRESSION-FREE SURVIVAL; FUTURE-DIRECTIONS; END-POINTS; ONCOLOGY; PROPOSAL; OUTCOMES; ISSUES; AGENTS AB The optimal design of phase II studies continues to be the subject of vigorous debate, especially studies of newer molecularly targeted agents. The observations that many new therapeutics "fail" in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials, further emphasize the critical importance of robust and efficient phase II design. The Clinical Trial Design Task Force (CTD-TF) of the National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on phase II trial design in Clinical Cancer Research. The IDSC has developed formal recommendations about aspects of phase II trial design that are the subject of frequent debate, such as endpoints (response versus progression-free survival), randomization (single-arm designs versus randomization), inclusion of biomarkers, biomarker-based patient enrichment strategies, and statistical design (e. g., two-stage designs versus multiple-group adaptive designs). Although these recommendations in general encourage the use of progression-free survival as the primary endpoint, randomization, inclusion of biomarkers, and incorporation of newer designs, we acknowledge that objective response as an endpoint and single-arm designs remain relevant in certain situations. The design of any clinical trial should always be carefully evaluated and justified based on characteristic specific to the situation. Clin Cancer Res; 16(6); 1764-9. (C) 2010 AACR. C1 [Seymour, Lesley] NCIC Clin Trials Grp, Kingston, ON K7L 3N6, Canada. [Ivy, S. Percy; Rubinstein, Larry] NCI, Bethesda, MD 20892 USA. [Sargent, Daniel] Mayo Clin, Div Biomed Stat & Informat, Rochester, MN USA. [Spriggs, David] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Baker, Laurence] Univ Michigan, Dept Med & Pharmacol, Ann Arbor, MI 48109 USA. [Ratain, Mark J.] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. [Le Blanc, Michael; Crowley, John] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Stewart, David; Berry, Donald] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Groshen, Susan] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Los Angeles, CA USA. [Humphrey, Jeffrey S.] Bristol Myers Squibb Co, Plainsboro, NJ USA. [West, Pamela] Emmes Corp, Rockville, MD USA. RP Seymour, L (reprint author), NCIC Clin Trials Grp, 10 Stuart St, Kingston, ON K7L 3N6, Canada. EM lseymour@ctg.queensu.ca OI Sargent, Daniel/0000-0002-2684-4741 FU NCI; IDSC FX The Clinical Trial Design Task Force would like to acknowledge the support of the NCI and the IDSC members and chairs, Amy Gravell, LeeAnn Jensen, the attendees of the original Phase II Workshop, as well as all Task Force members, past and present, especially Drs. Alex Adjei and Michaele Christian who originally led the Task Force (Table 2). NR 23 TC 67 Z9 70 U1 2 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2010 VL 16 IS 6 BP 1764 EP 1769 DI 10.1158/1078-0432.CCR-09-3287 PG 6 WC Oncology SC Oncology GA 608OT UT WOS:000278595600010 PM 20215557 ER PT J AU Wayne, AS Kreitman, RJ Findley, HW Lew, G Delbrook, C Steinberg, SM Stetler-Stevenson, M FitzGerald, DJ Pastan, I AF Wayne, Alan S. Kreitman, Robert J. Findley, Harry W. Lew, Glen Delbrook, Cynthia Steinberg, Seth M. Stetler-Stevenson, Maryalice FitzGerald, David J. Pastan, Ira TI Anti-CD22 Immunotoxin RFB4(dsFv)-PE38 (BL22) for CD22-Positive Hematologic Malignancies of Childhood: Preclinical Studies and Phase I Clinical Trial SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; HAIRY-CELL LEUKEMIA; CYTOTOXIC ACTIVITY; PEDIATRIC-PATIENTS; RESPONSE CRITERIA; CANCER; STANDARDS; DIAGNOSIS; SURVIVORS; LYMPHOMA AB Purpose: Although most children with B-lineage acute lymphoblastic leukemia (ALL) and non Hodgkin lymphoma are cured, new agents are needed to overcome drug resistance and reduce toxicities of chemotherapy. We hypothesized that the novel anti-CD22 immunotoxin, RFB4(dsFv)-PE38 (BL22, CAT-3888), would be active and have limited nonspecific side effects in children with CD22-expressing hematologic malignancies. We conducted the first preclinical and phase I clinical studies of BL22 in that setting. Experimental Design: Lymphoblasts from children with B-lineage ALL were assessed for CD22 expression by flow cytometry and for BL22 sensitivity by in vitro cytotoxicity assay. BL22 was evaluated in a human ALL murine xenograft model. A phase I clinical trial was conducted for pediatric subjects with CD22+ ALL and non-Hodgkin lymphoma. Results: All samples screened were CD22+. BL22 was cytotoxic to blasts in vitro (median IC(50), 9.8 ng/mL) and prolonged the leukemia-free survival of murine xenografts. Phase I trial cohorts were treated at escalating doses and schedules ranging from 10 to 40 mu g/kg every other day for three or six doses repeated every 21 or 28 days. Treatment was associated with an acceptable safety profile, adverse events were rapidly reversible, and no maximum tolerated dose was defined. Pharmacokinetics were influenced by disease burden consistent with rapid drug binding by CD22+ blasts. Although no responses were observed, transient clinical activity was seen in most subjects. Conclusions: CD22 represents an excellent target and anti-CD22 immunotoxins offer therapeutic promise in B-lineage hematologic malignancies of childhood. Clin Cancer Res; 16(6); 1894-903. (C) 2010 AACR. C1 [Wayne, Alan S.; Delbrook, Cynthia] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Kreitman, Robert J.; FitzGerald, David J.; Pastan, Ira] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Off Clin Director, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Stetler-Stevenson, Maryalice] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Findley, Harry W.; Lew, Glen] Emory Univ, Sch Med Childrens Healthcare Atlanta, Aflac Canc Ctr, Atlanta, GA 30322 USA. [Findley, Harry W.; Lew, Glen] Emory Univ, Sch Med Childrens Healthcare Atlanta, Blood Disorders Serv, Atlanta, GA 30322 USA. RP Wayne, AS (reprint author), NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bldg 10,Room 1-3750,9000 Rockville Pike,MSC 1104, Bethesda, MD 20892 USA. EM waynea@mail.nih.gov FU NIH, National Cancer Institute; Center for Cancer Research; Cooperative Research and Development Agreement; MedImmune, LLC FX Intramural Research Program of the NIH, National Cancer Institute, the Center for Cancer Research, and a Cooperative Research and Development Agreement between the NIH, National Cancer Institute, and MedImmune, LLC. NR 32 TC 91 Z9 99 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2010 VL 16 IS 6 BP 1894 EP 1903 DI 10.1158/1078-0432.CCR-09-2980 PG 10 WC Oncology SC Oncology GA 608OT UT WOS:000278595600023 PM 20215554 ER PT J AU McMahon, D Jones, J Wiegand, A Gange, SJ Kearney, M Palmer, S McNulty, S Metcalf, JA Acosta, E Rehm, C Coffin, JM Mellors, JW Maldarelli, F AF McMahon, D. Jones, J. Wiegand, A. Gange, S. J. Kearney, M. Palmer, S. McNulty, S. Metcalf, J. A. Acosta, E. Rehm, C. Coffin, J. M. Mellors, J. W. Maldarelli, F. TI Short-Course Raltegravir Intensification Does Not Reduce Persistent Low-Level Viremia in Patients with HIV-1 Suppression during Receipt of Combination Antiretroviral Therapy SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID INTEGRASE INHIBITOR RALTEGRAVIR; CENTRAL-NERVOUS-SYSTEM; VIRUS TYPE-1 RNA; INFECTED INDIVIDUALS; CEREBROSPINAL-FLUID; RESIDUAL VIREMIA; EXTENDED PERIODS; LATENT RESERVOIR; VIRAL RESERVOIR; P-GLYCOPROTEIN AB Background. Combination antiretroviral therapy suppresses but does not eradicate human immunodeficiency virus type 1 (HIV-1) in infected persons, and low-level viremia can be detected despite years of suppressive antiretroviral therapy. Short-course (28-day) intensification of standard antiretroviral combination therapy is a useful approach to determine whether complete rounds of HIV-1 replication in rapidly cycling cells contribute to persistent viremia. We investigated whether intensification with the integrase inhibitor raltegravir decreases plasma HIV-1 RNA levels in patients receiving suppressive antiretroviral therapy. Methods. Subjects (n=10) with long-term HIV-1 suppression receiving combination antiretroviral regimens had their regimens intensified for 4 weeks with raltegravir. Plasma HIV-1 RNA level was determined before, during, and after the 4-week intensification period, using a sensitive assay (limit of detection, 0.2 copies of HIV-1 RNA/mL of plasma). A 4-week intensification course was chosen to investigate potential HIV-1 replication in cells with relatively short (similar to 1-14-day) half-lives. Results. There was no evidence in any subject of a decline in HIV-1 RNA level during the period of raltegravir intensification or of rebound after discontinuation. Median levels of HIV-1 RNA before (0.17 log(10) copies/mL), during (0.04 log(10) copies/mL), and after (0.04 log(10) copies/mL) raltegravir intensification were not significantly different (P>.1 for all comparisons in parametric analyses). High-performance liquid chromatography and mass spectroscopy experiments confirmed that therapeutic levels of raltegravir were achieved in plasma during intensification. Conclusions. Intensification of antiretroviral therapy with a potent HIV-1 integrase inhibitor did not decrease persistent viremia in subjects receiving suppressive regimens, indicating that rapidly cycling cells infected with HIV-1 were not present. Eradication of HIV-1 from infected persons will require new therapeutic approaches. C1 [McMahon, D.; Jones, J.; McNulty, S.; Mellors, J. W.] Univ Pittsburgh, Dept Infect Dis, Pittsburgh, PA USA. [Wiegand, A.; Kearney, M.; Palmer, S.; Coffin, J. M.; Maldarelli, F.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21701 USA. [Gange, S. J.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Metcalf, J. A.; Rehm, C.] NIAID, Clin Res Sect, NIH, Bethesda, MD 20892 USA. [Acosta, E.] Univ Alabama, Dept Pharmacol, Birmingham, AL USA. RP Maldarelli, F (reprint author), NCI, NIH, Bldg 10,Rm 5A06, Bethesda, MD 20892 USA. EM fmalli@mail.nih.gov OI Gange, Stephen/0000-0001-7842-512X FU National Institute of Allergy and Infectious Diseases; National Institutes of Health [HHSN261200800001E]; SAIC [20XS190A]; George Kirby Foundation FX National Institute of Allergy and Infectious Diseases, National Institutes of Health (contract HHSN261200800001E to D. M.), and SAIC (contract 20XS190A to J. W. M.). J. W. M. is a research professor of the American Cancer Society with support from the George Kirby Foundation. NR 42 TC 129 Z9 129 U1 2 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 15 PY 2010 VL 50 IS 6 BP 912 EP 919 DI 10.1086/650749 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 557FW UT WOS:000274656000019 PM 20156060 ER PT J AU Hohmann, C Kang, EM Jancel, T AF Hohmann, Carina Kang, Elizabeth M. Jancel, Timothy TI Rifampin and Posaconazole Coadministration Leads to Decreased Serum Posaconazole Concentrations SO CLINICAL INFECTIOUS DISEASES LA English DT Letter ID PHARMACOKINETICS; ITRACONAZOLE; METABOLISM C1 [Jancel, Timothy] NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. [Hohmann, Carina] Klinikum Fulda gAG, Dept Pharm, Fulda, Germany. [Kang, Elizabeth M.] NIAID, Host Def Lab, Bethesda, MD 20892 USA. RP Jancel, T (reprint author), NIH, Ctr Clin, Dept Pharm, Bldg 10,Rm 1N257,10 Ctr Dr, Bethesda, MD 20892 USA. EM jancelt@mail.nih.gov NR 14 TC 13 Z9 13 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD MAR 15 PY 2010 VL 50 IS 6 BP 939 EP 940 DI 10.1086/650740 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 557FW UT WOS:000274656000028 PM 20166829 ER PT J AU Li, L Zheng, P Dean, J AF Li, Lei Zheng, Ping Dean, Jurrien TI Maternal control of early mouse development SO DEVELOPMENT LA English DT Review DE Maternal-effect genes; Mater (Nlrp5); Floped (Ooep); Padi6; Tle6; Filia; Embryonic cell lineage; Cleavage-stage arrest; Embryonic gene activation; Preimplantation development; Subcortical maternal complex ID EARLY EMBRYONIC-DEVELOPMENT; PRE-IMPLANTATION DEVELOPMENT; DE-NOVO METHYLATION; EFFECT GENE; PREIMPLANTATION DEVELOPMENT; DROSOPHILA EMBRYO; SELECTIVE DEGRADATION; MAMMALIAN DEVELOPMENT; SIGNALING PATHWAYS; FEMALE FERTILITY AB The hiatus between oocyte and embryonic gene transcription dictates a role for stored maternal factors in early mammalian development. Encoded by maternal-effect genes, these factors accumulate during oogenesis and enable the activation of the embryonic genome, the subsequent cleavage stages of embryogenesis and the initial establishment of embryonic cell lineages. Recent studies in mice have yielded new findings on the role of maternally provided proteins and multi-component complexes in preimplantation development. Nevertheless, significant gaps remain in our mechanistic understanding of the networks that regulate early mammalian embryogenesis, which provide an impetus and opportunities for future investigations. C1 [Li, Lei; Zheng, Ping; Dean, Jurrien] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Li, L (reprint author), Chinese Acad Sci, Inst Zool, State Key Lab Reprod Biol, Beijing 100101, Peoples R China. EM lil@ioz.ac.cn; jurrien@helix.nih.gov OI Li, Lei/0000-0001-5478-5681 FU National Institutes of Health, NIDDK FX We appreciate the critical review of the manuscript by Dr Scott Coonrod and the expert insight provided during the review process. The authors are funded by the Intramural Research Program of the National Institutes of Health, NIDDK. Deposited in PMC for release after 12 months. NR 122 TC 160 Z9 167 U1 3 U2 42 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAR 15 PY 2010 VL 137 IS 6 BP 859 EP 870 DI 10.1242/dev.039487 PG 12 WC Developmental Biology SC Developmental Biology GA 560FK UT WOS:000274887300002 PM 20179092 ER PT J AU Joseph, DS Malik, M Nurudeen, S Catherino, WH AF Joseph, Doina S. Malik, Minnie Nurudeen, Sahadat Catherino, William H. TI Myometrial cells undergo fibrotic transformation under the influence of transforming growth factor beta-3 SO FERTILITY AND STERILITY LA English DT Article DE Transforming growth factor beta 3; extracellular matrix; leiomyoma; myometrium; collagen; fibronectin; connective tissue growth factor; matrix metalloproteinases ID SMOOTH-MUSCLE-CELLS; GONADOTROPIN-RELEASING-HORMONE; MATRIX METALLOPROTEINASE INDUCER; UTERINE LEIOMYOMA CELLS; TGF-BETA; TISSUE INHIBITORS; GENE-EXPRESSION; DIFFERENTIAL EXPRESSION; HUMAN STROMELYSIN-3; REPERFUSION INJURY AB Objective: To examine the effect of transforming growth factor (TGF) beta 3 on immortalized myometrial and leiomyoma cell lines cloned from primary cell cultures of surgical specimens, and to determine whether such treatment alters myometrial cell extracellular matrix (ECM) expression. Design: Laboratory study. Setting: University hospital. Patient(s): Immortalized myometrial and leiomyoma cells from patients with symptomatic leiomyomata. Intervention(s): Tissue culture, followed by cellular, RNA, and protein analysis. Main Outcome Measure(s): Cell proliferation, alteration in ECM component expression. Result(s): Immortalized leiomyoma and myometrial cells demonstrate increased mRNA and protein production of the ECM proteins, collagen 1 A 1(15.0-fold), fibronectin 1 (2.93 fold), and connective tissue growth factor (9.40-fold) with exogenous TGF-beta 3 stimulation. Notably, the expression of collagen 1 A 1, fibronectin 1, and connective tissue growth factor in myometrial cells increase to similar expression levels as those found in leiomyoma cells. In addition, TGF-beta 3 decreased production of genes involved in matrix resorption, including matrix metalloproteinase 2 (0.65-fold) and -11 (0.68-fold). Conclusion(s): TGF-beta 3 induced a molecular phenotype in myometrial cells that was similar to leiomyoma cells, with elevated production of ECM-related genes and decreased production of ECM degradation related genes. (Fertil Steril (R) 2010;93:1500-8. (C)2010 by American Society for Reproductive Medicine.) C1 [Joseph, Doina S.; Malik, Minnie; Catherino, William H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Nurudeen, Sahadat] Georgetown Univ Hosp, Dept Obstet & Gynecol, Washington, DC 20007 USA. [Catherino, William H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Reprod Biol & Med Branch, NIH, Bethesda, MD USA. RP Catherino, WH (reprint author), Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bldg A,Room 3078,4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM wcatherino@usuhs.mil FU Berlex Foundation; Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health FX Supported by the Berlex Foundation and by the intramural research program of the Reproductive Biology and Medicine Branch, National Institute of Child Health and Human Development, National Institutes of Health. NR 61 TC 27 Z9 29 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 EI 1556-5653 J9 FERTIL STERIL JI Fertil. Steril. PD MAR 15 PY 2010 VL 93 IS 5 BP 1500 EP 1508 DI 10.1016/j.fertnstert.2009.01.081 PG 9 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 575BM UT WOS:000276038700016 PM 19328471 ER PT J AU Kaneko, KJ Kohn, MJ Liu, CY DePamphilis, ML AF Kaneko, Kotaro J. Kohn, Matthew J. Liu, Chengyu DePamphilis, Melvin L. TI The acrosomal protein Dickkopf-like 1 (DKKL1) is not essential for fertility SO FERTILITY AND STERILITY LA English DT Article DE Fertilization; acrosome; sperm; DKKL1; conditional knock-out ID MOUSE DEVELOPMENT; GENE-EXPRESSION; FAMILY; SOGGY AB Objective: To determine the role of Dkkl1 on mouse development, viability, and fertility. Design: Prospective experimental study. Setting: Government research institution. Animal(s): Mice of C57BL/6 and 129X1/SvJ strains, as well as transgenic mice of mixed C57BL/6 and 129X1/SvJ strains were used for the studies. Intervention(s): Mice were constructed that lacked a functional Dkkl1 gene. Main Outcome Measure(s): Deletion of the gene was confirmed by DNA, RNA, and protein analyses; in vivo fertility was examined by continuous mating scheme. Result(s): Previous studies have shown that Dkkl1, a gene unique to mammals, is expressed predominantly, if not exclusively, in developing spermatocytes, and the DKKL1 protein accumulates in the acrosome of mature sperm. Subsequent studies (reported in the accompanying article) demonstrate that Dkkl1 also is expressed in the trophectoderm/placental lineage. Taken together, these results strongly suggested that DKKL1 protein is required for terminal differentiation either of trophoblast giant cells or of sperm, both of which are directly involved in fertility. To challenge this hypothesis, conditional targeted mutagenesis was used to ablate the Dkkl1 gene in mice. Surprisingly, Dkkl1 nullizygous embryos developed into viable, fertile adults, despite the fact that they failed to produce any portion of the DKKL1 protein. Conclusion(s): DKKL1 is a mammalian-specific acrosomal protein that is not essential either for development or fertility. (Fertil Steril (R) 2010;93:1526-32. (C)2010 by American Society for Reproductive Medicine.) C1 [Kaneko, Kotaro J.; Kohn, Matthew J.; DePamphilis, Melvin L.] NICHHD, NIH, Bethesda, MD 20892 USA. [Liu, Chengyu] NHLBI, NIH, Bethesda, MD 20892 USA. RP DePamphilis, ML (reprint author), NICHHD, NIH, Bldg 6,Room 3A-15,9000 Rockville Pike,6 Ctr Dr MS, Bethesda, MD 20892 USA. EM depamphm@mail.nih.gov FU National Institute of Child Health and Human Development FX Supported by the intramural program of the National Institute of Child Health and Human Development. Animals were treated according to the Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Research, National Academy of Sciences, USA. The present address for Matthew J. Kohn is NYSTEM, New York State Department of Health, Albany, NY. NR 13 TC 2 Z9 2 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD MAR 15 PY 2010 VL 93 IS 5 BP 1526 EP 1532 DI 10.1016/j.fertnstert.2009.06.011 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 575BM UT WOS:000276038700019 PM 19596310 ER PT J AU Kohn, MJ Sztein, J Yagi, R DePamphilis, ML Kaneko, KJ AF Kohn, Matthew J. Sztein, Jorge Yagi, Rieko DePamphilis, Melvin L. Kaneko, Kotaro J. TI The acrosomal protein Dickkopf-like 1 (DKKL1) facilitates sperm penetration of the zona pellucida SO FERTILITY AND STERILITY LA English DT Article DE Fertilization; acrosome; sperm; zona pellucida; DKKL1; IVF ID MOUSE SPERM; MALE-MICE; MAMMALIAN FERTILIZATION; GENE-EXPRESSION; SPERMATOZOA; ASTHENOZOOSPERMIA; HYALURONIDASE; CAPACITATION; FERTILITY; CELLS AB Objective: To determine the role of Dkkl1 in mouse development, viability, and fertility. Design: Prospective experimental study. Setting: Government research institution. Animal(s): Mice of C57BL/6. B6D2F1/J, and 129X1/SvJ strains, as well as transgenic mice of mixed C57BL/6 and 129X1/SvJ strains were used for the studies. Intervention(s): Expression of the Dkkl1 gene was characterized during early mouse development, and the effects of Dkkl1 ablation on reproduction and fertility were characterized in vitro and in vivo. Main Outcome Measure(s): Dkkl1 RNA expression was determined by Northern blotting hybridization as well as quantitative reverse transcriptase-polymerase chain reaction assays. In vitro fertilization assays were used to assess fertility of sperm from male mice lacking functional Dkkl1. Result(s): Dkkl1 is a gene unique to mammals that is expressed primarily in developing spermatocytes and its product localized in the acrosome of mature sperm. Here we show that Dkkl1 also is expressed in the trophectoderm/placental lineage. Surprisingly, embryos lacking DKKL1 protein developed into viable, fertile adults. Nevertheless, the ability of sperm that lacked DKKL1 protein to fertilize wild-type eggs was severely compromised in vitro. Because this defect could be overcome either by removal of the zona pellucida or by the presence of wild-type sperm. Dkkl1, either directly or indirectly, facilitates the ability of sperm to penetrate the zona pellucida. Penetration of the zona pellucida by Dkkl1 sperm was delayed in vivo as well as in vitro, but the delay in vivo was compensated by other factors during preimplantation development. Accordingly, Dkkl1 I males offer an in vitro fertilization model for identifying factors that may contribute to infertility. Conclusion(s): DKKL1 is a mammalian-specific, acrosomal protein that strongly affects in vitro fertilization, although the effect is attenuated in vivo. (Fertil Steril (R) 2010;93:1533-7. (C)2010 by American Society for Reproductive Medicine.) C1 [Kohn, Matthew J.; Yagi, Rieko; DePamphilis, Melvin L.; Kaneko, Kotaro J.] NICHHD, NIH, Bethesda, MD 20892 USA. [Sztein, Jorge] NEI, Genet Engn Core Facil, NIH, Bethesda, MD 20892 USA. RP Kaneko, KJ (reprint author), NICHHD, NIH, Bldg 6,Room 3A-04,9000 Rockville Pike,6 Ctr Dr MS, Bethesda, MD 20892 USA. EM KanekoK@mail.nih.gov RI Sztein, Jorge/B-7165-2012; OI Sztein, Jorge Mario/0000-0001-7047-2634 FU National Institute of Child Health and Human Development FX This work was funded by the intramural program of the National Institute of Child Health and Human Development. Animals were treated according to the Guide for the Care and Use of Laboratory Animals, Institute of Laboratory Animal Research, National Academy of Sciences, USA. NR 36 TC 10 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD MAR 15 PY 2010 VL 93 IS 5 BP 1533 EP 1537 DI 10.1016/j.fertnstert.2009.06.010 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 575BM UT WOS:000276038700020 PM 19596312 ER PT J AU Taylor, JE Miller, BT Gray, KD Scott, RT Catherino, WH Segars, JH AF Taylor, Joelle E. Miller, Bradley T. Gray, Karen D. Scott, Richard T., Jr. Catherino, William H. Segars, James H. TI The mechanism responsible for the supraphysiologic gonadotropin surge in females treated with gonadotropin-releasing hormone (GnRH) agonist and primed with GnRH antagonist SO FERTILITY AND STERILITY LA English DT Article DE LH-RH; GnRH receptor; ovulation induction; LH surge; OHSS; ovarian hyperstimulation syndrome; pituitary ID FINAL OOCYTE MATURATION; IN-VITRO FERTILIZATION; OVARIAN HYPERSTIMULATION SYNDROME; FOLLICLE-STIMULATING-HORMONE; HUMAN CHORIONIC-GONADOTROPIN; MESSENGER-RIBONUCLEIC-ACID; PITUITARY LHRH RECEPTORS; LONG-TERM TREATMENT; LUTEINIZING-HORMONE; DOWN-REGULATION AB Objective: To elucidate the physiologic mechanism responsible for the supraphysiologic gonadotropin release from the pituitary induced by gonadotropin-releasing hormone (GnRH) agonist in female rats primed with GnRH antagonist. Design: Controlled experimental intervention. Setting: Government research facility. Animal(s): Forty 8-week-old Sprague-Dawley rats. Intervention(s): Forty oophorectomized rats were randomized into four treatment groups of 10: group A. control vehicles; group B. GnRH agonist (leuprolide acetate; 1.7 mu g/kg twice a day) on day 4; group C. GnRH antagonist (Nal-Lys; 3 mg/kg each day) days 1 to 4; or group D, GnRH antagonist (Nal-Lys; 3 mg/kg each day) days 1 to 4 plus GnRH agonist (1.7 mu g/kg twice a day) on day 4. Main Outcome Measure(s): Immunohistochemical methods, Northern and in situ hybridization to quantitate pituitary follicle-stimulating hormone beta (FSH-beta), luteinizing hormone beta (LH-beta), and GnRH receptor (GnRH-R) messenger RNA (mRNA), and receptor protein levels in all treatment groups. Result(s): Treatment with GnRH antagonist was associated with increased storage of gonadotropin in the pituitary for FSH-beta and LH-beta, but mRNA levels were unchanged. The GnRH-R mRNA decreased after GnRH-agonist treatment but remained stable in the GnRH-antagonist treatment groups. Levels of GnRH-R were decreased after GnRH-antagonist treatment. Conclusion(s): These data indicate that the in vivo mechanism responsible for the exaggerated release of gonadotropins in rats primed with GnRH antagonist and treated with GnRH agonist was an increase in releasable gonadotropin pools coupled with a reduction in GnRH-R, but receptor function was preserved. (Fertil Steril (R) 2010;93:1668-75. (C)2010 by American Society for Reproductive Medicine.) C1 [Taylor, Joelle E.; Miller, Bradley T.; Segars, James H.] NIH, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. [Taylor, Joelle E.] Wake Forest Univ, Bowman Gray Sch Med, Dept Obstet & Gynecol, Winston Salem, NC 27103 USA. [Miller, Bradley T.; Catherino, William H.; Segars, James H.] Uniformed Serv Univ Hlth Sci, Dept Obstet & Gynecol, Bethesda, MD 20814 USA. [Gray, Karen D.] NCI, NIH, Frederick, MD 21701 USA. [Scott, Richard T., Jr.] Reprod Med Associates New Jersey, Morristown, NJ USA. RP Segars, JH (reprint author), NICHD, Program Reprod & Adult Endocrinol, Bldg CRC,Room 1E3140,10 Ctr Dr, Bethesda, MD 20814 USA. EM segarsj@mail.nih.gov FU Intramural Research Program of the Reproductive Biology and Medicine Branch; NICHD; NIH FX Supported in part by the Intramural Research Program of the Reproductive Biology and Medicine Branch, NICHD, NIH. NR 43 TC 5 Z9 5 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD MAR 15 PY 2010 VL 93 IS 5 BP 1668 EP 1675 DI 10.1016/j.fertnstert.2008.12.047 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 575BM UT WOS:000276038700037 PM 19200975 ER PT J AU Bertoia, M Albanes, D Mayne, ST Mannisto, S Virtamo, J Wright, ME AF Bertoia, Monica Albanes, Demetrius Mayne, Susan T. Mannisto, Satu Virtamo, Jarmo Wright, Margaret E. TI No association between fruit, vegetables, antioxidant nutrients and risk of renal cell carcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE antioxidants; cohort study; diet; fruit; renal cell cancer; vegetables ID CANCER-RISK; SWEDISH WOMEN; DIET; COHORT; VITAMIN; QUESTIONNAIRE; CONSUMPTION; NUTRITION; PATTERNS; ETIOLOGY AB Previous epidemiologic studies that have examined the relationship between renal cell carcinoma (RCC) risk and intakes of plant foods and antioxidant nutrients have yielded inconsistent results. We therefore examined the associations between intakes of fruit, vegetables, carotenoids, flavonoids, vitamin E and vitamin C and RCC risk in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study cohort. At baseline, 27,062 male Finnish smokers aged 50-69 years completed a 276-item dietary questionnaire that included questions on frequency of consumption and portion size. During up to 19 years of follow-up, 255 men developed RCC. Cox proportional hazards models were utilized to estimate relative risks (RR) and 95% confidence intervals (CI). Despite a large range in intake, no association was observed between fruit, vegetables or antioxidant nutrients and RCC risk. For example, multivariate RRs and 95% CIs for the highest versus the lowest quartile of intake were 0.79 (0.55-1.14), 1.23 (0.85-1.79), 1.09 (0.74-1.60), 0.83 (0.57-1.21), 1.09 (0.73-1.64) and 0.99 (0.67-1.46) for fruit, vegetables, total carotenoids, total flavonoids, total vitamin E and vitamin C, respectively (all p values for trend > 0.05). Our results indicate that diet may not play a large role in the etiology of RCC in male smokers, although further examination of these associations in nonsmokers, women and diverse racial populations is warranted. C1 [Wright, Margaret E.] Univ Illinois, Dept Pathol, Chicago, IL 60612 USA. [Bertoia, Monica; Mayne, Susan T.] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Bertoia, Monica; Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Mannisto, Satu; Virtamo, Jarmo] Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. RP Wright, ME (reprint author), Univ Illinois, Dept Pathol MC 847, Coll Med, 840 S Wood St,CSN 130, Chicago, IL 60612 USA. EM mewright@uic.edu RI Albanes, Demetrius/B-9749-2015; OI Mannisto, Satu/0000-0002-8668-3046 FU NIH; DHHS FX The Intramural Research Program of the National Cancer Institute, NIH, DHHS NR 37 TC 19 Z9 19 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 15 PY 2010 VL 126 IS 6 BP 1504 EP 1512 DI 10.1002/ijc.24829 PG 9 WC Oncology SC Oncology GA 567GU UT WOS:000275434100021 PM 19685494 ER PT J AU Numaga, T Nishida, M Kiyonaka, S Kato, K Katano, M Mori, E Kurosaki, T Inoue, R Hikida, M Putney, JW Mori, Y AF Numaga, Takuro Nishida, Motohiro Kiyonaka, Shigeki Kato, Kenta Katano, Masahiro Mori, Emiko Kurosaki, Tomohiro Inoue, Ryuji Hikida, Masaki Putney, James W., Jr. Mori, Yasuo TI Ca2+ influx and protein scaffolding via TRPC3 sustain PKC beta and ERK activation in B cells SO JOURNAL OF CELL SCIENCE LA English DT Article DE B-cell receptor; Ca2+ signaling; Diacylglycerol; PKC beta; TRP channels ID RECEPTOR POTENTIAL CHANNELS; CA2+-PERMEABLE CATION CHANNEL; KINASE-C; TRANSIENT RECEPTOR; ANTIGEN RECEPTOR; SIGNAL-TRANSDUCTION; CALCIUM-CHANNELS; T-LYMPHOCYTES; ENTRY; MEMBRANE AB Ca2+ signaling mediated by phospholipase C that produces inositol 1,4,5-trisphosphate [Ins(1,4,5) P-3] and diacylglycerol (DAG) controls lymphocyte activation. In contrast to store-operated Ca2+ entry activated by Ins(1,4,5)P-3-induced Ca2+ release from endoplasmic reticulum, the importance of DAG-activated Ca2+ entry remains elusive. Here, we describe the physiological role of DAG-activated Ca2+ entry channels in B-cell receptor (BCR) signaling. In avian DT40 B cells, deficiency of transient receptor potential TRPC3 at the plasma membrane (PM) impaired DAG-activated cation currents and, upon BCR stimulation, the sustained translocation to the PM of protein kinase C beta (PKC beta) that activated extracellular signal-regulated kinase (ERK). Notably, TRPC3 showed direct association with PKC beta that maintained localization of PKC beta at the PM. Thus, TRPC3 functions as both a Ca2+-permeable channel and a protein scaffold at the PM for downstream PKC beta activation in B cells. C1 [Numaga, Takuro; Kiyonaka, Shigeki; Kato, Kenta; Katano, Masahiro; Mori, Emiko; Mori, Yasuo] Kyoto Univ, Grad Sch Engn, Dept Synthet Chem & Biol Chem, Kyoto 6158510, Japan. [Numaga, Takuro; Putney, James W., Jr.] NIEHS, Lab Signal Transduct, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Nishida, Motohiro] Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Pharmacol & Toxicol, Higashi Ku, Fukuoka 8128582, Japan. [Kiyonaka, Shigeki; Mori, Yasuo] JST, CREST, Chiyoda Ku, Tokyo 1020075, Japan. [Kurosaki, Tomohiro] RIKEN Res Ctr Allergy & Immunol, Lab Lymphocyte Differentiat, Tsurumi Ku, Kanagawa 2300045, Japan. [Inoue, Ryuji] Fukuoka Univ, Sch Med, Dept Physiol, Jonan Ku, Fukuoka 8140180, Japan. [Hikida, Masaki] Kyoto Univ, Grad Sch Med, Ctr Innovat Immunoregulat Technol & Therapeut, Kyoto 6068501, Japan. RP Mori, Y (reprint author), Kyoto Univ, Grad Sch Engn, Dept Synthet Chem & Biol Chem, Kyoto 6158510, Japan. EM mori@sbchem.kyoto-u.ac.jp RI Kurosaki, Tomohiro/D-1306-2009 OI Kurosaki, Tomohiro/0000-0002-6352-304X FU Ministry of Education, Culture, Sports, Science and Technology of Japan; Japan Society for the Promotion of Sciences; NIH; National Institute of Environmental Health Sciences FX We thank Y. Aiba and S. Yamamoto for much technical advice and helpful discussions, and R. Y. Tsien for mCherry and mStrawberry. This study was supported by research grants from Ministry of Education, Culture, Sports, Science and Technology of Japan and the Japan Society for the Promotion of Sciences, and in part by the Intramural Program of the NIH, National Institute of Environmental Health Sciences. Deposited in PMC for release after 12 months. NR 63 TC 29 Z9 30 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAR 15 PY 2010 VL 123 IS 6 BP 927 EP 938 DI 10.1242/jcs.061051 PG 12 WC Cell Biology SC Cell Biology GA 563UQ UT WOS:000275160800013 PM 20179100 ER PT J AU Liao, XH Buggey, J Kimmel, AR AF Liao, Xin-Hua Buggey, Jonathan Kimmel, Alan R. TI Chemotactic activation of Dictyostelium AGC-family kinases AKT and PKBR1 requires separate but coordinated functions of PDK1 and TORC2 SO JOURNAL OF CELL SCIENCE LA English DT Article DE PDK1; Chemotaxis; PI3K/PtdIns(3,4,5)P(3); BAR domains; PH domains; TORC2 ID RICTOR-MTOR COMPLEX; SUBSTRATE-SPECIFICITY; AKT/PKB; PROTEIN; IDENTIFICATION; DISCOIDEUM; DOMAIN; BAR; PHOSPHORYLATION; RESPONSES AB Protein kinases AKT and PKBR1 of Dictyostelium belong to the AGC protein kinase superfamily. AKT and PKBR1 are phosphorylated at similar sites by phosphoinositide-dependent kinase 1 (PDK1) and TORC2 kinases; however, they have different subcellular localizing domains. AKT has a phosphoinositide 3-kinase (PI3K)/phosphatidylinositol (3,4,5)-trisphosphate [PtdIns(3,4,5)P(3)]-regulated PH (pleckstrin homology) domain whereas PKBR1 is myristoylated and persistently membrane localized. Using strains defective for PI3K/PtdIns(3,4,5)P(3)-, PDK1- and TORC2-signaling or strains that express phospho-site mutants of AKT and PKBR1, we dissect the different roles of PI3K/PtdIns(3,4,5)P(3), PDK1 and TORC2. We show that activation of AKT and PKBR1 requires PDK1-site phosphorylation, but that phosphorylation by TORC2 is insufficient for AKT or PKBR1 activation. However, PDK1-site phosphorylation is dependent on phosphorylation by TORC2, which suggests that there is regulatory coordination among PDK1, TORC2 and their phospho-site targets. This defines a separate input for signaling in control of chemotaxis and dependency on PDK1 function. We also demonstrate that PDK1 in Dictyostelium functions independently of PI3K/PtdIns(3,4,5)P(3). Finally, we show that AKT and PKBR1 exhibit substrate selectivity and identify two novel lipid-interacting proteins preferentially phosphorylated by AKT. Despite certain similarities, AKT and PKBR1 have distinct regulatory paths that impact activation and effector targeting, with PDK1 serving a central role. C1 [Liao, Xin-Hua; Buggey, Jonathan; Kimmel, Alan R.] NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. RP Kimmel, AR (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM ark1@helix.nih.gov FU National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Xiuli Huang, Marielle Young and Colette Young for assistance in gene targeting experiments. David Eric Anderson was invaluable for mass spectrometric analyses. Finally, we thank Dictybase and colleagues for various strains. This research was supported by the Intramural Research Program of the National Institutes of Health, the National Institute of Diabetes and Digestive and Kidney Diseases. Deposited in PMC for release after 12 months. NR 35 TC 26 Z9 27 U1 1 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAR 15 PY 2010 VL 123 IS 6 BP 983 EP 992 DI 10.1242/jcs.064022 PG 10 WC Cell Biology SC Cell Biology GA 563UQ UT WOS:000275160800018 PM 20200230 ER PT J AU Wilson, MS Madala, SK Ramalingam, TR Gochuico, BR Rosas, IO Cheever, AW Wynn, TA AF Wilson, Mark S. Madala, Satish K. Ramalingam, Thirumalai R. Gochuico, Bernadette R. Rosas, Ivan O. Cheever, Allen W. Wynn, Thomas A. TI Bleomycin and IL-1 beta-mediated pulmonary fibrosis is IL-17A dependent SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CELL-MEDIATED PATHOLOGY; IL-17-PRODUCING T-CELLS; INDUCED LUNG INJURY; NF-KAPPA-B; TGF-BETA; IN-VIVO; INTERFERON-GAMMA; INTRATRACHEAL BLEOMYCIN; AUTOIMMUNE INFLAMMATION; NEUTROPHIL RECRUITMENT AB Idiopathic pulmonary fibrosis (IPF) is a destructive inflammatory disease with limited therapeutic options. To better understand the inflammatory responses that precede and concur with collagen deposition, we used three models of pulmonary fibrosis and identify a critical mechanistic role for IL-17A. After exposure to bleomycin (BLM), but not Schistosoma mansoni eggs, IL-17A produced by CD4(+) and gamma delta(+) T cells induced significant neutrophilia and pulmonary fibrosis. Studies conducted with C57BL/6 il17a(-/-) mice confirmed an essential role for IL-17A. Mechanistically, using ifn gamma(-/-), il10(-/-), il10(-/-) il12p40(-/-), and il10(-/-) il17a(-/-) mice and TGF-beta blockade, we demonstrate that IL-17A-driven fibrosis is suppressed by IL-10 and facilitated by IFN-gamma and IL-12/23p40. BLM-induced IL-17A production was also TGF-beta dependent, and recombinant IL-17A-mediated fibrosis required TGF-beta, suggesting cooperative roles for IL-17A and TGF-beta in the development of fibrosis. Finally, we show that fibrosis induced by IL-1 beta, which mimics BLM-induced fibrosis, is also highly dependent on IL-17A. IL-17A and IL-1 beta were also increased in the bronchoalveolar lavage fluid of patients with IPF. Together, these studies identify a critical role for IL-17A in fibrosis, illustrating the potential utility of targeting IL-17A in the treatment of drug and inflammation-induced fibrosis. C1 [Wilson, Mark S.; Madala, Satish K.; Ramalingam, Thirumalai R.; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. [Gochuico, Bernadette R.] NHGRI, NIH, Bethesda, MD 20892 USA. [Rosas, Ivan O.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Cheever, Allen W.] Biomed Res Inst, Rockville, MD 20852 USA. RP Wynn, TA (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU National Institutes of Health; National Institute of Allergy and Infectious Disease; National Human Genome Research Institute FX We are very grateful to the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Disease, and National Human Genome Research Institute, who supported this research. NR 79 TC 193 Z9 215 U1 6 U2 21 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAR 15 PY 2010 VL 207 IS 3 BP 535 EP 552 DI 10.1084/jem.20092121 PG 18 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 569KB UT WOS:000275593900009 PM 20176803 ER PT J AU Quezada, SA Simpson, TR Peggs, KS Merghoub, T Vider, J Fan, XZ Blasberg, R Yagita, H Muranski, P Antony, PA Restifo, NP Allison, JP AF Quezada, Sergio A. Simpson, Tyler R. Peggs, Karl S. Merghoub, Taha Vider, Jelena Fan, Xiaozhou Blasberg, Ronald Yagita, Hideo Muranski, Pawel Antony, Paul A. Restifo, Nicholas P. Allison, James P. TI Tumor-reactive CD4(+) T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID ANTITUMOR IMMUNE-RESPONSE; MINOR HISTOCOMPATIBILITY ANTIGEN; NEGATIVE CANCER-CELLS; METASTATIC MELANOMA; TH1 CELLS; IN-VIVO; ADOPTIVE IMMUNOTHERAPY; EFFECTOR-CELLS; CD4+T CELLS; THERAPY AB Adoptive transfer of large numbers of tumor-reactive CD8(+) cytotoxic T lymphocytes (CTLs) expanded and differentiated in vitro has shown promising clinical activity against cancer. However, such protocols are complicated by extensive ex vivo manipulations of tumor-reactive cells and have largely focused on CD8(+) CTLs, with much less emphasis on the role and contribution of CD4(+) T cells. Using a mouse model of advanced melanoma, we found that transfer of small numbers of naive tumor-reactive CD4(+) T cells into lymphopenic recipients induces substantial T cell expansion, differentiation, and regression of large established tumors without the need for in vitro manipulation. Surprisingly, CD4(+) T cells developed cytotoxic activity, and tumor rejection was dependent on class II-restricted recognition of tumors by tumor-reactive CD4(+) T cells. Furthermore, blockade of the co-inhibitory receptor CTL-associated antigen 4 (CTLA-4) on the transferred CD4(+) T cells resulted in greater expansion of effector T cells, diminished accumulation of tumor-reactive regulatory T cells, and superior antitumor activity capable of inducing regression of spontaneous mouse melanoma. These findings suggest a novel potential therapeutic role for cytotoxic CD4(+) T cells and CTLA-4 blockade in cancer immunotherapy, and demonstrate the potential advantages of differentiating tumor-reactive CD4(+) cells in vivo over current protocols favoring in vitro expansion and differentiation. C1 [Quezada, Sergio A.; Simpson, Tyler R.; Peggs, Karl S.; Fan, Xiaozhou; Allison, James P.] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, Ludwig Ctr Canc Immunotherapy, New York, NY 10021 USA. [Quezada, Sergio A.; Simpson, Tyler R.; Peggs, Karl S.; Merghoub, Taha; Fan, Xiaozhou; Allison, James P.] Mem Sloan Kettering Canc Ctr, Dept Immunol, New York, NY 10021 USA. [Vider, Jelena; Blasberg, Ronald] Mem Sloan Kettering Canc Ctr, Dept Neurol, New York, NY 10021 USA. [Yagita, Hideo] Juntendo Univ, Sch Med, Dept Immunol, Tokyo 1138421, Japan. [Muranski, Pawel; Restifo, Nicholas P.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Antony, Paul A.] Univ Maryland, Sch Med, Program Mol Microbiol & Immunol, Dept Pathol, Baltimore, MD 21201 USA. RP Allison, JP (reprint author), Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, Ludwig Ctr Canc Immunotherapy, New York, NY 10021 USA. EM allisonj@mskcc.org RI PEGGS, Karl/B-3869-2009; Restifo, Nicholas/A-5713-2008; Muranski, Pawel/E-5572-2010; Vider, Jelena/B-9663-2011; OI Vider, Jelena/0000-0003-1696-9812; Restifo, Nicholas P./0000-0003-4229-4580 FU Irvington Institute Fellowship Program of the Cancer Research Institute; Millennium Nucleus on Immunology and Immunotherapy; Pontificia Universidad Catolica de Chile; Canadian Institutes of Health; Leukaemia Research Fund; Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center; Swim Across America Foundation FX S. A. Quezada is a Research Fellow funded by the Irvington Institute Fellowship Program of the Cancer Research Institute and a junior member of the Millennium Nucleus on Immunology and Immunotherapy, Pontificia Universidad Catolica de Chile. T. R. Simpson is supported by a Canadian Institutes of Health Doctoral Research Award. K. S. Peggs is currently an investigator at the Department of Haematology, University College London Cancer Institute, University College London, and receives funding from the Leukaemia Research Fund. J.P. Allison is an investigator of the Howard Hughes Medical Institute and holds the David H. Koch Chair in Immunological Studies at the Memorial Sloan-Kettering Cancer Center. This work was also supported by the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center funded by W. H. Goodwin and A. Goodwin, and the Swim Across America Foundation. NR 49 TC 263 Z9 273 U1 1 U2 19 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAR 15 PY 2010 VL 207 IS 3 BP 637 EP 650 DI 10.1084/jem.20091918 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 569KB UT WOS:000275593900016 PM 20156971 ER PT J AU Xie, Y Akpinarli, A Maris, C Hipkiss, EL Lane, M Kwon, EKM Muranski, P Restifo, NP Antony, PA AF Xie, Ying Akpinarli, Akguel Maris, Charles Hipkiss, Edward L. Lane, Malcolm Kwon, Eun-Kyung M. Muranski, Pawel Restifo, Nicholas P. Antony, Paul Andrew TI Naive tumor-specific CD4(+) T cells differentiated in vivo eradicate established melanoma SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID SUPERIOR ANTITUMOR IMMUNITY; DENDRITIC CELLS; METASTATIC MELANOMA; CANCER REGRESSION; LYMPH-NODES; IFN-GAMMA; CLASS-II; HOMEOSTATIC PROLIFERATION; SECONDARY EXPANSION; STEM-CELLS AB In vitro differentiated CD8(+) T cells have been the primary focus of immunotherapy of cancer with little focus on CD4(+) T cells. Immunotherapy involving in vitro differentiated T cells given after lymphodepleting regimens significantly augments antitumor immunity in animals and human patients with cancer. However, the mechanisms by which lymphopenia augments adoptive cell therapy and the means of properly differentiating T cells in vitro are still emerging. We demonstrate that naive tumor/self-specific CD4(+) T cells naturally differentiated into T helper type 1 cytotoxic T cells in vivo and caused the regression of established tumors and depigmentation in lymphopenic hosts. Therapy was independent of vaccination, exogenous cytokine support, CD8(+), B, natural killer (NK), and NKT cells. Proper activation of CD4(+) T cells in vivo was important for tumor clearance, as naive tumor-specific CD4(+) T cells could not completely treat tumor in lymphopenic common gamma chain (gamma(c))-deficient hosts.. c signaling in the tumor-bearing host was important for survival and proper differentiation of adoptively transferred tumor-specific CD4(+) T cells. Thus, these data provide a platform for designing immunotherapies that incorporate tumor/self-reactive CD4(+) T cells. C1 [Antony, Paul Andrew] Univ Maryland, Sch Med, Program Mol Microbiol & Immunol, Baltimore, MD 21201 USA. [Xie, Ying; Kwon, Eun-Kyung M.; Antony, Paul Andrew] Univ Maryland, Sch Med, Lab Immunol & Canc Immunotherapy, Dept Pathol, Baltimore, MD 21201 USA. [Lane, Malcolm] Univ Maryland, Sch Med, Dept Epidemiol & Preventat Med, Baltimore, MD 21201 USA. [Antony, Paul Andrew] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Tumor Immunol & Immunotherapy Program, Baltimore, MD 21201 USA. [Antony, Paul Andrew] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Program Oncol, Baltimore, MD 21201 USA. [Akpinarli, Akguel] NIAID, Cellular & Mol Immunol Lab, Bethesda, MD 20892 USA. [Maris, Charles; Hipkiss, Edward L.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21287 USA. [Muranski, Pawel; Restifo, Nicholas P.] Ctr Canc Res, Surg Branch, Bethesda, MD 20892 USA. RP Antony, PA (reprint author), Univ Maryland, Sch Med, Program Mol Microbiol & Immunol, Baltimore, MD 21201 USA. EM pantony@som.umaryland.edu RI Restifo, Nicholas/A-5713-2008; Muranski, Pawel/E-5572-2010; OI Restifo, Nicholas P./0000-0003-4229-4580 FU Center for Cancer Research; K22 NCI [5K22CA125200]; Melanoma Research Foundation FX This research was initiated at the Surgery Branch of the National Cancer Institute and was supported by the Center for Cancer Research. The work was further supported by a K22 NCI career transition award (5K22CA125200 to P. A. Antony) and the Melanoma Research Foundation (P. A. Antony). NR 86 TC 166 Z9 171 U1 0 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAR 15 PY 2010 VL 207 IS 3 BP 651 EP 667 DI 10.1084/jem.20091921 PG 17 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 569KB UT WOS:000275593900017 PM 20156973 ER PT J AU Guimond, M Freud, AG Mao, HC Yu, JH Blaser, BW Leong, JW Vandeusen, JB Dorrance, A Zhang, JY Mackall, CL Caligiuri, MA AF Guimond, Martin Freud, Aharon G. Mao, Hsiaoyin C. Yu, Jianhua Blaser, Bradley W. Leong, Jeffrey W. Vandeusen, Jeffrey B. Dorrance, Adrienne Zhang, Jianying Mackall, Crystal L. Caligiuri, Michael A. TI In Vivo Role of Flt3 Ligand and Dendritic Cells in NK Cell Homeostasis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; HEMATOPOIETIC PROGENITOR CELLS; CD8(+) T-CELLS; TRANS PRESENTATION; MESSENGER-RNA; CUTTING EDGE; IL-15; INTERLEUKIN-15; IL-15R-ALPHA; EXPRESSION AB IL-15 is required for NK cell development and homeostasis in vivo. Because IL-15 is presented in traits via its high-affinity IL-15R alpha-chain to cells expressing the IL-15R beta gamma complex, we postulated that certain IL-15-bearing cells must be required for NK cell homeostasis. Using IL-15(WT/WT) and IL-15(-/-) mice, bone marrow chimeras with normal cellularity, and a selective depletion of CD11c(hi) dendritic cells (DCs), we demonstrate that ablation of the resting CD11c(hi) DC population results in a highly significant decrease in the absolute number of mature NK cells. In contrast, administration of Flt3 ligand increases the CD11c(hi) DC population, which, when expressing IL-15, significantly expands mature NK cells via enhanced survival and proliferation. In summary, a CD11c(hi) DC population expressing IL-15 is required to maintain NK cell homeostasis under conditions of normal cellularity and also is required to mediate Flt3 ligand-induced NK cell expansion in vivo. The Journal of Immunology, 2010, 184: 2769-2775. C1 [Caligiuri, Michael A.] Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Guimond, Martin; Mao, Hsiaoyin C.; Yu, Jianhua; Dorrance, Adrienne; Caligiuri, Michael A.] Ohio State Univ, Dept Mol Virol Immunol & Med Genet, Columbus, OH 43210 USA. [Freud, Aharon G.; Blaser, Bradley W.; Vandeusen, Jeffrey B.] Ohio State Univ, Med Sci Program, Columbus, OH 43210 USA. [Freud, Aharon G.; Blaser, Bradley W.; Vandeusen, Jeffrey B.] Ohio State Univ, Integrated Biomed Sci Grad Program, Columbus, OH 43210 USA. [Zhang, Jianying] Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. [Caligiuri, Michael A.] Ohio State Univ, Div Hematol & Oncol, Dept Internal Med, Columbus, OH 43210 USA. [Leong, Jeffrey W.; Mackall, Crystal L.] NCI, NIH, Bethesda, MD 20892 USA. RP Caligiuri, MA (reprint author), Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. EM Michael.Caligiuri@osumc.edu FU National Cancer Institute [CA95426, CA68458]; Ohio State University; James Cancer Hospital; Solove Research Institute FX This work was supported by National Cancer Institute Grants CA95426 and CA68458 (to M.A.C.) and the Intramural Program of the National Cancer Institute (to C.L.M.). M.G. is the recipient of the Up on The Roof fellowship award from The Ohio State University Comprehensive Cancer Center, James Cancer Hospital, and Solove Research Institute. NR 42 TC 26 Z9 27 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 MAR 15 PY 2010 VL 184 IS 6 BP 2769 EP 2775 DI 10.4049/jimmunol.0900685 PG 7 WC Immunology SC Immunology GA 566QW UT WOS:000275389000005 PM 20142363 ER PT J AU Dalet, A Vigneron, N Stroobant, V Hanada, K Van den Eynde, BJ AF Dalet, Alexandre Vigneron, Nathalie Stroobant, Vincent Hanada, Ken-ichi Van den Eynde, Benoit J. TI Splicing of Distant Peptide Fragments Occurs in the Proteasome by Transpeptidation and Produces the Spliced Antigenic Peptide Derived from Fibroblast Growth Factor-5 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID 20S PROTEASOME; THERMOPLASMA-ACIDOPHILUM; DEGRADATION; ACTIVATION; RESOLUTION; PROTEINS AB Peptide splicing is a newly described mode of production of antigenic peptides presented by MHC class I molecules, whereby two noncontiguous fragments of the parental protein are joined together after excision of the intervening segment. Three spliced peptides have been described. In two cases, splicing involved the excision of a short intervening segment of 4 or 6 aa and was shown to occur in the proteasome by transpeptidation resulting from the nucleophilic attack of an acyl-enzyme intermediate by the N terminus of the other peptide fragment. For the third peptide, which is derived from fibroblast growth factor-5 (FGF-5), the splicing mechanism remains unknown. In this case, the intervening segment is 40 aa long. This much greater length made the transpeptidation model more difficult to envision. Therefore, we evaluated the role of the proteasome in the splicing of this peptide. We observed that the spliced FGF-5 peptide was produced in vitro after incubation of proteasomes with a 49-aa-long precursor peptide. We evaluated the catalytic mechanism by incubating proteasomes with various precursor peptides. The results confirmed the transpeptidation model of splicing. By transfecting a series of mutant FGF-5 constructs, we observed that reducing the length of the intervening segment increased the production of the spliced peptide, as predicted by the transpeptidation model. Finally, we observed that traits-splicing (i.e., splicing of fragments from two distinct proteins) can occur in the cell, but with a much lower efficacy than splicing of fragments from the same protein. The Journal of Immunology, 2010, 184: 3016-3024. C1 [Van den Eynde, Benoit J.] Catholic Univ Louvain, Ludwig Inst Canc Res, Duve Inst, Brussels Branch, B-1200 Brussels, Belgium. [Hanada, Ken-ichi] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Van den Eynde, BJ (reprint author), Catholic Univ Louvain, Ludwig Inst Canc Res, Duve Inst, Brussels Branch, Ave Hippocrate 74,UCL 7459, B-1200 Brussels, Belgium. EM benoit.vandeneynde@bru.licr.org RI Hanada, Ken-ichi/L-2481-2013 OI Hanada, Ken-ichi/0000-0003-2959-1257 FU European Community [LSHC-2006-518234]; Fonds J. Maisin (Belgium); Fondation contre le Cancer (Belgium); Fonds National de la Recherche Scientifique (Belgium); Fonds National de la Recherche Scientifique FX This work was supported by the European Community under the Sixth Framework Programme (Grant LSHC-2006-518234: CancerImmunotherapy); by the Belgian Programme on Interuniversity Poles of Attraction initiated by the Belgian State, Prime Ministre's Office, Science Policy Programming: and by grants from the Fonds J. Maisin (Belgium), the Fondation contre le Cancer (Belgium), and the Fonds National de la Recherche Scientifique (Belgium). A.D. is supported by a Televie fellowship from the Fonds National de la Recherche Scientifique. and N.V. is a postdoctoral researcher with the Fonds National de la Recherche Scientifique. NR 24 TC 27 Z9 27 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 MAR 15 PY 2010 VL 184 IS 6 BP 3016 EP 3024 DI 10.4049/jimmunol.0901277 PG 9 WC Immunology SC Immunology GA 566QW UT WOS:000275389000030 PM 20154207 ER PT J AU Motiwala, AS Dai, Y Jones-Lopez, EC Hwang, SH Lee, JS Cho, SN Via, LE Barry, CE Alland, D AF Motiwala, Alifiya S. Dai, Yang Jones-Lopez, Edward C. Hwang, Soo-Hee Lee, Jong Seok Cho, Sang Nae Via, Laura E. Barry, Clifton E., III Alland, David TI Mutations in Extensively Drug-Resistant Mycobacterium tuberculosis That Do Not Code for Known Drug-Resistance Mechanisms SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID ETHAMBUTOL; VIRULENCE; EVOLUTION; STRAINS; COST AB Background. Highly lethal outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are increasing. Whole-genome sequencing of KwaZulu-Natal MDR and XDR outbreak strains prevalent in human immunodeficiency virus (HIV)-infected patients by the Broad Institute identified 22 novel mutations which were unique to the XDR genome or shared only by the MDR and XDR genomes and not already known to be associated with drug resistance. Methods. We studied the 12 novel mutations which were not located in highly-repetitive genes to identify mutations that were truly associated with drug resistance or were likely to confer a specific fitness advantage. Results. None of these mutations could be found in a phylogenetically and geographically diverse set of drug-resistant and drug-susceptible Mycobacterium tuberculosis isolates, suggesting that these mutations are unique to the KZN clone. Examination of the 600-basepair region flanking each mutation revealed 26 new mutations. We searched for a convergent evolutionary signal in the new mutations for evidence that they emerged under selective pressure, consistent with increased fitness. However, all but 1 rare mutation were monophyletic, indicating that the mutations were markers of strain phylogeny rather than fitness or drug resistance. Conclusions. Our results suggest that virulent XDR tuberculosis in immunocompromised HIV-infected patients can evolve without generalizable fitness changes or other XDR-specific mutations. C1 [Motiwala, Alifiya S.; Dai, Yang; Jones-Lopez, Edward C.; Alland, David] Univ Med & Dent New Jersey, New Jersey Med Sch, Div Infect Dis, Dept Med, Newark, NJ 07103 USA. [Motiwala, Alifiya S.; Dai, Yang; Jones-Lopez, Edward C.; Alland, David] Univ Med & Dent New Jersey, New Jersey Med Sch, Ruy V Lourenco Ctr Study Emerging & Reemerging Pa, Newark, NJ 07103 USA. [Hwang, Soo-Hee] Natl Masan TB Hosp, Masan, South Korea. [Lee, Jong Seok] Int TB Res Ctr, Masan, South Korea. [Cho, Sang Nae] Yonsei Univ, Coll Med, Dept Microbiol, Seoul, South Korea. [Via, Laura E.; Barry, Clifton E., III] NIH, Bethesda, MD 20892 USA. RP Alland, D (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Div Infect Dis, Dept Med, 185 S Orange Ave,MSB A920C, Newark, NJ 07103 USA. EM allandda@umdnj.edu RI Barry, III, Clifton/H-3839-2012; OI Via, Laura/0000-0001-6074-9521 FU National Institutes of Health [AI065663]; National Institutes of Health, National Institute of Allergy and Infectious Disease FX Financial support: National Institutes of Health grant AI065663 and the intramural research program of the National Institutes of Health, National Institute of Allergy and Infectious Disease. NR 15 TC 13 Z9 14 U1 3 U2 9 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2010 VL 201 IS 6 BP 881 EP 888 DI 10.1086/650999 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 557JH UT WOS:000274664900011 PM 20136412 ER PT J AU Rockx, B Donaldson, E Frieman, M Sheahan, T Corti, D Lanzavecchia, A Baric, RS AF Rockx, Barry Donaldson, Eric Frieman, Matthew Sheahan, Timothy Corti, Davide Lanzavecchia, Antonio Baric, Ralph S. TI Escape from Human Monoclonal Antibody Neutralization Affects In Vitro and In Vivo Fitness of Severe Acute Respiratory Syndrome Coronavirus SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID RECEPTOR-BINDING DOMAIN; SARS-CORONAVIRUS; STRUCTURAL BASIS; COV; DETERMINANTS; MUTANTS; SUBUNIT; DISEASE; EPITOPE; MICE AB Background. Severe acute respiratory syndrome (SARS) emerged as a human disease in 2002. Detailed phylogenetic analysis and epidemiologic studies have suggested that the SARS coronavirus (SARS-CoV) originated from animals. The spike (S) glycoprotein has been identified as a major target of protective immunity and contains >= 3 regions that are targeted by neutralizing antibodies in the S1 and S2 domains. We previously characterized a panel of neutralizing human monoclonal antibodies (MAbs), but the majority of epitopes recognized by the MAbs remain unknown. Methods. In the present study, we generated neutralization escape mutants and studied the effect of these neutralization escape mutations on human and animal receptor usage as well as on in vitro and in vivo fitness. Results. Distinct but partially overlapping sets of amino acids were identified that are critical to the binding of MAbs with differential neutralization profiles. We also identified possible interactions between the S1 and S2 domains of the SARS-CoV S glycoprotein. Finally, we showed that escape from neutralization usually attenuates SARS-CoV infection. Conclusions. These data provide a mechanism for overcoming neutralization escape by use of broadly cross-reactive cocktails of cross-neutralizing MAbs that recognize residues within the receptor-binding domain that are critical for virus replication and virulence. C1 [Rockx, Barry; Donaldson, Eric; Frieman, Matthew; Sheahan, Timothy; Baric, Ralph S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Baric, Ralph S.] Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. [Rockx, Barry] NIAID, Rocky Mt Lab, NIH, Hamilton, MT 59840 USA. [Corti, Davide; Lanzavecchia, Antonio] Biomed Res Inst, Bellinzona, Switzerland. RP Baric, RS (reprint author), Univ N Carolina, Dept Epidemiol, Campus Box 7435, Chapel Hill, NC 27599 USA. EM rbaric@email.unc.edu FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [P01-AI059443, AI059136]; European Union [N.SP22.CT.2004.511065] FX Financial support: National Institute of Allergy and Infectious Diseases, National Institutes of Health (grants P01-AI059443 and AI059136 to R.B.); and European Union (SARSVAC grant N.SP22.CT.2004.511065 to A.L.). NR 28 TC 24 Z9 26 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2010 VL 201 IS 6 BP 946 EP 955 DI 10.1086/651022 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 557JH UT WOS:000274664900018 PM 20144042 ER PT J AU Otto, M Wardenburg, JB Deleo, FR AF Otto, Michael Wardenburg, Juliane Bubeck DeLeo, Frank R. TI The Panton-Valentine Leukocidin Is a Virulence Factor in a Murine Model of Necrotizing Pneumonia Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID STAPHYLOCOCCUS-AUREUS; EXPRESSION; MUTATION C1 [Otto, Michael] NIAID, Lab Human Bacterial Pathogenesis, NIH, Bethesda, MD 20892 USA. [Wardenburg, Juliane Bubeck] Univ Chicago, Dept Microbiol, Chicago, IL 60637 USA. [DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT USA. RP Otto, M (reprint author), NIAID, Lab Human Bacterial Pathogenesis, NIH, 9000 Rockville Pike,Bldg 33, Bethesda, MD 20892 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 NR 11 TC 0 Z9 0 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD MAR 15 PY 2010 VL 201 IS 6 BP 969 EP 970 DI 10.1086/651027 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 557JH UT WOS:000274664900021 ER PT J AU Luo, QF Lu, H Lu, HB Yang, YH Gao, JH AF Luo, Qingfei Lu, Huo Lu, Hanbing Yang, Yihong Gao, Jia-Hong TI Comparison of visually evoked local field potentials in isolated turtle brain: Patterned versus blank stimulation SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE Turtle; Preparation; Local field potential; Visual; Cortex; Tectum ID NEURONAL CURRENTS; PYRAMIDAL NEURONS; RECEPTIVE FIELDS; STRIATE CORTEX; LIGHT-FLASHES; MRI; RESPONSES; CELLS; POPULATIONS; DIFFUSE AB Isolated turtle brain/eye preparation has recently been used as a bloodless animal model for detecting the magnetic resonance imaging (MRI) signal changes produced by visually evoked neuronal currents. The present work aims to determine whether checkerboard-patterned or full field flash (blank) stimulation should be used in order to achieve stronger neuronal responses in turtle brain/eye preparation. The knowledge gained in this study is essential for optimizing the visual stimulation methods in functional neuroimaging studies using turtle brain/eye preparation. In this study, visually evoked local field potentials (LFPs) were measured and compared in turtle visual cortex and optic tectum elicited by checkerboard and full field flash stimuli with three different inter-stimulus intervals (ISIs = 5, 10, and 16 s). It was found that the behavior of neuronal adaptation in the cortical and tectal LFP signals for checkerboard stimulation was comparable to flash stimulation. In addition, there was no significant difference in the LFP peak amplitudes (ISI = 16 s) between these two stimuli. These results indicate that the intensity of neuronal responses to checkerboard is comparable to flash stimulation. These two stimulation methods should be equivalent in functional neuroimaging studies using turtle brain/eye preparation. (C) 2009 Elsevier B.V. All rights reserved. C1 [Luo, Qingfei; Gao, Jia-Hong] Univ Chicago, Brain Res Imaging Ctr, Chicago, IL 60637 USA. [Luo, Qingfei; Gao, Jia-Hong] Univ Chicago, Dept Radiol, Chicago, IL 60637 USA. [Lu, Huo] Philadelphia Coll Osteopath Med, Dept Basic Sci, Suwanee, GA 30024 USA. [Lu, Hanbing; Yang, Yihong] NIDA, NIH, Baltimore, MD 21224 USA. [Gao, Jia-Hong] Univ Chicago, Dept Psychiat & Behav Neurosci, Chicago, IL 60637 USA. RP Gao, JH (reprint author), Univ Chicago, Brain Res Imaging Ctr, 5841 S Maryland Ave,MC 2026, Chicago, IL 60637 USA. EM jgao@uchicago.edu OI Luo, Qingfei/0000-0002-1078-799X FU NIH [RO1 EB004753]; NIH/NIDA FX We thank D. Senseman for helping with the experimental setup and valuable advice and comments. We also thank P. Ulinski for useful discussion. This work was supported by a NIH grant (RO1 EB004753 to JHG) and the Intramural Research Program of the NIH/NIDA. NR 28 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD MAR 15 PY 2010 VL 187 IS 1 BP 26 EP 32 DI 10.1016/j.jneumeth.2009.12.005 PG 7 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 571QP UT WOS:000275769900004 PM 20034520 ER PT J AU Thangavel, S Mendoza-Maldonado, R Tissino, E Sidorova, JM Yin, JH Wang, WD Monnat, RJ Falaschi, A Vindigni, A AF Thangavel, Saravanabhavan Mendoza-Maldonado, Ramiro Tissino, Erika Sidorova, Julia M. Yin, Jinhu Wang, Weidong Monnat, Raymond J., Jr. Falaschi, Arturo Vindigni, Alessandro TI Human RECQ1 and RECQ4 Helicases Play Distinct Roles in DNA Replication Initiation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ROTHMUND-THOMSON-SYNDROME; ORIGIN RECOGNITION COMPLEX; WERNER-SYNDROME PROTEIN; BLOOM-SYNDROME PROTEIN; CELL-CYCLE; SYNDROME GENE; S-PHASE; BLM HELICASE; FORK; ACTIVATION AB Cellular and biochemical studies support a role for all five human RecQ helicases in DNA replication; however, their specific functions during this process are unclear. Here we investigate the in vivo association of the five human RecQ helicases with three well-characterized human replication origins. We show that only RECQ1 (also called RECQL or RECQL1) and RECQ4 (also called RECQL4) associate with replication origins in a cell cycle-regulated fashion in unperturbed cells. RECQ4 is recruited to origins at late G(1), after ORC and MCM complex assembly, while RECQ1 and additional RECQ4 are loaded at origins at the onset of S phase, when licensed origins begin firing. Both proteins are lost from origins after DNA replication initiation, indicating either disassembly or tracking with the newly formed replisome. Nascent-origin DNA synthesis and the frequency of origin firing are reduced after RECQ1 depletion and, to a greater extent, after RECQ4 depletion. Depletion of RECQ1, though not that of RECQ4, also suppresses replication fork rates in otherwise unperturbed cells. These results indicate that RECQ1 and RECQ4 are integral components of the human replication complex and play distinct roles in DNA replication initiation and replication fork progression in vivo. C1 [Thangavel, Saravanabhavan; Mendoza-Maldonado, Ramiro; Tissino, Erika; Falaschi, Arturo; Vindigni, Alessandro] Int Ctr Genet Engn & Biotechnol, I-34149 Trieste, Italy. [Thangavel, Saravanabhavan; Falaschi, Arturo] Scuola Normale Super Pisa, Mol Biol Lab, I-56124 Pisa, Italy. [Sidorova, Julia M.; Monnat, Raymond J., Jr.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Monnat, Raymond J., Jr.] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. [Yin, Jinhu; Wang, Weidong] NIA, Genet Lab, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Falaschi, Arturo] CNR, Ist Fisiol Clin, I-56124 Pisa, Italy. RP Vindigni, A (reprint author), Int Ctr Genet Engn & Biotechnol, Padriciano 99, I-34149 Trieste, Italy. EM vindigni@icgeb.org OI Sidorova, Julia/0000-0001-5502-4323 FU Associazione Italiana per la Ricerca sul Cancro (AIRC); NCI [PO1 CA77852]; National Institute on Aging [AG000661-06]; National Institutes of Health FX This work was supported by a grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC) to A.V., by NCI grant PO1 CA77852 to R.J.M., by grants from the AIRC and the Instituto Toscano dei Tumori to A.F., and by the Intramural Research Program of the National Institute on Aging (grant AG000661-06), National Institutes of Health, to W.W. NR 71 TC 75 Z9 75 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 MAR 15 PY 2010 VL 30 IS 6 BP 1382 EP 1396 DI 10.1128/MCB.01290-09 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 562NH UT WOS:000275058100008 PM 20065033 ER PT J AU Penmatsa, H Zhang, WQ Yarlagadda, S Li, CY Conoley, VG Yue, JM Bahouth, SW Buddington, RK Zhang, GP Nelson, DJ Sonecha, MD Manganiello, V Wine, JJ Naren, AP AF Penmatsa, Himabindu Zhang, Weiqiang Yarlagadda, Sunitha Li, Chunying Conoley, Veronica G. Yue, Junming Bahouth, Suleiman W. Buddington, Randal K. Zhang, Guangping Nelson, Deborah J. Sonecha, Monal D. Manganiello, Vincent Wine, Jeffrey J. Naren, Anjaparavanda P. TI Compartmentalized Cyclic Adenosine 3 ',5 '-Monophosphate at the Plasma Membrane Clusters PDE3A and Cystic Fibrosis Transmembrane Conductance Regulator into Microdomains SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID AIRWAY EPITHELIAL-CELLS; PHOSPHODIESTERASE INHIBITORS; PROTEIN-KINASE; CHLORIDE CHANNEL; APICAL MEMBRANE; CL-SECRETION; CFTR; CAMP; DIFFUSION; AMP AB Formation of multiple-protein macromolecular complexes at specialized subcellular microdomains increases the specificity and efficiency of signaling in cells. In this study, we demonstrate that phosphodiesterase type 3A (PDE3A) physically and functionally interacts with cystic fibrosis transmembrane conductance regulator (CFTR) channel. PDE3A inhibition generates compartmentalized cyclic adenosine 3',5'-monophosphate (cAMP), which further clusters PDE3A and CFTR into microdomains at the plasma membrane and potentiates CFTR channel function. Actin skeleton disruption reduces PDE3A-CFTR interaction and segregates PDE3A from its interacting partners, thus compromising the integrity of the CFTR-PDE3A-containing macromolecular complex. Consequently, compartmentalized cAMP signaling is lost. PDE3A inhibition no longer activates CFTR channel function in a compartmentalized manner. The physiological relevance of PDE3A-CFTR interaction was investigated using pig trachea submucosal gland secretion model. Our data show that PDE3A inhibition augments CFTR-dependent submucosal gland secretion and actin skeleton disruption decreases secretion. C1 [Penmatsa, Himabindu; Zhang, Weiqiang; Yarlagadda, Sunitha; Conoley, Veronica G.; Yue, Junming; Naren, Anjaparavanda P.] Univ Tennessee, Hlth Sci Ctr, Dept Physiol, Memphis, TN 38163 USA. [Li, Chunying] Wayne State Univ, Sch Med, Dept Biochem & Mol Biol, Detroit, MI 48201 USA. [Bahouth, Suleiman W.] Univ Tennessee, Hlth Sci Ctr, Dept Pharmacol, Memphis, TN 38163 USA. [Buddington, Randal K.] Univ Memphis, Dept Hlth & Sports Sci, Memphis, TN 38152 USA. [Zhang, Guangping; Nelson, Deborah J.] Univ Chicago, Dept Neurobiol Pharmacol & Physiol, Chicago, IL 60637 USA. [Sonecha, Monal D.; Wine, Jeffrey J.] Stanford Univ, Cyst Fibrosis Res Lab, Stanford, CA 94305 USA. [Manganiello, Vincent] NHLBI, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Naren, AP (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Physiol, Memphis, TN 38163 USA. EM anaren@uthsc.edu FU National Institutes of Health [DK074996, DK080834]; American Heart Association [R079008141] FX We thank Dr. David Armbruster for critically editing the manuscript; Dr. Richard A. Heil-Chapdelaine for technical support with imaging; Dr. Bakhram K. Berdiev (Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL) for providing pcDNA3.1(-)-CFP and YFP-CFTR constructs; and Dr. Juan P. Ianowski for help with data analysis. This work was supported by grants from National Institutes of Health Grant DK074996 and DK080834 to A.P.N. and American Heart Association predoctoral fellowship R079008141 to H. P. NR 61 TC 45 Z9 45 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAR 15 PY 2010 VL 21 IS 6 BP 1097 EP 1110 DI 10.1091/mbc.E09-08-0655 PG 14 WC Cell Biology SC Cell Biology GA 567GQ UT WOS:000275433500023 PM 20089840 ER PT J AU Fan, JS Zeller, K Chen, YC Watkins, T Barnes, KC Becker, KG Dang, CV Cheadle, C AF Fan, JinShui Zeller, Karen Chen, Yu-Chi Watkins, Tonya Barnes, Kathleen C. Becker, Kevin G. Dang, Chi V. Cheadle, Chris TI Time-Dependent c-Myc Transactomes Mapped by Array-Based Nuclear Run-On Reveal Transcriptional Modules in Human B Cells SO PLOS ONE LA English DT Article ID GENE-EXPRESSION; GENOMIC TARGETS; RNA; ACTIVATION; NETWORK; CLUSTER; LINE AB Background: The definition of transcriptional networks through measurements of changes in gene expression profiles and mapping of transcription factor binding sites is limited by the moderate overlap between binding and gene expression changes and the inability to directly measure global nuclear transcription (coined ``transactome''). Methodology/Principal Findings: We developed a method to measure nascent nuclear gene transcription with an Arraybased Nuclear Run-On (ANRO) assay using commercial microarray platforms. This strategy provides the missing component, the transactome, to fully map transcriptional networks. ANRO measurements in an inducible c-Myc expressing human P4936 B cell model reveals time-dependent waves of transcription, with a transactome early after c-Myc induction that does not persist at a late, steady-state phase, when genes that are regulated by c-Myc and E2F predominate. Gene set matrix analysis further uncovers functionally related groups of genes putatively regulated by waves of transcription factor motifs following Myc induction, starting with AP1 and CREB that are followed by EGR1, NFkB and STAT, and ending with E2F, Myc and ARNT/HIF motifs. Conclusions/Significance: By coupling ANRO with previous global mapping of c-Myc binding sites by chromatin immunoprecipitation (ChIP) in P493-6 cells, we define a set of transcriptionally regulated direct c-Myc target genes and pave the way for the use of ANRO to comprehensively map any transcriptional network. C1 [Fan, JinShui; Chen, Yu-Chi; Watkins, Tonya; Barnes, Kathleen C.; Cheadle, Chris] Johns Hopkins Univ, Sch Med, Dept Med, Div Clin Immunol & Allergy,Lowe Family Genom Core, Baltimore, MD 21205 USA. [Zeller, Karen; Dang, Chi V.] Johns Hopkins Univ, Sch Med, Dept Med, Div Hematol, Baltimore, MD 21205 USA. [Dang, Chi V.] Johns Hopkins Univ, Sch Med, Dept Cell Biol, Baltimore, MD 21205 USA. [Dang, Chi V.] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Becker, Kevin G.] NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. RP Fan, JS (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Clin Immunol & Allergy,Lowe Family Genom Core, Baltimore, MD 21205 USA. EM cvdang@jhmi.edu; ccheadl1@jhmi.edu OI Becker, Kevin/0000-0002-6794-6656 FU National Institute on Aging, NIH [R01CA57341, R01CA51497]; Maryland Stem Cell Research Fund [2007-MSCRFE-0167-00, 2008-MSCRFE-0156-00]; Mary Beryl Patch Turnbull Scholar Program FX This work was partially supported in part by the Intramural Research Program of the NIH, National Institute on Aging, NIH grants R01CA57341 and R01CA51497 and Maryland Stem Cell Research Fund grants 2007-MSCRFE-0167-00 and 2008-MSCRFE-0156-00. KCB was supported in part by the Mary Beryl Patch Turnbull Scholar Program. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 27 TC 21 Z9 21 U1 1 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 MAR 15 PY 2010 VL 5 IS 3 AR e9691 DI 10.1371/journal.pone.0009691 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 569SM UT WOS:000275621000009 PM 20300622 ER PT J AU Auerbach, SS Shah, RR Mav, D Smith, CS Walker, NJ Vallant, MK Boorman, GA Irwin, RD AF Auerbach, Scott S. Shah, Ruchir R. Mav, Deepak Smith, Cynthia S. Walker, Nigel J. Vallant, Molly K. Boorman, Gary A. Irwin, Richard D. TI Predicting the hepatocarcinogenic potential of alkenylbenzene flavoring agents using toxicogenomics and machine learning SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Toxicogenomics; Cancer; Liver; Prediction; Alkenylbenzene; Rat ID NATIONAL-TOXICOLOGY-PROGRAM; CHRONIC TOXICITY CARCINOGENICITY; SUPPORT VECTOR MACHINES; AVAILABLE DATA; CANCER CLASSIFICATION; EXPRESSION PROFILES; RISK-EVALUATION; LIVER-TUMORS; IN-VIVO; GENE AB Identification of carcinogenic activity is the primary goal of the 2-year bioassay. The expense of these studies limits the number of chemicals that can be studied and therefore chemicals need to be prioritized based on a variety of parameters. We have developed an ensemble of support vector machine classification models based on male F344 rat liver gene expression following 2, 14 OF 90 days of exposure to a collection of hepatocarcinogens (aflatoxin B1, 1-amino-2,4-dibromoanthraquinone, N-nitrosodimethylamine, methyleugenol) and non-hepatocarcinogens (acetaminophen, ascorbic acid, tryptophan). Seven models were generated based on individual exposure durations (2, 14 or 90 days) or a combination of exposures (2 + 14, 2 + 90, 14 + 90 and 2 + 14 + 90 days). All sets of data, with the exception of one yielded models with 0% cross-validation error. Independent validation of the models was performed using expression data from the liver of rats exposed at 2 dose levels to a collection of alkenylbenzene flavoring agents. Depending on the model Used and the exposure duration of the test data, independent validation error rates ranged from 47% to 10%. The variable with the most notable effect on independent validation accuracy was exposure duration of the alkenylbenzene test data. All models generally exhibited improved performance as the exposure duration of the alkenylbenzene data increased. The models differentiated between hepatocarcinogenic (estragole and safrole) and non-hepatocarcinogenic (anethole, eugenol and isoeugenol) alkenylbenzenes previously studied in a carcinogenicity bioassay. In the case of safrole the models correctly differentiated between carcinogenic and non-carcinogenic dose levels. The models predict that two alkenylbenzenes not previously assessed in a carcinogenicity bioassay, myristicin and isosafrole, would be weakly hepatocarcinogenic if studied at a dose level of 2 mmol/kg bw/day for 2 years in male F344 rats; therefore suggesting that these chemicals should be a higher priority relative to other untested alkenylbenzenes for evaluation in the carcinogenicity bioassay. The results of the Study indicate that gene expression-based predictive models are an effective tool for identifying hepatocarcinogens. Furthermore, we find that exposure duration is a critical variable in the success or failure of such an approach, particularly when evaluating chemicals with unknown carcinogenic potency. Published by Elsevier Inc. C1 [Auerbach, Scott S.; Smith, Cynthia S.; Walker, Nigel J.; Vallant, Molly K.; Boorman, Gary A.; Irwin, Richard D.] NIEHS, Natl Toxicol Program, NIH, Res Triangle Pk, NC 27709 USA. [Shah, Ruchir R.; Mav, Deepak] SRA Int, Res Triangle Pk, NC 27709 USA. RP Irwin, RD (reprint author), NIEHS, Natl Toxicol Program, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM irwin@niehs.nih.gov RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 FU NIH; National Institute of Environmental Health Sciences [1 Z01 ESO45004-11] FX Funding: T is research was supported [in part] by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences under Research Project Number 1 Z01 ESO45004-11 BB. The authors would like to thank Drs. Julia Gohlke and Rick Paules to critical review of the article. NR 77 TC 42 Z9 45 U1 0 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAR 15 PY 2010 VL 243 IS 3 BP 300 EP 314 DI 10.1016/j.taap.2009.11.021 PG 15 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 567IZ UT WOS:000275441600004 PM 20004213 ER PT J AU Minor, RK Smith, DL Sossong, AM Kaushik, S Poosala, S Spangler, EL Roth, GS Lane, M Allison, DB de Cabo, R Ingram, DK Mattison, JA AF Minor, Robin K. Smith, Daniel L., Jr. Sossong, Alex M. Kaushik, Susmita Poosala, Suresh Spangler, Edward L. Roth, George S. Lane, Mark Allison, David B. de Cabo, Rafael Ingram, Donald K. Mattison, Julie A. TI Chronic ingestion of 2-deoxy-D-glucose induces cardiac vacuolization and increases mortality in rats SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE Deoxyglucose; Calorie restriction; Lifespan; Mortality; Cardiac vacuolarization ID CALORIE RESTRICTION; DIETARY RESTRICTION; OXIDATIVE STRESS; CONTROLLED-TRIAL; RISK-FACTORS; CELL-GROWTH; IN-VIVO; 2-DEOXYGLUCOSE; GLUCOSE; EXERCISE AB Calorie restriction (CR). the Purposeful reduction of energy intake with maintenance of adequate micronutrient intake, is well known to extend the lifespan of laboratory animals. Compounds like 2-deoxy-D-glucose (2DG) that can recapitulate the metabolic effects of CR are of great interest for their potential to extend lifespan. 2DG treatment has been shown to have potential therapeutic benefits for treating cancer and seizures. 2DG has also recapitulated some hallmarks of the CR phenotype including reduced body temperature and circulating insulin in short-term rodent trials, but one chronic feeding study in rats found toxic effects. The present studies were performed to further explore the long-term effects of 2DG in vivo. First we demonstrate that 2DG increases mortality of male Fischer-344 rats. Increased incidence of pheochromocytoma in the adrenal medulla was also noted in the 2DG treated rats. We reconfirm the cardiotoxicity of 2DG in a 6-week follow-up study evaluating male Brown Norway Fats and a natural form of 2DG in addition to again examining effects in Fischer-344 rats and the original synthetic 2DG. High levels of both 2DG Sources reduced weight gain secondary to reduced food intake in both strains. Histopathological analysis of the hearts revealed increasing vacuolarization of cardiac myocytes with dose, and tissue staining revealed the vacuoles were free of both glycogen and lipid. We did, however, observe higher expression of both cathepsin D and LC3 in the hearts of 2DG-treated rats which indicates an increase in autophagic flux. Although a remarkable CR-like phenotype can be reproduced with 2DG treatment, the ultimate toxicity of 2DG seriously challenges 2DG as a potential CR mimetic in mammals and also raises concerns about other therapeutic applications of the compound. Published by Elsevier Inc. C1 [Minor, Robin K.; Sossong, Alex M.; Spangler, Edward L.; de Cabo, Rafael; Mattison, Julie A.] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Smith, Daniel L., Jr.] Univ Alabama, Dept Nutr Sci, Birmingham, AL 35294 USA. [Kaushik, Susmita] Albert Einstein Coll Med, Marion Bessin Liver Res Ctr, Dept Dev & Mol Biol, Bronx, NY 10461 USA. [Kaushik, Susmita] Albert Einstein Coll Med, Marion Bessin Liver Res Ctr, Dept Anat & Struct Biol, Bronx, NY 10461 USA. [Poosala, Suresh] NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. [Roth, George S.] GeroScience Inc, Pylesville, MD 21132 USA. [Lane, Mark] Medimmune LLC, Gaithersburg, MD 20878 USA. [Allison, David B.] Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. [Ingram, Donald K.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA 70808 USA. RP Mattison, JA (reprint author), NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. EM donald.ingram@pbrc.edu; mattisonj@mail.nih.gov RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; Allison, David/0000-0003-3566-9399; , rafael/0000-0003-2830-5693 FU National Institute on Aging; National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. We would like to acknowledge the generous gift of 2DG from Regent Chemical Products and we also want to thank Dr. Deborah A. Banas of the Experimental Pathology Laboratories, Inc., for her careful pathological analysis of the rats in the survival study. None of the authors have any conflict of interest to disclose. NR 38 TC 47 Z9 48 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAR 15 PY 2010 VL 243 IS 3 BP 332 EP 339 DI 10.1016/j.taap.2009.11.025 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 567IZ UT WOS:000275441600007 PM 20026095 ER PT J AU Pecon-Slattery, J AF Pecon-Slattery, Jill TI Special Issue 9th International Feline Retrovirus Research Symposium 2008 Preface SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Editorial Material C1 NCI, Lab Genom Divers, NIH, Frederick, MD 21701 USA. RP Pecon-Slattery, J (reprint author), NCI, Lab Genom Divers, NIH, Frederick, MD 21701 USA. EM SlatterJ@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD MAR 15 PY 2010 VL 134 IS 1-2 SI SI BP 1 EP 2 DI 10.1016/j.vetimm.2009.10.002 PG 2 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 569TV UT WOS:000275625700001 PM 19931187 ER PT J AU Luttge, BG Freed, EO AF Luttge, Benjamin G. Freed, Eric O. TI FIV Gag: Virus assembly and host-cell interactions SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article; Proceedings Paper CT 9th International Feline Retrovirus Research Symposium CY AUG 24-27, 2008 CL Vienna, AUSTRIA DE FIV; HIV-1; Gag; Viral late domains; ESCRT; Virus-cell interactions ID HUMAN-IMMUNODEFICIENCY-VIRUS; GP41 CYTOPLASMIC TAIL; ROUS-SARCOMA-VIRUS; STABLE MICROTUBULE FORMATION; LATE-BUDDING DOMAINS; YPXL LATE DOMAINS; CYCLOPHILIN-A; TYPE-1 GAG; MATRIX PROTEIN; NUCLEOCAPSID PROTEIN AB Infection of domestic cats with virulent strains of the feline immunodeficiency virus (FIV) leads to an acquired immunodeficiency syndrome (AIDS), similar to the pathogenesis induced in humans by infection with human immunodeficiency virus type I (HIV-1). Thus, FIV is a highly relevant model for anti-HIV therapy and vaccine development. FIV is not infectious in humans, so it is also a potentially effective non-toxic gene therapy vector. To make better use of this model, it is important to define the cellular machinery utilized by each virus to produce virus particles so that relevant similarities can be identified. It is well understood that all replication-competent retroviruses encode gag, pol, and env genes, which provide core elements for virus replication. As a result, most antiretroviral therapy targets pol-derived enzymes (protease, reverse transcriptase, and integrase) or env-derived glycoproteins that mediate virus attachment and entry. However, resistance to drugs against these targets is a persistent problem, and novel targets must be identified to produce more effective drugs that can either substitute or be combined with current therapy. Elements of the gag gene (matrix, capsid, nucleocapsid, and "late" domains) have yet to be exploited as antiviral targets, even though the Gag precursor polyprotein is self-sufficient for the assembly and release of virus particles from cells. This process is far better understood in primate lentiviruses, especially HIV-1. However, there has been significant progress in recent years in defining how FIV Gag is targeted to the cellular plasma membrane, assembles into virions, incorporates FIV Env glycoproteins, and utilizes host cell machinery to complete virus release. Recent discoveries of intracellular restriction factors that target HIV-1 and FIV capsids after virus entry have also opened exciting new areas of research. This review summarizes currently known interactions involving HIV-1 and FIV Gag that affect virus release, infectivity, and replication. Published by Elsevier B.V. C1 [Luttge, Benjamin G.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Bldg 535-Rm 108,1050 Boyles St, Frederick, MD 21702 USA. EM efreed@nih.gov FU Intramural NIH HHS [Z01 BC010776-01] NR 143 TC 9 Z9 9 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD MAR 15 PY 2010 VL 134 IS 1-2 SI SI BP 3 EP 13 DI 10.1016/j.vetimm.2009.10.003 PG 11 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 569TV UT WOS:000275625700002 PM 19910057 ER PT J AU VandeWoude, S Troyer, J Poss, M AF VandeWoude, Sue Troyer, Jennifer Poss, Mary TI Restrictions to cross-species transmission of lentiviral infection gleaned from studies of FIV SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article; Proceedings Paper CT 9th International Feline Retrovirus Research Symposium CY AUG 24-27, 2008 CL Vienna, AUSTRIA DE FIV; Cross-species infection; Feline; Lentivirus; Pathogenesis ID FELINE IMMUNODEFICIENCY VIRUS; POLYMERASE ALPHA-PRIMASE; SMALL RUMINANT LENTIVIRUSES; MHC CLASS-II; DOMESTIC CAT; PHYLOGENETIC ANALYSIS; NONHUMAN-PRIMATES; PUMA LENTIVIRUSES; TYPE-1 HIV-1; GAG PROTEINS AB More than 40 species of primates and over 20 species of cats harbor antibodies that sero-react to lentiviral antigens. In nearly all cases where viral genetic analysis has been conducted, each host species is infected with a unique lentivirus. Though lentivirus clades within a species can be substantially divergent, they are typically monophyletic within that species. A notable significant departure from this observation is apparent cross-species transmission of FIV between bobcats (Lynx rufus) and pumas (Puma concolor) in Southern California that has occurred at least three times; evidence from one bobcat sequence suggests this cross-over may have also occurred in Florida between bobcats and the endangered Florida panther. Several other isolated reports demonstrate cross-species transmission of FIV isolates among captive animals housed in close proximity, and it is well established that HIV-1 and HIV-2 arose from human contact with SIN-infected non-human primates. Using an experimental model, we have determined that domestic cats (Felis catus) are susceptible to FIvs originating from pumas or lions. While infections are initially replicative, and animals seroconvert, within a relatively short period of time circulating virus is reduced to nearly undetectable levels in a majority of animals. This diminution of viral load is proportional to initial viral peak. Although viral reservoirs can be identified in gastrointestinal tissues, most viral genomes recovered peripherally are highly mutated, suggesting that the non-adapted host successfully inhibits normal viral replication, leading to replication incompetent viral progeny. Mechanisms possible for such restriction of cross-species infections in natural settings include: (1) Lack of contact conducive to lentiviral transmission between infected and shedding animals of different species; (2) Lack of suitable receptor repertoire to allow viral entry to susceptible cells of a new species; (3) Cellular machinery in the new host sufficiently divergent from the primary host to support viral replication (i.e. passive unfacilitated viral replication); (4) Intracellular restriction mechanisms present in the new host that is able to limit viral replication (i.e. active interrupted viral replication. These include factors that limit uncoating, replication, packaging, and virion release); (5) Unique ability of new host to raise sterilizing adaptive immunity, resulting in aborted infection and inability to spread infections among con-specifics; or (6) Production of defective or non-infectious viral progeny that lack cellular cofactors to render them infectious to con-specifics (i.e. particles lacking appropriate cellular components in viral Env to render them infectious to other animals of the same species). Data to support or refute the relative importance of each of these possibilities is described in this review. Insights based on our in vivo cross-species model suggest intracellular restriction mechanisms effectively inhibit rapid inter-specific transmission of lentiviruses. Further, limited contact both within and between species in natural populations is highly relevant to limiting the opportunity for spread of FIV strains. Studies of naturally occurring SIV and innate host restriction systems suggest these same two mechanisms are significant factors inhibiting widespread cross-species transmission of lentiviruses among primate species as well. (C) 2009 Elsevier B.V. All rights reserved. C1 [VandeWoude, Sue] Colorado State Univ, Dept Microbiol, Ft Collins, CO 80523 USA. [Troyer, Jennifer] NCI, SAIC Frederick, Lab Genom Divers, Frederick, MD 21702 USA. [Poss, Mary] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. RP VandeWoude, S (reprint author), Colorado State Univ, Dept Microbiol, Ft Collins, CO 80523 USA. EM suev@lamar.colostate.edu; jtroyer@ncifcrc.gov; mposs@bx.psu.edu RI Troyer, Jennifer/B-8415-2012 FU NHLBI NIH HHS [R01 HL092791-05A2, R01 HL092791]; NIAID NIH HHS [R01 AI052055, R01 AI052055-04] NR 75 TC 17 Z9 17 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD MAR 15 PY 2010 VL 134 IS 1-2 SI SI BP 25 EP 32 DI 10.1016/j.vetimm.2009.10.005 PG 8 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 569TV UT WOS:000275625700004 PM 19896218 ER PT J AU Brown, MA Munkhtsog, B Troyer, JL Ross, S Sellers, R Fine, AE Swanson, WF Roelke, ME O'Brien, SJ AF Brown, Meredith A. Munkhtsog, Bariushaa Troyer, Jennifer L. Ross, Steve Sellers, Rani Fine, Amanda E. Swanson, William F. Roelke, Melody E. O'Brien, Stephen J. TI Feline immunodeficiency virus (FIV) in wild Pallas' cats SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article; Proceedings Paper CT 9th International Feline Retrovirus Research Symposium CY AUG 24-27, 2008 CL Vienna, AUSTRIA DE FIV; Pallas' cat; Evolution; Histopathology; Felidae ID AFRICAN LIONS; SEQUENCE ALIGNMENT; OTOCOLOBUS-MANUL; DOMESTIC CAT; DIVERGENCE; INFECTION; TRANSMISSION; ORGANIZATION; POPULATION; PATTERNS AB Feline immunodeficiency virus (FIV), a feline lentivirus related to HIV, causes immune dysfunction in domestic and wild cats. The Pallas' cat is the only species from Asia known to harbor a species-specific strain of FIV designated FIV(Oma) in natural populations. Here, a 25% seroprevalence of FIV is reported from 28 wild Mongolian Pallas' cats sampled from 2000 to 2008. Phylogenetic analysis of proviral RT-Pol from eight FIV(Oma) isolates from Mongolia, Russia, China and Kazakhstan reveals a unique monophyletic lineage of the virus within the Pallas' cat population, most closely related to the African cheetah and leopard FIV strains. Histopathological examination of lymph node and spleen from infected and uninfected Pallas' cats suggests that FIV(Oma) causes immune depletion in its' native host. (C) 2009 Elsevier B.V. All rights reserved. C1 [Brown, Meredith A.; O'Brien, Stephen J.] NCI, Lab Genom Divers, Frederick, MD 21702 USA. [Munkhtsog, Bariushaa] Mongolian Acad Sci, Inst Biol, Ulaanbaatar 51, Bzd, Mongol Peo Rep. [Troyer, Jennifer L.; Roelke, Melody E.] SAIC Frederick Inc, Lab Genom Divers, Frederick, MD 21702 USA. [Ross, Steve] Univ Bristol, Sch Biol Sci, Bristol BS8 1UG, Avon, England. [Sellers, Rani] Yeshiva Univ, Albert Einstein Coll Med, Dept Pathol, Bronx, NY USA. [Fine, Amanda E.] Mongolia Country Program, Wildlife Conservat Soc, Ulaanbaatar 211238, Mongol Peo Rep. [Swanson, William F.] Ctr Conservat & Res Endangered Wildlife, Cincinnati, OH 45220 USA. RP Brown, MA (reprint author), NCI, Lab Genom Divers, Frederick, MD 21702 USA. EM brownmer@gmail.com RI Troyer, Jennifer/B-8415-2012 FU Intramural NIH HHS [Z01 BC010537-06]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 25 TC 9 Z9 10 U1 0 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD MAR 15 PY 2010 VL 134 IS 1-2 SI SI BP 90 EP 95 DI 10.1016/j.vetimm.2009.10.014 PG 6 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 569TV UT WOS:000275625700013 PM 19926144 ER PT J AU Bisht, H Brown, E Moss, B AF Bisht, Himani Brown, Erica Moss, Bernard TI Kinetics and intracellular location of intramolecular disulfide bond formation mediated by the cytoplasmic redox system encoded by vaccinia virus SO VIROLOGY LA English DT Article DE Protein disulfide bonds; Poxvirus morphogenesis; Viral membrane ID MEMBRANE-PROTEIN; L1 PROTEIN; MONOCLONAL-ANTIBODIES; ENDOPLASMIC-RETICULUM; VIRION MORPHOGENESIS; PATHWAY; ENTRY; GENE; GLUTAREDOXIN; VACCINATION AB Poxviruses encode a redox system for intramolecular disulfide bond formation in cytoplasmic domains of viral proteins. Our objectives were to determine the kinetics and intracellular location of disulfide bond formation. The vaccinia virus L1 myristoylated membrane protein, used as an example, has three intramolecular disulfide bonds. Reduced and disulfide-bonded forms of L1 were distinguished by electrophoretic mobility and reactivity with monoclonal and polyclonal antibodies. Because disulfide bonds formed during 5 min pulse labeling with radioactive amino acids, a protocol was devised in which dithiothreitol was present at this step. Disulfide bond formation was detected by 2 min after removal of reducing agent and was nearly complete in 10 min. When the penultimate glycine residue was mutated to prevent myristoylation, L1 was mistargeted to the endoplasmic reticulum and disulfide bond formation failed to occur. These data suggested that viral membrane association was required for oxidation of L1, providing specificity for the process. Published by Elsevier Inc. C1 [Bisht, Himani; Brown, Erica; Moss, Bernard] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20894 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bethesda, MD 20894 USA. EM bmoss@nih.gov FU Division of Intramural Research, MAID, NIH FX We thank Norman Cooper and Catherine Cotter of NIAID for providing cell cultures. The research was supported by the Division of Intramural Research, MAID, NIH. NR 27 TC 4 Z9 5 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 15 PY 2010 VL 398 IS 2 BP 187 EP 193 DI 10.1016/j.virol.2009.11.026 PG 7 WC Virology SC Virology GA 557KZ UT WOS:000274669300005 PM 20042211 ER PT J AU Derbala, M Shebl, FM Rashid, A Amer, A Bener, A AF Derbala, Moutaz Shebl, Fatma M. Rashid, Awad Amer, Aliaa Bener, Abdulbari TI Microalbuminuria in hepatitis C-genotype 4: Effect of pegylated interferon and ribavirin SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Hepatitis C virus; Genotype; Kidney diseases; Albuminuria; Proteinuria; Peginterferon alpha-2a; Ribavirin ID DIABETES-MELLITUS; VIRUS-INFECTION; KIDNEY-DISEASE; RISK-FACTORS; GLOMERULONEPHRITIS; ASSOCIATION; PREVALENCE; OUTCOMES AB AIM: To study the relation between hepatitis C virus (HCV) genotype 4 and microalbuminuria and renal impairment in relation to hepatic histology, and viremia in the absence of cryoglobulinemia, and to examine the effect of treatment on microalbuminuria. METHODS: Three hundred subjects, including 233 HCV genotype-4 infected patients, were tested for cryoglobulinemia, microalbuminuria, albumin creatinine ratio (ACR), urea, creatinine, and estimated glomerular filtration rate (eGFR). The parameters were measured again in the HCV patients after 48 wk of treatment with pegylated interferon and ribavirin. RESULTS: Significantly higher levels of microalbuminuria were detected in HCV-positive patients compared to HCV-negative controls (median 9.5 vs 5.9, respectively, Kruskal-Wallis P = 0.017). Log microalbuminuria was significantly correlated with hepatic inflammation (r = 0.13, P = 0.036) and fibrosis (r 0.12, P = 0.061), but not with viral load (r = -0.03, P 0.610), or alanine transaminase (r = -0.03, P = 0.617). Diabetes mellitus neither significantly moderated (chi(2) = 0.13, P = 0.720), nor mediated (Sobel test P = 0.49) the HCV effect. HCV status was significantly associated with log microalbuminuria (chi(2) = 4.97, P = 0.026), adjusting for age, gender, diabetes, cryoglobulinemia, urea and creatinine. A positive HCV status was not significantly associated with low eGFR (< 60 mL/min every 1.73 m(2)) [odds ratio (OR): 0.5, 95% confidence interval (CI): 0.2-1.4], nor with high ACR (OR: 1.7, 95% CI: 0.7-4.1). End-of-treatment response (ETR) was achieved in 51.9% of patients. Individuals with ETR had significantly lower microalbuminuria post-treatment (chi(2) = 8.19, P = 0.004). CONCLUSION: HCV affected the development of microalbuminuria independent of diabetes or cryoglobulinemia. Combination therapy of pegylated interferon-ribavirin had a positive effect in reducing microalbuminuria. (C) 2010 Baishideng. All rights reserved. C1 [Derbala, Moutaz] Hamad Med Corp, Dept Gastroenterol & Hepatol, Doha 00974, Qatar. [Derbala, Moutaz] Weill Cornell Med Coll, Dept Med, Doha 00974, Qatar. [Shebl, Fatma M.] NCI, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Shebl, Fatma M.] Natl Liver Inst, Epidemiol Branch, Menoufia 32511, Egypt. [Rashid, Awad] Hamad Med Corp, Dept Nephrol, Doha 00974, Qatar. [Amer, Aliaa] Hamad Med Corp, Dept Lab Med & Histopathol, Hematol Sect, Doha 00974, Qatar. [Bener, Abdulbari] Hamad Med Corp, Dept Med Stat & Epidemiol, Doha 00974, Qatar. RP Derbala, M (reprint author), Hamad Med Corp, Dept Gastroenterol & Hepatol, POB 3050, Doha 00974, Qatar. EM moutazderbala@hotmail.com NR 21 TC 4 Z9 4 U1 0 U2 1 PU W J G PRESS PI BEIJING PA APT 1066, YISHOU GARDEN, NO 58, NORTH LANGXINZHUANG RD, PO BOX 2345, BEIJING 100023, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD MAR 14 PY 2010 VL 16 IS 10 BP 1226 EP 1231 DI 10.3748/wjg.v16.i10.1226 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 571OS UT WOS:000275764200008 PM 20222166 ER PT J AU Jacobson, DL Lindsey, JC Gordon, CM Moye, J Hardin, DS Mulligan, K Aldrovandi, GM AF Jacobson, Denise L. Lindsey, Jane C. Gordon, Catherine M. Moye, Jack Hardin, Dana S. Mulligan, Kathleen Aldrovandi, Grace M. CA Pediat AIDS Clinical Trials Grp P1 TI Total body and spinal bone mineral density across Tanner stage in perinatally HIV-infected and uninfected children and youth in PACTG 1045 SO AIDS LA English DT Article DE antiretroviral; bone mass; children; DXA; perinatal HIV infection; Tanner stage ID QUANTITATIVE COMPUTED-TOMOGRAPHY; IMMUNODEFICIENCY-VIRUS-INFECTION; PEDIATRIC OFFICIAL POSITIONS; ANTIRETROVIRAL THERAPY; PROTEASE INHIBITOR; RANDOMIZED-TRIAL; ADOLESCENTS; STRENGTH; DISEASE; PUBERTY AB Objective: To characterize total body bone mineral content (BMC) and total body and spinal bone mineral density (BMD) in perinatally HIV-infected and uninfected children/youth across puberty. Design: HIV-infected (7-24 years) were randomly selected from six strata based on Tanner stage/protease inhibitor use. HIV-uninfected were frequency-matched by Tanner group and sociodemographic background to the HIV-infected. Methods: Dual-energy X-ray absorptiometry (DXA) measured BMC and BMD. Linear regression models tested differences in bone outcomes by HIV and the interaction of HIV by Tanner group (1-2, 3-4, 5). Models were performed separately by sex and adjusted for DXA scanner, race/ethnicity, height, age and lean body mass. Results: HIV-infected (N = 236) and uninfected (N = 143) were comparable on sex and race/ethnicity. HIV-infected were slightly older (median 12.6 versus 11.9 years). In adjusted models, HIV-infected males had significantly lower total body BMC and total body and spinal BMD at Tanner 5, lower BMC at Tanner 3-4 and similar BMC and BMD at Tanner 1-2, compared to HIV-uninfected males. HIV-infected and uninfected girls did not differ significantly on any bone outcome, but there was a marginally significant interaction of HIV and Tanner group for spinal BMD. Kaletra/ritonavir was associated with lower BMC and total body BMD and nevirapine was associated with higher spinal BMD in a model with all HIV-infected. Conclusions: Perinatally HIV-infected males showed more evidence of lower bone density especially in the final stage of pubertal development than HIV-infected girls and they may be at increased risk for bone disease during adulthood. (C) 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins C1 [Jacobson, Denise L.; Lindsey, Jane C.] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Gordon, Catherine M.] Childrens Hosp, Dept Adolescent Med, Boston, MA 02115 USA. [Gordon, Catherine M.] Childrens Hosp, Dept Endocrinol, Boston, MA 02115 USA. [Moye, Jack] NICHHD, Bethesda, MD 20892 USA. [Hardin, Dana S.] Nationwide Childrens Hosp, Columbus, OH USA. [Mulligan, Kathleen] Univ Calif San Francisco, San Francisco Gen Hosp, San Francisco, CA USA. [Aldrovandi, Grace M.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. RP Jacobson, DL (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, 651 Huntington Ave, Boston, MA 02115 USA. EM jacobson@sdac.harvard.edu OI moye, john/0000-0001-9976-8586 FU National Institute of Allergy and Infectious Diseases (NIAID) [U01 AI068632]; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); National Institute of Mental Health (NIMH) [AI068632]; National Institute of Allergy and Infectious Diseases [5 U01 AI41110]; Pediatric AIDS Clinical Trials Group (PACTG); IMPAACT Group [1 U01 AI068616]; NICHD [N01-DK-9-001/HHSN267200800001C]; National Center for Research Resources, NIH [MO1 RR00069]; [5U01A1068616]; [1 U01 AI068632-01] FX All authors were involved in the design phase of the study and contributed intellectually to writing the manuscript. J.C.L., D.L.J.,G. M. A. K. M. and C. M. G. participated during the analytic phase. This work was supported by 5U01A1068616 (D. L. J., J. C. L.) and 1 U01 AI068632-01 (G. M. A.).; Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) (U01 AI068632), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute of Mental Health (NIMH) (AI068632). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was supported by the Statistical and Data Analysis Center at Harvard School of Public Health, under the National Institute of Allergy and Infectious Diseases cooperative agreement #5 U01 AI41110 with the Pediatric AIDS Clinical Trials Group (PACTG) and #1 U01 AI068616 with the IMPAACT Group. Support of the sites was provided by the National Institute of Allergy and Infectious Diseases (NIAID) the NICHD International and Domestic Pediatric and Maternal HIV Clinical Trials Network funded by NICHD (contract number N01-DK-9-001/HHSN267200800001C).; The authors would like to thank the children who participated in this study, their families and the entire protocol 1045 team for their contributions and support. We would also like to thank Barb Heckman for outstanding support. The following sites and individuals have contributed to this study: Children's Hospital of Chicago; Tulane University School of Medicine, Charity Hospital of New Orleans: M. Silio, T. Alchediak, C. Borne, S. Bradford; SUNY Health Science Center, Stony Brook: S. Nachman, D. Ferraro, J. Perillo, S. Muniz; University of Puerto Rico; Harlem Hospital; NYU Medical Center/Bellevue; City Hospital at San Juan; New Jersey Medical School; Jacobi Medical Center; St. Jude Children's Hospital: M. Donohoe, N. Patel, S. Kaste, J. Utech; Boston Children's Hospital; University of North Carolina at Chapel Hill; University of South Florida Physicians Group; The Children's Hospital, University of Colorado, Denver: E. Barr, J. Maes, B. McFarland, S. Paul, Grant Number MO1 RR00069, GCRC Program, National Center for Research Resources, NIH; Medical College of Georgia; Duke University Medical Center: J. Hurwitz, J. Simonetti, M. Donnelly, C. Mathison; Texas Children's Hospital/Baylor; University of California San Francisco Medical Center and PCRC (RR001271); Yale University School of Medicine: W. Andiman, L. Hurst, S. Romano; Los Angeles County Medical/University of Southern California; Lincoln Medical and Mental Health; University of Rochester: G. Weinberg, B. Murante, S. Laverty; Metropolitan Hospital Center; Long Beach Memorial Medical Center; Johns Hopkins University Hospital; UCSD Medical Center; Children's Hospital at SUNY Downstate; Bronx- Lebanon Hospital; Harbor General - UCLA Medical Center; Children's National Medical Center - D. C.: D. Dobbins, T. Peron, D. Wimbley, H. Spiegel; Children's Diagnostic and Treatment Center of South Florida; Robert Wood Johnson University Hospital; Howard University Hospital; University of Florida at Gainesville; Mt. Sinai Hospital Medical Center, Women's and Children's HIV Program; SUNY Health Science Center, Syracuse; University of Alabama, Birmingham School of Medicine: R. Pass, M. Crain, N. Beatty, H. Charlton. NR 47 TC 34 Z9 34 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 EI 1473-5571 J9 AIDS JI Aids PD MAR 13 PY 2010 VL 24 IS 5 BP 687 EP 696 DI 10.1097/QAD.0b013e328336095d PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 563QQ UT WOS:000275148900008 PM 20168204 ER PT J AU Negus, SS Banks, ML Folk, JE Rice, KC AF Negus, S. S. Banks, M. L. Folk, J. E. Rice, K. C. TI Modulation of delta opioid agonist-induced antinociception by repeated morphine pretreatment in rhesus monkeys SO LIFE SCIENCES LA English DT Article DE Delta opioid agonist; Delta opioid receptor; Antinociception; SNC80; Morphine; Monkey ID DORSAL-ROOT GANGLIA; CHRONIC INFLAMMATION; THERMAL NOCICEPTION; MU; RECEPTORS; SNC80; RAT; TRAFFICKING; PAIN; HYPERALGESIA AB Aims: Repeated treatment with morphine increases antinociceptive effects of delta opioid agonists in rodents by a mechanism that may involve increased cell-surface expression of delta receptors. The present study evaluated effects of repeated morphine treatment on behavioral effects of the delta agonist SNC80 and the mu agonist fentanyl in rhesus monkeys. Main methods: In an assay of schedule-controlled responding, three monkeys responded for food reinforcement under a fixed-ratio 30 schedule. In an assay of thermal nociception, tail-withdrawal latencies were evaluated in three monkeys using thermal stimulus intensities of 48 and 54 degrees C. In both assays, the effects of SNC80 (0.032-3.2 mg/kg) and fentanyl (0.001-0.056 mg/kg) were evaluated after repeated treatment with saline or a regimen of morphine doses modeled on the regimen that enhanced delta agonist antinociception and apparent delta receptor availability in previous rodent studies. Key findings: Both SNC80 and fentanyl dose-dependently decreased rates of schedule-controlled responding, and repeated morphine treatment did not significantly alter these effects. In the assay of thermal nociception, SNC80 had little effect on tail-withdrawal latencies from water heated to 48 or 54 degrees C, whereas fentanyl increased tail-withdrawal latencies at both temperatures. Repeated morphine tended to increase the antinociceptive effects of SNC80 and to decrease the antinociceptive effects of fentanyl, but these effects of repeated morphine were small and were significant only at the higher stimulus intensity (54 degrees C). Significance: These results provide limited support for the proposition that prior stimulation of mu receptors selectively increases the antinociceptive effects of delta agonists in rhesus monkeys. (C) 2010 Elsevier Inc. All rights reserved. C1 [Negus, S. S.; Banks, M. L.] Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23220 USA. [Folk, J. E.; Rice, K. C.] NIDA, Chem Biol Res Branch, Rockville, MD 20852 USA. [Folk, J. E.; Rice, K. C.] NIAAA, NIH, Rockville, MD 20852 USA. RP Negus, SS (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, 410 N 12th St,POB 980613, Richmond, VA 23298 USA. EM ssnegus@vcu.edu; mbanks3@vcu.edu; kennerr@mail.nih.gov RI Banks, Matthew/K-4429-2014 OI Banks, Matthew/0000-0003-4949-5246 FU National Institute on Drug Abuse [R01-DA11460]; National Institutes of Health; National Institute on Drug Abuse; National Institute on Alcohol Abuse and Alcoholism FX This work was supported by Grant R01-DA11460 from the National Institute on Drug Abuse, National Institutes of Health. A portion of this work was also supported by the Intramural Research Programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism. These funding sources had no involvement in any aspect of the study. The authors would like to thank Katrina Schrode and Ember Morrissey for expert technical assistance. NR 37 TC 4 Z9 4 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD MAR 13 PY 2010 VL 86 IS 11-12 BP 385 EP 392 DI 10.1016/j.lfs.2010.01.006 PG 8 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 567ZP UT WOS:000275489900002 PM 20096291 ER PT J AU Hattacharjee, S Wang, ZM Ciampa, J Kraft, P Chanock, S Yu, K Chatterjee, N AF Hattacharjee, Samsiddhi Wang, Zhaoming Ciampa, Julia Kraft, Peter Chanock, Stephen Yu, Kai Chatterjee, Nilanjan TI Using Principal Components of Genetic Variation for Robust and Powerful Detection of Gene-Gene Interactions in Case-Control and Case-Only Studies SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; BREAST-CANCER; POPULATION STRATIFICATION; ENVIRONMENT INDEPENDENCE; MODELS; SUSCEPTIBILITY; REGRESSION; EPISTASIS; SELECTION; ALLELES AB Many popular methods for exploring gene-gene interactions, including the case-only approach, rely on the key assumption that physically distant loci are in linkage equilibrium in the underlying population. These methods utilize the presence of correlation between unlinked loci in a disease-enriched sample as evidence of interactions among the loci in the etiology of the disease. We use data from the CGEMS case-control genome-wide association study of breast cancer to demonstrate empirically that the case-only and related methods have the potential to create large-scale false positives because of the presence Of Population stratification (PS) that creates long-range linkage disequilibrium in the genome. We show that the bias can be removed by considering parametric and nonparametric methods that assume gene-gene independence between unlinked loci, not in the entire population, but only conditional on Population substructure that can be uncovered based on the principal components of a suitably large panel of PS markers. Applications in the CGEMS study as well as simulated data show that the proposed methods are robust to the presence of population stratification and are yet much more powerful, relative to standard logistic regression methods that are also commonly used as robust alternatives to the case-only type methods. C1 [Hattacharjee, Samsiddhi; Ciampa, Julia; Yu, Kai; Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. [Wang, Zhaoming] NCI, Adv Technol Ctr, NIH, Rockville, MD 20852 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Chanock, Stephen] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Gaithersburg, MD 20877 USA. RP Chatterjee, N (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. EM chattern@mail.nih.gov FU National Cancer Institute Intramural Program; National Heart, Lung, and Blood Institute; NIH [P01 CA87969] FX The authors would like to acknowledge Dr. Jay Sethuraman for helpful discussions on matching algorithms and Dr. B.J. Stone for proof reading and editing the manuscript. The research of S.B., J.C., K.Y., S.C., and N.C. was supported by the National Cancer Institute Intramural Program and a Gene-Environment Initiative (GEI) grant from the National Heart, Lung, and Blood Institute. The research of P.K. was Supported by NIH P01 CA87969. We would also like to thank three anonymous reviewers for their helpful comments to improve the manuscript. This Study utilized the high-performance Computational capabilities of the StatPro Linux cluster at the National Cancer Institute and the Bio-wulf Linux cluster at the National Institutes of Health, Bethesda, MD. NR 29 TC 0 Z9 1 U1 0 U2 0 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 MAR 12 PY 2010 VL 86 IS 3 BP 331 EP 342 DI 10.1016/j.ajhg.2010.01.026 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 570LG UT WOS:000275678800005 ER PT J AU Kennerson, ML Nicholson, GA Kaler, SG Kowalski, B Mercer, JFB Tang, JR Llanos, RM Chu, SN Takata, RI Speck-Martins, CE Baets, J Almeida-Souza, L Fischer, D Timmerman, V Taylor, PE Scherer, SS Ferguson, TA Bird, TD De Jonghe, P Feely, SME Shy, ME Garbern, JY AF Kennerson, Marina L. Nicholson, Garth A. Kaler, Stephen G. Kowalski, Bartosz Mercer, Julian F. B. Tang, Jingrong Llanos, Roxana M. Chu, Shannon Takata, Reinaldo I. Speck-Martins, Carlos E. Baets, Jonathan Almeida-Souza, Leonardo Fischer, Dirk Timmerman, Vincent Taylor, Philip E. Scherer, Steven S. Ferguson, Toby A. Bird, Thomas D. De Jonghe, Peter Feely, Shawna M. E. Shy, Michael E. Garbern, James Y. TI Missense Mutations in the Copper Transporter Gene ATP7A Cause X-Linked Distal Hereditary Motor Neuropathy SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SPINAL MUSCULAR-ATROPHY; OCCIPITAL-HORN-SYNDROME; MARIE-TOOTH-DISEASE; MENKES-DISEASE; NEURON DISEASE; CANDIDATE GENE; DEFICIENCY MYELONEUROPATHY; WILSON-DISEASE; PROTEIN; TRAFFICKING AB Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mutated in patients with Menkes disease, a severe infantile-onset neurodegenerative condition. We identified two unique ATP7A missense mutations (p.P1386S and p.T9941) in males with distal motor neuropathy in two families. These molecular alterations impact highly conserved amino acids in the carboxyl half of ATP7A and do not directly involve the copper transporter's known critical functional domains. Studies of p.P1386S revealed normal ATP7A mRNA and protein levels, a defect in ATP7A trafficking, and partial rescue of a S. cerevisiae copper transport knockout. Although ATP7A mutations are typically associated with severe Menkes disease or its milder allelic variant, occipital horn syndrome, we demonstrate here that certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency. This previously unrecognized genotype-phenotype correlation suggests an important role of the ATP7A copper transporter in motor-neuron maintenance and function. C1 [Kennerson, Marina L.; Nicholson, Garth A.; Kowalski, Bartosz; Chu, Shannon] Univ Sydney, ANZAC Res Inst, Northcott Neurosci Lab, Concord, Australia. [Kennerson, Marina L.; Nicholson, Garth A.] Concord Hosp, Mol Med Lab, Concord, Australia. [Kaler, Stephen G.; Tang, Jingrong] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Unit Human Copper Metab, Program Mol Med, NIH, Bethesda, MD USA. [Mercer, Julian F. B.; Llanos, Roxana M.; Taylor, Philip E.] Deakin Univ, Sch Life & Environm Sci, Ctr Cellular & Mol Biol, Burwood, Australia. [Takata, Reinaldo I.; Speck-Martins, Carlos E.] Sarah Network Rehabil Hosp, Brasilia, DF, Brazil. [Baets, Jonathan; Almeida-Souza, Leonardo; Timmerman, Vincent; De Jonghe, Peter] Flanders Inst Biotechnol, Dept Mol Genet, Antwerp, Belgium. [Baets, Jonathan; Almeida-Souza, Leonardo; Timmerman, Vincent; De Jonghe, Peter] Univ Antwerp, B-2020 Antwerp, Belgium. [Fischer, Dirk] Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland. [Fischer, Dirk] Univ Childrens Hosp Basel, Dept Neuropediat, Basel, Switzerland. [Scherer, Steven S.; Ferguson, Toby A.] Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. [Bird, Thomas D.] Univ Washington, Sch Med, Dept Neurol, Seattle, WA USA. [Bird, Thomas D.] Univ Washington, Sch Med, Dept Med Genet, Seattle, WA USA. [Bird, Thomas D.] Vet Affairs Puget Sound Hlth Care Syst, Seattle, WA USA. [Feely, Shawna M. E.; Shy, Michael E.; Garbern, James Y.] Wayne State Univ, Sch Med, Dept Neurol, Detroit, MI 48201 USA. [Feely, Shawna M. E.; Shy, Michael E.; Garbern, James Y.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48201 USA. RP Kennerson, ML (reprint author), Univ Sydney, ANZAC Res Inst, Northcott Neurosci Lab, Concord, Australia. EM marinak@anzac.edu.au RI Almeida-Souza, Leonardo/C-3437-2011; Kennerson, Marina/B-5058-2014 FU Motor Neuron Disease Research Institute of Australia; National Health and Medical Research Council of Australia; Intramural Research program of the National Institute of Child Health and Human Development; Methusalem project of the University of Antwerp; Fund for Scientific Research (FWO-Flanders); Medical Foundation Queen Elisabeth (GSKE); Interuniversity Attraction Poles program [P6/43]; Belgian Federal Science Policy Office (BELSPO) FX We thank the patients and family members for their participation in this study. We thank Rabia Chaudhry and Alison Blake for their assistance with Cell Cultures and Jose Centeno for fibroblast copper measurements. This work was supported by grants from the Motor Neuron Disease Research Institute of Australia, the National Health and Medical Research Council of Australia, the Intramural Research program of the National Institute of Child Health and Human Development, the Methusalem project of the University of Antwerp, the Fund for Scientific Research (FWO-Flanders), the Medical Foundation Queen Elisabeth (GSKE), and the Interuniversity Attraction Poles program (P6/43) of the Belgian Federal Science Policy Office (BELSPO). J.B. and L.S. are Supported by PhD fellowships of the FWO-Flanders and the University of Antwerp, respectively. We thank Professor David Handelsman for his useful constructive comments on the manuscript. NR 47 TC 79 Z9 81 U1 0 U2 4 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 MAR 12 PY 2010 VL 86 IS 3 BP 343 EP 352 DI 10.1016/j.ajhg.2010.01.027 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 570LG UT WOS:000275678800006 PM 20170900 ER PT J AU Rehman, AU Morell, RJ Belyantseva, IA Khan, SY Boger, ET Shahzad, M Ahmed, ZM Riazuddin, S Khan, SN Riazuddin, S Friedman, TB AF Rehman, Atteeq Ur Morell, Robert J. Belyantseva, Inna A. Khan, Shahid Y. Boger, Erich T. Shahzad, Mohsin Ahmed, Zubair M. Riazuddin, Saima Khan, Shaheen N. Riazuddin, Sheikh Friedman, Thomas B. TI Targeted Capture and Next-Generation Sequencing Identifies C9orf75, Encoding Taperin, as the Mutated Gene in Nonsyndromic Deafness DFNB79 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID AUTOSOMAL RECESSIVE DEAFNESS; COCHLEAR HAIR-CELLS; ANKLE-LINK COMPLEX; MYOSIN-XVA; GAMMA-ACTIN; PROTEIN; STEREOCILIA; MUTATIONS; DNA; BUNDLE AB Targeted genome capture combined with next-generation sequencing was used to analyze 2.9 Mb of the DFNB79 interval on chromosome 9q34.3, which includes 108 candidate genes. Genomic DNA from an affected member of a consanguineous family segregating recessive, nonsyndromic hearing loss was used to make a library of fragments covering the DFNB79 linkage interval defined by genetic analyses of four pedigrees. Homozygosity for eight previously unreported variants in transcribed sequences was detected by evaluating a library of 402,554 sequencing reads and was later confirmed by Sanger sequencing. Of these variants, six were determined to be polymorphisms in the Pakistani population, and one was in a noncoding gene that was subsequently excluded genetically from the DFNB79 linkage interval. The remaining variant was a nonsense mutation in a predicted gene, C9orf75, renamed TPRN. Evaluation of the other three DFNB79-linked families identified three additional frameshift Mutations, for a total of four truncating alleles of this gene. Although TPRN is expressed in many tissues, immunolocalization of the protein product in the mouse cochlea shows prominent expression in the taper region of hair cell stereocilia. Consequently, we named the protein taperin. C1 [Rehman, Atteeq Ur; Morell, Robert J.; Belyantseva, Inna A.; Boger, Erich T.; Friedman, Thomas B.] Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Rockville, MD 20850 USA. [Rehman, Atteeq Ur; Khan, Shahid Y.; Shahzad, Mohsin; Khan, Shaheen N.] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore, Pakistan. [Ahmed, Zubair M.] Cincinnati Childrens Hosp Res Fdn, Div Pediat Ophthalmol, Cincinnati, OH 45229 USA. [Ahmed, Zubair M.] Univ Cincinnati, Dept Ophthalmol, Cincinnati, OH 45229 USA. [Riazuddin, Saima] Childrens Hosp Res Fdn, Div Pediat Otolaryngol Head & Neck Surg, Cincinnati, OH 45229 USA. [Riazuddin, Saima] Childrens Hosp Res Fdn, Div Ophthalmol, Cincinnati, OH 45229 USA. [Riazuddin, Sheikh] Univ Hlth Sci, Allama Iqbal Med Coll, Lahore 54550, Pakistan. RP Friedman, TB (reprint author), Natl Inst Deafness & Other Commun Disorders, Mol Genet Lab, NIH, Rockville, MD 20850 USA. EM friedman@nidcd.nih.gov RI Nasim Khan, Shaheen/F-2135-2015; OI Morell, Robert/0000-0003-1537-7356 FU National Institute of Deafness and Other Communication Disorders [1 Z01 DC000039-12]; Higher Education Commission, Islamabad; Ministry of Science and Technology, Islamabad; International Center for Genetic Engineering and Biotechnology, Trieste [CRP/PAK08-01, 08/009] FX We are thankful to the family members who helped make this study possible. We thank Jonathan Bird, Byung Yoon Choi, Dennis Drayna, Meghan Drummond, Karen Friderici, Andrew Griffith, Changsoo Kang, Sue Lee, M. Hashirn Raza, Mary Vendetti, and Barbara Zwiesler. This work was supported by National Institutes of Health intramural funds from the National Institute of Deafness and Other Communication Disorders (1 Z01 DC000039-12) to T.B.F; by the Higher Education Commission, Islamabad; the Ministry of Science and Technology, Islamabad; and by the International Center for Genetic Engineering and Biotechnology, Trieste, project CRP/PAK08-01 (contract 08/009), to S.R. NR 36 TC 106 Z9 119 U1 1 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 MAR 12 PY 2010 VL 86 IS 3 BP 378 EP 388 DI 10.1016/j.ajhg.2010.01.030 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 570LG UT WOS:000275678800009 PM 20170899 ER PT J AU Woodard, GE Lopez, JJ Jardin, I Salido, GM Rosado, JA AF Woodard, Geoffrey E. Lopez, Jose J. Jardin, Isaac Salido, Gines M. Rosado, Juan A. TI TRPC3 Regulates Agonist-stimulated Ca2+ Mobilization by Mediating the Interaction between Type I Inositol 1,4,5-Trisphosphate Receptor, RACK1, and Orai1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OPERATED CALCIUM INFLUX; SMOOTH-MUSCLE-CELLS; PLASMA-MEMBRANE; STORE DEPLETION; CHANNEL FUNCTION; HUMAN PLATELETS; CELLULAR SIGNALS; TRIADIC PROTEINS; ARC CHANNELS; CRAC CHANNEL AB There is a body of evidence suggesting that Ca2+ handling proteins assemble into signaling complexes required for a fine regulation of Ca2+ signals, events that regulate a variety of critical cellular processes. Canonical transient receptor potential (TRPC) and Orai proteins have both been proposed to form Ca2+-permeable channels mediating Ca2+ entry upon agonist stimulation. A number of studies have demonstrated that inositol 1,4,5-trisphosphate receptors (IP(3)Rs) interact with plasma membrane TRPC channels; however, at present there is no evidence supporting the interaction between Orai proteins and IP(3)Rs. Here we report that treatment with thapsigargin or cellular agonists results in association of Orai1 with types I and II IP(3)Rs. In addition, we have found that TRPC3, RACK1 (receptor for activated protein kinase C-1), and STIM1 (stromal interaction molecule 1) interact with Orai1 upon stimulation with agonists. TRPC3 expression silencing prevented both the interaction of Orai1 with TRPC3 and, more interestingly, the association of Orai1 with the type I IP3R, but not with the type II IP3R, thus suggesting that TRPC3 selectively mediates interaction between Orai1 and type I IP3R. In addition, TRPC3 expression silencing attenuated ATP- and CCh-stimulated interaction between RACK1 and the type I IP3R, as well as Ca2+ release and entry. In conclusion, our results indicate that agonist stimulation results in the formation of an Orai1-STIM1-TRPC3-RACK1-type I IP3R complex, where TRPC3 plays a central role. This Ca2+ signaling complex might be important for both agonist-induced Ca2+ release and entry. C1 [Lopez, Jose J.; Jardin, Isaac; Salido, Gines M.; Rosado, Juan A.] Univ Extremadura, Cell Physiol Res Grp, Dept Physiol, Caceres 10071, Spain. [Woodard, Geoffrey E.] NIDDK, NIH, Bethesda, MD 20892 USA. RP Rosado, JA (reprint author), Univ Extremadura, Cell Physiol Res Grp, Dept Physiol, Caceres 10071, Spain. EM jarosado@unex.es RI Woodard, Geoffrey/A-8608-2009; Salido, Gines/A-4292-2009; rosado, juan/H-3488-2015; Jardin, Isaac/E-8310-2016; LOPEZ, JOSE/F-4602-2016 OI Salido, Gines/0000-0002-8687-2445; rosado, juan/0000-0002-9749-2325; Jardin, Isaac/0000-0003-4575-8264; LOPEZ, JOSE/0000-0002-5234-1478 FU Spanish Ministry of Science and Innovation [BFI2007-60104]; National Institutes of Health; Direccion General de Investigation (DGI) [BES-2005-6899, BFU2007-60104] FX This work was supported by Spanish Ministry of Science and Innovation Grant BFI2007-60104. This work was authored, in whole or in part, by National Institutes of Health staff.; 1Supported by Direccion General de Investigation (DGI) fellowship BES-2005-6899.; 2Supported by DGI fellowship BFU2007-60104. NR 60 TC 44 Z9 46 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 12 PY 2010 VL 285 IS 11 BP 8045 EP 8053 DI 10.1074/jbc.M109.033605 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567AE UT WOS:000275413800022 PM 20022948 ER PT J AU Baranova, IN Bocharov, AV Vishnyakova, TG Kurlander, R Chen, ZG Fu, D Arias, IM Csako, G Patterson, AP Eggerman, TL AF Baranova, Irina N. Bocharov, Alexander V. Vishnyakova, Tatyana G. Kurlander, Roger Chen, Zhigang Fu, Dong Arias, Irwin M. Csako, Gyorgy Patterson, Amy P. Eggerman, Thomas L. TI CD36 Is a Novel Serum Amyloid A (SAA) Receptor Mediating SAA Binding and SAA-induced Signaling in Human and Rodent Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACUTE-PHASE RESPONSE; C-REACTIVE PROTEIN; INTERLEUKIN-8 GENE-EXPRESSION; ARTHRITIS SYNOVIAL TISSUE; CORONARY-ARTERY-DISEASE; LOW-DENSITY-LIPOPROTEIN; B SCAVENGER RECEPTOR; N-TERMINAL KINASE; RHEUMATOID-ARTHRITIS; A-PROTEIN AB Serum amyloid A (SAA) is a major acute phase protein involved in multiple physiological and pathological processes. This study provides experimental evidence that CD36, a phagocyte class B scavenger receptor, functions as a novel SAA receptor mediating SAA proinflammatory activity. The uptake of Alexa Fluor (R) 488 SAA as well as of other well established CD36 ligands was increased 5-10-fold in HeLa cells stably transfected with CD36 when compared with mock-transfected cells. Unlike other apolipoproteins that bind to CD36, only SAA induced a 10-50-fold increase of interleukin-8 secretion in CD36-overexpressing HEK293 cells when compared with control cells. SAA-mediated effects were thermolabile, inhibitable by anti-SAA antibody, and also neutralized by association with high density lipoprotein but not by association with bovine serum albumin. SAA-induced cell activation was inhibited by a CD36 peptide based on the CD36 hexarelin-binding site but not by a peptide based on the thrombospondin-1-binding site. A pronounced reduction (up to 60-75%) of SAA- induced pro-inflammatory cytokine secretion was observed in cd36(-/-) rat macrophages and Kupffer cells when compared with wild type rat cells. The results of the MAPK phosphorylation assay as well as of the studies with NF-kappa B and MAPK inhibitors revealed that two MAPKs, JNK and to a lesser extent ERK1/2, primarily contribute to elevated cytokine production in CD36-overexpressing HEK293 cells. In macrophages, four signaling pathways involving NF-kappa B and three MAPKs all appeared to contribute to SAA-induced cytokine release. These observations indicate that CD36 is a receptor mediating SAA binding and SAA- induced pro-inflammatory cytokine secretion predominantly through JNK- and ERK1/2-mediated signaling. C1 [Baranova, Irina N.; Bocharov, Alexander V.; Vishnyakova, Tatyana G.; Kurlander, Roger; Chen, Zhigang; Csako, Gyorgy; Patterson, Amy P.; Eggerman, Thomas L.] NIDDK, Dept Lab Med, Ctr Clin, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Fu, Dong; Arias, Irwin M.] NIDDK, Cell Biol & Metab Branch, NICHD, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Patterson, Amy P.] NIDDK, Off Biotechnol Activ, Off Sci Policy, Off Director,NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Eggerman, Thomas L.] NIDDK, Div Diabet Endocrinol & Metab Dis, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Bocharov, AV (reprint author), 9 Mem Dr,Room 1W115,MSC 0919, Bethesda, MD 20892 USA. EM abocharov@mail.cc.nih.gov; Eggermant@niddk.nih.gov RI Fu, Dong /J-1426-2012 FU National Institutes of Health Intramural Research Programs of the Clinical Center; NIDDK; NIAID FX This work was supported, in whole or in part, by National Institutes of Health Intramural Research Programs of the Clinical Center, NIDDK, and NIAID. NR 93 TC 41 Z9 42 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 12 PY 2010 VL 285 IS 11 BP 8492 EP 8506 DI 10.1074/jbc.M109.007526 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567AE UT WOS:000275413800064 PM 20075072 ER PT J AU Liu, J Nussinov, R AF Liu, Jin Nussinov, Ruth TI Molecular Dynamics Reveal the Essential Role of Linker Motions in the Function of Cullin-RING E3 Ligases SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE linker; E3 ubiquitin ligase; polyubiquitin; conformational control; conformational selection ID SCF UBIQUITIN LIGASES; ALLOSTERIC REGULATION; TUMOR-SUPPRESSOR; STRUCTURAL BASIS; INTERDOMAIN LINKER; COMPLEX; PROTEIN; DOMAIN; RECOGNITION; INSIGHTS AB Tagging proteins by polyubiquitin is a key step in protein degradation. Cullin-RING E3 ubiquitin ligases facilitate ubiquitin transfer from the E2-conjugating enzyme to the substrate, yet crystallography indicates a large distance between the E2 and the substrate, raising the question of how this distance is bridged in the ubiquitin transfer reaction. Here, we demonstrate that the linker motions in the substrate binding proteins can allosterically shorten this distance to facilitate this crucial ubiquitin transfer step and increase this distance to allow polyubiquitination. We performed molecular dynamics simulations for five substrate binding proteins, Skp2, Fbw7, beta-TrCP1, Cdc4, and pVHL, in two forms: bound to their substrates and bound to both substrate and adaptor. The adaptor connects the substrate binding proteins to the cullin. In the bound-to-both forms of all cases, we observed rotations of the substrate binding domain, shortening the gap between the tip of the substrate peptide and the E2 active site by 7-12 angstrom compared with the crystal structures. Overall, together with our earlier simulations of the unbound forms and the bound-to-adaptor forms, the emerging picture is that the maximum distance of 51-73 angstrom between the substrate binding domain and the E2 active site in the modeled unbound forms of these five proteins shrinks to a minimum of 39-49 angstrom in the bound-to-both forms. This large distance range, the result of allosterically controlled linker motions, facilitates ubiquitin transfer and polyubiquitination and as such argues that the cullin-RING E3 ubiquitin ligase is under conformational control. We further observed that substrate binding proteins with multiple substrate acceptor lysines have a larger distance range between the substrate and the E2 as compared with beta-TrCP1, with only one acceptor lysine. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Liu, Jin; Nussinov, Ruth] Natl Canc Inst, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Dept Human Genet & Mol Med, Sackler Inst Mol Med, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), Natl Canc Inst, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov FU National Cancer Institute, National Institutes of Health [HHSN261200800001E]; NIH, National Cancer Institute, Center for Cancer Research FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services; nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was supported (in part) by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (Bethesda, MD; http://biowulf.nih.gov). NR 52 TC 26 Z9 26 U1 0 U2 5 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAR 12 PY 2010 VL 396 IS 5 BP 1508 EP 1523 DI 10.1016/j.jmb.2010.01.022 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 570PZ UT WOS:000275691500024 PM 20083119 ER PT J AU Finzi, A Xiang, SH Pacheco, B Wang, LP Haight, J Kassa, A Danek, B Pancera, M Kwong, PD Sodroski, J AF Finzi, Andres Xiang, Shi-Hua Pacheco, Beatriz Wang, Liping Haight, Jessica Kassa, Aemro Danek, Brenda Pancera, Marie Kwong, Peter D. Sodroski, Joseph TI Topological Layers in the HIV-1 gp120 Inner Domain Regulate gp41 Interaction and CD4-Triggered Conformational Transitions SO MOLECULAR CELL LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; EXTERIOR ENVELOPE GLYCOPROTEIN; SOLUBLE CD4; TRANSMEMBRANE GLYCOPROTEIN; RECEPTOR-BINDING; AIDS PATIENTS; VIRAL ENTRY; HTLV-III; TYPE-1; NEUTRALIZATION AB The entry of human immunodeficiency virus (HIV-1) into cells is initiated by binding of the gp120 exterior envelope glycoprotein to the receptor, CD4. How does CD4 binding trigger conformational changes in gp120 that allow the gp41 transmembrane envelope glycoprotein to mediate viral-cell membrane fusion? The transition from the unliganded to the CD4-bound state is regulated by two potentially flexible topological layers (layers 1 and 2) in the gp120 inner domain. Both layers apparently contribute to the noncovalent association of unliganded gp120 with gp41. After CD4 makes initial contact with the gp120 outer domain, layer 1-layer 2 interactions strengthen gp120-CD4 binding by reducing the off rate. Layer 1-layer 2 interactions also destabilize the activated state induced on HIV-1 by treatment with soluble CD4. Thus, despite lack of contact with CD4, the gp120 inner-domain layers govern CD4 triggering by participating in conformational transitions within gp120 and regulating the interaction with gp41. C1 [Finzi, Andres; Xiang, Shi-Hua; Pacheco, Beatriz; Wang, Liping; Haight, Jessica; Kassa, Aemro; Danek, Brenda; Sodroski, Joseph] Harvard Univ, Sch Med, Dept Pathol,Div AIDS, Dept Canc Immunol & AIDS,Dana Farber Can Inst, Boston, MA 02115 USA. [Pancera, Marie; Kwong, Peter D.] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Sodroski, Joseph] Harvard Univ, Sch Publ Hlth, Dept Immunol & Infect Dis, Boston, MA 02115 USA. RP Sodroski, J (reprint author), Harvard Univ, Sch Med, Dept Pathol,Div AIDS, Dept Canc Immunol & AIDS,Dana Farber Can Inst, Boston, MA 02115 USA. FU National Institutes of Health [AI24755, GM56550, AI67854]; International AIDS Vaccine Initiative FX We thank Ms Yvette McLaughlin and Ms Elizabeth Carpelan for manuscript preparation and Dr Lavanya Krishnan for Biacore advice This work was supported by grants from the National Institutes of Health (AI24755, GM56550, and AI67854), by the International AIDS Vaccine Initiative, and by the late William F McCarty-Cooper NR 58 TC 90 Z9 90 U1 0 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAR 12 PY 2010 VL 37 IS 5 BP 656 EP 667 DI 10.1016/j.molcel.2010.02.012 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 570UB UT WOS:000275702500010 PM 20227370 ER PT J AU Silliman, CC Stroncek, D AF Silliman, Christopher C. Stroncek, David TI Identification of the HNA-3a antigen SO BLOOD LA English DT Editorial Material ID ACUTE LUNG INJURY; ALLOANTIBODIES; NEUTROPHILS; DONORS; TRALI C1 NIH, Bethesda, MD 20892 USA. NR 10 TC 2 Z9 4 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 11 PY 2010 VL 115 IS 10 BP 1863 EP 1863 PG 1 WC Hematology SC Hematology GA 571KS UT WOS:000275751300005 PM 20223931 ER PT J AU Li, XG Hu, X Patel, B Zhou, Z Liang, S Ybarra, R Qiu, Y Felsenfeld, G Bungert, J Huang, SM AF Li, Xingguo Hu, Xin Patel, Bhavita Zhou, Zhuo Liang, Shermi Ybarra, River Qiu, Yi Felsenfeld, Gary Bungert, Joerg Huang, Suming TI H4R3 methylation facilitates beta-globin transcription by regulating histone acetyltransferase binding and H3 acetylation SO BLOOD LA English DT Article ID LOCUS-CONTROL REGION; ARGININE-METHYLTRANSFERASE; IN-VIVO; MAMMALIAN CHROMATIN; BARRIER-ELEMENT; GENE-EXPRESSION; ACTIVATION; LYSINE-4; RECEPTOR; COMPLEX AB Histone modifications play an important role in the process of transcription. However, in contrast to lysine methylation, the role of arginine methylation in chromatin structure and transcription has been under-explored. The globin genes are regulated by a highly organized chromatin structure that juxtaposes the locus control region (LCR) with downstream globin genes. We report here that the targeted recruitment of asymmetric dimethyl H4R3 catalyzed by PRMT1 (protein arginine methyltransferase 1) facilitates histone H3 acetylation on Lys9/Lys14. Dimethyl H4R3 provides a binding surface for P300/CBP-associated factor (PCAF) and directly enhances histone H3 acetylation in vitro. We show that these active modifications are essential for efficient interactions between the LCR and the beta(maj)-promoter as well as transcription of the beta-globin gene. Furthermore, knockdown (KD) of PRMT1 by RNA interference in erythroid progenitor cells prevents histone acetylation, enhancer and promoter interaction, and recruitment of transcription complexes to the active beta-globin promoter. Reintroducing rat PRMT1 into the PRMT1 KD MEL cells rescues PRMT1 binding, beta-globin transcription, and erythroid differentiation. Taken together, our data suggest that PRMT1-mediated dimethyl H4R3 facilitates histone acetylation and enhancer/promoter communications, which lead to the efficient recruitment of transcription preinitiation complexes to active promoters. (Blood. 2010; 115: 2028-2037) C1 [Huang, Suming] Univ Florida, Coll Med, Dept Biochem Mol Biol, Gainesville, FL 32610 USA. [Hu, Xin] Jilin Univ, Coll Life Sci, Edmond H Fischer Signal Transduct Lab, Changchun 130023, Peoples R China. [Qiu, Yi] Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. [Felsenfeld, Gary] NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Bungert, Joerg; Huang, Suming] Univ Florida, Genet Inst, Gainesville, FL 32610 USA. [Huang, Suming] Univ Florida, Shands Canc Ctr, Gainesville, FL 32610 USA. RP Huang, SM (reprint author), Univ Florida, Coll Med, Dept Biochem Mol Biol, POB 103633, Gainesville, FL 32610 USA. EM sumingh@ufl.edu FU National Institutes of Health [HL090589, HL091929, HL091929-01A1S1, DK52356]; Bankhead-Coley Cancer Research; Intramural Research program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health FX This work was supported by grants from the National Institutes of Health (S. H., HL090589, HL091929, and HL091929-01A1S1- the ARRA Administrative Supplement; J. B., DK52356) and by grants from the Bankhead-Coley Cancer Research (Y. Q. and S. H.). G. F. is supported by the Intramural Research program, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. NR 50 TC 37 Z9 37 U1 2 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 11 PY 2010 VL 115 IS 10 BP 2028 EP 2037 DI 10.1182/blood-2009-07-236059 PG 10 WC Hematology SC Hematology GA 571KS UT WOS:000275751300027 PM 20068219 ER PT J AU Song, YL Shao, Z Dexheimer, TS Scher, ES Pommier, Y Cushman, M AF Song, Yunlong Shao, Zhiyu Dexheimer, Thomas S. Scher, Evan S. Pommier, Yves Cushman, Mark TI Structure-Based Design, Synthesis, and Biological Studies of New Anticancer Norindenoisoquinoline Topoisomerase I Inhibitors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DNA COVALENT COMPLEX; NITRATED INDENOISOQUINOLINES; CELL-LINE; CAMPTOTHECIN ANALOGS; CURRENT PERSPECTIVES; CANCER; MECHANISM; IDENTIFICATION; OPTIMIZATION; ORIENTATION AB On the basis of the superimposition of the crystal structures of norindenoisoquinoline 5 and topotecan (2) bound in the topoisomerase 1-DNA covalent complex, as well as molecular docking and quantum chemical calculations, the Substituted norindenoisoquinoline 14a was designed by transporting the 9-dimethylaminomethyl group of topotecan to the 10-position of the norindenolsoquinoline 5. The desired compound 14a wits synthesized and found to possess topoisomerase I inhibitory activity that was slightly better than that of the starting compound 5. A focused set of 10-substitued norindenoisoquinoline analogues were then synthesized. The imidazole-substituted compound 14c was highly cytotoxic when evaluated in it series of human leukemia, ovarian, and breast cancer cells. C1 [Song, Yunlong; Shao, Zhiyu; Cushman, Mark] Purdue Univ, Sch Pharm & Pharmaceut Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. [Song, Yunlong; Shao, Zhiyu; Cushman, Mark] Purdue Univ, Ctr Canc Res, W Lafayette, IN 47907 USA. [Song, Yunlong] Second Mil Med Univ, Sch Pharm, Dept Med Chem, Shanghai 200433, Peoples R China. [Dexheimer, Thomas S.; Scher, Evan S.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharmaceut Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. EM cushman@purdue.edu FU National Institutes of Health (NIH) [UO1 CA89566]; National Institutes of Health [C06-14499] FX This work was made possible by the National Institutes of Health (NIH) through support of this work with Research Grant UO1 CA89566. Some of this research was conducted in a facility constructed with the financial support of a Research Facilities Improvement Program Grant C06-14499 from the National Institutes of Health. We thank the Rosen Center for Advanced Computing (RCAC), Purdue University, for providing computing facilities. NR 50 TC 25 Z9 26 U1 0 U2 9 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 MAR 11 PY 2010 VL 53 IS 5 BP 1979 EP 1989 DI 10.1021/jm901649x PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 562WT UT WOS:000275087000008 PM 20155916 ER PT J AU Ziolkowska, NE Michejda, CJ Bujacz, GD AF Ziolkowska, Natasza E. Michejda, Christopher J. Bujacz, Grzegorz D. TI Structural studies of series HIV-1 nonnucleoside reverse transcriptase inhibitors 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-benzimidazoles with different 4-substituents SO JOURNAL OF MOLECULAR STRUCTURE LA English DT Article DE AIDS; HIV-1; Reverse transcriptase inhibitor; Drug design; Crystal structure ID HUMAN-IMMUNODEFICIENCY-VIRUS; 2-ARYL-SUBSTITUTED BENZIMIDAZOLES; ANTIRETROVIRAL THERAPY; BIOLOGICAL-ACTIVITY; HIGHLY POTENT; INFECTION; BINDING; REPLICATION; DELAVIRDINE; MUTATIONS AB Over the past 10 years, several anti-viral drugs have become available to fight the HIV infection. Antiretroviral treatment reduces the mortality of AIDS. Nonnucleoside inhibitors of HIV-1 reverse transcriptase are specific and potentially nontoxic drugs against AIDS. The crystal structures of five nonnucleoside inhibitors of HIV-1 reverse transcriptase are presented here. The structural parameters, especially those describing the angular orientation of the pi-electron systems and influencing biological activity, were determined for all of the investigated inhibitors. The chemical character and orientation of the substituent at C4 position of the benzimidazole moiety substantially influences the anti-viral activity. The structural data of the investigated inhibitors is a good basis for modeling enzyme-inhibitor interactions for structure-assisted drug design. (C) 2009 Elsevier B.V. All rights reserved. C1 [Ziolkowska, Natasza E.; Bujacz, Grzegorz D.] Tech Univ Lodz, Inst Tech Biochem, PL-90924 Lodz, Poland. [Michejda, Christopher J.] NCI, Mol Aspects Drug Design Sect, Frederick, MD 21702 USA. RP Bujacz, GD (reprint author), Max Planck Inst Biochem, Klopferspitz 18, D-82152 Martinsried, Germany. EM gdbujacz@p.lodz.pl FU Polish Committee for Scientific Research, KBN [4130517 03114] FX This work was supported by the Polish Committee for Scientific Research, KBN, Grant No. 4130517 03114. Authors are grateful to Wieslaw Majzner for his assistance in collecting data on CAD4 diffractometer and to Jerry Aexandratos for editorial suggestions. NR 40 TC 0 Z9 0 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-2860 J9 J MOL STRUCT JI J. Mol. Struct. PD MAR 11 PY 2010 VL 966 IS 1-3 BP 53 EP 58 DI 10.1016/j.molstruc.2009.12.006 PG 6 WC Chemistry, Physical SC Chemistry GA 571QN UT WOS:000275769700009 ER PT J AU Hergenroeder, GW Moore, AN McCoy, JP Samsel, L Ward, NH Clifton, GL Dash, PK AF Hergenroeder, Georgene W. Moore, Anthony N. McCoy, J. Philip, Jr. Samsel, Leigh Ward, Norman H., III Clifton, Guy L. Dash, Pramod K. TI Serum IL-6: a candidate biomarker for intracranial pressure elevation following isolated traumatic brain injury SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID C-REACTIVE PROTEIN; CEREBROSPINAL-FLUID; INTERLEUKIN-6 LEVELS; TNF-ALPHA; CYTOKINE; DAMAGE; INFLAMMATION; ASSOCIATION; INDUCTION; CHILDREN AB Background: Increased intracranial pressure (ICP) is a serious, life-threatening, secondary event following traumatic brain injury (TBI). In many cases, ICP rises in a delayed fashion, reaching a maximal level 48-96 hours after the initial insult. While pressure catheters can be implanted to monitor ICP, there is no clinically proven method for determining a patient's risk for developing this pathology. Methods: In the present study, we employed antibody array and Luminex-based screening methods to interrogate the levels of inflammatory cytokines in the serum of healthy volunteers and in severe TBI patients (GCS <= 8) with or without incidence of elevated intracranial pressure (ICP). De-identified samples and ELISAs were used to confirm the sensitivity and specificity of IL-6 as a prognostic marker of elevated ICP in both isolated TBI patients, and polytrauma patients with TBI. Results: Consistent with previous reports, we observed sustained increases in IL-6 levels in TBI patients irrespective of their ICP status. However, the group of patients who subsequently experienced ICP >= 25 mm Hg had significantly higher IL-6 levels within the first 17 hours of injury as compared to the patients whose ICP remained <= 20 mm Hg. When blinded samples (n = 22) were assessed, a serum IL-6 cut-off of <5 pg/ml correctly identified 100% of all the healthy volunteers, a cut-off of >128 pg/ml correctly identified 85% of isolated TBI patients who subsequently developed elevated ICP, and values between these cut-off values correctly identified 75% of all patients whose ICP remained <= 20 mm Hg throughout the study period. In contrast, the marker had no prognostic value in predicting elevated ICP in polytrauma patients with TBI. When the levels of serum IL-6 were assessed in patients with orthopedic injury (n = 7) in the absence of TBI, a significant increase was found in these patients compared to healthy volunteers, albeit lower than that observed in TBI patients. Conclusions: Our results suggest that serum IL-6 can be used for the differential diagnosis of elevated ICP in isolated TBI. C1 [Moore, Anthony N.; Dash, Pramod K.] Univ Texas Houston, Sch Med, Dept Neurobiol & Anat, Houston, TX 77225 USA. [Hergenroeder, Georgene W.; Ward, Norman H., III; Clifton, Guy L.] Univ Texas Houston, Sch Med, Dept Neurosurg, Houston, TX 77225 USA. [Hergenroeder, Georgene W.] Univ Texas Houston, Sch Med, Vivian L Smith Ctr Neurol Res, Houston, TX 77225 USA. [McCoy, J. Philip, Jr.; Samsel, Leigh] NHLBI, NIH, Bethesda, MD 20892 USA. RP Dash, PK (reprint author), Univ Texas Houston, Sch Med, Dept Neurobiol & Anat, Houston, TX 77225 USA. EM p.dash@uth.tmc.edu OI Hergenroeder, Georgene/0000-0002-6170-2191 FU Mission Connect/TIRR Foundation; NHLBI FX The authors thank Dr. Shibani Pati and Dr. Aarif Khakoo for their assistance in facilitating this project. We would like to thank the Memorial Hermann Hospital Neurotrauma ICU, and Trauma and EMS coders; and Elizabeth Jones, MD, Molly S. Bray, PhD, Brian McFarlin, PhD, Ian Turpin, and Madelene Ottosen, MSN RN for assistance with recruiting orthopedic patients and healthy volunteers for the study. This work was supported in part by a grant from Mission Connect/TIRR Foundation and by the Intramural Research Program of NHLBI. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 35 Z9 35 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD MAR 11 PY 2010 VL 7 AR 19 DI 10.1186/1742-2094-7-19 PG 13 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 586BV UT WOS:000276877000001 PM 20222971 ER PT J AU Wang, J Krishnamoorthi, V Wang, E Yang, C Baptista, D Wu, XG Liu, MT Gardner, M Elkins, P Hines, J Liu, P AF Wang, Jennie Krishnamoorthi, Vidhya Wang, Euphemia Yang, Chun Baptista, Diego Wu, Xiaogang Liu, Mingtao Gardner, Michael Elkins, Phyllis Hines, John Liu, Paul TI LC/MS characterization of impurities and degradation products of a potent antitumor peptidic dimer, CU201 SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE CU201; B201; LC-MS; Impurities characterization; Peptidic dimer; Bradykinin antagonist ID BRADYKININ ANTAGONIST DIMER; CANCER CELL-LINES; GROWTH-FACTOR; CHROMATOGRAPHY; COMBINATION AB Compound CU201 [SUIM-(D-Arg-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-Arg)(2), where SUIM=suberimidyl; Hyp=trans-4-hydroxyproline; Igl=alpha-(2-indanyl)-glycine; Oic-octahydroindole-2-carboxylic acid], is a dimeric analog of the potent bradykinin antagonist peptide B9430. It blocks the G(alpha q.11) signal of the heterotrimeric G proteins, stimulates c-Jun kinases, and induces apoptosis in lung cancer cells with neuroendocrine features. CU201 shows potent inhibition for small-cell lung cancer cells in vitro (ED(50) = 0.15 mu M), as well as for small-cell lung cancer SHP-77 tumor growth in vivo. An HPLC method was developed, as part of a study supported by the National Cancer Institute's (NCI's) Rapid Access to Interventional Development (RAID) program, to assess the purity and stability of CU201. Impurities and degradation products were characterized by LC/MS. The identity of a major impurity, with I mass unit different from CU201, was confirmed by high resolution LC/MS and the investigation of model compounds. Susceptible linkages in the peptide chains were revealed by the degradation study. (C) 2009 Elsevier B.V. All rights reserved. C1 [Wang, Jennie; Krishnamoorthi, Vidhya; Wang, Euphemia; Yang, Chun; Baptista, Diego; Wu, Xiaogang; Liu, Mingtao] SRI Int, Analyt Chem, Menlo Pk, CA 94025 USA. [Gardner, Michael; Elkins, Phyllis; Hines, John] RTI Int, Res Triangle Pk, NC 27709 USA. [Liu, Paul] NCI, Pharmaceut Resources Branch, DCTD, Bethesda, MD 20892 USA. RP Wang, J (reprint author), SRI Int, Analyt Chem, 333 Ravenswood Ave, Menlo Pk, CA 94025 USA. EM jennie.wang@sri.com; hines@rti.org; liup@dtpepn.nci.nih.gov FU Developmental Therapeutics Program; Division of Cancer Treatment and Diagnosis; National Cancer Institute; National Institutes of Health; Department of Health and Human Services [N02-CM-27134, N02-CM-72203] FX 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 13 TC 4 Z9 4 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD MAR 11 PY 2010 VL 51 IS 4 BP 824 EP 833 DI 10.1016/j.jpba.2009.10.004 PG 10 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 542QT UT WOS:000273510600004 PM 19897331 ER PT J AU Craigie, R AF Craigie, Robert TI STRUCTURAL BIOLOGY When four become one SO NATURE LA English DT Editorial Material ID CATALYTIC DOMAIN; HIV-1 INTEGRASE C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Craigie, R (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM bobc@helix.nih.gov FU Intramural NIH HHS [Z01 DK036170-01] NR 7 TC 3 Z9 4 U1 1 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 11 PY 2010 VL 464 IS 7286 BP 167 EP 168 DI 10.1038/464167a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 566JO UT WOS:000275366100022 PM 20220826 ER PT J AU Chandrashekar, J Kuhn, C Oka, Y Yarmolinsky, DA Hummler, E Ryba, NJP Zuker, CS AF Chandrashekar, Jayaram Kuhn, Christina Oka, Yuki Yarmolinsky, David A. Hummler, Edith Ryba, Nicholas J. P. Zuker, Charles S. TI The cells and peripheral representation of sodium taste in mice SO NATURE LA English DT Article ID SINGLE CHORDA TYMPANI; GLOSSOPHARYNGEAL NERVE; RECEPTOR-CELLS; BITTER TASTE; SALT TASTE; AMILORIDE; CHANNEL; MOUSE; NACL; RAT AB Salt taste in mammals can trigger two divergent behavioural responses. In general, concentrated saline solutions elicit robust behavioural aversion, whereas low concentrations of NaCl are typically attractive, particularly after sodium depletion(1-5). Notably, the attractive salt pathway is selectively responsive to sodium and inhibited by amiloride, whereas the aversive one functions as a nonselective detector for a wide range of salts(1-3,6-9). Because amiloride is a potent inhibitor of the epithelial sodium channel (ENaC), ENaC has been proposed to function as a component of the salt-taste-receptor system(1,3,6-14). Previously, we showed that four of the five basic taste qualities-sweet, sour, bitter and umami-are mediated by separate taste-receptor cells (TRCs) each tuned to a single taste modality, and wired to elicit stereotypical behavioural responses(5,15-18). Here we show that sodium sensing is also mediated by a dedicated population of TRCs. These taste cells express the epithelial sodium channel ENaC(19,20), and mediate behavioural attraction to NaCl. We genetically engineered mice lacking ENaC alpha in TRCs, and produced animals exhibiting a complete loss of salt attraction and sodium taste responses. Together, these studies substantiate independent cellular substrates for all five basic taste qualities, and validate the essential role of ENaC for sodium taste in mice. C1 [Chandrashekar, Jayaram; Oka, Yuki; Yarmolinsky, David A.; Zuker, Charles S.] Univ Calif San Diego, Howard Hughes Med Inst, La Jolla, CA 92093 USA. [Chandrashekar, Jayaram; Oka, Yuki; Yarmolinsky, David A.; Zuker, Charles S.] Univ Calif San Diego, Dept Neurobiol, La Jolla, CA 92093 USA. [Chandrashekar, Jayaram; Oka, Yuki; Yarmolinsky, David A.; Zuker, Charles S.] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA. [Kuhn, Christina; Ryba, Nicholas J. P.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Hummler, Edith] Univ Lausanne, Fac Biol & Med, Dept Pharmacol & Toxicol, CH-1005 Lausanne, Switzerland. RP Zuker, CS (reprint author), Columbia Univ, Columbia Coll Phys & Surg, Howard Hughes Med Inst, Dept Biochem, New York, NY 10032 USA. EM cz2195@columbia.edu FU NIH, NIDCR FX We thank W. Guo and A. Becker for generation and maintenance of mouse lines, and K. Scott and members of our laboratories for valuable comments. This research was supported in part by the intramural research program of the NIH, NIDCR (N.J.P.R.). C.S.Z. is an investigator of the Howard Hughes Medical Institute. NR 30 TC 203 Z9 206 U1 8 U2 99 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 11 PY 2010 VL 464 IS 7286 BP 297 EP U182 DI 10.1038/nature08783 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 566JO UT WOS:000275366100051 PM 20107438 ER PT J AU Steidl, C Lee, T Shah, SP Farinha, P Han, G Nayar, T Delaney, A Jones, SJ Iqbal, J Weisenburger, DD Bast, MA Rosenwald, A Muller-Hermelink, HK Rimsza, LM Campo, E Delabie, J Braziel, RM Cook, JR Tubbs, RR Jaffe, ES Lenz, G Connors, JM Staudt, LM Chan, WC Gascoyne, RD AF Steidl, Christian Lee, Tang Shah, Sohrab P. Farinha, Pedro Han, Guangming Nayar, Tarun Delaney, Allen Jones, Steven J. Iqbal, Javeed Weisenburger, Dennis D. Bast, Martin A. Rosenwald, Andreas Muller-Hermelink, Hans-Konrad Rimsza, Lisa M. Campo, Elias Delabie, Jan Braziel, Rita M. Cook, James R. Tubbs, Ray R. Jaffe, Elaine S. Lenz, Georg Connors, Joseph M. Staudt, Louis M. Chan, Wing C. Gascoyne, Randy D. TI Tumor-Associated Macrophages and Survival in Classic Hodgkin's Lymphoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID REGULATORY T-CELLS; INDEPENDENT PROGNOSTIC-FACTOR; GENE-EXPRESSION; FOLLICULAR LYMPHOMA; DISEASE; MICROENVIRONMENT; CHEMOTHERAPY; MICROARRAY; SIGNATURES; PREDICTOR AB BACKGROUND Despite advances in treatments for Hodgkin's lymphoma, about 20% of patients still die from progressive disease. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on the International Prognostic Score. METHODS Using gene-expression profiling, we analyzed 130 frozen samples obtained from patients with classic Hodgkin's lymphoma during diagnostic lymph-node biopsy to determine which cellular signatures were correlated with treatment outcome. We confirmed our findings in an independent cohort of 166 patients, using immunohistochemical analysis. RESULTS Gene-expression profiling identified a gene signature of tumor-associated macrophages that was significantly associated with primary treatment failure (P = 0.02). In an independent cohort of patients, we found that an increased number of CD68+ macrophages was correlated with a shortened progression-free survival (P = 0.03) and with an increased likelihood of relapse after autologous hematopoietic stem-cell transplantation (P = 0.008), resulting in shortened disease-specific survival (P = 0.003). In multivariate analysis, this adverse prognostic factor outperformed the International Prognostic Score for disease-specific survival (P = 0.003 vs. P = 0.03). The absence of an elevated number of CD68+ cells in patients with limited-stage disease defined a subgroup of patients with a long-term disease-specific survival of 100% with the use of current treatment strategies. CONCLUSIONS An increased number of tumor-associated macrophages was strongly associated with shortened survival in patients with classic Hodgkin's lymphoma and provides a new biomarker for risk stratification. C1 [Steidl, Christian; Lee, Tang; Shah, Sohrab P.; Farinha, Pedro; Han, Guangming; Gascoyne, Randy D.] Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. [Nayar, Tarun; Delaney, Allen; Jones, Steven J.] Univ British Columbia, Genome Sci Ctr, Vancouver, BC V5Z 1M9, Canada. [Connors, Joseph M.] Univ British Columbia, Div Med Oncol, British Columbia Canc Agcy, Vancouver, BC V5Z 1M9, Canada. [Shah, Sohrab P.] Univ British Columbia, Dept Comp Sci, Vancouver, BC V6T 1W5, Canada. [Iqbal, Javeed; Weisenburger, Dennis D.; Bast, Martin A.; Chan, Wing C.] Univ Nebraska Med Ctr, Dept Pathol, Omaha, NE USA. [Rosenwald, Andreas; Muller-Hermelink, Hans-Konrad] Univ Wurzburg, Dept Pathol, D-8700 Wurzburg, Germany. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ USA. [Campo, Elias] Univ Barcelona, Hosp Clin, Barcelona, Spain. [Delabie, Jan] Radium Hosp, Dept Pathol, Oslo, Norway. [Cook, James R.; Tubbs, Ray R.] Cleveland Clin, Dept Pathol & Lab Med, Cleveland, OH 44106 USA. [Cook, James R.; Tubbs, Ray R.] Cleveland Clin, Lerner Coll Med, Dept Mol Pathol, Cleveland, OH 44106 USA. [Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Lenz, Georg; Staudt, Louis M.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gascoyne, RD (reprint author), British Columbia Canc Agcy, Dept Pathol & Adv Therapeut, 675 W 10th Ave,Rm 5-113, Vancouver, BC V5Z 1L3, Canada. EM rgascoyn@bccancer.bc.ca RI Lenz, Georg/I-6844-2012; Tang, Macy/B-9798-2014; Jones, Steven/C-3621-2009; OI Delabie, Jan/0000-0001-5023-0689; Farinha, Pedro/0000-0001-9364-9391; Campo, elias/0000-0001-9850-9793 FU Deutsche Forschungsgemeinschaft; Cancer Research Society; Lymphoma Research Foundation; Michael Smith Foundation for Health Research; Roche Molecular Systems; Canadian Institutes of Health Research [178536]; National Cancer Institute [UO1-CA114778-01]; National Cancer Institute (NCI) [UO1-CA 114778]; Roche Canada FX Supported by grants from Deutsche Forschungsgemeinschaft, the Cancer Research Society, and the Lymphoma Research Foundation (to Dr. Steidl), the Michael Smith Foundation for Health Research (to Drs. Steidl and Shah), Roche Molecular Systems, the Canadian Institutes of Health Research (178536, to Dr. Gascoyne), the National Cancer Institute (UO1-CA114778-01, to Dr. Chan), and the Intramural Research Program of the National Cancer Institute (NCI) and by an NCI Strategic Partnering to Evaluate Cancer Signatures (SPECS) grant (UO1-CA 114778) to the Lymphoma/Leukemia Molecular Profiling Project consortium.; Dr. Gascoyne reports receiving consulting fees from Genentech, Roche Canada, and Eli Lilly and research support from Roche Canada. No other potential conflict of interest relevant to this article was reported. NR 34 TC 500 Z9 517 U1 2 U2 31 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 11 PY 2010 VL 362 IS 10 BP 875 EP 885 DI 10.1056/NEJMoa0905680 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 566JM UT WOS:000275365900008 PM 20220182 ER PT J AU Hsieh, MM Tisdale, JF AF Hsieh, Matthew M. Tisdale, John F. TI Stem-Cell Transplantation for Sickle Cell Disease REPLY SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID VERSUS-HOST-DISEASE C1 [Hsieh, Matthew M.; Tisdale, John F.] NIH, Bethesda, MD 20892 USA. RP Hsieh, MM (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM johntis@mail.nih.gov NR 2 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 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 11 PY 2010 VL 362 IS 10 BP 956 EP 956 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 566JM UT WOS:000275365900023 ER PT J AU Bradford, PT Freedman, M Goldstein, AM Tucker, MA AF Bradford, Porcia T. Freedman, Michal Goldstein, Alisa M. Tucker, Margaret A. TI Increased Risk of Second Primary Cancers After a Diagnosis of Melanoma SO ARCHIVES OF DERMATOLOGY LA English DT Article ID CUTANEOUS MALIGNANT-MELANOMA; MULTIPLE PRIMARY MELANOMAS; GENOME-WIDE ASSOCIATION; FOLLOW-UP; PROGNOSTIC FACTORS; IMMUNE COMPETENCE; PRONE FAMILIES; LYMPHOMA; HISTORY; NEVI AB Objective: To quantify the risk of subsequent primary cancers among patients with primary Cutaneous malignant melanoma. Design: Population-based registry study. Setting: We evaluated data from 9 cancer registries of the Surveillance, Epidemiology, and End Results program from 1973-2006. Participants: We included 89 515 patients who Survived at least 2 months after their initial melanoma diagnosis. Results: Of the patients with melanoma, 10 857 (12.1%) developed I or more subsequent primary cancers. The overall risk of a subsequent primary cancer increased by 28% (observed to expected [O:E] ratio=1.28). One quarter of the cancers were subsequent primary melanomas (O:E=8.61). Women with head and neck melanoma and patients younger than 30 had markedly increased risks (O:E=13.22 and 13.40, respectively) of developing a subsequent melanoma. Second melanomas were more likely to be thin than were thefirst of multiple primary melanomas (thickness at diagnosis <1.00 mm, 77.9% vs 70.3%, respectively; P<.001). Melanoma survivors had increased risk of developing several cancers; the most common cancers with elevated risks were breast, prostate, and non-Hodgkin lymphoma (O:E=1.10, 1.15, and 1.25, respectively). Conclusions: Melanoma survivors have an approximately 9-fold increased risk of developing subsequent melanoma compared with the general population. The risk remains elevated more than 20 years after the initial melanoma diagnosis. This increased risk may be owing to behavioral factors, genetic. susceptibility, or medical surveillance. Although the percentage of subsequent primary melanomas thicker than 1 mm is lower than for the first of multiple primary melanomas, it is still substantial. Melanoma survivors should remain under surveillance not only for recurrence but also for future primary melanomas and other cancers. C1 [Bradford, Porcia T.; Goldstein, Alisa M.; Tucker, Margaret A.] NCI, Genet Epidemiol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Freedman, Michal] NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Bradford, PT (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Execut Plaza S,Room 7005, Rockville, MD 20852 USA. EM bradfordp@mail.nih.gov RI Tucker, Margaret/B-4297-2015 FU Intramural Research Program of the Division of Cancer Epidemiology and Genetics; National Cancer Institute; National Institutes of Health FX This study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health. NR 56 TC 67 Z9 67 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD MAR 10 PY 2010 VL 146 IS 3 BP 265 EP 272 PG 8 WC Dermatology SC Dermatology GA 569FU UT WOS:000275582800007 PM 20231496 ER PT J AU Miller, DD Cowen, EW Nguyen, JC McCalmont, TH Fox, LP AF Miller, Daniel D. Cowen, Edward W. Nguyen, Josephine C. McCalmont, Timothy H. Fox, Lindy P. TI Melanoma Associated With Long-term Voriconazole Therapy A New Manifestation of Chronic Photosensitivity SO ARCHIVES OF DERMATOLOGY LA English DT Article ID TRIAZOLE ANTIFUNGAL AGENT; XERODERMA-PIGMENTOSUM; SKIN-CANCER; PSEUDOPORPHYRIA; ASPERGILLOSIS; PREVENTION; CHILDREN; PATIENT AB Background: Voriconazole is a triazole antifungal agent approved by the US Food and Drug Administration for serious fungal infections, including with Aspergillus, Fusarium, Pseudallescheria, and Scedosporium species. In initial clinical trials, approximately 2% of patients developed cutaneous reactions, including photosensitivity, cheilitis, and xerosis. Subsequent reports have implicated voriconazole as a cause of severe photosensitivity and accelerated photoaging, pseudoporphyria cutanea tarda, and aggressive squamous cell carcinoma. Observation: We report 5 melanoma in situ lesions in the setting of extreme photosensitivity associated with long-term voriconazole therapy. Conclusions: We recommend surveillance for skin cancer formation in all patients who require long-term voriconazole treatment, particularly those who manifest signs or symptoms of photosensitivity or chronic photo-damage. Further study of the mechanism underlying voriconazole photosensitivity and oncogenesis is warranted. C1 [Miller, Daniel D.; McCalmont, Timothy H.; Fox, Lindy P.] Univ Calif San Francisco, Dept Dermatol, San Francisco, CA 94143 USA. [McCalmont, Timothy H.] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA. [Cowen, Edward W.] NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD USA. [Nguyen, Josephine C.] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. RP Fox, LP (reprint author), Univ Calif San Francisco, Dept Dermatol, 1701 Divisadero St, San Francisco, CA 94143 USA. EM foxli@derm.ucsf.edu NR 24 TC 55 Z9 57 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD MAR 10 PY 2010 VL 146 IS 3 BP 300 EP 304 PG 5 WC Dermatology SC Dermatology GA 569FU UT WOS:000275582800013 PM 20083676 ER PT J AU Turner, MLC AF Turner, Maria L. Chanco TI Sun, Drugs, and Skin Cancer A Continuing Saga SO ARCHIVES OF DERMATOLOGY LA English DT Editorial Material ID ULTRAVIOLET-A; XERODERMA-PIGMENTOSUM; CELL CARCINOMA; P53 MUTATIONS; MELANOMA; SUNLIGHT; KERATINOCYTES; VORICONAZOLE; PSORIASIS; PSORALEN C1 NCI, Dermatol Branch, Bethesda, MD 20892 USA. RP Turner, MLC (reprint author), NCI, Dermatol Branch, Bldg 10,Room 12N-238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM mlturner@mail.nih.gov NR 23 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-987X J9 ARCH DERMATOL JI Arch. Dermatol. PD MAR 10 PY 2010 VL 146 IS 3 BP 329 EP 331 PG 3 WC Dermatology SC Dermatology GA 569FU UT WOS:000275582800020 PM 20231508 ER PT J AU Bae, MA Dal Rhee, S Jung, WH Ahn, JH Song, BJ Cheon, HG AF Bae, Myung-Ae Dal Rhee, Sang Jung, Won Hoon Ahn, Jin Hee Song, Byoung-Joon Cheon, Hyae Gyeong TI Selective Inhibition of Activated Stellate Cells and Protection from Carbon Tetrachloride-Induced Liver Injury in Rats by a New PPAR gamma agonist KR62776 SO ARCHIVES OF PHARMACAL RESEARCH LA English DT Article DE PPAR gamma; Stellate cells; Collagen alpha 1(I); alpha-smooth muscle actin; KR62776 ID ACID-DEFINED DIET; RECEPTOR-GAMMA; IN-VITRO; HEPATIC-FIBROSIS; APOPTOSIS; PIOGLITAZONE; PROLIFERATION; HALOFUGINONE; METABOLISM; EXPRESSION AB Activated hepatic stellate cells (HSC) are the primary source of extracellular matrix proteins found in liver fibrosis/cirrhosis patients. Therefore, the prevention of HSC activation is an important strategy for treating severe liver injury. This study examined the effects of KR62776, a new peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, on the rate of cell proliferation and expression of alpha-smooth muscle actin (alpha-SAM) in rat hepatic stellate HSC-T6 cells. In addition, its effects on the liver damage induced by carbon tetrachloride were investigated. KR62776 caused the apoptosis of activated HSC-T6 cells with the concomitant decrease in the alpha-smooth muscle actin levels in a time- and concentration-dependent manner. However, KR62776 did not cause the apoptosis of human HepG2 and rat McARH7777 hepatoma cells, suggesting that KR62776 has a specific effect on stellate cells. KR62776 increased the levels of Gadd45, p27, p21 and PPAR gamma proteins but decreased the cell cycle-related proteins, such as cdk2, cyclin B and cyclin D1. These changes were reversed by BADGE, a specific PPAR gamma antagonist, indicating that the effects of KR62776 are, at least in part, PPAR gamma-dependent. In addition, KR62776 administration showed some protection against carbon tetrachloride-induced hepatocellular damage in rats. Overall, these results suggest that KR62776 may have potential in the chemoprevention of liver fibrosis/cirrhosis. C1 [Bae, Myung-Ae] Korea Res Inst Chem Technol, Div Med Sci, Drug Discovery Platform Technol Team, Taejon 305600, South Korea. [Dal Rhee, Sang; Jung, Won Hoon; Ahn, Jin Hee; Cheon, Hyae Gyeong] Korea Res Inst Chem Technol, Div Med Sci, Ctr Metab Syndrome Therapeut, Taejon 305600, South Korea. [Song, Byoung-Joon] NIAAA, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. RP Bae, MA (reprint author), Korea Res Inst Chem Technol, Div Med Sci, Drug Discovery Platform Technol Team, Taejon 305600, South Korea. EM mbae@krict.re.kr; hgcheon@krict.re.kr FU Ministry of Science and Technology, Korea FX This study was supported by grant from the Center for Biological Modulators of the 21th Century Frontier R&D Program, The Ministry of Science and Technology, Korea. NR 35 TC 8 Z9 10 U1 0 U2 6 PU PHARMACEUTICAL SOC KOREA PI SEOUL PA 1489-3 SUHCHO-DONG, SUHCHO-KU, SEOUL 137-071, SOUTH KOREA SN 0253-6269 J9 ARCH PHARM RES JI Arch. Pharm. Res. PD MAR 10 PY 2010 VL 33 IS 3 BP 433 EP 442 DI 10.1007/s12272-010-0313-3 PG 10 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 572HP UT WOS:000275819000014 PM 20361309 ER PT J AU Legeai, F Shigenobu, S Gauthier, JP Colbourne, J Rispe, C Collin, O Richards, S Wilson, ACC Murphy, T Tagu, D AF Legeai, F. Shigenobu, S. Gauthier, J. -P. Colbourne, J. Rispe, C. Collin, O. Richards, S. Wilson, A. C. C. Murphy, T. Tagu, D. TI AphidBase: a centralized bioinformatic resource for annotation of the pea aphid genome SO INSECT MOLECULAR BIOLOGY LA English DT Article DE AphidBase; pea aphid genome; annotation; manual curation; GMOD ID COMMUNITY ANNOTATION; GENE PREDICTION; DATABASE; PROGRAM; SEQUENCES; MODEL; RNA; TOOLS; DNA AB AphidBase is a centralized bioinformatic resource that was developed to facilitate community annotation of the pea aphid genome by the International Aphid Genomics Consortium (IAGC). The AphidBase Information System designed to organize and distribute genomic data and annotations for a large international community was constructed using open source software tools from the Generic Model Organism Database (GMOD). The system includes Apollo and GBrowse utilities as well as a wiki, blast search capabilities and a full text search engine. AphidBase strongly supported community cooperation and coordination in the curation of gene models during community annotation of the pea aphid genome. AphidBase can be accessed at http://www.aphidbase.com. C1 [Legeai, F.] INRIA, Equipe Symbiose, Ctr Rennes Bretagne Atlantique, F-35042 Rennes, France. [Legeai, F.; Gauthier, J. -P.; Rispe, C.; Tagu, D.] INRA, UMR, Le Rheu, France. [Shigenobu, S.] Princeton Univ, Dept Ecol & Evolutionary Biol, Princeton, NJ 08544 USA. [Shigenobu, S.] JST, PRESTO, Saitama, Japan. [Shigenobu, S.] Natl Inst Nat Sci, Okazaki Inst Integrat Biosci, Okazaki, Aichi 4448787, Japan. [Colbourne, J.] Indiana Univ, Ctr Genom & Bioinformat, Sch Informat, Bloomington, IN 47405 USA. [Colbourne, J.] Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. [Richards, S.] Baylor Coll Med, Human Genome Sequencing Ctr, Dept Mol & Human Genet, Houston, TX 77030 USA. [Wilson, A. C. C.] Univ Miami, Dept Biol, Coral Gables, FL 33124 USA. [Murphy, T.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Legeai, F (reprint author), INRIA, Equipe Symbiose, Ctr Rennes Bretagne Atlantique, Campus Beaulieu, F-35042 Rennes, France. EM fabrice.legeai@rennes.inra.fr RI Shigenobu, Shuji/B-6239-2011; UMR IGEPP, INRA/A-4054-2011; Colbourne, John/L-7748-2014 OI Shigenobu, Shuji/0000-0003-4640-2323; Tagu, Denis/0000-0002-6320-8648; Collin, Olivier/0000-0002-8959-8402; Colbourne, John/0000-0002-6966-2972 FU ANR Genoplante 'GnpAnnot'; American Genetic Association; NRI; CSREES; USDA [2007-04628]; NIH; National Library of Medicine FX The authors would like to acknowledge the International Aphid Genomics Consortium and in particular all the curators involved in gene model improvement. We thank Ed Lee, Olivier Arnaiz, Scott Cain, Dave Clements and the rest of the GMOD team, Stephanie Sibide-Bocs, Joelle Amselem and Michael Alaux from ANR GnpAnnot. The assistance of IT staff of AphidGenomics at Princeton University, and of Phillip Steinbachs for the establishment of the IAGC Wiki hosted by The Center for Genomics and Bioinformatics, Indiana University were fully appreciated. AphidBase is partly funded by ANR Genoplante 'GnpAnnot'. The Pea Aphid Genome Annotation Workshop I was supported by an American Genetic Association Special Event Award and an NRI, CSREES, USDA award 2007-04628 to ACCW. Work at NCBI was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 34 TC 51 Z9 51 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0962-1075 J9 INSECT MOL BIOL JI Insect Mol. Biol. PD MAR 10 PY 2010 VL 19 SU 2 BP 5 EP 12 DI 10.1111/j.1365-2583.2009.00930.x PG 8 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 560NK UT WOS:000274909200003 PM 20482635 ER PT J AU Van Eperen, L Marincola, FM Strohm, J AF Van Eperen, Laura Marincola, Francesco M. Strohm, Jennifer TI Bridging the Divide between Science and Journalism SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article AB There are countless reasons nearly every scientist should learn how to communicate effectively with the media, including increased understanding of critical research findings to attract or sustain funding and build new professional partnerships that will further propel forward research. But where do scientists begin? Bridging the Divide between Science and Journalism offers practical tips for any scientist looking to work with the media. Given the traditional and internet-based sources for medical research and healthcare-related news now available, it is imperative that scientists know how to communicate their latest findings through the appropriate channels. The credible media channels are managed by working journalists, so learning how to package vast, technical research in a form that is appetizing and "bite-sized" in order to get their attention, is an art. Reducing years of research into a headline can be extremely difficult and certainly doesn't come naturally to every scientist, so this article provides suggestions on how to work with the media to communicate your findings. C1 [Marincola, Francesco M.] NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. [Van Eperen, Laura; Strohm, Jennifer] Van Eperen & Co, Strateg Commun Consulting, Bethesda, MD 20817 USA. RP Marincola, FM (reprint author), NIH, IDIS, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM FMarincola@mail.cc.nih.gov NR 4 TC 0 Z9 0 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAR 10 PY 2010 VL 8 AR 25 DI 10.1186/1479-5876-8-25 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 579WA UT WOS:000276406300001 PM 20219123 ER PT J AU Lico, DTP Rosa, JC Degiorgis, JA de Vasconcelos, EJR Casaletti, L Tauhata, SBF Baqui, MMA Fukuda, M Moreira, JE Larson, RE AF Lico, D. T. P. Rosa, J. C. Degiorgis, J. A. de Vasconcelos, E. J. R. Casaletti, L. Tauhata, S. B. F. Baqui, M. M. A. Fukuda, M. Moreira, J. E. Larson, R. E. TI NOVEL 65 kDa RNA-BINDING PROTEIN IN SQUID PRESYNAPTIC TERMINALS SO NEUROSCIENCE LA English DT Article DE myosin V; hnRNP complex; RNP motifs; synaptosome; optic lobe; Loligo ID BRAIN MYOSIN-V; RAT CEREBRAL-CORTEX; MESSENGER-RNAS; GIANT SYNAPSE; UNCONVENTIONAL MYOSIN; ANTIBODY INJECTION; MOTOR PROTEINS; BUDDING YEAST; KINASE-II; TRANSPORT AB A polyclonal antibody (C4), raised against the head domain of chicken myosin Va, reacted strongly towards a 65 kDa polypeptide (p65) on Western blots of extracts from squid optic lobes but did not recognize the heavy chain of squid myosin V. This peptide was not recognized by other myosin Va antibodies, nor by an antibody specific for squid myosin V. In an attempt to identify it, p65 was purified from optic lobes of Loligo plei by cationic exchange and reverse phase chromatography. Several peptide sequences were obtained by mass spectroscopy from p65 cut from sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) gels. BLAST analysis and partial matching with expressed sequence tags (ESTs) from a Loligo pealei data bank indicated that p65 contains consensus signatures for the heterogeneous nuclear ribonucleoprotein (hnRNP) A/B family of RNA-binding proteins. Centrifugation of post mitochondrial extracts from optic lobes on sucrose gradients after treatment with RNase gave biochemical evidence that p65 associates with cytoplasmic RNP complexes in an RNA-dependent manner. Immunohistochemistry and immunofluorescence studies using the C4 antibody showed partial co-labeling with an antibody against squid synaptotagmin in bands within the outer plexiform layer of the optic lobes and at the presynaptic zone of the stellate ganglion. Also, punctate labeling by the C4 antibody was observed within isolated optic lobe synaptosomes. The data indicate that p65 is a novel RNA-binding protein located to the presynaptic terminal within squid neurons and may have a role in synaptic localization of RNA and its translation or processing. (C) 2010 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Lico, D. T. P.; Rosa, J. C.; de Vasconcelos, E. J. R.; Casaletti, L.; Tauhata, S. B. F.; Baqui, M. M. A.; Moreira, J. E.; Larson, R. E.] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Cellular & Mol Biol, BR-14049900 Sao Paulo, Brazil. [Degiorgis, J. A.; Moreira, J. E.] Marine Biol Lab, Woods Hole, MA 02543 USA. [Degiorgis, J. A.] Providence Coll, Dept Biol, Providence, RI 02918 USA. [Degiorgis, J. A.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. [Fukuda, M.] Tohoku Univ, Grad Sch Life Sci, Dept Dev Biol & Neurosci, Sendai, Miyagi 9808578, Japan. RP Larson, RE (reprint author), Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Cellular & Mol Biol, BR-14049900 Sao Paulo, Brazil. EM relarson@fmrp.usp.br RI Rosa, Jose /A-1966-2013; Baqui, Munira/H-5243-2013; Celulas tronco, Inct/I-1921-2013; Vasconcelos, Elton/O-5593-2014; Fukuda, MItsunori/I-1511-2015 OI Baqui, Munira/0000-0002-7945-2899; FU Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq); Fundacao de Apoio ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da FMRP-USP (FAEPA); Nation Center for Research Resources, NIH, Bethesda, MD [P20RR016457] FX We thank Domingos Pitta, Silvia Regina Andrade Nascimento, Maria Tereza Picinoto Maglia and Vani Maria Alves Correa for expert technical assistance. Special thanks to Dr. Thomas Reese, National Institute of Neurological Disorders and Strokes, NIH, in whose laboratory several critical experiments on Loligo pealei were first done. Live Loligo plei were obtained from the Centro de Biologia Marinha da Universidade de Sao Paulo (CEBIMar). REL, JCR and JEM received financial support from the Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP), the Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) and the Fundacao de Apoio ao Ensino, Pesquisa e Assistencia do Hospital das Clinicas da FMRP-USP (FAEPA). JAD received financial support from the RI-INBRE Program grant #P20RR016457 from the Nation Center for Research Resources, NIH, Bethesda, MD. DTPL, LC, SBFT, EJRV and MMAB were recipients of research fellowships from FAPESP and CNPq. REL and JEM received Productivity-in-Research fellowships from CNPq. The confocal work was performed on Leica microscopes in the Laboratorio Multiusuario de Microscopia Confocal do Departamento de Biologia Celular e Molecular e Bioagentes Patogenicos-FMRP/USP under the technical supervision of Dr. Lenaldo Branco Rocha. NR 56 TC 3 Z9 3 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 EI 1873-7544 J9 NEUROSCIENCE JI Neuroscience PD MAR 10 PY 2010 VL 166 IS 1 BP 73 EP 83 DI 10.1016/j.neuroscience.2009.12.005 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 555JT UT WOS:000274507500009 PM 20004709 ER PT J AU Karakasiliotis, I Vashist, S Bailey, D Abente, EJ Green, KY Roberts, LO Sosnovtsev, SV Goodfellow, IG AF Karakasiliotis, Ioannis Vashist, Surender Bailey, Dalan Abente, Eugenio J. Green, Kim Y. Roberts, Lisa O. Sosnovtsev, Stanislav V. Goodfellow, Ian G. TI Polypyrimidine Tract Binding Protein Functions as a Negative Regulator of Feline Calicivirus Translation SO PLOS ONE LA English DT Article ID RIBOSOME ENTRY SITE; NUCLEAR-PORE COMPLEX; VIRUS GENOMIC RNA; MOUTH-DISEASE VIRUS; CELLULAR-PROTEINS; MAMMALIAN-CELLS; CAPSID PROTEIN; INFECTED-CELLS; NONSTRUCTURAL POLYPROTEIN; POLY(A)-BINDING PROTEIN AB Background: Positive strand RNA viruses rely heavily on host cell RNA binding proteins for various aspects of their life cycle. Such proteins interact with sequences usually present at the 59 or 39 extremities of the viral RNA genome, to regulate viral translation and/or replication. We have previously reported that the well characterized host RNA binding protein polypyrimidine tract binding protein (PTB) interacts with the 5'end of the feline calicivirus (FCV) genomic and subgenomic RNAs, playing a role in the FCV life cycle. Principal Findings: We have demonstrated that PTB interacts with at least two binding sites within the 5'end of the FCV genome. In vitro translation indicated that PTB may function as a negative regulator of FCV translation and this was subsequently confirmed as the translation of the viral subgenomic RNA in PTB siRNA treated cells was stimulated under conditions in which RNA replication could not occur. We also observed that PTB redistributes from the nucleus to the cytoplasm during FCV infection, partially localizing to viral replication complexes, suggesting that PTB binding may be involved in the switch from translation to replication. Reverse genetics studies demonstrated that synonymous mutations in the PTB binding sites result in a cell-type specific defect in FCV replication. Conclusions: Our data indicates that PTB may function to negatively regulate FCV translation initiation. To reconcile this with efficient virus replication in cells, we propose a putative model for the function of PTB in the FCV life cycle. It is possible that during the early stages of infection, viral RNA is translated in the absence of PTB, however, as the levels of viral proteins increase, the nuclear-cytoplasmic shuttling of PTB is altered, increasing the cytoplasmic levels of PTB, inhibiting viral translation. Whether PTB acts directly to repress translation initiation or via the recruitment of other factors remains to be determined but this may contribute to the stimulation of viral RNA replication via clearance of ribosomes from viral RNA. C1 [Karakasiliotis, Ioannis; Vashist, Surender; Bailey, Dalan; Goodfellow, Ian G.] Univ London Imperial Coll Sci Technol & Med, Dept Virol, London, England. [Abente, Eugenio J.; Green, Kim Y.; Sosnovtsev, Stanislav V.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Abente, Eugenio J.] Univ Maryland, Dept Mol Genet & Cell Biol, College Pk, MD 20742 USA. [Roberts, Lisa O.] Univ Surrey, Fac Hlth & Med Sci, Guildford GU2 5XH, Surrey, England. RP Karakasiliotis, I (reprint author), BSRC Alexander Fleming, Lab Post Transcript Control, Vari, Greece. EM I.Goodfellow@imperial.ac.uk RI Roberts, Lisa/E-6365-2010; vashist, surender/H-5879-2013; OI Bailey, Dalan/0000-0002-5640-2266; Abente, Eugenio/0000-0002-3390-2786; Goodfellow, Ian/0000-0002-9483-510X FU Wellcome Trust; Biotechnology and Biological Sciences Research Council (BBSRC); National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, US FX This work was supported by the Wellcome Trust, Biotechnology and Biological Sciences Research Council (BBSRC) and in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, US. I.G. is a Wellcome Senior Fellow. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 64 TC 19 Z9 19 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 10 PY 2010 VL 5 IS 3 AR e9562 DI 10.1371/journal.pone.0009562 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565XE UT WOS:000275328800009 PM 20224775 ER PT J AU Wang, V Davis, DA Veeranna, RP Haque, M Yarchoan, R AF Wang, Victoria Davis, David A. Veeranna, Ravindra P. Haque, Muzammel Yarchoan, Robert TI Characterization of the Activation of Protein Tyrosine Phosphatase, Receptor-Type, Z Polypeptide 1 (PTPRZ1) by Hypoxia Inducible Factor-2 Alpha SO PLOS ONE LA English DT Article ID RENAL-CELL CARCINOMA; TRANSCRIPTION FACTORS; HIF-2-ALPHA PROMOTES; ENDOTHELIAL-CELLS; RESPONSE ELEMENTS; BINDING-SITES; BETA-CATENIN; C-MYC; GENE; EXPRESSION AB Background: Hypoxia inducible factors (HIFs) are the principal means by which cells upregulate genes in response to hypoxia and certain other stresses. There are two major HIFs, HIF-1 and HIF-2. We previously found that certain genes are preferentially activated by HIF-2. One was protein tyrosine phosphatase, receptor-type, Z polypeptide 1 (PTPRZ1). PTPRZ1 is overexpressed in a number of tumors and has been implicated in glioblastoma pathogenesis. Methodology/Principal Findings: To understand the preferential activation of PTPRZ1 by HIF-2, we studied the PTPRZ1 promoter in HEK293T cells and Hep3B cells. Through deletion and mutational analysis, we identified the principal hypoxia response element. This element bound to both HIF-1 and HIF-2. We further identified a role for ELK1, an E26 transformation-specific (Ets) factor that can bind to HIF-2 alpha but not HIF-1 alpha, in the HIF-2 responsiveness. Knock-down experiments using siRNA to ELK1 decreased HIF-2 activation by over 50%. Also, a deletion mutation of one of the two Ets binding motifs located near the principal hypoxia response element similarly decreased activation of the PTPRZ1 promoter by HIF-2. Finally, chromatin immunoprecipitation assays showed binding of HIF and ELK1 to the PTPRZ1 promoter region. Conclusions/Significance: These results identify HIF-binding and Ets-binding motifs on the PTPRZ1 promoter and provide evidence that preferential activation of PTPRZ1 by HIF-2 results at least in part from cooperative binding of HIF-2 and ELK1 to nearby sites on the PTPRZ1 promoter region. These results may have implications in tumor pathogenesis and in understanding neurobiology, and may help inform the development of novel tumor therapy. C1 [Wang, Victoria] NCI, HIV, NIH, Bethesda, MD 20892 USA. NCI, AIDS Malignancy Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wang, V (reprint author), NCI, HIV, NIH, Bethesda, MD 20892 USA. EM yarchoan@helix.nih.gov OI Ravindra, P V/0000-0003-4228-1843 FU National Institutes of Heath, National Cancer Institute FX This project was supported by the Intramural Research Program of the National Institutes of Heath, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 13 Z9 14 U1 3 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 10 PY 2010 VL 5 IS 3 AR e9641 DI 10.1371/journal.pone.0009641 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565XE UT WOS:000275328800032 PM 20224786 ER PT J AU O'Connor, SL Lhost, JJ Becker, EA Detmer, AM Johnson, RC MacNair, CE Wiseman, RW Karl, JA Greene, JM Burwitz, BJ Bimber, BN Lank, SM Tuscher, JJ Mee, ET Rose, NJ Desrosiers, RC Hughes, AL Friedrich, TC Carrington, M O'Connor, DH AF O'Connor, Shelby L. Lhost, Jennifer J. Becker, Ericka A. Detmer, Ann M. Johnson, Randall C. MacNair, Caitlin E. Wiseman, Roger W. Karl, Julie A. Greene, Justin M. Burwitz, Benjamin J. Bimber, Benjamin N. Lank, Simon M. Tuscher, Jennifer J. Mee, Edward T. Rose, Nicola J. Desrosiers, Ronald C. Hughes, Austin L. Friedrich, Thomas C. Carrington, Mary O'Connor, David H. TI MHC Heterozygote Advantage in Simian Immunodeficiency Virus-Infected Mauritian Cynomolgus Macaques SO SCIENCE TRANSLATIONAL MEDICINE LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; T-CELL RESPONSES; CLASS-I ALLELES; VIRAL LOAD; HIV-1 EVOLUTION; DISEASE PROGRESSION; LYMPHOCYTE ESCAPE; RHESUS MACAQUES; VACCINE; HLA AB The importance of a broad CD8 T lymphocyte (CD8-TL) immune response to HIV is unknown. Ex vivo measurements of immunological activity directed at a limited number of defined epitopes provide an incomplete portrait of the actual immune response. We examined viral loads in simian immunodeficiency virus (SIV)-infected major histocompatibility complex (MHC)-homozygous and MHC-heterozygous Mauritian cynomolgus macaques. Chronic viremia in MHC-homozygous macaques was 80 times that in MHC-heterozygous macaques. Virus from MHC-homozygous macaques accumulated 11 to 14 variants, consistent with escape from CD8-TL responses after 1 year of SIV infection. The pattern of mutations detected in MHC-heterozygous macaques suggests that their epitope-specific CD8-TL responses are a composite of those present in their MHC-homozygous counterparts. These results provide the clearest example of MHC heterozygote advantage among individuals infected with the same immunodeficiency virus strain, suggesting that broad recognition of multiple CD8-TL epitopes should be a key feature of HIV vaccines. C1 [O'Connor, Shelby L.; Lhost, Jennifer J.; Greene, Justin M.; Burwitz, Benjamin J.; O'Connor, David H.] Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. [Becker, Ericka A.; Detmer, Ann M.; MacNair, Caitlin E.; Wiseman, Roger W.; Karl, Julie A.; Bimber, Benjamin N.; Lank, Simon M.; Tuscher, Jennifer J.; Friedrich, Thomas C.; O'Connor, David H.] Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53706 USA. [Johnson, Randall C.] NCI, Lab Genom Divers, Sci Applicat Int Corp, Frederick, MD 21702 USA. [Johnson, Randall C.] Conservatoire Natl Arts & Metiers, Chaire Bioinfromat, F-75003 Paris, France. [Mee, Edward T.; Rose, Nicola J.] Natl Inst Biol Stand & Controls, Div Retrovirol, Potters Bar EN6 3QG, Herts, England. [Desrosiers, Ronald C.] Harvard Univ, New England Primate Res Ctr, Sch Med, Southborough, MA 01772 USA. [Hughes, Austin L.] Univ S Carolina, Dept Biol Sci, Columbia, SC 29208 USA. [Carrington, Mary] NCI, Canc & Inflammat Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. [Carrington, Mary] Ragon Inst MGH MIT & Harvard, Boston, MA 02114 USA. RP O'Connor, DH (reprint author), Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI 53706 USA. EM doconnor@primate.wisc.edu RI Johnson, Randall/B-1517-2014; OI Johnson, Randall/0000-0001-7754-0847; o'connor, david/0000-0003-2139-470X; Friedrich, Thomas/0000-0001-9831-6895 FU CCR NIH HHS [HHSN261200800001C]; Department of Health; Intramural NIH HHS; Medical Research Council [G9025730]; NCI NIH HHS [HHSN261200800001E]; NCRR NIH HHS [C06 RR015459, C06 RR020141, P40 RR019995, P51 RR000167-40, P51 RR000168, RR00168, P51 RR000167, P51 RR000168-430164]; NIAID NIH HHS [R01 AI077376, R01 AI084787, R01 AI084787-01, R21 AI068488, R21 AI082880, R21 AI082880-01, R01 AI077376-02, R21 AI068488-02]; NIGMS NIH HHS [R01 GM043940-11, GM43940, R01 GM043940] NR 49 TC 30 Z9 30 U1 0 U2 6 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 MAR 10 PY 2010 VL 2 IS 22 AR 22ra18 DI 10.1126/scitranslmed.3000524 PG 9 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 591MD UT WOS:000277303900002 PM 20375000 ER PT J AU Bermejo, GA Strub, MP Ho, C Tjandra, N AF Bermejo, Guillermo A. Strub, Marie-Paule Ho, Chien Tjandra, Nico TI Ligand-Free Open-Closed Transitions of Periplasmic Binding Proteins: The Case of Glutamine-Binding Protein SO BIOCHEMISTRY LA English DT Article ID PARAMAGNETIC RELAXATION ENHANCEMENT; MOLECULAR-STRUCTURE DETERMINATION; ESCHERICHIA-COLI; ACTIVE-TRANSPORT; SINORHIZOBIUM-MELILOTI; XPLOR-NIH; NMR; DYNAMICS; SPECIFICITY; RESOLUTION AB The ability to undergo large-scale domain rearrangements is essential for the substrate-binding function of periplasmic binding proteins (PBPs). which are indispensable for nutrient uptake in Gram-negative bacteria. Crystal structures Indicate that PBPs typically adopt either an "open" unliganded configuration or a "closed" liganded one. However. it is not clear whether, its a general rule, PBPs remain open until ligand-induced interdomain closure or are in equilibrium with a minor population of unliganded, closed species. Evidence for the latter has been recently reported oil maltose-binding, protein (MBP) in aqueous solution [Tang, C., et al. (2007) Nature 449, 1078-1082] via paramagnetic relaxation enhancement (PRE), a technique able to probe lowly populated regions of conformational spaces. Here, we use PRE to study the unliganded open-closed transition of another PBP: glutamine-binding protein (GlnBP). Through It combination of domain structure knowledge and Intermolecular and concentration dependence PRE experiments, a set of surface residues was found to be involved In intermolecular interactions. Barring such residues, PRE data oil ligand-free GlnBP, paramagnetically labeled at two sites (one at a time), could be appropriately explained by the unliganded, open crystal stricture in that it both yielded a good PRE fit and was not significantly affected by PRE-based refinement. Thus. contrary to MBP, our data did not particularly suggest the coexistence of a minor closed conformer. Several possibilities were explored to explain the observed differences in such Closely structurally related systems; among them, a particularly interesting one arises from close inspection of the interdomain "hinge" region of various PBPs: strong, hydrogen bond Interactions discourage large-scale interdomain dynamics. C1 [Bermejo, Guillermo A.; Strub, Marie-Paule; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. [Ho, Chien] Carnegie Mellon Univ, Dept Biol Sci, Pittsburgh, PA 15213 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, NIH, Bldg 50,Room 3503, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov RI Ho, Chien/O-6112-2016 OI Ho, Chien/0000-0002-4094-9232 FU NIH [GM-084614]; NHLBI FX This work was supported by NIH Grant GM-084614 to C.H. and by the Intramural Research program of the NIH, NHLBI, to N.T. NR 49 TC 34 Z9 35 U1 1 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 9 PY 2010 VL 49 IS 9 BP 1893 EP 1902 DI 10.1021/bi902045p PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 560UK UT WOS:000274928500010 PM 20141110 ER PT J AU Petrik, AF Strub, MP Lee, JC AF Petrik, Amy F. Strub, Marie-Paule Lee, Jennifer C. TI Energy Transfer Ligands of the GluR2 Ligand Binding Core SO BIOCHEMISTRY LA English DT Article ID IONOTROPIC GLUTAMATE RECEPTORS; TIME-RESOLVED FLUORESCENCE; TRYPTOPHAN FLUORESCENCE; CONFORMATIONAL DYNAMICS; CRYSTAL-STRUCTURES; ION CHANNELS; DOMAIN; AMPA; MECHANISMS; PROTEIN AB Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate excitatory signaling in the central nervous system. When a ligand binds to the extracellular domain of iGluRs, local conformational changes ensue and this motion is translated to the transmembrane domain, inducing channel opening. We have used an isolated ligand binding domain, GluR2-SlS2J (GluR2), as a model system to study the protein-ligand complex by steady-state and time-resolved intrinsic tryptophan fluorescence measurements. Specifically, we determined that the widely used and structurally characterized antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), acts as an efficient fluorescence energy transfer (FET) acceptor for Trp. Consistent with crystallographic data our results indicate that the four native tryptophans are within Forster's radius (R(o) similar to 33 angstrom) of the bound ligand. Additionally, we demonstrate the broader value of this technique by identifying an original FET ligand, 3-nitrotyrosine (3NY), for GluR2 (R(o) similar to 24 angstrom; apparent dissociation constant K(d) similar to 170 mu M). Estimated average donor-acceptor (Trp-ligand) distance extracted from tryptophan excited-state decays are similar for both ligands (similar to 24 angstrom), suggesting that 3NY binds in the structurally characterized ligand binding cleft. Moreover, an alternative competition assay utilizing Trp -> DNQX quenching for detection of ligand binding in GluR2 is described. C1 [Petrik, Amy F.; Strub, Marie-Paule; Lee, Jennifer C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Lee, JC (reprint author), NHLBI, Lab Mol Biophys, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM leej4@mail.nih.gov FU National Institutes of Health, National Heart, Lung, and Blood Institute FX This work is supported by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute. NR 38 TC 1 Z9 1 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 MAR 9 PY 2010 VL 49 IS 9 BP 2051 EP 2057 DI 10.1021/bi9020007 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 560UK UT WOS:000274928500026 PM 20155979 ER PT J AU Attardo, GM Ribeiro, JMC Wu, YN Berriman, M Aksoy, S AF Attardo, Geoffrey M. Ribeiro, Jose M. C. Wu, Yineng Berriman, Matthew Aksoy, Serap TI Transcriptome analysis of reproductive tissue and intrauterine developmental stages of the tsetse fly (Glossina morsitans morsitans) SO BMC GENOMICS LA English DT Article ID DROSOPHILA-MELANOGASTER; SEQUENCE ALIGNMENT; MOLECULAR ASPECTS; GENE ONTOLOGY; YOLK PROTEINS; PSI-BLAST; DATABASE; EXPRESSION; PHYLOGENY; FAMILIES AB Background: Tsetse flies, vectors of African trypanosomes, undergo viviparous reproduction (the deposition of live offspring). This reproductive strategy results in a large maternal investment and the deposition of a small number of progeny during a female's lifespan. The reproductive biology of tsetse has been studied on a physiological level; however the molecular analysis of tsetse reproduction requires deeper investigation. To build a foundation from which to base molecular studies of tsetse reproduction, a cDNA library was generated from female tsetse (Glossina morsitans morsitans) reproductive tissues and the intrauterine developmental stages. 3438 expressed sequence tags were sequenced and analyzed. Results: Analysis of a nonredundant catalogue of 1391 contigs resulted in 520 predicted proteins. 475 of these proteins were full length. We predict that 412 of these represent cytoplasmic proteins while 57 are secreted. Comparison of these proteins with other tissue specific tsetse cDNA libraries (salivary gland, fat body/milk gland, and midgut) identified 51 that are unique to the reproductive/immature cDNA library. 11 unique proteins were homologus to uncharacterized putative proteins within the NR database suggesting the identification of novel genes associated with reproductive functions in other insects (hypothetical conserved). The analysis also yielded seven putative proteins without significant homology to sequences present in the public database (unknown genes). These proteins may represent unique functions associated with tsetse's viviparous reproductive cycle. RTPCR analysis of hypothetical conserved and unknown contigs was performed to determine basic tissue and stage specificity of the expression of these genes. Conclusion: This paper identifies 51 putative proteins specific to a tsetse reproductive/ immature EST library. 11 of these proteins correspond to hypothetical conserved genes and 7 proteins are tsetse specific. C1 [Attardo, Geoffrey M.; Wu, Yineng; Aksoy, Serap] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Ribeiro, Jose M. C.] NIAID, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Rockville, MD USA. [Berriman, Matthew] Wellcome Trust Sanger Inst, Hinxton CB10 1SA, England. RP Aksoy, S (reprint author), Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. EM serap.aksoy@yale.edu RI Berriman, Matthew/A-7618-2011; OI Aksoy, Serap/0000-0001-9941-143X; Ribeiro, Jose/0000-0002-9107-0818 FU NIH [AI51584, AI081774, F32 GM077964]; National Institute of Allergy and Infectious Diseases; Wellcome Trust [WT 085775/Z/08/Z]; WHO/TDR FX This research was supported by grants from NIH AI51584 and AI081774 to SA, the NIH Ruth Kirschstein Postdoctoral Training Award F32 GM077964 to GMA and by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases to JMCR. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the government of the United States of America.; Because JMCR 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. MB is supported by the Wellcome Trust [grant number WT 085775/Z/08/Z]. This study is part of the International Glossina Genomics Initiative (IGGI), established in 2004 with support from WHO/TDR to promote knowledge on Glossina biology including host-pathogen interactions, genetics of vector competence, olfactory biology and population genetics to support vector control efforts. NR 41 TC 17 Z9 17 U1 0 U2 7 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 MAR 9 PY 2010 VL 11 AR 160 DI 10.1186/1471-2164-11-160 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 579IT UT WOS:000276363700002 PM 20214793 ER PT J AU Pemberton, VL McCrindle, BW Barkin, S Daniels, SR Barlow, SE Binns, HJ Cohen, MS Economos, C Faith, MS Gidding, SS Goldberg, CS Kavey, RE Longmuir, P Rocchini, AP Van Horn, L Kaltman, JR AF Pemberton, Victoria L. McCrindle, Brian W. Barkin, Shari Daniels, Stephen R. Barlow, Sarah E. Binns, Helen J. Cohen, Meryl S. Economos, Christina Faith, Myles S. Gidding, Samuel S. Goldberg, Caren S. Kavey, Rae-Ellen Longmuir, Patricia Rocchini, Albert P. Van Horn, Linda Kaltman, Jonathan R. TI Report of the National Heart, Lung, and Blood Institute's Working Group on Obesity and Other Cardiovascular Risk Factors in Congenital Heart Disease SO CIRCULATION LA English DT Article DE diet; exercise; heart defects, congenital; obesity; risk factors ID ARTERIAL SWITCH OPERATION; PHYSICAL-ACTIVITY LEVELS; RANDOMIZED CONTROLLED-TRIAL; OBSTRUCTIVE SLEEP-APNEA; QUALITY-OF-LIFE; CHILDHOOD OBESITY; CARDIAC REHABILITATION; SCIENTIFIC STATEMENT; EXERCISE CAPACITY; PRESSURE RESEARCH C1 [Pemberton, Victoria L.] NHLBI, NIH, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [McCrindle, Brian W.; Longmuir, Patricia] Univ Toronto, Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Barkin, Shari] Vanderbilt Univ, Nashville, TN USA. [Daniels, Stephen R.] Univ Colorado, Boulder, CO 80309 USA. [Barlow, Sarah E.] Baylor Coll Med, Houston, TX 77030 USA. [Binns, Helen J.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Binns, Helen J.; Van Horn, Linda] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Cohen, Meryl S.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Economos, Christina] Tufts Univ, Boston, MA 02111 USA. [Faith, Myles S.] Univ Penn, Philadelphia, PA 19104 USA. [Gidding, Samuel S.] Alfred I DuPont Hosp Children, Wilmington, DE USA. [Goldberg, Caren S.; Rocchini, Albert P.] Univ Michigan, Ann Arbor, MI 48109 USA. RP Pemberton, VL (reprint author), NHLBI, NIH, Div Cardiovasc Sci, 6701 Rockledge Dr,Room 8102, Bethesda, MD 20892 USA. EM pembertonv@nhlbi.nih.gov FU National Heart, Lung, and Blood Institute, National Institutes of Health FX The WG meeting was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health. NR 62 TC 37 Z9 38 U1 0 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 9 PY 2010 VL 121 IS 9 BP 1153 EP 1159 DI 10.1161/CIRCULATIONAHA.109.921544 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 565XR UT WOS:000275331600012 PM 20212294 ER PT J AU Narayan, KMV Aviles-Santa, L Oza-Frank, R Pandey, M Curb, JD McNeely, M Araneta, MRG Palaniappan, L Rajpathak, S Barrett-Connor, E AF Narayan, K. M. Venkat Aviles-Santa, Larissa Oza-Frank, Reena Pandey, Mona Curb, J. David McNeely, Marguerite Araneta, Maria Rosario G. Palaniappan, Latha Rajpathak, Swapnil Barrett-Connor, Elizabeth CA Cardiovasc Dis Asian Pacific Islan TI Report of a National Heart, Lung, and Blood Institute Workshop: Heterogeneity in Cardiometabolic Risk in Asian Americans in the US Opportunities for Research SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE cardiovascular disease; type 2 diabetes; Asian Americans; Pacific Islanders; ethnicity; disparity ID GESTATIONAL DIABETES-MELLITUS; JAPANESE-AMERICANS; CARDIOVASCULAR-DISEASE; VISCERAL ADIPOSITY; GLUCOSE-TOLERANCE; WHITE WOMEN; MULTIETHNIC POPULATION; CORONARY CALCIFICATION; INSULIN SENSITIVITY; ETHNIC-DIFFERENCES AB The Asian and Pacific Islander population (Asian Americans) in the U.S. has increased dramatically in the last few decades. Yet, data on cardiovascular disease (CVD) in this population are scarce. The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health conducted an Expert Workshop to: 1) assess the importance of studying CVD in Asian Americans in the U.S.; and 2) consider strategic options for further investigations of CVD in this population. There is considerable geographical, ethnic, cultural, and genetic diversity within this population. Limited data also suggest striking differences in the risk of CVD, obesity, type 2 diabetes mellitus, and other CVD risk factors across the Asian-American population. The Asian-American population is a new diverse pool with less contemporary genetic and cultural admixture relative to groups that have lived in the U.S. for generations, plus it is diverse in lifestyle including culture, diet, and family structure. This diversity provides a window of opportunity for research on genes and gene-environment interactions and also to investigate how acculturation/assimilation to U.S. lifestyles affects health and CVD risk among relatively homogenous groups of recent immigrants. Given the heterogeneity in body weight, body size, and CVD risk, the Asian-American population in the U.S. offers a unique model to study the interaction and relationships between visceral adiposity and adipose tissue distribution and beta cell function, insulin resistance, and atherosclerosis. (J Am Coll Cardiol 2010; 55: 966-73) (C) 2010 by the American College of Cardiology Foundation C1 [Narayan, K. M. Venkat; Oza-Frank, Reena] Emory Univ, Hubert Dept Global Hlth, Atlanta, GA 30322 USA. [Aviles-Santa, Larissa; Pandey, Mona] NHLBI, NIH, Bethesda, MD 20892 USA. [McNeely, Marguerite] Univ Washington, Seattle, WA 98195 USA. [Araneta, Maria Rosario G.; Barrett-Connor, Elizabeth] Univ Calif San Diego, La Jolla, CA 92093 USA. [Palaniappan, Latha] Palo Alto Med Fdn Res Inst, Palo Alto, CA USA. [Rajpathak, Swapnil] Yeshiva Univ, Albert Einstein Coll Med, New York, NY 10033 USA. RP Narayan, KMV (reprint author), Emory Univ, Hubert Dept Global Hlth, 1518 Clifton Rd, Atlanta, GA 30322 USA. EM knaraya@emory.edu RI Narayan, K.M. Venkat /J-9819-2012 OI Narayan, K.M. Venkat /0000-0001-8621-5405 FU National Heart, Lung, and Blood Institute at the National Institutes of Health; Zymogenetics FX This paper was a product of a workshop sponsored and conducted by the National Heart, Lung, and Blood Institute at the National Institutes of Health. Dr. McNeely has received salary support of <$6,000 from Zymogenetics for study on risk factors for coagulopathy in post-surgical patients (October 2008 to May 2009); this support is not directly related to this article. NR 65 TC 40 Z9 41 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 9 PY 2010 VL 55 IS 10 BP 966 EP 973 DI 10.1016/j.jacc.2009.07.075 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 563OW UT WOS:000275143200002 PM 20202512 ER PT J AU Bruni, AC Bernardi, L Colao, R Rubino, E Smirne, N Frangipane, F Terni, B Curcio, SAM Mirabelli, M Clodomiro, A Di Lorenzo, R Maletta, R Anfossi, M Gallo, M Geracitano, S Tomaino, C Muraca, MG Leotta, A Lio, SG Pinessi, L Rainero, I Sorbi, S Nee, L Milan, G Pappata, S Postiglione, A Abbamondi, N Forloni, G Hyslop, PSG Rogaeva, E Bugiani, O Giaccone, G Foncin, JF Spillantini, MG Puccio, G AF Bruni, A. C. Bernardi, L. Colao, R. Rubino, E. Smirne, N. Frangipane, F. Terni, B. Curcio, S. A. M. Mirabelli, M. Clodomiro, A. Di Lorenzo, R. Maletta, R. Anfossi, M. Gallo, M. Geracitano, S. Tomaino, C. Muraca, M. G. Leotta, A. Lio, S. G. Pinessi, L. Rainero, I. Sorbi, S. Nee, L. Milan, G. Pappata, S. Postiglione, A. Abbamondi, N. Forloni, G. Hyslop, P. St. George Rogaeva, E. Bugiani, O. Giaccone, G. Foncin, J. F. Spillantini, M. G. Puccio, G. TI Worldwide distribution of PSEN1 Met146Leu mutation A large variability for a founder mutation SO NEUROLOGY LA English DT Article ID ONSET ALZHEIMER-DISEASE; FRONTOTEMPORAL DEMENTIA; PRESENILIN-1 MUTATION; S182 GENE; FAMILIES; AD; PHENOTYPES AB Objective: Large kindreds segregating familial Alzheimer disease (FAD) offer the opportunity of studying clinical variability as observed for presenilin 1 (PSEN1) mutations. Two early-onset FAD (EOFAD) Calabrian families with PSEN1 Met146Leu (ATG/CTG) mutation constitute a unique population descending from a remote common ancestor. Recently, several other EOFAD families with the same mutation have been described worldwide. Methods: We searched for a common founder of the PSEN1 Met146Leu mutation in families with different geographic origins by genealogic and molecular analyses. We also investigated the phenotypic variability at onset in a group of 50 patients (mean age at onset 40.0 +/- 4.8 years) by clinical, neuropsychological, and molecular methodologies. Results: EOFAD Met146Leu families from around the world resulted to be related and constitute a single kindred originating from Southern Italy before the 17th century. Phenotypic variability at onset is broad: 4 different clinical presentations may be recognized, 2 classic for AD (memory deficits and spatial and temporal disorientation), whereas the others are expressions of frontal impairment. The apathetic and dysexecutive subgroups could be related to orbital-medial prefrontal cortex and dorsolateral prefrontal cortex dysfunction. Conclusions: Genealogic and molecular findings provided evidence that the PSEN1 Met146Leu families from around the world analyzed in this study are related and represent a single kindred originating from Southern Italy. The marked phenotypic variability might reflect early involvement by the pathologic process of different cortical areas. Although the clinical phenotype is quite variable, the neuropathologic and biochemical characteristics of the lesions account for neurodegenerative processes unmistakably of Alzheimer nature. Neurology (R) 2010; 74: 798-806 C1 [Bruni, A. C.; Bernardi, L.; Colao, R.; Smirne, N.; Frangipane, F.; Curcio, S. A. M.; Mirabelli, M.; Clodomiro, A.; Di Lorenzo, R.; Maletta, R.; Anfossi, M.; Gallo, M.; Geracitano, S.; Tomaino, C.; Muraca, M. G.; Puccio, G.] ASP Catanzaro, Ctr Reg Neurogenet, I-88046 Lamezia Terme, CZ, Italy. [Leotta, A.; Lio, S. G.] ASP Catanzaro, Dept Pathol, I-88046 Lamezia Terme, CZ, Italy. [Rubino, E.; Pinessi, L.; Rainero, I.] Univ Turin, Neurol Dept Neurosci 2, I-10124 Turin, Italy. [Terni, B.; Spillantini, M. G.] Brain Repair Ctr, Cambridge, England. [Sorbi, S.] Univ Florence, Dept Neurol Sci, I-50121 Florence, Italy. [Nee, L.] NIH, Bethesda, MD 20892 USA. [Milan, G.; Postiglione, A.] Univ Naples Federico 2, Dementia Study Ctr, Dept Clin & Expt Dis, Naples, Italy. [Milan, G.; Abbamondi, N.] ASL Napoli 1, Naples, Italy. [Pappata, S.] CNR, Inst Biomaging & Biostruct, I-80125 Naples, Italy. [Forloni, G.] Mario Negri Inst Pharmacol Res, Dept Neurosci, Milan, Italy. [Hyslop, P. St. George; Rogaeva, E.] Univ Toronto, Dept Med, Ctr Res Neurodegenerat Dis, Toronto, ON, Canada. [Bugiani, O.; Giaccone, G.] Neurol Inst Carlo Besta, Dept Neuropathol, Neurol Inst, Milan, Italy. [Foncin, J. F.] Lab Neurohistol EPHE, Brie Comte Robert, France. RP Bruni, AC (reprint author), ASP Catanzaro, Ctr Reg Neurogenet, Viale A Perugini, I-88046 Lamezia Terme, CZ, Italy. EM bruni@arn.it RI Giaccone, Giorgio/J-6212-2012; Rubino, Elisa/K-3282-2016; , raffaele/K-4421-2016 OI Rubino, Elisa/0000-0002-7553-7553; sorbi, sandro/0000-0002-0380-6670; , raffaele/0000-0002-0758-1835 FU Novartis; Boehringer Ingelheim; Wyeth; Canadian Institutes of Health; European Union; Medical Research Council UK; Alzheimer's Research Trust; Parkinson's Diseases Society UK; Multiple Sclerosis Society UK FX Dr. Bruni, Dr. Bernardi, Dr. Colao, Dr. Rubino, Dr. Smirne, Dr. Frangipane, Dr. Terni, Dr. Curcio, Dr. Mirabelli, Dr. Clodomiro, Dr. Di Lorenzo, Dr. Maletta, Dr. Anfossi, Dr. Gallo, Dr. Geracitano, Dr. Tomaino, Dr. Muraca, Dr. Leotta, Dr. Lio, and Dr. Pinessi report no disclosures. Dr. Rainero serves as an Associate Editor of the Journal of Headache and Pain. Dr. Sorbi has received research support from Novartis, Boehringer Ingelheim, and Wyeth. Dr. Nee, Dr. Milan, Dr. Pappata, Dr. Postiglione, Dr. Abbamondi, and Dr. Forloni report no disclosures. Dr. St. George Hyslop receives research support from the Canadian Institutes of Health. Dr. Rogaeva and Dr. Bugiani report no disclosures. Dr. Giaccone receives research support from the European Union. Dr. Foncin reports no disclosures. Dr. Spillantini has served/serves on scientific advisory boards for Fond de la Recherche and the Alzheimer's Research Trust; has received travel expenses and/or honoraria for lectures or educational activities not funded by industry; serves on the editorial advisory board of Brain Pathology Synapse Neurodegenerative Diseases; has filed a patent regarding artificial tau filaments; and receives research support from the Medical Research Council UK, the European Union, Alzheimer's Research Trust, Parkinson's Diseases Society UK, and Multiple Sclerosis Society UK. Dr. Puccio reports no disclosures. NR 31 TC 19 Z9 19 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 9 PY 2010 VL 74 IS 10 BP 798 EP 806 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 565XT UT WOS:000275331900004 PM 20164095 ER PT J AU Resnick, SM Sojkova, J Zhou, Y An, Y Ye, W Holt, DP Dannals, RF Mathis, CA Klunk, WE Ferrucci, L Kraut, MA Wong, DF AF Resnick, S. M. Sojkova, J. Zhou, Y. An, Y. Ye, W. Holt, D. P. Dannals, R. F. Mathis, C. A. Klunk, W. E. Ferrucci, L. Kraut, M. A. Wong, D. F. TI Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [C-11]PiB SO NEUROLOGY LA English DT Article ID PRECLINICAL ALZHEIMERS-DISEASE; REFERENCE TISSUE MODEL; NONDEMENTED INDIVIDUALS; SPATIAL CONSTRAINT; OLDER-ADULTS; IMPAIRMENT; PET; DEPOSITION; DEMENTIA; BRAIN AB Objective: To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (A beta) deposition in vivo in individuals without dementia. Method: [C-11]PiB images were obtained to measure fibrillar A beta burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [C-11]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations. Results: [C-11]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions. Conclusions: Higher A beta deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early A beta deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging. Neurology (R) 2010; 74: 807-815 C1 [Resnick, S. M.] NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. [Sojkova, J.; Zhou, Y.; Ye, W.; Holt, D. P.; Dannals, R. F.; Kraut, M. A.; Wong, D. F.] Johns Hopkins Univ, Dept Radiol, Baltimore, MD USA. [Wong, D. F.] Johns Hopkins Univ, Dept Psychiat & Neurosci, Baltimore, MD USA. [An, Y.] MedStar Res Inst, Hyattsville, MD USA. [Mathis, C. A.] Univ Pittsburgh, Dept Radiol, Pittsburgh, PA 15260 USA. [Klunk, W. E.] Univ Pittsburgh, Dept Psychiat & Neurol, Pittsburgh, PA 15260 USA. RP Resnick, SM (reprint author), NIA, Lab Personal & Cognit, NIH, 251 Bayview Blvd BRC Room 4B335, Baltimore, MD 21224 USA. EM susan.resnick@nih.gov OI Klunk, William/0000-0001-5512-0251 FU NIH/NIA; Elan Corporation; GE Healthcare; Bayer-Schering Pharma; IBA; Takeda Pharmaceutical Company Limited; Neuroptix Corporation; NIH [AG018402, NIA 5 R37 AG025516, NIA 1 P01 AG025204, NIA 1 U01 AG028526, NIA 5 P50 AG005133, NIA 2 R01 AG018402, NIA 5 U01 AG024904-03S3, NIBIB 1 R01 AG026240, NIA 1 R01 AG031110, NIMH 2 R01 MH085328-05A1, NIMH 1 R01 MH077852-1, NIA 300-N01-AG40012, NIAAA R01AA12839]; US Department of Energy; Dana Foundation; Elan Corporation/Janssen; Roche; AstraZeneca; Veterans Administration; Avid Radiopharmaceuticals, Inc.; AmgenBristol-Myers Squibb; Intra-Cellular Therapies, Inc.; Eli Lilly and Company; Merck Serono; Orexigen Therapeutics, Inc.; Otsuka Pharmaceutical Co., Ltd.; sanofi-aventis; Rett Syndrome Research Foundation FX GE Healthcare holds a license agreement with the University of Pittsburgh based on the PiB technology described in this manuscript. Drs. Klunk and Mathis are co-inventors of PiB and, as such, have a financial interest in this license agreement. Dr. Resnick serves as Action Editor for Brain and Cognition; and receives research support from the NIH/NIA Intramural Research Program. Dr. Sojkova, Dr. Zhou, Mr. An, Dr. Ye, Dr. Holt report no disclosures. Dr. Dannals serves as editor of the Journal of Labelled Compounds and Radiopharmaceuticals. Dr. Mathis serves on a scientific advisory board for Neuroptix Corporation; has received funding for travel and speaker honoraria from Elan Corporation, GE Healthcare, Bayer-Schering Pharma, IBA, and Takeda Pharmaceutical Company Limited; serves on the editorial board of Nuclear Medicine and Biology; may accrue revenue on over 20 active US and international patents, 1996present re: amyloid imaging agents; serves as a consultant for GE Healthcare, Elan Corporation, Wyeth, and Novartis; estimates that 30% of his academic effort is spent on PiB imaging, which might benefit the commercial license holder of the technology, GE Healthcare, and the University of Pittsburgh as the licensor of the technology; has received/ receives research support from GE Healthcare, Neuroptix Corporation, the NIH (AG018402 [PI]), the US Department of Energy, the Dana Foundation, and the Anonymous Foundation; holds stock options in Neuroptix Corporation; and has received license fees and will receive future royalties from GE Healthcare (amyloid imaging agents for brain applications) and Neuroptix Corporation (amyloid imaging agents for eye applications). Dr. Klunk serves on scientific advisory boards for GE Healthcare, Neuroptix Corporation, Elan Corporation/ Janssen, Roche, AstraZeneca; has received funding for travel from Elan Corporation/Janssen, Roche, AstraZeneca, and for lectures or educational activities not funded by industry; holds patents US 7,270,800 (plus related), issued 2007: PiB PET Imaging and US 6,168,776 (plus related), issued 2001: Chrysamine-G Derivatives for imaging and therapy; has received honoraria from Cerebrio LLC; receives research support from Neuroptix Corporation, the NIH (NIA 5 R37 AG025516 [PI], NIA 1 P01 AG025204 [PI], NIA 1 U01 AG028526 [PI], NIA 5 P50 AG005133 [Co-I], NIA 2 R01 AG018402 [Co-I], NIA 5 U01 AG024904-03S3 [Co-I], NIBIB 1 R01 AG026240 [Co-I], NIA 1 R01 AG031110 [Co-I]), and the Anonymous Foundation; has received license fees and will receive future royalties from GE Healthcare (PiB PET Imaging) and Neuroptix Corporation (Chrysamine G Derivatives); and holds stock in Neuroptix Corporation. Dr. Ferrucci serves as Editor-in-Chief of the Journals of Gerontology Medical Sciences. Dr. Kraut serves on the editorial board of the Journal of Magnetic Resonance Imaging; receives royalty from publication of Neural Basis of Semantic Memory (Cambridge University Press, 2007); receives research support from the NIH (NIMH 2 R01 MH085328-05A1 [Co-I], NIMH 1 R01 MH077852-1 [Co-I], NIA 300-N01-AG40012 [Co-I]), and from the Veterans Administration. Dr. Wong serves on editorial advisory boards for Neuropsychopharmacology, the Journal of Cerebral Blood Flow and Metabolism, and Molecular Imaging and Biology; and has received/ receives research support from Avid Radiopharmaceuticals, Inc., Amgen, Bristol-Myers Squibb, Intra-Cellular Therapies, Inc., Eli Lilly and Company, Merck Serono, Orexigen Therapeutics, Inc., Otsuka Pharmaceutical Co., Ltd.; , Roche, sanofi-aventis, the NIH (NIAAA R01AA12839 [PI], NIA K24, DA00412 [PI], NIMH R01 MH078175 [PI], NIAAA R01 AA010158 [Co-I], NIDA R21DA020777 [Co-I], NIMH R33 MH079017 [Co-I], NIMH R01 MH64823 [Co-I], NIMH U01 MH075378 [Co-I], NIDA R21 DA016182 [Co-I], NIDA R01DA022433 [PI on subcontract]), the DANA Foundation, and the Rett Syndrome Research Foundation. NR 17 TC 134 Z9 135 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 9 PY 2010 VL 74 IS 10 BP 807 EP 815 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 565XT UT WOS:000275331900005 PM 20147655 ER PT J AU Davis, M Auh, S Riva, M Richert, ND Frank, JA McFarland, HF Bagnato, F AF Davis, M. Auh, S. Riva, M. Richert, N. D. Frank, J. A. McFarland, H. F. Bagnato, F. TI Ring and nodular multiple sclerosis lesions A retrospective natural history study SO NEUROLOGY LA English DT Article ID MAGNETIZATION-TRANSFER MR; INTERFERON-BETA; GADOLINIUM ENHANCEMENT; SPIN-ECHO; SERIAL; EVOLUTION; DEMYELINATION; BREAKDOWN; ATROPHY; MARKER AB Background: In patients with multiple sclerosis (MS), contrast-enhancing lesions (CELs) on post-contrast MRI are considered markers of the inflammatory responses associated with blood-brain barrier breakdown. Based upon shape, CELs may be defined as nodular (nCEL) or ring (rCEL) lesions. Several short-term studies pointed towards the assumption that rCELs represent areas of a more aggressive inflammatory process. Methods: In the present long-term (i.e., 2 years) retrospective natural history study, we used monthly imaging to follow rCEL and nCELs evolution in 16 patients with MS during the natural history. New CELs were identified monthly on month 4-9 MRIs, using month 1-3 MRIs to ensure that all CELs were not previously enhancing. Chronic black holes (cBHs) were counted monthly upon CEL disappearance up to the 24th MRI. Generalized estimating equation methods investigated within-patient differences between rCELs and nCELs in volume and likelihood to convert into cBHs. Kaplan-Meier survival curves estimated differences in the length of persistence between cBHs originating from nCELs and cBHs deriving from rCELs. Results: Fifty-two new rCELs and 281 nCELs were identified. rCELs had larger mean (z = 5.06, p <= 0.0001) volumes than nCELs. The proportion of cBHs from rCELs was similar (z = 1.81, p = 0.0710) to the proportion of cBHs from nCELs. Likewise, the length of persistence of cBHs deriving from rCELs was similar (chi(2)(1) = 2.339, p = 0.1262) to the duration of cBHs from nCELs. Conclusions: Our data suggest that worse radiologic characteristics associated with the acute phase of ring contrast-enhancing lesions and nodular contrast-enhancing lesions do not necessarily reflect a poorer lesion outcome over time. Neurology (R) 2010; 74: 851-856 C1 [Davis, M.; Riva, M.; Richert, N. D.; McFarland, H. F.; Bagnato, F.] NINDS, NIB, NIH, Bethesda, MD 20892 USA. [Auh, S.] NINDS, Off Clin Director Biostat Unit, NIH, Bethesda, MD 20892 USA. [Frank, J. A.] NIH, Lab Radiol & Imaging Sci Clin Canter, Bethesda, MD 20892 USA. [Frank, J. A.] Natl Inst Biomed Imaging & Bioengn, Intramural Res Program, NIH, Bethesda, MD USA. RP Bagnato, F (reprint author), NINDS, NIB, NIH, Bldg 10,Room 5C103,10 Ctr Dr, Bethesda, MD 20892 USA. EM bagnatof@ninds.nih.gov OI Riva, Marco/0000-0003-4643-6451 FU NINDS, NIH FX Supported by the Intramural Research Program of the NINDS, NIH. NR 27 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 9 PY 2010 VL 74 IS 10 BP 851 EP 856 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 565XT UT WOS:000275331900012 PM 20211910 ER PT J AU Di Pasquale, G Kaludov, N Agbandje-McKenna, M Chiorini, JA AF Di Pasquale, Giovanni Kaludov, Nikola Agbandje-McKenna, Mavis Chiorini, John A. TI BAAV Transcytosis Requires an Interaction with beta-1-4 Linked-Glucosamine and gp96 SO PLOS ONE LA English DT Article ID BOVINE ADENOASSOCIATED VIRUS; GROWTH-FACTOR RECEPTOR; BLOOD-BRAIN-BARRIER; ESCHERICHIA-COLI; TYPE-2 INFECTION; EPITHELIAL-CELLS; INNER-EAR; PROTEIN; BINDING; CORECEPTOR AB Cell surface carbohydrates play an important role in virus entry and intracellular trafficking. Bovine Adeno-Associated Virus (BAAV) uses plasma membrane gangliosides for transduction and infection. In addition, independent of the infectious pathway, BAAV also has the ability to pass through barrier epithelia and endothelia using a transcytosis pathway dependent upon the presence of cell surface carbohydrates. Thus, in order to better define the carbohydrate interactions that are necessary for BAAV infection or transcytosis, a glycan microarray composed of both natural and synthetic carbohydrates was probed with HA-tagged BAAV particles. This identified chitotriose, a trimer of beta-1-4-linked N-acetyl glucosamine, as having an interaction with BAAV. Competition experiments showed that the BAAV interaction with this carbohydrate is not necessary for infection but is instead important in the transcytosis pathway. The beta-1-4-linked N-acetyl glucosamine modification has been reported on gp96, a glycoprotein involved in the transcytosis of bacteria and toxins. Significantly, immunoprecipitation and competition experiments with an anti-gp96 antibody and a soluble form of gp96, respectively, showed this glycoprotein can also interact with BAAV to serve as a receptor for its transcytosis. C1 [Di Pasquale, Giovanni; Kaludov, Nikola; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. [Agbandje-McKenna, Mavis] Univ Florida, Coll Med, Dept Biochem & Mol Biol, McKnight Brain Inst, Gainesville, FL 32610 USA. RP Di Pasquale, G (reprint author), Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, NIH, Bethesda, MD USA. EM jchiorini@dir.nidcr.nih.gov FU National Institutes of Health [R01 GM082946]; NIH National Institute of Dental and Craniofacial Research; National Institute of General Medical Sciences [GM62116] FX This work is also supported by National Institutes of Health R01 GM082946 to MAM and an NIH National Institute of Dental and Craniofacial Research intramural grant to JAC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Consortium for Functional Glycomics is funded by National Institute of General Medical Sciences grant GM62116. NR 40 TC 16 Z9 16 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 MAR 9 PY 2010 VL 5 IS 3 AR e9336 DI 10.1371/journal.pone.0009336 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565XA UT WOS:000275328300002 PM 20231878 ER PT J AU Ferrer-i-Cancho, R Elvevag, B AF Ferrer-i-Cancho, Ramon Elvevag, Brita TI Random Texts Do Not Exhibit the Real Zipf's Law-Like Rank Distribution SO PLOS ONE LA English DT Article ID INTERMITTENT SILENCE; POWER LAWS; LANGUAGE AB Background: Zipf's law states that the relationship between the frequency of a word in a text and its rank ( the most frequent word has rank 1, the 2nd most frequent word has rank 2,...) is approximately linear when plotted on a double logarithmic scale. It has been argued that the law is not a relevant or useful property of language because simple random texts-constructed by concatenating random characters including blanks behaving as word delimiters-exhibit a Zipf's law-like word rank distribution. Methodology/Principal Findings: In this article, we examine the flaws of such putative good fits of random texts. We demonstrate-by means of three different statistical tests-that ranks derived from random texts and ranks derived from real texts are statistically inconsistent with the parameters employed to argue for such a good fit, even when the parameters are inferred from the target real text. Our findings are valid for both the simplest random texts composed of equally likely characters as well as more elaborate and realistic versions where character probabilities are borrowed from a real text. Conclusions/Significance: The good fit of random texts to real Zipf's law-like rank distributions has not yet been established. Therefore, we suggest that Zipf's law might in fact be a fundamental law in natural languages. C1 [Ferrer-i-Cancho, Ramon] Univ Politecn Cataluna, Dept Llenguatges & Sistemes Informat, Barcelona, Catalonia, Spain. [Elvevag, Brita] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Ferrer-i-Cancho, R (reprint author), Univ Politecn Cataluna, Dept Llenguatges & Sistemes Informat, Barcelona, Catalonia, Spain. EM rferrericancho@lsi.upc.edu RI Ferrer-i-Cancho, Ramon/A-5424-2011 OI Ferrer-i-Cancho, Ramon/0000-0002-7820-923X FU Spanish Ministry of Science [TIN2008-06582-C03-01]; National Institute of Mental Health Intramural Research Program (NIMH-IRP) FX This work was partially supported by the project Secuencias Simbolicas: Analisis, Aprendizaje, Mineria y Evolucion, Barcelona (SESAAME-BAR) (TIN2008-06582-C03-01) of the Spanish Ministry of Science and Innovation, http://web.micinn.es/ (RFC); and the National Institute of Mental Health Intramural Research Program (NIMH-IRP), http://intramural.nimh.nih.gov/ (BE). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 34 TC 24 Z9 24 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 9 PY 2010 VL 5 IS 3 AR e9411 DI 10.1371/journal.pone.0009411 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565XA UT WOS:000275328300004 PM 20231884 ER PT J AU Kim, JH Park, JM Yea, K Kim, HW Suh, PG Ryu, SH AF Kim, Jong Hyun Park, Ji-Man Yea, Kyungmoo Kim, Hyun Wook Suh, Pann-Ghill Ryu, Sung Ho TI Phospholipase D1 Mediates AMP-Activated Protein Kinase Signaling for Glucose Uptake SO PLOS ONE LA English DT Article ID ADP-RIBOSYLATION FACTOR; RICH TYROSINE KINASE-2; MOUSE SKELETAL-MUSCLE; PLASMA-MEMBRANE; TRANSPORTER TRANSLOCATION; AS160 PHOSPHORYLATION; PHOSPHATIDIC-ACID; REGULATED KINASE; MAMMALIAN-CELLS; INSULIN AB Background: Glucose homeostasis is maintained by a balance between hepatic glucose production and peripheral glucose utilization. In skeletal muscle cells, glucose utilization is primarily regulated by glucose uptake. Deprivation of cellular energy induces the activation of regulatory proteins and thus glucose uptake. AMP-activated protein kinase (AMPK) is known to play a significant role in the regulation of energy balances. However, the mechanisms related to the AMPK-mediated control of glucose uptake have yet to be elucidated. Methodology/Principal Findings: Here, we found that AMPK-induced phospholipase D1 (PLD1) activation is required for (14)C-glucose uptake in muscle cells under glucose deprivation conditions. PLD1 activity rather than PLD2 activity is significantly enhanced by glucose deprivation. AMPK-wild type (WT) stimulates PLD activity, while AMPK-dominant negative (DN) inhibits it. AMPK regulates PLD1 activity through phosphorylation of the Ser-505 and this phosphorylation is increased by the presence of AMP. Furthermore, PLD1-S505Q, a phosphorylation-deficient mutant, shows no changes in activity in response to glucose deprivation and does not show a significant increase in (14)C-glucose uptake when compared to PLD1-WT. Taken together, these results suggest that phosphorylation of PLD1 is important for the regulation of (14)C-glucose uptake. In addition, extracellular signal-regulated kinase (ERK) is stimulated by AMPK-induced PLD1 activation through the formation of phosphatidic acid (PA), which is a product of PLD. An ERK pharmacological inhibitor, PD98059, and the PLD inhibitor, 1-BtOH, both attenuate (14)C-glucose uptake in muscle cells. Finally, the extracellular stresses caused by glucose deprivation or aminoimidazole carboxamide ribonucleotide (AICAR; AMPK activator) regulate (14)C-glucose uptake and cell surface glucose transport (GLUT) 4 through ERK stimulation by AMPK-mediated PLD1 activation. Conclusions/Significance: These results suggest that AMPK-mediated PLD1 activation is required for (14)C-glucose uptake through ERK stimulation. We propose that the AMPK-mediated PLD1 pathway may provide crucial clues to understanding the mechanisms involved in glucose uptake. C1 [Kim, Jong Hyun; Park, Ji-Man; Yea, Kyungmoo; Kim, Hyun Wook; Suh, Pann-Ghill; Ryu, Sung Ho] Pohang Univ Sci & Technol, Div Mol & Life Sci, Pohang, Kyungbuk, South Korea. [Kim, Jong Hyun] NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Kim, JH (reprint author), Pohang Univ Sci & Technol, Div Mol & Life Sci, Pohang, Kyungbuk, South Korea. EM sungho@postech.ac.kr RI Suh, Pann-Ghill/F-3610-2010 FU Ministry of Science and Technology in the Republic of Korea; National Institutes of Health (NIH) [GM 68849] FX This work was supported by a grant from the 21st Frontier Proteomics Research of the Ministry of Science and Technology in the Republic of Korea and National Institutes of Health (NIH) grant GM 68849 (W. C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 45 TC 10 Z9 10 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 MAR 9 PY 2010 VL 5 IS 3 AR e9600 DI 10.1371/journal.pone.0009600 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565XA UT WOS:000275328300016 PM 20231899 ER PT J AU Shea, PR Virtaneva, K Kupko, JJ Porcella, SF Barry, WT Wright, FA Kobayashi, SD Carmody, A Ireland, RM Sturdevant, DE Ricklefs, SM Babar, I Johnson, CA Graham, MR Gardner, DJ Bailey, JR Parnell, MJ DeLeo, FR Musser, JM AF Shea, Patrick R. Virtaneva, Kimmo Kupko, John J., III Porcella, Stephen F. Barry, William T. Wright, Fred A. Kobayashi, Scott D. Carmody, Aaron Ireland, Robin M. Sturdevant, Daniel E. Ricklefs, Stacy M. Babar, Imran Johnson, Claire A. Graham, Morag R. Gardner, Donald J. Bailey, John R. Parnell, Michael J. DeLeo, Frank R. Musser, James M. TI Interactome analysis of longitudinal pharyngeal infection of cynomolgus macaques by group A Streptococcus SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE epithelial growth factor receptor; host pathogen; microarray; Streptococcus pyogenes; transcriptome ID TRANSFER-RNA MODIFICATION; GROWTH-FACTOR RECEPTOR; T-CELL-ACTIVATION; GENE-EXPRESSION; ISOPRENOID BIOSYNTHESIS; PATHOGEN INTERACTIONS; ESCHERICHIA-COLI; HUMAN-SALIVA; PROTEIN; TRANSCRIPTOME AB Relatively little is understood about the dynamics of global host pathogen transcriptome changes that occur during bacterial infection of mucosal surfaces. To test the hypothesis that group A Streptococcus (GAS) infection of the oropharynx provokes a distinct host transcriptome response, we performed genome-wide transcriptome analysis using a nonhuman primate model of experimental pharyngitis. We also identified host and pathogen biological processes and individual host and pathogen gene pairs with correlated patterns of expression, suggesting interaction. For this study, 509 host genes and seven biological pathways were differentially expressed throughout the entire 32-day infection cycle. GAS infection produced an initial widespread significant decrease in expression of many host genes, including those involved in cytokine production, vesicle formation, metabolism, and signal transduction. This repression lasted until day 4, at which time a large increase in expression of host genes was observed, including those involved in protein translation, antigen presentation, and GTP-mediated signaling. The interactome analysis identified 73 host and pathogen gene pairs with correlated expression levels. We discovered significant correlations between transcripts of GAS genes involved in hyaluronic capsule production and host endocytic vesicle formation, GAS GTPases and host fibrinolytic genes, and GAS response to interaction with neutrophils. We also identified a strong signal, suggesting interaction between host gamma delta T cells and genes in the GAS mevalonic acid synthesis pathway responsible for production of isopentenyl-pyrophosphate, a short-chain phospholipid that stimulates these T cells. Taken together, our results are unique in providing a comprehensive understanding of the host-pathogen interactome during mucosal infection by a bacterial pathogen. C1 [Shea, Patrick R.; Musser, James M.] Methodist Hosp, Res Inst, Dept Pathol, Ctr Mol & Translat Human Infect Dis Res, Houston, TX 77030 USA. [Virtaneva, Kimmo; Kupko, John J., III; Porcella, Stephen F.; Carmody, Aaron; Sturdevant, Daniel E.; Ricklefs, Stacy M.; Babar, Imran; Johnson, Claire A.] NIAID, Genom Unit, Res Technol Sect, NIH, Hamilton, MT 59840 USA. [Kobayashi, Scott D.; Ireland, Robin M.; Graham, Morag R.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. [Gardner, Donald J.; Bailey, John R.; Parnell, Michael J.] NIAID, Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Barry, William T.; Wright, Fred A.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27599 USA. RP Musser, JM (reprint author), Methodist Hosp, Res Inst, Dept Pathol, Ctr Mol & Translat Human Infect Dis Res, 6535 Fannin, Houston, TX 77030 USA. EM jmmusser@tmhs.org OI DeLeo, Frank/0000-0003-3150-2516; Shea, Patrick/0000-0001-6804-5131 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Quantitative PCR (TaqMan) validation and correlation analysis were performed by Hannah Wilder and Craig Martens. We thank K. Stockbauer for assistance with figures. This work was supported in part by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 37 TC 15 Z9 15 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 9 PY 2010 VL 107 IS 10 BP 4693 EP 4698 DI 10.1073/pnas.0906384107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 566KF UT WOS:000275368400038 PM 20179180 ER PT J AU Biswal, BB Mennes, M Zuo, XN Gohel, S Kelly, C Smith, SM Beckmann, CF Adelstein, JS Buckner, RL Colcombe, S Dogonowski, AM Ernst, M Fair, D Hampson, M Hoptman, MJ Hyde, JS Kiviniemi, VJ Kotter, R Li, SJ Lin, CP Lowe, MJ Mackay, C Madden, DJ Madsen, KH Margulies, DS Mayberg, HS McMahon, K Monk, CS Mostofsky, SH Nagel, BJ Pekar, JJ Peltier, SJ Petersen, SE Riedl, V Rombouts, SARB Rypma, B Schlaggar, BL Schmidt, S Seidler, RD Siegle, GJ Sorg, C Teng, GJ Veijola, J Villringer, A Walter, M Wang, LH Weng, XC Whitfield-Gabrieli, S Williamson, P Windischberger, C Zang, YF Zhang, HY Castellanos, FX Milham, MP AF Biswal, Bharat B. Mennes, Maarten Zuo, Xi-Nian Gohel, Suril Kelly, Clare Smith, Steve M. Beckmann, Christian F. Adelstein, Jonathan S. Buckner, Randy L. Colcombe, Stan Dogonowski, Anne-Marie Ernst, Monique Fair, Damien Hampson, Michelle Hoptman, Matthew J. Hyde, James S. Kiviniemi, Vesa J. Kotter, Rolf Li, Shi-Jiang Lin, Ching-Po Lowe, Mark J. Mackay, Clare Madden, David J. Madsen, Kristoffer H. Margulies, Daniel S. Mayberg, Helen S. McMahon, Katie Monk, Christopher S. Mostofsky, Stewart H. Nagel, Bonnie J. Pekar, James J. Peltier, Scott J. Petersen, Steven E. Riedl, Valentin Rombouts, Serge A. R. B. Rypma, Bart Schlaggar, Bradley L. Schmidt, Sein Seidler, Rachael D. Siegle, Greg J. Sorg, Christian Teng, Gao-Jun Veijola, Juha Villringer, Arno Walter, Martin Wang, Lihong Weng, Xu-Chu Whitfield-Gabrieli, Susan Williamson, Peter Windischberger, Christian Zang, Yu-Feng Zhang, Hong-Ying Castellanos, F. Xavier Milham, Michael P. TI Toward discovery science of human brain function SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE database; neuroimaging; open access; reproducibility; resting state ID RESTING-STATE NETWORKS; BASE-LINE; SEXUAL-DIMORPHISM; CONNECTIVITY; MRI; ARCHITECTURE; CORTEX; FMRI; FLUCTUATIONS; ACTIVATION AB Although it is being successfully implemented for exploration of the genome, discovery science has eluded the functional neuroimaging community. The core challenge remains the development of common paradigms for interrogating the myriad functional systems in the brain without the constraints of a priori hypotheses. Resting-state functional MRI (R-fMRI) constitutes a candidate approach capable of addressing this challenge. Imaging the brain during rest reveals large-amplitude spontaneous low-frequency (< 0.1 Hz)fluctuations in the fMRI signal that are temporally correlated across functionally related areas. Referred to as functional connectivity, these correlations yield detailed maps of complex neural systems, collectively constituting an individual's "functional connectome." Reproducibility across datasets and individuals suggests the functional connectome has a common architecture, yet each individual's functional connectome exhibits unique features, with stable, meaningful interindividual differences in connectivity patterns and strengths. Comprehensive mapping of the functional connectome, and its subsequent exploitation to discern genetic influences and brain-behavior relationships, will require multicenter collaborative datasets. Here we initiate this endeavor by gathering R-fMRI data from 1,414 volunteers collected independently at 35 international centers. We demonstrate a universal architecture of positive and negative functional connections, as well as consistent loci of inter-individual variability. Age and sex emerged as significant determinants. These results demonstrate that independent R-fMRI datasets can be aggregated and shared. High-throughput R-fMRI can provide quantitative phenotypes for molecular genetic studies and biomarkers of developmental and pathological processes in the brain. To initiate discovery science of brain function, the 1000 Functional Connectomes Project dataset is freely accessible at www.nitrc.org/projects/fcon_1000/. C1 [Mennes, Maarten; Zuo, Xi-Nian; Kelly, Clare; Adelstein, Jonathan S.; Castellanos, F. Xavier; Milham, Michael P.] NYU, Phyllis Green & Randolph Cowen Inst Pediat Neuros, Ctr Child Study, Langone Med Ctr, New York, NY 10016 USA. [Biswal, Bharat B.; Gohel, Suril] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Radiol, Newark, NJ 07103 USA. [Smith, Steve M.; Beckmann, Christian F.; Mackay, Clare] Univ Oxford, FMRIB Ctr, Oxford OX3 9DU, England. [Buckner, Randy L.] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Colcombe, Stan] Univ Wales, Sch Psychol, Bangor, Gwynedd, Wales. [Dogonowski, Anne-Marie; Madsen, Kristoffer H.] Univ Copenhagen, Hvidovre Hosp, Danish Res Ctr Magnet Resonance, DK-2650 Hvidovre, Denmark. [Ernst, Monique] NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Fair, Damien] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97239 USA. [Hampson, Michelle] Yale Univ, Sch Med, Dept Diagnost Radiol, New Haven, CT 06511 USA. [Hoptman, Matthew J.; Castellanos, F. Xavier] Nathan S Kline Inst Psychiat Res, Div Clin Res, Orangeburg, NY 10962 USA. [Hyde, James S.; Li, Shi-Jiang] Med Coll Wisconsin, Biophys Res Inst, Milwaukee, WI 53226 USA. [Kiviniemi, Vesa J.] Oulu Univ Hosp, Dept Diagnost Radiol, Oulu, Finland. [Kotter, Rolf] Radboud Univ Nijmegen, Med Ctr, Donders Inst Brain Cognit & Behav, Ctr Neurosci, NL-6500 HB Nijmegen, Netherlands. [Lowe, Mark J.] Cleveland Clin, Imaging Inst, Cleveland, OH 44195 USA. [Madden, David J.; Wang, Lihong] Duke Univ, Med Ctr, Brain Imaging & Anal Ctr, Durham, NC 27710 USA. [Margulies, Daniel S.] Max Planck Inst Human Cognit & Brain Sci, Dept Cognit Neurol, D-04103 Leipzig, Germany. [Mayberg, Helen S.] Emory Univ, Sch Med, Dept Psychiat, Atlanta, GA 30322 USA. [Mayberg, Helen S.] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA. [McMahon, Katie] Univ Queensland, Ctr Adv Imaging, Brisbane, Qld, Australia. [Monk, Christopher S.; Seidler, Rachael D.] Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. [Mostofsky, Stewart H.] Kennedy Krieger Inst, Lab Neurocognit & Imaging Res, Baltimore, MD 21205 USA. [Nagel, Bonnie J.] Oregon Hlth & Sci Univ, Dept Psychiat, Portland, OR 97239 USA. [Pekar, James J.] Kennedy Krieger Inst, FM Kirby Res Ctr Funct Brain Imaging, Baltimore, MD 21205 USA. [Peltier, Scott J.] Univ Michigan, Funct MRI Lab, Ann Arbor, MI 48109 USA. [Petersen, Steven E.] Washington Univ, Sch Med, McDonnell Ctr Higher Brain Funct, St Louis, MO 63110 USA. [Riedl, Valentin] Tech Univ Munich, Klinikum Rechts Isar, Dept Neurol, D-81675 Munich, Germany. [Riedl, Valentin] Tech Univ Munich, Klinikum Rechts Isar, Dept Neuroradiol, D-81675 Munich, Germany. [Rombouts, Serge A. R. B.] Leiden Univ, Inst Psychol, Med Ctr, Leiden, Netherlands. [Rombouts, Serge A. R. B.] Leiden Univ, Dept Radiol, Med Ctr, Leiden, Netherlands. [Rypma, Bart] Univ Texas Dallas, Ctr Brain Hlth, Richardson, TX 75080 USA. [Rypma, Bart] Univ Texas Dallas, Sch Behav & Brain Sci, Richardson, TX 75080 USA. [Schlaggar, Bradley L.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Schmidt, Sein; Villringer, Arno] Charite, Dept Neurol, D-10117 Berlin, Germany. [Seidler, Rachael D.] Univ Michigan, Sch Kinesiol, Ann Arbor, MI 48109 USA. [Siegle, Greg J.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15213 USA. [Sorg, Christian] Tech Univ Munich, Klinikum Rechts Isar, Dept Psychiat, D-81675 Munich, Germany. [Teng, Gao-Jun; Zhang, Hong-Ying] Southeast Univ, Jiangsu Key Lab Mol & Funct Imaging, Dept Radiol, Zhong Da Hosp, Nanjing 210009, Peoples R China. [Veijola, Juha] Univ Oulu, Dept Psychiat, Inst Clin Med, Oulu 90014, Finland. [Veijola, Juha] Univ Oulu, Dept Publ Hlth Sci, Inst Hlth Sci, Oulu 90014, Finland. [Villringer, Arno] Berlin NeuroImaging Ctr, D-10099 Berlin, Germany. [Walter, Martin] Otto VonGuericke Univ Magdegurg, Dept Psychiat, D-39106 Magdeburg, Germany. [Weng, Xu-Chu] Chinese Acad Sci, Lab Higher Brain Funct, Inst Psychol, Beijing 100864, Peoples R China. [Whitfield-Gabrieli, Susan] MIT, Dept Brain & Cognit Sci, Harvard Mit Div Hlth Sci & Technol, Cambridge, MA 02139 USA. [Williamson, Peter] Univ Western Ontario, Dept Psychiat, London, ON N6A 3H8, Canada. [Windischberger, Christian] Med Univ Vienna, Ctr Med Phys & Biomed Engn, Vienna, Austria. [Zang, Yu-Feng] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. RP Milham, MP (reprint author), NYU, Phyllis Green & Randolph Cowen Inst Pediat Neuros, Ctr Child Study, Langone Med Ctr, 550 1St Ave, New York, NY 10016 USA. EM michael.milham@nyumc.org RI Riedl, Valentin/G-5466-2013; Margulies, Daniel/L-4719-2016; Hampson, Michelle/K-6732-2015; Li, Chong/F-4265-2015; Kelly, Clare/H-4629-2016; Zuo, Xi-Nian/A-7273-2009; Williamson, Peter/F-7462-2010; Mennes, Maarten/C-9924-2011; Beckmann, Christian/E-6374-2012; Wang, Lihong/D-8960-2011; McMahon, Katie/C-6440-2009; ZANG, Yu-Feng/J-1558-2012; Monk, Christopher/J-1805-2014; Milham, Michael/K-9501-2014; Madsen, Kristoffer Hougaard/M-9547-2014 OI Castellanos, Francisco/0000-0001-9192-9437; Riedl, Valentin/0000-0002-2861-8449; Margulies, Daniel/0000-0002-8880-9204; Mackay, Clare/0000-0001-6111-8318; Zuo, Xi-Nian/0000-0001-9110-585X; Hoptman, Matthew/0000-0003-4485-6102; Windischberger, Christian/0000-0002-9944-0190; Smith, Stephen/0000-0001-8166-069X; Hampson, Michelle/0000-0003-3173-4210; Kelly, Clare/0000-0001-8253-357X; Mennes, Maarten/0000-0002-7279-3439; McMahon, Katie/0000-0002-6357-615X; ZANG, Yu-Feng/0000-0003-1833-8010; Madsen, Kristoffer Hougaard/0000-0001-8606-7641 FU National Institutes of Mental Health [R01MH083246, R01MH081218]; National Institute on Drug Abuse [R03DA024775, R01DA016979]; Autism Speaks; National Institute of Neurological Disorders and Stroke [R01NS049176]; Howard Hughes Medical Institute; National Institutes of Health's Blueprint for Neurosciences Research [N02-EB-6-4281] FX We thank David Kennedy and www.nitrc.org for supporting the 1000 Functional Connectomes Project data release, Avi Snyder for providing helpful insights and advice concerning project goals, and Cameron Craddock for helpful advice on this study. Financial support for the 1000 Functional Connectomes project was provided by grants from the National Institutes of Mental Health (R01MH083246 and R01MH081218 to F. X. C. and M. P. M.), National Institute on Drug Abuse (R03DA024775, to C. K.; R01DA016979, to F. X. C.), Autism Speaks, National Institute of Neurological Disorders and Stroke (R01NS049176, to B. B.), and the Howard Hughes Medical Institute (to J.S.A. and R. L. B.), as well as gifts to the NYU Child Study Center from the Stavros Niarchos Foundation, Leon Levy Foundation, Joseph P. Healy, Linda and Richard Schaps, and Jill and Bob Smith and an endowment provided by Phyllis Green and Randolph Cowen. NITRC is funded by the National Institutes of Health's Blueprint for Neurosciences Research (neuro-scienceblueprint.nih.gov) (Contract N02-EB-6-4281, to TCG, Inc.). NR 50 TC 1025 Z9 1045 U1 24 U2 218 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 9 PY 2010 VL 107 IS 10 BP 4734 EP 4739 DI 10.1073/pnas.0911855107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 566KF UT WOS:000275368400045 PM 20176931 ER PT J AU Givens, JL Tjia, J Zhou, C Emanuel, E Ash, AS AF Givens, Jane L. Tjia, Jennifer Zhou, Chao Emanuel, Ezekiel Ash, Arlene S. TI Racial and Ethnic Differences in Hospice Use Among Patients With Heart Failure SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID OF-LIFE CARE; BLACK-AND-WHITE; AFRICAN-AMERICANS; OLDER-ADULTS; MEDICARE; ACCESS; CANCER; DIAGNOSES; BARRIERS; DEATH AB Background: Heart failure is the leading noncancer diagnosis for patients in hospice care and the leading cause of hospitalization among Medicare beneficiaries. Racial and ethnic differences in hospice patients are well documented for patients with cancer but poorly described for those with heart failure. Methods: On the basis of a national sample of 98 258 Medicare beneficiaries 66 years and older on January 1, 2001, with a diagnosis of heart failure who had at least 1 physician or hospital encounter and who were not enrolled in hospice care between January 1 and December 31, 2000, we determined the effect of race and ethnicity on hospice entry for patients with heart failure in 2001 after adjusting for sociodemographic, clinical, and geographic factors. Results: In unadjusted analysis, blacks ( odds ratio [OR], 0.52) and Hispanics (0.43) used hospice care for heart failure less than whites. Racial and ethnic differences in patients who received hospice care for heart failure persisted after adjusting for markers of income, urbanicity, severity of illness, local density of hospice use, and medical comorbidity ( adjusted OR for blacks, 0.59; 95% confidence interval, 0.47-0.73; and adjusted OR for Hispanics, 0.49; 95% confidence interval, 0.37-0.66; compared with whites). Advanced age, greater comorbidity, emergency department visits, hospitalizations, and greater local density of hospice use were also associated with hospice use. Conclusions: In a national sample of Medicare beneficiaries with heart failure, blacks and Hispanics used hospice care for heart failure less than whites after adjustment for individual and market factors. To understand the mechanisms underlying these findings, further examination of patient preferences and physician referral behavior is needed. C1 [Givens, Jane L.] Beth Israel Deaconess Med Ctr, Hebrew SeniorLife Inst Aging Res, Boston, MA 02131 USA. [Givens, Jane L.] Beth Israel Deaconess Med Ctr, Div Gerontol, Dept Med, Boston, MA 02131 USA. [Zhou, Chao; Ash, Arlene S.] Boston Univ, Sch Med, Hlth Care Res Unit, Boston, MA 02118 USA. [Tjia, Jennifer] Univ Massachusetts, Sch Med, Div Geriatr Med, Worcester, MA USA. [Emanuel, Ezekiel] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Givens, JL (reprint author), Beth Israel Deaconess Med Ctr, Hebrew SeniorLife Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA. EM janegivens@hrca.harvard.edu RI Max, Mad/E-5238-2010 OI Max, Mad/0000-0001-6966-6829 FU Department of Bioethics of the Clinical Center of the National Institutes of Health; National Institute on Aging Career Development [K08AG021527] FX This study was supported by contracts with the Department of Bioethics of the Clinical Center of the National Institutes of Health. Dr Tjia is supported by National Institute on Aging Career Development Award K08AG021527. NR 41 TC 34 Z9 34 U1 2 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 8 PY 2010 VL 170 IS 5 BP 427 EP 432 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 565PU UT WOS:000275307300006 PM 20212178 ER PT J AU Beauvais, G Jayanthi, S McCoy, MT Ladenheim, B Cadet, JL AF Beauvais, Genevieve Jayanthi, Subramaniam McCoy, Michael T. Ladenheim, Bruce Cadet, Jean Lud TI Differential effects of methamphetamine and SCH23390 on the expression of members of IEG families of transcription factors in the rat striatum SO BRAIN RESEARCH LA English DT Article DE IEG; RT-PCR; SCH23390; Signal transduction ID INDUCED NEURONAL APOPTOSIS; IMMEDIATE-EARLY GENES; EARLY REPRESSOR ICER; C-FOS; INDUCED NEUROTOXICITY; PROTEIN-KINASE; CELL-DEATH; REGULATED TRANSCRIPTION; SYNAPTIC PLASTICITY; TERMINAL KINASE AB Methamphetamine (METH) is a psychostimulant that can cause long-lasting neurodegenerative effects in humans and animals. These toxic effects appear to occur, in part, via activation of dopamine (DA) D1 receptors. This paper assessed the possibility that the DA D1 receptor antagonist, SCH23390, might inhibit METH-induced changes in the expression of several members of immediate early genes (IEGs) which are known to control more delayed expression of other genes. We found that injections of METH (4 x 10 mg/kg, given at 2 h intervals) caused significant increases in c-fos and fra-2 expression which lasted from 30 min to 4 h. Pre-treatment with SCH23390, given 30 min before each METH injection, completely blocked METH-induced expression of c-fos, but only partially inhibited fra-2 mRNA expression. These results were confirmed by Western blot analysis which showed METH-induced changes in c-Fos protein expression that were blocked by pretreatment with SCH23390. There were also delayed METH-induced DA D1 receptor- dependent effects on fosB mRNA expression. Even though fra-1 expression was not affected by pretreatment with METH alone, the repeated injections of SCH23390 caused substantial decreases in fra-1 mRNA expression in both the presence and absence of METH. The repeated injections of METH caused no changes in the mRNAs for c-jun, junB or junD. However, there were significant increases in the phosphorylation of c-Jun protein (ser63). Phosphorylation of c-Jun occurred in a delayed fashion (16 and 24 h after the last METH injections) and was attenuated by SCH23390 pretreatment. Interestingly, SCH23390 given alone caused significant decreases in phospho-c-Jun at all time-points. The METH injections also caused delayed induction in the expression of members of the Egr family of transcription factors in a DA D1 receptor- dependent fashion. Repeated injections of SCH23390 caused substantial suppression of basal striatal egr-1 and egr-2 mRNA expression but not of that of egr-3. Both crem and arc mRNA levels were induced by METH in a SCH23390-sensitive fashion. Moreover, multiple injections of SCH23390 given alone caused marked inhibition of basal arc expression. These results show that multiple injections of METH can differentially affect the expression of several IEGs, some of which occurred in a DA D1 receptor dependent fashion. The SCH23390-mediated suppression of basal fra-1, egr-1, and egr-2 mRNA levels suggests that their basal expression in the striatum might be dependent on tonic stimulation of the DA D1 receptor. Published by Elsevier B.V. C1 [Beauvais, Genevieve; Jayanthi, Subramaniam; McCoy, Michael T.; Ladenheim, Bruce; Cadet, Jean Lud] NIDA, Mol Neuropsychiat Res Branch, NIH, Intramural Res Program, Baltimore, MD 21224 USA. [Beauvais, Genevieve] Univ Paris 05, F-75006 Paris, France. RP Cadet, JL (reprint author), NIDA, Mol Neuropsychiat Res Branch, NIH, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM jcadet@intra.nida.nih.gov FU Intramural NIH HHS [ZIA DA000551-01] NR 43 TC 18 Z9 20 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAR 8 PY 2010 VL 1318 BP 1 EP 10 DI 10.1016/j.brainres.2009.12.083 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 565RS UT WOS:000275312600001 PM 20059987 ER PT J AU Mattson, MP AF Mattson, Mark P. TI The impact of dietary energy intake on cognitive aging SO FRONTIERS IN AGING NEUROSCIENCE LA English DT Review DE BDNF; diabetes; GLP-1; hippocampus; learning and memory; neurogenesis; synaptic plasticity AB Rodents that are insulin resistant and obese as the result of genetic factors, overeating and/or a sedentary lifestyle, exhibit cognitive deficits that worsen with advancing age compared to their more svelte counterparts. Data from epidemiological and clinical studies suggest similar adverse effects of excessive dietary energy intake and insulin resistance on cognition in humans. Our findings from studies of animal models suggest that dietary energy restriction can enhance neural plasticity and reduce the vulnerability of the brain to age-related dysfunction and disease. Dietary energy restriction may exert beneficial effects on the brain by engaging adaptive cellular stress response pathways resulting in the up-regulation of genes that encode proteins that promote neural plasticity and cell survival (e.g., neurotrophic factors, protein chaperones and redox enzymes). Two energy state-sensitive factors that are proving particularly important in regulating energy balance and improving/preserving cognitive function are brain-derived neurotrophic factor and glucagon-like peptide 1. Alternate day calorie restriction, novel insulin-sensitizing and neuroprotective agents, and drugs that activate adaptive stress response pathways, are examples of approaches for preserving cognitive function that show promise in preclinical studies. C1 NIA, Biomed Res Ctr, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), NIA, Biomed Res Ctr, Neurosci Lab, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov FU Intramural Research Program of the National Institute on Aging FX This work was supported by the Intramural Research Program of the National Institute on Aging. NR 124 TC 30 Z9 31 U1 2 U2 8 PU FRONTIERS RESEARCH FOUNDATION PI LAUSANNE PA PO BOX 110, LAUSANNE, 1015, SWITZERLAND SN 1663-4365 J9 FRONT AGING NEUROSCI JI Front. Aging Neurosci. PD MAR 8 PY 2010 VL 2 AR 5 DI 10.3389/neuro.24.005.2010 PG 12 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA V26PH UT WOS:000208557000001 PM 20552045 ER PT J AU Mukhopadhyay, D Arnaoutov, A Dasso, M AF Mukhopadhyay, Debaditya Arnaoutov, Alexei Dasso, Mary TI The SUMO protease SENP6 is essential for inner kinetochore assembly SO JOURNAL OF CELL BIOLOGY LA English DT Article ID MICROTUBULE INTERFACE; LIVING CELLS; CENP-A; COMPLEX; PATHWAY; MITOSIS; IDENTIFICATION; CENTROMERES; PROGRESSION; CHECKPOINT AB We have analyzed the mitotic function of SENP6, a small ubiquitin-like modifier (SUMO) protease that disassembles conjugated SUMO2/3 chains. Cells lacking SENP6 showed defects in spindle assembly and metaphase chromosome congression. Analysis of kinetochore composition in these cells revealed that a subset of proteins became undetectable on inner kinetochores after SENP6 depletion, particularly the CENP-H/I/K complex, whereas other changes in kinetochore composition mimicked defects previously reported to result from CENP-H/I/K depletion. We further found that CENP-I is degraded through the action of RNF4, a ubiquitin ligase which targets polysumoylated proteins for proteasomal degradation, and that SENP6 stabilizes CENP-I by antagonizing RNF4. Together, these findings reveal a novel mechanism whereby the finely balanced activities of SENP6 and RNF4 control vertebrate kinetochore assembly through SUMO-targeted destabilization of inner plate components. C1 [Mukhopadhyay, Debaditya; Arnaoutov, Alexei; Dasso, Mary] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Dasso, M (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, 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 (NICHD) [Z01 HD001902-14, Z01 HD008740-07] FX This work was supported by National Institute of Child Health and Human Development intramural funds (NICHD project #Z01 HD001902-14 and # Z01 HD008740-07). NR 39 TC 53 Z9 56 U1 0 U2 5 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 MAR 8 PY 2010 VL 188 IS 5 BP 681 EP 692 DI 10.1083/jcb.200909008 PG 12 WC Cell Biology SC Cell Biology GA 565XS UT WOS:000275331800008 PM 20212317 ER PT J AU Kedar, VP Darby, MK Williams, JG Blackshear, PJ AF Kedar, Vishram P. Darby, Martyn K. Williams, Jason G. Blackshear, Perry J. TI Phosphorylation of Human Tristetraprolin in Response to Its Interaction with the CbI Interacting Protein CIN85 SO PLOS ONE LA English DT Article ID TUMOR-NECROSIS-FACTOR; MESSENGER-RNA DECAY; ZINC-FINGER PROTEINS; GROWTH-FACTOR RECEPTORS; MAP KINASE PATHWAY; AU-RICH ELEMENTS; DOWN-REGULATION; TRANSCRIPTION FACTOR; DEFICIENCY SYNDROME; SIGNALING PATHWAY AB Background: Tristetraprolin (TTP) is the prototype member of a family of CCCH tandem zinc finger proteins and is considered to be an anti-inflammatory protein in mammals. TTP plays a critical role in the decay of tumor necrosis factor alpha (TNF) mRNA, among others, by binding AU-rich RNA elements in the 3'-untranslated regions of this transcript and promoting its deadenylation and degradation. Methodology/Principal Findings: We used yeast two-hybrid analysis to identify potential protein binding partners for human TTP (hTTP). Various regions of hTTP recovered 31 proteins that fell into 12 categories based on sequence similarities. Among these, the interactions between hTTP and CIN85, cytoplasmic poly (A) binding protein (PABP), nucleolin and heat shock protein 70 were confirmed by co-immunoprecipitation experiments. CIN85 and hTTP co-localized in the cytoplasm of cells as determined by confocal microscopy. CIN85 contains three SH3 domains that specifically bind a unique proline-arginine motif (PXXXPR) found in several CIN85 effectors. We found that the SH3 domains of CIN85 bound to a PXXXPR motif located near the C-terminus of hTTP. Co-expression of CIN85 with hTTP resulted in the increased phosphorylation of hTTP at serine residues in positions 66 and 93, possibly due in part to the demonstrated association of mitogen-activated protein kinase kinase kinase 4 (MEKK4) to both proteins. The presence of CIN85 did not appear to alter hTTP's binding to RNA probes or its stimulated breakdown of TNF mRNA. Conclusions/Significance: These studies describe interactions between hTTP and nucleolin, cytoplasmic PABP, heat shock protein 70 and CIN85; these interactions were initially discovered by two-hybrid analysis, and confirmed by coimmunoprecipitation. We found that CIN85 binding to a C-terminal motif within hTTP led to the increased phosphorylation of hTTP, possibly through enhanced association with MEKK4. The functional consequences to each of the members of this putative complex remain to be determined. C1 [Kedar, Vishram P.; Darby, Martyn K.; Blackshear, Perry J.] Natl Inst Environm Hlth Sci, Lab Signal Transduct, Res Triangle Pk, NC USA. [Williams, Jason G.] Natl Inst Environm Hlth Sci, Prot Microcharacterizat Core Facil, Res Triangle Pk, NC USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Kedar, VP (reprint author), Natl Inst Environm Hlth Sci, Lab Signal Transduct, Res Triangle Pk, NC USA. EM black009@niehs.nih.gov FU NIH; NIEHS FX This project was entirely supported by the Intramural Research Program of the NIH, NIEHS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 78 TC 17 Z9 17 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 8 PY 2010 VL 5 IS 3 BP A213 EP A227 AR e9588 DI 10.1371/journal.pone.0009588 PG 15 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565WZ UT WOS:000275328200020 PM 20221403 ER PT J AU Quaia, C Ying, HS Optican, LM AF Quaia, Christian Ying, Howard S. Optican, Lance M. TI The Viscoelastic Properties of Passive Eye Muscle in Primates. III: Force Elicited by Natural Elongations SO PLOS ONE LA English DT Article ID MODEL; TISSUE AB We have recently shown that in monkey passive extraocular muscles the force induced by a stretch does not depend on the entire length history, but to a great extent is only a function of the last elongation applied. This led us to conclude that Fung's quasi-linear viscoelastic (QLV) model, and more general nonlinear models based on a single convolution integral, cannot faithfully mimic passive eye muscles. Here we present additional data about the mechanical properties of passive eye muscles in deeply anesthetized monkeys. We show that, in addition to the aforementioned failures, previous models also grossly overestimate the force exerted by passive eye muscles during smooth elongations similar to those experienced during normal eye movements. Importantly, we also show that the force exerted by a muscle following an elongation is largely independent of the elongation itself, and it is mostly determined by the final muscle length. These additional findings conclusively rule out the use of classical viscoelastic models to mimic the mechanical properties of passive eye muscles. We describe here a new model that extends previous ones using principles derived from research on thixotropic materials. This model is able to account reasonably well for our data, and could thus be incorporated into models of the eye plant. C1 [Quaia, Christian; Optican, Lance M.] NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. [Ying, Howard S.] Johns Hopkins Univ Hosp, Wilmer Eye Inst, Dept Ophthalmol, Baltimore, MD 21287 USA. RP Quaia, C (reprint author), NEI, Sensorimotor Res Lab, Bldg 10, Bethesda, MD 20892 USA. EM quaiac@nei.nih.gov FU National Eye Institute (CQ, LMO); National Institutes of Health (NIH) [EY19347, EY15025]; Knights Templar Eye Foundation Young Investigator Award; Research to Prevent Blindness Core Grant FX This work was supported by the intramural research program of the National Eye Institute (CQ, LMO), by National Institutes of Health (NIH) grants NIH EY19347 and NIH EY15025 (HSY), the Knights Templar Eye Foundation Young Investigator Award (HSY), and Research to Prevent Blindness Core Grant (HSY). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 26 TC 10 Z9 10 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 8 PY 2010 VL 5 IS 3 BP A236 EP A254 AR e9595 DI 10.1371/journal.pone.0009595 PG 19 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 565WZ UT WOS:000275328200022 PM 20221406 ER PT J AU Thanos, PK Habibi, R Michaelides, M Patel, UB Suchland, K Anderson, BJ Robinson, JK Wang, GJ Grandy, DK Volkow, ND AF Thanos, Panayotis K. Habibi, Rahila Michaelides, Michael Patel, Ujval B. Suchland, Katherine Anderson, Brenda J. Robinson, John K. Wang, Gene-Jack Grandy, David K. Volkow, Nora D. TI Dopamine D4 receptor (D4R) deletion in mice does not affect operant responding for food or cocaine SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Reward; Addiction; Reinforcement; Cognition ID D-4 RECEPTOR; NOVELTY SEEKING; MUTANT MICE; GENE; POLYMORPHISM; DISORDER; RATS; IMPULSIVITY; D2 AB In this study we examined the genetic contribution of the D4R in food and cocaine self-administration using D4R mice. Mice were examined for operant responding to food pellets or intravenous cocaine. Compared to wild-type mice (D4R(+/+)), both heterozygous (D4R(+/-)) and knockout (D4R(-/-)) mice showed no difference in responding for food or cocaine. Our findings suggest that the D4R is not directly involved in mediating operant response behaviors for food or cocaine. Published by Elsevier B.V. C1 [Thanos, Panayotis K.; Habibi, Rahila; Michaelides, Michael; Patel, Ujval B.; Wang, Gene-Jack; Volkow, Nora D.] Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol & Neuroimaging Lab, Upton, NY 11973 USA. [Thanos, Panayotis K.; Volkow, Nora D.] NIAAA, Lab Neuroimaging, NIH, Bethesda, MD USA. [Thanos, Panayotis K.; Habibi, Rahila; Michaelides, Michael; Anderson, Brenda J.; Robinson, John K.] SUNY Stony Brook, Dept Psychol, Stony Brook, NY 11794 USA. [Suchland, Katherine; Grandy, David K.] Oregon Hlth & Sci Univ, Portland, OR USA. RP Thanos, PK (reprint author), Brookhaven Natl Lab, Dept Med, Behav Neuropharmacol & Neuroimaging Lab, Upton, NY 11973 USA. EM thanos@bnl.gov RI Michaelides, Michael/K-4736-2013 OI Michaelides, Michael/0000-0003-0398-4917 FU NIAAA (intramural Research Program, LNI); NIH IRTA program; Stony Brook URECA program; BNL SULI program FX Support contributed by: NIAAA (intramural Research Program, LNI), the NIH IRTA program, the Stony Brook URECA program and the BNL SULI program. We also thank N. Londono for her assistance with the D4 mouse breeding colony. NR 31 TC 9 Z9 9 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD MAR 5 PY 2010 VL 207 IS 2 BP 508 EP 511 DI 10.1016/j.bbr.2009.10.020 PG 4 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 558RC UT WOS:000274761800033 PM 19853629 ER PT J AU Suzuki, K Kimura, H Wu, H Kudo, N Kim, WB Suzuki, S Yoshida, A Caturegli, P Kohn, LD AF Suzuki, Koichi Kimura, Hiroaki Wu, Huhehasi Kudo, Naoko Kim, Won Bae Suzuki, Sayuri Yoshida, Akio Caturegli, Patrizio Kohn, Leonard D. TI Excess iodide decreases transcription of NIS and VEGF genes in rat FRTL-5 thyroid cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Iodide; Thyroid; NIS; VEGF; Thyroglobulin ID SODIUM/IODIDE SYMPORTER GENE; BLOOD-FLOW; STIMULATING HORMONE; LUGOL IODINE; EXPRESSION; HYPERTHYROIDISM; THYROGLOBULIN; SUPPRESSION; THYROTROPIN; FOLLICLES AB Although it is well known that an excess of iodide suppresses thyroid function and blood flow in vivo, the underlying molecular mechanisms are not fully known. The functional effect of iodide occurs at multiple steps, which include inhibition of sodium/iodide symporter (NIS) expression, transient block of organification, and inhibition of hormonal release. The vascular effect likely involves suppression of the vascular endothelial growth factor (VEGF) gene. In this report, we show that excess iodide coordinately suppresses the expression of the NIS and VEGF genes in FRTL-5 thyroid cells. We also demonstrate that the mechanism of iodide suppression of NIS gene expression is transcriptional, which is synergized by the addition of thyroglobulin. Based on the findings of reporter gene assays and electrophoretic gel mobility shift analysis, we also report two novel DNA binding proteins that responded specifically to iodide and modulated NIS promoter activity. The results suggest that excess iodide affects thyroid vascular function in addition to iodide uptake. This study provides additional insights into the mechanism of action of excess iodide on thyroid function. (C) 2010 Elsevier Inc. All rights reserved. C1 [Suzuki, Koichi; Wu, Huhehasi] Natl Inst Infect Dis, Leprosy Res Ctr, Lab Mol Diagnost, Higashimurayama, Tokyo 1890002, Japan. [Suzuki, Koichi; Kudo, Naoko; Kim, Won Bae; Yoshida, Akio; Kohn, Leonard D.] NIDDK, Cell Regulat Sect, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. [Suzuki, Koichi; Suzuki, Sayuri] Washington Hosp Ctr, Medstar Res Inst, Mol Endocrinol Lab, Washington, DC 20010 USA. [Kimura, Hiroaki; Caturegli, Patrizio] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD 21205 USA. [Kim, Won Bae] ASAN Med Ctr, Dept Internal Med, Div Endocrinol & Metab, Seoul 138736, South Korea. [Suzuki, Sayuri] Keio Univ, Sch Med, Dept Physiol, Tokyo 1608582, Japan. [Yoshida, Akio] Tottori Univ, Grad Sch Med, Dept Genet & Regenerat Med, Div Regenerat Med & Therapeut, Tottori 6838504, Japan. [Kohn, Leonard D.] Ohio Univ, Coll Osteopath Med, Edison Biotechnol Inst, Athens, OH 45701 USA. [Kohn, Leonard D.] Ohio Univ, Coll Osteopath Med, Dept Biomed Sci, Athens, OH 45701 USA. RP Suzuki, K (reprint author), Natl Inst Infect Dis, Leprosy Res Ctr, Lab Mol Diagnost, 4-2-1 Aoba Cho, Higashimurayama, Tokyo 1890002, Japan. EM koichis@nih.go.jp RI Suzuki, Sayuri/L-5291-2013; OI Kim, Won Bae/0000-0003-4544-1750 FU Ministry of Education, Culture, Sport, Science, and Technology of Japan [21591187]; NIH [DK55670] FX This work was supported in part by a Grant-in-Aid for Scientific Research by the Ministry of Education, Culture, Sport, Science, and Technology of Japan (21591187 to K.S.), and in part by an NIH grant (DK55670 to P.C.). NR 32 TC 15 Z9 18 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X EI 1090-2104 J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 5 PY 2010 VL 393 IS 2 BP 286 EP 290 DI 10.1016/j.bbrc.2010.01.123 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 573WT UT WOS:000275946700019 PM 20132794 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI The Incredible Expanding Ancestor of Eukaryotes SO CELL LA English DT Editorial Material ID EVOLUTION; GENOMES; COMPLEX; GENES C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov FU Intramural NIH HHS [ZIA LM000073-16] NR 9 TC 41 Z9 41 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 5 PY 2010 VL 140 IS 5 BP 606 EP 608 DI 10.1016/j.cell.2010.02.022 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 564EZ UT WOS:000275197400007 PM 20211127 ER PT J AU Lakatta, EG Maltsev, VA Vinogradova, TM AF Lakatta, Edward G. Maltsev, Victor A. Vinogradova, Tatiana M. TI A Coupled SYSTEM of Intracellular Ca2+ Clocks and Surface Membrane Voltage Clocks Controls the Timekeeping Mechanism of the Heart's Pacemaker SO CIRCULATION RESEARCH LA English DT Review DE sinoatrial node cells; ion channels; local Ca2+ releases; sarcoplasmic reticulum; ryanodine receptors ID RABBIT SINOATRIAL NODE; CELL-DERIVED CARDIOMYOCYTES; RECTIFIER POTASSIUM CURRENT; NA+-CA2+ EXCHANGE CURRENT; DEPENDENT PROTEIN-KINASE; PIG VENTRICULAR MYOCYTES; SUSTAINED INWARD CURRENT; SPONTANEOUS BEATING RATE; CAT RIGHT ATRIUM; SARCOPLASMIC-RETICULUM AB Ion channels on the surface membrane of sinoatrial nodal pacemaker cells (SANCs) are the proximal cause of an action potential. Each individual channel type has been thoroughly characterized under voltage clamp, and the ensemble of the ion channel currents reconstructed in silico generates rhythmic action potentials. Thus, this ensemble can be envisioned as a surface "membrane clock" (M clock). Localized subsarcolemmal Ca2+ releases are generated by the sarcoplasmic reticulum via ryanodine receptors during late diastolic depolarization and are referred to as an intracellular "Ca2+ clock," because their spontaneous occurrence is periodic during voltage clamp or in detergent-permeabilized SANCs, and in silico as well. In spontaneously firing SANCs, the M and Ca2+ clocks do not operate in isolation but work together via numerous interactions modulated by membrane voltage, subsarcolemmal Ca2+, and protein kinase A and CaMKII-dependent protein phosphorylation. Through these interactions, the 2 subsystem clocks become mutually entrained to form a robust, stable, coupled-clock system that drives normal cardiac pacemaker cell automaticity. G protein-coupled receptors signaling creates pacemaker flexibility, ie, effects changes in the rhythmic action potential firing rate, by impacting on these very same factors that regulate robust basal coupled-clock system function. This review examines evidence that forms the basis of this coupled-clock system concept in cardiac SANCs. (Circ Res. 2010; 106: 659-673.) C1 [Lakatta, Edward G.; Maltsev, Victor A.; Vinogradova, Tatiana M.] NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Gerontol Res Ctr, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM LakattaE@grc.nia.nih.gov FU National Institutes of Health, National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 105 TC 204 Z9 210 U1 4 U2 45 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD MAR 5 PY 2010 VL 106 IS 4 BP 659 EP 673 DI 10.1161/CIRCRESAHA.109.206078 PG 15 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 564CR UT WOS:000275190500007 PM 20203315 ER PT J AU Rada, B Leto, TL AF Rada, Balazs Leto, Thomas L. TI Characterization of hydrogen peroxide production by Duox in bronchial epithelial cells exposed to Pseudomonas aeruginosa SO FEBS LETTERS LA English DT Article DE NADPH oxidase; Hydrogen peroxide; Duox; Dual oxidase; Epithelial cell; Pseudomonas ID ATP-MEDIATED ACTIVATION; CYSTIC-FIBROSIS; HOST-DEFENSE; IMMUNE-RESPONSE; III SYSTEM; INFECTION; OXIDASES; CHILDREN AB Hydrogen peroxide production by the NADPH oxidase Duox1 occurs during activation of respiratory epithelial cells stimulated by purified bacterial ligands, such as lipopolysaccharide. Here, we characterize Duox activation using intact bacterial cells of several airway pathogens. We found that only Pseudomonas aeruginosa, not Burkholderia cepacia or Staphylococcus aureus, triggers H(2)O(2) production in bronchial epithelial cells in a calcium-dependent but predominantly ATP-independent manner. Moreover, by comparing mutant Pseudomonas strains, we identify several virulence factors that participate in Duox activation, including the type-three secretion system. These data provide insight on Duox activation by mechanisms unique to P. aeruginosa. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Rada, Balazs; Leto, Thomas L.] NIAID, Lab Host Defenses, NIH, Rockville, MD 20852 USA. RP Leto, TL (reprint author), NIAID, Lab Host Defenses, NIH, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM tleto@nih.gov FU NIH, National Institute of Allergy and Infectious Diseases FX We are grateful for research materials from the following sources: Anti-Duox antibodies (Dr. Corinne Dupuy, Institut Gustave-Roussy, FRE2939 CNRS), PAO1 strains (The Pseudomonas Mutant Library, UW, Seattle); PA14 strains (Dr. Frederick Ausubel, Massachusetts General Hospital, Boston); B. cepacia and S. aureus (Dr. Steven Holland, NIAID, NIH). This work was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. NR 20 TC 23 Z9 23 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAR 5 PY 2010 VL 584 IS 5 BP 917 EP 922 DI 10.1016/j.febslet.2010.01.025 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 559XK UT WOS:000274862900012 PM 20085766 ER PT J AU Rohrl, J Yang, D Oppenheim, JJ Hehlgans, T AF Roehrl, Johann Yang, De Oppenheim, Joost J. Hehlgans, Thomas TI Specific Binding and Chemotactic Activity of mBD4 and Its Functional Orthologue hBD2 to CCR6-expressing Cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN BETA-DEFENSINS; HUMAN BETA-DEFENSIN-3; DENDRITIC CELLS; EXPRESSION; IMMUNITY; KERATINOCYTES; INDUCTION; PEPTIDES; IMMATURE; INNATE AB beta-Defensins are small antimicrobial polypeptides that are mainly expressed by epithelial cells and play an important role in the antimicrobial innate immune response. In addition to the direct microbicidal effects of these polypeptides, members of the beta-defensin super family have the capacity to promote local innate inflammatory and systemic adaptive immune responses, which are in part mediated by the CC-chemokine receptor CCR6. Here we report the expression of recombinant mBD4 and its human orthologue hBD2 fused to the constant domain of human IgG(1) to obtain correct folding and to increase stability and solubility using the Drosophila S2 expression system. Purified recombinant mBD4:Ig and hBD2: Ig fusion proteins retained potent antimicrobial activity against Gram-negative and Gram-positive bacteria. Furthermore, these beta-defensin fusion proteins showed specific binding to CCR6-expressing cells as revealed by flow cytometry. Interestingly, although hBD2: Ig bound to both human and mouse CCR6-expressing cells, mBD4: Ig did only bind to mCCR6-expressing cells but not to hCCR6-expressing cells. Both beta-defensin fusion proteins demonstrated chemotactic activity for cells expressing the mouse CC-chemokine receptor CCR6. The chemokine ligand CCL20 competed with the beta-defensin fusion proteins for specific binding to CCR6 as analyzed by fluorescence-activated cell sorter analysis. Both beta-defensin fusion proteins demonstrated chemotactic activity for cells expressing the mouse CCR6 receptor, but mBD4: Ig did not induce chemotactic activity of cells expressing human CCR6. This result supports our finding that mBD4 does not interact with human CCR6-expressing cells. Further evidence for specific interaction of the beta-defensin fusion proteins with CCR6-expressing cells is demonstrated by the observation that CCL20 and beta-defensin fusion proteins desensitize each other in inducing chemotactic activity. In addition both mBD4: Ig and hBD2: Ig demonstrated CCR6-independent chemotaxis of freshly isolated mouse resident peritoneal cells and human peripheral blood mononuclear cells, indicating the interaction with another chemotaxis-inducing receptor. Thus, the beta-defensin fusion proteins used in this study retained their biological activity and are a feasible tool to identify and analyze specific beta-defensin receptor interactions. C1 [Hehlgans, Thomas] Univ Regensburg, Inst Immunol, D-93042 Regensburg, Germany. [Yang, De; Oppenheim, Joost J.] NCI Frederick, Mol Immunoregulat Lab, Canc & Inflammat Program, Ctr Canc Res,Div Basic Sci,NIH, Frederick, MD 21702 USA. RP Hehlgans, T (reprint author), Univ Regensburg, Inst Immunol, Franz Josef Strauss Allee 11, D-93042 Regensburg, Germany. EM thomas.hehlgans@klinik.uni-regensburg.de FU Bayerische Forschungsstifung [PDOK-62-08] FX This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported by Bayerische Forschungsstifung Grant PDOK-62-08 (to T.H.). NR 25 TC 37 Z9 39 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 5 PY 2010 VL 285 IS 10 BP 7028 EP 7034 DI 10.1074/jbc.M109.091090 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567AV UT WOS:000275415600016 PM 20068036 ER PT J AU Fletcher, PL Fletcher, MD Weninger, K Anderson, TE Martin, BM AF Fletcher, Paul L., Jr. Fletcher, Maryann D. Weninger, Keith Anderson, Trevor E. Martin, Brian M. TI Vesicle-associated Membrane Protein (VAMP) Cleavage by a New Metalloprotease from the Brazilian Scorpion Tityus serrulatus SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PANCREATIC ACINAR-CELLS; SNARE COMPLEX; REGULATED EXOCYTOSIS; SINGLE-MOLECULE; BOTULINUM NEUROTOXINS; SECRETORY GRANULES; GUINEA-PIG; FUSION; VENOM; BINDING AB We present evidence that venom from the Brazilian scorpion Tityus serrulatus and a purified fraction selectively cleave essential SNARE proteins within exocrine pancreatic tissue. Western blotting for vesicle-associated membrane protein type v-SNARE proteins (or synaptobrevins) reveals characteristic alterations to venom-treated excised pancreatic lobules in vitro. Immunocytochemistry by electron microscopy confirms both the SNARE identity as VAMP2 and the proteolysis of VAMP2 as a marked decrease in secondary antibody-conjugated colloidal gold particles that are predominantly associated with mature zymogen granules. Studies with recombinant SNARE proteins were used to determine the specific cleavage site in VAMP2 and the susceptibility of VAMP8 (endobrevin). The VAMP2 cleavage site is between the transmembrane anchor and the SNARE motif that assembles into the ternary SNARE complex. Inclusion of divalent chelating agents ( EDTA) with fraction nu, an otherwise active purified component from venom, eliminates SNARE proteolysis, suggesting the active protein is a metalloprotease. The unique cleavages of VAMP2 and VAMP8 may be linked to pancreatitis that develops following scorpion envenomation as both of these v-SNARE proteins are associated with zymogen granule membranes in pancreatic acinar cells. We have isolated antarease, a metalloprotease from fraction nu that cleaves VAMP2, and report its amino acid sequence. C1 [Fletcher, Paul L., Jr.; Fletcher, Maryann D.] E Carolina Univ, Dept Microbiol & Immunol, Brody Sch Med, Greenville, NC 27834 USA. [Weninger, Keith; Anderson, Trevor E.] N Carolina State Univ, Dept Phys, Raleigh, NC 27695 USA. [Martin, Brian M.] NIMH, Lab Neurotoxicol, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Fletcher, PL (reprint author), E Carolina Univ, Dept Microbiol & Immunol, Brody Sch Med, Greenville, NC 27834 USA. EM fletcherpa@ecu.edu FU East Carolina University Center for Coastal Informatics and Modeling Funds; Burroughs Wellcome Fund; National Institutes of Health; NIMH; Intramural Research Program FX This work was supported in part by the East Carolina University Center for Coastal Informatics and Modeling Funds ( to P. L. F.), a Career Award at the Scientific Interface from the Burroughs Wellcome Fund ( to K. W.), and by the National Institutes of Health, NIMH, Intramural Research Program (to B. M. M.). NR 55 TC 31 Z9 33 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 5 PY 2010 VL 285 IS 10 BP 7405 EP 7416 DI 10.1074/jbc.M109.028365 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567AV UT WOS:000275415600053 PM 20026600 ER PT J AU Umehara, T Nakamura, Y Jang, MK Nakano, K Tanaka, A Ozato, K Padmanabhan, B Yokoyama, S AF Umehara, Takashi Nakamura, Yoshihiro Jang, Moon Kyoo Nakano, Kazumi Tanaka, Akiko Ozato, Keiko Padmanabhan, Balasundaram Yokoyama, Shigeyuki TI Structural Basis for Acetylated Histone H4 Recognition by the Human BRD2 Bromodomain SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOTIC CHROMOSOMES; CRYSTAL-STRUCTURE; BINDING MODULES; LIVING CELLS; CHROMATIN; PROTEINS; MITOSIS; ACETYLTRANSFERASES; TRANSCRIPTION; ACTIVATION AB Recognition of acetylated chromatin by the bromodomains and extra-terminal domain (BET) family proteins is a hallmark for transcriptional activation and anchoring viral genomes to mitotic chromosomes of the host. One of the BET family proteins BRD2 interacts with acetylated chromatin during mitosis and leads to transcriptional activation in culture cells. Here, we report the crystal structures of the N-terminal bromodomain of human BRD2 (BRD2-BD1; residues 74-194) in complex with each of three different Lys-12-acetylated H4 peptides. The BRD2-BD1 recognizes the H4 tail acetylated at Lys-12 (H4K12ac), whereas the side chain of hypoacetylated Lys-8 of H4 binds at the cavity of the dimer interface of BRD2-BD1. From binding studies, we identified the BRD2-BD1 residues that are responsible for recognition of the Lys-12-acetylated H4 tail. In addition, mutationto Lys-8 in the Lys-12-acetylated H4 tail decreased the binding to BRD2-BD1, implicating the critical role of Lys-8 in the Lys-12-acetylated H4 tail for the recognition by BRD2-BD1. Our findings provide a structural basis for deciphering the histone code by the BET bromodomain through the binding with a long segment of the histone H4 tail, which presumably prevents erasure of the histone code during the cell cycle. C1 [Padmanabhan, Balasundaram; Yokoyama, Shigeyuki] RIKEN, Syst & Struct Biol Ctr, Yokohama, Kanagawa 2300045, Japan. [Jang, Moon Kyoo; Ozato, Keiko] NICHHD, Dept Mol Growth Regulat, Natl Inst Hlth, Bethesda, MD 20892 USA. [Yokoyama, Shigeyuki] Univ Tokyo, Dept Biophys & Biochem, Grad Sch Sci, Bunkyo Ku, Tokyo 1130033, Japan. RP Padmanabhan, B (reprint author), Aptuit Laurus Pvt, ICICI Knowledge Pk, Hyderabad 500078, Andhra Pradesh, India. EM paddy.b@aptuitlaurus.com; yokoyama@biochem.s.u-tokyo.ac.jp RI Umehara, Takashi/N-5683-2015; OI Umehara, Takashi/0000-0003-3464-2960; Yokoyama, Shigeyuki/0000-0003-3133-7338 FU National Institutes of Health; National Institute of Biomedical Innovation; RIKEN Structural Genomics/Proteomics Initiative; Ministry of Education, Culture, Sports, Science and Technology of Japan FX This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported in part by the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation, by the RIKEN Structural Genomics/Proteomics Initiative, and the National Project on Protein Structural and Functional Analyses, Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 41 TC 44 Z9 46 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 5 PY 2010 VL 285 IS 10 BP 7610 EP 7618 DI 10.1074/jbc.M109.062422 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567AV UT WOS:000275415600072 PM 20048151 ER PT J AU Wang, T Shah, YM Matsubara, T Zhen, YY Tanabe, T Nagano, T Fotso, S Krausz, KW Zabriskie, TM Idle, JR Gonzalez, FJ AF Wang, Ting Shah, Yatrik M. Matsubara, Tsutomu Zhen, Yueying Tanabe, Tomotaka Nagano, Tomokazu Fotso, Serge Krausz, Kristopher W. Zabriskie, T. Mark Idle, Jeffrey R. Gonzalez, Frank J. TI Control of Steroid 21-oic Acid Synthesis by Peroxisome Proliferator-activated Receptor alpha and Role of the Hypothalamic-Pituitary-Adrenal Axis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; ALDO-KETO REDUCTASE; NEUROPEPTIDE-Y NPY; NAKED PLASMID DNA; PPAR-ALPHA; ALDEHYDE DEHYDROGENASE; 20-ALPHA-HYDROXYSTEROID DEHYDROGENASE; SUCCESSIVE REACTIONS; TISSUE DISTRIBUTION; OXIDATIVE STRESS AB A previous study identified the peroxisome proliferator-activated receptor alpha (PPAR alpha) activation biomarkers 21-steroid carboxylic acids 11 beta-hydroxy-3,20-dioxopregn-4-en-21-oic acid (HDOPA) and 11 beta,20-dihydroxy-3-oxo-pregn-4-en-21-oic acid (DHOPA). In the present study, the molecular mechanism and the metabolic pathway of their production were determined. The PPAR alpha-specific time-dependent increases in HDOPA and 20 alpha-DHOPA paralleled the development of adrenal cortex hyperplasia, hypercortisolism, and spleen atrophy, which was attenuated in adrenalectomized mice. Wy-14,643 activation of PPAR alpha induced hepatic FGF21, which caused increased neuropeptide Y and agouti-related protein mRNAs in the hypothalamus, stimulation of the agouti-related protein/neuropeptide Y neurons, and activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased adrenal cortex hyperplasia and corticosterone production, revealing a link between PPAR alpha and the HPA axis in controlling energy homeostasis and immune regulation. Corticosterone was demonstrated as the precursor of 21-carboxylic acids both in vivo and in vitro. Under PPAR alpha activation, the classic reductive metabolic pathway of corticosterone was suppressed, whereas an alternative oxidative path-way was uncovered that leads to the sequential oxidation on carbon 21 resulting in HDOPA. The latter was then reduced to the end product 20 alpha-DHOPA. Hepatic cytochromes P450, aldehyde dehydrogenase (ALDH3A2), and 21-hydroxysteroid dehydrogenase (AKR1C18) were found to be involved in this pathway. Activation of PPAR alpha resulted in the induction of Aldh3a2 and Akr1c18, both of which were confirmed as target genes through introduction of promoter luciferase reporter constructs into mouse livers in vivo. This study underscores the power of mass spectrometry-based metabolomics combined with genomic and physiologic analyses in identifying downstream metabolic biomarkers and the corresponding upstream molecular mechanisms. C1 [Wang, Ting; Shah, Yatrik M.; Matsubara, Tsutomu; Zhen, Yueying; Tanabe, Tomotaka; Nagano, Tomokazu; Krausz, Kristopher W.; Idle, Jeffrey R.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fotso, Serge; Zabriskie, T. Mark] Oregon State Univ, Dept Pharmaceut Sci, Corvallis, OR 97331 USA. [Idle, Jeffrey R.] Charles Univ Prague, Inst Pharmacol, Fac Med 1, Prague 12800, Czech Republic. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov FU National Institutes of Health NCI Intramural Research; Center for Gastrointestinal Biology and Disease [P30 DK34987] FX This work was supported, in whole or in part, by National Institutes of Health NCI Intramural Research Program. This work was also supported by Center for Gastrointestinal Biology and Disease Grant P30 DK34987. NR 43 TC 11 Z9 11 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 5 PY 2010 VL 285 IS 10 BP 7670 EP 7685 DI 10.1074/jbc.M109.090175 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567AV UT WOS:000275415600077 PM 20032461 ER PT J AU Kloer, DP Rojas, R Ivan, V Moriyama, K van Vlijmen, T Murthy, N Ghirlando, R van der Sluijs, P Hurley, JH Bonifacino, JS AF Kloer, Daniel P. Rojas, Raul Ivan, Viorica Moriyama, Kengo van Vlijmen, Thijs Murthy, Namita Ghirlando, Rodolfo van der Sluijs, Peter Hurley, James H. Bonifacino, Juan S. TI Assembly of the Biogenesis of Lysosome-related Organelles Complex-3 (BLOC-3) and Its Interaction with Rab9 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HERMANSKY-PUDLAK-SYNDROME; MYOSIN-VA; VESICLE TRAFFICKING; GUNMETAL MOUSE; PROTEIN; GENE; FAMILY; HPS1; MELANOSOMES; TRANSPORT AB The Hermansky-Pudlak syndrome (HPS) is a genetic hypopigmentation and bleeding disorder caused by defective biogenesis of lysosome-related organelles (LROs) such as melanosomes and platelet dense bodies. HPS arises from mutations in any of 8 genes in humans and 16 genes in mice. Two of these genes, HPS1 and HPS4, encode components of the biogenesis of lysosome-related organelles complex-3 (BLOC-3). Herein we show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer. Analytical ultracentrifugation reveals that this complex has a molecular mass of 146 kDa, equivalent to that of the native complex and to the sum of the predicted molecular masses of HPS1 and HPS4. This indicates that HPS1 and HPS4 interact directly in the absence of any other protein as part of BLOC-3. Limited proteolysis and deletion analyses show that both subunits interact with one another throughout most of their lengths with the sole exception of a long, unstructured loop in the central part of HPS4. An interaction screen reveals a specific and strong interaction of BLOC-3 with the GTP-bound form of the endosomal GTPase, Rab9. This interaction is mediated by HPS4 and the switch I and II regions of Rab9. These characteristics indicate that BLOC-3 might function as a Rab9 effector in the biogenesis of LROs. C1 [Ghirlando, Rodolfo; Hurley, James H.] NIDDK, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. [Rojas, Raul; Moriyama, Kengo; Murthy, Namita; Bonifacino, Juan S.] Eunice Kennedy Shriver NICHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Ivan, Viorica; van Vlijmen, Thijs; van der Sluijs, Peter] Univ Med Ctr Utrecht, Dept Cell Biol, NL-3584 CX Utrecht, Netherlands. RP Hurley, JH (reprint author), NIDDK, NIH, Mol Biol Lab, Bldg 50 Rm 4517, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov; juan@helix.nih.gov RI van Vlijmen, Thijs/B-4069-2009; Ghirlando, Rodolfo/A-8880-2009; 何, 敏仪/E-6352-2015; OI van Vlijmen, Thijs/0000-0002-5882-6660; Bonifacino, Juan S./0000-0002-5673-6370 FU NICHD; NIDDK; Netherlands' Proteomics Center; DFG-NIH FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Programs of NICHD (to J. S. B.) and NIDDK (to J. H. H.), the Netherlands' Proteomics Center (to P. v. d. S.), and the DFG-NIH program (to D. P. K.). NR 45 TC 37 Z9 38 U1 2 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 5 PY 2010 VL 285 IS 10 BP 7794 EP 7804 DI 10.1074/jbc.M109.069088 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 567AV UT WOS:000275415600087 PM 20048159 ER PT J AU Pugeat, M Nader, N Hogeveen, K Raverot, G Dechaud, H Grenot, C AF Pugeat, Michel Nader, Nancy Hogeveen, Kevin Raverot, Gerald Dechaud, Henri Grenot, Catherine TI Sex hormone-binding globulin gene expression in the liver: Drugs and the metabolic syndrome SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Review DE SHBG; Sex steroid hormones; Risk factor; Diabetes; Metabolic syndrome; Fructose ID POLYCYSTIC-OVARY-SYNDROME; HUMAN HEPATOMA-CELLS; CARDIOVASCULAR RISK-FACTORS; POSTMENOPAUSAL WOMEN; SHBG GENE; ANOREXIA-NERVOSA; STEROID-HORMONES; THYROID-HORMONE; BREAST-CANCER; SERUM-LEVELS AB Sex hormone-binding globulin (SHBG) is the main transport binding protein for sex steroid hormones in plasma and regulates their accessibility to target cells. Plasma SHBG is secreted by the liver under the control of hormones and nutritional factors. In the human hepatoma cell line (HepG2), thyroid and estrogenic hormones, and a variety of drugs including the antioestrogen tamoxifen, the phytoestrogen, genistein and mitotane (Op'DDD) increase SHBG production and SHBG gene promoter activity. In contrast, monosaccharides (glucose or fructose) effectively decrease SHBG expression by inducing lipogenesis, which reduces hepatic HNF-4 alpha levels, a transcription factor that play a critical role in controlling the SHBG promoter. Interestingly, diminishing hepatic lipogenesis and free fatty acid liver biosynthesis also appear to be associated with the positive effects of thyroid hormones and PPAR gamma antagonists on SHBG expression. This mechanism provides a biological explanation for why SHBG is a sensitive biomarker of insulin resistance and the metabolic syndrome, and why low plasma SHBG levels are a risk factor for developing hyperglycemia and type 2 diabetes, especially in women. These important advances in our knowledge of the regulation of SHBG expression in the liver open new approaches for identifying and preventing metabolic disorder-associated diseases early in life. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Pugeat, Michel; Dechaud, Henri; Grenot, Catherine] Groupement Hosp Est, Hosp Civils Lyon, F-69677 Bron, France. [Pugeat, Michel; Hogeveen, Kevin; Raverot, Gerald] INSERM, U863, IFR 62, F-69003 Lyon, France. [Pugeat, Michel; Hogeveen, Kevin; Raverot, Gerald; Dechaud, Henri; Grenot, Catherine] Univ Lyon 1, F-69003 Lyon, France. [Nader, Nancy; Dechaud, Henri] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Pediat Endocrinol, Program Reprod & Adult Endocrinol, NIH, Bethesda, MD 20892 USA. RP Pugeat, M (reprint author), Groupement Hosp Est, Hosp Civils Lyon, 59 Bd Pinel, F-69677 Bron, France. EM michel.pugeat@chu-lyon.fr RI Perez , Claudio Alejandro/F-8310-2010; OI Perez , Claudio Alejandro/0000-0001-9688-184X; Raverot, Gerald/0000-0002-9517-338X NR 87 TC 40 Z9 44 U1 0 U2 16 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAR 5 PY 2010 VL 316 IS 1 SI SI BP 53 EP 59 DI 10.1016/j.mce.2009.09.020 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 553LR UT WOS:000274368700007 PM 19786070 ER PT J AU Ahlers, JD Belyakov, IM AF Ahlers, Jeffrey D. Belyakov, Igor M. TI Memories that last forever: strategies for optimizing vaccine T-cell memory SO BLOOD LA English DT Review ID MUCOSAL AIDS VACCINE; DENDRITIC CELLS; PROTECTIVE IMMUNITY; VIRAL-INFECTION; CUTTING EDGE; IN-VIVO; SECONDARY EXPANSION; EFFECTOR FUNCTIONS; RHESUS MACAQUES; THERAPEUTIC VACCINATION AB For acute self-limiting infections a vaccine is successful if it elicits memory at least as good as the natural experience; however, for persistent and chronic infections such as HIV, hepatitis C virus (HCV), human papillomavirus (HPV), and human herpes viruses, this paradigm is not applicable. At best, during persistent virus infection the person must be able to maintain the integrity of the immune system in equilibrium with controlling replicating virus. New vaccine strategies are required that elicit both potent high-avidity CD8(+) T-cell effector/memory and central memory responses that can clear the nidus of initial virus-infected cells at mucosal surfaces to prevent mucosal transmission or significantly curtail development of disease. The objective of an HIV-1 T-cell vaccine is to generate functional CD8(+) effector memory cells at mucosal portals of virus entry to prevent viral transmission. In addition, long-lived CD8(+) and CD4(+) central memory cells circulating through secondary lymphoid organs and resident in bone marrow, respectively, are needed to provide a concerted second wave of defense that can contain virus at mucosal surfaces and prevent systemic dissemination. Further understanding of factors which can influence long-lived effector and central memory cell differentiation will significantly contribute to development of effective T-cell vaccines. In this review we will focus on discussing mechanisms involved in T-cell memory and provide promising new approaches toward expanding current vaccine strategies to enhance antiviral memory. (Blood. 2010;115:1678-1689) C1 [Ahlers, Jeffrey D.] NIAID, NIH, Rockville, MD 20817 USA. [Belyakov, Igor M.] Midwest Res Inst, Frederick, MD USA. RP Ahlers, JD (reprint author), NIAID, NIH, 6700B Rockledge Dr,Rm 5138, Rockville, MD 20817 USA. EM jahlers@niaid.nih.gov; igorbelyakov@yahoo.com NR 133 TC 57 Z9 59 U1 1 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 4 PY 2010 VL 115 IS 9 BP 1678 EP 1689 DI 10.1182/blood-2009-06-227546 PG 12 WC Hematology SC Hematology GA 571KR UT WOS:000275751200007 PM 19903895 ER PT J AU Rutsch, S Neppalli, VT Shin, DM DuBois, W Morse, HC Goldschmidt, H Janz, S AF Rutsch, Sebastian Neppalli, Vishala T. Shin, Dong-Mi DuBois, Wendy Morse, Herbert C., III Goldschmidt, Hartmut Janz, Siegfried TI IL-6 and MYC collaborate in plasma cell tumor formation in mice SO BLOOD LA English DT Article ID HUMAN MULTIPLE-MYELOMA; C-MYC; BALB/C PLASMACYTOMAS; COMBINATION THERAPY; INTERLEUKIN-6 IL-6; BONE-MARROW; MOUSE MODEL; B-CELLS; GROWTH; NEOPLASMS AB Interleukin-6 (IL-6) plays a critical role in the natural history of human plasma cell neoplasms (PCNs), such as plasma cell myeloma and plasmacytoma (PCT). IL-6 is also at the center of neoplastic plasma cell transformation in BALB/c (C) mice carrying a transgene, H2-L(d)-IL6, that encodes human IL-6 under control of the major histocompatibility complex H2-L(d) promoter: strain C. H2-L(d)-IL6. These mice are prone to PCT, but tumor development is incomplete with long latencies (similar to 40% PCT at 12 months of age). To generate a more robust mouse model of IL-6-dependent PCN, we intercrossed strain C.H2-L(d)-IL6 with strains C.iMyc(E mu) or C.iMyc(C alpha), 2 interrelated gene-insertion models of the chromosomal T(12; 15) translocation causing deregulated expression of Myc in mouse PCT. Deregulation of MYC is also a prominent feature of human PCN. We found that double-transgenic C.H2L(d)-IL6/iMyc(E mu) and C.H2-L(d)-IL6/iMyc(C alpha) mice develop PCT with full penetrance (100% tumor incidence) and short latencies (3-6 months). The mouse tumors mimic molecular hallmarks of their human tumor counterparts, including elevated IL-6/Stat3/Bcl-X(L) signaling. The newly developed mouse strains may provide a good preclinical research tool for the design and testing of new approaches to target IL-6 in treatment and prevention of human PCNs. (Blood. 2010;115:1746-1754) C1 [Rutsch, Sebastian; Goldschmidt, Hartmut] Univ Heidelberg, Med Klin 5, Heidelberg, Germany. [Neppalli, Vishala T.; Janz, Siegfried] Natl Ctr Tumor Dis, Heidelberg, Germany. [Neppalli, Vishala T.; Janz, Siegfried] Univ Iowa, Dept Pathol, Roy J & Lucille A Carver Coll Med, Iowa City, IA 52242 USA. [Shin, Dong-Mi; Morse, Herbert C., III] NIAID, Immunopathol Lab, NIH, Rockville, MD USA. [DuBois, Wendy] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Janz, S (reprint author), 500 Newton Rd,1046 ML, Iowa City, IA 52242 USA. EM siegfried-janz@uiowa.edu OI Morse, Herbert/0000-0002-9331-3705 FU NIH; National Institute of Allergy and Infectious Diseases; NCI [P50CA097274] FX This work was supported in part by the Intramural Research Program of the NIH, the National Institute of Allergy and Infectious Diseases, and Award No. P50CA097274 from the NCI. NR 50 TC 27 Z9 27 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 MAR 4 PY 2010 VL 115 IS 9 BP 1746 EP 1754 DI 10.1182/blood-2009-08-237941 PG 9 WC Hematology SC Hematology GA 571KR UT WOS:000275751200015 PM 20018915 ER PT J AU Glauser, TA Cnaan, A Shinnar, S Hirtz, DG Dlugos, D Masur, D Clark, PO Capparelli, EV Adamson, PC AF Glauser, Tracy A. Cnaan, Avital Shinnar, Shlomo Hirtz, Deborah G. Dlugos, Dennis Masur, David Clark, Peggy O. Capparelli, Edmund V. Adamson, Peter C. CA Childhood Absence Epilepsy Study TI Ethosuximide, Valproic Acid, and Lamotrigine in Childhood Absence Epilepsy. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SEIZURES; MONOTHERAPY; CHILDREN; DIAGNOSIS AB Background: Childhood absence epilepsy, the most common pediatric epilepsy syndrome, is usually treated with ethosuximide, valproic acid, or lamotrigine. The most efficacious and tolerable initial empirical treatment has not been defined. Methods: In a double-blind, randomized, controlled clinical trial, we compared the efficacy, tolerability, and neuropsychological effects of ethosuximide, valproic acid, and lamotrigine in children with newly diagnosed childhood absence epilepsy. Drug doses were incrementally increased until the child was free of seizures, the maximal allowable or highest tolerable dose was reached, or a criterion indicating treatment failure was met. The primary outcome was freedom from treatment failure after 16 weeks of therapy; the secondary outcome was attentional dysfunction. Differential drug effects were determined by means of pairwise comparisons. Results: The 453 children who were randomly assigned to treatment with ethosuximide (156), lamotrigine (149), or valproic acid (148) were similar with respect to their demographic characteristics. After 16 weeks of therapy, the freedom-from-failure rates for ethosuximide and valproic acid were similar (53% and 58%, respectively; odds ratio with valproic acid vs. ethosuximide, 1.26; 95% confidence interval [CI], 0.80 to 1.98; P=0.35) and were higher than the rate for lamotrigine (29%; odds ratio with ethosuximide vs. lamotrigine, 2.66; 95% CI, 1.65 to 4.28; odds ratio with valproic acid vs. lamotrigine, 3.34; 95% CI, 2.06 to 5.42; P<0.001 for both comparisons). There were no significant differences among the three drugs with regard to discontinuation because of adverse events. Attentional dysfunction was more common with valproic acid than with ethosuximide (in 49% of the children vs. 33%; odds ratio, 1.95; 95% CI, 1.12 to 3.41; P=0.03). Conclusions: Ethosuximide and valproic acid are more effective than lamotrigine in the treatment of childhood absence epilepsy. Ethosuximide is associated with fewer adverse attentional effects. (ClinicalTrials.gov number, NCT00088452.) N Engl J Med 2010;362:790-9. C1 [Glauser, Tracy A.] Cincinnati Childrens Hosp, Div Neurol, Comprehens Epilepsy Ctr, Cincinnati, OH 45229 USA. [Glauser, Tracy A.] Univ Cincinnati, Coll Med, Cincinnati, OH USA. [Cnaan, Avital] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Shinnar, Shlomo; Masur, David] Albert Einstein Coll Med, Montefiore Med Ctr, New York, NY USA. [Hirtz, Deborah G.] NINDS, Bethesda, MD 20892 USA. [Dlugos, Dennis; Adamson, Peter C.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Capparelli, Edmund V.] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. [Capparelli, Edmund V.] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92103 USA. RP Glauser, TA (reprint author), Cincinnati Childrens Hosp, Div Neurol, Comprehens Epilepsy Ctr, 3333 Burnet Ave,MLC 2015, Cincinnati, OH 45229 USA. EM tracy.glauser@cchmc.org FU National Institutes of Health [NS045911, NS045803, 5 U10 HD031318, 5 U10 HD037249, 1 UL1 RR026314, P30 HD26979] FX Supported by grants from the National Institutes of Health (NS045911, NS045803, 5 U10 HD031318, 5 U10 HD037249, 1 UL1 RR026314, and P30 HD26979). NR 37 TC 185 Z9 191 U1 1 U2 32 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 4 PY 2010 VL 362 IS 9 BP 790 EP 799 DI 10.1056/NEJMoa0902014 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 563DQ UT WOS:000275108300006 PM 20200383 ER PT J AU Hesse, BW Moser, RP Rutten, LJ AF Hesse, Bradford W. Moser, Richard P. Rutten, Lila J. TI Surveys of Physicians and Electronic Health Information. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID NATIONAL TRENDS SURVEY; INTERNET C1 [Hesse, Bradford W.; Moser, Richard P.] NCI, Bethesda, MD 20892 USA. [Rutten, Lila J.] NCI, Frederick, MD 21701 USA. RP Hesse, BW (reprint author), NCI, Bethesda, MD 20892 USA. EM hesseb@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 NR 5 TC 58 Z9 59 U1 2 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAR 4 PY 2010 VL 362 IS 9 BP 859 EP 860 DI 10.1056/NEJMc0909595 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 563DQ UT WOS:000275108300031 PM 20200398 ER PT J AU Jantz, D Berg, JM AF Jantz, Derek Berg, Jeremy M. TI Probing the DNA-Binding Affinity and Specificity of Designed Zinc Finger Proteins SO BIOPHYSICAL JOURNAL LA English DT Article ID CONTROLLING GENE-EXPRESSION; FLUORESCENCE ANISOTROPY; TRANSCRIPTION FACTORS; PHAGE DISPLAY; EQUILIBRIUM BINDING; CHIMERIC NUCLEASES; ESTROGEN-RECEPTOR; CRYSTAL-STRUCTURE; SALT DEPENDENCE; LAC REPRESSOR AB Engineered transcription factors and endonucleases based on designed Cys(2)His(2) zinc finger domains have proven to be effective tools for the directed regulation and modification of genes. The introduction of this technology into both research and clinical settings necessitates the development of rapid and accurate means of evaluating both the binding affinity and binding specificity of designed zinc finger domains. Using a fluorescence anisotropy-based DNA-binding assay, we examined the DNA-binding properties of two engineered zinc finger proteins that differ by a single amino acid. We demonstrate that the protein with the highest affinity for a particular DNA site need not be the protein that binds that site with the highest degree of specificity. Moreover, by comparing the binding characteristics of the two proteins at varying salt concentrations, we show that the ionic strength makes significant and variable contributions to both affinity and specificity. These results have significant implications for zinc finger design as they highlight the importance of considering affinity, specificity, and environmental requirements in designing a DNA-binding domain for a particular application. C1 [Jantz, Derek; Berg, Jeremy M.] NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Berg, JM (reprint author), NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. EM bergj@mail.nih.gov OI Berg, Jeremy/0000-0003-3022-0963 FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of General Medical Sciences FX This work was Supported by the Intramural Research Program of the National Institute of Diabetes and Digestive and Kidney Diseases, and by the National Institute of General Medical Sciences. NR 52 TC 11 Z9 12 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAR 3 PY 2010 VL 98 IS 5 BP 852 EP 860 DI 10.1016/j.bpj.2009.11.021 PG 9 WC Biophysics SC Biophysics GA 564QV UT WOS:000275232100013 PM 20197039 ER PT J AU Hondares, E Rosell, M Gonzalez, FJ Giralt, M Iglesias, R Villarroya, F AF Hondares, Elayne Rosell, Meritxell Gonzalez, Frank J. Giralt, Marta Iglesias, Roser Villarroya, Francesc TI Hepatic FGF21 Expression Is Induced at Birth via PPAR alpha in Response to Milk Intake and Contributes to Thermogenic Activation of Neonatal Brown Fat SO CELL METABOLISM LA English DT Article ID FIBROBLAST GROWTH FACTOR-21; INSULIN SENSITIVITY; METABOLIC REGULATOR; LIPID-METABOLISM; GENE-EXPRESSION; MICE; LINK; FIBROBLAST-GROWTH-FACTOR-21; INDUCTION; OBESITY AB Plasma FGF21 levels and hepatic FGF21 gene expression increase dramatically after birth in mice. This induction is initiated by suckling, requires lipid intake, is impaired in PPAR alpha null neonates, and is mimicked by treatment with the PPAR alpha activator, Wy14,643. Neonates exhibit reduced FGF21 expression in response to fasting, in contrast to the upregulation occurring in adults. Changes in FGF21 expression due to suckling or nutritional manipulations were associated with circulating free fatty acid and ketone body levels. We mimicked the FGF21 postnatal rise by injecting FGF21 into fasting neonates, and found that this enhanced the expression of genes involved in thermogenesis within brown fat, and increased body temperature. Brown adipocytes treated with FGF21 exhibited increased expression of thermogenic genes, higher total and uncoupled respiration, and enhanced glucose oxidation. We propose that the induction of FGF21 production by the liver mediates direct activation of brown fat thermogenesis during the fetal-to-neonatal transition. C1 [Hondares, Elayne; Rosell, Meritxell; Giralt, Marta; Iglesias, Roser; Villarroya, Francesc] Univ Barcelona, Inst Biomed, Dept Bioquim & Biol Mol, E-08028 Barcelona, Catalonia, Spain. [Hondares, Elayne; Rosell, Meritxell; Giralt, Marta; Iglesias, Roser; Villarroya, Francesc] CIBER Fisiopatol Obesidad & Nutr CIBEROBN, Barcelona 08028, Catalonia, Spain. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Villarroya, F (reprint author), Univ Barcelona, Inst Biomed, Dept Bioquim & Biol Mol, E-08028 Barcelona, Catalonia, Spain. EM fvillarroya@ub.edu RI Giralt, Marta/A-4756-2013; Villarroya, Francesc/K-4357-2014; OI Giralt, Marta/0000-0001-7968-4190; Villarroya, Francesc/0000-0003-1266-9142 FU MCIN [SAF2008-01896]; Instituto de Salud Carlos III, Spain [PI081715] FX This work was supported by grants from MCIN (SAF2008-01896) and Instituto de Salud Carlos III (PI081715), Spain. NR 18 TC 153 Z9 157 U1 3 U2 21 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD MAR 3 PY 2010 VL 11 IS 3 BP 206 EP 212 DI 10.1016/j.cmet.2010.02.001 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 565WE UT WOS:000275325400007 PM 20197053 ER PT J AU Shi, Y Oury, F Yadav, VK Wess, J Liu, XS Guo, XE Murshed, M Karsenty, G AF Shi, Yu Oury, Franck Yadav, Vijay K. Wess, Juergen Liu, X. Sherry Guo, X. Edward Murshed, Monzur Karsenty, Gerard TI Signaling through the M-3 Muscarinic Receptor Favors Bone Mass Accrual by Decreasing Sympathetic Activity SO CELL METABOLISM LA English DT Article ID ACETYLCHOLINE-RECEPTOR; NERVOUS-SYSTEM; LEPTIN REGULATION; KNOCKOUT MICE; IN-VIVO; LACKING; GENE; STIMULATION; DISRUPTION; GROWTH AB Bone remodeling is regulated by various neuronal inputs, including sympathetic tone, which is known to inhibit bone mass accrual. This aspect of sympathetic nervous system function raises the prospect that the other arm of the autonomic nervous system, the parasympathetic nervous system, may also affect bone remodeling. Here, we use various mutant mouse strains, each lacking one of the muscarinic receptors that mediate parasympathetic activity, to show that the parasympathetic nervous system acting through the M-3 muscarinic receptor is a positive regulator of bone mass accrual, increasing bone formation and decreasing bone resorption. Gene expression studies, cell-specific gene deletion experiments, and analysis of compound mutant mice showed that the parasympathetic nervous system favors bone mass accrual by acting centrally and by decreasing the sympathetic tone. By showing that both arms of the autonomic nervous system affect bone remodeling, this study further underscores the importance of neuronal regulation of bone. C1 [Shi, Yu; Oury, Franck; Yadav, Vijay K.; Karsenty, Gerard] Columbia Univ, Coll Phys & Surg, Dept Genet & Dev, New York, NY 10032 USA. [Wess, Juergen] NIDDK, Mol Signaling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Liu, X. Sherry; Guo, X. Edward] Columbia Univ, Dept Biomed Engn, Bone Bioengn Lab, New York, NY 10027 USA. [Murshed, Monzur] McGill Univ, Fac Dent, Div Biomed Sci, Montreal, PQ H3A 1A4, Canada. [Murshed, Monzur] McGill Univ, Dept Med, Div Endocrinol & Metab, Montreal, PQ H3A 1A4, Canada. RP Karsenty, G (reprint author), Columbia Univ, Coll Phys & Surg, Dept Genet & Dev, New York, NY 10032 USA. EM gk2172@columbia.edu RI yadav, VIJAY /Q-2540-2016; OI yadav, VIJAY /0000-0003-2345-2846; Liu, Xiaowei/0000-0001-7247-2232 FU National Institutes of Health [DK58883] FX We thank Dr. Patricia Ducy for critical reading of the manuscript and constructive comments. This work was supported by grant DK58883 from National Institutes of Health (G.K.). NR 34 TC 33 Z9 36 U1 0 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD MAR 3 PY 2010 VL 11 IS 3 BP 231 EP 238 DI 10.1016/j.cmet.2010.01.005 PG 8 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 565WE UT WOS:000275325400010 PM 20197056 ER PT J AU Ng, L Lyubarsky, A Nikonov, SS Ma, M Srinivas, M Kefas, B St Germain, DL Hernandez, A Pugh, EN Forrest, D AF Ng, Lily Lyubarsky, Arkady Nikonov, Sergei S. Ma, Michelle Srinivas, Maya Kefas, Benjamin St Germain, Donald L. Hernandez, Arturo Pugh, Edward N., Jr. Forrest, Douglas TI Type 3 Deiodinase, a Thyroid-Hormone-Inactivating Enzyme, Controls Survival and Maturation of Cone Photoreceptors SO JOURNAL OF NEUROSCIENCE LA English DT Article ID DEVELOPING MOUSE RETINA; IODOTHYRONINE DEIODINASE; DEVELOPMENTAL EXPRESSION; ROD PHOTORESPONSE; RAINBOW-TROUT; COLOR-VISION; BRAIN; OPSINS; MICE; ACHROMATOPSIA AB Maturation of the mammalian nervous system requires adequate provision of thyroid hormone and mechanisms that enhance tissue responses to the hormone. Here, we report that the development of cones, the photoreceptors for daylight and color vision, requires protection from thyroid hormone by type 3 deiodinase, a thyroid hormone-inactivating enzyme. Type 3 deiodinase, encoded by Dio3, is expressed in the immature mouse retina. In Dio3(-/-) mice, similar to 80% of cones are lost through neonatal cell death. Cones that express opsin photopigments for response to both short (S) and medium-long (M) wavelength light are lost. Rod photoreceptors, which mediate dim light vision, remain essentially intact. Excessive thyroid hormone in wild-type pups also eliminates cones. Cone loss is mediated by cone-specific thyroid hormone receptor beta 2 (TR beta 2) as deletion of TR beta 2 rescues cones in Dio3(-/-) mice. However, rescued cones respond to short but not longer wavelength light because TR beta 2 under moderate hormonal stimulation normally induces M opsin and controls the patterning of M and S opsins over the retina. The results suggest that type 3 deiodinase limits hormonal exposure of the cone to levels that safeguard both cone survival and the patterning of opsins that is required for cone function. C1 [Ng, Lily; Ma, Michelle; Kefas, Benjamin; Forrest, Douglas] NIDDKD, NIH, Clin Endocrinol Branch, Bethesda, MD 20892 USA. [Lyubarsky, Arkady; Nikonov, Sergei S.; Pugh, Edward N., Jr.] Univ Penn, Sch Med, Dept Ophthalmol, Philadelphia, PA 19104 USA. [Srinivas, Maya] Mt Sinai Sch Med, Dept Human Genet, New York, NY 10029 USA. [St Germain, Donald L.; Hernandez, Arturo] Dartmouth Med Sch, Dept Physiol, Lebanon, NH 03766 USA. RP Forrest, D (reprint author), NIDDKD, NIH, Clin Endocrinol Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM forrestd@niddk.nih.gov FU National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases [HD09020, DK42271, EY02660] FX This work was supported in part by the intramural research program at National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases, a Hirshl Award (D.F.), and NIH Grants HD09020, DK42271 (D.L.S.), and EY02660 (E.N.P.). We thank V.A. Galton for advice on this study. NR 54 TC 68 Z9 69 U1 0 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 3 PY 2010 VL 30 IS 9 BP 3347 EP 3357 DI 10.1523/JNEUROSCI.5267-09.2010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 564CS UT WOS:000275191000020 PM 20203194 ER PT J AU Threlfell, S Clements, MA Khodai, T Pienaar, IS Exley, R Wess, J Cragg, SJ AF Threlfell, Sarah Clements, Michael A. Khodai, Tansi Pienaar, Ilse S. Exley, Richard Wess, Juergen Cragg, Stephanie J. TI Striatal Muscarinic Receptors Promote Activity Dependence of Dopamine Transmission via Distinct Receptor Subtypes on Cholinergic Interneurons in Ventral versus Dorsal Striatum SO JOURNAL OF NEUROSCIENCE LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTORS; LONG-TERM POTENTIATION; CAT CAUDATE-NUCLEUS; KNOCK-OUT MICE; MIDBRAIN DOPAMINE; PRIMATE STRIATUM; AUTORECEPTOR FUNCTION; M2-MUSCARINIC DRUGS; MEDIATED MODULATION; MONKEY STRIATUM AB Striatal dopamine (DA) and acetylcholine (ACh) regulate motivated behaviors and striatal plasticity. Interactions between these neurotransmitters may be important, through synchronous changes in parent neuron activities and reciprocal presynaptic regulation of release. How DA signaling is regulated by striatal muscarinic receptors (mAChRs) is unresolved; contradictory reports indicate suppression or facilitation, implicating several mAChR subtypes on various neurons. We investigated whether mAChR regulation of DA signaling varies with presynaptic activity and identified the mAChRs responsible in sensorimotor-versus limbic-associated striatum. We detected DA in real time at carbon fiber microelectrodes in mouse striatal slices. Broad-spectrum mAChR agonists [oxotremorine-M, APET (arecaidine propargyl ester tosylate)] decreased DA release evoked by low-frequency stimuli (1-10 Hz, four pulses) but increased the sensitivity of DA release to presynaptic activity, even enhancing release by high frequencies (e.g., >25 Hz for four pulses). These bidirectional effects depended on ACh input to striatal nicotinic receptors (nAChRs) on DA axons but not GABA or glutamate input. In caudate-putamen (CPu), knock-out of M(2)- or M(4)-mAChRs (not M(5)) prevented mAChR control of DA, indicating that M(2)- and M(4)-mAChRs are required. In nucleus accumbens (NAc) core or shell, mAChR function was prevented in M(4)-knock-outs, but not M(2)- or M(5)-knock-outs. These data indicate that striatal mAChRs, by inhibiting ACh release from cholinergic interneurons and thus modifying nAChR activity, offer variable control of DA release probability that promotes how DA release reflects activation of dopaminergic axons. Furthermore, different coupling of striatal M(2)/M(4)-mAChRs to the control of DA release in CPu versus NAc suggests targets to influence DA/ACh function differentially between striatal domains. C1 [Threlfell, Sarah; Clements, Michael A.; Khodai, Tansi; Pienaar, Ilse S.; Exley, Richard; Cragg, Stephanie J.] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3PT, England. [Khodai, Tansi] Univ Oxford, Dept Pharmacol, Oxford OX1 3QT, England. [Wess, Juergen] NIDDKD, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Cragg, SJ (reprint author), Univ Oxford, Dept Physiol Anat & Genet, Sherrington Bldg, Oxford OX1 3PT, England. EM stephanie.cragg@dpag.ox.ac.uk OI Threlfell, Sarah/0000-0002-3581-1327; Cragg, Stephanie/0000-0001-9677-2256 FU Parkinson's Disease Society [G-0808, G-4067]; Biotechnology and Biological Sciences Research Council-Eli Lilly Collaborative Award in Science and Engineering; International Brain Research Organization International FX This work was supported by Parkinson's Disease Society Grants G-0808 and G-4067, a Biotechnology and Biological Sciences Research Council-Eli Lilly Collaborative Award in Science and Engineering, and an International Brain Research Organization International Studentship (I.S.P.). We thank Dr. K. Jennings for critical reading of this manuscript. NR 78 TC 76 Z9 77 U1 1 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAR 3 PY 2010 VL 30 IS 9 BP 3398 EP 3408 DI 10.1523/JNEUROSCI.5620-09.2010 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 564CS UT WOS:000275191000025 PM 20203199 ER PT J AU Rodriguez, AC Schiffman, M Herrero, R Hildesheim, A Bratti, C Sherman, ME Solomon, D Guillen, D Alfaro, M Morales, J Hutchinson, M Katki, H Cheung, L Wacholder, S Burk, RD AF Cecilia Rodriguez, Ana Schiffman, Mark Herrero, Rolando Hildesheim, Allan Bratti, Concepcion Sherman, Mark E. Solomon, Diane Guillen, Diego Alfaro, Mario Morales, Jorge Hutchinson, Martha Katki, Hormuzd Cheung, Li Wacholder, Sholom Burk, Robert D. TI Longitudinal Study of Human Papillomavirus Persistence and Cervical Intraepithelial Neoplasia Grade 2/3: Critical Role of Duration of Infection SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CYTOLOGICALLY NORMAL WOMEN; COSTA-RICA; NATURAL-HISTORY; YOUNG-WOMEN; COLOMBIAN WOMEN; FOLLOW-UP; CANCER; RISK; COHORT; POPULATION AB Background The natural history of human papillomavirus (HPV) infections in older women is critical for preventive strategies, including vaccination and screening intervals, but is poorly understood. In a 7-year population-based cohort study in Guanacaste, Costa Rica, we examined whether women's age and the duration of carcinogenic HPV infections influenced subsequent persistence of infection and risk of cervical intraepithelial neoplasia grade 2 (CIN 2) or worse disease. Methods At enrollment, of the 9466 participants eligible for pelvic examination, 9175 were screened for cervical neoplasia using multiple methods; those with CIN 2 or worse disease were censored and treated. Participants at low risk of CIN 2 or worse (n = 6029) were rescreened at 5-7 years (passively followed), whereas higher-risk participants (n = 2115) and subsets of low-risk women (n = 540) and initially sexually inactive women (n = 410) were rescreened annually or semiannually (actively followed) for up to 7 years. HPV testing was done using a polymerase chain reaction-based method. We determined, by four age groups (18-25, 26-33, 34-41, and >= 42 years), the proportion of prevalent infections (found at baseline) and newly detected infections (first found during follow-up) that persisted at successive 1-year time points and calculated absolute risks of CIN 2 and CIN grade 3 (CIN 3) or worse during follow-up. P values are two-sided. Results Regardless of the woman's age, newly detected infections were associated with very low absolute risks of persistence, CIN 2, or worse disease. For newly detected infections, the rate of progression to CIN 2+ (or CIN 3+), after 3 years of follow-up, was not higher for women aged 34 years and older than for younger women. Moreover, rates of newly detected infections declined sharply with age (in the actively followed group, at ages 18-25, 26-33, 34-41, and >= 42 years, rates were 35.9%, 30.6%, 18.1%, and 13.5%, respectively; P <.001). Among prevalent infections, persistent infections among older women (>= 42 years) was higher than that among younger age groups or new infections at any age (P <.01 for comparison of eight groups). Most (66 of 85) CIN 2 or worse detected during follow-up was associated with prevalent infections. Only a small subset (25 of 1128) of prevalent infections persisted throughout follow-up without apparent CIN 2 or worse. Conclusions The rate of new infections declines with age, and new infections typically do not progress to CIN 2 or worse disease in older women; thus, overall potential benefit of prophylactic vaccination or frequent HPV screening to prevent or detect new carcinogenic HPV infections at older ages is low. C1 [Cecilia Rodriguez, Ana; Herrero, Rolando; Bratti, Concepcion; Guillen, Diego; Alfaro, Mario; Morales, Jorge] Fdn INCIENSA, San Jose 10203, Costa Rica. [Cecilia Rodriguez, Ana; Schiffman, Mark; Hildesheim, Allan; Sherman, Mark E.; Katki, Hormuzd; Wacholder, Sholom] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. [Solomon, Diane] NCI, Canc Prevent Div, NIH, DHHS, Rockville, MD USA. [Hutchinson, Martha] Brown Univ, Women & Infants Hosp, Dept Pathol, Providence, RI USA. [Cheung, Li] Informat Management Serv Inc, Silver Spring, MD USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Pediat, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Microbiol & Immunol, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. [Burk, Robert D.] Albert Einstein Coll Med, Dept Obstet Gynecol & Womens Hlth, Bronx, NY 10467 USA. RP Rodriguez, AC (reprint author), Fdn INCIENSA, 7Mo Piso, San Jose 10203, Costa Rica. EM acrodriguez@racsa.co.cr RI Katki, Hormuzd/B-4003-2015; OI Cheung, Li/0000-0003-1625-4331 FU National Institutes of Health [N01-CP-21081, N01-CP-33061, N01-CP40542, N01-CP-50535, N01-CP-81023, CA78527] FX National Institutes of Health (N01-CP-21081, N01-CP-33061, N01-CP40542, N01-CP-50535, N01-CP-81023, and intramural program CA78527 to R. D. B.). The Guanacaste cohort (design and conduct of the study, sample collection, management, analysis and interpretation of the data) for the enrollment and follow-up phases were supported by the National Cancer Institute, National Institutes of Health, Department of Health and Human Services. A. C. R. was supported by an appointment to the Senior Fellowship Program at the National Institutes of Health for analysis and manuscript preparation. The program is administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the US Department of Energy and the National Institutes of Health. NR 42 TC 137 Z9 146 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 MAR 3 PY 2010 VL 102 IS 5 BP 315 EP 324 DI 10.1093/jnci/djq001 PG 10 WC Oncology SC Oncology GA 564YL UT WOS:000275254600009 PM 20157096 ER PT J AU Guerreiro, RJ Beck, J Gibbs, JR Santana, I Rossor, MN Schott, JM Nalls, MA Ribeiro, H Santiago, B Fox, NC Oliveira, C Collinge, J Mead, S Singleton, A Hardy, J AF Guerreiro, Rita J. Beck, John Gibbs, J. Raphael Santana, Isabel Rossor, Martin N. Schott, Jonathan M. Nalls, Michael A. Ribeiro, Helena Santiago, Beatriz Fox, Nick C. Oliveira, Catarina Collinge, John Mead, Simon Singleton, Andrew Hardy, John TI Genetic Variability in CLU and Its Association with Alzheimer's Disease SO PLOS ONE LA English DT Article ID MULTILOCUS GENOTYPE DATA; GENOME-WIDE ASSOCIATION; APOLIPOPROTEIN-J; AMYLOID-BETA; CEREBROSPINAL-FLUID; IDENTIFIES VARIANTS; SENILE PLAQUES; CLUSTERIN GENE; BRAIN; EXPRESSION AB Background: Recently, two large genome wide association studies in Alzheimer disease (AD) have identified variants in three different genes (CLU, PICALM and CR1) as being associated with the risk of developing AD. The strongest association was reported for an intronic single nucleotide polymorphism (SNP) in CLU. Methodology/Principal Findings: To further characterize this association we have sequenced the coding region of this gene in a total of 495 AD cases and 330 healthy controls. A total of twenty-four variants were found in both cases and controls. For the changes found in more than one individual, the genotypic frequencies were compared between cases and controls. Coding variants were found in both groups (including a nonsense mutation in a healthy subject), indicating that the pathogenicity of variants found in this gene must be carefully evaluated. We found no common coding variant associated with disease. In order to determine if common variants at the CLU locus effect expression of nearby (cis) mRNA transcripts, an expression quantitative loci (eQTL) analysis was performed. No significant eQTL associations were observed for the SNPs previously associated with AD. Conclusions/Significance: We conclude that common coding variability at this locus does not explain the association, and that there is no large effect of common genetic variability on expression in brain tissue. We surmise that the most likely mechanism underpinning the association is either small effects of genetic variability on resting gene expression, or effects on damage induced expression of the protein. C1 [Guerreiro, Rita J.; Gibbs, J. Raphael; Nalls, Michael A.; Singleton, Andrew] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Guerreiro, Rita J.; Ribeiro, Helena; Oliveira, Catarina] Univ Coimbra, Ctr Neurosci & Cell Biol, Coimbra, Portugal. [Beck, John; Collinge, John; Mead, Simon] UCL Inst Neurol, Dept Neurodegenerat Dis, MRC, Prion Unit, London, England. [Gibbs, J. Raphael; Hardy, John] Reta Lila Weston Inst, London, England. [Gibbs, J. Raphael; Hardy, John] Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. [Gibbs, J. Raphael; Hardy, John] Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England. [Santana, Isabel; Ribeiro, Helena; Santiago, Beatriz; Oliveira, Catarina] Coimbra Univ Hosp, Neurol Serv, Coimbra, Portugal. [Rossor, Martin N.; Schott, Jonathan M.; Fox, Nick C.] UCL, Inst Neurol, Dementia Res Ctr, London, England. RP Guerreiro, RJ (reprint author), NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. EM Singleta@mail.nih.gov RI Oliveira, Catarina/F-3685-2010; Schott, Jonathan/A-9065-2011; Singleton, Andrew/C-3010-2009; Mead, Simon/E-9414-2011; Hardy, John/C-2451-2009; Guerreiro, Rita/A-1327-2011; Fox, Nick/B-1319-2009; OI Schott, Jonathan/0000-0003-2059-024X; Mead, Simon/0000-0002-4326-1468; Fox, Nick/0000-0002-6660-657X; Oliveira, Catarina/0000-0001-6942-4328; Santana, Isabel/0000-0002-8114-9434 FU Intramural Research Program of the National Institute on Aging; National Institutes of Health, Department of Health and Human Services [Z01 AG000950-06]; MRC Prion Unit and Fundacao para a Ciencia e Tecnologia, Portugal [SFRH/BD/29647/2006, PIC/IC/83206/2007]; UK cohort; Department of Health National Institute for Health Research Biomedical Research Centres; MRC; HEFCE/NHS Senior lecturership FX This work was supported in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project number Z01 AG000950-06; MRC Prion Unit and Fundacao para a Ciencia e Tecnologia, Portugal [grant SFRH/BD/29647/2006 and project PIC/IC/83206/2007]. The UK Medical Research Council funded the analysis of the UK cohort. Some of this work was done at University College London Hospitals/University College London which received a proportion of funding from the Department of Health National Institute for Health Research Biomedical Research Centres funding scheme. The Dementia Research Centre in the Department of Neurodegenerative Disease, UCL is an Alzheimer Research Trust Coordinating Centre. NCF is funded by the MRC; JMS is in receipt of a HEFCE/NHS Senior lecturership and JH of a MRC Returning Scientist Grant. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 36 TC 34 Z9 34 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 MAR 3 PY 2010 VL 5 IS 3 AR e9510 DI 10.1371/journal.pone.0009510 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 562OZ UT WOS:000275063400016 PM 20209083 ER PT J AU Mohanty, JG Shukla, HD Williamson, JD Launer, LJ Saxena, S Rifkind, JM AF Mohanty, Joy G. Shukla, Hem D. Williamson, Jefferey D. Launer, Lenore J. Saxena, Satya Rifkind, Joseph M. TI Alterations in the red blood cell membrane proteome in alzheimer's subjects reflect disease-related changes and provide insight into altered cell morphology SO PROTEOME SCIENCE LA English DT Article ID KNOCK-OUT MICE; ERYTHROCYTE-MEMBRANE; GEL-ELECTROPHORESIS; MASS-SPECTROMETRY; OXIDATIVE STRESS; LIQUID-CHROMATOGRAPHY; ALPHA-CHYMOTRYPSIN; ENDOTHELIAL-CELLS; PROTEINS; EXPRESSION AB Background: Our earlier studies have shown that red blood cell (RBC) morphology in Alzheimer's disease (AD) subjects was altered (> 15% of the RBCs were elongated as compared to 5.9% in normal controls (p < 0.0001)). These results suggested alterations in the RBC membrane architecture in AD subjects, possibly due to RBC-beta-amyloid interactions and/or changes in the expression of membrane proteins. We hypothesized that the observed changes could be due to changes in the level of the protein components of the cytoskeleton and those linked to the RBC membrane. To examine this, we performed a proteomic analysis of RBC membrane proteins of AD subjects, and their age-matched controls using one pool of samples from each group, following their separation by SDS-PAGE, in-gel Tryptic digestion, LC-MS-MS of peptides generated, and a label-free approach of semi-quantitative analysis of their relative MS spectral intensities. Results: The data suggest, (1) RBC shape/morphology changes in AD subjects are possibly attributed primarily to the changes (elevation or decrease) in the level of a series of membrane/cytoskeleton proteins involved in regulating the stability and elasticity of the RBC membrane, and (2) changes (elevation or decrease) in the level of a second series of proteins in the RBC membrane proteome reflect similar changes reported earlier by various investigators in AD or animal model of AD. Of particular interest, elevation of oxidative stress response proteins such as heat shock 90 kDa protein 1 alpha in AD subjects has been confirmed by western blot analysis in the RBC membrane proteome. Conclusions: The results suggest that this study provides a potential link between the alterations in RBC membrane proteome in AD subjects and AD pathology. C1 [Mohanty, Joy G.; Shukla, Hem D.; Saxena, Satya; Rifkind, Joseph M.] NIA, Baltimore, MD 21224 USA. [Williamson, Jefferey D.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Launer, Lenore J.] NIA, Bethesda, MD 20892 USA. RP Mohanty, JG (reprint author), NIA, Baltimore, MD 21224 USA. EM MohantyJ@mail.nih.gov FU Intramural Research Program of NIA FX This research was supported entirely by the Intramural Research Program of NIA, NIH although blood samples were obtained from Wake Forest University. We are thankful to Agilent Technologies for their help in analysis of RBC membrane proteome MS-MS data by SpectrumMill software. There is no potential conflict with any institutions where work was done. This is to state that all financial and material support for this research has been born by the above mentioned two institutions, and there are no potential conflicts. We are also thankful to Dr. Michel Bernier of NIA for providing us a sample of cell extract expressing high level of HSP-90 for our positive control, anti-HSP90 and anti-actin antibodies for western blot analysis as a gift. NR 53 TC 14 Z9 14 U1 2 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1477-5956 J9 PROTEOME SCI JI Proteome Sci. PD MAR 3 PY 2010 VL 8 AR 11 DI 10.1186/1477-5956-8-11 PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 577HZ UT WOS:000276214900001 PM 20199679 ER PT J AU Motsinger-Reif, AA Antas, PRZ Oki, NO Levy, S Holland, SM Sterling, TR AF Motsinger-Reif, Alison A. Antas, Paulo R. Z. Oki, Noffisat O. Levy, Shawn Holland, Steven M. Sterling, Timothy R. TI Polymorphisms in IL-1 beta, vitamin D receptor Fok1, and Toll-like receptor 2 are associated with extrapulmonary tuberculosis SO BMC MEDICAL GENETICS LA English DT Article ID MULTIFACTOR-DIMENSIONALITY REDUCTION; NRAMP1 GENE POLYMORPHISMS; INNATE IMMUNE-RESPONSES; SLC11A1 FORMERLY NRAMP1; INTERFERON-GAMMA GENE; PULMONARY TUBERCULOSIS; MYCOBACTERIUM-TUBERCULOSIS; WEST-AFRICA; P2X(7) GENE; SUSCEPTIBILITY AB Background: Human genetic variants may affect tuberculosis susceptibility, but the immunologic correlates of the genetic variants identified are often unclear. Methods: We conducted a pilot case-control study to identify genetic variants associated with extrapulmonary tuberculosis in patients with previously characterized immune defects: low CD4+ lymphocytes and low unstimulated cytokine production. Two genetic association approaches were used: 1) variants previously associated with tuberculosis risk; 2) single nucleotide polymorphisms (SNPs) in candidate genes involved in tuberculosis pathogenesis. Single locus association tests and multifactor dimensionality reduction (MDR) assessed main effects and multi-locus interactions. Results: There were 24 extrapulmonary tuberculosis cases (18 black), 24 pulmonary tuberculosis controls (19 black) and 57 PPD+ controls (49 black). In approach 1, 22 SNPs and 3 microsatellites were assessed. In single locus association tests, interleukin (IL)-1 beta + 3953 C/T was associated with extrapulmonary tuberculosis compared to PPD+ controls (P = 0.049). Among the sub-set of patients who were black, genotype frequencies of the vitamin D receptor (VDR) Fok1 A/G SNP were significantly different in extrapulmonary vs. pulmonary TB patients (P = 0.018). In MDR analysis, the toll-like receptor (TLR) 2 microsatellite had 76% prediction accuracy for extrapulmonary tuberculosis in blacks (P = 0.002). In approach 2, 613 SNPs in 26 genes were assessed. None were associated with extrapulmonary tuberculosis. Conclusions: In this pilot study among extrapulmonary tuberculosis patients with well-characterized immune defects, genetic variants in IL-1 beta, VDR Fok1, and TLR2 were associated with an increased risk of extrapulmonary disease. Additional studies of the underlying mechanism of these genetic variants are warranted. C1 [Antas, Paulo R. Z.; Sterling, Timothy R.] Vanderbilt Univ, Sch Med, Div Infect Dis, Dept Med, Nashville, TN 37212 USA. [Motsinger-Reif, Alison A.; Oki, Noffisat O.] N Carolina State Univ, Dept Stat, Bioinformat Res Ctr, Raleigh, NC 27695 USA. [Levy, Shawn] Vanderbilt Univ, Sch Med, Dept Biomed Informat, Nashville, TN 37212 USA. [Holland, Steven M.] NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. [Sterling, Timothy R.] Vanderbilt Univ, Sch Med, Ctr Hlth Serv Res, Dept Med, Nashville, TN 37212 USA. RP Sterling, TR (reprint author), Vanderbilt Univ, Sch Med, Div Infect Dis, Dept Med, Nashville, TN 37212 USA. EM timothy.sterling@vanderbilt.edu FU Vanderbilt Ingram Cancer Center [P30 CA68485]; Vanderbilt Digestive Disease Center [P30 DK58404]; Vanderbilt Vision Center [P30 EY08126]; National Institutes of Allergy and Infectious Diseases [K23 AI01654, K24 AI065298]; CAPES Foundation (Brazil); Johns Hopkins Hospital General Clinical Research Center [M01-RR00052]; Vanderbilt University Department of Medicine FX This work was presented in part at the 2007 Keystone Tuberculosis Symposium, March 20-25, 2007, Vancouver, British Columbia. Abstract 341. The authors thank the Vanderbilt DNA Sequencing and Genotyping Facility of the Vanderbilt Institute for Integrative Genomics for assistance with performing microsatellite genotyping (Robert Woodhall). They also thank the Vanderbilt Center for Human Genetics Research for polymorphism analysis (DNA Resources Core; Ping Mayo and Cara B. Sutcliffe) and advice regarding study design (Marylyn D. Ritchie, Ph. D.). All array-based genotyping was performed in the Vanderbilt Microarray Shared Resource (John Mote). The Vanderbilt Microarray Shared Resource is supported by the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Digestive Disease Center (P30 DK58404), and the Vanderbilt Vision Center (P30 EY08126). This work was supported by the National Institutes of Allergy and Infectious Diseases (K23 AI01654, K24 AI065298, and the intramural program), the CAPES Foundation (Brazil), the Johns Hopkins Hospital General Clinical Research Center (M01-RR00052 from the National Center for Research Resources, National Institutes of Health), and the Vanderbilt University Department of Medicine. NR 52 TC 33 Z9 36 U1 1 U2 5 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 MAR 2 PY 2010 VL 11 AR 37 DI 10.1186/1471-2350-11-37 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 569ZU UT WOS:000275642200001 PM 20196868 ER PT J AU Wacholder, S Chen, BE Wilcox, A Macones, G Gonzalez, P Befano, B Hildesheim, A Rodriguez, AC Solomon, D Herrero, R Schiffman, M AF Wacholder, Sholom Chen, Bingshu Eric Wilcox, Allen Macones, George Gonzalez, Paula Befano, Brian Hildesheim, Allan Cecilia Rodriguez, Ana Solomon, Diane Herrero, Rolando Schiffman, Mark CA CVT Grp TI Risk of miscarriage with bivalent vaccine against human papillomavirus (HPV) types 16 and 18: pooled analysis of two randomised controlled trials SO BRITISH MEDICAL JOURNAL LA English DT Article ID QUADRIVALENT VACCINE; DOUBLE-BLIND AB Objective To assess whether vaccination against human papillomavirus (HPV) increases the risk of miscarriage. Design Pooled analysis of two multicentre, phase three masked randomised controlled trials Setting Multicentre trials in several continents and in Costa Rica. Participants 26 130 women aged 15-25 at enrolment; 3599 pregnancies eligible for analysis. Interventions Participants were randomly assigned to receive three doses of bivalent HPV 16/18 VLP vaccine with AS04 adjuvant (n=13 075) or hepatitis A vaccine as control (n=13 055) over six months. Main outcome measures Miscarriage and other pregnancy outcomes. Results The estimated rate of miscarriage was 11.5% in pregnancies in women in the HPV arm and 10.2% in the control arm. The one sided P value for the primary analysis was 0.16; thus, overall, there was no significant increase in miscarriage among women assigned to the HPV vaccine arm. In secondary descriptive analyses, miscarriage rates were 14.7% in the HPV vaccine arm and 9.1% in the control arm in pregnancies that began within three months after nearest vaccination. Conclusion There is no evidence overall for an association between HPV vaccination and risk of miscarriage. C1 [Wacholder, Sholom; Hildesheim, Allan; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Chen, Bingshu Eric] Queens Univ, NCIC Clin Trials Grp, Kingston, ON K7L 3N6, Canada. [Wilcox, Allen] Natl Inst Environm Hlth Sci, Div Intramural Res, Res Triangle Pk, NC 27709 USA. [Macones, George] Washington Univ, Dept Obstet & Gynecol, St Louis, MO 63130 USA. [Gonzalez, Paula; Cecilia Rodriguez, Ana; Herrero, Rolando] Fdn INCIENSA, San Jose, Costa Rica. [Befano, Brian] Informat Management Serv Inc, Silver Spring, MD 20904 USA. [Solomon, Diane] NCI, Canc Prevent Div, Rockville, MD 20852 USA. RP Wacholder, S (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20852 USA. EM WacholdS@mail.nih.gov RI Hildesheim, Allan/B-9760-2015; OI Hildesheim, Allan/0000-0003-0257-2363; Wilcox, Allen/0000-0002-3376-1311 FU National Cancer Institute, NIH Office for Research on Women's Health in agreement with the Ministry of Health of Costa Rica [N01-CP-11005]; GSK Biologicals; National Cancer Institute (NCI), National Institutes of Health; National Institute of Environmental Health Sciences, National Institutes of Health FX The CVT trial is sponsored and funded by the National Cancer Institute (N01-CP-11005) with support from the NIH Office for Research on Women's Health and conducted in agreement with the Ministry of Health of Costa Rica. PATRICIA is funded by GSK Biologicals. GSK Biologicals contributed data from PATRICIA to the analysis, and commented on aspects of the trial at the design stage and after the results were shared with investigators of both trials, with the permission of the Data Safety Monitoring Board of CVT. GSK Biologicals had no role in study design and the collection, analysis, and interpretation of data from CVT in this paper, or in the writing of the article. GSK Biologicals took no part in the decision to submit an article for publication. The pooled analysis reported here was supported by the Intramural Research Programs of the National Cancer Institute (NCI) and the National Institute of Environmental Health Sciences, both parts of the National Institutes of Health. NR 13 TC 43 Z9 44 U1 1 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD MAR 2 PY 2010 VL 340 AR c712 DI 10.1136/bmj.c712 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 565FI UT WOS:000275274300023 PM 20197322 ER PT J AU Wu, YL Brosh, RM AF Wu, Yuliang Brosh, Robert M., Jr. TI Distinct roles of RECQ1 in the maintenance of genomic stability SO DNA REPAIR LA English DT Review DE RECQ1 (RECQL); RecQ; Helicase; Genomic stability; DNA repair ID BLOOMS-SYNDROME HELICASE; REPLICATION PROTEIN-A; STRAND-ANNEALING ACTIVITIES; HOLLIDAY JUNCTION DISSOLVASOME; ROTHMUND-THOMSON-SYNDROME; TOPOISOMERASE-III-ALPHA; WERNER-SYNDROME PROTEIN; DNA HELICASE; HOMOLOGOUS RECOMBINATION; NEUROSPORA-CRASSA AB Five human RecQ helicases (WRN, BLM, RECQ4, RECQ5, RECQ1) exist in humans. Of these, three are genetically linked to diseases of premature aging and/or cancer. Neither RECQ1 nor RECQ5 has yet been implicated in a human disease. However, cellular studies and genetic analyses of model organisms indicate that RECQ1 (and RECQ5) play an important role in the maintenance of genomic stability. Biochemical studies of purified RECQ1 protein demonstrate that the enzyme catalyzes DNA unwinding and strand annealing, and these activities are likely to be important for its role in DNA repair. RECQ1 also physically and functionally interacts with proteins involved in genetic recombination. In this review, we will summarize our current knowledge of RECQ1 roles in cellular nucleic acid metabolism and propose avenues of investigation for future studies. Published by Elsevier B.V. C1 [Wu, Yuliang; Brosh, Robert M., Jr.] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM broshr@mail.nih.gov FU NIH; National Institute on Aging FX This work was supported by the Intramural Research program of the NIH, National Institute on Aging. NR 115 TC 23 Z9 23 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAR 2 PY 2010 VL 9 IS 3 SI SI BP 315 EP 324 DI 10.1016/j.dnarep.2009.12.010 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 574TO UT WOS:000276016800012 PM 20061189 ER PT J AU Rossi, ML Ghosh, AK Bohr, VA AF Rossi, Marie L. Ghosh, Avik K. Bohr, Vilhelm A. TI Roles of Werner syndrome protein in protection of genome integrity SO DNA REPAIR LA English DT Review DE Werner Syndrome; WRN; RecQ helicases ID BASE-EXCISION-REPAIR; DOUBLE-STRAND BREAKS; ROTHMUND-THOMSON-SYNDROME; SYNDROME GENE-PRODUCT; DNA-POLYMERASE-DELTA; SYNDROME RECQ HELICASE; REPLICATION FORK PROGRESSION; WRN EXONUCLEASE ACTIVITY; BLOOM-SYNDROME HELICASES; CORONARY-ARTERY-DISEASE AB Werner syndrome protein (WRN) is one of a family of five human RecQ helicases implicated in the maintenance of genome stability. The conserved RecQ family also includes RecQ1, Bloom syndrome protein (BLM), RecQ4, and RecQ5 in humans, as well as Sgs1 in Saccharomyces cerevisiae, Rqh1 in Schizosaccharomyces pombe, and homologs in Caenorhabditis elegans, Xenopus laevis, and Drosophila melanogaster. Defects in three of the RecQ helicases, RecQ4, BLM, and WRN, cause human pathologies linked with cancer predisposition and premature aging. Mutations in the WRN gene are the causative factor of Werner syndrome (WS). WRN is one of the best characterized of the RecQ helicases and is known to have roles in DNA replication and repair, transcription, and telomere maintenance. Studies both in vitro and in vivo indicate that the roles of WRN in a variety of DNA processes are mediated by post-translational modifications, as well as several important protein-protein interactions. In this work, we will summarize some of the early studies on the cellular roles of WRN and highlight the recent findings that shed some light on the link between the protein with its cellular functions and the disease pathology. Published by Elsevier B.V. C1 [Rossi, Marie L.; Ghosh, Avik K.; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIH, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM BohrV@grc.nia.nih.gov FU National Institutes of Health; National Institute on Aging FX We thank Dr. Dharmendra K. Singh and Mr. Joshua A. Sommers for helpful comments on the manuscript. This work was supported entirely by funds from the Intramural Research Program of the National Institutes of Health, National Institute on Aging. We regret that space limitations and the breadth of this field prevented us from citing every relevant reference. NR 244 TC 96 Z9 98 U1 3 U2 17 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAR 2 PY 2010 VL 9 IS 3 SI SI BP 331 EP 344 DI 10.1016/j.dnarep.2009.12.011 PG 14 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 574TO UT WOS:000276016800014 PM 20075015 ER PT J AU Simons-Morton, DG Donato, K Loria, CM Pratt, CA Ershow, AG Morrissette, MA Czajkowski, S Arteaga, SS Obarzanek, E AF Simons-Morton, Denise G. Donato, Karen Loria, Catherine M. Pratt, Charlotte A. Ershow, Abby G. Morrissette, Meredith A. Czajkowski, Susan Arteaga, S. Sonia Obarzanek, Eva TI Obesity Research and Programs at the National Heart, Lung, and Blood Institute SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article DE obesity; body weight; mechanistic research; epidemiology; efficacy; effectiveness; translation ID RANDOMIZED CONTROLLED-TRIAL; LIFE-STYLE MODIFICATION; CORONARY RISK-FACTORS; PHYSICAL-ACTIVITY; CARDIOVASCULAR-DISEASE; WEIGHT-LOSS; DIETARY PATTERNS; HEALTH-PROGRAM; CLINICAL-TRIAL; PRIMARY-CARE C1 [Simons-Morton, Denise G.; Donato, Karen; Loria, Catherine M.; Pratt, Charlotte A.; Ershow, Abby G.; Morrissette, Meredith A.; Czajkowski, Susan; Arteaga, S. Sonia; Obarzanek, Eva] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. RP Simons-Morton, DG (reprint author), NHLBI, Div Cardiovasc Sci, 6701 Rockledge Dr,Suite 10018,MSC 7936, Bethesda, MD 20892 USA. EM simonsd@nhlbi.nih.gov NR 30 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 2 PY 2010 VL 55 IS 9 BP 917 EP 920 DI 10.1016/j.jacc.2009.09.058 PG 4 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 559XS UT WOS:000274865100012 PM 20185044 ER PT J AU Yugeta, A Terao, Y Fukuda, H Hikosaka, O Yokochi, F Okiyama, R Taniguchi, M Takahashi, H Hamada, I Hanajima, R Ugawa, Y AF Yugeta, A. Terao, Y. Fukuda, H. Hikosaka, O. Yokochi, F. Okiyama, R. Taniguchi, M. Takahashi, H. Hamada, I. Hanajima, R. Ugawa, Y. TI Effects of STN stimulation on the initiation and inhibition of saccade in Parkinson disease SO NEUROLOGY LA English DT Article ID SUBTHALAMIC NUCLEUS STIMULATION; LOCAL DOPAMINE DEPLETION; MEMORY-GUIDED SACCADES; NIGRA PARS RETICULATA; EYE-MOVEMENT CONTROL; SUPERIOR COLLICULUS; BASAL GANGLIA; OCULOMOTOR FUNCTIONS; REMEMBERED SACCADES; HUNTINGTONS-DISEASE AB Objectives: The basal ganglia (BG) play an important role in controlling saccades. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is widely used as a treatment of Parkinson disease (PD) by altering the function of the BG. Nevertheless, the effects of STN DBS on saccade performance are not fully clarified in a systematic manner. In this study, we examined the effects of bilateral STN DBS on both the initiation and inhibition of saccades in PD. Methods: Thirty-two patients with PD performed 4 oculomotor tasks. Two tasks (visually guided saccades and gap saccades) were reflexive and 2 (memory-guided saccades [MGS] and antisaccades) were volitional. While taking their regular doses of antiparkinsonian drugs, patients performed these tasks under 2 conditions: during DBS (DBS-on condition) and without DBS (DBS-off condition). Fifty-one age-matched subjects served as controls. Results: In the DBS-on condition, parameters of saccade initiation were improved in all tasks, with shorter latencies and increased amplitudes, except for MGS latency. STN DBS improved the ability to suppress unwanted saccades to the cue stimulus in the MGS task. However, it did not suppress prosaccades during the antisaccade task. Conclusions: These results suggest that deep brain stimulation (DBS) of the subthalamic nucleus (STN) affects the neural pathway common to both reflexive and volitional saccades, possibly by acting on the STN-substantia nigra pars reticulata-superior colliculi pathway. STN DBS may set the functional level of the superior colliculi appropriate for both saccade initiation and inhibition through this pathway. These findings provide novel insights into the pathophysiology of Parkinson disease and may yield better treatment strategies. Neurology (R) 2010; 74: 743-748 C1 [Yugeta, A.; Terao, Y.; Hanajima, R.] Univ Tokyo, Dept Neurol, Grad Sch Med, Bunkyo Ku, Tokyo 1138655, Japan. [Fukuda, H.] Natl Inst Occupat Safety & Hlth, Kanagawa, Japan. [Hikosaka, O.] NEI, Sensorimotor Res Lab, Natl Inst Hlth, Bethesda, MD USA. [Yokochi, F.; Okiyama, R.; Taniguchi, M.; Takahashi, H.] Tokyo Metropolitan Neurol Hosp, Tokyo, Japan. [Hamada, I.] Tokyo Metropolitan Inst Neurosci, Tokyo, Japan. [Ugawa, Y.] Fukushima Med Univ, Sch Med, Dept Neurol, Fukushima, Japan. RP Yugeta, A (reprint author), Univ Tokyo, Dept Neurol, Grad Sch Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan. EM yugetaa-tky@umin.ac.jp FU Ministry of Education, Culture, Sports, Science, and Technology of Japan [18590928, 16500194]; Ministry of Health, Labor and Welfare of Japan [17231401]; Research Committee on Dystonia; Ministry of Health, Labor and Welfare of Japan; Committee of the Study of Human Exposure; Ministry of Internal Affairs and Communications; Fukushima Medical University; National Eye Institute Intramural Research; Ministry of Internal Affairs and Communications/Committee of the Study of Human Exposure FX Supported by Research Project Grant-in-Aid for Scientific Research No. 18590928, a grant from the Support Center for Advanced Telecommunications Technology Research, Research Project Grants-in-Aid for Scientific Research No. 16500194 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, and grants for the Research Committee on rTMS Treatment of Movement Disorders from the Ministry of Health, Labor and Welfare of Japan (17231401), the Research Committee on Dystonia, the Ministry of Health, Labor and Welfare of Japan, grants from the Committee of the Study of Human Exposure to EMF, Ministry of Internal Affairs and Communications, and a grant from Fukushima Medical University Research Project.; Dr. Yugeta reports no disclosures. Dr. Terao serves on the editorial board of Clinical Neurophysiology and is funded by Research Project Grant-in-Aid for Scientific Research No. 18590928. Dr. Fukuda reports no disclosures. Dr. Hikosaka serves on the editorial boards of Neuroscience Research, Neural Networks, and Current Opinion in Neurobiology; and is funded by the National Eye Institute Intramural Research Program. Dr. Okiyama, Dr. Yokochi, Dr. Taniguchi, Dr. Takahashi, and Dr. Hamada report no disclosures. Dr. Hanajima serves on the editorial board of Clinical Neurophysiology. Dr. Ugawa served on the editorial board and now serves as an Associate Editor of Clinical Neurophysiology; serves on the editorial boards of Movement Disorders, Brain Stimulation, and The Cerebellum; and receives research support from the Ministry of Education, Culture, Sports, Science, and Technology of Japan/Research Project Grants-in-Aid for Scientific Research No. 16500194, the Ministry of Health, Labor and Welfare of Japan/Research Committee on rTMS Treatment of Movement Disorders, 17231401, and the Ministry of Internal Affairs and Communications/Committee of the Study of Human Exposure to EMF. NR 38 TC 30 Z9 31 U1 2 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 2 PY 2010 VL 74 IS 9 BP 743 EP 748 DI 10.1212/WNL.0b013e3181d31e0b PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 562GG UT WOS:000275037300008 PM 20194913 ER PT J AU Pardini, M Krueger, F Raymont, V Grafman, J AF Pardini, Matteo Krueger, Frank Raymont, Vanessa Grafman, Jordan TI Ventromedial prefrontal cortex modulates fatigue after penetrating traumatic brain injury SO NEUROLOGY LA English DT Article ID MULTIPLE-SCLEROSIS; MACAQUE MONKEYS; HEAD-INJURY; DISORDERS; DEPRESSION; REGIONS; SCALE; RAT; MRI AB Background: Fatigue is a common and disabling symptom in neurologic disorders including traumatic penetrating brain injury (PBI). Despite fatigue's prevalence and impact on quality of life, its pathophysiology is not understood. Studies on effort perception in healthy subjects, animal behavioral paradigms, and recent evidence in different clinical populations suggest that ventromedial prefrontal cortex could play a significant role in fatigue pathophysiology in neurologic conditions. Methods: We enrolled 97 PBI patients and 37 control subjects drawn from the Vietnam Head Injury Study registry. Fatigue was assessed with a self-report questionnaire and a clinician-rated instrument; lesion location and volume were evaluated on CT scans. PBI patients were divided in 3 groups according to lesion location: a nonfrontal lesion group, a ventromedial prefrontal cortex lesion (vmPFC) group, and a dorso/lateral prefrontal cortex (d/lPFC) group. Fatigue scores were compared among the 3 PBI groups and the healthy controls. Results: Individuals with vmPFC lesions were significantly more fatigued than individuals with d/lPFC lesions, individuals with nonfrontal lesions, and healthy controls, while these 3 latter groups were equally fatigued. VmPFC volume was correlated with fatigue scores, showing that the larger the lesion volume, the higher the fatigue scores. Conclusions: We demonstrated that ventromedial prefrontal cortex lesion (vmPFC) plays a critical role in penetrating brain injury-related fatigue, providing a rationale to link fatigue to different vmPFC functions such as effort and reward perception. The identification of the anatomic and cognitive basis of fatigue can contribute to developing pathophysiology-based treatments for this disabling symptom. Neurology (R) 2010; 74: 749-754 C1 [Pardini, Matteo; Krueger, Frank; Raymont, Vanessa; Grafman, Jordan] NINCDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Pardini, Matteo] Univ Genoa, Dept Neurosci Ophthalmol & Genet, Genoa, Italy. [Krueger, Frank] George Mason Univ, Krasnow Inst Adv Study, Fairfax, VA 22030 USA. [Raymont, Vanessa] Natl Naval Med Ctr, Vietnam Head Injury Study, Henry M Jackson Fdn, Bethesda, MD USA. RP Grafman, J (reprint author), NINCDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 7D43,MSC 1440, Bethesda, MD 20892 USA. EM GrafmanJ@ninds.nih.gov RI Pardini, Matteo/F-8414-2010; OI Pardini, Matteo/0000-0002-4740-1982; Grafman, Jordan H./0000-0001-8645-4457 FU NIH/National Institute of Neurological Disorders and Stroke/CNS; Henry M. Jackson Foundation [DAMD17-01-1-0675]; NIH/NINDS FX Supported by the Intramural Research Program of the NIH/National Institute of Neurological Disorders and Stroke/CNS and project grant from the United States Army Medical Research and Material Command and administered by the Henry M. Jackson Foundation (Vietnam Head Injury Study Phase III: A 30 Year Post-Injury Follow-Up Study: Grant number: DAMD17-01-1-0675).; Dr. Pardini, Dr. Krueger, and Dr. Raymont report no disclosures. Dr. Grafman serves as Coeditor of Cortex and receives research support from the Intramural Research Program NIH/NINDS and the Henry M. Jackson Foundation. NR 31 TC 22 Z9 22 U1 1 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 MAR 2 PY 2010 VL 74 IS 9 BP 749 EP 754 DI 10.1212/WNL.0b013e3181d25b6b PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 562GG UT WOS:000275037300009 PM 20194914 ER PT J AU Marongiu, M Deiana, M Meloni, A Marcia, L Puddu, A Cao, A Schlessinger, D Crisponi, L AF Marongiu, Mara Deiana, Manila Meloni, Alessandra Marcia, Loredana Puddu, Alessandro Cao, Antonio Schlessinger, David Crisponi, Laura TI The Forkhead Transcription Factor Foxl2 Is Sumoylated in Both Human and Mouse: Sumoylation Affects Its Stability, Localization, and Activity SO PLOS ONE LA English DT Article ID GRANULOSA-CELLS; SEX REVERSAL; EXPRESSION; RECEPTOR; PROTEIN; SUMO-1; SOX9; SPERMATOGENESIS; INDUCTION; REPRESSES AB The FOXL2 forkhead transcription factor is expressed in ovarian granulosa cells, and mutated FOXL2 causes the blepharophimosis, ptosis and epicanthus inversus syndrome (BPES) and predisposes to premature ovarian failure. Inactivation of Foxl2 in mice demonstrated its indispensability for female gonadal sex determination and ovary development and revealed its antagonism of Sox9, the effector of male testis development. To help to define the regulatory activities of FOXL2, we looked for interacting proteins. Based on yeast two-hybrid screening, we found that FOXL2 interacts with PIAS1 and UBC9, both parts of the sumoylation machinery. We showed that human FOXL2 is sumoylated in transfected cell lines, and that endogenous mouse Foxl2 is comparably sumoylated. This modification changes its cellular localization, stability and transcriptional activity. It is intriguing that similar sumoylation and regulatory consequences have also been reported for SOX9, the male counterpart of FOXL2 in somatic gonadal tissues. C1 [Marongiu, Mara; Deiana, Manila; Meloni, Alessandra; Marcia, Loredana; Puddu, Alessandro; Cao, Antonio; Crisponi, Laura] CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. [Puddu, Alessandro] Univ Cagliari, Cagliari, Italy. [Schlessinger, David] NIA, NIH, Baltimore, MD 21224 USA. RP Marongiu, M (reprint author), CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. EM laura.crisponi@inn.cnr.it OI MARONGIU, MARA/0000-0002-7321-2384; Puddu, Alessandro/0000-0002-9415-0477 FU Telethon Grant [GP0049Y01]; National Institute on Aging, National Institutes of Health (NIH) FX This work was supported by Telethon Grant GP0049Y01 to LC and in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH) to DS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 23 TC 16 Z9 16 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 MAR 2 PY 2010 VL 5 IS 3 AR e9477 DI 10.1371/journal.pone.0009477 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 562OY UT WOS:000275063300004 PM 20209145 ER PT J AU Buzza, MS Netzel-Arnett, S Shea-Donohue, T Zhao, AP Lin, CY List, K Szabo, R Fasano, A Bugge, TH Antalis, TM AF Buzza, Marguerite S. Netzel-Arnett, Sarah Shea-Donohue, Terez Zhao, Aiping Lin, Chen-Yong List, Karin Szabo, Roman Fasano, Alessio Bugge, Thomas H. Antalis, Toni M. TI Membrane-anchored serine protease matriptase regulates epithelial barrier formation and permeability in the intestine SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE claudin-2; intestinal barrier; St14; type II transmembrane serine protease; tight junction ID SURFACE PROTEOLYTIC-ENZYMES; INFLAMMATORY-BOWEL-DISEASE; KINASE C-ZETA; TIGHT JUNCTIONS; CELL-LINES; EXPRESSION; ACTIVATION; CLAUDIN-2; DIFFERENTIATION; INHIBITION AB The intestinal epithelium serves as a major protective barrier between the mammalian host and the external environment. Here we show that the transmembrane serine protease matriptase plays a pivotol role in the formation and integrity of the intestinal epithelial barrier. St14 hypomorphic mice, which have a 100-fold reduction in intestinal matriptase mRNA levels, display a 35% reduction in intestinal transepithelial electrical resistance (TEER). Matriptase is expressed during intestinal epithelial differentiation and colocalizes with E-cadherin to apical junctional complexes (AJC) in differentiated polarized Caco-2 monolayers. Inhibition of matriptase activity using a specific peptide inhibitor or by knockdown of matriptase by siRNA disrupts the development of TEER in barrier-forming Caco-2 monolayers and increases paracellular permeability to macromolecular FITC-dextran. Loss of matriptase was associated with enhanced expression and incorporation of the permeability associated, "leaky" tight junction protein claudin-2 at intercellular junctions. Knockdown of claudin-2 enhanced the development of TEER in matriptase-silenced Caco-2 monolayers, suggesting that the reduced barrier integrity was caused, at least in part, by an inability to regulate claudin-2 expression and incorporation into junctions. We find that matriptase enhances the rate of claudin-2 protein turnover, and that this is mediated indirectly through an atypical PKC zeta-dependent signaling pathway. These results support a key role for matriptase in regulating intestinal epithelial barrier competence, and suggest an intriguing link between pericellular serine protease activity and tight junction assembly in polarized epithelia. C1 [Buzza, Marguerite S.; Netzel-Arnett, Sarah; Antalis, Toni M.] Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Baltimore, MD 21201 USA. [Buzza, Marguerite S.; Netzel-Arnett, Sarah; Antalis, Toni M.] Univ Maryland, Sch Med, Dept Physiol, Baltimore, MD 21201 USA. [Shea-Donohue, Terez; Zhao, Aiping; Fasano, Alessio] Univ Maryland, Sch Med, Mucosal Biol Res Ctr, Baltimore, MD 21201 USA. [Lin, Chen-Yong] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [List, Karin] Wayne State Univ, Dept Pharmacol, Detroit, MI 48201 USA. [List, Karin] Karmanos Canc Inst, Detroit, MI 48201 USA. [Szabo, Roman; Bugge, Thomas H.] Natl Inst Dent & Cranofacial Res, Proteases & Tissue Remodeling Sect, NIH, Bethesda, MD 20892 USA. RP Antalis, TM (reprint author), Univ Maryland, Sch Med, Ctr Vasc & Inflammatory Dis, Baltimore, MD 21201 USA. EM tantalis@som.umaryland.edu FU National Institutes of Health ( NIH): [DK081376, CA098369, HL084387, DK48373, AI/DK49316, HL07698, CA096851]; NIH Intramural Program; Australian National Health and Medical Research Council [384359] FX We thank E. Smith, J. Stiltz, and R. Sun for technical assistance. CVS-3983 was provided by Dr. Ed Madison and Corvas International ( San Diego, CA). This work was supported in part by grants from the National Institutes of Health ( NIH): DK081376, CA098369, and HL084387 ( to T. M. A.); DK48373 ( to A. F.); AI/DK49316 ( to T. S. D.); HL07698 ( to S.N.A.); CA096851 ( to . Y.L.) and the NIH Intramural Program ( T. H. B.). M. B. was supported by Australian National Health and Medical Research Council CJ Martin Fellowship 384359. NR 28 TC 79 Z9 79 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 2 PY 2010 VL 107 IS 9 BP 4200 EP 4205 DI 10.1073/pnas.0903923107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KP UT WOS:000275131100047 PM 20142489 ER PT J AU Yim, YI Sun, T Wu, LG Raimondi, A De Camilli, P Eisenberg, E Greene, LE AF Yim, Yang-In Sun, Tao Wu, Ling-Gang Raimondi, Andrea De Camilli, Pietro Eisenberg, Evan Greene, Lois E. TI Endocytosis and clathrin-uncoating defects at synapses of auxilin knockout mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Hsc70; gene targeting; synaptic transmission; vesicle recycling ID G-ASSOCIATED KINASE; SYNAPTIC VESICLE ENDOCYTOSIS; KISS-AND-RUN; MEDIATED ENDOCYTOSIS; PHOSPHOINOSITIDE METABOLISM; HIPPOCAMPAL SYNAPSES; NERVE-TERMINALS; MULTIPLE ROLES; COATED PITS; ATPASE AB Neuronally expressed auxilin and ubiquitously expressed cyclin-G-dependent kinase (GAK) are homologous proteins that act as cochaperones to support the Hsc70-dependent clathrin uncoating of clathrin-coated vesicles. GAK was previously shown to be essential in mouse during embryonic development and in the adult. We have now engineered an auxilin knockout mouse. Mutant mice had a high rate of early postnatal mortality and surviving pups generally had a lower body weight than wild-type pups, although they had a normal life span. GAK was up-regulated as much as 3-fold in the brains of both surviving neonates and adult mutant mice. An increased number of clathrin-coated vesicles and empty cages were present at knockout synapses both in situ and in primary neuronal cultures. Additionally, clathrin-mediated endocytosis of synaptic vesicles in knockout hippocampal neurons was impaired, most likely due to sequestration of coat components in assembled coats and cages. Collectively, our results demonstrate the specialized role of auxilin in the recycling of synaptic vesicles at synapses, but also show that its function can be partially compensated for by up-regulation of GAK. C1 [Raimondi, Andrea; De Camilli, Pietro] Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06510 USA. [Raimondi, Andrea; De Camilli, Pietro] Yale Univ, Sch Med, Howard Hughes Med Inst, Program Cellular Neurosci Neurodegenerat & Repair, New Haven, CT 06510 USA. [Yim, Yang-In; Eisenberg, Evan; Greene, Lois E.] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Sun, Tao; Wu, Ling-Gang] NINDS, Synapt Transmiss Sect, NIH, Bethesda, MD 20892 USA. RP De Camilli, P (reprint author), Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06510 USA. EM pietro.decamilli@yale.edu; greenel@helix.nih.gov FU National Institutes of Health [NS36251, DA018343] FX We thank Dr. Chengyu Liu for assistance in making the knockout mice, Valentina Cappello for help with electron microscopy, Dr. Mary Anne Conti for helpful discussions, and Dr. JingPing Lin for help with the statistical analysis. This work was supported in part by National Institutes of Health Grants NS36251 and DA018343 to P.D.C. NR 31 TC 31 Z9 32 U1 1 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 2 PY 2010 VL 107 IS 9 BP 4412 EP 4417 DI 10.1073/pnas.1000738107 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 563KP UT WOS:000275131100083 PM 20160091 ER PT J AU Passwell, JH Ashkenzi, S Banet-Levi, Y Ramon-Saraf, R Farzam, N Lerner-Geva, L Even-Nir, H Yerushalmi, B Chu, CY Shiloach, J Robbins, JB Schneerson, R AF Passwell, Justen H. Ashkenzi, Shai Banet-Levi, Yonit Ramon-Saraf, Reut Farzam, Nahid Lerner-Geva, Liat Even-Nir, Hadas Yerushalmi, Baruch Chu, Chiayung Shiloach, Joseph Robbins, John B. Schneerson, Rachel CA Israeli Shigella Study Grp TI Age-related efficacy of Shigella O-specific polysaccharide conjugates in 1-4-year-old Israeli children SO VACCINE LA English DT Article DE Shigellosis; Vaccines; Efficacy; Age-related ID VACCINE DEVELOPMENT; DYSENTERIAE TYPE-1; ESCHERICHIA-COLI; FLEXNERI TYPE-2A; IMMUNOGENICITY; SONNEI; ANTIBODIES; SAFETY; LIPOPOLYSACCHARIDE; ANTIGENS AB Background: Despite its high worldwide morbidity and mortality, there is yet no licensed vaccine for shigellosis. We reported the safety and immunogenicity of Shigella O-specific polysaccharide-protein conjugates in adults and young children and efficacy ofShigella sonnei conjugate in young adults. Methods: A double-blinded, randomized and vaccine-controlled Phase3 evaluation of S. sonnei and Shigella flexneri 2a O-SP-rEPA conjugates, 25 mu Lg, injected IM twice, 6 weeks apart, into healthy 1 -4 years old, is reported. The children were followed for 2 years by telephone every other week and stool cultures were obtained for each episode of acute diarrhea (>= 3 loose stools/day or a bloody/mucous stool). Sera were taken randomly from 10% of the participants for IgG anti-LPS and anti-carrier levels. Results: Of the 2799 enrollees, 1433 received S. sonnei and 1366 S. flexneri 2a conjugates; 2699 (96.4%) completed the 2-year follow-up. Local reactions occurred in similar to 5% and similar to 4% had temperatures >= 38.0 degrees C lasting 1-2 days. There were no serious adverse events attributable to the vaccines. Of the 3295 stool cultures obtained, 125 yielded S. sonnei and 21 S. flexneri 2a. Immunogenicity and efficacy were age-related. The overall efficacy of the S. sonnei conjugate was 27.5%; 71.1% (P= 0.043) in the 3-4 years old. The numbers for S.flexneri 2a were too few for meaningful analysis. Cross-protection by S.flexneri 2a for non-vaccine S. flextierl types was found, but the numbers were too few for statistical significance. There was an age-related rise of vaccine-specific IgG anti-LPS in both groups, peaking at about 10 weeks and declining thereafter, but remaining >= 4-fold higher than in the controls 2 years after the second dose. Conclusions: Shigella conjugates are safe and immunogenic in 1-4 years old. The S. sonnei conjugate elicited 71.1% efficacy in the 3-4 years old and can be predicted to be efficacious in individuals older than 3 years of age. These results urge studies with our improved conjugates. Published by Elsevier Ltd. C1 [Chu, Chiayung; Robbins, John B.; Schneerson, Rachel] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Passwell, Justen H.; Banet-Levi, Yonit; Ramon-Saraf, Reut; Farzam, Nahid; Even-Nir, Hadas] Safra Childrens Hosp, Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Ashkenzi, Shai] Schneider Childrens Med Ctr, IL-49202 Petah Tiqwa, Israel. [Lerner-Geva, Liat] Gertner Inst Epidemiol & Hlth Policy Res, IL-52621 Tel Hashomer, Israel. [Yerushalmi, Baruch] Soroka Med Ctr, Saban Pediat Ctr, IL-84141 Beer Sheva, Israel. [Shiloach, Joseph] NIDDK, NIH, Bethesda, MD 20892 USA. RP Schneerson, R (reprint author), NICHD, NIH, PDMI, 31 Ctr Dr,Room 2A29, Bethesda, MD 20892 USA. EM schneerr@exchange.nih.gov RI Berkun, Yackov/A-1694-2009 NR 33 TC 40 Z9 42 U1 0 U2 4 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAR 2 PY 2010 VL 28 IS 10 BP 2231 EP 2235 DI 10.1016/j.vaccine.2009.12.050 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 573RZ UT WOS:000275933600013 PM 20056180 ER PT J AU Pierce, MA Ellis, RD Martin, LB Malkin, E Tierney, E Miura, K Fay, MP Marjason, J Elliott, SL Mullen, GED Rausch, K Zhu, DM Long, CA Miller, LH AF Pierce, Mark A. Ellis, Ruth D. Martin, Laura B. Malkin, Elissa Tierney, Eveline Miura, Kazutoyo Fay, Michael P. Marjason, Joanne Elliott, Suzanne L. Mullen, Gregory E. D. Rausch, Kelly Zhu, Daming Long, Carole A. Miller, Louis H. TI Phase 1 safety and immunogenicity trial of the Plasmodium falciparum blood-stage malaria vaccine AMA1-C1/ISA 720 in Australian adults SO VACCINE LA English DT Article DE AMA1; Malaria; ISA 720 ID APICAL MEMBRANE ANTIGEN-1; MONTANIDE ISA 720; RANDOMIZED CONTROLLED-TRIAL; CLINICAL-TRIAL; IN-VITRO; CANDIDATE; ADJUVANT; CHILDREN; ANTIBODIES; EFFICACY AB A Phase I trial was conducted in malaria-naive adults to evaluate the recombinant protein vaccine apical membrane antigen I -Combination 1 (AMA1-C1) formulated in Montanide (R) ISA 720 (SEPPIC, France), a water-in-oil adjuvant. Vaccinations were halted early due to a formulation issue unrelated to stability or potency. Twenty-four subjects (12 in each group) were enrolled and received 5 or 20 mu g protein at 0 and 3 months and four subjects were enrolled and received one vaccination of 80 mu g protein. After first vaccination, nearly all subjects experienced mild to moderate local reactions and six experienced delayed local reactions occurring at Day 9 or later. After the second vaccination, three subjects experienced transient grade 3 (severe) local reactions; the remainder experienced grade I or 2 local reactions. All related systemic reactogenicity was grade 1 or 2, except one instance ofgrade 3 malaise. Anti-AMA1-C1 antibody responses were dose dependent and seen following each vaccination, with mean antibody levels 2-3 fold higher in the 20 mu g group compared to the 5 mu g group at most time points. In vitro growth-inhibitory activity was a function of the anti-AMA1 antibody titer. AMA1-C1 formulated in ISA 720 is immunogenic in malaria-naive Australian adults. It is reasonably tolerated, though some transient, severe, and late local reactions are seen. Published by Elsevier Ltd. C1 [Pierce, Mark A.; Ellis, Ruth D.; Martin, Laura B.; Miura, Kazutoyo; Mullen, Gregory E. D.; Rausch, Kelly; Zhu, Daming; Miller, Louis H.] NIAID, MVDB, NIH, Rockville, MD 20852 USA. [Malkin, Elissa; Tierney, Eveline] PATH Malaria Vaccine Initiat, Bethesda, MD USA. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Rockville, MD 20852 USA. [Marjason, Joanne; Elliott, Suzanne L.] Q Pharm Pty Ltd, Brisbane, Qld, Australia. [Long, Carole A.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Ellis, RD (reprint author), NIAID, MVDB, NIH, Twinbrook 1,Room 1119,5640 Fishers Lane, Rockville, MD 20852 USA. EM ellisru@niaid.nih.gov RI Martin, Laura/N-1789-2013; OI Martin, Laura/0000-0002-4431-4381; Fay, Michael P./0000-0002-8643-9625 FU Intramural NIH HHS [Z01 AI001005-01, Z99 AI999999, ZIA AI001005-03] NR 31 TC 21 Z9 22 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD MAR 2 PY 2010 VL 28 IS 10 BP 2236 EP 2242 DI 10.1016/j.vaccine.2009.12.049 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 573RZ UT WOS:000275933600014 PM 20051276 ER PT J AU Guo, DL Myrdal, PB Karlage, KL O'Connell, SP Wissinger, TJ Tabibi, SE Yalkowsky, SH AF Guo, Duoli Myrdal, Paul B. Karlage, Kelly L. O'Connell, Sean P. Wissinger, Travis J. Tabibi, S. Esmail Yalkowsky, Samuel H. TI Stability of 5-Fluoro-2 '-deoxycytidine and Tetrahydrouridine in Combination SO AAPS PHARMSCITECH LA English DT Article DE degradation mechanism; FdCyd; NSC-112907; NSC-48006; THU ID METHYLTRANSFERASE INHIBITOR 5-FLUORO-2'-DEOXYCYTIDINE; CYTIDINE DEAMINASE; METABOLISM; MICE AB In vivo, the DNA methyltransferase inhibitor, 5-fluoro-2'-deoxycytidine (FdCyd, NSC-48006), is rapidly converted to its unwanted metabolites. Tetrahydrouridine (THU, NSC-112907), a cytidine deaminase inhibitor can block the first metabolic step in FdCyd catabolism. Clinical studies have shown that co-administration with THU can inhibit the metabolism of FdCyd. The National Cancer Institute is particularly interested in a 1:5 FdCyd/THU formulation. The purpose of this study was to investigate the in vitro pH stability of FdCyd and THU individually and in combination. A stability-indicating high-performance liquid chromatography method for the quanti. cation of both compounds and their degradants was developed using a ZIC (R)-HILIC column. The effect of THU and FdCyd on the in vitro degradation of each other was studied as a function of pH from 1.0 to 7.4 in aqueous solutions at 37 degrees C. The degradation of FdCyd appears to be first-order and acid-catalyzed. THU equilibrates with at least one of its degradants. The combination of FdCyd and THU in solution does not affect the stability of either compound. The stability and compatibility of FdCyd and THU in the solid state at increased relative humidity and at various temperatures are also evaluated. C1 [Guo, Duoli; Myrdal, Paul B.; Karlage, Kelly L.; O'Connell, Sean P.; Wissinger, Travis J.; Yalkowsky, Samuel H.] Univ Arizona, Coll Pharm, Tucson, AZ 85721 USA. [Tabibi, S. Esmail] NCI, Pharmaceut Resources Branch, Bethesda, MD 20892 USA. RP Guo, DL (reprint author), Univ Arizona, Coll Pharm, 1703 E Mabel, Tucson, AZ 85721 USA. EM guod@pharmacy.arizona.edu FU National Cancer Institute [N01-CM-27142] FX This work was supported by National Cancer Institute under the contract N01-CM-27142. NR 5 TC 6 Z9 7 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1530-9932 J9 AAPS PHARMSCITECH JI AAPS PharmSciTech PD MAR PY 2010 VL 11 IS 1 BP 247 EP 252 DI 10.1208/s12249-010-9383-2 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 612SC UT WOS:000278921800031 PM 20151336 ER PT J AU Lehner, T Insel, T AF Lehner, Thomas Insel, Thomas TI Psychiatric Education in the Genomic Era SO ACADEMIC PSYCHIATRY LA English DT Editorial Material ID GENETICS C1 [Lehner, Thomas] NIMH, Div Neurosci & Basic Behav Sci, NIH, Bethesda, MD 20892 USA. RP Lehner, T (reprint author), NIMH, Div Neurosci & Basic Behav Sci, NIH, 6001 Execut Blvd,Rm 7189,MSC 9643, Bethesda, MD 20892 USA. EM tlehner@mail.nih.gov NR 15 TC 4 Z9 4 U1 1 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1042-9670 J9 ACAD PSYCHIATR JI Acad. Psych. PD MAR-APR PY 2010 VL 34 IS 2 BP 87 EP 89 PG 3 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA 567GX UT WOS:000275434500002 PM 20224010 ER PT J AU Bluemke, DA AF Bluemke, David A. TI Magnetic Fields and the Brain at High Field Strengths What Do We Know? SO ACADEMIC RADIOLOGY LA English DT Editorial Material C1 Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. RP Bluemke, DA (reprint author), Natl Inst Biomed Imaging & Bioengn, 10 Ctr Dr,Room 10-1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU Intramural NIH HHS [ZIA CL090019-01, ZIA EB000072-01] NR 4 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 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD MAR PY 2010 VL 17 IS 3 BP 269 EP 270 DI 10.1016/j.acra.2009.12.008 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 564RX UT WOS:000275235500001 PM 20152723 ER PT J AU Ouimet, MC Simons-Morton, BG Zador, PL Lerner, ND Freedman, M Duncan, GD Wang, J AF Ouimet, Marie Claude Simons-Morton, Bruce G. Zador, Paul L. Lerner, Neil D. Freedman, Mark Duncan, Glen D. Wang, Jing TI Using the US National Household Travel Survey to estimate the impact of passenger characteristics on young drivers' relative risk of fatal crash involvement SO ACCIDENT ANALYSIS AND PREVENTION LA English DT Article DE Fatality; Crash risk; Adolescents; Young drivers; Passengers; Gender ID QUASI-INDUCED EXPOSURE; TEENAGE PASSENGERS; VEHICLE; DEATHS; INJURY; GENDER AB Motor vehicle crashes are the main cause of morbidity and mortality in teenagers and young adults in the United States. Driving exposure and passenger presence, which can both vary by driver and passenger characteristics, are known to influence crash risk. Some studies have accounted for driving exposure in calculating young driver fatal crash risk in the presence of passengers, but none have estimated crash risk by driver sex and passenger age and sex. One possible reason for this gap is that data collection on driving exposure often precludes appropriate analyses. The purpose of this study was to examine, per 10 million vehicle trips (VT) and vehicle-miles traveled (VMT), the relative risk of fatal crash involvement in 15-20-year-old male and female drivers as a function of their passenger's age and sex, using solo driving as the referent. The Fatality Analysis Reporting System provided fatal motor vehicle crash data from 1999 to 2003 and the 2001 National Household Travel Survey (NHTS) provided VT and VMT. The NHTS collects driving exposure for both household and non-household members (e.g., friends. colleagues), but demographic characteristics only on household members. Missing age and sex of non-household passengers were imputed with hot deck using information from household passengers' trips with non-household drivers, thereby enabling the calculation of crash rate and relative risk estimates based upon driver and passenger characteristics. Using this approach, the highest risk was found for young male drivers with 16-20-year-old passengers (relative risk [RR] per 10 million VT = 7.99: 95% confidence interval [CI], 7.34-8.69: RR per 10 million VMT = 9.94; 95% CI, 9.13-10.81). Relative risk was also high for 21-34-year-old passengers, again particularly when both drivers and passengers were male. These effects warrant further investigation and underscore the importance of considering driving exposure by passenger characteristics in understanding crash risk. Additionally, as all imputation techniques are imperfect, a more accurate estimation of U.S. fatal crash risk per distance driven would require national surveys to collect data on non-household passenger characteristics. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Ouimet, Marie Claude] Univ Sherbrooke, Fac Med & Hlth Sci, Longueuil, PQ J4K 0A8, Canada. [Ouimet, Marie Claude; Simons-Morton, Bruce G.; Wang, Jing] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, NIH, Bethesda, MD USA. [Zador, Paul L.; Lerner, Neil D.; Freedman, Mark] WESTAT Corp, Rockville, MD 20850 USA. RP Ouimet, MC (reprint author), Univ Sherbrooke, Fac Med & Hlth Sci, 150 Charles Le Moyne PL,Room 200, Longueuil, PQ J4K 0A8, Canada. EM Marie.Claude.Ouimet@USherbrooke.ca OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [ZIA HD001707-11]; NICHD NIH HHS [263-HD-510791] NR 30 TC 40 Z9 41 U1 1 U2 12 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0001-4575 J9 ACCIDENT ANAL PREV JI Accid. Anal. Prev. PD MAR PY 2010 VL 42 IS 2 BP 689 EP 694 DI 10.1016/j.aap.2009.10.017 PG 6 WC Ergonomics; Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary; Transportation SC Engineering; Public, Environmental & Occupational Health; Social Sciences - Other Topics; Transportation GA 568GO UT WOS:000275510600043 PM 20159095 ER PT J AU Ma, BY Tsai, CJ Pan, YP Nussinov, R AF Ma, Buyong Tsai, Chung-Jung Pan, Yongping Nussinov, Ruth TI Why Does Binding of Proteins to DNA or Proteins to Proteins Not Necessarily Spell Function? SO ACS CHEMICAL BIOLOGY LA English DT Article ID LATENT EVOLUTIONARY POTENTIALS; ESTROGEN-RECEPTOR; CONFORMATIONAL-CHANGES; MOLECULAR-DYNAMICS; FOLDING FUNNELS; NETWORK MOTIFS; ALLOSTERY; ENZYME; SPECIFICITY; COMPLEX AB Studies of binding are often question: first, is the observed binding functional, and second, if it is, which function? Is it activation or repression? The first question relates to binding at different sites; the second relates to binding at similar sites. These questions apply to transcription factors binding to genomic DNA and to protein interaction domains binding to their partners. Here, we explain that both can be understood in terms of allostery and the cellular (or in vitro) environment. The idea is simple yet powerful; it emphasizes the role of allostery in defining whether binding between transcription factors and (cognate or noncognate) DNA sequences will lead to function and to the type of function. Allosteric effects are the outcome of dynamically shifting populations; thus binding to even slightly different DNA sequences will lead to different transcription factor conformations that can be reflected in the binding sites to their co-regulators. Currently, allostery is not considered when trying to understand how binding phenomena determine the functional outcome. Allosteric effects can enhance the binding specificity in a function-oriented manner. Here we provide a biological rationale that considers cellular crowding effects. C1 [Ma, Buyong; Tsai, Chung-Jung; Pan, Yongping; Nussinov, Ruth] NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Sci Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. EM ruthnu@helix.nih.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU National Cancer Institute, National Institutes of Health [HHSN261200800001E] FX This project has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number HHSN261200800001E The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U S. Government This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research NR 58 TC 22 Z9 22 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1554-8929 J9 ACS CHEM BIOL JI ACS Chem. Biol. PD MAR PY 2010 VL 5 IS 3 BP 265 EP 272 DI 10.1021/cb900293a PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 569VA UT WOS:000275629200002 PM 20151694 ER PT J AU Robbins, AH Coman, RM Bracho-Sanchez, E Fernandez, MA Gilliland, CT Li, M Agbandje-McKenna, M Wlodawer, A Dunn, BM McKenna, R AF Robbins, Arthur H. Coman, Roxana M. Bracho-Sanchez, Edith Fernandez, Marty A. Gilliland, C. Taylor Li, Mi Agbandje-McKenna, Mavis Wlodawer, Alexander Dunn, Ben M. McKenna, Robert TI Structure of the unbound form of HIV-1 subtype A protease: comparison with unbound forms of proteases from other HIV subtypes SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID NON-B-SUBTYPES; DRUG-RESISTANCE; X-RAY; C PROTEASE; REVERSE-TRANSCRIPTASE; CRYSTAL-STRUCTURE; GENETIC SUBTYPES; MOLECULAR EPIDEMIOLOGY; ANTIRETROVIRAL THERAPY; INHIBITOR RESISTANCE AB The crystal structure of the unbound form of HIV-1 subtype A protease (PR) has been determined to 1.7 angstrom resolution and refined as a homodimer in the hexagonal space group P6(1) to an R(cryst) of 20.5%. The structure is similar in overall shape and fold to the previously determined subtype B, C and F PRs. The major differences lie in the conformation of the flap region. The flaps in the crystal structures of the unbound subtype B and C PRs, which were crystallized in tetragonal space groups, are either semi-open or wide open. In the present structure of subtype A PR the flaps are found in the closed position, a conformation that would be more anticipated in the structure of HIV protease complexed with an inhibitor. The amino-acid differences between the subtypes and their respective crystal space groups are discussed in terms of the differences in the flap conformations. C1 [Robbins, Arthur H.; Coman, Roxana M.; Bracho-Sanchez, Edith; Fernandez, Marty A.; Gilliland, C. Taylor; Agbandje-McKenna, Mavis; Dunn, Ben M.; McKenna, Robert] Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. [Li, Mi] SAIC Frederick, Basic Res Program, Frederick, MD USA. [Li, Mi; Wlodawer, Alexander] NCI, Macromol Crystallog Lab, Frederick, MD 21701 USA. RP Dunn, BM (reprint author), Univ Florida, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. EM bdunn@ufl.edu; rmckenna@ufl.edu FU US Department of Energy, Office of Science, Office of Basic Energy Sciences [W-31-109-Eng-38]; NIH [AI-28571, HHSN2612008000001E]; National Cancer Institute; Center for Cancer Research FX 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 US Department of Energy, Office of Science, Office of Basic Energy Sciences under Contract No. W-31-109-Eng-38. This project was supported in part by NIH grant AI-28571 to BMD, in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research (AW) and in part by Federal funds from the National Cancer Institute, NIH under Contract No. HHSN2612008000001E (ML). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products NR 65 TC 14 Z9 14 U1 0 U2 2 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 MAR PY 2010 VL 66 BP 233 EP 242 DI 10.1107/S0907444909054298 PN 3 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 555SX UT WOS:000274536400002 PM 20179334 ER PT J AU Munasinghe, JP Banerjee, M Acosta, MT Banks, M Heffer, A Silva, AC Koretsky, A Theodore, WH AF Munasinghe, J. P. Banerjee, M. Acosta, M. T. Banks, M. Heffer, A. Silva, A. C. Koretsky, A. Theodore, W. H. TI Arterial spin labeling demonstrates that focal amygdalar glutamatergic agonist infusion leads to rapid diffuse cerebral activation SO ACTA NEUROLOGICA SCANDINAVICA LA English DT Article DE glutamate receptors; KA; ATPA; AMPA; MRI; CBF; seizures ID TEMPORAL-LOBE EPILEPSY; GENERALIZED STATUS EPILEPTICUS; REGIONAL NEURONAL DAMAGE; GLUR5 KAINATE RECEPTORS; BLOOD-FLOW; KAINIC ACID; STRUCTURAL ALTERATIONS; IMAGING ABNORMALITIES; ANESTHETIZED RATS; SEIZURES AB Objectives - To investigate acute effects of intra-amygdalar excitatory amino acid administration on blood flow, relaxation time and apparent diffusion coefficient in rat brain. Materials and methods - Several days after MR-compatible cannula placement in right basolateral amygdala, anesthetized rats were imaged at 7 T. Relative cerebral blood flow (CBF) was measured before and 60 min after infusion of 10 nmol KA, cAMPA, ATPA, or normal saline using arterial spin labeling. Quantitative T(2) and diffusion-weighted images were acquired. rCBF, T(2) and ADC values were evaluated in bilateral basolateral amygdala, hippocampus, basal ganglia, frontal and parietal regions. Results KA led to the highest, and ATPA lowest bilateral rCBF increases. Time courses varied among drugs. T(2) for KA and AMPA was higher while ADC was lower for KA. Conclusions - Intra-amygdalar injection of GluR agonists evoked bilateral seizure activity and increased rCBF, greater for KA and AMPA than selective ATPA GluR5 activation. C1 [Acosta, M. T.; Theodore, W. H.] Natl Inst Neurol Disorders & Stroke, Clin Epilepsy Sect, NIH, Bethesda, MD 20892 USA. [Munasinghe, J. P.; Heffer, A.; Silva, A. C.; Koretsky, A.] Natl Inst Neurol Disorders & Stroke, MRI Res Facil, Bethesda, MD 20892 USA. [Banerjee, M.; Acosta, M. T.; Banks, M.] Natl Inst Neurol Disorders & Stroke, Epilepsy Res Sect, Bethesda, MD 20892 USA. [Heffer, A.] NICHHD, NIH, Bethesda, MD 20892 USA. RP Theodore, WH (reprint author), Natl Inst Neurol Disorders & Stroke, Clin Epilepsy Sect, NIH, Bldg 10,Room 5N-250, Bethesda, MD 20892 USA. EM theodorw@ninds.nih.gov RI Silva, Afonso/A-7129-2009; Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS002236-32] NR 36 TC 2 Z9 2 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0001-6314 J9 ACTA NEUROL SCAND JI Acta Neurol. Scand. PD MAR PY 2010 VL 121 IS 3 BP 209 EP 216 DI 10.1111/j.1600-0404.2009.01188.x PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 548TV UT WOS:000273991300011 PM 19951270 ER PT J AU Racz, GZ Bori, E Foldes, A Demeter, I Toth, M Qi, S Varga, G AF Racz, G. Z. Bori, E. Foldes, A. Demeter, I Toth, M. Qi, S. Varga, G. TI Toward an artificial salivary gland to treat xerostomia SO ACTA PHYSIOLOGICA HUNGARICA LA English DT Meeting Abstract C1 [Racz, G. Z.; Bori, E.; Foldes, A.; Demeter, I; Varga, G.] Semmelweis Univ, Dept Oral Biol, H-1085 Budapest, Hungary. [Toth, M.] Semmelweis Univ, Dept Hlth Sci & Sports Med, H-1085 Budapest, Hungary. [Qi, S.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AKADEMIAI KIADO RT PI BUDAPEST PA PRIELLE K U 19, PO BOX 245,, H-1117 BUDAPEST, HUNGARY SN 0231-424X J9 ACTA PHYSIOL HUNG JI Acta Physiol. Hung. PD MAR PY 2010 VL 97 IS 1 BP 130 EP 130 PG 1 WC Physiology SC Physiology GA 570AU UT WOS:000275644800100 ER PT J AU Wu, LT Pan, JJ Yang, CM Reeve, BB Blazer, DG AF Wu, Li-Tzy Pan, Jeng-Jong Yang, Chongming Reeve, Bryce B. Blazer, Dan G. TI An item response theory analysis of DSM-IV criteria for hallucinogen abuse and dependence in adolescents SO ADDICTIVE BEHAVIORS LA English DT Article DE Differential item functioning; Ecstasy; Hallucinogen use disorder; Item response theory; MDMA ID NATIONAL EPIDEMIOLOGIC SURVEY; USE DISORDERS; MDMA 3,4-METHYLENEDIOXYMETHAMPHETAMINE; CANNABIS ABUSE; DRUG-ABUSE; ALCOHOL; METHAMPHETAMINE; ECSTASY; USERS AB Aim: This study applied both item response theory (IRT) and multiple indicators-multiple causes (MIMIC) methods to evaluate item-level psychometric properties of diagnostic questions for hallucinogen use disorders (HUDs), differential item functioning (DIF), and predictors of latent HUD. Methods: Data were drawn from 2004-2006 National Surveys on Drug Use and Health. Analyses were based on 1548 past-year hallucinogen users aged 12-17 years. Substance use and symptoms were assessed by audio computer-assisted self-interviewing methods. Results: Abuse and dependence criteria empirically were arrayed along a single continuum of severity. All abuse criteria indicated middle-to-high severity on the IRT-defined HUD continuum, while dependence criteria captured a wider range from the lowest (tolerance and time spent) to the highest (taking larger amounts and inability to cut down) severity levels. There was indication of DIF by hallucinogen users' age, gender, race/ethnicity, and ecstasy use status. Adjusting for DIF, ecstasy users (vs. non-ecstasy hallucinogen users), females (vs. males), and whites (vs. Hispanics) exhibited increased odds of HUD. Conclusions: Symptoms of hallucinogen abuse and dependence empirically do not reflect two discrete conditions in adolescents. Trends and problems related to hallucinogen use among girls and whites should be examined further to inform the designs of effective gender-appropriate and culturally sensitive prevention programs. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Wu, Li-Tzy; Blazer, Dan G.] Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Sch Med,Duke Clin Res Inst, Durham, NC 27710 USA. [Pan, Jeng-Jong] Vet Hlth Adm, Washington, DC 20420 USA. [Yang, Chongming] Duke Univ, Social Sci Res Inst, Durham, NC 27705 USA. [Reeve, Bryce B.] NCI, Bethesda, MD 20814 USA. RP Wu, LT (reprint author), Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Sch Med,Duke Clin Res Inst, Box 3419, Durham, NC 27710 USA. EM litzy.wu@duke.edu FU National Institute on Drug Abuse of the National Institutes of Health [R01DA019623, R01DA019901] FX This work was supported by research grants from the National Institute on Drug Abuse of the National Institutes of Health (R01DA019623 and R01DA019901; Principal investigator Li-Tzy Wu). The sponsoring agency had no further role in study design and analysis. in the writing of the report, and in the decision to submit the paper for publication, The opinions expressed in this paper are solely those of the authors. NR 30 TC 8 Z9 8 U1 2 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD MAR PY 2010 VL 35 IS 3 BP 273 EP 277 DI 10.1016/j.addbeh.2009.10.009 PG 5 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 552BV UT WOS:000274262500017 PM 19896773 ER PT J AU Ernst, M Luckenbaugh, DA Moolchan, ET Temple, VA Jennessa, J Korelitz, KE London, ED Kimes, AS AF Ernst, Monique Luckenbaugh, David A. Moolchan, Eric T. Temple, Veronica A. Jennessa, Jessica Korelitz, Katherine E. London, Edythe D. Kimes, Alane S. TI Decision-making and facial emotion recognition as predictors of substance-use initiation among adolescents SO ADDICTIVE BEHAVIORS LA English DT Article DE Smoking; Alcohol; Marijuana; Adolescent development; Drug experimentation ID PREFRONTAL CORTEX; ALCOHOL-USE; ADULTS AB This 4-year longitudinal study examined whether performance on a decision-making task and an emotion-processing task predicted the initiation of tobacco, marijuana, or alcohol use among 77 adolescents. Of the participants, 64% met criteria for an externalizing behavioral disorder; 33% did not initiate substance use; 13% used one of the three substances under investigation, 18% used two, and 36% used all three. Initiation of substance use was associated with enhanced recognition of angry emotion. but not with risky decision-making. In conclusion, adolescents who initiate drug use present vulnerability in the form of bias towards negative emotion but not toward decisions that involve risk. (C) 2009 Published by Elsevier Ltd. C1 [Ernst, Monique; Luckenbaugh, David A.; Temple, Veronica A.; Jennessa, Jessica; Korelitz, Katherine E.] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Moolchan, Eric T.; Kimes, Alane S.] NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [London, Edythe D.] Univ Calif Los Angeles, Semel Inst, David Geffen Sch Med, Los Angeles, CA 90024 USA. [London, Edythe D.] Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90024 USA. RP Ernst, M (reprint author), Bldg 15K,9000 Rockville Pike, Bethesda, MD 20892 USA. EM ernstm@mail.nih.gov RI Reis, Aline/G-9573-2012 FU National Institute of Mental Health; National Institute on Drug Abuse; Philip Morris FX Funding comes from the Intramural Research Program of the National Institute of Mental Health and the National Institute on Drug Abuse. Work by Dr. London was supported in part by a grant to UCLA from Philip Morris which has no involvement with the design, collection, analyses, or interpretation of data, writing the manuscript or the decision to submit the manuscript for publication. NR 12 TC 9 Z9 10 U1 5 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD MAR PY 2010 VL 35 IS 3 BP 286 EP 289 DI 10.1016/j.addbeh.2009.10.014 PG 4 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 552BV UT WOS:000274262500020 PM 19914005 ER PT J AU Pringle, B Chambers, D Wang, PS AF Pringle, Beverly Chambers, David Wang, Philip S. TI Toward Enough of the Best for All: Research to Transform the Efficacy, Quality, and Reach of Mental Health Care for Youth SO ADMINISTRATION AND POLICY IN MENTAL HEALTH AND MENTAL HEALTH SERVICES RESEARCH LA English DT Editorial Material ID DISORDERS C1 [Pringle, Beverly; Chambers, David] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Wang, Philip S.] NIMH, Off Director, Bethesda, MD 20892 USA. RP Pringle, B (reprint author), NIMH, Div Serv & Intervent Res, Room 7165,Mail Stop 9631,6001 Execut Blvd, Bethesda, MD 20892 USA. EM bpringle@mail.nih.gov; dchamber@mail.nih.gov; wangphi@mail.nih.gov NR 17 TC 6 Z9 6 U1 1 U2 3 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 0894-587X J9 ADM POLICY MENT HLTH JI Adm. Policy. Ment. Health PD MAR PY 2010 VL 37 IS 1-2 SI SI BP 191 EP 196 DI 10.1007/s10488-010-0266-3 PG 6 WC Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 602AJ UT WOS:000278110200029 PM 20112059 ER PT J AU Gallagher, AR Germino, GG Somlo, S AF Gallagher, Anna Rachel Germino, Gregory G. Somlo, Stefan TI Molecular Advances in Autosomal Dominant Polycystic Kidney Disease SO ADVANCES IN CHRONIC KIDNEY DISEASE LA English DT Article DE Polycystic kidney; Cilia; Polycystin; TRP channel; GPS cleavage AB Autosomal dominant polycystic disease (ADPKD) is the most common form of inherited kidney disease that results in renal failure. The understanding of the pathogenesis of ADPKD has advanced significantly since the discovery of the 2 causative genes, PKD1 and PKD2. Dominantly inherited gene mutations followed by somatic second-hit mutations inactivating the normal copy of the respective gene result in renal tubular cyst formation that deforms the kidney and eventually impairs its function. The respective gene products, polycystin-1 and polycystin-2, work together in a common cellular pathway. Polycystin-1, a large receptor molecule, forms a receptor-channel complex with polycystin-2, which is a cation channel belonging to the TRP family. Both polycystin proteins have been localized to the primary cilium, a nonmotile microtubule-based structure that extends from the apical membrane of tubular cells into the lumen. Here we discuss recent insights in the pathogenesis of ADPKD including the genetics of ADPKD, the properties of the respective polycystin proteins, the role of cilia, and some cell-signaling pathways that have been implicated in the pathways related to PKD1 and PKD2. (C) 2010 by the National Kidney Foundation, Inc. All rights reserved. C1 [Germino, Gregory G.] NIDDK, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. RP Germino, GG (reprint author), NIDDK, NIH, MSC 2560,31 Ctr Dr,Bldg 31,Rm 9A52, Bethesda, MD 20892 USA. EM germinogg@niddk.nih.gov; stefan.somlo@yale.edu OI Germino, Gregory/0000-0002-3609-5588 FU NIH/NIDDK [DK51041, DK54053, DK57328] FX Supported by grants from NIH/NIDDK including DK51041, DK54053 and DK57328 (SS) and the Intramural Research Program of the NIH, NIDDK (GGG). NR 104 TC 70 Z9 72 U1 1 U2 10 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1548-5595 J9 ADV CHRONIC KIDNEY D JI Adv. Chronic Kidney Dis. PD MAR PY 2010 VL 17 IS 2 BP 118 EP 130 DI 10.1053/j.ackd.2010.01.002 PG 13 WC Urology & Nephrology SC Urology & Nephrology GA V24KE UT WOS:000208408500003 PM 20219615 ER PT J AU Jayachandran, M Preston, CC Hunter, LW Jahangir, A Owen, WG Korach, KS Miller, VM AF Jayachandran, Muthuvel Preston, Claudia C. Hunter, Larry W. Jahangir, Arshad Owen, Whyte G. Korach, Kenneth S. Miller, Virginia M. TI Loss of estrogen receptor beta decreases mitochondrial energetic potential and increases thrombogenicity of platelets in aged female mice SO AGE LA English DT Article DE Aging; Estrogen receptors; Microparticles; Mitochondria; Platelet energy metabolism; Procoagulant activity ID ER-BETA; CARDIOVASCULAR-DISEASE; ELECTRON-TRANSPORT; GENE ESR2; IN-VITRO; MICROPARTICLES; ALPHA; EXPRESSION; BLOOD; CELL AB Platelets derived from aged (reproductively senescent) female mice with genetic deletion of estrogen receptor beta (beta ER) are more thrombogenic than those from age-matched wild-type (WT) mice. Intracellular processes contributing to this increased thrombogenicity are not known. Experiments were designed to identify subcellular localization of estrogen receptors and evaluate both glycolytic and mitochondrial energetic processes which might affect platelet activation. Platelets and blood from aged (22-24 months) WT and estrogen receptor beta knockout (beta ERKO) female mice were used in this study. Body, spleen weight, and serum concentrations of follicle-stimulating hormone and 17 beta-estradiol were comparable between WT and beta ERKO mice. Number of spontaneous deaths was greater in the beta ERKO colony (50% compared to 30% in WT) over the course of 24 months. In resting (nonactivated) platelets, estrogen receptors did not appear to colocalize with mitochondria by immunostaining. Lactate production and mitochondrial membrane potential of intact platelets were similar in both groups of mice. However, activities of NADH dehydrogenase, cytochrome bc (1) complex, and cytochrome c oxidase of the electron transport chain were reduced in mitochondria isolated from platelets from beta ERKO compared to WT mice. There were a significantly higher number of phosphatidylserine-expressing platelet-derived microvesicles in the plasma and a greater thrombin-generating capacity in beta ERKO compared to WT mice. These results suggest that deficiencies in beta ER affect energy metabolism of platelets resulting in greater production of circulating thrombogenic microvesicles and could potentially explain increased predisposition to thromboembolism in some elderly females. C1 [Jayachandran, Muthuvel; Miller, Virginia M.] Mayo Clin, Coll Med, Dept Physiol & Biomed Engn, Rochester, MN 55905 USA. [Jayachandran, Muthuvel; Hunter, Larry W.; Miller, Virginia M.] Mayo Clin, Coll Med, Dept Surg, Rochester, MN 55905 USA. [Preston, Claudia C.; Jahangir, Arshad] Mayo Clin, Coll Med, Div Cardiovasc Dis, Rochester, MN 55905 USA. [Owen, Whyte G.] Mayo Clin, Coll Med, Div Hematol, Rochester, MN 55905 USA. [Owen, Whyte G.] Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. [Korach, Kenneth S.] Natl Inst Environm Hlth Sci, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC USA. RP Jayachandran, M (reprint author), Mayo Clin, Coll Med, Dept Physiol & Biomed Engn, 200 1st St SW, Rochester, MN 55905 USA. EM jaya.m@mayo.edu OI Korach, Kenneth/0000-0002-7765-418X FU National Institutes of Health [NHLBI HL78638, NHLBI HL089542]; National Institute of Aging [AG 21201]; American Heart Association [AHA 08-30503Z]; Mayo Foundation; Division of Intramural Research of the NIEHS FX This work is supported by the National Institutes of Health (NHLBI HL78638 and NHLBI HL089542), the National Institute of Aging (AG 21201), the American Heart Association (AHA 08-30503Z), the Mayo Foundation, and Division of Intramural Research of the NIEHS. NR 64 TC 21 Z9 21 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 J9 AGE JI Age PD MAR PY 2010 VL 32 IS 1 BP 109 EP 121 DI 10.1007/s11357-009-9119-y PG 13 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 561GD UT WOS:000274963000011 PM 19908165 ER PT J AU Blagosklonny, MV Campisi, J Sinclair, DA Bartke, A Blasco, MA Bonner, WM Bohr, VA Brosh, RM Brunet, A DePinho, RA Donehower, LA Finch, CE Finkel, T Gorospe, M Gudkov, AV Hall, MN Hekimi, S Helfand, SL Karlseder, J Kenyon, C Kroemer, G Longo, V Nussenzweig, A Osiewacz, HD Peeper, DS Rando, TA Rudolph, KL Sassone-Corsi, P Serrano, M Sharpless, NE Skulachev, VP Tilly, JL Tower, J Verdin, E Vijg, J AF Blagosklonny, Mikhail V. Campisi, Judy Sinclair, David A. Bartke, Andrzej Blasco, Maria A. Bonner, William M. Bohr, Vilhelm A. Brosh, Robert M., Jr. Brunet, Anne DePinho, Ronald A. Donehower, Lawrence A. Finch, Caleb E. Finkel, Toren Gorospe, Myriam Gudkov, Andrei V. Hall, Michael N. Hekimi, Siegfried Helfand, Stephen L. Karlseder, Jan Kenyon, Cynthia Kroemer, Guido Longo, Valter Nussenzweig, Andre Osiewacz, Heinz D. Peeper, Daniel S. Rando, Thomas A. Rudolph, K. Lenhard Sassone-Corsi, Paolo Serrano, Manuel Sharpless, Norman E. Skulachev, Vladimir P. Tilly, Jonathan L. Tower, John Verdin, Eric Vijg, Jan TI Impact papers on aging in 2009 SO AGING-US LA English DT Review DE aging; senescence; signal transduction; genes for longevity ID LIFE-SPAN EXTENSION; SINGLE-NUCLEOTIDE POLYMORPHISMS; TELOMERE-DYSFUNCTIONAL MICE; STEM-CELL HOMEOSTASIS; DNA-DAMAGE RESPONSE; DROSOPHILA-MELANOGASTER; DIETARY RESTRICTION; PROTEIN-KINASE; GENETICALLY INTERACTS; CALORIE RESTRICTION AB The editorial board of Aging reviews research papers published in 2009, which they believe have or will have a significant impact on aging research. Among many others, the topics include genes that accelerate aging or in contrast promote longevity in model organisms, DNA damage responses and telomeres, molecular mechanisms of life span extension by calorie restriction and pharmacologic interventions into aging. The emerging message in 2009 is that aging is not random but determined by a genetically-regulated longevity network and can be decelerated both genetically and pharmacologically. C1 [Blagosklonny, Mikhail V.] Roswell Pk Canc Inst, Dept Cell Stress Biol, BLSC, Buffalo, NY 14263 USA. [Campisi, Judy] Buck Inst Age Res, Novato, CA USA. [Sinclair, David A.] Harvard Univ, Sch Med, Boston, MA USA. [Bartke, Andrzej] So Illinois Univ, Springfield, IL USA. [Blasco, Maria A.; Serrano, Manuel] Spanish Natl Canc Ctr, Madrid, Spain. [Bonner, William M.; Nussenzweig, Andre] NCI, NIH, Bethesda, MD 20892 USA. [Bohr, Vilhelm A.; Brosh, Robert M., Jr.; Gorospe, Myriam] NIA, NIH, Baltimore, MD 21224 USA. [Brunet, Anne; Rando, Thomas A.] Stanford Univ, Stanford, CA 94305 USA. [DePinho, Ronald A.] Dana Farber Canc Inst, Boston, MA 02115 USA. [Donehower, Lawrence A.] Baylor Coll Med, Houston, TX 77030 USA. [Finch, Caleb E.; Longo, Valter; Tower, John] Univ So Calif, Los Angeles, CA USA. [Finkel, Toren] NHLBI, NIH, Bethesda, MD 20892 USA. [Hall, Michael N.] Univ Basel, Basel, Switzerland. [Hekimi, Siegfried] McGill Univ, Montreal, PQ, Canada. [Helfand, Stephen L.] Brown Univ, Providence, RI 02912 USA. [Karlseder, Jan] Salk Inst Biol Studies, La Jolla, CA USA. [Kenyon, Cynthia; Verdin, Eric] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Kroemer, Guido] INSERM, U848, Villejuif, France. [Osiewacz, Heinz D.] Goethe Univ Frankfurt, Frankfurt, Germany. [Peeper, Daniel S.] Netherlands Canc Inst, Amsterdam, Netherlands. [Rudolph, K. Lenhard] Hannover Med Sch, D-3000 Hannover, Germany. [Sassone-Corsi, Paolo] Univ Calif Irvine, Irvine, CA USA. [Sharpless, Norman E.] Univ N Carolina, Chapel Hill, NC USA. [Skulachev, Vladimir P.] Moscow MV Lomonosov State Univ, Moscow, Russia. [Tilly, Jonathan L.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Vijg, Jan] Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Blagosklonny, MV (reprint author), Roswell Pk Canc Inst, Dept Cell Stress Biol, BLSC, L3-312,Elm & Carlton St, Buffalo, NY 14263 USA. EM Blagosklonny@oncotarget.com RI Osiewacz, Heinz/D-3454-2011; Sassone-Corsi, Paolo/H-6182-2011; Skulachev, Vladimir/J-4164-2012; Kroemer, Guido/B-4263-2013; Serrano, Manuel/H-2634-2015; Blasco , Maria A./M-1694-2014; Bartke, Andzej/D-6640-2017; OI Skulachev, Vladimir/0000-0003-4886-2243; Serrano, Manuel/0000-0001-7177-9312; Blasco , Maria A./0000-0002-4211-233X; Bartke, Andzej/0000-0002-2569-557X; Verdin, Eric/0000-0003-3703-3183; Sinclair, David/0000-0002-9936-436X FU NCI NIH HHS [R01 CA084628]; NIA NIH HHS [R01 AG011833, R01 AG024353, R01 AG028730] NR 115 TC 19 Z9 20 U1 0 U2 7 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD MAR PY 2010 VL 2 IS 3 BP 111 EP 121 PG 11 WC Cell Biology SC Cell Biology GA 589AE UT WOS:000277115300001 PM 20351400 ER PT J AU Schug, TT Li, XL AF Schug, Thaddeus T. Li, Xiaoling TI Surprising sirtuin crosstalk in the heart SO AGING-US LA English DT Article DE Sirtuins; insulin-like growth factor; cardiac hypertrophy ID CALORIE RESTRICTION; OXIDATIVE STRESS; LIFE-SPAN; RESISTANCE; DISEASE; CARDIOMYOCYTES; TRANSCRIPTION; DEACETYLASE; PROTECTS; MICE C1 [Schug, Thaddeus T.; Li, Xiaoling] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Schug, TT (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM schugt@niehs.nih.gov NR 22 TC 9 Z9 10 U1 0 U2 3 PU IMPACT JOURNALS LLC PI ALBANY PA 6211 TIPTON HOUSE, STE 6, ALBANY, NY 12203 USA SN 1945-4589 J9 AGING-US JI Aging-US PD MAR PY 2010 VL 2 IS 3 BP 129 EP 132 PG 4 WC Cell Biology SC Cell Biology GA 589AE UT WOS:000277115300003 PM 20375467 ER PT J AU Milner, JA Trujillo, EB AF Milner, John A. Trujillo, Elaine B. TI Public Health Genomics: translating nutrigenomics research into population health benefits SO AGRO FOOD INDUSTRY HI-TECH LA English DT Article DE Nutritional genomics; nutrigenomics; nutrigenetics; epigenomics; public health; genetic testing; personalized nutrition; bioactive food components; DNA; single nucleotide polymorphism ID DIET; POLYMORPHISMS; NUTRITION; OBESITY; RISK; FAT AB The "omics of nutrition", which includes nutrigenetics, epigenomics, transcriptomics, proteomics, and metabolomics are fundamental to the understanding of genetic-diet interactions that influence key cellular processes and ultimately affect phenotype. A multitude of food components have been reported to alter the expression of a gene or its products. However, the response is highly dependent on the quantity and duration of exposures and variation in the target being influenced by the food component(s). Personalized nutrition, which builds on knowledge of the "omics", will assist in identifying those who benefit most, or put themselves at risk, as a result of dietary intervention strategies. C1 [Milner, John A.; Trujillo, Elaine B.] NCI, NIH, Nutr Sci Res Grp, Canc Prevent Div, Rockville, MD 20892 USA. RP Milner, JA (reprint author), NCI, NIH, Nutr Sci Res Grp, Canc Prevent Div, 6130 Execut Blvd,Suite 3164, Rockville, MD 20892 USA. NR 24 TC 0 Z9 0 U1 1 U2 7 PU TEKNOSCIENZE PUBL PI MILANO PA VIALE BRIANZA 22, 20127 MILANO, ITALY SN 1722-6996 J9 AGRO FOOD IND HI TEC JI Agro Food Ind. Hi-Tech PD MAR-APR PY 2010 VL 21 IS 2 BP 32 EP 34 PG 3 WC Biotechnology & Applied Microbiology; Food Science & Technology SC Biotechnology & Applied Microbiology; Food Science & Technology GA 601YM UT WOS:000278104200008 ER PT J AU Phillips, KA Cofrancesco, J Sisson, S Wu, AW Bass, EB Berkenblit, G AF Phillips, Karran A. Cofrancesco, Joseph, Jr. Sisson, Stephen Wu, Albert W. Bass, Eric B. Berkenblit, Gail TI A Multicenter Study of Internal Medicine Residents' Perceptions of Training, Competence, and Performance in Outpatient HIV Care SO AIDS PATIENT CARE AND STDS LA English DT Article ID UNITED-STATES; PHYSICIANS; INFECTION; AIDS; VIRUS AB Routine HIV screening is recommended by the Centers for Disease Control and Prevention (CDC), but it is unknown how well internal medicine residents are trained in HIV risk assessment, testing, counseling, and initial management of HIV patients. We sought to determine internal medicine residents' attitudes about HIV training and the factors that influence their HIV care performance utilizing a cross-sectional survey of 321 second-and third-year internal medicine residents from four programs in Baltimore, Boston, Detroit, and New York City between March and June 2006. Measurements included HIV care experience; attitudes, competency, and adequacy of HIV training; and basic HIV care performance and factors impacting performance. Two hundred twenty-three residents (69%) completed the survey. While 50% of residents reported over 30 HIV inpatient encounters in the past year, the majority of residents had limited outpatient exposure providing care for only 1-5 HIV outpatients. Managing HIV patients was rated an excellent educational opportunity by 89% of residents and 77% planned to care for HIV patients in the future. However, 39% stated that they did not feel competent to provide HIV outpatient care. Higher rates of residents reported deficiency in oupatient HIV training compared to outpatient non-HIV training (p<0.05) or inpatient HIV training (p<0.05). Residents reported substandard HIV risk assessment, testing, counseling, and initial management performance. Self-reported proficiency correlated with the number of HIV outpatients cared for and perceived training adequacy. Current residency training in HIV care remains largely inpatient-based and residents frequently rate HIV outpatient training as inadequate. C1 [Phillips, Karran A.] Natl Inst Drug Abuse, Natl Inst Hlth, Baltimore, MD USA. [Cofrancesco, Joseph, Jr.; Sisson, Stephen; Wu, Albert W.; Bass, Eric B.; Berkenblit, Gail] Johns Hopkins Sch Med, Baltimore, MD USA. RP Berkenblit, G (reprint author), 601 N Caroline St, Baltimore, MD 21287 USA. EM gberken@jhmi.edu FU Osler Center for Clinical Excellence FX We would like to acknowledge the assistance of Ms. Jeanne Macrae, Mr. Bruce Martin, Ms. Elizabeth Thompson, and Dr. Baker-Genaw in technical support of the survey administration. We acknowledge methodological consultation provided by Hsin-Chieh Yeh, Ph. D., Core Faculty of the Johns Hopkins General Internal Medicine Methods Core. This project was supported by the Osler Center for Clinical Excellence at Johns Hopkins. NR 20 TC 4 Z9 4 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1087-2914 J9 AIDS PATIENT CARE ST JI Aids Patient Care STDS PD MAR PY 2010 VL 24 IS 3 BP 159 EP 164 DI 10.1089/apc.2009.0302 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 566EI UT WOS:000275352500004 PM 20214483 ER PT J AU Magnusson, A Goransson, M Heilig, M AF Magnusson, Asa Goransson, Mona Heilig, Markus TI Early onset alcohol dependence with high density of family history is not "male limited" SO ALCOHOL LA English DT Article DE Alcoholism; Women; Subtypes; Personality; Heritability; Illicit drugs ID SUBSTANCE USE DISORDERS; IDENTIFICATION TEST AUDIT; CROSS-FOSTERING ANALYSIS; PERSONALITY-TRAITS; UNITED-STATES; PSYCHIATRIC-DISORDERS; EPIDEMIOLOGIC SURVEY; GENDER-DIFFERENCES; MENTAL-DISORDERS; DRUG-DEPENDENCE AB Objective: Based on classical adoption studies, early onset type II alcoholism was originally described as "male limited." We examined the possible expression of this subtype in present day alcohol-dependent women. Detailed systematic assessment was obtained from 200 treatment-seeking alcohol-dependent women and 189 healthy population controls. Women fulfilling type II alcoholism criteria had higher alcoholism severity as measured by The Alcohol Use Disorders Identification Test and markedly higher use of illicit drugs. Both alcoholism subtypes scored higher than normal on anxiety and impulsivity traits, but type II women scored markedly higher on aggression subscales than either of the other groups. Importantly, density of family history was markedly higher in type II women, suggesting a higher heritability. Despite its original description as male limited, early onset alcoholism with high density of family history is likely to be a valid construct in women. Its recognition has important implications for diagnosis, treatment, and research. Published by Elsevier Inc. C1 [Heilig, Markus] NIAAA, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. [Magnusson, Asa; Goransson, Mona; Heilig, Markus] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, 10 Ctr Dr,10-1E-5334, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov OI Heilig, Markus/0000-0003-2706-2482 FU County of Stockholm; National Institute on Alcohol Abuse and Alcoholism FX The authors gratefully acknowledge the help by staffs at the participating treatment centers and input on the manuscript by Prof Nancy Pedersen. This work was supported by funding from the County of Stockholm and National Institute on Alcohol Abuse and Alcoholism intramural research funds. The authors have no competing interests. NR 60 TC 9 Z9 9 U1 2 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 EI 1873-6823 J9 ALCOHOL JI Alcohol PD MAR PY 2010 VL 44 IS 2 BP 131 EP 139 DI 10.1016/j.alcohol.2010.01.001 PG 9 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 626LW UT WOS:000279968500001 PM 20193873 ER PT J AU Kohlstadt, I Vitiello, B AF Kohlstadt, Ingrid Vitiello, Benedetto TI Use of Atypical Antipsychotics in Children: Balancing Safety and Effectiveness SO AMERICAN FAMILY PHYSICIAN LA English DT Editorial Material C1 [Kohlstadt, Ingrid] US FDA, Off Pediat Therapeut, Rockville, MD 20857 USA. [Vitiello, Benedetto] NIMH, Bethesda, MD 20892 USA. RP Kohlstadt, I (reprint author), US FDA, Off Pediat Therapeut, Rockville, MD 20857 USA. EM kohlstadt@fda.hhs.gov NR 9 TC 5 Z9 5 U1 2 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 MAR 1 PY 2010 VL 81 IS 5 BP 585 EP + PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 565MK UT WOS:000275297200002 PM 20187594 ER PT J AU Leosdottir, M Willenheimer, R Plehn, J Borgquist, R Gudmundsson, P Harris, TB Launer, LJ Bjornsdottir, H Nilsson, PM Gudnason, V AF Leosdottir, Margret Willenheimer, Ronnie Plehn, Jonathan Borgquist, Rasmus Gudmundsson, Petri Harris, Tamara B. Launer, Lenore J. Bjornsdottir, Halldora Nilsson, Peter M. Gudnason, Vilmundur TI Myocardial structure and function by echocardiography in relation to glucometabolic status in elderly subjects from 2 population-based cohorts: A cross-sectional study SO AMERICAN HEART JOURNAL LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; VENTRICULAR DIASTOLIC FUNCTION; CONGESTIVE-HEART-FAILURE; DIABETIC CARDIOMYOPATHY; STANDARDS COMMITTEE; OF-ECHOCARDIOGRAPHY; INSULIN-RESISTANCE; QUANTIFICATION; FRAMINGHAM; RECOMMENDATIONS AB Background Left ventricular (LV) diastolic dysfunction has been associated with impaired glucometabolic status. However, studies of older subjects are lacking. We examined associations between echocardiographic indices of LV diastolic function and LV mass index (LVMI) and glucometabolic status among middle-aged and elderly subjects free from heart disease, hypothesizing that the associations would be comparative to younger cohorts. Methods We examined the Age Gene/Environment Susceptibility Reykjavik Study (Iceland; n = 607, 76 +/- 6 years) and the Malmo Preventive Project Re-Examination Study (MPP-RES) cohorts (Sweden; n = 1,519, 67 +/- 6 years), evaluating associations with multivariable regression analysis. Results In the Age Gene/Environment Susceptibility Reykjavik Study, LVMI was positively correlated with glycosylated hemoglobin (HbA1c) (P = .001). Otherwise, echocardiographic variables were not associated with glucometabolic status. In the MPP-RES, LVMI increased with increasing glucometabolic disturbance among both older (7-80 years) and middle-aged (57-69 years) subjects. Among older subjects, HbA1c was positively correlated with 2 variables reflecting LV diastolic function: late transmitral peak flow velocity (A) (P = .001) and early transmitral peak flow velocity (E)/early diastolic peak tissue velocity (Em) (P = .046). In middle-aged MPP-RES subjects, increasing glucometabolic disturbance was correlated with increasing late diastolic peak tissue velocity (Am) (P = .002) and, after age adjustment, with increasing A (P = .001) and decreasing Em/Am (P = .009). With age adjustment, Am and A were positively correlated with fasting glucose and HbA1c. Conclusions Contrary to our hypothesis, in 2 independent cohorts of older individuals, associations between glucometabolic status and LV diastolic function were generally weak. These contrast with previous reports, as well as with observations among middle-aged subjects in the present study. Changes in LV diastolic function may be more age-related than associated with glucose metabolism in older subjects. (Am Heart J 2010; 159: 414-420.e4.) C1 [Leosdottir, Margret] Malmo Univ Hosp, Dept Cardiol, S-20502 Malmo, Sweden. [Willenheimer, Ronnie; Nilsson, Peter M.] Lund Univ, Malmo Univ Hosp, Dept Clin Sci, Malmo, Sweden. [Willenheimer, Ronnie] Heart Hlth Grp, Malmo, Sweden. [Plehn, Jonathan] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. [Borgquist, Rasmus] Univ Lund Hosp, Dept Cardiol, S-22185 Lund, Sweden. [Gudmundsson, Petri] Malmo Univ, Dept Biomed Lab Sci, Malmo, Sweden. [Harris, Tamara B.; Launer, Lenore J.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Bjornsdottir, Halldora; Gudnason, Vilmundur] Iceland Heart Assoc, Kopavogur, Iceland. [Gudnason, Vilmundur] Univ Iceland, Reykjavik, Iceland. RP Leosdottir, M (reprint author), Malmo Univ Hosp, Dept Cardiol, S-20502 Malmo, Sweden. EM margret.leosdottir@med.lu.se RI Gudnason, Vilmundur/K-6885-2015; OI Gudnason, Vilmundur/0000-0001-5696-0084; Leosdottir, Margret/0000-0003-1677-1566 FU NIH [N01-AG-12100]; NIA Intramural Research Program, Bethesda; Swedish Heart-Lung Foundation; Merck, Sharp Dohme; Hulda and E Conrad Mossfelts Foundation; Ernhold Lundstroms Foundation (Sweden); Helga Jonsdottir and Sigurlidi Kristjansson Memorial Foundation (Iceland) FX The AGES-RS study was funded by an NIH contract N01-AG-12100, the NIA Intramural Research Program, Bethesda (MD), Hjartavernd (the Icelandic Heart Association, Iceland), and the Althingi (the Icelandic Parliament). Additionally, this study was supported by The Swedish Heart-Lung Foundation; Merck, Sharp & Dohme; Hulda and E Conrad Mossfelts Foundation; Ernhold Lundstroms Foundation (Sweden); and Helga Jonsdottir and Sigurlidi Kristjansson Memorial Foundation (Iceland). NR 26 TC 16 Z9 16 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD MAR PY 2010 VL 159 IS 3 BP 414 EP U113 DI 10.1016/j.ahj.2009.12.028 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 571XH UT WOS:000275788900012 PM 20211303 ER PT J AU Flegal, KM Graubard, BI Williamson, DF Gail, MH AF Flegal, Katherine M. Graubard, Barry I. Williamson, David F. Gail, Mitchell H. TI Sources of differences in estimates of obesity-associated deaths from first National Health and Nutrition Examination Survey (NHANES I) hazard ratios SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID UNITED-STATES; BODY-MASS; OVERWEIGHT; MORTALITY; SMOKING; RISK; UNDERWEIGHT; POPULATION; FRACTIONS; MORBIDITY AB Background: Estimates of obesity-associated deaths in the United States for 1991 were published by Allison et al (JAMA 1999; 282: 1530-8) and subsequently for 2000 by Mokdad et al (JAMA 2004; 291: 1238-45). Flegal et al (JAMA 2005; 293: 1861-7) then published lower estimates of obesity-associated deaths for 2000. All 3 studies incorporated data from the first National Health and Nutrition Examination Survey (NHANES I). Objective: The objective was to clarify the effects of methodologic differences between the 3 studies in estimates of obesity-associated deaths in the US population by using NHANES I hazard ratios. Design: The earlier reports used imputed smoking data for much of the NHANES I sample rather than the available reported data and applied a method of calculating attributable fractions that did not adjust for the effects of age, sex, and smoking on mortality in the target US population and did not account for effect modification by age. The effects of these and other methodologic factors were examined. Results: The NHANES I hazard ratios in the earlier reports were too low, probably because of the imputed smoking data. The low hazard ratios obscured the magnitude and direction of the bias arising from the incompletely adjusted attributable fraction method. When corrected hazard ratios were used, the incompletely adjusted attributable fraction method overestimated obesity-associated mortality in the target population by > 100,000 deaths. Conclusion: Methodologic sources of bias in the reports by Allison et al and Mokdad et al include the assessment of smoking status in NHANES I and the method of calculating attributable fractions. Am J Clin Nutr 2010;91:519-27. C1 [Flegal, Katherine M.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. [Graubard, Barry I.; Gail, Mitchell H.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Williamson, David F.] Emory Univ, Rollins Sch Publ Hlth, Hubert Dept Global Hlth, Atlanta, GA 30322 USA. RP Flegal, KM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, 3311 Toledo Rd,Room 4201, Hyattsville, MD 20782 USA. EM kmf2@cdc.gov RI Flegal, Katherine/A-4608-2013; OI Flegal, Katherine/0000-0002-0838-469X NR 33 TC 14 Z9 14 U1 0 U2 5 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2010 VL 91 IS 3 BP 519 EP 527 DI 10.3945/ajcn.2009.28222 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 557YM UT WOS:000274706500005 PM 20107197 ER PT J AU Yang, G Gao, YT Shu, XO Cai, QY Li, GL Li, HL Ji, BT Rothman, N Dyba, M Xiang, YB Chung, FL Chow, WH Zheng, W AF Yang, Gong Gao, Yu-Tang Shu, Xiao-Ou Cai, Qiuyin Li, Guo-Liang Li, Hong-Lan Ji, Bu-Tian Rothman, Nathaniel Dyba, Marcin Xiang, Yong-Bing Chung, Fung-Lung Chow, Wong-Ho Zheng, Wei TI Isothiocyanate exposure, glutathione S-transferase polymorphisms, and colorectal cancer risk SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID CRUCIFEROUS VEGETABLE CONSUMPTION; ABERRANT CRYPT FOCI; COLON-CANCER; DIETARY ISOTHIOCYANATES; MULTIETHNIC COHORT; BROCCOLI SPROUTS; COOKING DURATION; WOMENS HEALTH; SHANGHAI; HUMANS AB Background: Isothiocyanates, compounds found primarily in cruciferous vegetables, have been shown in laboratory studies to possess anticarcinogenic activity. Glutathione S-transferases (GSTs) are involved in the metabolism and elimination of isothiocyanates; thus, genetic variations in these enzymes may affect in vivo bioavailability and the activity of isothiocyanates. Objective: The objective was to prospectively evaluate the association between urinary isothiocyanate concentrations and colorectal cancer risk as well as the potential modifying effect of GST genotypes on the association. Design: A nested case-control study of 322 cases and 1251 controls identified from the Shanghai Women's Health Study was conducted. Results: Urinary isothiocyanate concentrations were inversely associated with colorectal cancer risk; the inverse association was statistically significant or nearly significant in the GSTM1-null (P for trend = 0.04) and the GSTT1-null (P for trend = 0.07) genotype groups. The strongest inverse association was found among individuals with both the GSTM1-null and the GSTT1-null genotypes, with an adjusted odds ratio of 0.51 (95% CI: 0.27, 0.95), in a comparison of the highest with the lowest tertile of urinary isothiocyanates. No apparent associations between isothiocyanate concentration and colorectal cancer risk were found among individuals who carried either the GSTM1 or GSTT1 gene (P for interaction, 0.05). Conclusion: This study suggests that isothiocyanate exposure may reduce the risk of colorectal cancer, and this protective effect may be modified by the GSTM1 and GSTT1 genes. Am J Clin Nutr 2010; 91: 704-11. C1 [Yang, Gong; Shu, Xiao-Ou; Cai, Qiuyin; Li, Guo-Liang; Zheng, Wei] Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Div Epidemiol,Dept Med, Nashville, TN 37203 USA. [Gao, Yu-Tang; Li, Hong-Lan; Xiang, Yong-Bing] Shanghai Canc Inst, Shanghai, Peoples R China. [Ji, Bu-Tian; Rothman, Nathaniel; Chow, Wong-Ho] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Dyba, Marcin; Chung, Fung-Lung] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. RP Yang, G (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Epidemiol Ctr,Div Epidemiol,Dept Med, 6th Floor,Suite 600,2525West End Ave, Nashville, TN 37203 USA. EM gong.yang@vanderbilt.edu RI LI, GUOLIANG/E-7359-2015; OI LI, GUOLIANG/0000-0001-8493-4684; Dyba, Marcin/0000-0001-6311-6877 FU USPHS [R01CA70867, R01CA 122364]; NIH [N02 CP1101066]; [P30CA68485] FX Supported by USPHS grant R01CA70867. The Shanghai Women's Health Study was supported in part by the NIH Intramural Research Program (N02 CP1101066). GY was supported in part by USPHS grant R01CA 122364. The biospecimens were prepared at the Survey and Biospecimen Shared Resource, which is supported in part by P30CA68485. NR 48 TC 31 Z9 33 U1 0 U2 2 PU AMER SOC NUTRITION-ASN PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0002-9165 EI 1938-3207 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2010 VL 91 IS 3 BP 704 EP 711 DI 10.3945/ajcn.2009.28683 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 557YM UT WOS:000274706500027 PM 20042523 ER PT J AU Hall, KD Chow, CC AF Hall, Kevin D. Chow, Carson C. TI Estimating the quantitative relation between food energy intake and changes in body weight SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter C1 [Hall, Kevin D.; Chow, Carson C.] 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; Chow, Carson/A-7970-2009 NR 4 TC 7 Z9 7 U1 0 U2 2 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD MAR PY 2010 VL 91 IS 3 BP 816 EP 816 DI 10.3945/ajcn.2009.28922 PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 557YM UT WOS:000274706500042 PM 20071643 ER PT J AU Jenkins, RA AF Jenkins, Richard A. TI Applied Roles and the Future of Community Psychology SO AMERICAN JOURNAL OF COMMUNITY PSYCHOLOGY LA English DT Article DE Practice; Participation; Future directions ID DECISION-MAKING; HIV; THAILAND; TRIAL AB The roles for community psychologists have changed over the past several decades. These changes have implications for training, traditional academic roles, and the capacity of the field to maintain its integrity and further development. Changes in the scope of community psychology as a field as well as the roles of community psychologists are described with consideration of how they may affect participation in the field, retention of membership in SCRA, and potential directions for training. C1 NIDA, Prevent Res Branch, NIH, Bethesda, MD 20892 USA. RP Jenkins, RA (reprint author), NIDA, Prevent Res Branch, NIH, 6001 Executive Blvd,Rm 5185 MSC 9589, Bethesda, MD 20892 USA. EM jenkinsri@mail.nih.gov NR 15 TC 1 Z9 3 U1 1 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-0562 J9 AM J COMMUN PSYCHOL JI Am. J. Community Psychol. PD MAR PY 2010 VL 45 IS 1-2 BP 68 EP 72 DI 10.1007/s10464-009-9285-1 PG 5 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Social Work SC Public, Environmental & Occupational Health; Psychology; Social Work GA 562YU UT WOS:000275092800005 PM 20094769 ER PT J AU Jensen, RA Shea, S Ranjit, N Diez-Roux, A Wong, TY Klein, R Klein, BEK Cotch, MF Siscovick, DS AF Jensen, Richard A. Shea, Steven Ranjit, Nalini Diez-Roux, Ana Wong, Tien Y. Klein, Ronald Klein, Barbara E. K. Cotch, Mary Frances Siscovick, David S. TI Psychosocial Risk Factors and Retinal Microvascular Signs SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE anger; anxiety; depression; microvessels; psychology; social; retina; social support ID CORONARY-HEART-DISEASE; BLUE MOUNTAINS EYE; ATHEROSCLEROSIS RISK; VESSEL DIAMETERS; BLOOD-PRESSURE; CARDIOVASCULAR-DISEASE; YOUNG-ADULTS; DIABETIC-RETINOPATHY; ARTERIOLAR DIAMETER; DEPRESSION SYMPTOMS AB The association between psychosocial risk factors and retinal microvascular signs was examined in the Multi-Ethnic Study of Atherosclerosis. Subjects were recruited from Baltimore, Maryland; Chicago, Illinois; Forsyth County, North Carolina; Los Angeles County, California; New York, New York; and St. Paul, Minnesota. Levels of depressive symptoms, trait anger, trait anxiety, chronic burdens, emotional support, and cynical distrust were assessed by questionnaire (from July 2000 to July 2002). Digital retinal images (from August 2002 to January 2004) from 6,147 participants were used to evaluate retinopathy and retinal vascular caliber. After controlling for potential confounding factors, the authors found that subjects without access to emotional support (Enriched Social Support Instrument score of < 19 vs. >= 19) had 60% greater odds of retinopathy (odds ratio = 1.6, 95% confidence interval (CI): 1.3, 2.0). Subjects with high Spielberger trait-anxiety scale scores (>= 22 vs. < 14) and subjects with high depressive symptoms (Center for Epidemiology Studies Depression Scale score, >= 16 vs. < 16) were also more likely to have retinopathy (odds ratio = 1.4, 95% CI: 1.1, 1.9 and odds ratio = 1.5, 95% CI: 1.2, 1.9), respectively. In this cross-sectional study, lack of emotional support, increased trait anxiety, and more depressive symptoms were associated with retinopathy signs, independently of other known risk factors. C1 [Jensen, Richard A.; Siscovick, David S.] Univ Washington, Dept Epidemiol, Seattle, WA 98195 USA. [Shea, Steven] Columbia Univ, Dept Med & Epidemiol, New York, NY USA. [Ranjit, Nalini; Diez-Roux, Ana] Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ctr Social Epidemiol & Populat Hlth, Ann Arbor, MI 48109 USA. [Wong, Tien Y.] Univ Melbourne, Ctr Eye Res, Melbourne, Vic, Australia. [Wong, Tien Y.] Natl Univ Singapore, Yong Loo Lin Sch Med, Singapore Eye Res Inst, Singapore 117595, Singapore. [Klein, Ronald; Klein, Barbara E. K.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Hlth, Madison, WI USA. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Siscovick, David S.] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA. RP Jensen, RA (reprint author), 1730 Minor Ave,Suite 1360, Seattle, WA 98101 USA. EM richaj@uw.edu OI Cotch, Mary Frances/0000-0002-2046-4350 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95165, N01-HC-95169, T32HL007902]; National Institutes of Health [Z01Ey000403] FX This work was supported by the National Heart, Lung, and Blood Institute (contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 to MESA); a National Institutes of Health Intramural Research Award (National Eye Institute award Z01Ey000403 to M. F. C.); and a National Heart, Lung, and Blood Institute Training Grant (T32HL007902 to R.A.J.). NR 57 TC 8 Z9 8 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 1 PY 2010 VL 171 IS 5 BP 522 EP 531 DI 10.1093/aje/kwp414 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558YY UT WOS:000274786500002 PM 20035010 ER PT J AU Rodondi, N Marques-Vidal, P Butler, J Sutton-Tyrrell, K Cornuz, J Satterfield, S Harris, T Bauer, DC Ferrucci, L Vittinghoff, E Newman, AB AF Rodondi, Nicolas Marques-Vidal, Pedro Butler, Javed Sutton-Tyrrell, Kim Cornuz, Jacques Satterfield, Suzanne Harris, Tamara Bauer, Douglas C. Ferrucci, Luigi Vittinghoff, Eric Newman, Anne B. CA Hlth Aging Body Compisition Study TI Markers of Atherosclerosis and Inflammation for Prediction of Coronary Heart Disease in Older Adults SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE atherosclerosis; cohort studies; coronary disease; inflammation ID C-REACTIVE PROTEIN; ANKLE BRACHIAL INDEX; CARDIOVASCULAR EVENTS; RISK PREDICTION; MYOCARDIAL-INFARCTION; MULTIPLE BIOMARKERS; ROC CURVE; ALL-CAUSE; HEALTH; MORTALITY AB Although both inflammatory and atherosclerosis markers have been associated with coronary heart disease (CHD) risk, data directly comparing their predictive value are limited. The authors compared the value of 2 atherosclerosis markers (ankle-arm index (AAI) and aortic pulse wave velocity (aPWV)) and 3 inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha)) in predicting CHD events. Among 2,191 adults aged 70-79 years at baseline (1997-1998) from the Health, Aging, and Body Composition Study cohort, the authors examined adjudicated incident myocardial infarction or CHD death ("hard" events) and "hard" events plus hospitalization for angina or coronary revascularization (total CHD events). During 8 years of follow-up between 1997-1998 and June 2007, 351 participants developed total CHD events (197 "hard" events). IL-6 (highest quartile vs. lowest: hazard ratio = 1.82, 95% confidence interval: 1.33, 2.49; P-trend < 0.001) and AAI (AAI < 0.9 vs. AAI 1.01-1.30: hazard ratio = 1.57, 95% confidence interval: 1.14, 2.18) predicted CHD events above traditional risk factors and modestly improved global measures of predictive accuracy. CRP, TNF-alpha, and aPWV had weaker associations. IL-6 and AAI accurately reclassified 6.6% and 3.3% of participants, respectively (P's < 0.05). Results were similar for "hard" CHD, with higher reclassification rates for AAI. IL-6 and AAI are associated with future CHD events beyond traditional risk factors and modestly improve risk prediction in older adults. C1 [Rodondi, Nicolas; Cornuz, Jacques] Univ Lausanne, Fac Biol & Med, Dept Ambulatory Care & Community Med, CH-1011 Lausanne, Switzerland. [Marques-Vidal, Pedro] Univ Lausanne, Univ Inst Social & Prevent Med, CH-1011 Lausanne, Switzerland. [Marques-Vidal, Pedro] Univ Lausanne, Ctr Cardiovasc & Metab Res CardioMet, CH-1011 Lausanne, Switzerland. [Butler, Javed] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. [Sutton-Tyrrell, Kim; Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Satterfield, Suzanne] Univ Tennessee, Coll Med, Dept Prevent Med, Memphis, TN USA. [Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ferrucci, Luigi] NIA, Intramural Res Program, Baltimore, MD 21224 USA. [Bauer, Douglas C.; Vittinghoff, Eric] Univ Calif San Francisco, Sch Med, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Sch Med, Dept Med, Div Gen Internal Med, San Francisco, CA 94143 USA. RP Rodondi, N (reprint author), Univ Lausanne, Fac Biol & Med, Dept Ambulatory Care & Community Med, Bugnon 44, CH-1011 Lausanne, Switzerland. EM nicolas.rodondi@hospvd.ch RI Newman, Anne/C-6408-2013; Marques-Vidal, Pedro/C-9449-2009 OI Newman, Anne/0000-0002-0106-1150; Marques-Vidal, Pedro/0000-0002-4548-8500 FU National Institute on Aging, US National Institutes of Health [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institute on Aging; Swiss National Science Foundation [3200B0-116097] FX This research was supported by grants N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 from the National Institute on Aging, US National Institutes of Health, and in part by the Intramural Research Program of the National Institute on Aging. The National Institute on Aging funded the Health, Aging, and Body Composition study, reviewed the manuscript, and approved its publication. This research was partially supported by grant 3200B0-116097 to Dr. Nicolas Rodondi from the Swiss National Science Foundation. NR 35 TC 40 Z9 48 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 1 PY 2010 VL 171 IS 5 BP 540 EP 549 DI 10.1093/aje/kwp428 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 558YY UT WOS:000274786500004 PM 20110287 ER PT J AU Koster, A van Gool, CH Kempen, GIJM Penninx, BWJH Lee, JS Rubin, SM Tylavsky, FA Yaffe, K Newman, AB Harris, TB Pahor, M Ayonayon, HN van Eijk, JTM Kritchevsky, SB AF Koster, Annemarie van Gool, Coen H. Kempen, Gertrudis I. J. M. Penninx, Brenda W. J. H. Lee, Jung Sun Rubin, Susan M. Tylavsky, Frances A. Yaffe, Kristine Newman, Anne B. Harris, Tamara B. Pahor, Marco Ayonayon, Hilsa N. van Eijk, Jacques Th. M. Kritchevsky, Stephen B. CA Hlth ABC Study TI Late-Life Depressed Mood and Weight Change Contribute to the Risk of Each Other SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE Depression; weight change; aging ID OLDER PERSONS; BODY-COMPOSITION; AMSTERDAM; SYMPTOMS; STRESS; HEALTH; WOMEN; DISABILITY; COMMUNITY; FRAILTY AB Objective: Weight change may be considered an effect of depression. In turn, depression may follow weight change. Deteriorations in health may mediate these associations. The objective was to examine reciprocal associations between depressed mood and weight change, and the potentially mediating role of deteriorations in health (interim hospitalizations and incident mobility imitation) in these associations. Methods: Data were from 2406 black and white men and women, aged 70-79 from Pittsburgh, Pennsylvania and Memphis, Tennessee participating in the Health, Aging and Body composition (Health ABC) study. Depressed mood at baseline (T1) and 3-year follow-up (T4) was measured with the CES-D scale. Three weight change groups (T1-T4) were created: loss (>= 5% loss), stable (within +/- 5% loss or gain), and weight gain (>= 5% gain). Results: At T1 and T4, respectively 4.4% and 9.5% of the analysis sample had depressed mood. T1 depressed mood was associated with weight gain over the 3-year period (OR: 1.91; 95% CI: 1.13-3.22). Weight loss over the 3-year period was associated with T4 depressed mood (OR: 1.51; 95% CI: 1.05-2.16). Accounting for deteriorations in health in the reciprocal associations between weight change and depressed mood reduced effect sizes between 16-27%. Conclusions: In this study, depressed mood predicted weight gain over three years, while weight loss over three years predicted depressed mood. These associations were partly mediated through deteriorations in health. Implications for clinical practice and prevention include increased awareness that depressed mood can cause weight change, but can also be preceded by deteriorations in health and weight change. (Am J Geriatr Psychiatry 2010; 18: 236-244) C1 [Koster, Annemarie; Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Koster, Annemarie; van Gool, Coen H.; Kempen, Gertrudis I. J. M.; van Eijk, Jacques Th. M.] Univ Maastricht, Fac Hlth Med & Life Sci, Care & Publ Hlth Res Inst, Maastricht, Netherlands. [Penninx, Brenda W. J. H.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, Amsterdam, Netherlands. [Lee, Jung Sun] Univ Georgia, Dept Food, Athens, GA USA. [Lee, Jung Sun] Univ Georgia, Dept Nutr, Athens, GA USA. [Rubin, Susan M.; Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Epidemiol, San Francisco, CA 94143 USA. [Rubin, Susan M.; Ayonayon, Hilsa N.] Univ Calif San Francisco, Dept Biostat, San Francisco, CA 94143 USA. [Tylavsky, Frances A.] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Yaffe, Kristine] Univ Calif San Francisco, Dept Psychiat Neurol & Epidemiol, San Francisco, CA 94143 USA. [Newman, Anne B.] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. [Pahor, Marco] Univ Florida, Coll Med, Inst Aging, Dept Aging & Geriatr Res, Gainesville, FL USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Dept Internal Med, Sticht Ctr Aging & Rehabil, Winston Salem, NC 27103 USA. RP Koster, A (reprint author), NIA, Lab Epidemiol Demog & Biometry, 7201 Wisconsin Ave,Suite 3C309, Bethesda, MD 20892 USA. EM kostera@mail.nih.gov RI Koster, Annemarie/E-7438-2010; Newman, Anne/C-6408-2013; Kempen, Gertrudis/H-5978-2016; OI Newman, Anne/0000-0002-0106-1150; Kempen, Gertrudis/0000-0002-7053-2198; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institute on Aging [N01-AG-6 -2101, N01-AG-6 -2103, N01-AG-6-2106]; Intramural Research Program of NIH; National Institute on Aging FX This study was supported by National Institute on Aging contracts N01-AG-6 -2101, N01-AG-6 -2103, and N01-AG-6-2106. This research was supported (in part) by the Intramural Research Program of NIH, National Institute on Aging. NR 39 TC 16 Z9 17 U1 4 U2 15 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2010 VL 18 IS 3 BP 236 EP 244 DI 10.1097/JGP.0b013e3181c65837 PG 9 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 567PD UT WOS:000275458200007 PM 20224519 ER PT J AU Taylor, WD Neigh, GN Aizenstein, HJ Evans, JD AF Taylor, Warren D. Neigh, Gretchen N. Aizenstein, Howard J. Evans, Jovier D. TI NEUROSCIENCE ADVANCES IN THE STUDY OF LATE LIFE DEPRESSION SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Meeting Abstract CT Annual Meeting of the American-Association-of-Geriatric-Psychiatry CY MAR 05-08, 2010 CL Savannah, GA SP Amer Assoc Geriat Psychiat C1 [Taylor, Warren D.] Duke Univ, Med Ctr, Durham, NC USA. [Aizenstein, Howard J.] Univ Pittsburgh, Pittsburgh, PA USA. [Neigh, Gretchen N.] Emory Univ, Atlanta, GA 30322 USA. [Evans, Jovier D.] NIMH, Bethesda, MD 20892 USA. RI Neigh, Gretchen/G-3662-2011 OI Neigh, Gretchen/0000-0003-0955-9161 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2010 VL 18 IS 3 SU 1 BP S22 EP S23 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 753PB UT WOS:000289790800023 ER PT J AU Li, YH Zheng, TZ Kilfoy, BA Lan, Q Holford, T Han, XS Zhao, P Dai, M Leaderer, B Rothman, N Zhang, YW AF Li, Yonghong Zheng, Tongzhang Kilfoy, Briseis A. Lan, Qing Holford, Theodore Han, Xuesong Zhao, Ping Dai, Min Leaderer, Brian Rothman, Nat Zhang, Yawei TI Genetic polymorphisms in cytochrome P450s, GSTs, NATs, alcohol consumption and risk of non-Hodgkin lymphoma SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter ID TOBACCO SMOKING; EXPOSURE OCCURS; DRINKING; WOMEN; ASSOCIATION; METABOLISM; INDUCTION; IMPACT; CANCER; RATS AB The aim of this study was to investigate whether genetic polymorphisms in cytochrome P450s (CYPs), glutathione S-transferases (GSTs), and N-acetyltransterases (NATs) genes modify the relationship between alcohol consumption and risk of non-Hodgkin's lymphoma (NHL) in a population-based, case-control study including 1,115 Connecticut women. Although we did not find strong evidence that the genetic polymorphisms modify the relationship between alcohol consumption and risk of NHL, we identified significant interactions for multiple GSTs and NATs and alcohol intake among persons with DLBCL. Our results confer support investigation of the gene-environment interaction in a larger study population of DLBCL. C1 [Li, Yonghong; Zheng, Tongzhang; Holford, Theodore; Han, Xuesong; Leaderer, Brian; Zhang, Yawei] Yale Univ, Sch Publ Hlth, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. [Li, Yonghong] China CDC, Natl Inst Environm Hlth & Related Prod Safety, Dept Epidemiol, Beijing, Peoples R China. [Kilfoy, Briseis A.; Lan, Qing; Rothman, Nat] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. [Zhao, Ping; Dai, Min] Chinese Acad Med Sci, Canc Inst Hosp, Beijing 100037, Peoples R China. RP Zhang, YW (reprint author), Yale Univ, Sch Publ Hlth, Dept Epidemiol & Publ Hlth, 60 Coll St,LEPH 440, New Haven, CT 06520 USA. EM yawei.zhang@yale.edu RI Aschebrook-Kilfoy, Briseis/A-2537-2012 FU FIC NIH HHS [D43 TW008323, D43 TW007864]; Intramural NIH HHS [Z01 CP010123-12]; NCI NIH HHS [R01 CA062006]; NCRR NIH HHS [UL1 RR024139] NR 30 TC 2 Z9 2 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 MAR PY 2010 VL 85 IS 3 BP 213 EP 215 DI 10.1002/ajh.21608 PG 3 WC Hematology SC Hematology GA 568GK UT WOS:000275510100011 PM 20131310 ER PT J AU Nelson, RG Tuttle, KR AF Nelson, Robert G. Tuttle, Katherine R. TI Prevention of Diabetic Kidney Disease: Negative Clinical Trials With Renin-Angiotensin System Inhibitors SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID BLOOD-GLUCOSE CONTROL; TYPE-2; COMPLICATIONS; MICROALBUMINURIA; PROGRESSION; MELLITUS; NEPHROPATHY; METFORMIN; OUTCOMES; THERAPY C1 [Nelson, Robert G.] NIH, Phoenix, AZ 85014 USA. [Tuttle, Katherine R.] Univ Washington, Spokane, WA USA. [Tuttle, Katherine R.] Univ Washington, Sch Med, Seattle, WA USA. RP Nelson, RG (reprint author), NIH, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM rgnelson@mail.nih.gov RI Nelson, Robert/B-1470-2012 FU Intramural NIH HHS [Z99 DK999999] NR 23 TC 6 Z9 6 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2010 VL 55 IS 3 BP 426 EP 430 DI 10.1053/j.ajkd.2009.10.001 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 563DW UT WOS:000275109000007 PM 20005029 ER PT J AU Muntner, P Anderson, A Charleston, J Chen, Z Ford, V Makos, G O'Connor, A Perumal, K Rahman, M Steigerwalt, S Teal, V Townsend, R Weir, M Wright, JT AF Muntner, Paul Anderson, Amanda Charleston, Jeanne Chen, Zhen Ford, Virginia Makos, Gail O'Connor, Andrew Perumal, Kalyani Rahman, Mahboob Steigerwalt, Susan Teal, Valerie Townsend, Raymond Weir, Matthew Wright, Jackson T., Jr. CA CRIC Study Investigators TI Hypertension Awareness, Treatment, and Control in Adults With CKD: Results From the Chronic Renal Insufficiency Cohort (CRIC) Study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Hypertension; awareness; treatment; control; chronic kidney disease ID CHRONIC KIDNEY-DISEASE; UNITED-STATES; BLOOD-PRESSURE; CONTROLLED TRIALS; RISK-FACTORS; PREVALENCE; METAANALYSIS; POPULATION; REDUCTION AB Background: A low rate of blood pressure control has been reported in patients with chronic kidney disease (CKD). These data were derived from population-based samples with a low rate of CKD awareness. Study Design: Cross-sectional. Setting & Participants: Data from the baseline visit of the Chronic Renal Insufficiency Cohort (CRIC) Study (n = 3,612) were analyzed. Participants with an estimated glomerular filtration rate of 20-70 mL/min/1.73 m(2) were identified from physician offices and review of laboratory databases. Outcomes: Prevalence and awareness of hypertension, treatment patterns, control rates, and factors associated with hypertension control. Measurements: Following a standardized protocol, blood pressure was measured 3 times by trained staff, and hypertension was defined as systolic blood pressure >= 140 mm Hg and/or diastolic blood pressure >= 90 mm Hg and/or self-reported antihypertensive medication use. Patients' awareness and treatment of hypertension were defined using self-report, and 2 levels of hypertension control were evaluated: systolic/diastolic blood pressure <140/90 and <130/80 mm Hg. Results: The prevalence of hypertension was 85.7%, and 98.9% of CRIC participants were aware of this diagnosis and 98.3% were treated with medications, whereas 67.1% and 46.1% had hypertension controlled to <140/90 and <130/80 mm Hg, respectively. Of CRIC participants with hypertension, 15%, 25%, 26%, and 32% were using 1, 2, 3, and >= 4 antihypertensive medications, respectively. After multivariable adjustment, older patients, blacks, and those with higher urinary albumin excretion were less likely, whereas participants using angiotensin-converting enzyme inhibitors and angiotensin receptor blockers were more likely to have controlled their hypertension to <140/90 and <130/80 mm Hg. Limitations: Data were derived from a single study visit. Conclusions: Despite almost universal hypertension awareness and treatment in this cohort of patients with CKD, rates of hypertension control were suboptimal. Am J Kidney Dis 00:00-00 (C) 2009 by the National Kidney Foundation, Inc Am J Kidney Dis 55: 441-451. (C) 2010 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Muntner, Paul] Univ Alabama, Dept Epidemiol, Birmingham, AL 35294 USA. [Anderson, Amanda; Ford, Virginia; Teal, Valerie; Townsend, Raymond] Univ Penn, Philadelphia, PA 19104 USA. [Charleston, Jeanne] Johns Hopkins Univ, Baltimore, MD USA. [Chen, Zhen] NIH, Rockville, MD USA. [Makos, Gail; Steigerwalt, Susan] St Johns Hosp, Detroit, MI USA. [Rahman, Mahboob] Case Western Reserve Univ, Univ Hosp Case Med Ctr, Louis Stokes Cleveland VA Med Ctr, Cleveland, OH 44106 USA. [Perumal, Kalyani] Univ Illinois, Chicago, IL USA. [Weir, Matthew] Univ Maryland, Sch Med, Div Nephrol, Baltimore, MD 21201 USA. RP Muntner, P (reprint author), Univ Alabama, Dept Epidemiol, 1665 Univ Blvd,Ste 230J, Birmingham, AL 35294 USA. EM pmuntner@uab.edu OI Teal, Valerie/0000-0001-7116-5353 FU National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD [K01 DK064860, 5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, 5U01DK060902] FX Dr Muntner received support through a career development grant (K01 DK064860) from the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD. The CRIC Study is supported by cooperative agreement project grants 5U01DK060990, 5U01DK060984, 5U01DK06102, 5U01DK061021, 5U01DK061028, 5U01DK60980, 5U01DK060963, and 5U01DK060902 from the NIDDK, NIH. NR 15 TC 75 Z9 91 U1 1 U2 8 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2010 VL 55 IS 3 BP 441 EP 451 DI 10.1053/j.ajkd.2009.09.014 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 563DW UT WOS:000275109000009 PM 19962808 ER PT J AU Hoerger, TJ Wittenborn, JS Segel, JE Burrows, NR Imai, K Eggers, P Pavkov, ME Jordan, R Hailpern, SM Schoolwerth, AC Williams, DE AF Hoerger, Thomas J. Wittenborn, John S. Segel, Joel E. Burrows, Nilka R. Imai, Kumiko Eggers, Paul Pavkov, Meda E. Jordan, Regina Hailpern, Susan M. Schoolwerth, Anton C. Williams, Desmond E. CA Ctr Dis Control & Prevent CKD Init TI A Health Policy Model of CKD: 1. Model Construction, Assumptions, and Validation of Health Consequences SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease; cost-effectiveness; model; validation ID CHRONIC KIDNEY-DISEASE; LEFT-VENTRICULAR HYPERTROPHY; CORONARY HEART-DISEASE; ALL-CAUSE MORTALITY; CARDIOVASCULAR-DISEASE; RENAL-DISEASE; US ADULTS; NATIONAL-HEALTH; UNITED-STATES; PREVALENCE AB Background: A cost-effectiveness model that accurately represents disease progression, outcomes, and associated costs is necessary to evaluate the cost-effectiveness of interventions for chronic kidney disease (CKD). Study Design: We developed a microsimulation model of the incidence, progression, and treatment of CKD. The model was validated by comparing its predictions with survey and epidemiologic data sources. Setting & Population: US patients. Model, Perspective, & Timeframe: The model follows up disease progression in a cohort of simulated patients aged 30 until age 90 years or death. The model consists of 7 mutually exclusive states representing no CKD, 5 stages of CKD, and death. Progression through the stages is governed by a person's glomerular filtration rate and albuminuria status. Diabetes, hypertension, and other risk factors influence CKD and the development of CKD complications in the model. Costs are evaluated from the health care system perspective. Intervention: Usual care, including incidental screening for persons with diabetes or hypertension. Outcomes: Progression to CKD stages, complications, and mortality. Results: The model provides reasonably accurate estimates of CKD prevalence by stage. The model predicts that 47.1% of 30-year-olds will develop CKD during their lifetime, with 1.7%, 6.9%, 27.3%, 6.9%, and 4.4% ending at stages 1-5, respectively. Approximately 11% of persons who reach stage 3 will eventually progress to stage 5. The model also predicts that 3.7% of persons will develop end-stage renal disease compared with an estimate of 3.0% based on current end-stage renal disease lifetime incidence. Limitations: The model synthesizes data from multiple sources rather than a single source and relies on explicit assumptions about progression. The model does not include acute kidney failure. Conclusion: The model is well validated and can be used to evaluate the cost-effectiveness of CKD interventions. The model also can be updated as better data for CKD progression become available. Am J Kidney Dis 55: 452-462. (C) 2010 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Hoerger, Thomas J.; Wittenborn, John S.; Segel, Joel E.] RTI Int, Res Triangle Pk, NC 27709 USA. [Burrows, Nilka R.; Pavkov, Meda E.; Jordan, Regina; Hailpern, Susan M.; Williams, Desmond E.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Imai, Kumiko] UNICEF Swaziland, Mbabane, Swaziland. [Eggers, Paul] NIDDKD, Bethesda, MD 20892 USA. [Schoolwerth, Anton C.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. RP Hoerger, TJ (reprint author), RTI Int, 3040 Cornwallis Rd,POB 12194, Res Triangle Pk, NC 27709 USA. EM tjh@rti.org FU CDC [200-2002-00776] FX This research was supported by funding (contract 200-2002-00776) from the CDC. NR 39 TC 30 Z9 30 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2010 VL 55 IS 3 BP 452 EP 462 DI 10.1053/j.ajkd.2009.11.016 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 563DW UT WOS:000275109000010 PM 20116911 ER PT J AU Hoerger, TJ Wittenborn, JS Segel, JE Burrows, NR Imai, K Eggers, P Pavkov, ME Jordan, R Hailpern, SM Schoolwerth, AC Williams, DE AF Hoerger, Thomas J. Wittenborn, John S. Segel, Joel E. Burrows, Nilka R. Imai, Kumiko Eggers, Paul Pavkov, Meda E. Jordan, Regina Hailpern, Susan M. Schoolwerth, Anton C. Williams, Desmond E. CA Ctr Dis Control & Prevent CKD Init TI A Health Policy Model of CKD: 2. The Cost-Effectiveness of Microalbuminuria Screening SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Chronic kidney disease; cost-effectiveness; model; microalbuminuria; screening; renal; end-stage renal disease (ESRD) ID CHRONIC KIDNEY-DISEASE; GLOMERULAR-FILTRATION-RATE; CONVERTING ENZYME-INHIBITORS; RANDOMIZED CONTROLLED-TRIAL; NONDIABETIC RENAL-DISEASE; SERUM CREATININE; UNITED-STATES; NEPHROPATHY; OUTCOMES; PROTEINURIA AB Background: Microalbuminuria screening may detect chronic kidney disease in its early stages, allowing for treatment that delays or prevents disease progression. The cost-effectiveness of microalbuminuria screening has not been determined. Study Design: A cost-effectiveness model simulating disease progression and costs. Setting & Population: US patients. Model, Perspective, and Timeframe: The microsimulation model follows up disease progression and costs in a cohort of simulated patients from age 50 to 90 years or death. Costs are evaluated from the health care system perspective. Intervention: Microalbuminuria screening at 1-, 2-, 5-, or 10-year intervals followed by treatment with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. We considered universal screening, as well as screening targeted at persons with diabetes, persons with hypertension but no diabetes, and persons with neither diabetes nor hypertension. Outcomes: Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. Results: For the full model population, universal screening increases costs and increases QALYs. Universal annual screening starting at age 50 years has a cost-effectiveness ratio of $73,000/QALY relative to no screening and $145,000/QALY relative to usual care. Cost-effectiveness ratios improved with longer screening intervals. Relative to no screening, targeted annual screening has cost-effectiveness ratios of $21,000/QALY, $55,000/QALY, and $155,000/QALY for persons with diabetes, those with hypertension, and those with neither current diabetes nor current hypertension, respectively. Limitations: Results necessarily are based on a microsimulation model because of the long time horizon appropriate for chronic kidney disease. The model includes only health care costs. Conclusions: Microalbuminuria screening is cost-effective for patients with diabetes or hypertension, but is not cost-effective for patients with neither diabetes nor hypertension unless screening is conducted at longer intervals or as part of existing physician visits. Am J Kidney Dis 55: 463-473. (C) 2010 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Hoerger, Thomas J.; Wittenborn, John S.; Segel, Joel E.] RTI Int, Res Triangle Pk, NC 27709 USA. [Burrows, Nilka R.; Pavkov, Meda E.; Jordan, Regina; Hailpern, Susan M.; Williams, Desmond E.] Ctr Dis Control & Prevent, Atlanta, GA USA. [Imai, Kumiko] UNICEF Swaziland, Mbabane, Swaziland. [Eggers, Paul] NIDDKD, Bethesda, MD 20892 USA. [Schoolwerth, Anton C.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. RP Hoerger, TJ (reprint author), RTI Int, 3040 Cornwallis Rd,POB 12194, Res Triangle Pk, NC 27709 USA. EM tjh@rti.org FU CDC [200-2002-00776] FX This research was supported by funding (contract 200-2002-00776) from the CDC. NR 39 TC 54 Z9 54 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2010 VL 55 IS 3 BP 463 EP 473 DI 10.1053/j.ajkd.2009.11.017 PG 11 WC Urology & Nephrology SC Urology & Nephrology GA 563DW UT WOS:000275109000011 PM 20116910 ER PT J AU Jolly, SE Burrows, NR Chen, SC Li, SY Jurkovitz, CT Narva, AS Norris, KC Shlipak, MG AF Jolly, Stacey E. Burrows, Nilka Rios Chen, Shu-Cheng Li, Suying Jurkovitz, Claudine T. Narva, Andrew S. Norris, Keith C. Shlipak, Michael G. TI Racial and Ethnic Differences in Albuminuria in Individuals With Estimated GFR Greater Than 60 mL/min/1.73 m(2): Results From the Kidney Early Evaluation Program (KEEP) SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE Albuminuria; health disparities; Kidney Early Evaluation Program (KEEP); screening ID GLOMERULAR-FILTRATION-RATE; SERUM CREATININE VALUES; RENAL-DISEASE; NONDIABETIC INDIVIDUALS; CARDIOVASCULAR EVENTS; GENERAL-POPULATION; AMERICAN-INDIANS; NATIONAL-HEALTH; HEART-FAILURE; UNITED-STATES AB Background: Albuminuria is an important marker for chronic kidney disease and progression to end-stage renal disease in the general population; understanding racial and ethnic differences can help inform efforts to reduce health disparities. We sought to estimate independent associations of race/ethnicity with albuminuria to determine whether observed differences were attributable to known kidney disease risk factors. Methods: This cross-sectional study included 64,161 Kidney Early Evaluation Program (KEEP) participants, 2000-2008, with estimated glomerular filtration rate >= 60 mL/min/1.73 m(2), not on regular dialysis therapy, and without a previous kidney transplant. Albuminuria (urine albumin-creatinine ratio >= 30 mg/g) was examined by self-reported race and ethnicity. Covariates were age, sex, educational level, body mass index, diabetes status or glucose level, hypertension status or blood pressure measurement, smoking status, health insurance status, and geographic region. Results: Albuminuria prevalences were 8% (n = 2,303) in whites, 11% (n = 2,310) in African Americans, 9% (n = 730) in Hispanics, 10% (n = 381) in Asians, and 15% (n = 344) in American Indians/ Alaska Natives. Compared with whites, odds of albuminuria were higher for all groups after multivariate adjustment. Odds were highest for American Indians/Alaska Natives (adjusted OR, 1.93; 95% CI, 1.70-2.20), then Asians (adjusted OR, 1.42; 95% CI, 1.26-1.61), African Americans (adjusted OR, 1.38; 95% CI, 1.29-1.47), and Hispanics (adjusted OR, 1.19; 95% CI, 1.08-1.31). Conclusions: In the KEEP study population, albuminuria prevalence was higher in African Americans, Hispanics, Asians, and American Indians/Alaska Natives than in non-Hispanic whites, suggesting a need for screening for early detection of kidney damage, especially in people at increased risk, in the community primary care setting. Am J Kidney Dis 55(S2):S15-S22. (c) 2010 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved. C1 [Jolly, Stacey E.] Cleveland Clin, Inst Med, Cleveland, OH 44195 USA. [Burrows, Nilka Rios] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Chen, Shu-Cheng; Li, Suying] Minneapolis Med Res Fdn Inc, Chron Dis Res Grp, Minneapolis, MN USA. [Jurkovitz, Claudine T.] Christiana Care Hlth Syst, Ctr Outcomes Res, Newark, DE USA. [Narva, Andrew S.] NIDDK, Bethesda, MD USA. [Norris, Keith C.] Charles R Drew Univ Med & Sci, Dept Internal Med, Los Angeles, CA 90059 USA. [Shlipak, Michael G.] Univ Calif San Francisco, San Francisco VA Med Ctr, San Francisco, CA 94143 USA. RP Jolly, SE (reprint author), Cleveland Clin, Inst Med, 9500 Euclid Ave,G10, Cleveland, OH 44195 USA. EM jollys@ccf.org FU National Kidney Foundation Inc; Amgen; Abbott; Novartis; Siemens; Genentech; Genzyme; Nephroceuticals; Pfizer; LifeScan; Suplena; National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK 066488] FX The KEEP is a program of the National Kidney Foundation Inc and is supported by Amgen, Abbott, Novartis, Siemens, Genentech, Genzyme, Nephroceuticals, Pfizer, LifeScan, and Suplena. Dr Shlipak's work was supported by the American Heart Association Established Investigator Award and R01 DK 066488 from the National Institute of Diabetes and Digestive and Kidney Diseases. NR 41 TC 18 Z9 19 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD MAR PY 2010 VL 55 IS 3 SU 2 BP S15 EP S22 DI 10.1053/j.ajkd.2009.09.034 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 559WU UT WOS:000274859800003 PM 20172444 ER PT J AU Kaplan, L Foster, R Shen, YP Parry, DM McMaster, ML O'Leary, MC Gusella, JF AF Kaplan, Lee Foster, Rosemary Shen, Yiping Parry, Dilys M. McMaster, Mary L. O'Leary, Melanie Collins Gusella, James F. TI Monozygotic Twins Discordant for Neurofibromatosis 1 SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE neurofibromatosis type 1; monozygotic twins; discordance; post-zygotic mutation ID SEGMENTAL NEUROFIBROMATOSIS; NF1 GENE; TYPE-1 NF1; VONRECKLINGHAUSEN NEUROFIBROMATOSIS; NONSENSE MUTATION; MOSAICISM; POLYMORPHISMS; METHYLATION; FREQUENCY; SEQUENCE AB We present monozygotic twins discordant for the autosomal dominant disorder neurofibromatosis type 1 (NF1). The affected twin was diagnosed with NF1 at age 12, based upon accepted clinical criteria for the disorder. Both twins were re-examined at ages 35 and 57, at which times the unaffected twin continued to show no clinical manifestations of NF1. Short tandem repeat marker (STR) genotyping at 10 loci on chromosome 17 and 10 additional loci dispersed across the genome revealed identical genotypes for the twins, confirming their monozygosity. The affected twin has three children, two of whom also have NF1, while the unaffected twin has two children, both unaffected. Using lymphoblastoid, fibroblast, and buccal cell samples collected from both twins and from other family members in three generations, we discovered a pathogenic nonsense mutation in exon 40 of the NF1 gene. This mutation was found in all cell samples from the affected twin and her affected daughter, and in lymphoblastoid and buccal cells but not fibroblasts from the unaffected twin. We also found a novel non-synonymous change in exon 16 of the NF1 gene that was transmitted from the unaffected mother to both twins and co-segregated with the pathogenic mutation in the ensuing generation. All cells from the twins were heterozygous for this apparent exon 16 polymorphism and for single nucleotide polymorphisms (SNPs) within 2.5 kb flanking the site of the exon 40 nonsense mutation. This suggests that the NF1 gene of the unaffected twin differed in the respective lymphoblastoid cells and fibroblasts only at the mutation site itself, making post-zygotic mutation leading to mosaicism the most likely mechanism of phenotypic discordance. Although the unaffected twin is a mosaic, the distribution of the mutant allele among different cells and tissues appears to be insufficient to cause overt clinical manifestations of NF1. (C) 2010 Wiley-Liss, Inc. C1 [Kaplan, Lee; Shen, Yiping; O'Leary, Melanie Collins; Gusella, James F.] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. [Kaplan, Lee; Shen, Yiping; O'Leary, Melanie Collins; Gusella, James F.] Harvard Univ, Sch Med, Ctr Neurofibromatosis & Allied Disorders, Boston, MA USA. [Foster, Rosemary] Massachusetts Gen Hosp, Ctr Canc, Boston, MA USA. [Foster, Rosemary] Ctr Regenerat Med, Boston, MA USA. [Foster, Rosemary] Harvard Stem Cell Inst, Boston, MA USA. [Shen, Yiping] Childrens Hosp, DNA Diagnost Lab, Dept Lab Med, Boston, MA 02115 USA. [Parry, Dilys M.; McMaster, Mary L.] NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Gusella, James F.] Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. RP Gusella, JF (reprint author), Massachusetts Gen Hosp, Ctr Human Genet Res, CPZN-5830,185 Cambridge St, Boston, MA 02114 USA. EM gusella@helix.mgh.harvard.edu FU NINDS [NS22224, NS24279]; Neurofibromatosis, Inc., Northeast; S. Sydney De Young Foundation FX The authors would like to thank the family members who have contributed samples and time in the clinic so that we could perform this research project. Also we thank Mary Anne Anderson and the CHGR Cell Culture Resource for making the stable cell lines, James Mull for technical assistance, and Tammy Gillis and the CHGR Genomics Resource for DNA sequence analysis. Funded by grants from the NINDS (NS22224, NS24279), Neurofibromatosis, Inc., Northeast, and the S. Sydney De Young Foundation. NR 43 TC 20 Z9 20 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1552-4825 EI 1552-4833 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR PY 2010 VL 152A IS 3 BP 601 EP 606 DI 10.1002/ajmg.a.33271 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 576OV UT WOS:000276155200010 PM 20186797 ER PT J AU van den Berg, L Delemarre-van de Waa, H Han, JC Ylstra, B Eijk, P Nesterova, M Heutink, P Stratakis, CA AF van den Berg, Linda Delemarre-van de Waa, Henriette Han, Joan C. Ylstra, Bauke Eijk, Paul Nesterova, Maria Heutink, Peter Stratakis, Constantine A. TI Investigation of a Patient With a Partial Trisomy 16q Including the Fat Mass and Obesity Associated Gene (FTO): Fine Mapping and FTO Gene Expression Study SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE 16q duplication; obesity; FTO; CGH; qPCR; imprinting; SLC6A2; ADHD; BBS2 ID IN-SITU HYBRIDIZATION; INTERSTITIAL DUPLICATION; PRENATAL-DIAGNOSIS; ADULT OBESITY; VARIANTS; MICROARRAY; RESOLUTION; CHILDHOOD; ANOMALIES; INFANT AB A female patient with a partial trisomy 16q was described previously. Her clinical characteristics included obesity, severe anisomastia, moderate to severe mental retardation, attention deficit hyperactivity disorder, dysmorphic facies, and contractions of the small joints. In this article, we describe a more detailed analysis of the genetic anomaly in this patient. We were particularly interested in the involvement of the fat mass and obesity associated gene (PTO) in her duplication. Single nucleotide polymorphisms in FTO have been associated with obesity. The breakpoints of the duplication were precisely mapped using high-resolution oligonucleotide array comparative genomic hybridization (CGH). We found that the duplication spans 11.45 Mb on 16q11.2 to 16q13 and it includes FTO. The increased copy number of FTO was confirmed with a qPCR on genomic DNA of the patient. We investigated the influence of the increased FTO copy number on FTO gene expression in immortalized lymphocytes from the patient using qPCR. No evidence of increased FTO expression was detected in the patient's lymphocytes. We discuss these findings and we review clinical findings in patients with overlapping 16q duplications to determine the relationship between increased FTO copy number and obesity. Our review suggests that duplication of the FTO gene does not necessarily result in obesity. (C) 2010 Wiley-Liss, Inc. C1 [van den Berg, Linda; Heutink, Peter] Vrije Univ Amsterdam, Dept Clin Genet, Sect Med Genom, Med Ctr, NL-1081 BT Amsterdam, Netherlands. [van den Berg, Linda; Delemarre-van de Waa, Henriette] Leiden Univ, Dept Pediat, Med Ctr, Leiden, Netherlands. [van den Berg, Linda] Leiden Univ, Dept Human Genet, Med Ctr, NL-2300 RA Leiden, Netherlands. [Han, Joan C.; Nesterova, Maria; Stratakis, Constantine A.] NICHHD, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Ylstra, Bauke; Eijk, Paul] Vrije Univ Amsterdam, Micro Array Core Facil, Dept Pathol, Med Ctr, NL-1081 BT Amsterdam, Netherlands. RP Heutink, P (reprint author), Vrije Univ Amsterdam, Dept Clin Genet, Sect Med Genom, Med Ctr, van der Boechorststr 7, NL-1081 BT Amsterdam, Netherlands. EM p.heutink@vumc.nl RI Ylstra, Bauke/D-2906-2012 OI Ylstra, Bauke/0000-0001-9479-3010 FU U.S. Public Health Service FX We thank Burcu Anar, Carola van Berkel, Koen de Groot, Katarina Rak, Patrizia Rizzu, and Claudia Ruivenkamp for technical assistance. Zoltan Bochdanovits, Martijn Breuning, Mikael Kubista, Jan Ruijter, Erik Sistermans, Sabine Spijker, Jo Vandesompele, and Mark van de Wiel are thanked for their advice on data analysis. We thank Goran Anneren, John Barber, Angela Barnicoat, Christine de Die, John Engelen, Jean-Pierre Fryns, and Peter Gustavsson for providing information about the obesity phenotype of their patients. JCH is a commissioned officer in the U.S. Public Health Service. NR 35 TC 14 Z9 14 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD MAR PY 2010 VL 152A IS 3 BP 630 EP 637 DI 10.1002/ajmg.a.33229 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 576OV UT WOS:000276155200014 PM 20186806 ER PT J AU Goes, FS Willour, VL Zandi, PP Belmonte, PL MacKinnon, DF Mondimore, FM Schweizer, B DePaulo, JR Gershon, ES McMahon, FJ Potash, JB AF Goes, F. S. Willour, V. L. Zandi, P. P. Belmonte, P. L. MacKinnon, D. F. Mondimore, F. M. Schweizer, B. DePaulo, J. R., Jr. Gershon, E. S. McMahon, F. J. Potash, J. B. CA Natl Inst Mental Hlth Genetics Ini TI Sex-Specific Association of the Reelin Gene With Bipolar Disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE genetics; bipolar disorder; schizophrenia; overlap; neurodevelopment ID MAJOR DEPRESSION; SCHIZOPHRENIA; LINKAGE; BRAIN; NEURONS; DEMETHYLATION; METAANALYSIS; POPULATION; RECEPTORS; PEDIGREES AB The Reelin gene (RELN) encodes a secretory glycoprotein critical for brain development and synaptic plasticity. Post-mortem studies have shown lower Reelin protein levels in the brains of patients with schizophrenia and bipolar disorder (BP) compared with controls. In a recent genome-wide association study of schizophrenia, the strongest association was found in a marker within RELN, although this association was seen only in women. In this study, we investigated whether genetic variation in RELN is associated with BP in a large family sample. We genotyped 75 tagSNPs and 6 coding SNPs in 1,188 individuals from 318 nuclear families, including 554 affected offspring. Quality control measures, transmission-disequilibrium tests (TDTs), and empirical simulations were performed in PLINK. We found a significant overtransmission of the C allele of rs362719 to BP offspring (OR=1.47, P=5.9 x 10(-4)); this withstood empirical correction for testing of multiple markers (empirical P=0.048). In a hypothesis-driven secondary analysis, we found that the association with rs362719 was almost entirely accounted for by overtransmission of the putative risk allele to affected females (OR(Female)=1.79, P=8.9x10(-5) vs. OR(Male)=1.12, P=0.63). These results provide preliminary evidence that genetic variation in RELN is associated with susceptibility to BP and, in particular, to BP in females. However, our findings should be interpreted with caution until further replication and functional assays provide convergent support. (C) 2009 Wiley-Liss, Inc. C1 [Goes, F. S.; Willour, V. L.; Zandi, P. P.; Belmonte, P. L.; MacKinnon, D. F.; Mondimore, F. M.; Schweizer, B.; DePaulo, J. R., Jr.; Potash, J. B.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. [Willour, V. L.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. [Gershon, E. S.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. [McMahon, F. J.] NIMH, Genet Basis Mood & Anxiety Disorders Unit, Mood & Anxiety Program, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Potash, JB (reprint author), Meyer 4-119,600 N Wolfe St, Baltimore, MD 21287 USA. EM jpotash@jhmi.edu OI McMahon, Francis/0000-0002-9469-305X FU NIMH NIH HHS [K01 MH072866, K01 MH072866-01, K99 MH086049-02, K99 MH086049] NR 36 TC 29 Z9 29 U1 2 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD MAR PY 2010 VL 153B IS 2 BP 549 EP 553 DI 10.1002/ajmg.b.31018 PG 5 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 566NI UT WOS:000275377900022 PM 19691043 ER PT J AU Wang, Y Adamczyk, A Shugart, YY Samuels, JF Grados, MA Greenberg, BD Knowles, JA McCracken, JT Rauch, SL Murphy, DL Rasmussen, SA Cullen, B Pinto, A Fyer, AJ Piacentini, J Pauls, DL Bienvenu, OJ Riddle, M Liang, KY Valle, D Wang, T Nestadt, G AF Wang, Y. Adamczyk, A. Shugart, Y. Y. Samuels, J. F. Grados, M. A. Greenberg, B. D. Knowles, J. A. McCracken, J. T. Rauch, S. L. Murphy, D. L. Rasmussen, S. A. Cullen, B. Pinto, A. Fyer, A. J. Piacentini, J. Pauls, D. L. Bienvenu, O. J. Riddle, M. Liang, K. Y. Valle, D. Wang, T. Nestadt, G. TI A Screen of SLC1A1 for OCD-Related Alleles SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE OCD; SLC1A1; polymorphism ID OBSESSIVE-COMPULSIVE DISORDER; CONFORMATION POLYMORPHISM; TRANSPORTER GENE; ASSOCIATION; AUGMENTATION; LINKAGE AB SLC1A1, which encodes the neuronal and epithelial glutamate transporter, is a promising candidate gene for obsessive-compulsive disorder (OCD). In this study, we conducted capillary electrophoresis single-strand conformation polymorphism (CE-SSCP) screen for all 12 identified exons, including all coding regions and similar to 50 bp of flanking introns of the human SLC1A1 in 378 OCD-affected individuals. Full sequencing was completed on samples that showed an aberrant SSCP tracing for identification of the underlying sequence variants. Our aim was to determine if there are differences in the frequencies of relatively common alleles, or rare functional alleles, in 378 OCD cases and 281 ethnically matched controls. We identified one non-synonymous coding SNP (c.490A > G, T164A) and three synonymous coding SNP (c.81G>C, A27A; c.414A>G, T138T; c.1110T > C, T370T) in case samples. We found no statistical differences in genotype and allele frequencies of common cSNPs in SLC1A1 between the OCD cases and controls. The rare variant T164A was found only in one family. Further investigation of this variant is necessary to determine whether and how it is related to OCD. There was no other evidence of significant accumulation of deleterious coding mutations in SLC1A1 in the OCD cases. (C) 2009 Wiley-Liss, Inc. C1 [Wang, Y.; Samuels, J. F.; Grados, M. A.; Cullen, B.; Bienvenu, O. J.; Riddle, M.; Nestadt, G.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Adamczyk, A.; Valle, D.; Wang, T.] Johns Hopkins Univ, Sch Med, Dept Pediat, Mckusick Nathan Inst Genet Med, Baltimore, MD 21205 USA. [Shugart, Y. Y.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Greenberg, B. D.; Rasmussen, S. A.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Knowles, J. A.] Univ So Calif, Dept Psychiat, Los Angeles, CA USA. [McCracken, J. T.; Piacentini, J.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. [Rauch, S. L.; Pauls, D. L.] Harvard Univ, Sch Med, Boston, MA USA. [Rauch, S. L.; Pauls, D. L.] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Rauch, S. L.; Pauls, D. L.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Murphy, D. L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Pinto, A.; Fyer, A. J.] Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. [Liang, K. Y.] Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. RP Wang, Y (reprint author), 1629 Thames St,Suite 401, Baltimore, MD 21231 USA. EM ywang37@jhmi.edu RI Piacentini, John/C-4645-2011; Liang, Kung-Yee/F-8299-2011; Adamczyk, Abby/E-4457-2014; Pinto, Anthony/D-2718-2017; OI Adamczyk, Abby/0000-0001-7653-295X; Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 NR 16 TC 18 Z9 19 U1 1 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD MAR PY 2010 VL 153B IS 2 BP 675 EP 679 DI 10.1002/ajmg.b.31001 PG 5 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 566NI UT WOS:000275377900036 PM 19569082 ER PT J AU Romero, R Conde-Agudelo, A AF Romero, Roberto Conde-Agudelo, Agustin TI What gestation cut-off should be used for magnesium sulfate treatment of women threatening to deliver preterm? REPLY SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Letter ID CONTROLLED-TRIAL; CEREBRAL-PALSY; PREVENTION; BIRTH C1 [Romero, Roberto; Conde-Agudelo, Agustin] NICHD, Perinatol Res Branch, NIH, DHHS, Detroit, MI 48201 USA. RP Romero, R (reprint author), NICHD, Perinatol Res Branch, NIH, DHHS, 3990 John R,4 Brush, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu NR 6 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 MAR PY 2010 VL 202 IS 3 BP E9 EP E10 DI 10.1016/j.ajog.2009.09.011 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 568IV UT WOS:000275516900047 ER PT J AU Bailit, JL Gregory, KD Reddy, UM Gonzalez-Quintero, VH Hibbard, JU Ramirez, MM Branch, DW Burkman, R Haberman, S Hatjis, CG Hoffman, MK Kominiarek, M Landy, HJ Learman, LA Troendle, J Van Veldhuisen, P Wilkins, I Sun, LP Zhang, J AF Bailit, Jennifer L. Gregory, Kimberly D. Reddy, Uma M. Gonzalez-Quintero, Victor H. Hibbard, Judith U. Ramirez, Mildred M. Branch, D. Ware Burkman, Ronald Haberman, Shoshana Hatjis, Christos G. Hoffman, Matthew K. Kominiarek, Michelle Landy, Helain J. Learman, Lee A. Troendle, James Van Veldhuisen, Paul Wilkins, Isabelle Sun, Liping Zhang, Jun TI Maternal and neonatal outcomes by labor onset type and gestational age SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 30th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 01-06, 2010 CL Chicago, IL SP Soc Maternal Fetal Med DE elective delivery; hysterectomy; maternal outcomes; neonatal outcomes ID PRETERM BIRTH; TERM; RATES AB OBJECTIVE: We sought to determine maternal and neonatal outcomes by labor onset type and gestational age. STUDY DESIGN: We used electronic medical records data from 10 US institutions in the Consortium on Safe Labor on 115,528 deliveries from 2002 through 2008. Deliveries were divided by labor onset type (spontaneous, elective induction, indicated induction, unlabored cesarean). Neonatal and maternal outcomes were calculated by labor onset type and gestational age. RESULTS: Neonatal intensive care unit admissions and sepsis improved with each week of gestational age until 39 weeks (P < .001). After adjusting for complications, elective induction of labor was associated with a lower risk of ventilator use (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.28-0.53), sepsis (OR, 0.36; 95% CI, 0.26-0.49), and neonatal intensive care unit admissions (OR, 0.52; 95% CI, 0.48-0.57) compared to spontaneous labor. The relative risk of hysterectomy at term was 3.21 (95% CI, 1.08-9.54) with elective induction, 1.16 (95% CI, 0.24-5.58) with indicated induction, and 6.57 (95% CI, 1.78-24.30) with cesarean without labor compared to spontaneous labor. CONCLUSION: Some neonatal outcomes improved until 39 weeks. Babies born with elective induction are associated with better neonatal outcomes compared to spontaneous labor. Elective induction may be associated with an increased hysterectomy risk. C1 [Bailit, Jennifer L.] Case Western Reserve Univ, Div Maternal Fetal Med, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. [Bailit, Jennifer L.] Case Western Reserve Univ, Ctr Hlth Care Res & Policy, MetroHealth Med Ctr, Cleveland, OH 44106 USA. [Gregory, Kimberly D.] Cedars Sinai Med Ctr, Burns & Allen Res Inst, Los Angeles, CA 90048 USA. [Reddy, Uma M.; Troendle, James; Sun, Liping; Zhang, Jun] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Gonzalez-Quintero, Victor H.] Univ Miami, Sch Med, Miami, FL USA. [Hibbard, Judith U.; Wilkins, Isabelle] Univ Illinois, Dept Obstet & Gynecol, Sch Med, Chicago, IL 60612 USA. [Ramirez, Mildred M.] Univ Texas Med Sch Houston, Dept Obstet & Gynecol, Houston, TX USA. [Branch, D. Ware] Intermt HealthCare, Salt Lake City, UT USA. [Burkman, Ronald] Baystate Med Ctr, Dept Obstet & Gynecol, Springfield, MA USA. [Haberman, Shoshana] Maimonides Hosp, Dept Obstet & Gynecol, Brooklyn, NY 11219 USA. [Hatjis, Christos G.] Summa Hlth Syst, Akron, OH USA. [Hoffman, Matthew K.] Christiana Care Hlth Syst, Wilmington, DE USA. [Kominiarek, Michelle; Learman, Lee A.] Indiana Univ Clarian Hlth, Indianapolis, IN USA. [Landy, Helain J.] MedStar Hlth, Washington, DC USA. [Van Veldhuisen, Paul] Emmes Corp, Rockville, MD USA. RP Bailit, JL (reprint author), Case Western Reserve Univ, Div Maternal Fetal Med, Dept Obstet & Gynecol, Cleveland, OH 44106 USA. FU Intramural NIH HHS; NICHD NIH HHS [HHSN267200603425C]; None [8421358] NR 7 TC 21 Z9 23 U1 0 U2 8 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD MAR PY 2010 VL 202 IS 3 AR 245.e1 DI 10.1016/j.ajog.2010.01.051 PG 12 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 568IV UT WOS:000275516900013 PM 20207242 ER PT J AU Hashima, JN Lai, YL Wapner, RJ Sorokin, Y Dudley, DJ Peaceman, A Spong, CY Iams, JD Leveno, KJ Harper, M Caritis, SN Varner, M Miodovnik, M Mercer, BM Thorp, JM O'Sullivan, MJ Ramin, SM Carpenter, M Rouse, DJ Sibai, B AF Hashima, Jason N. Lai, Yinglei Wapner, Ronald J. Sorokin, Yoram Dudley, Donald J. Peaceman, Alan Spong, Catherine Y. Iams, Jay D. Leveno, Kenneth J. Harper, Margaret Caritis, Steve N. Varner, Michael Miodovnik, Menachem Mercer, Brian M. Thorp, John M. O'Sullivan, Mary J. Ramin, Susan M. Carpenter, Marshall Rouse, Dwight J. Sibai, Baha CA Eunice Kennedy Shriver Natl Inst C TI The effect of maternal body mass index on neonatal outcome in women receiving a single course of antenatal corticosteroids SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 29th Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY JAN 26-31, 2009 CL San Diego, CA SP Soc Maternal Fetal Med DE antenatal corticosteroids; BMI; neonatal morbidity; obesity; prematurity ID PREGNANCY; OBESITY; RISK AB OBJECTIVE: The aim of this study was to determine the effect of maternal body mass index on the incidence of neonatal prematurity morbidities in those who receive corticosteroids. STUDY DESIGN: This was a secondary analysis of a trial of corticosteroids in women at risk for preterm birth. Women receiving a single course of corticosteroids were classified by their prepregnancy body mass index (<25 and >= 25) and compared on a composite outcome comprised of several neonatal morbidities and on each individual outcome. RESULTS: Of 183 eligible women, 96 (52.5%) had a body mass index of <25 and 87 (47.5%) had a body mass index of >= 25. The composite outcome occurred more frequently in the body mass index of >= 25 group (28.7%), compared with those with a body mass index of <25 (18.8%), although this was not statistically significant (odds ratio, 1.75; 95% confidence interval, 0.83-3.72). Body mass index was not associated with outcomes after adjusting for confounding. CONCLUSION: Maternal body mass index did not affect neonatal prematurity morbidities in those receiving corticosteroids. C1 [Hashima, Jason N.] Oregon Hlth & Sci Univ, Dept Obstet & Gynecol, Portland, OR 97201 USA. [Lai, Yinglei] George Washington Univ, Ctr Biostat, Washington, DC USA. [Wapner, Ronald J.] Drexel Univ, Philadelphia, PA 19104 USA. [Sorokin, Yoram] Wayne State Univ, Detroit, MI USA. [Dudley, Donald J.; Varner, Michael] Univ Utah, Salt Lake City, UT USA. [Peaceman, Alan] Northwestern Univ, Chicago, IL 60611 USA. [Spong, Catherine Y.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Iams, Jay D.] Ohio State Univ, Columbus, OH 43210 USA. [Leveno, Kenneth J.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Harper, Margaret] Wake Forest Univ Hlth Sci, Winston Salem, NC USA. [Caritis, Steve N.] Univ Pittsburgh, Pittsburgh, PA USA. [Miodovnik, Menachem] Columbia Univ, New York, NY USA. [Miodovnik, Menachem] Univ Cincinnati, Cincinnati, OH USA. [Mercer, Brian M.] Case Western Reserve Univ, Cleveland, OH 44106 USA. [Thorp, John M.] Univ N Carolina, Chapel Hill, NC USA. [O'Sullivan, Mary J.] Univ Miami, Miami, FL USA. [Ramin, Susan M.] Univ Texas Hlth Sci Ctr Houston, Houston, TX USA. [Carpenter, Marshall] Brown Univ, Providence, RI 02912 USA. [Rouse, Dwight J.] Univ Alabama, Birmingham, AL USA. [Sibai, Baha] Univ Tennessee, Memphis, TN USA. RP Hashima, JN (reprint author), 181 SW Sam Jackson Pk Rd,L458, Portland, OR 97239 USA. EM hashimaj@ohsu.edu RI Varner, Michael/K-9890-2013; OI caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973; Peaceman, Alan/0000-0002-4515-4850 FU NCATS NIH HHS [UL1 TR000005]; NCRR NIH HHS [M01 RR000080, M01-RR-000080]; NICHD NIH HHS [U10 HD027917-12, HD21410, HD21414, HD27860, HD27861, HD27869, HD27915, HD27917, HD34116, HD34136, HD34208, HD36801, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, R24 HD050924, U01 HD036801, U01 HD036801-02, U01 HD036801-03, U01 HD036801-04, U01 HD036801-05, U01 HD036801-06, U01 HD036801-07, U01 HD036801-08, U01 HD036801-09, U01 HD036801-10, U01 HD036801-10S1, U01 HD036801-10S2, U10 HD021410, U10 HD021410-14, U10 HD021410-15, U10 HD021410-15S1, U10 HD021410-16, U10 HD021410-16S1, U10 HD021410-17, U10 HD021410-17S1, U10 HD021410-18, U10 HD021410-19, U10 HD021410-20, U10 HD021410-21, U10 HD021410-22, U10 HD021414-09S1, U10 HD021414-14, U10 HD021414-14S1, U10 HD021414-15, U10 HD021414-15S1, U10 HD021414-15S2, U10 HD027860, U10 HD027860-09, U10 HD027860-10, U10 HD027860-11, U10 HD027860-11S1, U10 HD027860-12, U10 HD027860-12S1, U10 HD027860-13, U10 HD027860-14, U10 HD027860-15, U10 HD027860-15S1, U10 HD027861-09, U10 HD027861-10, U10 HD027861-10S1, U10 HD027861-10S2, U10 HD027869, U10 HD027869-09, U10 HD027869-10, U10 HD027869-10S1, U10 HD027869-11, U10 HD027869-12, U10 HD027869-13, U10 HD027869-14, U10 HD027869-15, U10 HD027869-16, U10 HD027869-16S1, U10 HD027869-17, U10 HD027869-18, U10 HD027905, U10 HD027905-09, U10 HD027905-10, U10 HD027915, U10 HD027915-08, U10 HD027915-09, U10 HD027915-10, U10 HD027915-11, U10 HD027915-12, U10 HD027915-13, U10 HD027915-14, U10 HD027915-15, U10 HD027915-16, U10 HD027915-17, U10 HD027915-18, U10 HD027917, U10 HD027917-09, U10 HD027917-09S1, U10 HD027917-10, U10 HD027917-10S1, U10 HD027917-11, U10 HD027917-13, U10 HD027917-14, U10 HD027917-15, U10 HD027917-16, U10 HD027917-17, U10 HD027917-18, U10 HD034116, U10 HD034116-04, U10 HD034116-05, U10 HD034116-05S1, U10 HD034116-06, U10 HD034116-07, U10 HD034116-08, U10 HD034116-09, U10 HD034116-10, U10 HD034116-11, U10 HD034116-11S1, U10 HD034116-12, U10 HD034116-13, U10 HD034122, U10 HD034122-04, U10 HD034122-04S1, U10 HD034122-05, U10 HD034136, U10 HD034136-04, U10 HD034136-05, U10 HD034136-06, U10 HD034136-07, U10 HD034136-08, U10 HD034136-09, U10 HD034136-10, U10 HD034136-10S1, U10 HD034136-10S2, U10 HD034208, U10 HD034208-04, U10 HD034208-05, U10 HD034208-05S1, U10 HD034208-06, U10 HD034208-06S1, U10 HD034208-07, U10 HD034208-08, U10 HD034208-08S1, U10 HD034208-09, U10 HD034208-10, U10 HD034208-11, U10 HD034208-12, U10 HD036801, U10 HD036801-11, U10 HD040485, U10 HD040485-01, U10 HD040485-02, U10 HD040485-03, U10 HD040485-04, U10 HD040485-05, U10 HD040485-06, U10 HD040485-07, U10 HD040485-07S1, U10 HD040485-08, U10 HD040485-09, U10 HD040500, U10 HD040500-01, U10 HD040500-01S1, U10 HD040500-02, U10 HD040500-03, U10 HD040500-04, U10 HD040500-05, U10 HD040500-06, U10 HD040500-07, U10 HD040500-08, U10 HD040500-09, U10 HD040512, U10 HD040512-01, U10 HD040512-02, U10 HD040512-02S1, U10 HD040512-03, U10 HD040512-04, U10 HD040512-05, U10 HD040512-06, U10 HD040512-07, U10 HD040512-08, U10 HD040512-09, U10 HD040544, U10 HD040544-01, U10 HD040544-02, U10 HD040544-03, U10 HD040544-04, U10 HD040544-05, U10 HD040544-06, U10 HD040544-07, U10 HD040544-08, U10 HD040544-09, U10 HD040545, U10 HD040545-01, U10 HD040545-02, U10 HD040545-02S1, U10 HD040545-03, U10 HD040545-04, U10 HD040545-05, U10 HD040545-06, U10 HD040545-07, U10 HD040545-08, U10 HD040545-09, U10 HD040560, U10 HD040560-01, U10 HD040560-02, U10 HD040560-03, U10 HD040560-04, U10 HD040560-05, U10 HD040560-06, U10 HD040560-07, U10 HD040560-08, U10 HD040560-09, UG1 HD027869, UG1 HD027915, UG1 HD034116, UG1 HD034208, UG1 HD040485, UG1 HD040500, UG1 HD040512, UG1 HD040544, UG1 HD040545, UG1 HD040560] NR 10 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 MAR PY 2010 VL 202 IS 3 AR 263.e1 DI 10.1016/j.ajog.2009.10.859 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 568IV UT WOS:000275516900019 PM 20022589 ER PT J AU Daniel, E Thorne, JE Newcomb, CW Pujari, SS Kacmaz, RO Levy-Clarke, GA Nussenblatt, RB Rosenbaum, JT Suhler, EB Foster, CS Jabs, DA Kempen, JH AF Daniel, Ebenezer Thorne, Jennifer E. Newcomb, Craig W. Pujari, Siddharth S. Kacmaz, R. Oktay Levy-Clarke, Grace A. Nussenblatt, Robert B. Rosenbaum, James T. Suhler, Eric B. Foster, C. Stephen Jabs, Douglas A. Kempen, John H. TI Mycophenolate Mofetil for Ocular Inflammation SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Article ID EYE DISEASE; IMMUNOSUPPRESSIVE THERAPY; UVEITIS; AGENT; DRUGS AB PURPOSE: To evaluate mycophenolate mofetil as a single noncorticosteroid immunosuppressive treatment for noninfectious ocular inflammatory diseases. DESIGN: Retrospective cohort study. METHODS: Characteristics of patients with noninfectious ocular inflammation treated with mycophenolate mofetil at 4 subspecialty clinics from 1995 to 2007 were abstracted by expert reviewers in a standardized chart review of every eye at every visit. Main outcomes measured were control of inflammation, corticosteroid-sparing effects, and discontinuation of mycophenolate mofetil (including the reasons for discontinuation). Survival analysis was used to estimate the incidence of outcomes, and to identify risk factors for each. RESULTS: Among 236 patients (397 eyes) treated with mycophenolate mofetil monotherapy, 20.3%, 11.9%, and 39.8% had anterior uveitis, intermediate uveitis, and posterior uveitis or panuveitis respectively; 14% had scleritis; 7.6% had mucous membrane pemphigoid; and 6.4% had other ocular inflammatory diseases. By Kaplan-Meier estimation, complete control of inflammation-sustained over consecutive visits spanning at least 28 days-was achieved in 53% and 73% of patients within 6 months and 1 year respectively. Systemic corticosteroid dosage was reduced to 10 mg of prednisone or less, while maintaining sustained control of inflammation, in 41% and 55% of patients in 6 months and 1 year respectively. Twelve percent of patients discontinued mycophenolate mofetil within the first year because of side effects of therapy. CONCLUSIONS: Given sufficient time, mycophenolate mofetil was effective in managing ocular inflammation in approximately half of the treated patients. Treatment, limiting side effects were observed in 12% of patients and typically were reversible. (Am J Ophthalmol 2010;149: 423-432. (C) 2010 by Elsevier Inc. All rights reserved.) C1 [Kempen, John H.] Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Sch Med, Philadelphia, PA 19104 USA. [Daniel, Ebenezer] Univ Penn, Sch Med, Fundus Photograph Reading Ctr, Philadelphia, PA 19104 USA. [Newcomb, Craig W.; Jabs, Douglas A.] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Newcomb, Craig W.; Kempen, John H.] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Dept Ophthalmol, Baltimore, MD USA. [Thorne, Jennifer E.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Pujari, Siddharth S.; Kacmaz, R. Oktay; Foster, C. Stephen] Massachusetts Eye Res & Surg Inst, Cambridge, MA USA. [Levy-Clarke, Grace A.] St Lukes Cataract & Laser Inst, Dept Ophthalmol, Tarpon Springs, FL USA. [Levy-Clarke, Grace A.; Nussenblatt, Robert B.] NEI, Immunol Lab, Bethesda, MD 20892 USA. [Rosenbaum, James T.; Suhler, Eric B.] Oregon Hlth & Sci Univ, Dept Ophthalmol, Portland, OR 97201 USA. [Rosenbaum, James T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Suhler, Eric B.] Portland VA Med Ctr, Portland, OR USA. [Foster, C. Stephen] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA USA. [Kacmaz, R. Oktay; Jabs, Douglas A.] Mt Sinai Sch Med, Dept Ophthalmol, New York, NY USA. [Jabs, Douglas A.] Mt Sinai Sch Med, Dept Med, New York, NY USA. RP Kempen, JH (reprint author), Univ Penn, Dept Ophthalmol, Ctr Prevent Ophthalmol & Biostat, Sch Med, 3535 Market St,Suite 700, Philadelphia, PA 19104 USA. EM john.kempen@uphs.upenn.edu OI Daniel, Ebenezer/0000-0002-2027-2316 FU NEI NIH HHS [R01 EY014943-05, EY014943, R56 EY014943, R01 EY014943] NR 27 TC 77 Z9 81 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD MAR PY 2010 VL 149 IS 3 BP 423 EP 432 DI 10.1016/j.ajo.2009.09.026 PG 10 WC Ophthalmology SC Ophthalmology GA 565MD UT WOS:000275296400011 PM 20042178 ER PT J AU Olsen, RJ Kobayashi, SD Ayeras, AA Ashraf, M Graves, SF Ragasa, W Humbird, T Greaver, JL Cantu, C Swain, JL Jenkins, L Blasdel, T Cagle, PT Gardner, DJ DeLeo, FR Musser, JM AF Olsen, Randall J. Kobayashi, Scott D. Ayeras, Ara A. Ashraf, Madiha Graves, Shawna F. Ragasa, Willie Humbird, Tammy Greaver, Jamieson L. Cantu, Constance Swain, Jody L. Jenkins, Leslie Blasdel, Terry Cagle, Philip T. Gardner, Donald J. DeLeo, Frank R. Musser, James M. TI Lack of a Major Role of Staphylococcus aureus Panton-Valentine Leukocidin in Lower Respiratory Tract Infection in Nonhuman Primates SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID LYMPHOID-TISSUE IBALT; VIRULENCE DETERMINANTS; NECROTIZING PNEUMONIA; SKIN INFECTIONS; HEALTHY-ADULTS; INFLUENZA; DISEASE; EPIDEMIOLOGY; USA300; VIRUS AB Panton-Valentine leukocidin (PVL) is a two-component cytolytic toxin epidemiologically linked to community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) infections, including serious invasive infections caused by the epidemic clone referred to as strain USA300. Although PVL has long been known to be a S. aureus virulence molecule in vitro, the relative contribution of this leukotoxin to invasive CA-MRSA infections such as pneumonia remains controversial. We developed a nonhuman primate model of CA-MRSA pneumonia and used it to test the hypothesis that PVL contributes to lower respiratory tract infections caused by S. aureus strain USA300. The lower respiratory tract disease observed in this monkey model mimicked the clinical and pathological features of early mild to moderate S. aureus pneumonia in humans, including fine-structure histopathology. In this experiment using a large sample of monkeys and multiple time points of examination, no involvement of PVL in virulence could be de-tected. Compared with the wild-type parental USA300 strain, the isogenic PVL deletion-mutant strain caused equivalent lower respiratory tract pathology. We conclude that PVL does not contribute to lower respiratory tract infection in this nonhuman primate model of human CA-MRSA pneumonia. (Am J Pathol 2010, 176:1346-1354; DOI: 10.2353/ajpath.2010.090960) C1 [Olsen, Randall J.; Ayeras, Ara A.; Ashraf, Madiha; Ragasa, Willie; Cantu, Constance; Cagle, Philip T.; Musser, James M.] Methodist Hosp, Res Inst, Ctr Mol & Translat Human Infect Dis Res, Houston, TX 77030 USA. [Gardner, Donald J.] Methodist Hosp, Res Inst, Comparat Med Program, Houston, TX 77030 USA. [Olsen, Randall J.; Musser, James M.] Methodist Hosp, Dept Pathol, Houston, TX 77030 USA. [Ashraf, Madiha] Methodist Hosp, Dept Med, Houston, TX 77030 USA. [Kobayashi, Scott D.; Graves, Shawna F.; DeLeo, Frank R.] NIAID, Lab Human Bacterial Pathogenesis, Rocky Mt Labs, NIH, Hamilton, MT USA. [Swain, Jody L.] NIAID, Vet Branch, Rocky Mt Labs, NIH, Hamilton, MT USA. [Humbird, Tammy; Greaver, Jamieson L.; Blasdel, Terry] Univ Houston, Div Res, Houston, TX 77004 USA. [Jenkins, Leslie] Baylor Coll Med, Ctr Comparat Med, Houston, TX 77030 USA. RP Musser, JM (reprint author), Methodist Hosp, Res Inst, Ctr Mol & Translat Human Infect Dis Res, B490,6565 Fannin St, Houston, TX 77030 USA. EM jmmusser@tmhs.org OI DeLeo, Frank/0000-0003-3150-2516 FU American Heart Association Fellow-to-Faculty Transition Award; National Institutes of Health, National Institute of Allergy and Infectious Diseases FX Supported by American Heart Association Fellow-to-Faculty Transition Award (to R.J.O.) and Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 50 TC 29 Z9 30 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 MAR PY 2010 VL 176 IS 3 BP 1346 EP 1354 DI 10.2353/ajpath.2010.090960 PG 9 WC Pathology SC Pathology GA 565MI UT WOS:000275297000031 PM 20093487 ER PT J AU Ghosh, S Hoenerhoff, MJ Clayton, N Myers, P Stumpo, DJ Maronpot, RR Blackshear, PJ AF Ghosh, Sanjukta Hoenerhoff, Mark J. Clayton, Natasha Myers, Page Stumpo, Deborah J. Maronpot, Robert R. Blackshear, Perry J. TI Left-Sided Cardiac Valvulitis in Tristetraprolin-Deficient Mice The Role of Tumor Necrosis Factor alpha SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID MESSENGER-RNA STABILITY; AORTIC-VALVE SCLEROSIS; AU-RICH ELEMENTS; TNF-ALPHA; TRANSGENIC MICE; RHEUMATOID-ARTHRITIS; MONOCLONAL-ANTIBODY; HEART-DISEASE; RECEPTOR; OVEREXPRESSION AB Inflammation may play a role in the etiology of both degenerative and rheumatic cardiac valve diseases. We report here that mice deficient in tristetraprolin (TTP), a protein with known anti-inflammatory functions, develop severe left-sided cardiac valvulitis. TTP is an mRNA binding protein that inhibits inflammation by destabilizing the mRNA encoding tumor necrosis factor alpha (TNF). This leads in turn to a TNF-excess syndrome characterized by systemic inflammation. Evaluation of hearts from TrP(-/-) mice demonstrated gross thickening of the mitral and aortic but not the tricuspid or pulmonary valves, accompanied by inflammatory cell infiltrates. To determine whether TNF played a role in the development of this valvulitis, we examined mice deficient in both TNF receptors and in TTP; four of five of these mice exhibited no histological evidence of valvulitis, but one mouse had aortic valve leaflet thickening with a cellular infiltrate. Four additional mice had no external evidence of valvular thickening. Cardiac valves of transgenic mice expressing human TNF developed mild aortic valve leaflet edema without evidence of hypercellularity. Thus, TTP deficiency in mice leads to left-sided cardiac valvulitis with prominent inflammatory cell involvement, due, at least in part, to excess TNF. These findings support the potential involvement of TNF and inflammation in the development of cardiac valve disease in man. (Am J Pathol 2010, 176:1484-1493; DOI: 10.2353/ajpath.2010.090498) C1 [Ghosh, Sanjukta; Stumpo, Deborah J.; Blackshear, Perry J.] NIEHS, Labs Signal Transduct, Res Triangle Pk, NC 27709 USA. [Myers, Page] NIEHS, Comparat Med Branch, Res Triangle Pk, NC 27709 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Blackshear, Perry J.] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA. RP Blackshear, PJ (reprint author), NIEHS, Labs Signal Transduct, Box F1-13,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM black009@niehs.nih.gov FU NIH, NIEHS FX Supported by the Intramural Research Program of the NIH, NIEHS. NR 55 TC 10 Z9 10 U1 0 U2 0 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 MAR PY 2010 VL 176 IS 3 BP 1484 EP 1493 DI 10.2353/ajpath.2010.090498 PG 10 WC Pathology SC Pathology GA 565MI UT WOS:000275297000044 PM 20093488 ER PT J AU Hall, KD AF Hall, Kevin D. TI Predicting metabolic adaptation, body weight change, and energy intake in humans SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE mathematical model; energy metabolism; macronutrient metabolism; body composition ID NONEXERCISE ACTIVITY THERMOGENESIS; RANDOMIZED CONTROLLED-TRIAL; DIETARY-PROTEIN INTAKE; AMINO-ACID OXIDATION; HIGH-FAT DIET; ADAPTIVE THERMOGENESIS; INDIRECT CALORIMETRY; LOSS MAINTENANCE; ADIPOSE-TISSUE; IN-VIVO AB Hall KD. Predicting metabolic adaptation, body weight change, and energy intake in humans. Am J Physiol Endocrinol Metab 298: E449-E466, 2010. First published November 24, 2009; doi:10.1152/ajpendo.00559.2009.-Complex interactions between carbohydrate, fat, and protein metabolism underlie the body's remarkable ability to adapt to a variety of diets. But any imbalances between the intake and utilization rates of these macronutrients will result in changes in body weight and composition. Here, I present the first computational model that simulates how diet perturbations result in adaptations of fuel selection and energy expenditure that predict body weight and composition changes in both obese and nonobese men and women. No model parameters were adjusted to fit these data other than the initial conditions for each subject group (e.g., initial body weight and body fat mass). The model provides the first realistic simulations of how diet perturbations result in adaptations of whole body energy expenditure, fuel selection, and various metabolic fluxes that ultimately give rise to body weight change. The validated model was used to estimate free-living energy intake during a long-term weight loss intervention, a variable that has never previously been measured accurately. C1 NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Hall, KD (reprint author), NIDDK, Lab Biol Modeling, NIH, 12 S Dr,Rm 4007, Bethesda, MD 20892 USA. EM kevinh@niddk.nih.gov RI Hall, Kevin/F-2383-2010 FU National Institutes of Health/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/National Institute of Diabetes and Digestive and Kidney Diseases. NR 119 TC 74 Z9 75 U1 3 U2 20 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAR PY 2010 VL 298 IS 3 BP E449 EP E466 DI 10.1152/ajpendo.00559.2009 PG 18 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 557YA UT WOS:000274705200010 PM 19934407 ER PT J AU Zemkova, H Kucka, M Li, S Gonzalez-Iglesias, AE Tomic, M Stojilkovic, SS AF Zemkova, Hana Kucka, Marek Li, Shuo Gonzalez-Iglesias, Arturo E. Tomic, Melanija Stojilkovic, Stanko S. TI Characterization of purinergic P2X(4) receptor channels expressed in anterior pituitary cells SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE adenosine 5 '-triphosphatase; adenosine 5 '-triphosphatase-gated receptor channels; calcium; lactotrophs; prolactin; ivermectin ID EXTRACELLULAR NUCLEOTIDES; PROLACTIN-RELEASE; ATP RECEPTORS; INTRACELLULAR CALCIUM; HORMONE-RELEASE; P2 RECEPTORS; RAT; TRIPHOSPHATE; DESENSITIZATION; NEURONS AB Zemkova H, Kucka M, Li S, Gonzalez-Iglesias AE, Tomic M, Stojilkovic SS. Characterization of purinergic P2X(4) receptor channels expressed in anterior pituitary cells. Am J Physiol Endocrinol Metab 298: E644-E651, 2010. First published December 15, 2009; doi:10.1152/ajpendo.00558.2009.-Anterior pituitary cells express cation-conducting P2X receptor channels (P2XRs), but their molecular identity, electrophysiological properties, cell-specific expression pattern, and physiological roles have been only partially characterized. In this study, we show by quantitative RT-PCR that mRNA transcripts for the P2X4 subunit are the most abundant in rat anterior pituitary tissue and confirm the P2X(4)R protein expression by Western blot analysis. Single-cell patch-clamp recordings show that extracellular ATP induced an inward depolarizing current in a majority of thyrotropin-releasing hormone-responsive pituitary cells, which resembled the current profile generated by recombinant P2X4R. The channels were activated and desensitized in a dose-dependent manner and deactivated rapidly. Activation of these channels led to stimulation of electrical activity and promotion of voltage-gated and voltage-insensitive Ca2+ influx. In the presence of ivermectin, a specific allosteric modulator of P2X(4)Rs, there was an approximately fourfold increase in the maximum amplitude of the ATP-induced inward current, accompanied by an increase in the sensitivity of receptors for ATP, slowed deactivation of receptors, and enhanced ATP-induced prolactin release. These results indicate that thyrotropin-releasing hormone-responsive cells, including lactotrophs, express homomeric and/or heteromeric P2X(4)Rs, which facilitate Ca2+ influx and hormone secretion. C1 [Zemkova, Hana; Kucka, Marek; Li, Shuo; Gonzalez-Iglesias, Arturo E.; Tomic, Melanija; Stojilkovic, Stanko S.] NICHHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bethesda, MD 20892 USA. [Zemkova, Hana] Acad Sci Czech Republic, Inst Physiol, Dept Cellular & Mol Neuroendocrinol, Prague, Czech Republic. RP Stojilkovic, SS (reprint author), NICHHD, Sect Cellular Signaling, Program Dev Neurosci, NIH, Bldg 49,Rm 6A-36,49 Convent Dr, Bethesda, MD 20892 USA. EM stankos@helix.nih.gov RI Zemkova, Hana/C-1844-2012; Tomic, Melanija/C-3371-2016 FU National Institute of Child Health and Human Development; National Institutes of Health; Grant Agency of the Czech Republic [305/07/0681]; Centrum for Neuroscience [LC554] FX This work was supported by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health, the Grant Agency of the Czech Republic (305/07/0681), and Centrum for Neuroscience Grant LC554. NR 52 TC 15 Z9 15 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 EI 1522-1555 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAR PY 2010 VL 298 IS 3 BP E644 EP E651 DI 10.1152/ajpendo.00558.2009 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 557YA UT WOS:000274705200028 PM 20009029 ER PT J AU Ohse, T Vaughan, MR Kopp, JB Krofft, RD Marshall, CB Chang, AM Hudkins, KL Alpers, CE Pippin, JW Shankland, SJ AF Ohse, Takamoto Vaughan, Michael R. Kopp, Jeffrey B. Krofft, Ronald D. Marshall, Caroline B. Chang, Alice M. Hudkins, Kelly L. Alpers, Charles E. Pippin, Jeffrey W. Shankland, Stuart J. TI De novo expression of podocyte proteins in parietal epithelial cells during experimental glomerular disease SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE glomerulonephritis; differentiation; phenotype; FSGS; membranous nephropathy ID EXPERIMENTAL MEMBRANOUS NEPHROPATHY; FOCAL SEGMENTAL GLOMERULOSCLEROSIS; TO-MESENCHYMAL TRANSITION; CRESCENTIC GLOMERULONEPHRITIS; DIFFERENTIAL EXPRESSION; PROGENITOR CELLS; NEPHRIN; ACTIN; PROLIFERATION; MOUSE AB Ohse T, Vaughan MR, Kopp JB, Krofft RD, Marshall CB, Chang AM, Hudkins KL, Alpers CE, Pippin JW, Shankland SJ. De novo expression of podocyte proteins in parietal epithelial cells during experimental glomerular disease. Am J Physiol Renal Physiol 298: F702-F711, 2010. First published December 9, 2009; doi:10.1152/ajprenal.00428.2009.-Studies have shown that certain cells of the glomerular tuft begin to express proteins considered unique to other cell types upon injury. Little is known about the response of parietal epithelial cells (PEC) to injury. To determine whether PECs change their phenotype upon injury to also express proteins traditionally considered podocyte specific, the following four models of glomerular disease were studied: the transforming growth factor (TGF)-beta 1 transgenic mouse model of global glomerulosclerosis, the adriamycin model of focal segmental glomerulosclerosis (FSGS), the anti-glomerular basement membrane (GBM) model of crescentic glomerulonephritis, and the passive Heymann nephritis model of membranous nephropathy. Double immunostaining was performed with antibodies to podocyte-specific proteins (synaptopodin and Wilms' tumor 1) and antibodies to PEC specific proteins (paired box gene 8 and claudin-1). No double staining was detected in normal mice. In contrast, the results showed a statistical increase in the number of cells attached to Bowman basement membrane that were double-positive for both podocyte/PEC proteins in TGF-beta;1 transgenic, anti-GBM, and membranous animals. Double-positive cells for both podocyte and PEC proteins were also statistically increased in the glomerular tuft in TGF-beta 1 transgenic, anti-GBM, and FSGS mice. These results are consistent with glomerular cells coexpressing podocyte and PEC proteins in experimental glomerular disease, but not under normal circumstances. C1 [Ohse, Takamoto; Vaughan, Michael R.; Krofft, Ronald D.; Marshall, Caroline B.; Chang, Alice M.; Pippin, Jeffrey W.; Shankland, Stuart J.] Univ Washington, Div Nephrol, Seattle, WA 98195 USA. [Kopp, Jeffrey B.] Univ Washington, Dept Pathol, Seattle, WA 98195 USA. [Hudkins, Kelly L.; Alpers, Charles E.] Natl Inst Diabet Digest & Kidney Dis, Kidney Dis Sect, NIH, Bethesda, MD USA. RP Shankland, SJ (reprint author), Univ Washington, Div Nephrol, Box 356521,BB-1265 HSB,1959 NE Pacific St, Seattle, WA 98195 USA. EM stuartjs@u.washington.edu OI Kopp, Jeffrey/0000-0001-9052-186X FU National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program [ZO1 DK043308] FX This work was supported by a National Institutes of Health to S. J. Shankland. J. B. Kopp is supported by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program (ZO1 DK043308). NR 43 TC 50 Z9 51 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2010 VL 298 IS 3 BP F702 EP F711 DI 10.1152/ajprenal.00428.2009 PG 10 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 572TM UT WOS:000275856000024 PM 20007346 ER PT J AU Sakairi, T Abe, Y Kajiyama, H Bartlett, LD Howard, LV Jat, PS Kopp, JB AF Sakairi, Toru Abe, Yoshifusa Kajiyama, Hiroshi Bartlett, Linda D. Howard, Lilian V. Jat, Parmijit S. Kopp, Jeffrey B. TI Conditionally immortalized human podocyte cell lines established from urine SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE focal segmental glomerulosclerosis; SV40 large T antigen; human telomerase ID MESSENGER-RNA EXPRESSION; GENE-EXPRESSION; SEGMENTAL GLOMERULOSCLEROSIS; EPITHELIAL-CELLS; GLOMERULAR PODOCYTES; DIABETIC-NEPHROPATHY; RENAL-DISEASE; EXCRETION; NEPHRIN; INJURY AB Sakairi T, Abe Y, Kajiyama H, Bartlett LD, Howard LV, Jat PS, Kopp JB. Conditionally immortalized human podocyte cell lines established from urine. Am J Physiol Renal Physiol 298: F557-F567, 2010. First published December 9, 2009; doi:10.1152/ajprenal.00509.2009.-Evidence suggests that loss of podocytes into urine contributes to development of glomerular diseases; shed podocytes are frequently viable and proliferate in culture conditions. To determine the phenotypic characteristics of viable urinary cells derived from human subjects, we established long-term urinary cell culture from two patients with focal segmental glomerulosclerosis and two healthy volunteers, via transformation with the thermosensitive SV40 large T antigen (U19tsA58) together with human telomerase (hTERT). Characterization of arbitrarily selected two clonal cell lines from each human subject was carried out. mRNA expression for the podocyte markers synaptopodin, nestin, and CD2AP were detected in all eight clones. Podocin mRNA was absent from all eight clones. The expression of nephrin, Wilms' tumor 1 (WT1), and podocalyxin mRNA varied among the clones, which may be due to transformation and/or cloning. These results suggest that podocyte cell lines can be established consistently from human urine. The generation of podocyte cell lines from urine of patients and healthy volunteers is novel and will help to advance studies of podocyte cell biology. Further improvements in the approaches to cell transformation and/or cell culture techniques are needed to allow cultured podocytes to fully reproduce in vivo characteristics. C1 [Sakairi, Toru; Abe, Yoshifusa; Bartlett, Linda D.; Howard, Lilian V.; Kopp, Jeffrey B.] Natl Inst Diabet Digest & Kidney Dis, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. [Kajiyama, Hiroshi] Saitama Med Univ, Dept Rheumatol & Appl Immunol, Saitama, Japan. [Jat, Parmijit S.] UCL, Inst Neurol, Dept Neurodegenerat Dis, London, England. RP Kopp, JB (reprint author), Natl Inst Diabet Digest & Kidney Dis, Kidney Dis Sect, Kidney Dis Branch, NIH, Bethesda, MD 20892 USA. EM jbkopp@nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU National Institute of Diabetes and Digestive and Kidney Diseases [ZO1 DK043308] FX This study was supported by the Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases (project ZO1 DK043308). NR 44 TC 27 Z9 27 U1 0 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAR PY 2010 VL 298 IS 3 BP F557 EP F567 DI 10.1152/ajprenal.00509.2009 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 572TM UT WOS:000275856000009 PM 19955187 ER PT J AU Farhat, T Iannotti, RJ Simons-Morton, BG AF Farhat, Tilda Iannotti, Ronald J. Simons-Morton, Bruce G. TI Overweight, Obesity, Youth, and Health-Risk Behaviors SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID BODY-MASS INDEX; CORONARY-HEART-DISEASE; CHILDHOOD OBESITY; PHYSICAL-ACTIVITY; BULLYING BEHAVIORS; MENTAL-HEALTH; WEIGHT; ADOLESCENCE; CHILDREN; ASSOCIATIONS AB Background: The prevalence and severity of obesity have increased among children and adolescents. Although the medical and psychosocial consequences of youth obesity have been well documented, comparatively less information exists on the association of overweight/obesity with healthrisk behaviors, which are considered to be a primary threat to adolescent health. Purpose: This study aims to examine the association of overweight and obesity with health-risk behaviors among U.S. youth. Methods: Self-reported height and weight, substance use, violence, and bullying were assessed in a nationally representative sample of students aged 11-17 years (N=7825) who participated in the 2005-2006 Health Behaviors in School-Aged Children survey. Data were analyzed in 2009. Results: Significant gender and age differences in the relationship of overweight/ obesity with risk behaviors were observed. Overweight and obesity were significantly associated with substance use among girls only: Frequent smoking and drinking were associated with overweight and obesity among younger girls, whereas these behaviors were associated with obesity arriong older girls. Frequent smoking and cannabis use were associated with over-weight among younger girls only. Relationships between violent behavior and overweight/obesity were mainly observed among boys: Younger obese boys were more likely to be victims of bullying, whereas older obese boys were more likely to carry weapons compared to boys of normal weight. Conclusions: Overweight and obese young people are at risk of developing health-compromising behaviors that may compound medical and social problems associated with excess weight. (Am J Prev Med 2010;38(3):258-267) Published by Elsevier Inc. on behalf of Arrierican journal of Preventive Medicine C1 [Farhat, Tilda; Iannotti, Ronald J.; Simons-Morton, Bruce G.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Farhat, T (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B13C, Bethesda, MD 20892 USA. EM farhatti@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU NIH; Eunice Kennedy Shriver National Institute of Child Health and Human Development [N01-HD-5-3401] FX This research was supported in part by the intramural research program of the NIH, Eunice Kennedy Shriver National Institute of Child Health and Human Development (Contract N01-HD-5-3401).; No financial disclosures were reported by the authors of this paper. NR 50 TC 79 Z9 84 U1 3 U2 29 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 MAR PY 2010 VL 38 IS 3 BP 258 EP 267 DI 10.1016/j.amepre.2009.10.038 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 566OW UT WOS:000275383100003 PM 20171527 ER PT J AU Abrams, DB Graham, AL Levy, DT Mabry, PL Orleans, CT AF Abrams, David B. Graham, Amanda L. Levy, David T. Mabry, Patricia L. Orleans, C. Tracy TI Boosting Population Quits Through Evidence-Based Cessation Treatment and Policy SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID CLINICAL PREVENTIVE SERVICES; RANDOMIZED CONTROLLED-TRIAL; NICOTINE PATCH THERAPY; TREATING TOBACCO USE; SMOKING-CESSATION; UNITED-STATES; HEALTH-CARE; SIMULATION-MODEL; CIGARETTE-SMOKING; MEDICAID COVERAGE AB Only large increases in adult cessation will rapidly reduce population smoking prevalence. Evidence-based smoking-cessation treatments and treatment policies exist but are underutilized. More needs to be done to coordinate the widespread, efficient dissemination and implementation of effective treatments and policies. This paper is the first in a series of three to demonstrate the impact of an integrated, comprehensive systems approach to cessation treatment and policy. This paper provides an analytic framework and selected literature review that guide the two subsequent computer simulation modeling papers to show how critical leverage points may have an impact on reductions in smoking prevalence. Evidence is reviewed from the U.S. Public Health Service 2008 clinical practice guideline and other sources regarding the impact of five cessation treatment policies on quit attempts, use of evidence-based treatment, and quit rates. Cessation treatment policies would: (1) expand cessation treatment coverage and provider reimbursement; (2) mandate adequate funding for the use and promotion of evidence-based state-sponsored telephone quitlines; (3) support healthcare systems changes to prompt, guide, and incentivize tobacco treatment; (4) support and promote evidence-based treatment via the Internet; and (5) improve individually tailored, stepped-care approaches and the long-term effectiveness of evidence-based treatments. This series of papers provides an analytic framework to inform heuristic simulation models in order to take a new look at ways to markedly increase population smoking cessation by implementing a defined set of treatments and treatment-related policies with the potential to improve motivation to quit, evidence-based treatment use, and long-term effectiveness. (Am J Prev Med 2010;38(3S):S351-S363) (C) 2010 American journal of Preventive Medicine C1 [Abrams, David B.; Graham, Amanda L.] Amer Legacy Fdn, Steven Schroeder Inst Tobacco Res & Policy Studie, Washington, DC 20036 USA. [Levy, David T.] Univ Baltimore, Pacific Inst Res & Evaluat, Calverton, MD USA. [Mabry, Patricia L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Orleans, C. Tracy] Robert Wood Johnson Fdn, Princeton, NJ 08540 USA. RP Abrams, DB (reprint author), Amer Legacy Fdn, Steven Schroeder Inst Tobacco Res & Policy Studie, 1724 Massachusetts Ave NW, Washington, DC 20036 USA. EM dabrams@americanlegacy.org OI Graham, Amanda/0000-0003-3036-9653 FU Office of Behavioral and Social Sciences Research (OBSSR) at the NIH; Robert Wood Johnson Foundation (RWJF) FX This paper was conducted under the auspices of the national Consumer Demand Roundtable and was supported by funds provided by the Office of Behavioral and Social Sciences Research (OBSSR) at the NIH and the Robert Wood Johnson Foundation (RWJF). The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the American Legacy Foundation, the University of Baltimore, OBSSR, or RWJF. NR 96 TC 37 Z9 37 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAR PY 2010 VL 38 IS 3 SU 3 BP S351 EP S363 DI 10.1016/j.amepre.2009.12.011 PG 13 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 566OX UT WOS:000275383200009 PM 20176308 ER PT J AU Backinger, CL Malarcher, AM AF Backinger, Cathy L. Malarcher, Ann M. TI The Things That Get Measured Are the Things That Get Done SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article C1 [Backinger, Cathy L.] NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. [Malarcher, Ann M.] CDC, Epidemiol Branch, Off Smoking & Hlth, Atlanta, GA 30333 USA. RP Backinger, CL (reprint author), NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4050, Rockville, MD 20852 USA. EM backingc@mail.nih.gov FU National Cancer Institute; CDC FX The authors thank Allison Rose and Rene Arrazola for their assistance in reviewing the state and national survey questions, Ami Hurd for her assistance in gathering and organizing background materials for the commentary, and Dr. C. Tracy Orleans and Dr. Gary Giovino for their input into the conceptualization of the major themes for the commentary.; The findings and conclusions in this report are those of the authors and do not necessarily represent any official position of the National Cancer Institute, the NIH, or the CDC.; This work was supported by the National Cancer Institute and the CDC. NR 18 TC 4 Z9 4 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAR PY 2010 VL 38 IS 3 SU 3 BP S433 EP S436 DI 10.1016/j.amepre.2009.12.005 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 566OX UT WOS:000275383200020 PM 20176319 ER PT J AU Backinger, CL Thornton-Bullock, A Miner, C Orleans, CT Siener, K DiClemente, CC Phillips, TM Rowden, JN Arkin, E AF Backinger, Cathy L. Thornton-Bullock, Amber Miner, Cindy Orleans, C. Tracy Siener, Karen DiClemente, Carlo C. Phillips, Todd M. Rowden, Jessica N. Arkin, Elaine TI Building Consumer Demand for Tobacco-Cessation Products and Services The National Tobacco Cessation Collaborative's Consumer Demand Roundtable SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID SMOKING-CESSATION; CIGARETTE-SMOKING; SMOKERS; PROGRAMS; IMPACT; SALES C1 [Phillips, Todd M.; Rowden, Jessica N.; Arkin, Elaine] Acad Educ Dev, Washington, DC 20009 USA. [Backinger, Cathy L.] NCI, Bethesda, MD 20892 USA. [Miner, Cindy] Natl Inst Drug Abuse, Bethesda, MD USA. [DiClemente, Carlo C.] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. [Thornton-Bullock, Amber] Amer Legacy Fdn, Washington, DC USA. [Orleans, C. Tracy] Robert Wood Johnson Fdn, Princeton, NJ 08540 USA. [Siener, Karen] CDC, Atlanta, GA 30333 USA. RP Phillips, TM (reprint author), Acad Educ Dev, 1825 Connecticut Ave NW, Washington, DC 20009 USA. EM tphillip@aed.org NR 32 TC 18 Z9 19 U1 0 U2 0 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 MAR PY 2010 VL 38 IS 3 SU 3 BP S307 EP S311 DI 10.1016/j.amepre.2009.12.002 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 566OX UT WOS:000275383200002 PM 20176301 ER PT J AU Levy, DT Mabry, PL Graham, AL Orleans, CT Abrams, DB AF Levy, David T. Mabry, Patricia L. Graham, Amanda L. Orleans, C. Tracy Abrams, David B. TI Reaching Healthy People 2010 by 2013 A SimSmoke Simulation SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID NICOTINE REPLACEMENT THERAPIES; REDUCING SMOKING PREVALENCE; TOBACCO CONTROL OBJECTIVES; PUBLIC-POLICIES; NATIONAL QUITLINE; CIGARETTE-SMOKING; UNITED-STATES; MODEL; CESSATION; DEMAND AB Background: Healthy People (HP2010) set as a goal to reduce adult smoking prevalence to 12% by 2010. Purpose: This paper uses simulation modeling to examine the effects of three tobacco control policies and cessation treatment policies-alone and in conjunction-on population smoking prevalence. Methods: Building on previous versions of the SimSmoke model, the effects of a defined set of policies on quit attempts, treatment use, and treatment effectiveness are estimated as potential levers to reduce smoking prevalence. The analysis considers the effects of (1) price increases through cigarette tax increases, (2) smokefree indoor air laws, (3) mass media/educational policies, and (4) evidence-based and promising cessation treatment policies. Results: Evidence-based cessation treatment policies have the strongest effect, boosting the population quit rate by 78.8% in relative terms. Treatment policies are followed by cigarette tax increases (65.9%); smokefree air laws (31.8%); and mass media/educational policies (18.2%). Relative to the status quo in 2020, the model projects that smoking prevalence is reduced by 14.3% through a nationwide tax increase of $2.00, by 7.2% through smokefree laws, by 4.7% through mass media/educational policies, and by 16.5% through cessation treatment policies alone. Implementing all of the above policies at the same time would increase the quit rate by 296%, such that the HP2010 smoking prevalence goal of 12% is reached by 2013. Conclusions: The impact of a combination of policies led to some surprisingly positive possible futures in lowering smoking prevalence to 12% within just several years. Simulation models can be a useful tool for evaluating complex scenarios in which policies are implemented simultaneously, and for which there are limited data. (Am J Prev Med 2010;38(3S):S373-S381) (C) 2010 American Journal of Preventive Medicine C1 [Levy, David T.] Univ Baltimore, Pacific Inst Res & Evaluat, Calverton, MD 20705 USA. [Mabry, Patricia L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Graham, Amanda L.; Abrams, David B.] Amer Legacy Fdn, Steven A Schroeder Inst Tobacco Res & Policy Stud, Washington, DC USA. [Orleans, C. Tracy] Robert Wood Johnson Fdn, Princeton, NJ 08540 USA. RP Levy, DT (reprint author), Univ Baltimore, Pacific Inst Res & Evaluat, 11720 Beltsville Dr,Suite 900, Calverton, MD 20705 USA. EM Levy@pire.org OI Graham, Amanda/0000-0003-3036-9653 FU Office of Behavioral and Social Sciences Research (OBSSR) at the NIH; Robert Wood Johnson Foundation (RWJF); Cancer Intervention and Surveillance Modeling Network (CISNET) of the Division of Cancer Control and Population Sciences (DCCPS), National Cancer Institute (NCI) [UO1-CA97450-02] FX This paper was conducted under the auspices of the national Consumer Demand Roundtable and was supported by funds provided by the Office of Behavioral and Social Sciences Research (OBSSR) at the NIH and the Robert Wood Johnson Foundation (RWJF). David Levy also received funding from the Cancer Intervention and Surveillance Modeling Network (CISNET) of the Division of Cancer Control and Population Sciences (DCCPS), National Cancer Institute (NCI) under grant UO1-CA97450-02. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the American Legacy Foundation, the University of Baltimore, NCI, OBSSR, or RWJF. NR 61 TC 22 Z9 23 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAR PY 2010 VL 38 IS 3 SU 3 BP S373 EP S381 DI 10.1016/j.amepre.2009.11.018 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 566OX UT WOS:000275383200011 PM 20176310 ER PT J AU Levy, DT Graham, AL Mabry, PL Abrams, DB Orleans, CT AF Levy, David T. Graham, Amanda L. Mabry, Patricia L. Abrams, David B. Orleans, C. Tracy TI Modeling the Impact of Smoking-Cessation Treatment Policies on Quit Rates SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID OVER-THE-COUNTER; NICOTINE REPLACEMENT; SIMULATION-MODEL; METAANALYSIS; BENEFITS AB Background: Smoking-cessation treatment policies could yield substantial increases in adult quit rates in the U.S. Purpose: The goals of this paper are to model the effects of individual cessation treatment policies on population quit rates, and to illustrate the potential benefits of combining policies to leverage their synergistic effects. Methods: A mathematical model is updated to examine the impact of five cessation treatment policies on quit attempts, treatment use, and treatment effectiveness. Policies include: (1) expand cessation treatment coverage and provider reimbursement; (2) mandate adequate funding for the use and promotion of evidence-based, state-sponsored telephone quitlines; (3) support healthcare system changes to prompt, guide, and incentivize tobacco treatment; (4) support and promote evidence-based treatment via the Internet; and (5) improve individually tailored, stepped-care approaches and the long-term effectiveness of evidence-based treatments. Results: The annual baseline population quit rate is 4.3% of all current smokers. implementing any policy in isolation is projected to increase the quit rate to between 4.5% and 6%. By implementing all five policies in combination, the quit rate is projected to increase to 10.9%, or 2.5 times the baseline rate. Conclusions: if fully implemented in a coordinated fashion, cessation treatment policies could reduce smoking prevalence from its current rate of 20.5% to 17.2% within 1 year. By modeling the policy impacts on the components of the population quit rate (quit attempts, treatment use, treatment effectiveness), key indicators are identified that need to be analyzed in attempts to improve the effect of cessation treatment policies. (Am J Prev Med 2010;38(3S):S364-S372) (C) 2010 American journal of Preventive Medicine C1 [Levy, David T.] Univ Baltimore, Pacific Inst Res & Evaluat, Calverton, MD 20705 USA. [Mabry, Patricia L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Graham, Amanda L.; Abrams, David B.] Amer Legacy Fdn, Steven A Schroeder Inst Tobacco Res & Policy Stud, Washington, DC USA. [Orleans, C. Tracy] Robert Wood Johnson Fdn, Princeton, NJ 08540 USA. RP Levy, DT (reprint author), Univ Baltimore, Pacific Inst Res & Evaluat, 11720 Beltsville Dr,Suite 900, Calverton, MD 20705 USA. EM Levy@pire.org OI Graham, Amanda/0000-0003-3036-9653 FU Office of Behavioral and Social Sciences Research (OBSSR) at the NIH; Robert Wood Johnson Foundation (RWJF); Cancer Intervention and Surveillance Modeling Network (CISNET) of the Division of Cancer Control and Population Sciences (DCCPS), National Cancer Institute (NCI) [UO1-CA97450-02] FX This paper was conducted under the auspices of the national Consumer Demand Roundtable and was supported by funds provided by the Office of Behavioral and Social Sciences Research (OBSSR) at the NIH and the Robert Wood Johnson Foundation (RWJF). David Levy also received funding from the Cancer Intervention and Surveillance Modeling Network (CISNET) of the Division of Cancer Control and Population Sciences (DCCPS), National Cancer Institute (NCI) under grant UO1-CA97450-02. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the American Legacy Foundation, the University of Baltimore, NCI, OBSSR, or RWJF. NR 30 TC 38 Z9 39 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 EI 1873-2607 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAR PY 2010 VL 38 IS 3 SU 3 BP S364 EP S372 DI 10.1016/j.amepre.2009.11.016 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 566OX UT WOS:000275383200010 PM 20176309 ER PT J AU Orleans, CT Mabry, PL Abrams, DB AF Orleans, C. Tracy Mabry, Patricia L. Abrams, David B. TI Increasing Tobacco Cessation in America A Consumer Demand Perspective SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID PRESCRIPTION DRUGS; SCIENCE; HEALTH C1 [Orleans, C. Tracy] Robert Wood Johnson Fdn, Princeton, NJ 08543 USA. [Mabry, Patricia L.] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Abrams, David B.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Behav & Soc, Washington, DC USA. Amer Legacy Fdn, Schroeder Inst Tobacco Res & Policy Studies, Washington, DC USA. RP Orleans, CT (reprint author), Robert Wood Johnson Fdn, Coll Rd E, Princeton, NJ 08543 USA. EM torlean@rwjf.org NR 30 TC 9 Z9 10 U1 0 U2 1 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 MAR PY 2010 VL 38 IS 3 SU 3 BP S303 EP S306 DI 10.1016/j.amepre.2010.01.013 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 566OX UT WOS:000275383200001 PM 20176300 ER PT J AU Vick, SJ Paukner, A AF Vick, Sarah-Jane Paukner, Annika TI Variation and Context of Yawns in Captive Chimpanzees (Pan troglodytes) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE chimpanzee; yawn; chimpFACS; facial expression ID MACACA-FASCICULARIS; PRIMATES; BEHAVIOR; ARCTOIDES; ANXIETY; HUMANS; SPHINX AB Primate yawns are usually categorized according to context (e.g. as a threat, anxious, or rest yawn), but there has been little consideration of whether these yawns are best regarded as a unitary behavior that only differs with respect to the context in which it is observed. This study examined the context and precise morphology of yawns in a group of 11 captive chimpanzees. Focal video sampling was used to describe the morphology and intensity of 124 yawns using ChimpFACS, a system for coding facial movements. Two distinct forms of yawn were identified, a full yawn and a yawn which is modified by additional actions that reduce the mouth aperture. These modified yawns may indicate some degree of voluntary control over facial movement in chimpanzees and, consequently, multiple functions of yawning according to context. To assess context effects, mean activity levels (resting, locomotion, and grooming) and scratching rates were compared one minute before and after each yawn. Locomotion was significantly increased following both types of yawn, whereas scratching rates significantly increased following modified yawns but decreased following full yawns. In terms of individual differences, males did not yawn more than females, although male yawns were of higher intensity, both in the degree of mouth opening and in the amount of associated head movement. These data indicate that yawning is associated with a change in activity levels in chimpanzees, but only modified yawns may be related to increased arousal. Different types of yawn can therefore be differentiated at the morphological level as well as context level. Am. J. Primatol. 72:262-269, 2010. (C) 2009 Wiley-Liss, Inc. C1 [Vick, Sarah-Jane; Paukner, Annika] Univ Stirling, Dept Psychol, Stirling FK9 4LA, Scotland. [Paukner, Annika] NIH, Comparat Ethol Lab, Anim Ctr, Poolesville, MD USA. RP Vick, SJ (reprint author), Univ Stirling, Dept Psychol, Stirling FK9 4LA, Scotland. EM sarah-jane.vick@stir.ac.uk RI Vick, Sarah-Jane/B-5426-2009 OI Vick, Sarah-Jane/0000-0001-8741-9653 FU Royal Zoological Society of Scotland (RZSS); Amercian Society of Primatology FX Contract grant sponsors: Royal Zoological Society of Scotland (RZSS); Amercian Society of Primatology's Principles. NR 49 TC 13 Z9 13 U1 1 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAR PY 2010 VL 72 IS 3 BP 262 EP 269 DI 10.1002/ajp.20781 PG 8 WC Zoology SC Zoology GA 555KF UT WOS:000274508900007 PM 20014109 ER PT J AU Fee, E Bu, LP AF Fee, Elizabeth Bu, Liping TI Isaac Williams Brewer (1867-1928): An Unsung Hero SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Fee, Elizabeth] NIH, Hist Med Div, Natl Lib Med, Bethesda, MD 20892 USA. [Bu, Liping] Alma Coll, Dept Hist, Alma, MI USA. RP Fee, E (reprint author), NIH, Hist Med Div, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2010 VL 100 IS 3 BP 423 EP 423 DI 10.2105/AJPH.2009.184424 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 564YD UT WOS:000275253800014 PM 20075307 ER PT J AU Bu, LP Fee, E AF Bu, Liping Fee, Elizabeth TI Communicating With Pictures: The Vision of Chinese Anti-Malaria Posters SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Bu, Liping] Alma Coll, Dept Hist, Alma, MI 48801 USA. [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Bu, LP (reprint author), Alma Coll, Dept Hist, 614 W Super St, Alma, MI 48801 USA. EM bulipi@alma.edu NR 3 TC 1 Z9 1 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2010 VL 100 IS 3 BP 424 EP 425 DI 10.2105/AJPH.2009.177667 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 564YD UT WOS:000275253800015 PM 20075311 ER PT J AU Mazaki-Tovi, S Vaisbuch, E Romero, R Kusanovic, JP Chaiworapongsa, T Kim, SK Nhan-Chang, CL Gomez, R Yoon, BH Yeo, L Mittal, P Ogge, G Gonzalez, JM Hassan, SS AF Mazaki-Tovi, Shali Vaisbuch, Edi Romero, Roberto Kusanovic, Juan Pedro Chaiworapongsa, Tinnakorn Kim, Sun Kwon Nhan-Chang, Chia-Ling Gomez, Ricardo Yoon, Bo H. Yeo, Lami Mittal, Pooja Ogge, Giovanna Gonzalez, Juan M. Hassan, Sonia S. TI Maternal Plasma Concentration of the Pro-Inflammatory Adipokine Pre-B-Cell-Enhancing Factor (PBEF)/Visfatin Is Elevated In Pregnant Patients with Acute Pyelonephritis SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Article DE Acute bacterial infection; adipokines; BMI; cytokine; infection; inflammation; maternal obesity; overweight; pregnancy; urinary tract infection ID GESTATIONAL DIABETES-MELLITUS; SERUM ADIPONECTIN MULTIMERS; RESPIRATORY-DISTRESS-SYNDROME; FACTOR GENE POLYMORPHISMS; VISFATIN CONCENTRATIONS; AMNIOTIC-FLUID; ADIPOSE-TISSUE; PRETERM LABOR; BIRTH-WEIGHT; INSULIN-RESISTANCE AB Problem Visfatin/pre-B-cell-enhancing factor (PBEF) has been implicated in the regulation of the innate immune system, as well as in glucose metabolism. Specifically, visfatin plays a requisite role in delayed neutrophil apoptosis in patients with sepsis. The aim of this study was to determine whether pyelonephritis during pregnancy is associated with changes in maternal plasma visfatin concentration in normal weight and overweight/obese patients. Method of study This cross-sectional study included the following groups: (1) normal pregnant women (n = 200) and (2) pregnant women with pyelonephritis (n = 40). Maternal plasma visfatin concentrations were determined by ELISA. Non-parametric statistics was used for analyses. Results (1) The median maternal plasma visfatin concentration was significantly higher in patients with pyelonephritis than in those with a normal pregnancy; (2) among overweight/obese pregnant women, those with pyelonephritis had a significantly higher median plasma visfatin concentration than women with a normal pregnancy; and (3) pyelonephritis was independently associated with higher maternal plasma visfatin concentrations after adjustment for maternal age, pre-gestational body mass index, smoking status, gestational age at sampling, and birthweight. Conclusion Acute pyelonephritis during pregnancy is associated with a high circulating maternal visfatin concentration. These findings suggest that visfatin/PBEF may play a role in the regulation of the complex and dynamic crosstalk between inflammation and metabolism during pregnancy. C1 [Mazaki-Tovi, Shali; Vaisbuch, Edi; Romero, Roberto; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Kim, Sun Kwon; Nhan-Chang, Chia-Ling; Yeo, Lami; Mittal, Pooja; Ogge, Giovanna; Gonzalez, Juan M.; Hassan, Sonia S.] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Detroit, MI 48201 USA. [Mazaki-Tovi, Shali; Vaisbuch, Edi; Romero, Roberto; Kusanovic, Juan Pedro; Chaiworapongsa, Tinnakorn; Kim, Sun Kwon; Nhan-Chang, Chia-Ling; Yeo, Lami; Mittal, Pooja; Ogge, Giovanna; Gonzalez, Juan M.; Hassan, Sonia S.] Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Bethesda, MD USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. [Gomez, Ricardo] Pontificia Univ Catolica Chile, CEDIP Ctr Perinatal Diag & Res, Dept Obstet & Gynecol, Sotero del Rio Hosp, Santiago, Chile. [Yoon, Bo H.] Seoul Natl Univ, Dept Obstet & Gynecol, Seoul, South Korea. RP Romero, R (reprint author), Hutzel Womens Hosp, Perinatol Res Branch, Intramural Div, NICHD,NIH,DHHS, Box 4,3990 John R, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu RI Yoon, Bo Hyun/H-6344-2011; OI Vaisbuch, Edi/0000-0002-8400-9031 FU Intramural NIH HHS [Z01 HD002400-17, ZIA HD002400-18] NR 99 TC 11 Z9 11 U1 0 U2 6 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1046-7408 J9 AM J REPROD IMMUNOL JI Am. J. Reprod. Immunol. PD MAR PY 2010 VL 63 IS 3 BP 252 EP 262 DI 10.1111/j.1600-0897.2009.00804.x PG 11 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 553SV UT WOS:000274388000011 PM 20085562 ER PT J AU Cho, KJ Seo, JM Shin, Y Yoo, MH Park, CS Lee, SH Chang, YS Cho, SH Kim, JH AF Cho, Kyung-Jin Seo, Ji-Min Shin, YoungHyun Yoo, Min-Hyuk Park, Choon-Sik Lee, Shin-Hwa Chang, Yoon-Seok Cho, Sang-Heon Kim, Jae-Hong TI Blockade of Airway Inflammation and Hyperresponsiveness by Inhibition of BLT2, a Low-Affinity Leukotriene B-4 Receptor SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Article DE asthma; lipid mediator; inflammation; reactive oxygen species; BLT2 ID NF-KAPPA-B; T-CELL RECRUITMENT; EOSINOPHIL ACCUMULATION; TRANSCRIPTION FACTOR; MEDIATES CHEMOTAXIS; OXIDATIVE STRESS; NADPH OXIDASE; MURINE MODEL; MOUSE MODEL; ASTHMA AB BLT2 is a low-affinity receptor for leukotriene B-4 (LTB4), a potent lipid mediator of inflammation generated from arachidonic acid via the 5-lipoxygenase pathway. Unlike BLT1, a high-affinity receptor for LTB4, no clear physiological function has yet been identified for BLT2, especially with regard to the pathogenesis of asthma. The aim of this study was to investigate whether BLT2 plays a role in the pathogenesis of asthma. A murine model of allergic asthma was used to evaluate the role of BLT2 in ovalbumin-induced airway inflammation and airway hyperresponsiveness. The levels of BLT2 mRNA and its ligand, LTB4, in the lung airway were highly elevated after ovalbumin challenge, and down-regulation of BLT2 with antisense BLT2 oligonucleotides markedly attenuated airway inflammation and airway hyperresponsiveness. Further analysis, aimed at identifying mediators downstream of BLT2, revealed that BLT2 activation led to elevation of reactive oxygen species and subsequent activation of NF-kappa B, thus inducing the expression of vascular cell adhesion molecule-1, which is known to be involved in eosinophil infiltration into the lung airway. Together, our results suggest that BLT2 plays a pivotal, mediatory role in the pathogenesis of asthma, acting through a "reactive oxygen species-NF-kappa B"-linked inflammatory signaling pathway. C1 [Cho, Kyung-Jin; Seo, Ji-Min; Shin, YoungHyun; Kim, Jae-Hong] Korea Univ, Sch Life Sci & Biotechnol, Seoul 136701, South Korea. [Yoo, Min-Hyuk] NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Park, Choon-Sik; Lee, Shin-Hwa] Soonchunhyang Univ, Div Allergy & Resp Dis, Puchon, South Korea. [Chang, Yoon-Seok; Cho, Sang-Heon] Seoul Natl Univ, Coll Med, Dept Internal Med, Seoul 151, South Korea. RP Kim, JH (reprint author), Korea Univ, Sch Life Sci & Biotechnol, 5-1 Anam Dong, Seoul 136701, South Korea. EM jhongkim@korea.ac.kr RI Cho, Sang Heon/J-2793-2012; Chang, Yoon-Seok/J-5628-2012; Kim, Jae-Hong/B-2530-2009; OI Park, Choon-Sik/0000-0003-2977-0255; Chang, Yoon-Seok/0000-0003-3157-0447 FU New Drug Target Discovery; Korean Ministry of Education, Science, and Technology FX This work was supported by the New Drug Target Discovery grant and the Diseases Network Research Program grant from the Korean Ministry of Education, Science, and Technology. NR 49 TC 29 Z9 30 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD MAR PY 2010 VL 42 IS 3 BP 294 EP 303 DI 10.1165/rcmb.2008-0445OC PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 562UQ UT WOS:000275080900006 PM 19448154 ER PT J AU Klimstra, DS Modlin, IR Adsay, NV Chetty, R Deshpande, V Gonen, M Jensen, RT Kidd, M Kulke, MH Lloyd, RV Moran, C Moss, SF Oberg, K O'Toole, D Rindi, G Robert, ME Suster, S Tang, LH Tzen, CY Washington, MK Wiedenmann, B Yao, J AF Klimstra, David S. Modlin, Irvin R. Adsay, N. Volkan Chetty, Runjan Deshpande, Vikram Goenen, Mithat Jensen, Robert T. Kidd, Mark Kulke, Matthew H. Lloyd, Ricardo V. Moran, Cesar Moss, Steven F. Oberg, Kjell O'Toole, Dermot Rindi, Guido Robert, Marie E. Suster, Saul Tang, Laura H. Tzen, Chin-Yuan Washington, Mary Kay Wiedenmann, Betram Yao, James TI Pathology Reporting of Neuroendocrine Tumors: Application of the Delphic Consensus Process to the Development of a Minimum Pathology Data Set SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE neuroendocrine tumor; consensus; carcinoid tumor; Delphic; classification ID PANCREATIC ENDOCRINE TUMORS; SMALL-CELL CARCINOMA; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; MOLECULAR TARGETED THERAPY; PROGNOSTIC-FACTORS; GASTROINTESTINAL-TRACT; LOW-GRADE; GASTROENTEROPANCREATIC TUMORS; CLASSIFICATION-SYSTEM; PRECURSOR LESIONS AB Epithelial neuroendocrine tumors (NETs) have been the subject of much debate regarding their optimal classification. Although multiple systems of nomenclature, grading, and staging have been proposed, none has achieved universal acceptance. To help define the underlying common features of these classification systems and to identify the minimal pathology data that should be reported to ensure consistent clinical management and reproducibility of data from therapeutic trials, a multidisciplinary team of physicians interested in NETs was assembled. At a group meeting, the participants discussed a series of "yes'' or "no'' questions related to the pathology of NETs and the minimal data to be included in the reports. After discussion, anonymous votes were taken, using the Delphic principle that 80% agreement on a vote of either yes or no would define a consensus. Questions that failed to achieve a consensus were rephrased once or twice and discussed, and additional votes were taken. Of 108 questions, 91 were answerable either yes or no by more than 80% of the participants. There was agreement about the importance of proliferation rate for tumor grading, the landmarks to use for staging, the prognostic factors assessable by routine histology that should be reported, the potential for tumors to progress biologically with metastasis, and the current status of advanced immunohistochemical and molecular testing for treatment-related biomarkers. The lack of utility of a variety of immunohistochemical stains and pathologic findings was also agreed upon. A consensus could not be reached for the remaining 17 questions, which included both minor points related to extent of disease assessment and some major areas such as terminology, routine immunohistochemical staining for general neuroendocrine markers, use of Ki67 staining to assess proliferation, and the relationship of tumor grade to degree of differentiation. On the basis of the results of the Delphic voting, a minimum pathology data set was developed. Although there remains disagreement among experts about the specific classification system that should be used, there is agreement about the fundamental pathology data that should be reported. Examination of the areas of disagreement reveals significant opportunities for collaborative study to resolve unanswered questions. C1 [Klimstra, David S.] Mem Sloan Kettering Canc Ctr, Dept Pathol, Surg Pathol Serv, New York, NY 10065 USA. [Goenen, Mithat] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA. [Modlin, Irvin R.; Kidd, Mark] Yale Univ, Sch Med, Dept Surg, New Haven, CT 06510 USA. [Robert, Marie E.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. [Adsay, N. Volkan] Emory Univ, Dept Pathol, Atlanta, GA 30322 USA. [Chetty, Runjan] Toronto Gen Hosp, Dept Pathol, Toronto, ON, Canada. [Deshpande, Vikram] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA. [Kulke, Matthew H.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Jensen, Robert T.] Natl Inst Diabet Digest & Kidney Dis, Bethesda, MD USA. [Lloyd, Ricardo V.] Mayo Clin, Dept Pathol, Rochester, MN USA. [Moran, Cesar] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Yao, James] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. [Moss, Steven F.] Brown Univ, Rhode Isl Hosp, Dept Med, Providence, RI 02903 USA. [Oberg, Kjell] Univ Upsalla, Dept Med Sci, Upsalla, Sweden. [O'Toole, Dermot] St James Hosp, Dept Med, Dublin, Ireland. [O'Toole, Dermot] Trinity Coll Dublin, Dublin, Ireland. [Rindi, Guido] Univ Parma, Dept Pathol & Lab Med, I-43100 Parma, Italy. [Suster, Saul] Med Coll Wisconsin, Dept Pathol, Milwaukee, WI 53226 USA. [Tzen, Chin-Yuan] Cathay Gen Hosp, Dept Pathol, Taipei, Taiwan. [Washington, Mary Kay] Vanderbilt Univ Sch Med, Dept Pathol, Nashville, TN USA. [Wiedenmann, Betram] Univ Berlin, Charite Hosp, Dept Internal Med, Berlin, Germany. RP Klimstra, DS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Pathol, Surg Pathol Serv, 1275 York Ave, New York, NY 10065 USA. EM klimstrd@mskcc.org RI Gonen, Mithat/E-4826-2012; OI RINDI, Guido/0000-0003-2996-4404 FU Novartis Corporation FX Supported by Novartis Corporation. NR 100 TC 151 Z9 173 U1 0 U2 4 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 MAR PY 2010 VL 34 IS 3 BP 300 EP 313 DI 10.1097/PAS.0b013e3181ce1447 PG 14 WC Pathology; Surgery SC Pathology; Surgery GA 570RZ UT WOS:000275697000002 PM 20118772 ER PT J AU Dojcinov, SD Venkataraman, G Raffeld, M Pittaluga, S Jaffe, ES AF Dojcinov, Stefan D. Venkataraman, Girish Raffeld, Mark Pittaluga, Stefania Jaffe, Elaine S. TI EBV Positive Mucocutaneous Ulcer-A Study of 26 Cases Associated With Various Sources of Immunosuppression SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE Epstein Barr virus; immunosuppression; mucocutaneous; lymphoproliferative ID EPSTEIN-BARR-VIRUS; CELL LYMPHOPROLIFERATIVE DISORDERS; CD8(+) T-CELLS; OPTIMAL PRIMER SELECTION; CHAIN-REACTION ANALYSIS; NON-HODGKINS-LYMPHOMAS; PERIPHERAL-BLOOD; ELDERLY-PATIENTS; CYTOMEGALOVIRUS SEROPOSITIVITY; LYMPHOCYTE SUBPOPULATIONS AB We describe a series of Epstein Barr virus (EBV)-positive circumscribed, ulcerative lesions associated with various types of immunosuppression (IS). The study group (26 patients) comprised 10 males and 16 females, median age 77 years (range 42 to 101). IS in 9 cases included azathioprine (AZA), methotrexate (MTX) or cyclosporin-A (CyA). Seventeen patients had age-related immunosenescence. Patients presented with isolated sharply circumscribed ulcers involving oropharyngeal mucosa (16), skin (6), and gastrointestinal tract (4). Lesions were histologically characterized by a polymorphous infiltrate and atypical large B-cell blasts often with Hodgkin/Reed-Sternberg (HRS) cell-like morphology. The B cells showed strong CD30 and EBER positivity, some with reduced CD20 expression, in a background of abundant T cells. CD15 was positive in 43% of cases (10/23). The pathologic features were identical regardless of the anatomic site or cause of IS. Polymerase chain reaction revealed 39% (7/18) clonal Ig gene rearrangements with 38% (6/16) and 31% (5/16) clonal and restricted T-cell patterns, respectively. Twenty-five percent of patients (5/20) received standard chemotherapy and/or radiotherapy. Forty-five percent (9/20) regressed spontaneously with no treatment and 15% (3/20) were characterized by a relapsing and remitting course. All of the iatrogenic lesions (6/6) with available follow-up responded to reduction of IS. All patients achieved complete remission with no disease-associated deaths over a median follow-up period of 22 months (range 3 to 72). We propose EBV-positive mucocutaneous ulcer as a newly recognized clinicopathologic entity with Hodgkin-like features and a self-limited, indolent course, generally responding well to conservative management. Association with various forms of IS implies a common pathogenetic mechanism. The localized nature of the disease may be owing to a minimal and localized lapse in immunosurveillance over EBV. C1 [Dojcinov, Stefan D.] Univ Wales Hosp, Dept Pathol, All Wales Lymphoma Panel, Cardiff CF14 4XN, S Glam, Wales. [Venkataraman, Girish; Raffeld, Mark; Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Dojcinov, SD (reprint author), Univ Wales Hosp, Dept Pathol, All Wales Lymphoma Panel, Heath Pk, Cardiff CF14 4XN, S Glam, Wales. EM dojcinov@cf.ac.uk OI Venkataraman, Girish/0000-0002-8674-2608; Jaffe, Elaine/0000-0003-4632-0301 FU Center for Cancer Research, National Cancer Institute, National Institutes of Health; British Division of the International Academy of Pathology; British Society for Haematology FX Supported by funding from: The Center for Cancer Research, National Cancer Institute, National Institutes of Health, and the British Division of the International Academy of Pathology and the British Society for Haematology. NR 71 TC 132 Z9 135 U1 1 U2 2 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 MAR PY 2010 VL 34 IS 3 BP 405 EP 417 DI 10.1097/PAS.0b013e3181cf8622 PG 13 WC Pathology; Surgery SC Pathology; Surgery GA 570RZ UT WOS:000275697000013 PM 20154586 ER PT J AU Henkin, RI Potolicchio, SJ Levy, LM Moharram, R Velicu, I Martin, BM AF Henkin, Robert I. Potolicchio, Samuel J. Levy, Lucien M. Moharram, Ramy Velicu, Irina Martin, Brian M. TI Carbonic Anhydrase I, II, and VI, Blood Plasma, Erythrocyte and Saliva Zinc and Copper Increase After Repetitive Transcranial Magnetic Stimulation SO AMERICAN JOURNAL OF THE MEDICAL SCIENCES LA English DT Article DE Carbonic anhydrase; Zinc; Copper; Sensory changes after transcranial magnetic stimulation; Mass spectrometry ID MOTOR CORTEX EXCITABILITY; IDIOPATHIC PARKINSONS-DISEASE; OLFACTORY-BULB NEURONS; HUMAN PAROTID-SALIVA; CEREBROSPINAL-FLUID LEVELS; HUMAN NASAL MUCUS; ALZHEIMERS-DISEASE; MULTIPLE-SCLEROSIS; DOPAMINE RELEASE; ELECTROMAGNETIC-FIELDS AB Introduction: Repetitive transcranial magnetic stimulation (rTMS) has been used to treat symptoms from many disorders; biochemical changes occurred with this treatment. Preliminary studies with rTMS in patients with taste and smell dysfunction improved sensory function and increased salivary carbonic anhydrase (CA) VI and erythrocyte CA I, II. To obtain more information about these changes after rTMS, we measured changes in several CA enzymes, proteins, and trace metals in their blood plasma, erythrocytes, and saliva. Methods: Ninety-three patients with taste and smell dysfunction were studied before and after rTMS in an open clinical trial. Before and after rTMS, we measured erythrocyte CA I, II and salivary CA VI, zinc and copper in parotid saliva, blood plasma, and erythrocytes, and appearance of novel salivary proteins by using mass spectrometry. Results: After rTMS, CA I, II and CA VI activity and zinc and copper in saliva, plasma, and erythrocytes increased with significant sensory benefit. Novel salivary proteins were induced at an m/z value of 21.5K with a repetitive pattern at intervals of 5K m/z. Conclusions: rTMS induced biochemical changes in specific enzymatic activities, trace metal concentrations, and induction of novel salivary proteins, with sensory improvement in patients with taste and smell dysfunction. Because patients with several neurologic disorders exhibit taste and smell dysfunction, including Parkinson disease, Alzheimer disease, and multiple sclerosis, and because rTMS improved their clinical symptoms, the biochemical changes we observed may be relevant not only in our patients with taste and smell dysfunction but also in patients with neurologic disorders with these sensory abnormalities. C1 [Henkin, Robert I.; Moharram, Ramy; Velicu, Irina] Taste & Smell Clin, Washington, DC 20016 USA. [Potolicchio, Samuel J.; Levy, Lucien M.] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Moharram, Ramy; Martin, Brian M.] NIMH, NIH, DHHS, Bethesda, MD 20892 USA. RP Henkin, RI (reprint author), Taste & Smell Clin, 5125 MacArthur Blvd NW, Washington, DC 20016 USA. EM doc@tasteandsmell.com FU Intramural NIH HHS [ZIA MH002344-24] NR 202 TC 4 Z9 4 U1 3 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0002-9629 J9 AM J MED SCI JI Am. J. Med. Sci. PD MAR PY 2010 VL 339 IS 3 BP 249 EP 257 DI 10.1097/MAJ.0b013e3181cda0e3 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 567CD UT WOS:000275419000011 PM 20090508 ER PT J AU Zhu, WH Zhu, DS Madan, RA Gulley, JL Figg, WD Dahut, WL AF Zhu, Wenhui Zhu, David S. Madan, Ravi A. Gulley, James L. Figg, William D. Dahut, William L. TI Treatment of Castration-Resistant Prostate Cancer: Updates on Therapeutics Targeting the Androgen Receptor Signaling Pathway SO AMERICAN JOURNAL OF THERAPEUTICS LA English DT Review DE androgen receptor; castration-resistant prostate cancer; MDV3100; abiraterone ID SECONDARY HORMONAL-THERAPY; PHASE-II TRIAL; DEPRIVATION THERAPY; PTEN EXPRESSION; IN-VITRO; INHIBITORS; PROGRESSION; ACTIVATION; MECHANISM; CARCINOMA AB Androgens play a critical role in the progression of castration-resistant prostate cancer through androgen receptor (AR)-regulated signaling pathways. Progress has been made in the development of potent agents designed to suppress androgen function by blocking the AR, inhibiting the synthesis of androgens, or targeting downstream AR signaling pathways. This review summarizes the development of novel therapies based on current insights into AR signaling pathways in castration-resistant prostate cancer. C1 [Zhu, Wenhui; Zhu, David S.; Madan, Ravi A.; Gulley, James L.; Figg, William D.; Dahut, William L.] NCI, Med Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Dahut, WL (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Room 12N226, Bethesda, MD 20892 USA. EM dahutw@mail.nih.gov RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 53 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1075-2765 EI 1536-3686 J9 AM J THER JI Am. J. Ther. PD MAR-APR PY 2010 VL 17 IS 2 BP 176 EP 181 DI 10.1097/MJT.0b013e3181c6c0b2 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 574SX UT WOS:000276014900008 PM 20019584 ER PT J AU Calsyn, DA Cousins, SJ Hatch-Maillette, MA Forcehimes, A Mandler, R Doyle, SR Woody, G AF Calsyn, Donald A. Cousins, Sarah J. Hatch-Maillette, Mary A. Forcehimes, Alyssa Mandler, Raul Doyle, Suzanne R. Woody, George TI Sex under the Influence of Drugs or Alcohol: Common for Men in Substance Abuse Treatment and Associated with High-Risk Sexual Behavior SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID CONDOM USE; SELF-REPORTS; HIV; USERS; METAANALYSIS; DRINKING; PARTNERS AB Sex under the influence of drugs or alcohol is associated with high-risk sexual behavior. Heterosexual men (n = 505) in substance abuse treatment completed a computer-administered interview assessing sexual risk behaviors. Most men (73.3%) endorsed sex under the influence in the prior 90 days, and 39.1% endorsed sex under the influence during their most recent sexual event. Sex under the influence at the most recent event was more likely to involve anal intercourse, sex with a casual partner, and less condom use. Patients might benefit from interventions targeting sexual behavior and substance use as mutual triggers. C1 [Calsyn, Donald A.; Hatch-Maillette, Mary A.; Doyle, Suzanne R.] Univ Washington, Alcohol & Drug Abuse Inst, Seattle, WA 98105 USA. [Calsyn, Donald A.; Hatch-Maillette, Mary A.] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98105 USA. [Cousins, Sarah J.] Univ Calif Los Angeles, Intergrated Subst Abuse Programs, Los Angeles, CA USA. [Forcehimes, Alyssa] Univ New Mexico, Ctr Alcoholism Subst Abuse & Addict, Albuquerque, NM 87131 USA. [Mandler, Raul] NIDA, Ctr Clin Trials Network, Rockville, MD USA. [Woody, George] Univ Penn, Sch Med, Dept Psychiat, Philadelphia, PA 19104 USA. [Woody, George] Treatment Res Inst, Philadelphia, PA USA. RP Calsyn, DA (reprint author), Univ Washington, Alcohol & Drug Abuse Inst, 1107 NE 45th St,Ste 120, Seattle, WA 98105 USA. EM calsyn@u.washington.edu FU NIDA NIH HHS [U10 DA13711, U10 DA13045, U10 DA13043, U10 DA13038, U10 DA013711, U10 DA013045, U10 DA013043, U10 DA013038, U10 DA013727, U10 DA013035, U10 DA013714, U10 DA013714-05, U10 DA013732, U10 DA015815, U10 DA015833, U10 DA13035, U10 DA13714, U10 DA13727, U10 DA13732, U10 DA15815, U10 DA15833] NR 32 TC 13 Z9 13 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD MAR-APR PY 2010 VL 19 IS 2 BP 119 EP 127 DI 10.1111/j.1521-0391.2009.00022.x PG 9 WC Substance Abuse SC Substance Abuse GA 556VJ UT WOS:000274621100003 PM 20163383 ER PT J AU Weiss, RD Potter, JS Copersino, ML Prather, K Jacobs, P Provost, S Chim, D Selzer, J Ling, W AF Weiss, Roger D. Potter, Jennifer S. Copersino, Marc L. Prather, Kristi Jacobs, Petra Provost, Scott Chim, David Selzer, Jeffrey Ling, Walter TI Conducting Clinical Research with Prescription Opioid Dependence: Defining the Population SO AMERICAN JOURNAL ON ADDICTIONS LA English DT Article ID METHADONE-MAINTENANCE TREATMENT; PRIMARY-CARE; HEROIN DEPENDENCE; DRUG-USE; BUPRENORPHINE; USERS; ABUSE AB Most treatment studies of opioid-dependent populations have focused predominantly on heroin users, despite a recent increase in those dependent upon prescription opioids. A key methodological challenge involved in studying the latter group involves defining the population. Specifically, researchers must decide whether to include (1) concurrent heroin users and (2) individuals with pain. The multi-site Prescription Opioid Addiction Treatment Study is examining treatments for this population. This paper describes various inclusion criteria considered by the study team related to heroin use and pain. The goal was to recruit a distinct but generalizable population of individuals dependent upon prescription opioids. C1 [Weiss, Roger D.; Potter, Jennifer S.; Copersino, Marc L.; Provost, Scott] McLean Hosp, Belmont, MA 02478 USA. [Weiss, Roger D.; Potter, Jennifer S.; Copersino, Marc L.; Provost, Scott] Harvard Univ, Sch Med, Dept Psychiat, Belmont, MA 02178 USA. [Potter, Jennifer S.] Univ Texas San Antonio, Dept Psychiat, San Antonio, TX USA. [Prather, Kristi] Duke Univ, Clin Res Inst, Durham, NC USA. [Jacobs, Petra] NIDA, Ctr Clin Trials Network, Rockville, MD USA. [Chim, David; Ling, Walter] Univ Calif Los Angeles, Integrated Subst Abuse Programs, Los Angeles, CA USA. [Selzer, Jeffrey] Long Isl Jewish Med Ctr, Addict Recovery Serv, Long Isl City, NY USA. RP Weiss, RD (reprint author), McLean Hosp, 115 Mill St, Belmont, MA 02478 USA. EM rweiss@mclean.harvard.edu RI Chim, David/E-9855-2010; Potter, Jennifer/C-6720-2008 OI Potter, Jennifer/0000-0002-7250-4422 FU NIDA NIH HHS [K23 DA022297, K24 DA022288, K24 DA022288-03, T32 DA007272, T32 DA07272, U10 DA013035, U10 DA013045, U10 DA015831, U10 DA015831-08, U10 DA13035, U10 DA15831] NR 19 TC 9 Z9 9 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1055-0496 J9 AM J ADDICTION JI Am. J. Addict. PD MAR-APR PY 2010 VL 19 IS 2 BP 141 EP 146 DI 10.1111/j.1521-0391.2009.00017.x PG 6 WC Substance Abuse SC Substance Abuse GA 556VJ UT WOS:000274621100006 PM 20163386 ER PT J AU Yeum, KJ Orioli, M Regazzoni, L Carini, M Rasmussen, H Russell, RM Aldini, G AF Yeum, Kyung-Jin Orioli, Marica Regazzoni, Luca Carini, Marina Rasmussen, Helen Russell, Robert M. Aldini, Giancarlo TI Profiling histidine dipeptides in plasma and urine after ingesting beef, chicken or chicken broth in humans SO AMINO ACIDS LA English DT Article DE Carnosine; Anserine; Histidine-dipeptides; Absorption kinetic; Chicken ID TANDEM MASS-SPECTROMETRY; CONTAINING PEPTIDES; SERUM CARNOSINASE; MICHAEL ADDUCTS; MUSCLE; ANSERINE; TISSUES; HOMOCARNOSINE; CONSTITUENTS; ABSORPTION AB The in vitro metabolic stability of histidine-dipeptides (HD), carnosine (CAR) and anserine (ANS), in human serum, and their absorption kinetics after ingesting pure carnosine or HD rich foods in humans have been investigated. Healthy women (n = 4) went through four phases of taking one dose of either 450 mg of pure carnosine, 150 g beef (B), 150 g chicken (C), or chicken broth (CB) from 150 g chicken with a > 2-week washout period between each phase. Blood samples were collected at 0, 30, 60, 100, 180, 240, and 300 min, and urine samples before and after (up to 7 h) ingesting pure carnosine or food. Both plasma and urine samples were analyzed for HD concentrations using a sensitive and selective LC-ESI-MS/MS method. CAR was undetectable in plasma after ingesting pure carnosine, B, C or CB. By contrast, plasma ANS concentration was significantly increased (P < 0.05) after ingesting C or CB, respectively. Urinary concentrations of both CAR and ANS were 13- to 14-fold increased after ingesting B, and 14.8- and 243-fold after CB ingestion, respectively. Thus, dietary HD, which are rapidly hydrolyzed by carnosinase in plasma, and excreted in urine, may act as reactive carbonyl species sequestering agents. C1 [Yeum, Kyung-Jin; Rasmussen, Helen] Tufts Univ, Jean Mayer USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Orioli, Marica; Regazzoni, Luca; Carini, Marina; Aldini, Giancarlo] Univ Milan, Fac Pharm, Dept Pharmaceut Sci, I-20133 Milan, Italy. [Russell, Robert M.] NIH, Off Director, Washington, DC USA. RP Yeum, KJ (reprint author), Tufts Univ, Jean Mayer USDA, Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM kyungjin.yeum@tufts.edu RI orioli, marica/F-7606-2015; Regazzoni, Luca/D-4212-2014; CARINI, MARINA/D-3084-2015 OI aldini, giancarlo/0000-0002-2355-6744; orioli, marica/0000-0003-1558-9551; Regazzoni, Luca/0000-0001-7199-7141; CARINI, MARINA/0000-0003-3407-5425 FU U. S. Department of Agriculture [581950-9-001] FX This research has been supported by the U. S. Department of Agriculture, under agreement number 581950-9-001. Any opinions, findings, conclusion, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the U. S. Department of Agriculture. NR 35 TC 18 Z9 21 U1 1 U2 19 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0939-4451 J9 AMINO ACIDS JI Amino Acids PD MAR PY 2010 VL 38 IS 3 BP 847 EP 858 DI 10.1007/s00726-009-0291-2 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 569WT UT WOS:000275634200019 PM 19381778 ER PT J AU Johann, DJ Wei, BR Prieto, DA Chan, KC Ye, XY Valera, VA Simpson, RM Rudnick, PA Xiao, Z Issaq, HJ Linehan, WM Stein, SE Veenstra, TD Blonder, J AF Johann, Donald J., Jr. Wei, Bih-Rong Prieto, DaRue A. Chan, King C. Ye, Xiaying Valera, Vladimir A. Simpson, R. Mark Rudnick, Paul A. Xiao, Zhen Issaq, Haleem J. Linehan, W. Marston Stein, Stephen E. Veenstra, Timothy D. Blonder, Josip TI Combined Blood/Tissue Analysis for Cancer Biomarker Discovery: Application to Renal Cell Carcinoma SO ANALYTICAL CHEMISTRY LA English DT Article ID GENE-EXPRESSION; BREAST-CANCER; PROTEOMICS; TUMOR; CADHERIN; COMPLEX AB A method that relies on subtractive tissue-directed shotgun proteomics to identify tumor proteins in the blood of a patient newly diagnosed with cancer is described. To avoid analytical and statistical biases caused by physiologic variability of protein expression in the human population, this method was applied on clinical specimens obtained from a single patient diagnosed with nonmetastatic renal cell carcinoma (RCC). The proteomes extracted from tumor, normal adjacent tissue and preoperative plasma were analyzed using 2D-liquid chromatography-mass spectrometry (LC-MS). The lists of identified proteins were filtered to discover proteins that (i) were found in the tumor but not normal tissue, (ii) were identified in matching plasma, and (iii) whose spectral count was higher in tumor tissue than plasma. These filtering criteria resulted in identification of eight tumor proteins in the blood. Subsequent Western-blot analysis confirmed the presence of cadherin-5, cadherin-11, DEAD-box protein-23, and pyruvate kinase in the blood of the patient in the study as well as in the blood of four other patients diagnosed with RCC. These results demonstrate the utility of a combined blood/tissue analysis strategy that permits the detection of tumor proteins in the blood of a patient diagnosed with RCC. C1 [Prieto, DaRue A.; Chan, King C.; Ye, Xiaying; Xiao, Zhen; Issaq, Haleem J.; Veenstra, Timothy D.; Blonder, Josip] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Johann, Donald J., Jr.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Wei, Bih-Rong; Simpson, R. Mark] NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. [Valera, Vladimir A.; Linehan, W. Marston] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Rudnick, Paul A.; Stein, Stephen E.] Natl Inst Stand & Technol, NIST Mass Spectrometry Data Ctr, Gaithersburg, MD 20899 USA. RP Blonder, J (reprint author), NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, POB B, Frederick, MD 21702 USA. EM blonderj@mail.nih.gov FU National Cancer Institute; National Institutes of Health [N01-CO-12400] FX The authors declare that they have no competing financial interests, This project has been funded in whole or in part with federal funds front the National Cancer Institute, National Institutes of Health, under Contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services nor does mention of trade names, commercial products, or organizations imply endorsement by the United States Government. NR 25 TC 21 Z9 22 U1 2 U2 6 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 MAR 1 PY 2010 VL 82 IS 5 BP 1584 EP 1588 DI 10.1021/ac902204k PG 5 WC Chemistry, Analytical SC Chemistry GA 559QN UT WOS:000274841300005 PM 20121140 ER PT J AU Tuleuova, N Jones, CN Yan, J Ramanculov, E Yokobayashi, Y Revzin, A AF Tuleuova, Nazgul Jones, Caroline N. Yan, Jun Ramanculov, Erlan Yokobayashi, Yohei Revzin, Alexander TI Development of an Aptamer Beacon for Detection of Interferon-Gamma SO ANALYTICAL CHEMISTRY LA English DT Article ID ELECTROCHEMICAL DETECTION; PROTEIN; FLUORESCENCE; BINDING; IMMOBILIZATION; QUANTITATION; MICROARRAYS; MOLECULES; SWITCH; CELLS AB Traditional antibody-based affinity sensing strategies employ multiple reagents and washing steps and are unsuitable for real-time detection of analyte binding. Aptamers, on the other hand, may be designed to monitor binding events directly, in real-time, without the need for secondary labels. The goal of the present study was to design ail aptamer beacon for fluorescence resonance energy transfer (FRET)based detection of interferon-gamma (IFN-gamma)-an important inflammatory cytokine. Variants of DNA aptamer modified with biotin moieties and spacers were immobilized oil avidin-coated surfaces and characterized by surface plasmon resonance (SPR). The SPR studies showed that immobilization of aptamer via the 3' end resulted in the best binding IFN-gamma (K(d) = 3.44 nM). This optimal aptamer variant was then used to construct a beacon by hybridizing fluorophore-labeled aptamer with an antisense oligonucleotide strand carrying a quencher. SPR studies revealed that IFN-gamma binding with an aptamer beacon occurred within 15 min of analyte introduction-suggesting dynamic replacement of the quencher-complementary strand by IFN-gamma molecules. To further highlight biosensing applications, aptamer beacon molecules were immobilized inside microfluidic channels and challenged with varying concentration of analyte. Fluorescence microscopy revealed low fluorescence in the absence of analyte and high fluorescence after introduction of IFN-gamma. Importantly, unlike traditional antibody-based immunoassays, tire signal was observed directly upon binding of analyte without the need for multiple washing steps. The surface immobilized aptamer beacon had a linear range from 5 to 100 nM and a lower limit of detection of 5 nM IFN-gamma. In conclusion, we designed a FRET-based aptamer beacon for monitoring of an inflammatory cytokine-IFN-gamma. In the future, this biosensing strategy will be employed to monitor dynamics of cytokine production by the immune cells. C1 [Tuleuova, Nazgul; Jones, Caroline N.; Yan, Jun; Yokobayashi, Yohei; Revzin, Alexander] Univ Calif Davis, Dept Biomed Engn, Davis, CA 95616 USA. [Tuleuova, Nazgul; Ramanculov, Erlan] Natl Biotechnol Ctr, Astana, Kazakhstan. RP Revzin, A (reprint author), Univ Calif Davis, Dept Biomed Engn, 451 E Hlth Sci Dr 2519, Davis, CA 95616 USA. EM arevzin@ucdavis.edu RI Yokobayashi, Yohei/B-5898-2009; Yan, Jun/E-8783-2012; Ramanculov, Erlan/E-2823-2013 OI Yokobayashi, Yohei/0000-0002-2417-1934; FU National Center for Biotechnology, Republic of Kazakhstan; NSF EFRI FX We thank Prof. Laura Marcu and Dr. Yinghua Sun in the Department of Biomedical Engineering at UC Davis for use of fluorescence microscope. NT was supported by a fellowship from the National Center for Biotechnology, Republic of Kazakhstan. These studies were supported by an NSF EFRI grant awarded to AR. NR 35 TC 73 Z9 75 U1 4 U2 78 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 MAR 1 PY 2010 VL 82 IS 5 BP 1851 EP 1857 DI 10.1021/ac9025237 PG 7 WC Chemistry, Analytical SC Chemistry GA 559QN UT WOS:000274841300043 PM 20121141 ER PT J AU Mehrotra, N Freire, AX Bauer, DC Harris, TB Newman, AB Kritchevsky, SB Meibohm, B AF Mehrotra, Nitin Freire, Amado X. Bauer, Douglas C. Harris, Tamara B. Newman, Anne B. Kritchevsky, Stephen B. Meibohm, Bernd TI Predictors of Mortality in Elderly Subjects with Obstructive Airway Disease: The PILE Score SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE Obstructive Airway Disease; Mortality; Elderly; Interleukin-6; Cox Proportional Hazards Modeling ID C-REACTIVE PROTEIN; PERIPHERAL MUSCLE WEAKNESS; PULMONARY-DISEASE; LUNG-FUNCTION; HEALTH ABC; SYSTEMIC INFLAMMATION; RESPIRATORY SYMPTOMS; EXERCISE CAPACITY; SKELETAL-MUSCLE; COPD PATIENTS AB PURPOSE: To identify significant covariates in addition to spirometry that predict mortality in elderly subjects with obstructive airway disease (OAD). METHODS: Two hundred sixty-eight (268) participants with OAD from the Health, Aging and Body Composition study, a community-based observational cohort of well-functioning elderly aged 70-79 years, were followed on average for 6.1 years. Covariates related to pulmonary and physical function, comorbidity, demographics, and three inflammatory markers (interleukin-6, tumor necrosis factor-alpha, C-reactive protein) were evaluated for their association with all-cause mortality (31%) by means of Kaplan Meier analysis and Cox proportional hazards modeling. RESULTS: Percent predicted forced expiratory volume in one second (PPFEV1; hazard ratio [HR] = 2.03, p < 0.0001). knee extensor strength (HR = 1.36, p = 0.0002), interleukin-6 (HR = 1.37, p = 0.0002) and 400 m corridor walk time (HR = 1.24, p = 0.008) significantly predicted mortality. A multidimensional index, the PILE score, was constructed from PPFEV(1), interleukin-6, and knee extensor strength. Each one-point increase in PILE score (range: 1-10) was associated with a 30% increase in mortality (95% confidence interval: 0.16-0.47) after adjusting for age, race, gender, smoking, and comorbidity, resulting in a 10.4-fold higher risk of death between the highest and lowest risk category. CONCLUSIONS: Subjects with OAD have a wide gradient of risk for mortality that can potentially he incorporated in clinical decision making. Ann Epidemiol 2010;20:223-232. (C) 2010 Elsevier Inc. All rights reserved, C1 [Meibohm, Bernd] Univ Tennessee, Hlth Sci Ctr, Dept Pharmaceut Sci, Coll Pharm, Memphis, TN 38163 USA. [Freire, Amado X.] Univ Tennessee, Hlth Sci Ctr, Dept Med, Memphis, TN 38163 USA. [Bauer, Douglas C.] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol & Med, Pittsburgh, PA USA. [Kritchevsky, Stephen B.] Wake Forest Univ, Sticht Ctr Aging, Winston Salem, NC 27109 USA. RP Meibohm, B (reprint author), Univ Tennessee, Hlth Sci Ctr, Dept Pharmaceut Sci, Coll Pharm, 874 Union Ave,Suite 5P, Memphis, TN 38163 USA. EM bmeibohm@utmem.edu RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Freire, Amado/0000-0001-7500-8291; Kritchevsky, Stephen/0000-0003-3336-6781 FU National Institutes of Health [R01-HL-074104, N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106]; National Institute on Aging FX This work was supported by research grants and contracts R01-HL-074104, N01-AG-6-2101, N01-AG-6-2103, and N01-AG-6-2106 by the National Institutes of Health. This research, was also supported in part by the Intramural Research Program of the NIH, National Institute On Aging. NR 52 TC 17 Z9 17 U1 2 U2 4 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 MAR PY 2010 VL 20 IS 3 BP 223 EP 232 DI 10.1016/j.annepidem.2009.11.005 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 584MZ UT WOS:000276757700007 PM 20159492 ER PT J AU Hopping, SB Joshi, AS Tanna, N Janjanin, S AF Hopping, Steven B. Joshi, Arjun S. Tanna, Neil Janjanin, Sasa TI Volumetric Facelift: Evaluation of Rhytidectomy With Alloplastic Augmentation SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE aging; alloplast; face; facelift; implant; rhytidectomy ID SURGERY; COMPLICATIONS AB Objectives: Facial aging occurs as a result of soft tissue atrophy and resorption of the bony skeleton which results in a loss of soft tissue volume and laxity of the overlying skin Volumetric augmentation is a key component of facial rejuvenation surgery, and should be considered of equal importance to soft tissue lining Augmentation can be accomplished with synthetic fillers. autologous grafts, soft tissue repositioning techniques, and/or alloplastic implants Only alloplastic implants. however, provide truly long-term volumetric correction To date. there have been no large series dealing with the complications and results of implantation performed concurrently with rhytidectomy. which we have termed-volumetric rhytidectomy We present our experience with 100 patients treated with a combination of malar and chin implants and rhytidectomy. compared to 200 patients who underwent rhytidectomy alone Methods: The authors performed a retrospective review of patients treated with a combination of silicone malar and chin augmentation with rhytidectomy versus patients treated with rhytidectomy alone Both groups of patients underwent close postoperative evaluation at 3 days. 1 week, 2 weeks, and 1 month All patients were surveyed at 6 months to assess aesthetic satisfaction Complication rates were noted and tabulated Statistical analysis was performed to evaluate for any differences in the two groups Results: Between 2002 and 2006, 100 patients underwent malar and chin implantation along with rhytidectomy, 200 patients underwent rhytidectomy alone In the first group, there were a total of 6 cases in which implant removal was necessary, and 2 cases m which revision was required There were no statistically significant differences (p<0 05) observed between the two groups with respect to major or minor hematoma, seroma, infection, sensory nerve injury, facial nerve injury. hypertrophic scarring. dehiscence. skin sloughing. or revision. Conclusions: Volumetric rhytidectomy reliably augments the malar and mental areas, allows for subtle skeletal contouring. and results in successful rejuvenation Rhytidectomy is relatively safe to perform concurrently with silicone augmentation. and does not result in an increased complication rate as compared to rhytidectomy alone C1 [Hopping, Steven B.] George Washington Univ, Ctr Cosmet Surg, Washington, DC 20037 USA. [Hopping, Steven B.; Joshi, Arjun S.; Tanna, Neil] George Washington Univ, Div Otolaryngol Head & Neck Surg, Washington, DC 20037 USA. [Tanna, Neil] Univ Calif Los Angeles, Div Plast Surg, Los Angeles, CA USA. [Janjanin, Sasa] NIAMSD, NIH, Bethesda, MD 20892 USA. RP Hopping, SB (reprint author), George Washington Univ, Ctr Cosmet Surg, 2440 M St NW,Suite 205, Washington, DC 20037 USA. NR 18 TC 10 Z9 10 U1 0 U2 0 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD MAR PY 2010 VL 119 IS 3 BP 174 EP 180 PG 7 WC Otorhinolaryngology SC Otorhinolaryngology GA 580BH UT WOS:000276421300005 PM 20392030 ER PT J AU Merion, RM Shearon, TH Berg, CL Everhart, JE Abecassis, MM Shaked, A Fisher, RA Trotter, JF Brown, RS Terrault, NA Hayashi, PH Hong, JC AF Merion, Robert M. Shearon, Tempie H. Berg, Carl L. Everhart, James E. Abecassis, Michael M. Shaked, Abraham Fisher, Robert A. Trotter, James F. Brown, Robert S., Jr. Terrault, Norah A. Hayashi, Paul H. Hong, Johnny C. CA A2ALL Study Grp TI Hospitalization Rates Before and After Adult-to-Adult Living Donor or Deceased Donor Liver Transplantation SO ANNALS OF SURGERY LA English DT Article ID BILIARY COMPLICATIONS; RESOURCE UTILIZATION; BILE-DUCT; RECONSTRUCTION; RECIPIENTS; CIRRHOSIS; OUTCOMES; A2ALL; STRICTURES; COHORT AB Objective: To compare rates of hospitalization before and after adult-to-adult living donor liver transplant (LDLT) and deceased donor liver transplant (DDLT). Summary Background Data: LDLT recipients have been reported to have lower mortality but a higher complication rate than DDLT recipients. The higher complication rate may be associated with greater consumption of inpatient hospital resources and a higher burden of disease for LDLT recipients. Methods: Data from the 9-center Adult-to-Adult Living Donor Liver Transplantation retrospective cohort study were analyzed to determine pretransplant, transplant, and posttransplant hospitalizations among LDLT candidates (potential living donor was evaluated) who received LDLT or DDLT. Hospital days and admission rates for LDLT and DDLT patients were calculated per patient-year at risk, starting from the date of initial potential donor history and physical examination. Rates were compared using over-dispersed Poisson regression models. Results: Among 806 candidates, 384 received LDLT and 215 received DDLT. In addition to the 599 transplants, there were 1913 recipient hospitalizations (485 pretransplant; 1428 posttransplant). Mean DDLT recipient pretransplant, transplant, and posttransplant lengths of stay were 5.8 +/- 6.3, 27.0 +/- 32.6, and 9.0 +/- 14.1 days, respectively, and for LDLT were 4.1 +/- 3.7, 21.4 +/- 24.3, and 7.8 +/- 11.4 days, respectively. Compared with DDLT, LDLT recipients had significantly lower adjusted pretransplant hospital day and admission rates, but significantly higher posttransplant rates. Significantly higher LDLT admission rates were observed for biliary tract morbidity throughout the second posttransplant year. Overall hospitalization rates starting from the point of potential donor evaluation were significantly higher for eventual recipients of LDLT. Conclusions: LDLT recipients, despite lower acuity of disease, have higher hospitalization requirements when compared with DDLT recipients. Continuing efforts are warranted to reduce the incidence of complications requiring post-LDLT inpatient admission, with particular emphasis on biliary tract issues. C1 [Merion, Robert M.] Univ Michigan, Dept Surg, Ann Arbor, MI 48103 USA. [Shearon, Tempie H.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48103 USA. [Berg, Carl L.] Univ Virginia, Dept Med, Charlottesville, VA USA. [Everhart, James E.] NIDDKD, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. [Abecassis, Michael M.] Northwestern Univ, Dept Surg, Chicago, IL 60611 USA. [Shaked, Abraham] Univ Penn, Dept Surg, Philadelphia, PA 19104 USA. [Fisher, Robert A.] Virginia Commonwealth Univ, Med Coll Virginia, Dept Surg, Richmond, VA 23298 USA. [Trotter, James F.] Univ Colorado, Dept Surg, Aurora, CO USA. [Brown, Robert S., Jr.] Columbia Univ Coll Phys & Surg, Dept Med, New York, NY 10032 USA. [Terrault, Norah A.] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Hayashi, Paul H.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Hong, Johnny C.] Univ Calif Los Angeles, Dept Surg, Los Angeles, CA 90024 USA. RP Merion, RM (reprint author), Univ Michigan, Dept Surg, 315 W Huron,Suite 240, Ann Arbor, MI 48103 USA. EM merionb@umich.edu RI Abecassis, Michael/F-7977-2011 FU National Institutes of Health (NIDDK) [U01-DK62536, U01-DK62444, U01-DK62467, U01-DK62483, U01-DK62484, U01-DK62494, U01-DK62496, U01-DK62498, U01-DK62505, U01-DK62531]; American Society of Transplant Surgeons; US Department of Health and Human Services, Health Resources and Services Administration FX Supported in part by the National Institutes of Health (NIDDK grant numbers U01-DK62536, U01-DK62444, U01-DK62467, U01-DK62483, U01-DK62484, U01-DK62494, U01-DK62496, U01-DK62498, U01-DK62505, U01-DK62531), the American Society of Transplant Surgeons, and the US Department of Health and Human Services, Health Resources and Services Administration. NR 20 TC 16 Z9 16 U1 0 U2 2 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 MAR PY 2010 VL 251 IS 3 BP 542 EP 549 DI 10.1097/SLA.0b013e3181ccb370 PG 8 WC Surgery SC Surgery GA 562OD UT WOS:000275060800025 PM 20130466 ER PT J AU Sharma, S Gao, P Steele, VE AF Sharma, Sheela Gao, Pu Steele, Vernon E. TI Quantitative Morphometry of Respiratory Tract Epithelial Cells as a Tool for Testing Chemopreventive Agent Efficacy SO ANTICANCER RESEARCH LA English DT Article DE Nuclear density; morphometry; chemopreventive agents; rat tracheal epithelial cells ID MALE F344 RATS; FUMARIC-ACID; COLON CARCINOGENESIS; IN-VITRO; OLTIPRAZ; HEPATOCARCINOGENESIS; TRANSFORMATION; AZOXYMETHANE; INHIBITION; MICE AB Previously, we developed a 30-day transformation assay (focus inhibition, FIA) of rat tracheal epithelial (RTE) cells to identify cancer preventive agents. This study reports nuclear density (ND) as a morphometric biomarker for efficacy evaluation of at an early stage before transformed foci appear. Positive (oltipraz, D-carvone, fumaric acid, and 2-amino-4-methylpyridine or 2-A-MPR) and negative agents (myristoleic acid, anethole trithione, hydrocortisone, and 3'-hydro-xyflavanone), identified from FIA, were tested for their effect on ND. RTE cells plated for 24 h were treated with a carcinogen, benzo[a] pyrene (B[c]P) or plus a test agent. The data based on the number of nuclei in agent-treated and control cells at day 14 showed that all FIA-positive agents inhibited ND from 23-66% at 0.3-1000.0 mu M and except for myristoleic acid, all of the FIA-negative compounds were also negative in the morphometty assay. As there is strong correlation between the FIA and morphometry data, morphometry analysis is useful for rapid screening of potential chemopreventive agents. C1 [Sharma, Sheela; Gao, Pu] Alion Sci & Technol Inc, Cellular & Mol Toxicol Program, Res Triangle Pk, NC 27709 USA. [Steele, Vernon E.] NCI, Chemoprevent Agent Dev Res Grp, NIH, Bethesda, MD 20892 USA. RP Sharma, S (reprint author), Hamner Inst Hlth Sci, Div Toxicol & Preclin Studies, POB 12137, Res Triangle Pk, NC 27709 USA. EM ssharma@thehamner.org FU National Cancer Institute [N01-CN-43301] FX This study was supported by funds from the National Cancer Institute (N01-CN-43301), U.S.A. NR 30 TC 0 Z9 1 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD MAR PY 2010 VL 30 IS 3 BP 737 EP 742 PG 6 WC Oncology SC Oncology GA 581YH UT WOS:000276561300005 PM 20392991 ER PT J AU Fabrega, A Martin, RG Rosner, JL Tavio, MM Vila, J AF Fabrega, Anna Martin, Robert G. Rosner, Judah L. Tavio, M. Mar Vila, Jordi TI Constitutive SoxS Expression in a Fluoroquinolone-Resistant Strain with a Truncated SoxR Protein and Identification of a New Member of the marA-soxS-rob Regulon, mdtG SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID MULTIPLE-ANTIBIOTIC-RESISTANCE; ESCHERICHIA-COLI STRAINS; MEDIATED QUINOLONE RESISTANCE; URINARY-TRACT-INFECTIONS; ACRAB EFFLUX PUMP; TRANSCRIPTIONAL ACTIVATOR; CIPROFLOXACIN RESISTANCE; REGULATORY PROTEIN; MUTATIONS; GENES AB Elevated levels of fluoroquinolone resistance are frequently found among Escherichia coli clinical isolates. This study investigated the antibiotic resistance mechanisms of strain NorE5, derived in vitro by exposing an E. coli clinical isolate, PS5, to two selection steps with increasing concentrations of norfloxacin. In addition to the amino acid substitution in GyrA (S83L) present in PS5, NorE5 has an amino acid change in ParC (S80R). Furthermore, we now find by Western blotting that NorE5 has a multidrug resistance phenotype resulting from the overexpression of the antibiotic resistance efflux pump AcrAB-TolC. Microarray and gene fusion analyses revealed significantly increased expression in NorE5 of soxS, a transcriptional activator of acrAB and tolC. The high soxS activity is attributable to a frameshift mutation that truncates SoxR, rendering it a constitutive transcriptional activator of soxS. Furthermore, microarray and reverse transcription-PCR analyses showed that mdtG (yceE), encoding a putative efflux pump, is overexpressed in the resistant strain. SoxS, MarA, and Rob activated an mdtG::lacZ fusion, and SoxS was shown to bind to the mdtG promoter, showing that mdtG is a member of the marA-soxS-rob regulon. The mdtG marbox sequence is in the backward or class I orientation within the promoter, and its disruption resulted in a loss of inducibility by MarA, SoxS, and Rob. Thus, chromosomal mutations in parC and soxR are responsible for the increased antibiotic resistance of NorE5. C1 [Vila, Jordi] Univ Barcelona, Microbiol Serv, Ctr Diagnost Biomed, Hosp Clin,Fac Med,Dept Microbiol,Sch Med, E-08036 Barcelona, Spain. [Tavio, M. Mar] Univ Las Palmas Gran Canaria, Sch Hlth Sci, Las Palmas Gran Canaria 35016, Spain. [Martin, Robert G.; Rosner, Judah L.] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Vila, J (reprint author), Univ Barcelona, Microbiol Serv, Ctr Diagnost Biomed, Hosp Clin,Fac Med,Dept Microbiol,Sch Med, Villarroel 170, E-08036 Barcelona, Spain. EM jvila@ub.edu RI Vila, Jordi/P-3613-2016; OI Vila, Jordi/0000-0002-8025-3926; Fabrega-Santamaria, Anna/0000-0002-3866-2291 FU Spanish Ministry of Health [FIS 05/0068]; Departament d'Universitats, Recerca i Societat de la Informacio de la Generalitat de Catalunya; Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases [REIPI RE06/0008]; European Community [HEALTH-F3-2008-223031] FX This study has been supported by the Spanish Ministry of Health (FIS 05/0068), by 2009 SGR 1256 from the Departament d'Universitats, Recerca i Societat de la Informacio de la Generalitat de Catalunya, and by the Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI RE06/0008). This work has also been supported by funding from the European Community (TROCAR contract HEALTH-F3-2008-223031). NR 49 TC 13 Z9 16 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2010 VL 54 IS 3 BP 1218 EP 1225 DI 10.1128/AAC.00944-09 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 558HY UT WOS:000274733300035 PM 20008776 ER PT J AU Pyrgos, V Mickiene, D Sein, T Cotton, M Fransesconi, A Mizrahi, I Donoghue, M Bundrant, N Kim, SY Hardwick, M Shoham, S Walsh, TJ AF Pyrgos, Vasilios Mickiene, Diane Sein, Tin Cotton, Margaret Fransesconi, Andrea Mizrahi, Isaac Donoghue, Martha Bundrant, Nikkida Kim, Su-Young Hardwick, Matthew Shoham, Shmuel Walsh, Thomas J. TI Effects of Immunomodulatory and Organism-Associated Molecules on the Permeability of an In Vitro Blood-Brain Barrier Model to Amphotericin B and Fluconazole SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; CEREBROSPINAL-FLUID; FUNGAL-INFECTIONS; STEADY-STATE; PHARMACOKINETICS; PENETRATION; SERUM; EFFICACY; DISEASE; HUMANS AB Amphotericin B (AMB) is used to treat fungal infections of the central nervous system (CNS). However, AMB shows poor penetration into the CNS and little is known about the factors affecting its permeation through the blood-brain barrier (BBB). Therefore, we studied immunomodulatory and organism-associated molecules affecting the permeability of an in vitro BBB model to AMB. We examined the effects of interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), lipopolysaccharide (LPS), lipoteichoic acid (LTA), zymosan (ZYM), dexamethasone (DEX), cyclosporine, and tacrolimus on transendothelial electrical resistance (TEER); endothelial tight junctions; filamentous actin; and permeability to deoxycholate AMB (DAMB), liposomal AMB (LAMB), and fluconazole. Proinflammatory cytokines and organism-associated molecules significantly decreased the mean TEER by 40.7 to 100% (P <= 0.004). DEX increased the mean TEER by 18.2 to 26.4% (P <= 0.04). TNF-alpha and LPS increased the permeability to AMB by 8.2 to 14.5% compared to that for the controls (1.1 to 2.4%) (P <= 0.04). None of the other molecules affected the model's permeability to AMB. By comparison, the BBB model's permeability to fluconazole was > 78% under all conditions studied, without significant differences between the controls and the experimental groups. LPS and TNF-alpha decreased tight-junction protein zona occludens 1 (ZO-1) between endothelial cells. In conclusion, IL-1 beta, ZYM, and LTA increased the permeability of the BBB to small ions but not to AMB, whereas TNF-alpha and LPS, which disrupted the endothelial layer integrity, increased the permeability to AMB. C1 [Pyrgos, Vasilios; Mickiene, Diane; Sein, Tin; Cotton, Margaret; Fransesconi, Andrea; Donoghue, Martha; Bundrant, Nikkida; Walsh, Thomas J.] NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Mizrahi, Isaac; Hardwick, Matthew; Shoham, Shmuel] Washington Hosp Ctr, Infect Dis Sect, Washington, DC 20010 USA. [Donoghue, Martha] Childrens Natl Med Ctr, Dept Hematol Oncol, Washington, DC 20010 USA. [Hardwick, Matthew; Shoham, Shmuel] MedStar Hlth, MedStar Res Inst, Hyattsville, MD USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10,Room 13N-240, Bethesda, MD 20892 USA. EM thomaswalshmd@gmail.com FU National Cancer Institute FX The research was funded by the intramural program of the National Cancer Institute. NR 20 TC 7 Z9 7 U1 0 U2 6 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2010 VL 54 IS 3 BP 1305 EP 1310 DI 10.1128/AAC.01263-09 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 558HY UT WOS:000274733300047 PM 19995929 ER PT J AU Wang, GS Watson, KM Peterkofsky, A Buckheit, RW AF Wang, Guangshun Watson, Karen M. Peterkofsky, Alan Buckheit, Robert W., Jr. TI Identification of Novel Human Immunodeficiency Virus Type 1-Inhibitory Peptides Based on the Antimicrobial Peptide Database SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID HIV; MICROBICIDES; REPLICATION; INHIBIT; AGENTS; ASSAY AB To identify novel anti-HIV-1 peptides based on the antimicrobial peptide database (APD; http://aps.unmc.edu/AP/main.php), we have screened 30 candidates and found 11 peptides with 50% effective concentrations (EC(50)) of < 10 mu M and therapeutic indices (TI) of up to 17. Furthermore, among the eight peptides ( with identical amino acid compositions but different sequences) generated by shuffling the sequence of an aurein 1.2 analog, two had a TI twice that of the original sequence. Because antiviral peptides in the database have an arginine/lysine (R/K) ratio of >1, increases in the Arg contents of amphibian maximin H5 and dermaseptin S9 peptides and the database-derived GLK-19 peptide improved the TIs. These examples demonstrate that the APD is a rich resource and a useful tool for developing novel HIV-1-inhibitory peptides. C1 [Wang, Guangshun] Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. [Watson, Karen M.; Buckheit, Robert W., Jr.] ImQuest BioSci Inc, Frederick, MD 21704 USA. [Peterkofsky, Alan] NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, GS (reprint author), Univ Nebraska Med Ctr, Eppley Canc Inst, Room ECI 3018,986805 Nebraska Med Ctr, Omaha, NE 68198 USA. EM gwang@unmc.edu FU UNEMED; Nebraska Medical Center; NHLBI FX This study was financially supported by funds from UNEMED and the Eppley Institute of the University of Nebraska Medical Center (to G.W.) and, in part, by intramural funds from the NHLBI (to A.P.). NR 23 TC 43 Z9 45 U1 1 U2 9 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAR PY 2010 VL 54 IS 3 BP 1343 EP 1346 DI 10.1128/AAC.01448-09 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 558HY UT WOS:000274733300056 PM 20086159 ER PT J AU Ishizuya-Oka, A Hasebe, T Shi, YB AF Ishizuya-Oka, Atsuko Hasebe, Takashi Shi, Yun-Bo TI Apoptosis in amphibian organs during metamorphosis SO APOPTOSIS LA English DT Article DE Amphibian metamorphosis; Apoptosis; Thyroid hormone; Organ remodeling; Cell-ECM interactions ID THYROID-HORMONE-RECEPTOR; PROGRAMMED CELL-DEATH; XENOPUS-LAEVIS TADPOLES; MATRIX-METALLOPROTEINASE STROMELYSIN-3; GENE-EXPRESSION PROGRAM; ANURAN LARVAL SKIN; DUPLICATED MATRIX-METALLOPROTEINASE-9 GENES; INTESTINAL EPITHELIAL-CELLS; DEPENDENT TAIL REGRESSION; MESENCEPHALIC 5TH NUCLEUS AB During amphibian metamorphosis, the larval tissues/organs rapidly degenerate to adapt from the aquatic to the terrestrial life. At the cellular level, a large quantity of apoptosis occurs in a spatiotemporally-regulated fashion in different organs to ensure timely removal of larval organs/tissues and the development of adult ones for the survival of the individuals. Thus, amphibian metamorphosis provides us a good opportunity to understand the mechanisms regulating apoptosis. To investigate this process at the molecular level, a number of thyroid hormone (TH) response genes have been isolated from several organs of Xenopus laevis tadpoles and their expression and functional analyses are now in progress using modern molecular and genetic technologies. In this review, we will first summarize when and where apoptosis occurs in typical larva-specific and larval-to-adult remodeling amphibian organs to highlight that the timing of apoptosis is different in different tissues/organs, even though all are induced by the same circulating TH. Next, to discuss how TH spatiotemporally regulates the apoptosis, we will focus on apoptosis of the X. laevis small intestine, one of the best characterized remodeling organs. Functional studies of TH response genes using transgenic frogs and culture techniques have shown that apoptosis of larval epithelial cells can be induced by TH either cell-autonomously or indirectly through interactions with extracellular matrix (ECM) components of the underlying basal lamina. Here, we propose that multiple intra- and extracellular apoptotic pathways are coordinately controlled by TH to ensure massive but well-organized apoptosis, which is essential for the proper progression of amphibian metamorphosis. C1 [Ishizuya-Oka, Atsuko; Hasebe, Takashi] Nippon Med Sch, Dept Biol, Kawasaki Ku, Kanagawa 2110063, Japan. [Shi, Yun-Bo] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Ishizuya-Oka, A (reprint author), Nippon Med Sch, Dept Biol, Kawasaki Ku, Kanagawa 2110063, Japan. EM a-oka@nms.ac.jp; shi@helix.nih.gov FU JSPS [20570060]; Intramural Research Program of NICHD; NIH FX This work was supported in part by the JSPS Grants-in-Aid for Scientific Research (C) (Grant number 20570060 to A.I.-O.) and in part by the Intramural Research Program of NICHD, NIH. NR 153 TC 28 Z9 30 U1 0 U2 12 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1360-8185 J9 APOPTOSIS JI Apoptosis PD MAR PY 2010 VL 15 IS 3 SI SI BP 350 EP 364 DI 10.1007/s10495-009-0422-y PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 567EG UT WOS:000275425400010 PM 20238476 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 BCL6, MUM1, and CD10 Expression in Mantle Cell Lymphoma SO APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY LA English DT Article DE malignant lymphoma; mantle cell lymphoma; BCL-6; CD10; MUM1; immunohistochemistry; t(11;14); FISH ID V-H GENES; MUM1/IRF4 EXPRESSION; ABERRANT EXPRESSION; TISSUE MICROARRAY; MULTIPLE-MYELOMA; CD5; HETEROGENEITY; REARRANGEMENT; HISTOGENESIS; MUTATIONS AB Mantle cell lymphoma (MCL) characteristically express CD20, CD5, and cyclin-D1, carries the translocation t(11; 14) (q13; q32) and typically has no expression of germinal center cell markers. So-called aberrant phenotypes such as CD5 negative and cyclin-D1-negative MCL have been described. Also few cases with CD10 and/or BCL-6 protein expression have been reported. We analyzed 127 MCL looking for the frequency of aberrant immunophenotype, CD10, BCL-6, and MUM1 expression. All cases were CD20 and cyclin-D1 positive, 96% expressed CD5, and 98% showed the t(11; 14). BCL-6 expression was observed in 12% of the cases and MUM1 in 35%. No one case showed CD10 positivity in 30% or more neoplastic cells. Only 3 cases showed 10% to 20% of tumoral cells positive for CD10. MUM1 expression was observed in 67% of the BCL-6 positive cases. Thirty-two percent of the cases showed a MUM1+/BCL-6-/CD10- phenotype and 56% had a triple-negative-pattern. Aberrant phenotype is infrequent but not rare, and does not rule out a diagnosis of MCL in an otherwise typical case. C1 [Gualco, Gabriela; Bacchi, Carlos E.] Consultoria Patol, BR-18602010 Botucatu, SP, Brazil. [Harrington, William J., Jr.] Univ Miami, Miller Sch Med, Miami, FL 33136 USA. [Harrington, William J., Jr.] Fogarty Int Ctr, Sylvester Canc Ctr, AIDS & TB Program, Miami, FL USA. [Weiss, Lawrence M.] City Hope Natl Med Ctr, Div Pathol, Duarte, CA 91010 USA. RP Bacchi, CE (reprint author), Consultoria Patol, Rua Major Leonidas 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.). No conflict of interest to declare. NR 35 TC 17 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-3345 J9 APPL IMMUNOHISTO M M JI Appl. Immunohistochem. PD MAR PY 2010 VL 18 IS 2 BP 103 EP 108 DI 10.1097/PAI.0b013e3181bb9edf PG 6 WC Anatomy & Morphology; Medical Laboratory Technology; Pathology SC Anatomy & Morphology; Medical Laboratory Technology; Pathology GA 563UI UT WOS:000275160000001 PM 19826251 ER PT J AU Diskin, B Thomas, JL AF Diskin, Boris Thomas, James L. TI Notes on accuracy of finite-volume discretization schemes on irregular grids SO APPLIED NUMERICAL MATHEMATICS LA English DT Article DE Irregular grids; Accuracy analysis; Truncation error; Discretization error ID DIFFERENCE SCHEMES; SUPRACONVERGENCE; CONVERGENCE; MESHES AB These notes rebut some overreaching conclusions of Svard et al., 2008 [19] concerning relations between truncation and discretization errors on irregular grids. Convergence of truncation errors severely degrades on general irregular grids. Such degradation does not necessarily imply a less than design-order convergence of discretization errors. (C) 2009 IMACS. Published by Elsevier B.V. All rights reserved. C1 [Diskin, Boris] NIA, Hampton, VA 23681 USA. [Diskin, Boris] Univ Virginia, Dept Mech & Aerosp Engn, Charlottesville, VA 22902 USA. [Thomas, James L.] NASA, Computat Aerosci Branch, Langley Res Ctr, Hampton, VA 23681 USA. RP Diskin, B (reprint author), NIA, 100 Explorat Way, Hampton, VA 23681 USA. EM bdiskin@nianet.org; James.L.Thomas@nasa.gov NR 22 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-9274 EI 1873-5460 J9 APPL NUMER MATH JI Appl. Numer. Math. PD MAR PY 2010 VL 60 IS 3 BP 224 EP 226 DI 10.1016/j.apnum.2009.12.001 PG 3 WC Mathematics, Applied SC Mathematics GA 585PP UT WOS:000276839200005 ER PT J AU Iwamoto, FM Fine, HA AF Iwamoto, Fabio M. Fine, Howard A. TI Bevacizumab for Malignant Gliomas SO ARCHIVES OF NEUROLOGY LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; ANTI-ANGIOGENIC THERAPY; RECURRENT GLIOBLASTOMA; PLUS IRINOTECAN; END-POINT; SURVIVAL; TUMORS; PROGRESSION; PHASE-2; ADULTS AB Malignant gliomas are the most common and aggressive primary brain tumors in adults. Despite optimal treatment with surgery, radiotherapy, and temozolomide, tumor recurrences are frequent and patients with malignant gliomas continue to have poor prognoses. Malignant gliomas are often highly vascularized, and significant advances have been made in the last few decades in our understanding of the mechanisms of tumor angiogenesis. Recently, bevacizumab, an antibody against vascular endothelial growth factor, has demonstrated significant activity in recurrent glioblastomas, resulting in US Food and Drug Administration approval and raising the prospect for other antiangiogenic drugs now entering clinical trials. Arch Neurol. 2010; 67(3): 285-288 C1 [Fine, Howard A.] NCI, Neurooncol Branch, Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. RP Fine, HA (reprint author), NCI, Neurooncol Branch, Natl Inst Neurol Disorders & Stroke, NIH, 9030 Old Georgetown Rd,Bloch Bldg 82,Room 225, Bethesda, MD 20892 USA. EM hfine@mail.nih.gov FU National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health (Center for Cancer Research of the National Cancer Institute and National Institute of Neurological Disorders and Stroke). NR 32 TC 27 Z9 27 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-9942 EI 1538-3687 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD MAR PY 2010 VL 67 IS 3 BP 285 EP 288 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 565QG UT WOS:000275308600004 PM 20212225 ER PT J AU Ambrosius, WT Danis, RP Goff, DC Greven, CM Gerstein, HC Cohen, RM Riddle, MC Miller, ME Buse, JB Bonds, DE Peterson, KA Rosenberg, YD Perdue, LH Esser, BA Seaquist, LA Felicetta, JV Chew, EY AF Ambrosius, Walter T. Danis, Ronald P. Goff, David C., Jr. Greven, Craig M. Gerstein, Hertzel C. Cohen, Robert M. Riddle, Matthew C. Miller, Michael E. Buse, John B. Bonds, Denise E. Peterson, Kevin A. Rosenberg, Yves D. Perdue, Letitia H. Esser, Barbara A. Seaquist, Lea A. Felicetta, James V. Chew, Emily Y. CA ACCORD Study Grp TI Lack of Association Between Thiazolidinediones and Macular Edema in Type 2 Diabetes The ACCORD Eye Substudy SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID MYOCARDIAL-INFARCTION; HARD EXUDATE; RETINOPATHY; ROSIGLITAZONE; RISK; PIOGLITAZONE; MELLITUS; EVENTS AB Objective: To assess the cross-sectional association of thiazolidinediones with diabetic macular edema (DME). Methods: The cross-sectional association of DME and visual acuity with thiazolidinediones was examined by means of baseline fundus photographs and visual acuity measurements from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Visual acuity was assessed in 9690 participants in the ACCORD trial, and 3473 of these participants had fundus photographs that were centrally read in a standardized fashion by masked graders to assess DME and retinopathy from October 23, 2003, to March 10, 2006. Results: Among the subsample, 695 (20.0%) people had used thiazolidinediones, whereas 217 (6.2%) people had DME. Thiazolidinedione use was not associated with DME in unadjusted (odds ratio [OR], 1.01; 95% confidence interval [CI], 0.71-1.44; P=.95) and adjusted (OR, 0.97; 95% CI, 0.67-1.40; P=.86) analyses. Significant associations with DME were found for retinopathy severity (P<.001) and age (OR, 0.97; 95% CI, 0.952-0.997; P=.03) but not for hemoglobin A(1c) (P=.06), duration of diabetes (P=.65), sex (P=.72), and ethnicity (P=.20). Thiazolidinedione usewas associated with slightly greater visual acuity (0.79 letter; 95% CI, 0.20-1.38; P=.009) of uncertain clinical significance. Conclusions: In a cross-sectional analysis of data from the largest study to date, no association was observed between thiazolidinedione exposure and DME in patients with type 2 diabetes; however, we cannot exclude a modest protective or harmful association. Trial Registration: clinicaltrials.gov Identifier: NCT00542178 C1 [Ambrosius, Walter T.; Miller, Michael E.; Perdue, Letitia H.] Wake Forest Univ, Sch Med, Dept Biostat Sci, Winston Salem, NC 27109 USA. [Goff, David C., Jr.] Wake Forest Univ, Sch Med, Dept Epidemiol & Prevent, Winston Salem, NC 27109 USA. [Greven, Craig M.] Wake Forest Univ, Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27109 USA. [Greven, Craig M.] Wake Forest Univ, Sch Med, Dept Ophthalmol, Winston Salem, NC 27109 USA. [Danis, Ronald P.; Esser, Barbara A.] Univ Wisconsin, Dept Ophthalmol, Fundus Photograph Reading Ctr, Madison, WI USA. [Gerstein, Hertzel C.] McMaster Univ, Hamilton, ON, Canada. [Gerstein, Hertzel C.] Hamilton Hlth Sci, Hamilton, ON, Canada. [Cohen, Robert M.] Univ Cincinnati, Med Ctr, Dept Internal Med, Div Endocrinol Diabet & Metab, Cincinnati, OH 45267 USA. [Riddle, Matthew C.] Oregon Hlth & Sci Univ, Dept Med, Div Endocrinol Diabet Clin Nutr, Portland, OR 97201 USA. [Buse, John B.] Univ N Carolina, Sch Med, Dept Med, Chapel Hill, NC USA. [Bonds, Denise E.] NHLBI, Div Prevent & Populat Sci, NIH, Bethesda, MD 20892 USA. [Rosenberg, Yves D.] NHLBI, Div Cardiovasc Dis, NIH, Bethesda, MD 20892 USA. [Chew, Emily Y.] NEI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. [Peterson, Kevin A.; Seaquist, Lea A.] Univ Minnesota, Sch Med, Dept Family Med & Community Hlth, Minneapolis, MN 55455 USA. [Felicetta, James V.] Phoenix VA Hlth Care Syst, Phoenix, AZ USA. RP Ambrosius, WT (reprint author), Wake Forest Univ Hlth Sci, Dept Biostat Sci, Div Publ Hlth Sci, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM wambrosi@wfubmc.edu OI Peterson, Kevin/0000-0002-6914-8586 FU National Eye Institute and the National Heart, Lung, and Blood Institute of the National Institutes of Health FX This study was funded by the National Eye Institute and the National Heart, Lung, and Blood Institute of the National Institutes of Health. NR 41 TC 26 Z9 28 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 MAR PY 2010 VL 128 IS 3 BP 312 EP 318 PG 7 WC Ophthalmology SC Ophthalmology GA 565QC UT WOS:000275308100006 PM 20212201 ER PT J AU Bradley, KT Arber, DA Brown, MS Chang, CC Coupland, SE de Baca, ME Ellis, DW Foucar, K Hsi, ED Jaffe, ES Lill, MC McClure, SP Medeiros, LJ Perkins, SL Hussong, JW AF Bradley, Kyle T. Arber, Daniel A. Brown, Michael S. Chang, Chung-Che Coupland, Sarah E. de Baca, Monica E. Ellis, David W. Foucar, Kathryn Hsi, Eric D. Jaffe, Elaine S. Lill, Michael C. McClure, Stephen P. Medeiros, L. Jeffrey Perkins, Sherrie L. Hussong, Jerry W. CA Members Canc Comm Coll Amer Pathologists TI Protocol for the Examination of Specimens From Patients With Hematopoietic Neoplasms of the Ocular Adnexa SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID LYMPHOID-TISSUE-TYPE; CELL LYMPHOMA; REAL CLASSIFICATION; FEATURES; ORBIT; CONJUNCTIVA; TUMORS C1 [Hussong, Jerry W.] Cedars Sinai Med Ctr, Dept Pathol & Lab Med, Los Angeles, CA 90048 USA. [Lill, Michael C.] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. [Bradley, Kyle T.] Emory Univ Hosp, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Arber, Daniel A.] Stanford Univ, Dept Pathol, Sch Med, Stanford, CA 94305 USA. [Brown, Michael S.] Yellowstone Pathol Inst Inc, Billings, MT USA. [Chang, Chung-Che] Methodist Hosp, Dept Pathol, Houston, TX 77030 USA. [Coupland, Sarah E.] Royal Liverpool Univ Hosp, Dept Pathol, Liverpool, Merseyside, England. [de Baca, Monica E.] Phys Lab Ltd, Dept Pathol & Lab Med, Sioux Falls, SD USA. [Ellis, David W.] Flinders Med Ctr, Dept Anat Pathol, Bedford Pk, SA, Australia. [Foucar, Kathryn] Univ New Mexico, Dept Pathol, Albuquerque, NM 87131 USA. [Hsi, Eric D.] Cleveland Clin, Dept Clin Pathol, Cleveland, OH 44106 USA. [Jaffe, Elaine S.] NCI, Dept Pathol, Bethesda, MD 20892 USA. [McClure, Stephen P.] Presbyterian Pathol Grp, Dept Pathol & Lab Med, Charlotte, NC USA. [Medeiros, L. Jeffrey] Univ Texas Houston, MD Anderson Canc Ctr, Dept Hematopathol, Houston, TX 77030 USA. [Perkins, Sherrie L.] Univ Utah, Hlth Sci Ctr, Dept Pathol, Salt Lake City, UT 84132 USA. RP Hussong, JW (reprint author), Cedars Sinai Med Ctr, Dept Pathol & Lab Med, 8700 Beverly Blvd,Room 4708, Los Angeles, CA 90048 USA. EM hussongj@cshs.org NR 27 TC 1 Z9 1 U1 0 U2 2 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD MAR PY 2010 VL 134 IS 3 BP 336 EP 340 PG 5 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 568NL UT WOS:000275529200003 PM 20196660 ER PT J AU Barnes, W D'Angelo, L Yamazaki, M Belzer, M Schroeder, S Palmer-Castor, J Futterman, D Kapogiannis, B Muenz, L Harris, DR Ellen, JM AF Barnes, William D'Angelo, Lawrence Yamazaki, Michiyo Belzer, Marvin Schroeder, Sybil Palmer-Castor, Judith Futterman, Donna Kapogiannis, Bill Muenz, Larry Harris, D. Robert Ellen, Jonathan M. CA Adolescent Trials Network HIV AIDS TI Identification of HIV-Infected 12-to 24-Year-Old Men and Women in 15 US Cities Through Venue-Based Testing SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID UNITED-STATES; PREVALENCE AB Objective: To test whether "venue-based testing" could identify human immunodeficiency virus (HIV) infection in US youth, 12 to 24 years of age, who were otherwise not aware of their infection. Racial and ethnic minority women and men who have sex with men (WSM and MSM) compose the majority of new HIV cases among adolescents and young adults. Design: Cross-sectional study. Setting: Selected venues in communities surrounding the 15 Adolescent Trials Network for HIV/AIDS Interventions (ATN) clinical sites over a 3-month period. Participants: At each venue, ATN sites recruited 20 to 30 English-or Spanish-speaking at-risk youth (12 to 24 years of age), resulting in a total of 1217 study participants, including 611 MSM and 606 WSM. Intervention: Venue-based HIV testing with 2 components: an anonymous audio computer-assisted self-administered interview and an anonymous HIV antibody assay. Main Outcome Measure: The prevalence of HIV infection in MSM and WSM. Results: The prevalence of HIV infection in MSM and WSM was 15.3% and 0.3%, respectively. Sixty percent of the MSM and 100% of the WSM claimed to not know of their infection. Conclusion: Venue-based testing may be an important strategy to identify HIV-infected younger MSM; however, other strategies are needed for WSM. Arch Pediatr Adolesc Med. 2010; 164(3): 273-276 C1 [Barnes, William; D'Angelo, Lawrence] Childrens Natl Med Ctr, Div Adolescent & Young Adult Med, Washington, DC 20010 USA. [Muenz, Larry; Harris, D. Robert] Westat Corp, Washington, DC USA. [Yamazaki, Michiyo; Ellen, Jonathan M.] Johns Hopkins Sch Med, Div Gen Pediat & Adolescent Med, Dept Pediat, Baltimore, MD USA. [Kapogiannis, Bill] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Rockville, MD USA. [Belzer, Marvin] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Los Angeles, CA 90033 USA. [Schroeder, Sybil] Tulane Sch Med, Sect Adolescent Med, Dept Pediat, New Orleans, LA USA. [Palmer-Castor, Judith] Childrens Hosp, Div Adolescent & Young Adult Med, Boston, MA 02115 USA. [Futterman, Donna] Albert Einstein Coll Med, Dept Pediat, Bronx, NY USA. RP Yamazaki, M (reprint author), Ctr Tower,5200 Eastern Ave,Ste 4200, Baltimore, MD 21224 USA. FU ATN and Connect through the National Institute of Child Health and Human Development; National Institutes on Drug Abuse, Mental Health, and Alcohol Abuse and Alcoholism FX Funding/Support: The ATN and Connect to Protect were funded, at the time of this study, through the National Institute of Child Health and Human Development (Dr Kapogiannis, Audrey Rogers, PhD, MPH, Robert Nugent, PhD, Leslie Serchuck, MD, and Sonia Lee, PhD), with supplemental funding from the National Institutes on Drug Abuse (Nicolette Borek, PhD), Mental Health (Andrew Forsyth, PhD, Pim Brouwers, PhD), and Alcohol Abuse and Alcoholism (Kendall Bryant, PhD). NR 8 TC 15 Z9 15 U1 0 U2 8 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD MAR PY 2010 VL 164 IS 3 BP 273 EP 276 PG 4 WC Pediatrics SC Pediatrics GA 562IA UT WOS:000275042300011 PM 20194262 ER PT J AU Rivara, FP Alexander, D AF Rivara, Frederick P. Alexander, Duane TI Randomized Controlled Trials and Pediatric Research SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Editorial Material C1 [Rivara, Frederick P.] Univ Washington, Inst Child Hlth, Seattle, WA 98115 USA. [Alexander, Duane] NIH, Bethesda, MD 20892 USA. RP Rivara, FP (reprint author), Univ Washington, Inst Child Hlth, 6200 NE 74th St,Ste 110, Seattle, WA 98115 USA. EM fpr@uw.edu NR 5 TC 4 Z9 4 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD MAR PY 2010 VL 164 IS 3 BP 296 EP 297 PG 3 WC Pediatrics SC Pediatrics GA 562IA UT WOS:000275042300017 PM 20194268 ER PT J AU Safaeian, M van Doorslaer, K Schiffman, M Chen, ZG Rodriguez, AC Herrero, R Hildesheim, A Burk, RD AF Safaeian, Mahboobeh van Doorslaer, Koenraad Schiffman, Mark Chen, Zigui Rodriguez, Ana Cecilia Herrero, Rolando Hildesheim, Allan Burk, Robert D. TI Lack of heterogeneity of HPV16 E7 sequence compared with HPV31 and HPV73 may be related to its unique carcinogenic properties SO ARCHIVES OF VIROLOGY LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; POPULATION; VARIANTS AB To assess the role of human papillomavirus virus (HPV) genetics in cervical lesions, we sequenced the E7 gene of HPV16, 31, or 73 from singly infected women who (1) cleared the infection quickly, (2) had type-specific persistent infection, or (3) progressed to CIN2 or worse lesions. Four of the 296 HPV16 E7 nucleotides were variable, compared with 7 of 296 for HPV31 E7 and 4 of 296 for HPV73 E7. While most of the polymorphisms in HPV31 and -73 resulted in non-synonymous amino acid changes, the polymorphisms in the HPV16 E7 resulted in synonymous changes. The lack of heterogeneity of HPV16 E7 suggests high evolutionary purifying selection that might be related to the unique carcinogenicity of HPV16. C1 [Safaeian, Mahboobeh; Schiffman, Mark; Hildesheim, Allan] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [van Doorslaer, Koenraad; Chen, Zigui; Burk, Robert D.] Albert Einstein Coll Med, Bronx, NY 10467 USA. [Rodriguez, Ana Cecilia; Herrero, Rolando] Fdn INCIENSA, Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. RP Safaeian, M (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. EM safaeianm@mail.nih.gov RI Hildesheim, Allan/B-9760-2015; Chen, Zigui/E-8490-2017; OI Hildesheim, Allan/0000-0003-0257-2363; Van Doorslaer, Koenraad/0000-0002-2985-0733 FU NCI NIH HHS [R01 CA078527, U01 CA078527, U01 CA078527-12] NR 10 TC 3 Z9 3 U1 0 U2 0 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PD MAR PY 2010 VL 155 IS 3 BP 367 EP 370 DI 10.1007/s00705-009-0579-2 PG 4 WC Virology SC Virology GA 560XW UT WOS:000274939600009 PM 20049619 ER PT J AU Ward, MM AF Ward, Michael M. TI Medicare Reimbursement and the Use of Biologic Agents: Incentives, Access, the Public Good, and Optimal Care SO ARTHRITIS CARE & RESEARCH LA English DT Editorial Material ID RHEUMATOID-ARTHRITIS; MODERNIZATION ACT; CHEMOTHERAPY; ETANERCEPT; INFLIXIMAB; IMPACT C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS [Z01 AR041153-03, Z01 AR041153-04, ZIA AR041170-02, Z01 AR041170-01, ZIA AR041153-05] NR 16 TC 3 Z9 3 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 2151-464X J9 ARTHRIT CARE RES JI Arthritis Care Res. PD MAR PY 2010 VL 62 IS 3 BP 293 EP 295 DI 10.1002/acr.20088 PG 3 WC Rheumatology SC Rheumatology GA 639MP UT WOS:000280979200001 PM 20391473 ER PT J AU Feingold, KR Kazemi, MR Magra, AL McDonald, CM Chui, LG Shigenaga, JK Patzek, SM Chan, ZW Londos, C Grunfeld, C AF Feingold, Kenneth R. Kazemi, Mahmood R. Magra, Amy L. McDonald, Carol M. Chui, Lisa G. Shigenaga, Judy K. Patzek, Sophie M. Chan, Zoe W. Londos, Constantine Grunfeld, Carl TI ADRP/ADFP and Mal1 expression are increased in macrophages treated with TLR agonists SO ATHEROSCLEROSIS LA English DT Article DE Acute phase response; Atherosclerosis; Endotoxin; Zymosan; Foam cell ID DIFFERENTIATION-RELATED PROTEIN; TOLL-LIKE RECEPTOR-4; LOW-DENSITY-LIPOPROTEIN; PAT FAMILY PROTEINS; FOAM CELL-FORMATION; BINDING PROTEIN; LIPID-ACCUMULATION; CHLAMYDIA-PNEUMONIAE; MURINE MACROPHAGES; APOLIPOPROTEIN-E AB Activation of macrophages by TLR agonists enhances foam cell formation, but the underlying mechanisms are not understood. We examined the effects of TLR agonists on ADRP/ADFP, a protein associated with forming lipid droplets, and Mal1 a fatty acid-binding protein, in two mouse macrophage cell lines and human monocytes. Low doses of LPS, a TLR4 agonist increased both mRNA and protein levels of ADRP/ADFP and Mal1 in RAW 264.7 macrophages. Following pretreatment with Intralipid, fatty acids, or acetyl-LDL to increase triglyceride or cholesterol ester storage, LPS treatment still increased ADRP/ADFP and Mal1 mRNA levels. LPS also induced ADRP/ADFP and Mal1 in J774 macrophages and ADRP/ADFP in human monocytes. Zymosan, a fungal product that activates TLR2, poly-I:C, a viral mimetic that activates TLR3, and imiquimod, a TLR7 agonist, also increased ADRP/ADFP. Zymosan, but not poly-I: C or imiquimod, induced Mal1. In contrast, neither gene was induced by TNF alpha, IL-1 beta, IL-6, or interferon-gamma. Thus TLR agonists induce ADRP/ADFP and Mal1, which likely contributes to macrophage triglyceride and cholesterol ester storage leading to foam cell formation. Published by Elsevier Ireland Ltd. C1 [Feingold, Kenneth R.; Kazemi, Mahmood R.; McDonald, Carol M.; Chui, Lisa G.; Shigenaga, Judy K.; Patzek, Sophie M.; Chan, Zoe W.; Grunfeld, Carl] Dept Vet Affairs Med Ctr, Metab Sect, San Francisco, CA USA. [Feingold, Kenneth R.; Kazemi, Mahmood R.; McDonald, Carol M.; Chui, Lisa G.; Shigenaga, Judy K.; Patzek, Sophie M.; Chan, Zoe W.; Grunfeld, Carl] Univ Calif San Francisco, Dept Med, San Francisco, CA USA. [Magra, Amy L.; Londos, Constantine] NIDDKD, NIH, Bethesda, MD 20892 USA. RP Feingold, KR (reprint author), SFVAMC Metab Sect, 4150 Clement St,111F, San Francisco, CA 94121 USA. EM kenneth.feingold@ucsf.edu FU Research Service of the Department of Veterans Affairs, National Institutes of Health [5R01HD029706]; Albert L. and Janet A. Shultz Supporting Foundation FX This work was supported by grants from the Research Service of the Department of Veterans Affairs, National Institutes of Health Grant 5R01HD029706, and the Albert L. and Janet A. Shultz Supporting Foundation. NR 45 TC 24 Z9 32 U1 0 U2 7 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 MAR PY 2010 VL 209 IS 1 BP 81 EP 88 DI 10.1016/j.atherosclerosis.2009.08.042 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 563BV UT WOS:000275101500013 PM 19748622 ER PT J AU Lleo, A Invernizzi, P Gao, B Podda, M Gershwin, ME AF Lleo, Ana Invernizzi, Pietro Gao, Bin Podda, Mauro Gershwin, M. Eric TI Definition of human autoimmunity - autoantibodies versus autoimmune disease SO AUTOIMMUNITY REVIEWS LA English DT Article DE Autoantibody; Autoantigen; Tolerance; B cell; Autoimmune disease ID PRIMARY BILIARY-CIRRHOSIS; SYSTEMIC-LUPUS-ERYTHEMATOSUS; CONGENITAL HEART-BLOCK; B-CELLS; ANTIMITOCHONDRIAL ANTIBODIES; ANTIPHOSPHOLIPID ANTIBODIES; APOPTOTIC NEUTROPHILS; NATURAL ANTIBODIES; PATHOGENIC ROLE; MARGINAL ZONE AB The critical function of the immune system is to discriminate self from non-self. Tolerance against self-antigens is a highly regulated process and, in order to maintain it, the immune system must be able to distinguish self-reactive lymphocytes as they develop. The presence of autoantibodies is the consequence of breakdown of tolerance and, although they are an important serological feature of autoimmune diseases, their presence is not exclusive of these conditions. Antibodies against self-antigens are also found in cancer, during massive tissue damage and even in healthy subjects. Natural autoantibodies provide immediate protection against infection and also prevent inflammation by facilitating the clearance of oxidized lipids, oxidized proteins, and apoptotic cells: their role in development of autoimmunity is still unclear. Detection of serum autoantibodies in clinical practice has become more available to clinicians worldwide while providing a powerful diagnostic tool. This review discusses the clinical significance of autoantibodies, their pathogenic mechanisms in autoimmune diseases and, finally, illustrates the technology available for appropriate autoantibody detection. (C) 2009 Elsevier By. All rights reserved. C1 [Gershwin, M. Eric] Univ Calif Davis, Sch Med, Genome & Biomed Sci Facil, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. [Lleo, Ana; Invernizzi, Pietro; Podda, Mauro] IRCCS Ist Clin Humanitas, Div Internal Med, Rozzano, Italy. [Lleo, Ana; Invernizzi, Pietro; Podda, Mauro] IRCCS Ist Clin Humanitas, Hepatobiliary Immunopathol Unit, Rozzano, Italy. [Podda, Mauro] Univ Milan, Dept Translat Med, I-20122 Milan, Italy. [Gao, Bin] NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD USA. RP Gershwin, ME (reprint author), Univ Calif Davis, Sch Med, Genome & Biomed Sci Facil, Div Rheumatol Allergy & Clin Immunol, 451 E Hlth Sci Dr,Suite 6510, Davis, CA 95616 USA. EM megershwin@ucdavis.edu OI LLEO DE NALDA, Ana/0000-0002-0561-7902; Invernizzi, Pietro/0000-0003-3262-1998 NR 60 TC 99 Z9 101 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 EI 1873-0183 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD MAR PY 2010 VL 9 IS 5 SI SI BP A259 EP A266 DI 10.1016/j.autrev.2009.12.002 PG 8 WC Immunology SC Immunology GA 580SN UT WOS:000276470100003 PM 19963079 ER PT J AU Fouchier, RAM Smith, DI AF Fouchier, Ron A. M. Smith, Derek I. TI Use of Antigenic Cartography in Vaccine Seed Strain Selection SO AVIAN DISEASES LA English DT Article; Proceedings Paper CT 7th International Symposium on Avian Influenza CY APR 05-08, 2009 CL Univ Georgia, Athens, GA HO Univ Georgia DE influenza A virus; vaccine; HI antibodies; antigenic drift ID AVIAN INFLUENZA-VIRUS; A H3N2 VIRUSES; SEASONAL INFLUENZA; GENETIC EVOLUTION; DISEASE; BURDEN AB Human influenza A viruses are classic examples of antigenically variable pathogens that have a seemingly endless capacity to evade the host's immune response. The viral hemagglutinin (HA) and neuraminidase (NA) proteins are the main targets of our antibody response to combat infections. HA and NA continuously change ro escape from Immoral immunity, a process known as antigenic drift. As a result of antigenic drift, the human influenza vaccine is updated frequently. The World Health Organization (WHO) coordinates a global influenza surveillance network that, by the hemagglutination inhibition (HI) assay, routinely characterizes the antigenic properties of circulating strains in order to select new seed viruses for such vaccine updates. To facilitate a quantitative interpretation and easy visualization of HI data, a new computational technique called "antigenic cartography" was developed. Since its development, antigenic cartography has been applied routinely to assist the WHO with influenza surveillance activities. Until recently, antigenic variation was not considered a serious issue with influenza vaccines for poultry. However, because of the diversification of the Asian H5N1 lineage since 1996 into multiple genetic clades and subclades, and because of the long-term use of poultry vaccines against H5 in some parts of the world, this issue needs to be re-addressed. The antigenic properties of panels of avian H5N1 viruses were characterized by HI assay, using mammalian or avian antisera, and analyzed using antigenic cartography methods. These analyses revealed antigenic differences between circulating H5N1 viruses and the H5 viruses used in poultry vaccines. Considerable antigenic variation was also observed within and between H5N1 clades. These observations have important implications for the efficacy and long-term use of poultry vaccines. C1 [Fouchier, Ron A. M.; Smith, Derek I.] Erasmus MC, Dept Virol, NL-3015 GE Rotterdam, Netherlands. [Smith, Derek I.] Univ Cambridge, Dept Zool, Cambridge CB2 3EJ, England. [Smith, Derek I.] Fogarty Int Ctr, NIH, Bethesda, MD 20892 USA. RP Fouchier, RAM (reprint author), Erasmus MC, Dept Virol, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. EM r.fouchier@erasmusmc.nl RI Fouchier, Ron/A-1911-2014 OI Fouchier, Ron/0000-0001-8095-2869 FU NIH HHS [DP1-OD000490-01]; NINDS NIH HHS [HHNSN266200700010C] NR 14 TC 22 Z9 22 U1 1 U2 6 PU AMER ASSOC AVIAN PATHOLOGISTS PI ATHENS PA 953 COLLEGE STATION RD, ATHENS, GA 30602-4875 USA SN 0005-2086 J9 AVIAN DIS JI Avian Dis. PD MAR PY 2010 VL 54 IS 1 SU S BP 220 EP 223 DI 10.1637/8740-032509-ResNote.1 PG 4 WC Veterinary Sciences SC Veterinary Sciences GA 580NF UT WOS:000276455300009 PM 20521635 ER PT J AU Schmitt, JE Wallace, GL Lenroot, RK Ordaz, SE Greenstein, D Clasen, L Kendler, KS Neale, MC Giedd, JN AF Schmitt, J. Eric Wallace, Gregory L. Lenroot, Rhoshel K. Ordaz, Sarah E. Greenstein, Dede Clasen, Liv Kendler, Kenneth S. Neale, Michael C. Giedd, Jay N. TI A Twin Study of Intracerebral Volumetric Relationships SO BEHAVIOR GENETICS LA English DT Article DE Twin; Cerebrum; MRI; Genetics; Pediatrics ID HUMAN BRAIN EVOLUTION; CORTICAL DEVELOPMENT; FACTOR MODELS; HOMO-SAPIENS; MRI DATA; MULTIVARIATE; MULTIMETHOD; MULTITRAIT; SIZE; HERITABILITY AB Using high resolution magnetic resonance imaging data, we examined the interrelationships between eight cerebral lobar volumetric measures via both exploratory and confirmatory factor analyses in a large sample (N = 484) of pediatric twins and singletons. These analyses suggest the presence of strong genetic correlations between cerebral structures, particularly between regions of like tissue type or in spatial proximity. Structural modeling estimated that most of the variance in all structures is associated with highly correlated lobar latent factors, with differences in genetic covariance and heritability driven by a common genetic factor that influenced gray and white matter differently. Reanalysis including total brain volume as a covariate dramatically reduced the total residual variance and disproportionately influenced the additive genetic variance in all regions of interest. C1 [Schmitt, J. Eric; Kendler, Kenneth S.; Neale, Michael C.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA 23298 USA. [Wallace, Gregory L.; Lenroot, Rhoshel K.; Greenstein, Dede; Clasen, Liv; Giedd, Jay N.] NIMH, Pediat Imaging Unit, Child Psychiat Branch, Bethesda, MD 20892 USA. [Ordaz, Sarah E.] Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. RP Schmitt, JE (reprint author), Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, 800 E Leigh St,Suite 100,POB 980003, Richmond, VA 23298 USA. EM eric.schmitt@stanfordalumni.org RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Wallace, Gregory/0000-0003-0329-5054 FU NIH [MH-65322, MH-20030, DA-18673] FX This research was supported by the intramural research program of the NIH as well as NIH grants MH-65322, MH-20030, and DA-18673. NR 42 TC 17 Z9 17 U1 8 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD MAR PY 2010 VL 40 IS 2 SI SI BP 114 EP 124 DI 10.1007/s10519-010-9332-6 PG 11 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 561GM UT WOS:000274964000002 PM 20112130 ER PT J AU Wallace, GL Lee, NR Prom-Wormley, EC Medland, SE Lenroot, RK Clasen, LS Schmitt, JE Neale, MC Giedd, JN AF Wallace, Gregory L. Lee, Nancy Raitano Prom-Wormley, Elizabeth C. Medland, Sarah E. Lenroot, Rhoshel K. Clasen, Liv S. Schmitt, James E. Neale, Michael C. Giedd, Jay N. TI A Bivariate Twin Study of Regional Brain Volumes and Verbal and Nonverbal Intellectual Skills During Childhood and Adolescence SO BEHAVIOR GENETICS LA English DT Article DE Twin; Magnetic resonance imaging; Brain; Intelligence; Verbal; Nonverbal ID GENETIC INFLUENCES; MRI DATA; INTELLIGENCE; CHILDREN AB Twin studies indicate that both intelligence and brain structure are moderately to highly heritable. Recent bivariate studies of adult twins also suggest that intelligence and brain morphometry are influenced by shared genetic factors. The current study examines shared genetic and environmental factors between brain morphometry and intelligence in a sample of children and adolescents (twins, twin siblings, and singletons; n = 649, ages 4-19). To extend previous studies, brain morphometric data were parsed into subregions (lobar gray/white matter volumes, caudate nucleus, lateral ventricles) and intelligence into verbal and nonverbal skills (Wechsler Vocabulary and Block Design subtests). Phenotypic relationships between brain volumes and intelligence were small. Verbal skills shared unique environmental effects with gray matter volumes while nonverbal skills shared genetic effects with both global and regional gray and white matter. These results suggest that distinct mechanisms contribute to the small phenotypic relationships between brain volumes and verbal versus nonverbal intelligence. C1 [Wallace, Gregory L.; Lee, Nancy Raitano; Lenroot, Rhoshel K.; Clasen, Liv S.; Giedd, Jay N.] NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Prom-Wormley, Elizabeth C.; Medland, Sarah E.; Schmitt, James E.; Neale, Michael C.] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. [Medland, Sarah E.] Queensland Inst Med Res, Genet Epidemiol Unit, Brisbane, Qld 4006, Australia. RP Wallace, GL (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,4C110,MSC-1367,10 Ctr Dr, Bethesda, MD 20892 USA. EM gregwallace@mail.nih.gov RI Lee, Nancy Raitano/F-2565-2011; Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Medland, Sarah/C-7630-2013; Giedd, Jay/J-9644-2015; Lee, Nancy/M-7492-2016; OI Giedd, Jay/0000-0003-0827-3460; Medland, Sarah/0000-0003-1382-380X; Giedd, Jay/0000-0003-2002-8978; Lee, Nancy/0000-0002-6663-0713; Prom-Wormley, Elizabeth/0000-0001-9230-9723; Wallace, Gregory/0000-0003-0329-5054 FU NIH [MH-20030]; National Institute of Mental Health; NHMRC Australia, Sidney [443036; SEM] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Mental Health (GW, NRL, LSC, RL, JG), extramural grant funding from the NIH (MH-20030; EP-W, SEM, JES, MCN), and an NHMRC Australia, Sidney Sax Public Fellowship (443036; SEM). We would like to express our gratitude to the individuals who volunteered their time to contribute to this research. NR 47 TC 14 Z9 14 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD MAR PY 2010 VL 40 IS 2 SI SI BP 125 EP 134 DI 10.1007/s10519-009-9329-1 PG 10 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 561GM UT WOS:000274964000003 PM 20112131 ER PT J AU Arellano-Plancarte, A Hernandez-Aranda, J Catt, KJ Olivares-Reyes, JA AF Arellano-Plancarte, Araceli Hernandez-Aranda, Judith Catt, Kevin J. Olivares-Reyes, J. Alberto TI Angiotensin-induced EGF receptor transactivation inhibits insulin signaling in C9 hepatic cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE Angiotensin II; Insulin; EGF receptor transactivation; Insulin resistance; Akt ID EPIDERMAL-GROWTH-FACTOR; SMOOTH-MUSCLE-CELLS; PROTEIN-KINASE-C; SERINE PHOSPHORYLATION; SKELETAL-MUSCLE; MAP KINASE; CROSS-TALK; SERINE/THREONINE PHOSPHORYLATION; TYROSINE PHOSPHORYLATION; GLUCOSE-TRANSPORT AB To investigate the potential interactions between the angiotensin II (Ang II) and insulin signaling systems, regulation of IRS-1 phosphorylation and insulin-induced Akt activation by Ang II were examined in clone 9 (C9) hepatocytes. In these cells, Ang II specifically inhibited activation of insulininduced Akt Thr(308) and its immediate downstream substrate GSK-3 alpha/beta in a time-dependent fashion, with similar to 70% reduction at 15 min. These inhibitory actions were associated with increased IRS-1 phosphorylation of Ser(636)/Ser(639) that was prevented by selective blockade of EGFR tyrosine kinase activity with AG1478. Previous studies have shown that insulin-induced phosphorylation of IRS-1 on Ser(636)/Ser(639) is mediated mainly by the PI3K/mTOR/S6K-1 sequence. Studies with specific inhibitors of PI3K (wortmannin) and mTOR (rapamycin) revealed that Ang II stimulates IRS-1 phosphorylation of Ser(636)/Ser(639) via the PI3K/mTOR/S6K-1 pathway. Both inhibitors blocked the effect of Ang II on insulin-induced activation of Akt. Studies using the specific MEK inhibitor, PD98059, revealed that ERK1/2 activation also mediates Ang II-induced S6K-1 and IRS-1 phosphorylation, and the impairment of Akt Thr308 and GSK-3 alpha/beta phosphorylation. Further studies with selective inhibitors showed that PI3K activation was upstream of ERK, suggesting a new mechanism for Ang II-induced impairment of insulin signaling. These findings indicate that Ang 11 has a significant role in the development of insulin resistance by a mechanism that involves EGFR transactivation and the PI3K/ERK1/2/mTOR-S6K-1 pathway. (c) 2009 Elsevier Inc. All rights reserved. C1 [Arellano-Plancarte, Araceli; Hernandez-Aranda, Judith; Olivares-Reyes, J. Alberto] Cinvestav IPN, Lab Signal Transduct, Dept Biochem, Ctr Res & Adv Studies,Natl Polytech Inst, Mexico City 07360, DF, Mexico. [Catt, Kevin J.] NICHHD, Sect Hormonal Regulat, PDEGEN, NIH, Bethesda, MD 20892 USA. RP Olivares-Reyes, JA (reprint author), Cinvestav IPN, Lab Signal Transduct, Dept Biochem, Ctr Res & Adv Studies,Natl Polytech Inst, AP 14-740, Mexico City 07360, DF, Mexico. EM jolivare@cinvestav.mx FU Cinvestav-IPN; CONACYT/SEP Research Grants [39485-Q/48777, 169944] FX This research was supported by Cinvestav-IPN and CONACYT/SEP Research Grants 39485-Q/48777 (to J.A. O.-R.); by CONACYT fellowship grant, No. 169944 and Apoyo Integral para la Formacion de Doctores en Ciencia, Modalidad A, Tesista de Doctorado, CONACYT (to A. A.-P.). The authors thank Norma Cirnes for her help in the preparation of the figures. NR 70 TC 11 Z9 12 U1 0 U2 2 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 MAR 1 PY 2010 VL 79 IS 5 BP 733 EP 745 DI 10.1016/j.bcp.2009.10.014 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 546SN UT WOS:000273831800009 PM 19879250 ER PT J AU Kristie, TM Liang, Y Vogel, JL AF Kristie, Thomas M. Liang, Yu Vogel, Jodi L. TI Control of alpha-herpesvirus IE gene expression by HCF-1 coupled chromatin modification activities SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE HCF-1; Herpesvirus; Coactivator; Set1; LSD1 ID SIMPLEX-VIRUS TYPE-1; HOST-CELL FACTOR; LATENCY-ASSOCIATED TRANSCRIPT; HISTONE ACETYLTRANSFERASE COMPLEX; DNA-BINDING STRUCTURE; IMMEDIATE-EARLY GENES; COACTIVATOR HCF-1; LYTIC INFECTION; HOMEO DOMAIN; METHYLTRANSFERASE COMPLEX AB The immediate early genes of the alpha-herpesviruses HSV and VZV are transcriptionally regulated by viral and cellular factors in a complex combinatorial manner. Despite this complexity and the apparent redundancy of activators, the expression of the viral IE genes is critically dependent upon the cellular transcriptional coactivator HCF-1. Although the role of HCF-1 had remained elusive, recent studies have demonstrated that the protein is a component of multiple chromatin modification complexes including the Set1/MLL1 histone H3K4 methyltransferases. Studies using model viral promoter-reporter systems as well as analyses of components recruited to the viral genome during the initiation of infection have elucidated the significance of HCF-1 chromatin modification complexes in contributing to the final state of modified histones assembled on the viral IE promoters. Strikingly, the absence of HCF-1 results in the accumulation of nucleosomes bearing repressive marks on the viral IE promoters and silencing of viral gene expression. Published by Elsevier B.V. C1 [Kristie, Thomas M.; Liang, Yu; Vogel, Jodi L.] NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Kristie, TM (reprint author), NIAID, Viral Dis Lab, NIH, 4-129,4 Ctr Dr, Bethesda, MD 20892 USA. EM Thomas_kristie@nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We thank T. Pierson for the critical reading of this manuscript. Studies done in the Kristie Laboratory were supported by the Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 108 TC 40 Z9 40 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD MAR-APR PY 2010 VL 1799 IS 3-4 SI SI BP 257 EP 265 DI 10.1016/j.bbagrm.2009.08.003 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 578UF UT WOS:000276320800011 PM 19682612 ER PT J AU de Souza, RF Iyer, LM Aravind, L AF de Souza, Robson F. Iyer, Lakshminarayan M. Aravind, L. TI Diversity and evolution of chromatin proteins encoded by DNA viruses SO BIOCHIMICA ET BIOPHYSICA ACTA-GENE REGULATORY MECHANISMS LA English DT Review DE Chromatin; SWI2/SNF2; E6; E7; E1A; PHD; Treble clef; LXCXE; RecA; A18R; Topoisomerase; ATPase; Rad52; HEH; Histone; Methylase; Demethylase; Jumonji ID HERPES-SIMPLEX-VIRUS; SARCOMA-ASSOCIATED HERPESVIRUS; STRAND ANNEALING PROTEINS; LARGE TUMOR-ANTIGEN; CELL-CYCLE CONTROL; RNA-POLYMERASE-II; BINDING-PROTEIN; VACCINIA VIRUS; CRYSTAL-STRUCTURE; COMPARATIVE GENOMICS AB Double-stranded DNA viruses display a great variety of proteins that interact with host chromatin. Using the wealth of available genomic and functional information, we have systematically surveyed chromatin-related proteins encoded by dsDNA viruses. The distribution of viral chromatin-related proteins is primarily influenced by viral genome size and the superkingdom to which the host of the virus belongs. Smaller viruses usually encode multifunctional proteins that mediate several distinct interactions with host chromatin proteins and viral or host DNA. Larger viruses additionally encode several enzymes, which catalyze manipulations of chromosome structure, chromatin remodeling and covalent modifications of proteins and DNA. Among these viruses, it is also common to encounter transcription factors and DNA-packaging proteins such as histones and IHF/HU derived from cellular genomes, which might play a role in constituting virus-specific chromatin states. Through all size ranges a subset of domains in viral chromatin proteins appears to have been derived from those found in host proteins. Examples include the Zn-finger domains of the E6 and E7 proteins of papillomaviruses, SET domain methyltransferases and Jumonji-related demethylases in certain nucleocytoplasmic large DNA viruses and BEN domains in poxviruses and polydnaviruses. In other cases, chromatin-interacting modules, such as the LXCXE motif, appear to have been widely disseminated across distinct viral lineages, resulting in similar retinoblastoma targeting strategies. Viruses, especially those with large linear genomes, have evolved a number of mechanisms to manipulate viral chromosomes in the process of replication-associated recombination. These include topoisomerases, Rad50/SbcC-like ABC ATPases and a novel recombinase system in bacteriophages utilizing RecA and Rad52 homologs. Larger DNA viruses also encode SWI2/SNF2 and A18-like ATPases which appear to play specialized roles in transcription and recombination. Finally, it also appears that certain domains of viral provenance have given rise to key functions in eukaryotic chromatin such as a HEH domain of chromosome tethering proteins and the TET/JBP-like cytosine and thymine hydroxylases. Published by Elsevier B.V. C1 [de Souza, Robson F.; Iyer, Lakshminarayan M.; Aravind, L.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM aravind@mail.nih.gov FU National Library of Medicine, NIH FX Work by the authors is supported by the intramural funds of the National Library of Medicine, NIH. Due to space considerations we have been regrettably unable to cite a large number of original works in this field. NR 169 TC 26 Z9 26 U1 1 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1874-9399 J9 BBA-GENE REGUL MECH JI Biochim. Biophys. Acta-Gene Regul. Mech. PD MAR-APR PY 2010 VL 1799 IS 3-4 SI SI BP 302 EP 318 DI 10.1016/j.bbagrm.2009.10.006 PG 17 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 578UF UT WOS:000276320800016 PM 19878744 ER PT J AU Taymans, JM Cookson, MR AF Taymans, Jean-Marc Cookson, Mark R. TI Mechanisms in dominant parkinsonism: The toxic triangle of LRRK2, alpha-synuclein, and tau SO BIOESSAYS LA English DT Article DE genetics; kinases; microtubule; neurodegeneration; Parkinson's disease; synapse ID DISEASE-ASSOCIATED MUTATIONS; COUPLED RECEPTOR KINASES; LEWY BODY DISEASE; MICE LACKING; MOUSE-BRAIN; GENE LRRK2; LEUCINE-RICH-REPEAT-KINASE-2 LRRK2; NEUROFIBRILLARY TANGLES; DOPAMINERGIC-NEURONS; ALZHEIMERS-DISEASE AB Parkinson's disease (PD) is generally sporadic but a number of genetic diseases have parkinsonism as a clinical feature. Two dominant genes, a-synuclein (SNCA) and leucine-rich repeat kinase 2 (LRRK2), are important for understanding inherited and sporadic PD. SNCA is a major component of pathologic inclusions termed Lewy bodies found in PD. LRRK2 is found in a significant proportion of PD cases. These two proteins may be linked as most LRRK2 PD cases have SNCA-positive Lewy bodies. Mutations in both proteins are associated with toxic effects in model systems although mechanisms are unclear. LRRK2 is an intracellular signaling protein possessing both GTPase and kinase activities that may contribute to pathogenicity. A third protein, tau, is implicated as a risk factor for PD. We discuss the potential relationship between these genes and suggest a model for PD pathogenesis where LRRK2 is upstream of pathogenic effects through SNCA, tau, or both proteins. C1 [Taymans, Jean-Marc; Cookson, Mark R.] NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Taymans, Jean-Marc] Katholieke Univ Leuven, Lab Neurobiol & Gene Therapy, Div Mol Med, Dept Mol & Cellular Med, Leuven, Belgium. RP Cookson, MR (reprint author), NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, NIH, 35 Convent Dr, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov OI Taymans, Jean-Marc/0000-0001-5503-5524 FU NIH; NIH, National Institute on Aging; Flemish fund for scientific research (FWO, Flanders, Belgium) FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging. J-MT is a postdoctoral researcher of the Flemish fund for scientific research (FWO, Flanders, Belgium) and a Fulbright research scholar. NR 116 TC 48 Z9 48 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0265-9247 J9 BIOESSAYS JI Bioessays PD MAR PY 2010 VL 32 IS 3 BP 227 EP 235 DI 10.1002/bies.200900163 PG 9 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 568FY UT WOS:000275508900006 PM 20127702 ER PT J AU Drevets, WC Furey, ML AF Drevets, Wayne C. Furey, Maura L. TI Replication of Scopolamine's Antidepressant Efficacy in Major Depressive Disorder: A Randomized, Placebo-Controlled Clinical Trial SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Anticholinergic; antimuscarinic; mood disorders; treatment ID INDUCTION TEST; RATING-SCALE; CHRM2 GENE; SLEEP; SENSITIVITY; GLUTAMATE; SUPERSENSITIVITY; PHARMACOTHERAPY; ASSOCIATION; HIPPOCAMPUS AB Background: We previously reported that intravenous (IV) scopolamine administration produced rapid and robust antidepressant effects in a sample consisting of both unipolar and bipolar depressives. The present study aimed to replicate this finding in an independent sample limited to unipolar depressives. Methods: Outpatients with major depressive disorder (MDD; n = 23; 22 were included in analyses) participated in a double-blind, placebo-controlled, crossover trial. Subjects were randomized into either a P/S or S/P sequence (P = block of three placebo sessions; S = block of three scopolamine sessions; [4.0 mu g/kg IV]). Sessions occurred 3 to 5 days apart, such that time spent in each block lasted 1.5 to 2 weeks and the interval between blocks was 3 to 5 days. The Montgomery-Asberg Depression Rating Scale (MADRS) served as the primary outcome measure. Results: Following the initial block, the group receiving scopolamine first (S/P) showed a 32% reduction in MADRS scores (p < .001), which exceeded the corresponding change of 6.5% under placebo (P/S;p = .009), confirming the a-priori hypothesis. Improvement was significant at the first evaluation that followed scopolamine administration (p = .011). In Block 2, the P/S group showed a 53% reduction in MADRS scores (p = .001) following scopolamine versus placebo, whereas the reduction seen in S/P subjects who received scopolamine during Block 1 persisted as they received placebo during Block 2. Scopolamine induced drowsiness, blurred vision, dry mouth, light-headedness, and reduced blood pressure, which were sufficiently well tolerated that no subject dropped out because of side effects. Conclusions: These results replicate previous finding that scopolamine produces a rapid and robust antidepressant response. C1 [Drevets, Wayne C.; Furey, Maura L.] NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Furey, ML (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, Bldg 15K,Room 201, Bethesda, MD 20892 USA. EM mfurey@mail.nih.gov RI Furey, Maura/H-5273-2013 FU National Institutes of Health, National Institute of Mental Health FX We thank Ashish Khanna, Mark Opal, Summer Peck, and Elana Hoffman for technical support; Michele Drevets and Joan Williams for patient recruitment and evaluation; David Luckenbaugh for statistical advice; and Paul Carlson, Alan Mallinger, Carlos Zarate, Meena Vythilingam, and the 5SW Day Hospital nursing staff for medical support. This research was supported by the National Institutes of Health, National Institute of Mental Health Intramural Research Program. NR 41 TC 103 Z9 107 U1 3 U2 14 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 MAR 1 PY 2010 VL 67 IS 5 BP 432 EP 438 DI 10.1016/j.biopsych.2009.11.021 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 563BL UT WOS:000275100300006 PM 20074703 ER PT J AU Perez-Edgar, K Bar-Haim, Y McDermott, JM Gorodetsky, E Hodgkinson, CA Goldman, D Ernst, M Pine, DS Fox, NA AF Perez-Edgar, Koraly Bar-Haim, Yair McDermott, Jennifer Martin Gorodetsky, Elena Hodgkinson, Colin A. Goldman, David Ernst, Monique Pine, Daniel S. Fox, Nathan A. TI Variations in the serotonin-transporter gene are associated with attention bias patterns to positive and negative emotion faces SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE Anxiety; Attention bias; Serotonin-transporter gene polymorphism; 5-HTTLPR; Dot-probe task; Intermediate phenotypes ID 5-HTTLPR GENOTYPE; ANXIETY-DISORDER; STRESS-RESPONSE; AMYGDALA; CHILDREN; THREAT; RISK; ADOLESCENTS; ACTIVATION; DEPRESSION AB Both attention biases to threat and a serotonin-transporter gene polymorphism (5-HTTLPR) have been linked to heightened neural activation to threat and the emergence of anxiety. The short allele of 5-HTTLPR may act via its effect on neurotransmitter availability, while attention biases shape broad patterns of cognitive processing. We examined individual differences in attention bias to emotion faces as a function of 5-HTTLPR genotype. Adolescents (N = 117) were classified for presumed SLC6A4 expression based on 5-HTTLPR low (SS, SL(G), or L(G)L(G)), intermediate (SL(A) or L(A)L(G)), or high (L(A)L(A)). Participants completed the dot-probe task, measuring attention biases toward or away from angry and happy faces. Biases for angry faces increased with the genotype-predicted neurotransmission levels (low > intermediate > high). The reverse pattern was evident for happy faces. The data indicate a linear relation between 5-HTTLPR allelic status and attention biases to emotion, demonstrating a genetic mechanism for biased attention using ecologically valid stimuli that target socioemotional adaptation. (C) 2009 Elsevier B.V. All rights reserved. C1 [Perez-Edgar, Koraly] George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. [Bar-Haim, Yair] Tel Aviv Univ, Tel Aviv, Israel. [McDermott, Jennifer Martin] Univ Wisconsin, Madison, WI USA. [Gorodetsky, Elena; Ernst, Monique; Pine, Daniel S.] NIMH, Bethesda, MD USA. [Hodgkinson, Colin A.; Goldman, David] NIAAA, Bethesda, MD USA. [Fox, Nathan A.] Univ Maryland, College Pk, MD 20742 USA. RP Perez-Edgar, K (reprint author), George Mason Univ, Dept Psychol, 4400 Univ Dr,MS3F5, Fairfax, VA 22030 USA. EM kperezed@gmu.edu RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Perez-Edgar, Koraly/0000-0003-4051-9563 FU John D. and Catherine T. MacArthur Foundation; NIH [MH074454, HD17899]; NIMH [MH073569]; NARSAD (Blowitz-Ridgeway Young Investigator Award) FX We would like to thank Stacey Barton, Melissa Ghera, Dalit H. Marshall, and Kirsten VanMeenen for their assistance in data collection. Funding for the study was provided by grants to Nathan A. Fox from the John D. and Catherine T. MacArthur Foundation and NIH (MH074454 and HD17899) and to Koraly Perez-Edgar from the NIMH (MH073569) and NARSAD (Blowitz-Ridgeway Young Investigator Award). NR 24 TC 35 Z9 35 U1 6 U2 27 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD MAR PY 2010 VL 83 IS 3 BP 269 EP 271 DI 10.1016/j.biopsycho.2009.08.009 PG 3 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 576EI UT WOS:000276126700013 ER PT J AU Nakamura, N Mori, C Eddy, EM AF Nakamura, Noriko Mori, Chisato Eddy, Edward M. TI Molecular Complex of Three Testis-Specific Isozymes Associated with the Mouse Sperm Fibrous Sheath: Hexokinase 1, Phosphofructokinase M, and Glutathione S-Transferase mu class 5 SO BIOLOGY OF REPRODUCTION LA English DT Article DE flagellum; gamete biology; gametogenesis; glycolysis; multienzyme complex; sperm; spermatogenesis; testis ID GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE-S; PORIN-BINDING DOMAIN; SPERMATOGENIC CELLS; GLYCOLYTIC ENZYME; MAMMALIAN SPERMATOZOA; MALE-FERTILITY; RAT TESTIS; GENE; EXPRESSION; LACTATE AB Mammalian sperm require ATP for motility, and most of it is generated by glycolysis. The glycolytic enzymes segregate to the principal piece region of the flagellum, where some are bound tightly to a novel cytoskeletal structure defining this region, the fibrous sheath (FS), and others are easily extracted with detergents. One of the latter is the spermatogenic cell-specific variant isozyme of hexokinase type 1 (HK1S), characterized by an N-terminal 24-amino acid spermatogenic cell-specific region (SSR). Yeast two-hybrid screens carried out using the SSR as bait determined that HK1S is tethered to muscle-type phosphofructokinase (PFKM) in the principal piece region. This led to the identification of four testis-specific Pfkm splice variants, one that overlapped a variant reported previously (Pfkm_v1) and three that were novel (Pfkm_v2, Pfkm_v3, and Pfkm_v4). They differ from Pfkm transcripts found in somatic cells by encoding a novel 67-amino acid N-terminal extension, the testis-specific region (TSR), producing a spermatogenic cell-specific PFKM variant isozyme (PFKMS). An antiserum generated to the TSR demonstrated that PFKMS is present in the principal piece and is insoluble in 1% Triton X-100 detergent. In subsequent yeast two-hybrid screens, the TSR was found to interact with glutathione S-transferase mu class 5 (GSTM5), identified previously as a spermatogenic cell-specific component of the FS. These results demonstrated that HK1S is tethered in the principal piece region by PFKMS, which in turn is bound tightly to GSTM5 in the FS. C1 [Nakamura, Noriko; Eddy, Edward M.] NIEHS, Gamete Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Mori, Chisato] Chiba Univ, Grad Sch Med, Dept Bioenvironm Med, Chuo Ku, Chiba, Japan. RP Eddy, EM (reprint author), NIEHS, Gamete Biol Sect, Reprod & Dev Toxicol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM eddy@niehs.nih.gov FU NIH, National Institute of Environmental Health Sciences FX Supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. NR 43 TC 20 Z9 25 U1 0 U2 1 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD MAR PY 2010 VL 82 IS 3 BP 504 EP 515 DI 10.1095/biolreprod.109.080580 PG 12 WC Reproductive Biology SC Reproductive Biology GA 557YY UT WOS:000274707900005 PM 19889946 ER PT J AU Hosnijeh, FS Krop, EJM Portengen, L Rabkin, CS Linseisen, J Vineis, P Vermeulen, R AF Hosnijeh, Fatemeh Saberi Krop, Esmeralda J. M. Portengen, Luetzen Rabkin, Charles S. Linseisen, Jakob Vineis, Paolo Vermeulen, Roel TI Stability and reproducibility of simultaneously detected plasma and serum cytokine levels in asymptomatic subjects SO BIOMARKERS LA English DT Article DE Cytokine; freeze-thaw cycle; reproducibility ID SOLUBLE ACTIVATION MARKERS; BEAD-BASED IMMUNOASSAYS; NON-HODGKIN-LYMPHOMA; MULTIPLEX IMMUNOASSAY; SAMPLE; COLLECTION; ASSAYS; CELLS AB Blood levels of cyto- and chemokines might reflect immune deregulations which might be related to lymphomagenesis. Potential utility of stored blood samples of a prospective cohort was evaluated by the effect of different blood sample types and freeze-thaw cycles on analyte levels. Bead-based immunoassays were performed on two fresh samples (serum, citrate and heparin plasma) of 10 asymptomatic adults collected 14 days apart and on aliquots of the first samples which were put through one to three freeze-thaw cycles to measure 11 cytokines, four chemokines and two adhesion molecules. Median coefficients of variation (CVs) of the measured analytes were 20%, 24% and 32% in serum, citrate and heparin plasma, respectively. Strong correlations (rank correlation coefficient 0.74-0.98) were observed between sample types, although small differences in analyte levels were observed for most analytes. Freeze-thaw cycles did not markedly change analyte levels. Our study supports the use of this assay among asymptomatic subjects in epidemiological studies. C1 [Hosnijeh, Fatemeh Saberi; Krop, Esmeralda J. M.; Portengen, Luetzen; Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, NL-3584 CK Utrecht, Netherlands. [Hosnijeh, Fatemeh Saberi] Zanjan Univ Med Sci, Zanjan, Iran. [Rabkin, Charles S.] NCI, Rockville, MD USA. [Linseisen, Jakob] Helmholtz Zentrum Munchen, Inst Epidemiol, Munich, Germany. [Vineis, Paolo] Univ London Imperial Coll Sci Technol & Med, London SW7 2AZ, England. [Vermeulen, Roel] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, Utrecht, Netherlands. RP Vermeulen, R (reprint author), Univ Utrecht, Inst Risk Assessment Sci, Div Environm Epidemiol, Jenalaan 18D, NL-3584 CK Utrecht, Netherlands. EM R.C.H.Vermeulen@uu.nl RI Linseisen, Jakob/B-5353-2014; Vermeulen, Roel/F-8037-2011; Saberi Hosnijeh, Fatemeh/N-6684-2013 OI Linseisen, Jakob/0000-0002-9386-382X; Vermeulen, Roel/0000-0003-4082-8163; FU ECNIS Network of Excellence, European Union [FOOD-CT-2005-513943]; Iranian Ministry of Health and Medical Education at Utrecht University FX We thank all the anonymous blood donors who participated in this study. This work was supported by the ECNIS Network of Excellence (Environmental Cancer Risk, Nutrition and Individual Susceptibility), operating within the European Union 6th Framework Program, Priority 5: 'Food Quality and Safety (FOOD-CT-2005-513943). The first author also acknowledges the Iranian Ministry of Health and Medical Education for support of a PhD programme at Utrecht University. NR 21 TC 20 Z9 20 U1 0 U2 2 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1354-750X J9 BIOMARKERS JI Biomarkers PD MAR PY 2010 VL 15 IS 2 BP 140 EP 148 DI 10.3109/13547500903340570 PG 9 WC Biotechnology & Applied Microbiology; Toxicology SC Biotechnology & Applied Microbiology; Toxicology GA 612OA UT WOS:000278907900006 PM 19848603 ER PT J AU Yang, S Prentice, R AF Yang, Song Prentice, Ross TI Improved Logrank-Type Tests for Survival Data Using Adaptive Weights SO BIOMETRICS LA English DT Article DE Clinical trials; Proportional and nonproportional hazards; Survival analysis; Time-varying treatment effect; Weighted logrank tests ID RIGHT-CENSORED DATA; LOG-RANK TEST; STATISTICS; EFFICIENCY; TRIALS; MODEL AB P>For testing for treatment effects with time-to-event data, the logrank test is the most popular choice and has some optimality properties under proportional hazards alternatives. It may also be combined with other tests when a range of nonproportional alternatives are entertained. We introduce some versatile tests that use adaptively weighted logrank statistics. The adaptive weights utilize the hazard ratio obtained by fitting the model of Yang and Prentice (2005, Biometrika 92, 1-17). Extensive numerical studies have been performed under proportional and nonproportional alternatives, with a wide range of hazard ratios patterns. These studies show that these new tests typically improve the tests they are designed to modify. In particular, the adaptively weighted logrank test maintains optimality at the proportional alternatives, while improving the power over a wide range of nonproportional alternatives. The new tests are illustrated in several real data examples. C1 [Yang, Song] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Prentice, Ross] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. RP Yang, S (reprint author), NHLBI, Off Biostat Res, 6701 Rockledge Dr MSC 7913, Bethesda, MD 20892 USA. EM yangso@nhlbi.nih.gov; rprentic@whi.org FU NIH [CA 53996] FX The authors are grateful to editor Dr David M. Zucker, the associate editor, and the referee for their helpful comments that led to improvement of the article. The research of RP is supported by NIH grant CA 53996. NR 29 TC 11 Z9 11 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD MAR PY 2010 VL 66 IS 1 BP 30 EP 38 DI 10.1111/j.1541-0420.2009.01243.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 571CH UT WOS:000275727200005 PM 19397582 ER PT J AU Huang, CY Qin, J Wang, MC AF Huang, C. -Y. Qin, J. Wang, M. -C. TI Semiparametric Analysis for Recurrent Event Data with Time-Dependent Covariates and Informative Censoring SO BIOMETRICS LA English DT Article DE Comparable recurrence times; Frailty; Pairwise pseudolikelihood; Proportional rate model ID PANEL COUNT DATA; REGRESSION-ANALYSIS; ASYMPTOTIC PROPERTIES; FRAILTY MODELS; SURVIVAL AB P>Recurrent event data analyses are usually conducted under the assumption that the censoring time is independent of the recurrent event process. In many applications the censoring time can be informative about the underlying recurrent event process, especially in situations where a correlated failure event could potentially terminate the observation of recurrent events. In this article, we consider a semiparametric model of recurrent event data that allows correlations between censoring times and recurrent event process via frailty. This flexible framework incorporates both time-dependent and time-independent covariates in the formulation, while leaving the distributions of frailty and censoring times unspecified. We propose a novel semiparametric inference procedure that depends on neither the frailty nor the censoring time distribution. Large sample properties of the regression parameter estimates and the estimated baseline cumulative intensity functions are studied. Numerical studies demonstrate that the proposed methodology performs well for realistic sample sizes. An analysis of hospitalization data for patients in an AIDS cohort study is presented to illustrate the proposed method. C1 [Huang, C. -Y.; Qin, J.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Wang, M. -C.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. RP Huang, CY (reprint author), NIAID, Biostat Res Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM huangchi@niaid.nih.gov FU National Institutes of Health [R01 AI078835]; NIDA [DA 04334, DA 08009] FX MCW's work was supported by National Institutes of Health grant R01 AI078835. The authors thank Drs David Vlahov and Steffanie Strathdee for providing the data from the ALIVE study, which was supported by NIDA grants DA 04334 and DA 08009. Comments from Drs Mike Proschan and Dean Follmann have improved the presentation of this article. NR 31 TC 19 Z9 19 U1 0 U2 12 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X EI 1541-0420 J9 BIOMETRICS JI Biometrics PD MAR PY 2010 VL 66 IS 1 BP 39 EP 49 DI 10.1111/j.1541-0420.2009.01266.x PG 11 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 571CH UT WOS:000275727200006 PM 19459839 ER PT J AU Yu, K Wheeler, W Li, QZ Bergen, AW Caporaso, N Chatterjee, N Chen, JB AF Yu, Kai Wheeler, William Li, Qizhai Bergen, Andrew W. Caporaso, Neil Chatterjee, Nilanjan Chen, Jinbo TI A Partially Linear Tree-based Regression Model for Multivariate Outcomes SO BIOMETRICS LA English DT Article DE Generalized estimating equation; Genetic association study; Model selection; Multiple-comparison adjustment; Tree-based model ID CLASSIFICATION TREES; LONGITUDINAL DATA; ASSOCIATION AB P>In the genetic study of complex traits, especially behavior related ones, such as smoking and alcoholism, usually several phenotypic measurements are obtained for the description of the complex trait, but no single measurement can quantify fully the complicated characteristics of the symptom because of our lack of understanding of the underlying etiology. If those phenotypes share a common genetic mechanism, rather than studying each individual phenotype separately, it is more advantageous to analyze them jointly as a multivariate trait to enhance the power to identify associated genes. We propose a multilocus association test for the study of multivariate traits. The test is derived from a partially linear tree-based regression model for multiple outcomes. This novel tree-based model provides a formal statistical testing framework for the evaluation of the association between a multivariate outcome and a set of candidate predictors, such as markers within a gene or pathway, while accommodating adjustment for other covariates. Through simulation studies we show that the proposed method has an acceptable type I error rate and improved power over the univariate outcome analysis, which studies each component of the complex trait separately with multiple-comparison adjustment. A candidate gene association study of multiple smoking-related phenotypes is used to demonstrate the application and advantages of this new method. The proposed method is general enough to be used for the assessment of the joint effect of a set of multiple risk factors on a multivariate outcome in other biomedical research settings. C1 [Yu, Kai; Li, Qizhai; Caporaso, Neil; Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Wheeler, William] Informat Management Serv Inc, Rockville, MD 20892 USA. [Li, Qizhai] CAS, Acad Math & Syst Sci, Beijing 100190, Peoples R China. [Bergen, Andrew W.] SRI Int, Ctr Hlth Sci, Mol Genet Program, Menlo Pk, CA 94025 USA. [Chen, Jinbo] Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. RP Yu, K (reprint author), NCI, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. EM yuka@mail.nih.gov OI Bergen, Andrew/0000-0002-1237-7644 FU NIH; National Cancer Institute; National Science Foundation of China [10371126]; [U01 DA020830] FX This research utilized the high-performance computational capabilities of the Biowulf PC/Linux cluster at the National Institutes of Health, Bethesda, Maryland, USA (http://biowulf.nih.gov). The work of KY, QL, NC, and NC was supported in part by the Intramural Program of the NIH and the National Cancer Institute. The work of QL was also partially supported by the National Science Foundation of China, No. 10371126. AWB was supported by U01 DA020830. NR 21 TC 8 Z9 8 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2010 VL 66 IS 1 BP 89 EP 96 DI 10.1111/j.1541-0420.2009.01235.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 571CH UT WOS:000275727200011 PM 19432770 ER PT J AU Zheng, G Li, ZH Gail, MH Gastwirth, JL AF Zheng, Gang Li, Zhaohai Gail, Mitchell H. Gastwirth, Joseph L. TI Impact of Population Substructure on Trend Tests for Genetic Case-Control Association Studies SO BIOMETRICS LA English DT Article DE Allele frequency matching; Bias; Cryptic relatedness; Disease rate heterogeneity; Population stratification; Variance distortion ID GENOMIC CONTROL; SAMPLE-SIZE; STRATIFICATION; VARIANTS; MARKERS; POWER AB P>Hidden population substructure in case-control data has the potential to distort the performance of Cochran-Armitage trend tests (CATTs) for genetic associations. Three possible scenarios that may arise are investigated here: (i) heterogeneity of genotype frequencies across unidentified subpopulations (PSI), (ii) heterogeneity of genotype frequencies and disease risk across unidentified subpopulations (PSII), and (iii) cryptic correlations within unidentified subpopulations. A unified approach is presented for deriving the bias and variance distortion under the three scenarios for any CATT in a general family. Using these analytical formulas, we evaluate the excess type I errors of the CATTs numerically in the presence of population substructure. Our results provide insight into the properties of some proposed corrections for bias and variance distortion and show why they may not fully correct for the effects of population substructure. C1 [Zheng, Gang] NHLBI, Off Biostat Res, DPPS, Bethesda, MD 20892 USA. [Li, Zhaohai; Gastwirth, Joseph L.] George Washington Univ, Dept Stat, Washington, DC 20052 USA. [Li, Zhaohai; Gail, Mitchell H.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, EPS, Bethesda, MD 20892 USA. RP Zheng, G (reprint author), NHLBI, Off Biostat Res, DPPS, 6701 Rockledge Dr,MSC 7913, Bethesda, MD 20892 USA. EM zhengg@nhlbi.nih.gov FU NIH [EY014478]; NSF FX We thank Dr Hong Zhang for several helpful discussions and suggestions. We also thank the editor, an associate editor, and a reviewer for their very thoughtful and useful suggestions and comments, which greatly improved our presentation. The work of ZL was partially supported by an NIH grant EY014478. The work of JLG was partially supported by an NSF grant. NR 30 TC 4 Z9 4 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2010 VL 66 IS 1 BP 196 EP 204 DI 10.1111/j.1541-0420.2009.01264.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 571CH UT WOS:000275727200023 PM 19432788 ER PT J AU Joo, J Kwak, MJ Zheng, G AF Joo, Jungnam Kwak, Minjung Zheng, Gang TI Improving Power for Testing Genetic Association in Case-Control Studies by Reducing the Alternative Space SO BIOMETRICS LA English DT Article DE Genetic models; Hardy-Weinberg disequilibrium; MAX; Robust tests; Trend tests ID GENOME-WIDE ASSOCIATION; EFFICIENCY ROBUST-TESTS; SAMPLE-SIZE; DISEQUILIBRIUM; STATISTICS; SURVIVAL; DISEASES; MARKERS; MODELS AB To detect association between a genetic marker and a disease in case-control studies, the Cochran-Armitage trend test is typically used. The trend test is locally optimal when the genetic model is correctly specified. However, in practice, the underlying genetic model, and hence the optimal trend test, are usually unknown. In this case, Pearson's chi-squared test, the maximum of three trend test statistics (optimal for the recessive, additive, and dominant models), and the test based on genetic model selection (GMS) are useful. In this article, we first modify the existing GMS method so that it can be used when the risk allele is unknown. Then we propose a new approach by excluding a genetic model that is not supported by the data. Using either the model selection or exclusion, the alternative space is reduced conditional on the observed data, and hence the power to detect a true association can be increased. Simulation results are reported and the proposed methods are applied to the genetic markers identified from the genome-wide association studies conducted by the Wellcome Trust Case-Control Consortium. The results demonstrate that the genetic model exclusion approach usually performs better than existing methods under its worst situation across scientifically plausible genetic models we considered. C1 [Joo, Jungnam; Kwak, Minjung; Zheng, Gang] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. RP Joo, J (reprint author), NHLBI, Off Biostat Res, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM jooj@nhlbi.nih.gov NR 25 TC 11 Z9 12 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2010 VL 66 IS 1 BP 266 EP 276 DI 10.1111/j.1541-0420.2009.01241.x PG 11 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 851OO UT WOS:000297280600008 PM 19397584 ER PT J AU Yu, BB Ghosh, P AF Yu, Binbing Ghosh, Pulak TI Joint Modeling for Cognitive Trajectory and Risk of Dementia in the Presence of Death SO BIOMETRICS LA English DT Article DE Change point; Competing risks; Dementia; Markov chain Monte Carlo ID CHANGE-POINT; DECLINE; CHANGEPOINT; EDUCATION AB Dementia is characterized by accelerated cognitive decline before and after diagnosis as compared to normal aging. It has been known that cognitive impairment occurs long before the diagnosis of dementia. For individuals who develop dementia, it is important to determine the time when the rate of cognitive decline begins to accelerate and the subsequent gap time to dementia diagnosis. For normal aging individuals, it is also useful to understand the trajectory of cognitive function until their death. A Bayesian change-point model is proposed to fit the trajectory of cognitive function for individuals who develop dementia. In real life, people in older ages are subject to two competing risks, e. g., dementia and dementia-free death. Because the majority of people do not develop dementia, a mixture model is used for survival data with competing risks, which consists of dementia onset time after the change point of cognitive function decline for demented individuals and death time for nondemented individuals. The cognitive trajectories and the survival process are modeled jointly and the parameters are estimated using the Markov chain Monte Carlo method. Using data from the Honolulu Asia Aging Study, we show the trajectories of cognitive function and the effect of education, apolipoprotein E 4 genotype, and hypertension on cognitive decline and the risk of dementia. C1 [Yu, Binbing] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Ghosh, Pulak] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA. [Ghosh, Pulak] Emory Univ, Dept Biostat, Atlanta, GA 30322 USA. RP Yu, BB (reprint author), NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. EM yubi@mail.nih.gov; pulakghosh@gmail.com FU National Institute on Aging FX This research was supported in part by the Intramural Research Program of the National Institute on Aging. We thank two anonymous reviewers and the associate editor for their helpful suggestions. NR 25 TC 11 Z9 11 U1 8 U2 10 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2010 VL 66 IS 1 BP 294 EP 300 DI 10.1111/j.1541-0420.2009.01261.x PG 7 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 851OO UT WOS:000297280600011 PM 19432791 ER PT J AU Jha, A Mukherjee, C Prasad, AK Parmar, VS Vadaparti, M Das, U De Clercq, E Balzarini, J Stables, JP Shrivastav, A Sharma, RK Dimmock, JR AF Jha, Amitabh Mukherjee, Chandrani Prasad, Ashok K. Parmar, Virinder S. Vadaparti, Manjula Das, Umashankar De Clercq, Erik Balzarini, Jan Stables, James P. Shrivastav, Anuraag Sharma, Rajendra K. Dimmock, Jonathan R. TI Derivatives of aryl amines containing the cytotoxic 1,4-dioxo-2-butenyl pharmacophore SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE 1,4-Dioxo-2-butenyl; Cytotoxicity; N-Arylmaleamates; N-Arylfumaramates; N-Arylmaleimides; N-Arylisomaleimides; Structure-activity relationships; Molecular modeling ID AGENTS; INHIBITION; CYSTEINE AB Several series of compounds containing the 1,4-dioxo-2-butenyl moiety have been prepared as candidate cytotoxins, including the methyl N-arylmaleamates, methyl N-arylfumaramates, and N-arylmaleimides. In addition, the N-arylisomaleimides were synthesized which are the structural isomers of N-arylmaleimides. These compounds were evaluated against human Molt 4/C8 and CEM T-lymphocytes as well as murine L1210 cells. Methyl N-arylfumaramates showed the highest cytotoxic potencies and, in particular, methyl N-(3,4-dichlorophenyl)fumaramate is six times more potent than melphalan towards L1210 cells and is equipotent with this drug in the Molt 4/C8 assay. Electrophilicity of compounds under investigation was demonstrated by carrying out thiolation using model benzyl mercaptan on representative compounds. Methyl N-(3,4-dichlorophenyl)fumaramate and methyl N-(4-chlorophenyl)maleamate inhibited human N- myristoyltransferase, a possible molecular target, in high micromolar range. QSAR and molecular modeling revealed some correlations between different structural features of a number of the molecules and cytotoxic potencies. Methyl N-arylfumaramates were well tolerated in mice in comparison to the analogs in other series of compounds tested. The data obtained in this investigation affords guidelines for preparing new series of molecules with greater potencies. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Jha, Amitabh; Mukherjee, Chandrani; Vadaparti, Manjula] Acadia Univ, Dept Chem, Wolfville, NS B4P 2R6, Canada. [Mukherjee, Chandrani; Prasad, Ashok K.; Parmar, Virinder S.] Univ Delhi, Dept Chem, Delhi 110007, India. [Das, Umashankar; Dimmock, Jonathan R.] Univ Saskatchewan, Coll Pharm & Nutr, Saskatoon, SK S7N 5C9, Canada. [De Clercq, Erik; Balzarini, Jan] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. [Stables, James P.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20852 USA. [Shrivastav, Anuraag; Sharma, Rajendra K.] Univ Saskatchewan, Coll Med, Dept Pathol, Saskatoon, SK S7N 4H4, Canada. [Shrivastav, Anuraag; Sharma, Rajendra K.] Canc Res Unit, Saskatoon, SK S7N 4H4, Canada. RP Jha, A (reprint author), Acadia Univ, Dept Chem, Wolfville, NS B4P 2R6, Canada. EM ajha@acadiau.ca RI Jha, Amitabh/B-5452-2010 OI Jha, Amitabh/0000-0002-6305-0721 FU Nova Scotia Health Research Foundation; Canadian Institutes of Health Research; Fonds voor Wetenschappelijk Onderzoek-Vlaanderen; Department of Biotechnology, DBT, New Delhi FX The authors thank the following agencies for financial support, namely the Nova Scotia Health Research Foundation (A.J.), Canadian Institutes of Health Research (A.J., J.R.D., R.K. S), Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (J.B., E.D.C.), and the Department of Biotechnology, DBT, New Delhi (A.K.P.). Appreciation is extended to Mrs. Lizette van Berckelaer for conducting the Molt 4/C8, CEM and L1210 assays, and the National Institute of Neurological Disorders and Stroke, MD, U. S. A. for undertaking the short-term toxicity studies in mice. Dr Mike Lumsden of Atlantic Region Magnetic Resonance Centre, Dalhousie University is thanked for his help in recording 1D NOESY experiments on certain samples. NR 22 TC 9 Z9 10 U1 0 U2 8 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 MAR 1 PY 2010 VL 20 IS 5 BP 1510 EP 1515 DI 10.1016/j.bmcl.2010.01.098 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 558BG UT WOS:000274714600008 PM 20149656 ER PT J AU Ballet, S Marczak, ED Feytens, D Salvadori, S Sasaki, Y Abell, AD Lazarus, LH Balboni, G Tourwe, D AF Ballet, Steven Marczak, Ewa D. Feytens, Debby Salvadori, Severo Sasaki, Yusuke Abell, Andrew D. Lazarus, Lawrence H. Balboni, Gianfranco Tourwe, Dirk TI Novel multiple opioid ligands based on 4-aminobenzazepinone (Aba), azepinoindole (Aia) and tetrahydroisoquinoline (Tic) scaffolds SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Designed multiple ligands; Constrained amino acids; Dual mu/delta opioid antagonists ID RECEPTOR ANTAGONISTS; BIVALENT LIGANDS; DOUBLE-ENKEPHALINS; SIDE-CHAIN; ANALOGS; AGONISTS; PHARMACOPHORE; PEPTIDE; POTENT; BINALTORPHIMINE AB The dimerization and trimerization of the Dmt-Tic, Dmt-Aia and Dmt-Aba pharmacophores provided multiple ligands which were evaluated in vitro for opioid receptor binding and functional activity. Whereas the Tic-and Aba multimers proved to be dual and balanced delta/mu antagonists, as determined by the functional [S(35)] GTP gamma S binding assay, the dimerization of potent Aia-based 'parent' ligands unexpectedly resulted in substantial less efficient receptor binding and non-active dimeric compounds. (C) 2010 Elsevier Ltd. All rights reserved. C1 [Ballet, Steven; Feytens, Debby; Tourwe, Dirk] Vrije Univ Brussels, Dept Organ Chem, B-1050 Brussels, Belgium. [Ballet, Steven; Abell, Andrew D.] Univ Adelaide, Sch Chem & Phys, Adelaide, SA 5005, Australia. [Marczak, Ewa D.; Lazarus, Lawrence H.] Natl Inst Environm Hlth Sci, Med Chem Grp, LP, Res Triangle Pk, NC 27709 USA. [Salvadori, Severo] Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. [Salvadori, Severo] Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. [Sasaki, Yusuke] Tohoku Pharmaceut Univ, Dept Pharmacol, Aoba Ku, Sendai, Miyagi 9818558, Japan. [Balboni, Gianfranco] Univ Cagliari, Dept Toxicol, I-09124 Cagliari, Italy. RP Ballet, S (reprint author), Vrije Univ Brussels, Dept Organ Chem, B-1050 Brussels, Belgium. EM sballet@vub.ac.be OI SALVADORI, Severo/0000-0002-8224-2358 FU Scientific Research-Flanders (Belgium); Australian Research Council [20103228]; NIH; NIEHS FX S. Ballet and D. Feytens are Research Assistants of the Fund of Scientific Research-Flanders (Belgium). This research was supported by the Australian Research Council (Grant 20103228) and in part supported by the Intramural Research Program of the NIH and NIEHS. We also thank Professor Peter Schiller (IRCM, Montreal) for the valuable comments during the preparation of this manuscript. NR 38 TC 5 Z9 5 U1 0 U2 3 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 MAR 1 PY 2010 VL 20 IS 5 BP 1610 EP 1613 DI 10.1016/j.bmcl.2010.01.055 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 558BG UT WOS:000274714600032 PM 20137938 ER PT J AU Otani, T Hashizume, T Nagaoka, T Fukuda, T Tang, CK Salomon, DS Seno, M AF Otani, Takayuki Hashizume, Toshihiro Nagaoka, Tadahiro Fukuda, Tomoko Tang, Careen K. Salomon, David S. Seno, Masaharu TI Production of biologically active IgG hinge-tag soluble epidermal growth factor receptors (ErbB) SO BIOTECHNOLOGY LETTERS LA English DT Article DE Epidermal growth factor receptors; ErbB; Extracellular domain; Hinge region; Homodimer; Soluble receptor ID EXTRACELLULAR DOMAINS; BINDING; AFFINITY; LIGAND; CELLS AB The extracellular domains (ECD) of epidermal growth factor receptors, ErbB1, 2, 3 and 4, were designed as soluble dimeric forms. Each ECD was fused to a short hinge region derived from IgG, such that the stable dimer could be formed with disulfide bridges. This hinge-tagged design minimized the molecular weight to approximately 50% of the conventional Fc-fusion design without an Fc domain of IgG. The refolded dimers could be easily analyzed and characterized by SDS-PAGE. Hinge-tagged soluble ErbBs demonstrated significant affinity for betacellulin and heregulin. The IgG hinge-tag should be a simple method to design soluble dimers that would be useful for high throughput screening of ligands, antagonists or derivatives. C1 [Otani, Takayuki; Hashizume, Toshihiro; Fukuda, Tomoko; Seno, Masaharu] Okayama Univ, Dept Med & Bioengn Sci, Grad Sch Nat Sci & Technol, Kita Ku, Okayama 7008530, Japan. [Nagaoka, Tadahiro; Salomon, David S.] NCI, Tumor Growth Factor Sect, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Tang, Careen K.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. RP Seno, M (reprint author), Okayama Univ, Dept Med & Bioengn Sci, Grad Sch Nat Sci & Technol, Kita Ku, 3-1-1 Tsushima Naka, Okayama 7008530, Japan. EM mseno@cc.okayama-u.ac.jp RI SENO, Masaharu /B-2092-2011; OI SENO, Masaharu /0000-0001-8547-6259; Nagaoka, Tadahiro/0000-0002-9391-0243 FU Ministry of Education, Culture, Sports, Science and Technology [18300164, 21300179] FX We thank Ms. N. Hironaka for the construction of sErbB2 and sErbB3 expression plasmid. This research was partly supported by the Ministry of Education, Culture, Sports, Science and Technology Grant-in-Aid for Scientific Research (B) Nos. 18300164 and 21300179. NR 15 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-5492 J9 BIOTECHNOL LETT JI Biotechnol. Lett. PD MAR PY 2010 VL 32 IS 3 BP 361 EP 366 DI 10.1007/s10529-009-0160-9 PG 6 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 555UW UT WOS:000274542600004 PM 19898750 ER PT J AU Suppes, T Hellemann, G Frye, MA McElroy, S Nolen, W Kupka, R Leverich, G Grunze, H AF Suppes, T. Hellemann, G. Frye, M. A. McElroy, S. Nolen, W. Kupka, R. Leverich, G. Grunze, H. TI Mixed depression in bipolar disorder: prevalence rate and clinical correlates during naturalistic follow up SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 4th Biennial Conference of the International-Society-for-Bipolar-Disorders CY MAR 17-20, 2010 CL Sao Paulo, BRAZIL SP Int Soc Bipolar Disorders C1 [Suppes, T.] Stanford Univ, Stanford, CA 94305 USA. [Hellemann, G.] Univ Calif Los Angeles, Los Angeles, CA USA. [Frye, M. A.] Mayo Clin, Dept Psychiat, Rochester, MN USA. [McElroy, S.] Lindner Ctr HOPE, Mason, OH USA. [Nolen, W.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Kupka, R.] Univ Med Ctr, Utrecht, Netherlands. [Kupka, R.] Altrecht Inst Mental Hlth Care, Utrecht, Netherlands. [Leverich, G.] NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. [Grunze, H.] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England. RI Nolen, Willem/E-9006-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 EI 1399-5618 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2010 VL 12 SU 1 BP 52 EP 52 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 566BL UT WOS:000275344600188 ER PT J AU Post, RM Nolen, WA Kupka, RW Altshuler, LL Frye, MA Suppes, T McElroy, SL Keck, PE Grunze, H Rowe, M Leverich, GS AF Post, R. M. Nolen, W. A. Kupka, R. W. Altshuler, L. L. Frye, M. A. Suppes, T. McElroy, S. L. Keck, P. E. Grunze, H. Rowe, M. Leverich, G. S. TI Increased risk factors and poor long-term outcome in the US compared to Holland and Germany SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 4th Biennial Conference of the International-Society-for-Bipolar-Disorders CY MAR 17-20, 2010 CL Sao Paulo, BRAZIL SP Int Soc Bipolar Disorders C1 [Post, R. M.] Bipolar Collaborat Network, Bethesda, MD USA. [Nolen, W. A.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Kupka, R. W.] Altrecht Inst Mental Hlth Care, Utrecht, Netherlands. [Kupka, R. W.] Univ Med Ctr, Utrecht, Netherlands. [Altshuler, L. L.] Univ Calif Los Angeles, Neuropsychiat Inst & Hosp, Mood Disorders Res Program, Los Angeles, CA 90024 USA. [Frye, M. A.] Mayo Clin, Dept Psychiat, Rochester, MN USA. [Suppes, T.] Stanford Univ, Stanford, CA 94305 USA. [McElroy, S. L.; Keck, P. E.] Lindner Ctr HOPE, Mason, OH USA. [Grunze, H.] Newcastle Univ, Inst Neurosci, Newcastle Upon Tyne, Tyne & Wear, England. [Rowe, M.; Leverich, G. S.] NIMH, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. RI Nolen, Willem/E-9006-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2010 VL 12 SU 1 BP 62 EP 63 PG 2 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 566BL UT WOS:000275344600226 ER PT J AU Schulze, T AF Schulze, T. TI Genome-wide association studies in bipolar disorder and beyond SO BIPOLAR DISORDERS LA English DT Meeting Abstract CT 4th Biennial Conference of the International-Society-for-Bipolar-Disorders CY MAR 17-20, 2010 CL Sao Paulo, BRAZIL SP Int Soc Bipolar Disorders C1 [Schulze, T.] NIMH, Unit Genet Basis Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. [Schulze, T.] Johns Hopkins Univ, Dept Psychiat & Behav Sci, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2010 VL 12 SU 1 BP 64 EP 64 PG 1 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 566BL UT WOS:000275344600232 ER PT J AU Gracious, BL Chirieac, MC Costescu, S Finucane, TL Youngstrom, EA Hibbeln, JR AF Gracious, Barbara L. Chirieac, Madalina C. Costescu, Stefan Finucane, Teresa L. Youngstrom, Eric A. Hibbeln, Joseph R. TI Randomized, placebo-controlled trial of flax oil in pediatric bipolar disorder SO BIPOLAR DISORDERS LA English DT Article DE adolescents; bipolar disorder; children; flax oil; omega-3 fatty acid ID POLYUNSATURATED FATTY-ACIDS; POSTMORTEM ORBITOFRONTAL CORTEX; BLOOD-CELL MEMBRANES; DOUBLE-BLIND; EICOSAPENTAENOIC ACID; DOCOSAHEXAENOIC ACID; CHOLESTERYL ESTERS; DEPRESSED-PATIENTS; ARACHIDONIC-ACID; MOOD DISORDERS AB Objectives: This clinical trial evaluated whether supplementation with flax oil, containing the omega-3 fatty acid alpha-linolenic acid (alpha-LNA), safely reduced symptom severity in youth with bipolar disorder. Methods: Children and adolescents aged 6-17 years with symptomatic bipolar I or bipolar II disorder (n = 51), manic, hypomanic, mixed, or depressed, were randomized to either flax oil capsules containing 550 mg alpha-LNA per 1 gram or an olive oil placebo adjunctively or as monotherapy. Doses were titrated to 12 capsules per day as tolerated over 16 weeks. Primary outcomes included changes in the Young Mania Rating Scale, Child Depression Rating Scale-Revised, and Clinical Global Impressions-Bipolar ratings using Kaplan-Meier survival analyses. Results: There were no significant differences in primary outcome measures when compared by treatment assignment. However, clinician-rated Global Symptom Severity was negatively correlated with final serum omega-3 fatty acid compositions: %alpha-LNA (r = -0.45, p < 0.007), % eicosapentaenoic acid (EPA) (r = -0.47, p < 0.005); and positively correlated with final arachidonic acid (AA) (r = 0.36, p < 0.05) and docosapentaenoic acid (DPA) n-6 (r = 0.48, p < 0.004). The mean duration of treatment for alpha-LNA was 11.8 weeks versus 8 weeks for placebo; however, the longer treatment duration for alpha-LNA was not significant after controlling for baseline variables. Subjects discontinued the study for continued depressive symptoms. Conclusions: Studies of essential fatty acid supplementation are feasible and well tolerated in the pediatric population. Although flax oil may decrease severity of illness in children and adolescents with bipolar disorder who have meaningful increases in serum EPA percent levels and/or decreased AA and DPA n-6 levels, individual variations in conversion of alpha-LNA to EPA and docosahexaenoic acid as well as dosing burden favor the use of fish oil both for clinical trials and clinical practice. Additionally, future research should focus on adherence and analysis of outcome based on changes in essential fatty acid tissue compositions, as opposed to group randomization alone. C1 [Gracious, Barbara L.; Chirieac, Madalina C.; Costescu, Stefan; Finucane, Teresa L.] Univ Rochester, Lab Mood Disorders Children & Adolescents, Strong Mem Hosp, Dept Psychiat,Med Ctr, Rochester, NY 14642 USA. [Youngstrom, Eric A.] Univ N Carolina, Dept Psychiat & Psychol, Chapel Hill, NC USA. [Hibbeln, Joseph R.] NIAAA, Sect Nutr Neurochem, NIH, Bethesda, MD USA. RP Gracious, BL (reprint author), Univ Rochester, Med Ctr, Dept Psychiat, 300 Crittenden Blvd, Rochester, NY 14642 USA. EM barbara_gracious@urmc.rochester.edu FU Stanley Medical Research Foundation; National Research Service Award Institutional Training [T32-MH-018911]; National Center for Research Resources (NCRR) [1-KL2-RR024136-1]; National Institutes of Health (NIH) FX This research was funded by the Stanley Medical Research Foundation, and National Research Service Award Institutional Training Grant T32-MH-018911. This publication was made possible by Grant #1-KL2-RR024136-1 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and the NIH Roadmap for Medical Research. Its contents are solely the responsibility of the authors and do not necessarily represent the official view of the NCRR or the NIH. Information on the NCRR is available at http://www.ncrr.nih.gov/. Information on re-engineering the Clinical Research Enterprise can be obtained from http://nihroadmap.nih.gov/clinicalresearch/overview-translational. asp. We thank the families who participated in the study and also thank Dr. Ann Moser, Jeffrey Swan, Resa Whipkey, Lauren Rios, Stephen Bean, Michael Banchy, and Carolyn Myers for their assistance. NR 59 TC 36 Z9 36 U1 2 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD MAR PY 2010 VL 12 IS 2 BP 142 EP 154 PG 13 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 574SR UT WOS:000276014200003 PM 20402707 ER PT J AU Mathew, S Fu, LZ Hasebe, T Ishizuya-Oka, A Shi, YB AF Mathew, Smita Fu, Liezhen Hasebe, Takashi Ishizuya-Oka, Atsuko Shi, Yun-Bo TI Tissue-Dependent Induction of Apoptosis by Matrix Metalloproteinase Stromelysin-3 During Amphibian Metamorphosis SO BIRTH DEFECTS RESEARCH PART C-EMBRYO TODAY-REVIEWS LA English DT Review DE matrix metalloproteinase; stromelysin-3; metamorphosis; Xenopus laevis; tumor invasion; apoptosis ID THYROID-HORMONE RECEPTOR; XENOPUS-LAEVIS METAMORPHOSIS; 67-KDA LAMININ RECEPTOR; DUPLICATED MATRIX-METALLOPROTEINASE-9 GENES; IMPLICATES DISTINCT FUNCTIONS; INDUCED TAIL RESORPTION; EXTRACELLULAR-MATRIX; BREAST-CANCER; FROG METAMORPHOSIS; TADPOLE TAIL AB Matrix metalloproteinases (MMPs) are a superfamily of Zn(2+)-dependent proteases that are capable of cleaving the proteinaceous component of the extracellular matrix (ECM). The ECM is a critical medium for cell-cell interactions and can also directly signal cells through cell surface ECM receptors, such as integrins. In addition, many growth factors and signaling molecules are stored in the ECM. Thus, ECM remodeling and/or degradation by MMPs are expected to affect cell fate and behavior during many developmental and pathological processes. Numerous studies have shown that the expression of MMP mRNAs and proteins associates tightly with diverse developmental and pathological processes, such as tumor metastasis and mammary gland involution. In vivo evidence to support the roles of MMPs in these processes has been much harder to get. Here, we will review some of our studies on MMP11, or stromelysin-3, during the thyroid hormone-dependent amphibian metamorphosis, a process that resembles the so-called postembryonic development in mammals (from a few months before to several months after birth in humans when organ growth and maturation take place). Our investigations demonstrate that stromelysin-3 controls apoptosis in different tissues via at least two distinct mechanisms. Birth Defects Research (Part C) 90:55-66,2010. (C) 2010 Wiley-Liss, Inc. C1 [Hasebe, Takashi; Ishizuya-Oka, Atsuko] Nippon Med Sch, Dept Biol, Kawasaki 2110063, Japan. [Mathew, Smita; Fu, Liezhen; Shi, Yun-Bo] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Mol Morphogenesis, Lab Gene Regulat & Dev, Program Cellular Regulat & Metab,NIH, Bethesda, MD 20892 USA. RP Ishizuya-Oka, A (reprint author), Nippon Med Sch, Dept Biol, Kawasaki 2110063, Japan. EM a-oka@nms.ac.jp; shi@helix.nih.gov FU NIH; JSPS [20570060] FX Supported by the Intramural Research Program of NICHD, NIH, and a grant from JSPS Grants-in-Aid for Scientific Research (C) (20570060) NR 130 TC 8 Z9 8 U1 2 U2 6 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-975X J9 BIRTH DEFECTS RES C JI Birth Defects Res. Part C-Embryo Today-Rev. PD MAR PY 2010 VL 90 IS 1 BP 55 EP 66 DI 10.1002/bdrc.20170 PG 12 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 578IJ UT WOS:000276286600005 PM 20301218 ER PT J AU Aronin, CEP Tuan, RS AF Aronin, Caren E. Petrie Tuan, Rocky S. TI Therapeutic Potential of the Immunomodulatory Activities of Adult Mesenchymal Stem Cells SO BIRTH DEFECTS RESEARCH PART C-EMBRYO TODAY-REVIEWS LA English DT Review DE mesenchymal stem cells; immunomodulation; regenerative medicine ID MARROW STROMAL CELLS; TOLL-LIKE RECEPTOR-4; VERSUS-HOST-DISEASE; PROLIFERATION IN-VITRO; HUMAN ADIPOSE-TISSUE; BONE-MARROW; EXTRACELLULAR-MATRIX; T-CELLS; LYMPHOCYTE-PROLIFERATION; PROGENITOR CELLS AB Adult mesenchymal stem cells (MSCs) include a select population of resident cells within adult tissues, which retain the ability to differentiate along several tissue-specific lineages under defined media conditions and have finite expansion potential in vitro. These adult progenitor populations have been identified in various tissues, but it remains unclear exactly what role both transplanted and native MSCs play in processes of disease and regeneration. Interestingly, increasing evidence reveals a unique antiinflammatory immunomodulatory phenotype shared among this population, lending support to the idea that MSCs play a central role in early tissue remodeling responses where a controlled inflammatory response is required. However, additional evidence suggests that MSCs may not retain infinite immune privilege and that the context with which these cells are introduced in vivo may influence their immune phenotype. Therefore, understanding this dynamic micro-environment in which MSCs participate in complex feedback loops acting upon and being influenced by a plethora of secreted cytokines, extracellular matrix molecules, and fragments will be critical to elucidating the role of MSCs in the intertwined processes of immunomodulation and tissue repair. Birth Defects Research (Part C) 90:67-74, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Tuan, Rocky S.] Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, Pittsburgh, PA 15219 USA. [Aronin, Caren E. Petrie; Tuan, Rocky S.] NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), Univ Pittsburgh, Sch Med, Dept Orthopaed Surg, Ctr Cellular & Mol Engn, 450 Technol Dr,Room 221, Pittsburgh, PA 15219 USA. EM rst13@pitt.edu FU NIH [201 AR41131]; Pennsylvania Department of Health FX Grant sponsor: Intramural Research Program, NIH; Grant number: 201 AR41131; and Pennsylvania Department of Health. NR 95 TC 33 Z9 34 U1 1 U2 11 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-975X EI 1542-9768 J9 BIRTH DEFECTS RES C JI Birth Defects Res. Part C-Embryo Today-Rev. PD MAR PY 2010 VL 90 IS 1 BP 67 EP 74 DI 10.1002/bdrc.20174 PG 8 WC Developmental Biology; Reproductive Biology SC Developmental Biology; Reproductive Biology GA 578IJ UT WOS:000276286600006 ER PT J AU Lynch, AM Murphy, JR Gibbs, RS Levine, RJ Giclas, PC Salmon, JE Holers, VM AF Lynch, A. M. Murphy, J. R. Gibbs, R. S. Levine, R. J. Giclas, P. C. Salmon, J. E. Holers, V. M. TI The interrelationship of complement-activation fragments and angiogenesis-related factors in early pregnancy and their association with pre-eclampsia SO BJOG-AN INTERNATIONAL JOURNAL OF OBSTETRICS AND GYNAECOLOGY LA English DT Article DE Angiogenesis-related factors; complement-activating factors; obesity; pre-eclampsia ID PLACENTAL GROWTH-FACTOR; INTRAUTERINE GROWTH; ANTIANGIOGENIC FACTORS; ALTERNATIVE PATHWAY; SOLUBLE ENDOGLIN; ADIPOSE-TISSUE; 2 PARTS; RISK; RESTRICTION; IMMUNOLOGY AB Objective To determine the interrelationships during early pregnancy of complement-activation fragments Bb, C3a and sC5b-9, and angiogenesis-related factors placental growth factor (PiGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng), and their associations with pre-eclampsia. Design Prospective cohort study. Setting Denver complement study (June 2005-June 2008). Population A total of 668 pregnant women with singleton gestations, recruited between 10 and 15 weeks of gestation. Methods Using univariable and multivariable logistic regression analysis, concentrations of complement-activation fragments and angiogenesis-related factors were compared between 10 and 15 weeks of gestation in women who subsequently did or did not develop pre-eclampsia. Interrelationships between these variables were tested using the non-parametric Spearman rank correlation coefficient. Main outcome measure Pre-eclampsia. The association of complement-activation fragments and angiogenesis-related factors with obesity was also examined. Results The mean (+/-SD) levels of complement Bb in early pregnancy among women who did and did not develop pre-eclampsia were 0.84 (+/-0.26) mu g/ml and 0.69 (+/-0.2) mu g/ml, respectively (P = 0.001). Concentrations of PiGF were significantly (P = 0.01) lower (31 +/- 12 pg/ml) in early pregnancy in the pre-eclamptic group of women, as compared with the normotensive group (39 +/- 32 pg/ml). The adjusted odds ratio (AOR) of Bb and PiGF were 2.1 (CI = 1.4-3.1, P < 0.0003) and 0.2 (CI = 0.07-0.7, P = 0.01), respectively. There was no significant difference in the levels of C3a, sC5b-9, sFlt-1 and sEng in early pregnancy among women who developed pre-eclampsia, compared with women who remained normotensive during pregnancy. Higher levels of Bb (P = 0.0001) and C3a (P = 0.03), and lower levels of sFlt-1 (P = 0.0002) and sEng (P = 0.0001) were found among women with obesity, compared with non-obese controls. No meaningful relationships were found between the complement-activation fragments and the angiogenesis-related factors. Conclusions In this cohort during early pregnancy, increased concentrations of complement-activation factor Bb and lower concentrations of PiGF were associated with the development of pre-eclampsia later in pregnancy. C1 [Lynch, A. M.; Gibbs, R. S.] Univ Colorado, Denver Sch Med, Dept Obstet & Gynecol, Aurora, CO 80045 USA. [Murphy, J. R.] Natl Jewish Hlth, Denver, CO USA. [Levine, R. J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. [Giclas, P. C.] Natl Jewish Hlth, Div Allergy & Immunol, Dept Pediat, Denver, CO USA. [Salmon, J. E.] Hosp Special Surg, Weill Cornell Med Ctr, New York, NY 10021 USA. [Holers, V. M.] Univ Colorado, Denver Sch Med, Div Rheumatol, Dept Med, Aurora, CO 80045 USA. [Holers, V. M.] Univ Colorado, Denver Sch Med, Div Rheumatol, Dept Immunol, Aurora, CO 80045 USA. RP Lynch, AM (reprint author), Univ Colorado, Denver Sch Med, Dept Obstet & Gynecol, Mail Stop B198,12631 E 17th Ave, Aurora, CO 80045 USA. EM anne.lynch@ucdenver.edu FU American Heart Association [0865481G]; Center for Women's Health Research; List Family Foundation; University of Colorado Denver; NICHD [K23 HD049684]; NIH [R01 AI 55007, R01 AR49772]; Eunice Kennedy Shriver National Institute of Child Health and Human Development FX This research was supported by grants to AML from the American Heart Association (0865481G), the Center for Women's Health Research and the List Family Foundation, University of Colorado Denver, and the NICHD (K23 HD049684). VMH is supported by NIH R01 AI 55007 and JES is supported by NIH R01 AR49772. RJL is supported by the intramural research programme of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. NR 37 TC 35 Z9 40 U1 0 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1470-0328 J9 BJOG-INT J OBSTET GY JI BJOG PD MAR PY 2010 VL 117 IS 4 BP 456 EP 462 DI 10.1111/j.1471-0528.2009.02473.x PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 553SX UT WOS:000274388200011 PM 20074261 ER PT J AU Pierorazio, PM Ferrucci, L Kettermann, A Longo, DL Metter, EJ Carter, HB AF Pierorazio, Phillip M. Ferrucci, Luigi Kettermann, Anna Longo, Dan L. Metter, E. Jeffrey Carter, H. Ballentine TI Serum testosterone is associated with aggressive prostate cancer in older men: results from the Baltimore Longitudinal Study of Aging SO BJU INTERNATIONAL LA English DT Article DE prostate cancer; testosterone; high-risk ID RANDOMIZED CONTROLLED-TRIAL; RADICAL PROSTATECTOMY; PATHOLOGICAL STAGE; REPLACEMENT THERAPY; HORMONE-LEVELS; LEVEL; HYPOGONADISM; PREDICTOR; RISK AB OBJECTIVE To evaluate the relationship between testosterone levels and the development of high-risk prostate cancer, by prospectively examining serum androgen concentrations in a well-studied cohort, as the role of testosterone in prostate cancer progression is debated. PATIENTS AND METHODS The study comprised 781 men in the Baltimore Longitudinal Study of Aging who had sex steroid measurements before a diagnosis of prostate cancer, or at their last visit for those without cancer (no cancer, 636; cancer, not high risk, 109; cancer, high risk, 36). High-risk cancer was defined as death from prostate cancer, a prostate specific antigen (PSA) level of >= 20 ng/mL at diagnosis, or a Gleason score of >= 8. The hazard ratio (HR) of high-risk disease was determined using a Cox proportional hazards regression model with simple updating, and risk rates were stratified by age and tercile for androgens of interest based on the proportional hazards analyses. RESULTS The likelihood of high-risk prostate cancer doubled per unit (0.1) increase in the free testosterone index (FTI) for patients aged > 65 years (HR 2.07, 95% confidence interval, CI, 1.01-4.23; P = 0.047); the likelihood for men aged < 65 years was inversely related to the FTI (HR 0.96, 95% CI 0.35-2.6; P = 0.9). The risk rate per person-years increased from lowest to highest tercile of FTI for the oldest men (age > 70 years) but this trend was not apparent among younger men. CONCLUSION Higher levels of serum free testosterone are associated with an increased risk of aggressive prostate cancer among older men. These data highlight the importance of prospective trials to insure the safety of testosterone-replacement therapy. C1 [Pierorazio, Phillip M.; Kettermann, Anna; Carter, H. Ballentine] Johns Hopkins Univ, Sch Med, Dept Urol, James Buchanan Brady Urol Inst,Johns Hopkins Hosp, Baltimore, MD 21287 USA. [Ferrucci, Luigi; Longo, Dan L.; Metter, E. Jeffrey] NIA, Intramural Res Program, Baltimore, MD 21224 USA. RP Pierorazio, PM (reprint author), Johns Hopkins Univ, Sch Med, Dept Urol, James Buchanan Brady Urol Inst,Johns Hopkins Hosp, Marburg 100,600 N Wolfe St, Baltimore, MD 21287 USA. EM philpierorazio@jhmi.edu FU NIH; National Institute on Ageing FX Supported by the Intramural Research Program of the NIH, National Institute on Ageing. NR 28 TC 28 Z9 29 U1 0 U2 1 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1464-4096 J9 BJU INT JI BJU Int. PD MAR PY 2010 VL 105 IS 6 BP 824 EP 829 DI 10.1111/j.1464-410X.2009.08853.x PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 560VY UT WOS:000274933400013 PM 19751256 ER PT J AU Tay, K Dunleavy, K Wilson, WH AF Tay, Kevin Dunleavy, Kieron Wilson, Wyndham H. TI Novel agents for B-cell non-Hodgkin lymphoma: Science and the promise SO BLOOD REVIEWS LA English DT Review DE Drug targets; Lymphoma; Novel agents; Small molecules; Immunotherapy ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ANTI-CD20 MONOCLONAL-ANTIBODY; NF-KAPPA-B; PROTEASOME INHIBITOR BORTEZOMIB; REFRACTORY FOLLICULAR LYMPHOMA; HISTONE DEACETYLASE INHIBITORS; CHIMERIC ANTIGEN RECEPTOR; BCL-2 FAMILY-MEMBERS; MULTICENTER PHASE-II; C-BETA INHIBITOR AB There has been tremendous insight gained in the last two decades from basic science research. New molecular targets in neoplastic cells are emerging and provide the rationale for clinical development of novel agents in non-Hodgkin lymphoma. These novel agents can be broadly categorized into two groups. The first is by immunotherapy which includes novel monoclonal antibodies and immunomodulating drugs, which takes advantage of or optimizes immune system function. The other group of drugs target small molecules that may play an important role in tumorigenesis. The mechanisms of anti-tumor activity include targeting apoptotic pathways, inhibition of proteasomes, mammalian target of rapamycin (mTOR), cyclin-dependent kinases and histone deacetylases. The purpose of this review is to focus on these novel agents and the various treatment approaches that are currently being evaluated in non-Hodgkin lymphoma. Published by Elsevier Ltd. C1 [Tay, Kevin; Dunleavy, Kieron; Wilson, Wyndham H.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wilson, WH (reprint author), NCI, Ctr Canc Res, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM wilsonw@mail.nih.gov NR 143 TC 6 Z9 8 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0268-960X EI 1532-1681 J9 BLOOD REV JI Blood Rev. PD MAR PY 2010 VL 24 IS 2 BP 69 EP 82 DI 10.1016/j.blre.2010.01.001 PG 14 WC Hematology SC Hematology GA 576CM UT WOS:000276121500003 PM 20153097 ER PT J AU Senchenko, VN Anedchenko, EA Kondratieva, TT Krasnov, GS Dmitriev, AA Zabarovska, VI Pavlova, TV Kashuba, VI Lerman, MI Zabarovsky, ER AF Senchenko, Vera N. Anedchenko, Ekaterina A. Kondratieva, Tatiana T. Krasnov, George S. Dmitriev, Alexei A. Zabarovska, Veronika I. Pavlova, Tatiana V. Kashuba, Vladimir I. Lerman, Michael I. Zabarovsky, Eugene R. TI Simultaneous down-regulation of tumor suppressor genes RBSP3/CTDSPL, NPRL2/G21 and RASSF1A in primary non-small cell lung cancer SO BMC CANCER LA English DT Article ID HUMAN-CHROMOSOME 3P21.3; HUMAN EPITHELIAL MALIGNANCIES; HOMOZYGOUS DELETION REGION; REAL-TIME PCR; IN-VIVO; EPIGENETIC INACTIVATION; PROGNOSTIC-SIGNIFICANCE; CARCINOMA; EXPRESSION; PROMOTER AB Background: The short arm of human chromosome 3 is involved in the development of many cancers including lung cancer. Three bona fide lung cancer tumor suppressor genes namely RBSP3 (AP20 region), NPRL2 and RASSF1A (LUCA region) were identified in the 3p21.3 region. We have shown previously that homozygous deletions in AP20 and LUCA sub-regions often occurred in the same tumor (P < 10(-6)). Methods: We estimated the quantity of RBSP3, NPRL2, RASSF1A, GAPDH, RPN1 mRNA and RBSP3 DNA copy number in 59 primary non-small cell lung cancers, including 41 squamous cell and 18 adenocarcinomas by real-time reverse transcription-polymerase chain reaction based on TaqMan technology and relative quantification. Results: We evaluated the relationship between mRNA level and clinicopathologic characteristics in non-small cell lung cancer. A significant expression decrease (>= 2) was found for all three genes early in tumor development: in 85% of cases for RBSP3; 73% for NPRL2 and 67% for RASSF1A (P < 0.001), more strongly pronounced in squamous cell than in adenocarcinomas. Strong suppression of both, NPRL2 and RBSP3 was seen in 100% of cases already at Stage I of squamous cell carcinomas. Deregulation of RASSF1A correlated with tumor progression of squamous cell (P = 0.196) and adenocarcinomas (P < 0.05). Most likely, genetic and epigenetic mechanisms might be responsible for transcriptional inactivation of RBSP3 in non-small cell lung cancers as promoter methylation of RBSP3 according to NotI microarrays data was detected in 80% of squamous cell and in 38% of adenocarcinomas. With NotI microarrays we tested how often LUCA (NPRL2, RASSF1A) and AP20 (RBSP3) regions were deleted or methylated in the same tumor sample and found that this occured in 39% of all studied samples (P < 0.05). Conclusion: Our data support the hypothesis that these TSG are involved in tumorigenesis of NSCLC. Both genetic and epigenetic mechanisms contribute to down-regulation of these three genes representing two tumor suppressor clusters in 3p21.3. Most importantly expression of RBSP3, NPRL2 and RASSF1A was simultaneously decreased in the same sample of primary NSCLC: in 39% of cases all these three genes showed reduced expression (P < 0.05). C1 [Senchenko, Vera N.; Anedchenko, Ekaterina A.; Krasnov, George S.; Dmitriev, Alexei A.; Zabarovsky, Eugene R.] Russian Acad Sci, VA Engelhardt Mol Biol Inst, Lab Struct & Funct Genom, Moscow, Russia. [Senchenko, Vera N.; Zabarovska, Veronika I.; Pavlova, Tatiana V.; Kashuba, Vladimir I.; Zabarovsky, Eugene R.] Karolinska Inst, Ctr Microbiol & Tumor Biol, Dept Clin Sci & Educ, Stockholm, Sweden. [Kondratieva, Tatiana T.] Russian Acad Sci, Blokhin Canc Res Ctr, Moscow, Russia. [Kashuba, Vladimir I.] Ukrainian Acad Sci, Inst Mol Biol & Genet, UA-252627 Kiev, Ukraine. [Lerman, Michael I.] NCI, Canc Causing Genes Sect, Immunobiol Lab, Ctr Canc Res, Frederick, MD 21701 USA. RP Senchenko, VN (reprint author), Russian Acad Sci, VA Engelhardt Mol Biol Inst, Lab Struct & Funct Genom, Moscow, Russia. EM versen@eimb.ru; Eugene.Zabarovsky@ki.se RI Dmitriev, Alexey/D-6109-2011; Senchenko, Vera/C-8992-2014; Krasnov, George/E-6529-2014; OI Dmitriev, Alexey/0000-0002-6827-9584; Senchenko, Vera/0000-0002-3119-515X; Krasnov, George/0000-0002-6493-8378 FU Russian Foundation for Basic Research [05-04-49408]; Agency of Science and Innovations [02.512.11.2241, 1-2008/07/07]; Swedish Cancer Society; Swedish Research Council; Swedish Foundation for International Cooperation in Research and Higher Education (STINT); Swedish Institute; Karolinska Institute FX The authors are grateful to Ms. Leah V. Lerman, esq. for the help in preparation of the manuscript. This study was financially supported by the Russian Foundation for Basic Research (project no 05-04-49408), The Agency of Science and Innovations (State Contracts no 02.512.11.2241, Agreement 1-2008/07/07) and by research grants from the Swedish Cancer Society, the Swedish Research Council, the Swedish Foundation for International Cooperation in Research and Higher Education (STINT), the Swedish Institute, and Karolinska Institute. NR 51 TC 30 Z9 36 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD MAR 1 PY 2010 VL 10 AR 75 DI 10.1186/1471-2407-10-75 PG 13 WC Oncology SC Oncology GA 571ZW UT WOS:000275796400001 PM 20193080 ER PT J AU Anderlini, P Pedersen, T Confer, D Pulsipher, M Rizzo, D Stroncek, D Leitman, S O'Donnell, P AF Anderlini, P. Pedersen, T. Confer, D. Pulsipher, M. Rizzo, D. Stroncek, D. Leitman, S. O'Donnell, P. TI Evaluation, consent and care of related donors and recipients at haematopoietic stem cell transplant centres in the United States: practice patterns and potential for conflict of interest SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 36th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantat/9th Meeting of the EBMT Data-Management-Group/26th Meeting of the EBMT Nurses Group/2nd EBMT Qual Management Meeting CY MAR 21-24, 2010 CL Vienna, AUSTRIA SP European Grp Blood & Marrow Transplantat, EBMT Data Management Grp, EBMT Nurses Grp C1 [Anderlini, P.] UTMDACC, Houston, TX USA. [Pedersen, T.; Confer, D.] NMDP, Minneapolis, MN USA. [Pulsipher, M.] Univ Utah, Med Ctr, Salt Lake City, UT USA. [Rizzo, D.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Stroncek, D.; Leitman, S.] NIH, Bethesda, MD 20892 USA. [O'Donnell, P.] FHCRC, Seattle, WA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2010 VL 45 SU 2 BP S70 EP S71 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 595LF UT WOS:000277611300171 ER PT J AU Rezvani, K Yong, A Mielke, S Jafarpour, B Savani, B Le, Q Eniafe, R Boss, C Kurlander, R Barrett, J AF Rezvani, K. Yong, A. Mielke, S. Jafarpour, B. Savani, B. Le, Q. Eniafe, R. Boss, C. Kurlander, R. Barrett, J. TI Repeated vaccination with PR1 and WT1 peptides admixed in Montanide adjuvant fails to induce sustained anti-leukaemia responses in patients with myeloid malignancies SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 36th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantat/9th Meeting of the EBMT Data-Management-Group/26th Meeting of the EBMT Nurses Group/2nd EBMT Qual Management Meeting CY MAR 21-24, 2010 CL Vienna, AUSTRIA SP European Grp Blood & Marrow Transplantat, EBMT Data Management Grp, EBMT Nurses Grp C1 [Rezvani, K.] Hammersmith Hosp, London, England. [Yong, A.; Jafarpour, B.; Le, Q.; Eniafe, R.; Boss, C.; Kurlander, R.; Barrett, J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2010 VL 45 SU 2 BP S83 EP S83 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 595LF UT WOS:000277611300201 ER PT J AU Sirohi, B Chandrasekar, P Seibel, N Ruhnke, M Powles, R Taylor, T AF Sirohi, B. Chandrasekar, P. Seibel, N. Ruhnke, M. Powles, R. Taylor, T. TI Efficacy of micafungin neutropenic patients with invasive candidiasis and candidaemia SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 36th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantat/9th Meeting of the EBMT Data-Management-Group/26th Meeting of the EBMT Nurses Group/2nd EBMT Qual Management Meeting CY MAR 21-24, 2010 CL Vienna, AUSTRIA SP European Grp Blood & Marrow Transplantat, EBMT Data Management Grp, EBMT Nurses Grp C1 [Sirohi, B.] Max Can Ctr, New Delhi, India. [Chandrasekar, P.] Wayne State Univ, Sch Med, Detroit, MI USA. [Seibel, N.] Natl Inst Hlth, Bethesda, MD USA. [Ruhnke, M.] Humboldt Univ, Campus Charite Mitte, Berlin, Germany. [Powles, R.] Parkside Oncol Clin, Wimbledon, England. [Taylor, T.] Astellas Pharma Europe, Staines, England. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2010 VL 45 SU 2 BP S220 EP S221 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 595LF UT WOS:000277611301020 ER PT J AU Williams, K Pavletic, S Hnatiuk, O Hakim, F Mitchell, S Gea-Banacloche, J Comis, L Cowen, E Baird, K Louie, A Shelhamer, J Blacklock-Schuver, B Avila, D Carpenter, A Gress, R AF Williams, K. Pavletic, S. Hnatiuk, O. Hakim, F. Mitchell, S. Gea-Banacloche, J. Comis, L. Cowen, E. Baird, K. Louie, A. Shelhamer, J. Blacklock-Schuver, B. Avila, D. Carpenter, A. Gress, R. TI Preliminary results of a phase II trial of montelukast for the treatment of bronchiolitis obliterans syndrome after HSCT SO BONE MARROW TRANSPLANTATION LA English DT Meeting Abstract CT 36th Annual Meeting of the European-Group-for-Blood-and-Marrow-Transplantat/9th Meeting of the EBMT Data-Management-Group/26th Meeting of the EBMT Nurses Group/2nd EBMT Qual Management Meeting CY MAR 21-24, 2010 CL Vienna, AUSTRIA SP European Grp Blood & Marrow Transplantat, EBMT Data Management Grp, EBMT Nurses Grp C1 [Williams, K.; Pavletic, S.; Hakim, F.; Gea-Banacloche, J.; Baird, K.; Blacklock-Schuver, B.; Avila, D.; Carpenter, A.; Gress, R.] NCI, Bethesda, MD 20892 USA. [Hnatiuk, O.; Mitchell, S.; Comis, L.; Cowen, E.; Louie, A.; Shelhamer, J.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD MAR PY 2010 VL 45 SU 2 BP S48 EP S48 PG 1 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 595LF UT WOS:000277611300117 ER PT J AU Levesque, S Wilson, B Gregoria, V Thorpe, LB Dallas, S Polikov, VS Hong, JS Block, ML AF Levesque, Shannon Wilson, Belinda Gregoria, Vincent Thorpe, Laura B. Dallas, Shannon Polikov, Vadim S. Hong, Jau-Shyong Block, Michelle L. TI Reactive microgliosis: extracellular mu-calpain and microglia-mediated dopaminergic neurotoxicity SO BRAIN LA English DT Article DE microglia; inflammation-mediated neurodegeneration; oxidative stress; chronic neurotoxicity; extracellular mu-calpain; reactive microgliosis; Parkinson's disease ID LIPOPOLYSACCHARIDE-INDUCED NEUROTOXICITY; ACUTE BRAIN-DAMAGE; PARKINSONS-DISEASE; NADPH OXIDASE; SUBSTANTIA-NIGRA; OXIDATIVE STRESS; ACTIVATED MICROGLIA; SURROGATE MARKERS; CELL-MIGRATION; LIVER-INJURY AB Microglia, the innate immune cells in the brain, can become chronically activated in response to dopaminergic neuron death, fuelling a self-renewing cycle of microglial activation followed by further neuron damage (reactive microgliosis), which is implicated in the progressive nature of Parkinson's disease. Here, we use an in vitro approach to separate neuron injury factors from the cellular actors of reactive microgliosis and discover molecular signals responsible for chronic and toxic microglial activation. Upon injury with the dopaminergic neurotoxin 1-methyl-4-phenylpyridinium, N27 cells (dopaminergic neuron cell line) released soluble neuron injury factors that activated microglia and were selectively toxic to dopaminergic neurons in mixed mesencephalic neuron-glia cultures through nicotinamide adenine dinucleotide phosphate oxidase. mu-Calpain was identified as a key signal released from damaged neurons, causing selective dopaminergic neuron death through activation of microglial nicotinamide adenine dinucleotide phosphate oxidase and superoxide production. These findings suggest that dopaminergic neurons may be inherently susceptible to the pro-inflammatory effects of neuron damage, i.e. reactive microgliosis, providing much needed insight into the chronic nature of Parkinson's disease. C1 [Levesque, Shannon; Gregoria, Vincent; Thorpe, Laura B.; Block, Michelle L.] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Richmond, VA 23298 USA. [Wilson, Belinda; Hong, Jau-Shyong] Natl Inst Environm Hlth Sci, Dept Neuropharmacol, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. [Dallas, Shannon] Natl Inst Environm Hlth Sci, Intracellular Regulat Sect, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. [Polikov, Vadim S.] Duke Univ, Dept Biomed Engn, Durham, NC 27708 USA. RP Block, ML (reprint author), Virginia Commonwealth Univ, Dept Anat & Neurobiol, Sanger Hall,Room 9-048,1101 E Marshall St,Med Cam, Richmond, VA 23298 USA. EM mblock@vcu.edu FU National Institute of Environmental Health Sciences/National Institute of Health Pathway [R00ES01549]; NIH; National Institute of Environmental Health Sciences [K99ES015409-01] FX National Institute of Environmental Health Sciences/National Institute of Health Pathway to Independence Award (R00ES01549) and in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences, in fulfilment of the Pathway to Independence Award (K99ES015409-01). NR 52 TC 51 Z9 56 U1 0 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAR PY 2010 VL 133 BP 808 EP 821 DI 10.1093/brain/awp333 PN 3 PG 14 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 575DI UT WOS:000276046000016 PM 20123724 ER PT J AU Shaikh, AG Hong, S Liao, K Tian, J Solomon, D Zee, DS Leigh, RJ Optican, LM AF Shaikh, Aasef G. Hong, Simon Liao, Ke Tian, Jing Solomon, David Zee, David S. Leigh, R. John Optican, Lance M. TI Oculopalatal tremor explained by a model of inferior olivary hypertrophy and cerebellar plasticity SO BRAIN LA English DT Article DE vestibular; gap junction; connexin; motor disorders; eye movement ID HARMALINE-INDUCED TREMOR; ESSENTIAL PALATAL TREMOR; OLIVOCEREBELLAR SYSTEM; VESTIBULAR NUCLEUS; PENDULAR NYSTAGMUS; NEURONS; MYOCLONUS; MONKEY; CAT; IMMUNOCYTOCHEMISTRY AB The inferior olivary nuclei clearly play a role in creating oculopalatal tremor, but the exact mechanism is unknown. Oculopalatal tremor develops some time after a lesion in the brain that interrupts inhibition of the inferior olive by the deep cerebellar nuclei. Over time the inferior olive gradually becomes hypertrophic and its neurons enlarge developing abnormal soma-somatic gap junctions. However, results from several experimental studies have confounded the issue because they seem inconsistent with a role for the inferior olive in oculopalatal tremor, or because they ascribe the tremor to other brain areas. Here we look at 3D binocular eye movements in 15 oculopalatal tremor patients and compare their behaviour to the output of our recent mathematical model of oculopalatal tremor. This model has two mechanisms that interact to create oculopalatal tremor: an oscillator in the inferior olive and a modulator in the cerebellum. Here we show that this dual mechanism model can reproduce the basic features of oculopalatal tremor and plausibly refute the confounding experimental results. Oscillations in all patients and simulations were aperiodic, with a complicated frequency spectrum showing dominant components from 1 to 3 Hz. The model's synchronized inferior olive output was too small to induce noticeable ocular oscillations, requiring amplification by the cerebellar cortex. Simulations show that reducing the influence of the cerebellar cortex on the oculomotor pathway reduces the amplitude of ocular tremor, makes it more periodic and pulse-like, but leaves its frequency unchanged. Reducing the coupling among cells in the inferior olive decreases the oscillation's amplitude until they stop (at similar to 20% of full coupling strength), but does not change their frequency. The dual-mechanism model accounts for many of the properties of oculopalatal tremor. Simulations suggest that drug therapies designed to reduce electrotonic coupling within the inferior olive or reduce the disinhibition of the cerebellar cortex on the deep cerebellar nuclei could treat oculopalatal tremor. We conclude that oculopalatal tremor oscillations originate in the hypertrophic inferior olive and are amplified by learning in the cerebellum. C1 [Shaikh, Aasef G.; Tian, Jing; Solomon, David; Zee, David S.] Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. [Hong, Simon; Optican, Lance M.] NEI, Sensorimotor Res Lab, NIH, DHHS, Bethesda, MD 20892 USA. [Liao, Ke; Leigh, R. John] Vet Affairs Med Ctr, Dept Neurol, Cleveland, OH 44106 USA. [Liao, Ke; Leigh, R. John] Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Optican, LM (reprint author), 49 Convent Dr,Room 2A50, Bethesda, MD 20892 USA. EM lanceoptican@nih.gov RI liao, ke/B-1453-2010 FU Office of Research and Development, Medical Research Service, Department of Veterans Affairs; National Eye Institute [EY01849, EY06717, EY08060]; Evenor Armington Fund; National Eye Institute, NIH, DHHS FX Office of Research and Development, Medical Research Service, Department of Veterans Affairs; National Eye Institute (grants EY01849, EY06717 and EY08060); Evenor Armington Fund; Intramural Research Program, National Eye Institute, NIH, DHHS; Philanthropic funds to the JHH vestibular laboratory and JHH movement disorders division (Fellowship support to A. S.). NR 67 TC 40 Z9 40 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD MAR PY 2010 VL 133 BP 923 EP 940 DI 10.1093/brain/awp323 PN 3 PG 18 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 575DI UT WOS:000276046000026 PM 20080879 ER PT J AU Correia, S Hubbard, E Hassenstab, J Yip, A Vymazal, J Herynek, V Giedd, J Murphy, DL Greenberg, BD AF Correia, Stephen Hubbard, Emily Hassenstab, Jason Yip, Agustin Vymazal, Josef Herynek, Vit Giedd, Jay Murphy, Dennis L. Greenberg, Benjamin D. TI Basal Ganglia MR Relaxometry in Obsessive-Compulsive Disorder: T2 Depends Upon Age of Symptom Onset SO BRAIN IMAGING AND BEHAVIOR LA English DT Article DE Obsessive-compulsive disorder; Basal ganglia; Age of onset; Iron; Magnetic Resonance Imaging ID VOXEL-BASED MORPHOMETRY; BRAIN FERRITIN IRON; GRAY-MATTER; CAUDATE-NUCLEUS; NEURODEGENERATIVE DISEASES; STRUCTURAL ABNORMALITIES; PARKINSONS-DISEASE; TOURETTES-SYNDROME; RELAXATION-TIMES; LESIONS AB Dysfunction in circuits linking frontal cortex and basal ganglia (BG) is strongly implicated in obsessive-compulsive disorder (OCD). On MRI studies, neuropsychiatric disorders with known BG pathology have abnormally short T2 relaxation values (a putative biomarker of elevated iron) in this region. We asked if BG T2 values are abnormal in OCD. We measured volume and T2 and T1 relaxation rates in BG of 32 adults with OCD and 33 matched controls. There were no group differences in volume or T1 values in caudate, putamen, or globus pallidus (GP). The OCD group had lower T2 values (suggesting higher iron content) in the right GP, with a trend in the same direction for the left GP. This effect was driven by patients whose OCD symptoms began from around adolescence to early adulthood. The results suggest a possible relationship between age of OCD onset and iron deposition in the basal ganglia. C1 [Correia, Stephen] Brown Univ, Dept Psychiat & Human Behav, Alpert Med Sch, Vet Affairs Med Ctr, Providence, RI 02908 USA. [Hubbard, Emily] Oregon Hlth & Sci Univ, Sch Med, Portland, OR 97201 USA. [Yip, Agustin; Greenberg, Benjamin D.] Brown Univ, Dept Psychiat & Human Behav, Alpert Med Sch, Butler Hosp, Providence, RI 02908 USA. [Vymazal, Josef] Hosp Homolca, MR Unit, Dept Radiodiagnost, Prague, Czech Republic. [Herynek, Vit] Inst Clin & Expt Med, Dept Radiodiagnost & Intervent Radiol, MRI Unit, Prague, Czech Republic. [Giedd, Jay] NIMH, Unit Brain Imaging, Clin Psychiat Branch, Intramural Res Ctr,NIH,Clin Ctr, Bethesda, MD 20892 USA. [Murphy, Dennis L.] NIMH, Clin Sci Lab, Intramural Res Program, Bethesda, MD 20892 USA. RP Correia, S (reprint author), Brown Univ, Dept Psychiat & Human Behav, Alpert Med Sch, Vet Affairs Med Ctr, 830 Chalkstone Ave, Providence, RI 02908 USA. EM stephen_correia@brown.edu RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015; OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978; Yip, Agustin/0000-0003-2641-3439 FU National Institute of Mental Health; Department of Veterans Affairs FX We wish to thank David Strong, Ph.D. for his contribution to the statistical analyses. This work was supported by the Intramural Research Program at the National Institute of Mental Health and the Department of Veterans Affairs. The contents of this manuscript do not represent the views of the Department of Veterans Affairs or the United States. NR 84 TC 7 Z9 7 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1931-7557 J9 BRAIN IMAGING BEHAV JI Brain Imaging Behav. PD MAR PY 2010 VL 4 IS 1 BP 35 EP 45 DI 10.1007/s11682-009-9083-2 PG 11 WC Neuroimaging SC Neurosciences & Neurology GA 583DK UT WOS:000276652900003 PM 20503112 ER PT J AU Kato, GJ Taylor, JG AF Kato, Gregory J. Taylor, James G. TI Pleiotropic effects of intravascular haemolysis on vascular homeostasis SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review DE sickle cell disease; thalassaemia; vasculopathy; haemolysis; nitric oxide ID SICKLE-CELL-DISEASE; NITRIC-OXIDE BIOAVAILABILITY; BETA-THALASSEMIA MAJOR; PRIAPISM FOLLOWING SPLENECTOMY; PYRUVATE-KINASE DEFICIENCY; REGURGITANT JET VELOCITY; VON-WILLEBRAND-FACTOR; PULMONARY-HYPERTENSION; PLATELET ACTIVATION; ENDOTHELIAL-CELLS AB The breakdown of senescent or defective red blood cells releases red cell contents, especially haemoglobin, which scavenges nitric oxide (NO) and decomposes to haem and free iron. These are potent oxidants, all of which have promoted the evolution of inducible and vasculoprotective compensatory pathways to rapidly clear and detoxify haemoglobin, haem and iron. Chronic haemolytic red cell disorders as diverse as sickle cell disease, thalassaemia, unstable haemoglobinopathy, cytoskeletal defects and enzymopathies have been linked to a clinical constellation of pulmonary hypertension, priapism, leg ulceration and possibly cerebrovascular disease and thrombosis. Besides free haemoglobin, haemolysis has been associated with extracellular arginase that limits substrate availability to NO synthase, endogenous inhibitors of NO synthase activity, and inappropriate activation of haemostatic pathways. This article reviews the haemolytic disorders that have been reported to manifest vascular complications, and explores the speculative possibility that haemolysis mediates some of the vascular complications of inflammation and diabetes. C1 [Kato, Gregory J.] NHLBI, Sickle Cell Vasc Dis Sect, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Taylor, James G.] NIH, Dept Crit Care Med, Ctr Clin, 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; Taylor, James/0000-0002-4421-1809 FU Intramural NIH HHS [ZIA HL006014-01, ZIA HL006014-02] NR 130 TC 31 Z9 31 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAR PY 2010 VL 148 IS 5 BP 690 EP 701 DI 10.1111/j.1365-2141.2009.08004.x PG 12 WC Hematology SC Hematology GA 554AF UT WOS:000274407200002 PM 19958359 ER PT J AU Andersson, TML Lambert, PC Derolf, AR Kristinsson, SY Eloranta, S Landgren, O Bjorkholm, M Dickman, PW AF Andersson, Therese M. -L. Lambert, Paul C. Derolf, Asa Rangert Kristinsson, Sigurdur Yngvi Eloranta, Sandra Landgren, Ola Bjorkholm, Magnus Dickman, Paul W. TI Temporal trends in the proportion cured among adults diagnosed with acute myeloid leukaemia in Sweden 1973-2001, a population-based study SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE acute myeloid leukaemia; cure models; survival; relative survival; population-based study ID STEM-CELL TRANSPLANTATION; ACUTE NONLYMPHOCYTIC LEUKEMIA; CANCER SURVIVAL ANALYSIS; CONSOLIDATION THERAPY; REGRESSION-MODELS; PATIENT SURVIVAL; ELDERLY-PATIENTS; REMISSION; CYTARABINE; 1ST AB P>Large age-dependant differences in temporal trends in 1- and 5-year relative survival have been observed in patients with acute myeloid leukaemia (AML) in Sweden. This investigation used an alternative approach to studying patient survival that simultaneously estimated the proportion of patients cured from their cancer and the survival of the 'uncured'. We conducted a population-based study including 6439 AML patients aged 19-80 years in Sweden between 1973 and 2001. Mixture cure models were estimated, with age at diagnosis categorised (19-40, 41-60, 61-70 and 71-80) and year of diagnosis modelled using splines. In 1975 the cure proportion was < 6% in all age groups and the median survival time for 'uncured' patients was < 0 center dot 5 years. In 2000 the cure proportion was 68% (95% confidence interval 56-77%) in the youngest group, and 32% (25-39%), 8% (3-21%), and 4% (2-8%) in the other groups, respectively. The median survival times for 'uncured' were 0 center dot 74 (0 center dot 43-1 center dot 26), 0 center dot 71 (0 center dot 53-0 center dot 97), 0 center dot 69 (0 center dot 51-0 center dot 95) and 0 center dot 37 (0 center dot 31-0 center dot 44) years, respectively. A dramatic improvement in the cure proportion was seen in younger patients, whereas improvement in older ages was mainly within the survival of the 'uncured'. This novel approach of analysing survival data could be a valuable tool for physicians, patients, health care planners and health economists. C1 [Andersson, Therese M. -L.; Lambert, Paul C.; Eloranta, Sandra; Dickman, Paul W.] Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. [Lambert, Paul C.] Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. [Derolf, Asa Rangert; Kristinsson, Sigurdur Yngvi; Landgren, Ola; Bjorkholm, Magnus] Karolinska Inst, Karolinska Univ Hosp Solna, Dept Med, Div Haematol, SE-17177 Stockholm, Sweden. [Landgren, Ola] NCI, NIH, Bethesda, MD 20892 USA. RP Andersson, TML (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Box 281, SE-17177 Stockholm, Sweden. EM therese.m-l.andersson@ki.se RI Dickman, Paul/B-4572-2013; Kristinsson, Sigurdur /M-2910-2015; Andersson, Therese/E-7107-2016 OI Dickman, Paul/0000-0002-5788-3380; Kristinsson, Sigurdur /0000-0002-4964-7476; Andersson, Therese/0000-0001-8644-9041 FU Swedish Cancer Society; Swedish Research Council; Stockholm County Council; Karolinska Institutet Foundations FX This work was supported by grants from the Swedish Cancer Society, Swedish Research Council, Stockholm County Council, and the Karolinska Institutet Foundations. NR 42 TC 8 Z9 8 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAR PY 2010 VL 148 IS 6 BP 918 EP 924 DI 10.1111/j.1365-2141.2009.08026.x PG 7 WC Hematology SC Hematology GA 562ZM UT WOS:000275094900011 PM 19995394 ER PT J AU Lee, S Tsang, A Kessler, RC Jin, R Sampson, N Andrade, L Karam, EG Mora, MEM Merikangas, K Nakane, Y Popovici, DG Posada-Villa, J Sagar, R Wells, JE Zarkov, Z Petukhova, M AF Lee, Sing Tsang, Adley Kessler, Ronald C. Jin, Robert Sampson, Nancy Andrade, Laura Karam, Elie G. Medina Mora, Maria Elena Merikangas, Kathleen Nakane, Yoshibumi Popovici, Daniela Georgeta Posada-Villa, Jose Sagar, Rajesh Wells, J. Elisabeth Zarkov, Zahari Petukhova, Maria TI Rapid-cycling bipolar disorder: cross-national community study SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Article ID WORLD-HEALTH-ORGANIZATION; TREATMENT ENHANCEMENT PROGRAM; WEEKLY SYMPTOMATIC STATUS; NATURAL-HISTORY; I-DISORDER; UNMET NEED; STEP-BD; DSM-IV; VALIDITY; VERSION AB Background The epidemiology of rapid-cycling bipolar disorder in the community is largely unknown. Aims To investigate the epidemiological characteristics of rapid cycling and non-rapid-cycling bipolar disorder in a large cross-national community sample. Method The Composite International Diagnostic interview (CIDI version 3.0) was used to examine the prevalence, severity, comorbidity, impairment, suicidality, sociodemographics, childhood adversity and treatment of rapid-cycling and non-rapid-cycling bipolar disorder in ten countries (n=54257). Results The 12-month prevalence of rapid-cycling bipolar disorder was 0.3%. Roughly a third and two-fifths of participants with lifetime and 12-month bipolar disorder respectively met criteria for rapid cycling. Compared with the non-rapid-cycling, rapid-cycling bipolar disorder was associated with younger age at onset, higher persistence, more severe depressive symptoms, greater impairment from depressive symptoms, more out-of-role days from mania/hypomania, more anxiety disorders and an increased likelihood of using health services. Associations regarding childhood, family and other sociodemographic correlates were less clear cut. Conclusions The community epidemiological profile of rapid-cycling bipolar disorder confirms most but not all current clinically based knowledge about the illness. Declaration of interest R.C.K. has been a consultant for GlaxoSmithKline Inc, Kaiser Permanente, Pfizer Inc, Sanofi-Aventis, Shire Pharmaceuticals and Wyeth-Ayerst; has served on advisory boards for Eli Lilly & Company and Wyeth-Ayerst, and has had research support for his epidemiological studies from Bristol-Myers Squibb, Eli Lilly & Company, GlaxoSmithKline, Johnson & Johnson Pharmaceuticals, Ortho-McNeil Pharmaceuticals Inc, Pfizer Inc and Sanofi-Avertis. C1 [Lee, Sing] Chinese Univ Hong Kong, Dept Psychiat, Hong Kong, Hong Kong, Peoples R China. [Tsang, Adley] Chinese Univ Hong Kong, Hong Kong Mood Disorders Ctr, Hong Kong, Hong Kong, Peoples R China. [Kessler, Ronald C.; Jin, Robert; Sampson, Nancy] Harvard Univ, Sch Med, Dept Hlth Care Policy, Cambridge, MA 02138 USA. [Andrade, Laura] Univ Sao Paulo, LIM Dept 23, Sect Psychiat Epidemiol, BR-05508 Sao Paulo, Brazil. [Andrade, Laura] Univ Sao Paulo, Sch Med, Inst Psychiat, BR-05508 Sao Paulo, Brazil. [Karam, Elie G.] Balamand Univ, IDRAAC, MIND, St George Hosp Univ Med Ctr,Fac Med, Beirut, Lebanon. [Medina Mora, Maria Elena] Natl Inst Psychiat, Mexico City, DF, Mexico. [Merikangas, Kathleen] NIMH, Mood & Anxiety Disorders Programs, Div Intramural Res Programs, Bethesda, MD 20892 USA. [Nakane, Yoshibumi] Nagasaki Int Univ, Grad Sch Nagasaki, Div Human Sociol, Nagasaki, Japan. [Posada-Villa, Jose] Colegio Mayor de Cundinamarca Univ, Bogota, Colombia. [Sagar, Rajesh] All India Inst Med Sci, Dept Psychiat, Delhi, India. [Wells, J. Elisabeth] Christchurch Sch Med & Hlth Sci, Dept Publ Hlth & Gen Practice, Christchurch, New Zealand. [Zarkov, Zahari] Natl Ctr Publ Hlth Protect, Sofia, Bulgaria. [Petukhova, Maria] Harvard Univ, Sch Med, Dept Hlth Care Policy, Cambridge, MA 02138 USA. RP Lee, S (reprint author), Prince Wales Hosp, Hong Kong Mood Disorders Ctr, 7A,Block E,Staff Quarters, Shatin, Hong Kong, Peoples R China. EM singlee@cuhk.edu.hk RI Andrade, Laura Helena/F-3023-2010; Lee, Sing/O-2136-2015 OI Andrade, Laura Helena/0000-0002-2362-3521; FU Bristol-Myers Squibb; Eli Lilly Company; GlaxoSmithKline; Johnson & Johnson Pharmaceuticals; Ortho-McNeil Pharmaceuticals Inc; Pfizer Inc; Sanofi-Avertis FX R.C.K. has been a consultant for GlaxoSmithKline Inc, Kaiser Permanente, Pfizer Inc, Sanofi-Aventis, Shire Pharmaceuticals and Wyeth-Ayerst; has served on advisory boards for Eli Lilly & Company and Wyeth-Ayerst, and has had research support for his epidemiological studies from Bristol-Myers Squibb, Eli Lilly & Company, GlaxoSmithKline, Johnson & Johnson Pharmaceuticals, Ortho-McNeil Pharmaceuticals Inc, Pfizer Inc and Sanofi-Avertis. NR 45 TC 14 Z9 15 U1 2 U2 3 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD MAR PY 2010 VL 196 IS 3 BP 217 EP 225 DI 10.1192/bjp.bp.109.067843 PG 9 WC Psychiatry SC Psychiatry GA 568IL UT WOS:000275515800011 PM 20194545 ER PT J AU Binet, R Ythier, D Robles, A Collado, M Larrieu, D Brambilla, E Brambilla, C Serrano, M Harris, C Pedeux, R AF Binet, Romuald Ythier, Damien Robles, Ana Collado, Manuel Larrieu, Delphine Brambilla, Elisabeth Brambilla, Christian Serrano, Manuel Harris, Curtis Pedeux, Remy TI WNT16B, a new biomarker of senescent cells in vitro and in vivo, is necessary for the p53-dependent activation of p21WAF1 in cellular senescence SO BULLETIN DU CANCER LA English DT Meeting Abstract C1 INSERM, U823, F-75654 Paris 13, France. UJF, Inst Albert Bonniot, Grenoble, France. NCI, LHC, NIH, Bethesda, MD USA. CNIO, Madrid, Spain. INSERM, U917, Rennes, France. EM romuald.binet@e.ujf-grenoble.fr RI Binet, Romuald/I-7938-2012; Brambilla, Elisabeth/L-8796-2013; BRAMBILLA, CHRISTIAN/K-2285-2013; Collado, Manuel/K-8140-2014 OI Binet, Romuald/0000-0003-0636-2195; Collado, Manuel/0000-0002-0330-0880 NR 1 TC 0 Z9 0 U1 0 U2 2 PU JOHN LIBBEY EUROTEXT LTD PI MONTROUGE PA 127 AVE DE LA REPUBLIQUE, 92120 MONTROUGE, FRANCE SN 0007-4551 J9 B CANCER JI Bull. Cancer PD MAR PY 2010 VL 97 SI SI BP S67 EP S67 PG 1 WC Oncology SC Oncology GA 584CD UT WOS:000276726700081 ER PT J AU Baum, CE Price, DK Figg, WD AF Baum, Caitlin E. Price, Douglas K. Figg, William D. TI Sarcosine as a potential prostate cancer biomarker and therapeutic target SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE sarcosine; prostate cancer; biomarker; PSA; metastasis C1 [Baum, Caitlin E.; Price, Douglas K.; Figg, William D.] NCI, Mol Pharmacol Sect, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU Intramural NIH HHS [NIH0012636439]; PHS HHS [NIH0012636439] NR 7 TC 10 Z9 10 U1 1 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAR 1 PY 2010 VL 9 IS 5 BP 341 EP 342 PG 2 WC Oncology SC Oncology GA 584SQ UT WOS:000276773500002 PM 20150759 ER PT J AU Baum, CE Ockers, SB English, BC Price, DK Sartor, O Figg, WD AF Baum, Caitlin E. Ockers, Sandra B. English, Bevin C. Price, Douglas K. Sartor, Oliver Figg, William D. TI Androgen receptor sequence and variations in several common prostate cancer cell lines SO CANCER BIOLOGY & THERAPY LA English DT Article DE androgen receptor; prostate cancer; LnCAP; SNP; CAG; repeat; genotype; DU145 ID GENE; INDEPENDENCE; PROGRESSION; MUTATIONS; DOMAIN AB The androgen receptor gene (AR) plays an important role in molecular signaling and regulation and the subsequent cellular growth of prostate cancer. In addition, it is a highly variable region of the genome. We used direct nucleotide sequencing to genotype the entire exogenous coding region of the androgen receptor in ten commonly used prostate cancer cell lines. Our analysis confirmed the presence or absence of several known SNPs in the cell lines studied. We also assayed the number of CAG-repeat and GGC-repeat sequences for each for the ten cell lines. Our analysis identified three new mutations, one each in the DU145, LnCAP and RWPE-2 cell lines. In DU145, the DNA isolated in our lab was heterozygous at G527G (T>C transition), a polymorphism not previously reported. The LnCAP cells cultured in our lab were found to have a T>C transition (heterozygous), resulting in a S641P change that was not present in the ATCC cell line DNA. Lastly, a homozygous G>T transversion was found in RWPE-2 cells, resulting in the S187I change. This is potentially significant for use in cell culture and future cell model development. C1 [Baum, Caitlin E.; Ockers, Sandra B.; English, Bevin C.; Price, Douglas K.; Figg, William D.] NCI, Mol Pharmacol Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sartor, Oliver] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Sartor, Oliver] Tulane Univ, Sch Med, Dept Urol, New Orleans, LA 70112 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 FU National Institutes of Health, National Cancer Institute, Bethesda, MD; Southwest Oncology Group (SWOG); National Cancer Institute, NIH, Department of Health and Human Services [P01CA106451] FX This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Bethesda, MD.; The authors thank Southwest Oncology Group (SWOG) for the support during this study. This work is supported by National Cancer Institute, NIH, Department of Health and Human Services grant P01CA106451. NR 13 TC 0 Z9 0 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAR 1 PY 2010 VL 9 IS 5 BP 383 EP 388 PG 6 WC Oncology SC Oncology GA 584SQ UT WOS:000276773500009 PM 20061791 ER PT J AU Koshiol, J Rotunno, M Consonni, D Pesatori, AC De Matteis, S Goldstein, AM Chaturvedi, AK Wacholder, S Landi, MT Lubin, JH Caporaso, NE AF Koshiol, Jill Rotunno, Melissa Consonni, Dario Pesatori, Angela Cecilia De Matteis, Sara Goldstein, Alisa M. Chaturvedi, Anil K. Wacholder, Sholom Landi, Maria Teresa Lubin, Jay H. Caporaso, Neil E. TI Lower Risk of Lung Cancer after Multiple Pneumonia Diagnoses SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CIGARETTE-SMOKING; FAMILY-HISTORY; EPIDEMIOLOGIC EVIDENCE; RESPIRATORY-DISEASE; PULMONARY-DISEASE; NONSMOKING WOMEN; UNITED-STATES; CHINA; INTENSITY; TUBERCULOSIS AB Background: Although pneumonia has been suggested as a risk factor for lung cancer, previous studies have not evaluated the influence of number of pneumonia diagnoses in relation to lung cancer risk. Methods: The Environment And Genetics in Lung cancer Etiology (EAGLE) population-based study of 2,100 cases and 2,120 controls collected information on pneumonia more than 1 year before enrollment from 1,890 cases and 2,078 controls. Results: After adjusting for study design variables, smoking, and chronic bronchitis, pneumonia was associated with decreased risk of lung cancer [odds ratio (OR), 0.79; 95% confidence interval (CI), 0.64-0.97], especially among individuals with three or more diagnoses versus none (OR, 0.35; 95% CI, 0.16-0.75). Adjustment for chronic bronchitis contributed to this inverse association. In comparison, pulmonary tuberculosis was not associated with lung cancer (OR, 0.96; 95% CI, 0.62-1.48). Conclusions: The apparent protective effect of pneumonia among individuals with multiple pneumonia diagnoses may reflect an underlying difference in immune response and requires further investigation and confirmation. Therefore, careful evaluation of the number of pneumonia episodes may shed light on lung cancer etiology. Cancer Epidemiol Biomarkers Prev; 19(3); 716-21. (C) 2010 AACR. C1 [Koshiol, Jill; Rotunno, Melissa; Goldstein, Alisa M.; Chaturvedi, Anil K.; Wacholder, Sholom; Landi, Maria Teresa; Lubin, Jay H.; Caporaso, Neil E.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Consonni, Dario; Pesatori, Angela Cecilia; De Matteis, Sara] Univ Milan, Dept Occupat & Environm Hlth, EPOCA Res Ctr, Milan, Italy. [Consonni, Dario; Pesatori, Angela Cecilia; De Matteis, Sara] Fdn IRCCS Ca Granda Osped Maggiore Policlin, Epidemiol Unit, Milan, Italy. RP Koshiol, J (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,MSC 7248, Bethesda, MD 20892 USA. EM koshiolj@mail.nih.gov RI Chaturvedi, Anil/J-2024-2015; OI Chaturvedi, Anil/0000-0003-2696-8899; pesatori, angela/0000-0002-0261-3252 FU NIH; National Cancer Institute; Office of Preventive Oncology, National Cancer Institute, Bethesda, MD FX Intramural Research Program of the NIH and the National Cancer Institute and the Cancer Prevention Fellowship Program, Office of Preventive Oncology, National Cancer Institute, Bethesda, MD. NR 26 TC 5 Z9 5 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2010 VL 19 IS 3 BP 716 EP 721 DI 10.1158/1055-9965.EPI-09-0873 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607CF UT WOS:000278475300011 PM 20200440 ER PT J AU Orom, H Kiviniemi, MT Underwood, W Ross, L Shavers, VL AF Orom, Heather Kiviniemi, Marc T. Underwood, Willie, III Ross, Levi Shavers, Vickie L. TI Perceived Cancer Risk: Why Is It Lower Among Nonwhites than Whites? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER; FAMILY-HISTORY; AFRICAN-AMERICAN; COLON-CANCER; ETHNIC-DIFFERENCES; SOCIAL NETWORKS; UNITED-STATES; POPULATION; PREDICTORS; WOMEN AB Background: We explored racial/ethnic differences in perceived cancer risk and determinants of these differences in a nationally representative sample of whites, blacks, Hispanics, and Asians. Methods: Multiple regression techniques, including mediational analyses, were used to identify determinants and quantify racial/ethnic differences in the perception of the risk of developing cancer among 5,581 adult respondents to the 2007 Health Information Trends Survey (HINTS). Results: Blacks, Hispanics, and Asians reported lower perceived cancer risk than whites [Bs = -0.40, -0.34, and -0.69, respectively; (Ps < 0.001)]. Contributing factors included relatively lower likelihood of reporting a family history of cancer, lower likelihood of having smoked, and a less strong belief that everything causes cancer among nonwhites than among whites. Racial/ethnic differences in perceived risk were attenuated in older respondents because perceived cancer risk was negatively associated with age for whites but not for nonwhites. Conclusions: Nonwhites had lower perceptions of cancer risk than whites. Some of the racial/ethnic variability in perceived risk may be due to racial and ethnic differences in awareness of one's family history of cancer and its relevance for cancer risk, experiences with behavioral risk factors, and salience of cancer risk information. Cancer Epidemiol Biomarkers Prev; 19(3); 746-54. (C) 2010 AACR. C1 [Orom, Heather] SUNY Buffalo, Dept Hlth Behav, Sch Publ Hlth & Hlth Profess, Buffalo, NY 14214 USA. [Underwood, Willie, III] Roswell Pk Canc Inst, Dept Urol Oncol, Buffalo, NY 14263 USA. [Underwood, Willie, III; Ross, Levi] Roswell Pk Canc Inst, Dept Hlth Dispar, Buffalo, NY 14263 USA. [Shavers, Vickie L.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Orom, H (reprint author), SUNY Buffalo, Dept Hlth Behav, Sch Publ Hlth & Hlth Profess, 304 Kimball Tower,3435 Main St, Buffalo, NY 14214 USA. EM horom@buffalo.edu RI Kiviniemi, Marc/B-8513-2013; OI Kiviniemi, Marc/0000-0002-1299-8416; Ross, Levi/0000-0002-3833-0836 FU NIH [K07CA106225]; Astella/AUA Foundation FX During the preparation of this manuscript, supported was granted by NIH grant K07CA106225 (M. T. Kiviniemi) and by an Astella/AUA Foundation Rising Star in Urology Award (W. Underwood). NR 40 TC 45 Z9 45 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2010 VL 19 IS 3 BP 746 EP 754 DI 10.1158/1055-9965.EPI-09-1085 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607CF UT WOS:000278475300015 PM 20160278 ER PT J AU Meyer, TE O'Brien, TG Andreotti, G Yu, K Li, QZ Gao, YT Rashid, A Shen, MC Wang, BS Han, TQ Zhang, BH Niwa, S Fraumeni, JF Hsing, AW AF Meyer, Tamra E. O'Brien, Thomas G. Andreotti, Gabriella Yu, Kai Li, Qizhai Gao, Yu-Tang Rashid, Asif Shen, Ming-Chang Wang, Bing-Sheng Han, Tian-Quan Zhang, Bai-He Niwa, Shelley Fraumeni, Joseph F., Jr. Hsing, Ann W. TI Androgen Receptor CAG Repeat Length and Risk of Biliary Tract Cancer and Stones SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID X-CHROMOSOME INACTIVATION; TESTOSTERONE LEVELS; PROSTATE-CANCER; BREAST-CANCER; HEALTHY-MEN; POLYMORPHISM; GENE; WOMEN; FLUTAMIDE; HIRSUTISM AB Biliary tract cancers, encompassing cancers of the gallbladder, extrahepatic bile ducts, and ampulla of Vater, are rare but highly fatal. Gallstones represent the major risk factor for biliary tract cancer, and share with gallbladder cancer a female predominance and an association with reproductive factors and obesity. Although estrogens have been implicated in earlier studies of gallbladder cancer, there are no data on the role of androgens. Because intracellular androgen activity is mediated through the androgen receptor (AR), we examined associations between AR CAG repeat length [(CAG)(n)] and the risk of biliary tract cancers and stones in a population-based study of 331 incident cancer cases, 837 gallstone cases, and 750 controls from Shanghai, China, where the incidence rates for biliary tract cancer are rising sharply. Men with (CAG)(n) >24 had a significant 2-fold risk of gallbladder cancer [odds ratio (OR), 2.00; 95% confidence interval (CI), 1.07-3.73], relative to those with (CAG)(n) <= 22. In contrast, women with (CAG)(n) >24 had reduced gallbladder cancer isk (OR, 0.69; 95% CI, 0.43-1.09) relative to those with (CAG)(n) <= 22; P interaction sex = 0.01, which was most pronounced for women ages 68 to 74 (OR, 0.48; 95% CI, 0.25-0.93; P interaction age = 0.02). No associations were found for bile duct cancer or gallstones. Reasons for the heterogeneity of genetic effects by gender and age are unclear but may reflect an interplay between AR and the levels of androgen as well as estrogen in men and older women. Further studies are needed to confirm these findings and clarify the mechanisms involved. Cancer Epidemiol Biomarkers Prev; 19(3); 787-93. (C) 2010 AACR. C1 [Meyer, Tamra E.; Andreotti, Gabriella; Yu, Kai; Li, Qizhai; Fraumeni, Joseph F., Jr.; Hsing, Ann W.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [O'Brien, Thomas G.] Lankenau Inst Med Res, Wynnewood, PA USA. [Li, Qizhai] Chinese Acad Sci, Acad Math & Syst Sci, Key Lab Syst & Control, Beijing, Peoples R China. [Rashid, Asif] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai 200433, Peoples R China. [Shen, Ming-Chang] Shanghai Tumor Hosp, Shanghai, Peoples R China. [Wang, Bing-Sheng] Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. [Han, Tian-Quan] Shanghai Med Univ 2, Ruijin Hosp, Dept Surg, Shanghai, Peoples R China. [Zhang, Bai-He] Second Mil Med Univ, Inst Oriental Hepatobiliary Surg, Shanghai, Peoples R China. [Niwa, Shelley] WESTAT Corp, Rockville, MD 20850 USA. RP Meyer, TE (reprint author), NCI, Div Canc Epidemiol & Genet, EPS Room 5032,6120 Execut Blvd, Rockville, MD 20852 USA. EM meyerte@mail.nih.gov FU NIH; National Cancer Institute, NIH [N01-CO-12400] FX Grant Support; Intramural Research Program of the NIH and National Cancer Institute, NIH under contract N01-CO-12400. The contents of this publication do 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 39 TC 3 Z9 3 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 EI 1538-7755 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2010 VL 19 IS 3 BP 787 EP 793 DI 10.1158/1055-9965.EPI-09-0973 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607CF UT WOS:000278475300019 PM 20200439 ER PT J AU Wideroff, L Garceau, AO Greene, MH Dunn, M McNeel, T Mai, P Willis, G Gonsalves, L Martin, M Graubard, BI AF Wideroff, Louise Garceau, Anne O. Greene, Mark H. Dunn, Marsha McNeel, Timothy Mai, Phuong Willis, Gordon Gonsalves, Lou Martin, Michael Graubard, Barry I. TI Coherence and Completeness of Population-based Family Cancer Reports SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PRIMARY-CARE; COLORECTAL-CANCER; RISK-ASSESSMENT; HISTORY; IMPACT; DISPARITIES; PREVALENCE; PREVENTION; PROSTATE; DISEASES AB Background: Although family history of cancer is widely ascertained in research and clinical care, little is known about assessment methods, accuracy, or other quality measures. Given its widespread use in cancer screening and surveillance, better information is needed about the clarity and accuracy of family history information reported in the general population. Methods: This telephone survey in Connecticut examined coherence and completeness of reports from 1,019 respondents about 20,504 biological relatives. Results: Of 2,657 cancer reports, 97.7% were judged consistent with malignancy (versus benign or indeterminate conditions); 79% were site specific, 10.1% had unspecified cancer sites, and 8.6% had "ill-defined" sites. Only 6.1% of relatives had unknown histories. Unknown histories and ambiguous sites were significantly higher for second-degree relatives. The adjusted percentage of first-degree relative reports with ambiguous sites increased with decreasing education and African-American race of survey respondents, and with deceased vital status of relatives. Ambiguous second-degree relative reports were also associated with deceased vital status and with male gender of respondents. Conclusions: These findings suggest that family history of cancer reports from the general population are generally complete and coherent. Impact: Strategies are needed to improve site specificity and thus maximize the utility of such information in primary care settings. Cancer Epidemiol Biomarkers Prev; 19(3); 799-810. (C) 2010 AACR. C1 [Wideroff, Louise; Garceau, Anne O.; Greene, Mark H.; Mai, Phuong; Willis, Gordon; Graubard, Barry I.] NCI, Bethesda, MD 20892 USA. [Dunn, Marsha] Westat Corp, Rockville, MD USA. [McNeel, Timothy] Informat Management Serv Inc, Silver Spring, MD USA. [Gonsalves, Lou] Connecticut Tumor Registry, Hartford, CT USA. [Martin, Michael] Sligo Gen Hosp, Dept Med Oncol, Sligo, Ireland. RP Wideroff, L (reprint author), NIDA, Epidemiol Res Branch, Div Epidemiol Serv & Prevent Res, 6001 Execut Blvd,Suite 5153 MSC 9589, Bethesda, MD 20892 USA. EM wideroff@nih.gov RI Hernandez, Jessica/G-6527-2011 FU Division of Cancer Control and Population Sciences, National Cancer Institute [N01-PC-95039, N02-PC-25001]; Department of Health and Human Services, NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics FX Grant Support; Division of Cancer Control and Population Sciences, National Cancer Institute contracts N01-PC-95039 and N02-PC-25001 and Intramural Research Program of the Department of Health and Human Services, NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics (M. H. Greene, P. Mai, M. Martin, and B. I. Graubard). NR 50 TC 8 Z9 8 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2010 VL 19 IS 3 BP 799 EP 810 DI 10.1158/1055-9965.EPI-09-1138 PG 12 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607CF UT WOS:000278475300021 PM 20160272 ER PT J AU Lindstrom, S Hunter, DJ Gronberg, H Stattin, P Wiklund, F Xu, JF Chanock, SJ Hayes, R Kraft, P AF Lindstroem, Sara Hunter, David J. Gronberg, Henrik Stattin, Par Wiklund, Fredrik Xu, Jianfeng Chanock, Stephen J. Hayes, Richard Kraft, Peter TI Sequence Variants in the TLR4 and TLR6-1-10 Genes and Prostate Cancer Risk. Results Based on Pooled Analysis from Three Independent Studies SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ASSOCIATION; TOLL-LIKE-RECEPTOR-4 AB Background: Genetic variation in two members of the Toll-like receptor family, TLR4 and the gene cluster TLR6-1-10, has been implicated in prostate cancer in several studies but the associated alleles have not been consistent across reports. Methods: We did a pooled analysis combining genotype data from three case-control studies, Cancer of the Prostate in Sweden, the Health Professionals Follow-up Study, and the Prostate, Lung, Colon and Ovarian Cancer Screening Trial, with data from 3,101 prostate cancer cases and 2,523 controls. We did imputation to obtain dense coverage of the genes and comparable genotype data for all cohorts. In total, 58 single nucleotide polymorphisms in TLR4 and 96 single nucleotide polymorphisms in TLR6-1-10 were genotyped or imputed and analyzed in the entire data set. We did a cohort-specific analysis as well as meta-analysis and pooled analysis. We also evaluated whether the analyses differed by age or disease severity. Results: We observed no overall association between genetic variation at the TLR4 and TLR6-1-10 loci and risk of prostate cancer. Conclusions: Common germ line genetic variation in TLR4 and TLR6-1-10 did not seem to have a strong association with risk of prostate cancer. Impact: This study suggests that earlier associations between prostate cancer risk and TLR4 and TLR6-1-10 sequence variants were chance findings. To definitely assess the causal relationship between TLR sequence variants and prostate cancer risk, very large sample sizes are needed. Cancer Epidemiol Biomarkers Prev; 19(3); 873-6. (C) 2010 AACR. C1 [Lindstroem, Sara; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Lindstroem, Sara; Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Boston, MA 02115 USA. [Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Hunter, David J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Gronberg, Henrik; Wiklund, Fredrik] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Stattin, Par] Umea Univ, Dept Surg & Perioperat Sci Urol & Androl, Umea, Sweden. [Xu, Jianfeng] Wake Forest Univ, Bowman Gray Sch Med, Ctr Human Genom, Winston Salem, NC USA. [Chanock, Stephen J.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Hayes, Richard] NYU, Div Epidemiol, Langone Med Ctr, New York, NY USA. RP Lindstrom, S (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Bldg 2,Room 249B,655 Huntington Ave, Boston, MA 02115 USA. EM slindstr@hsph.harvard.edu OI Hayes, Richard/0000-0002-0918-661X FU NCI NIH HHS [U01 CA098233-04, CA098233, U01 CA098233] NR 11 TC 22 Z9 23 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2010 VL 19 IS 3 BP 873 EP 876 DI 10.1158/1055-9965.EPI-09-0618 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607CF UT WOS:000278475300030 PM 20200442 ER PT J AU Lee, KH Shu, XO Gao, YT Ji, BT Yang, G Blair, A Rothman, N Zheng, W Chow, WH Kang, D AF Lee, Kyoung-Ho Shu, Xiao-Ou Gao, Yu-Tang Ji, Bu-Tian Yang, Gong Blair, Aaron Rothman, Nathaniel Zheng, Wei Chow, Wong-Ho Kang, Daehee TI Breast Cancer and Urinary Biomarkers of Polycyclic Aromatic Hydrocarbon and Oxidative Stress in the Shanghai Women's Health Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID LIPID-PEROXIDATION; ANTIOXIDANT STATUS; CHINESE WOMEN; DNA ADDUCTS; RISK; MALONDIALDEHYDE; 1-HYDROXYPYRENE; CARCINOGENESIS; SMOKING; DAMAGE AB Polycyclic aromatic hydrocarbon (PAH) exposure and oxidative stress from such and other exposures have been associated with breast cancer in some studies. To further evaluate the role of PAH metabolites and oxidative stress on the development of breast cancer, we conducted a nested case-control study in the Shanghai Women's Health Study. We measured urinary 1-hydroxypyrene and 2-naphthol as PAH metabolites and urinary levels of 8-hydroxy-2'-deoxyguanosine and malondialdehyde as oxidative stress biomarkers in 327 breast cancer cases and 654 controls in the Shanghai Women's Health Study. Information on demographic characteristics, past medical history, lifestyles, history of menstruation, pregnancy history, eating and drinking habit, history of residence, employment history, family history, husband's information, and physical activity were collected by a self-administered questionnaire. The mean age was 52.3 in breast cancer cases (n = 354) and 52.5 in controls (n = 708). Age at menarche (P = 0.04), months of breast-feeding the first baby (P = 0.05), and grade of education (P(trend) < 0.01) were significantly different between cases and controls. No association was observed for PAH metabolites and the oxidative stress biomarkers of urinary malondialdehyde and 8-hydroxy-2'-deoxyguanosine and risk of breast cancer. This nested case-control study provides no evidence of association between PAH exposure and oxidative stress and risk of breast cancer in Shanghai women. Cancer Epidemiol Biomarkers Prev; 19(3); 877-83. (C) 2010 AACR. C1 [Lee, Kyoung-Ho; Kang, Daehee] Seoul Natl Univ, Dept Prevent Med, Coll Med, Inst Environm Med,SNUMRC, Seoul 110799, South Korea. [Shu, Xiao-Ou; Yang, Gong; Zheng, Wei] Vanderbilt Univ, Div Epidemiol, Dept Med, Vanderbilt Epidemiol Ctr, Nashville, TN USA. [Gao, Yu-Tang] Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. [Ji, Bu-Tian; Blair, Aaron; Rothman, Nathaniel; Chow, Wong-Ho] NCI, Occupat & Environm Epidemiol Branch, Rockville, MD USA. [Blair, Aaron] Canc Care Ontario, Occupat Canc Res Ctr, Toronto, ON, Canada. [Kang, Daehee] Seoul Natl Univ, Dept Mol Med & Biopharmaceut Sci, Grad Sch Convergence Sci & Technol, Seoul 110799, South Korea. [Kang, Daehee] Seoul Natl Univ, Coll Med, Seoul 110799, South Korea. RP Kang, D (reprint author), Seoul Natl Univ, Dept Prevent Med, Coll Med, Inst Environm Med,SNUMRC, 28 Yongon Dong, Seoul 110799, South Korea. EM dhkang@snu.ac.kr RI Kang, Dae Hee/E-8631-2012 FU NCI NIH HHS [N02 CP1101066, P30CA68485, R01 CA064277, R01 CA064277-11, R37 CA70867] NR 32 TC 12 Z9 12 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2010 VL 19 IS 3 BP 877 EP 883 DI 10.1158/1055-9965.EPI-09-1098 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 607CF UT WOS:000278475300031 PM 20160264 ER PT J AU Garg, H Salcedo, R Trinchieri, G Blumenthal, R AF Garg, H. Salcedo, R. Trinchieri, G. Blumenthal, R. TI Improved nonviral cancer suicide gene therapy using survivin promoter-driven mutant Bax SO CANCER GENE THERAPY LA English DT Article DE gene therapy; cancer; apoptosis; Bax; survivin promoter ID CONDITIONALLY REPLICATIVE ADENOVIRUSES; IN-VIVO; PROAPOPTOTIC FUNCTION; ANTITUMOR-ACTIVITY; INDUCED APOPTOSIS; OVARIAN-CANCER; BREAST-CANCER; LUNG-CANCER; CELL-DEATH; EXPRESSION AB Suicide gene vectors are being developed in many laboratories as an attractive approach to cancer therapy. However, the development of these therapies is hampered by safety concerns and limitations of efficacy. The use of tumor-specific promoters, such as survivin promoter, can provide much needed specificity to target tumor cells. However, the expression levels from these promoters is often suboptimal and hence it is imperative to enhance the activity of the cytotoxic gene of interest. We tested apoptotic activity of several mutants of proapoptotic gene bax that constitutively translocate to the mitochondria and induce apoptosis. One of these mutants with deletion of serine at position S184 (S184del) was found to be most active and showed significant antitumor activity when expressed by the survivin promoter. In vitro testing shows that this vector (Sur-BaxS184del) induces cell killing in a variety of tumor cell lines of different origin with significantly higher efficacy than wild-type bax (Sur-BaxWT). The increase in cytotoxicity was a result of enhanced induction of apoptosis in tumor cells. In contrast to cytomegalovirus (CMV) promoter-driven bax (CMV-Bax), Sur-BaxS184del caused minimum toxicity in normal human dermal fibroblasts validating its specificity and safety. In a mouse tumor model (DA-3, murine breast cancer cells), we show that intratumoral injection of Sur-BaxS184del resulted in tumor growth retardation to the same level as CMV-Bax. This study highlights the effectiveness of using bax mutants in combination with survivin promoter for tumor-targeted suicide gene therapy in a nonviral vector. Cancer Gene Therapy (2010) 17, 155-163; doi:10.1038/cgt.2009.63; published online 9 October 2009 C1 [Garg, H.; Blumenthal, R.] NCI, Nanobiol Program, Ctr Canc Res, Frederick, MD 21702 USA. [Salcedo, R.; Trinchieri, G.] NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. [Garg, H.] Texas Tech Univ, Hlth Sci Ctr, Ctr Excellence Infect Dis, El Paso, TX USA. [Salcedo, R.] NCI, SAIC Frederick Inc, Ctr Canc Res, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), NCI, Nanobiol Program, Ctr Canc Res, POB B,Bldg 469,Room 152,Miller Dr, Frederick, MD 21702 USA. EM blumenthalr@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX We thank Rei Ming Dai, Loretta Scheetz and Donna Butcher for technical help. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 35 TC 11 Z9 11 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD MAR PY 2010 VL 17 IS 3 BP 155 EP 163 DI 10.1038/cgt.2009.63 PG 9 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 555KC UT WOS:000274508500002 PM 19816523 ER PT J AU Boehm, AL Higgins, J Franzusoff, A Schlom, J Hodge, JW AF Boehm, Amanda L. Higgins, Jack Franzusoff, Alex Schlom, Jeffrey Hodge, James W. TI Concurrent vaccination with two distinct vaccine platforms targeting the same antigen generates phenotypically and functionally distinct T-cell populations SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE Vaccinia; Saccharomyces cerevisiae; Carcinoembryonic antigen (CEA); T-cell populations; Antitumor immunity ID THERAPEUTIC ANTITUMOR RESPONSES; BOOST IMMUNIZATION STRATEGIES; SEMLIKI-FOREST-VIRUS; IMMUNE-RESPONSES; DIVERSIFIED PRIME; REPERTOIRE DIVERSITY; DNA PRIME; ADENOVIRUS; CARCINOMA; AVIDITY AB Studies comparing two or more vaccine platforms have historically evaluated each platform based on its ability to induce an immune response and may conclude that one vaccine is more efficacious than the other(s), leading to a recommendation for development of the more effective vaccine for clinical studies. Alternatively, these studies have documented the advantages of a diversified prime and boost regimen due to amplification of the antigen-specific T-cell population. We hypothesize here that two vaccine platforms targeting the same antigen might induce shared and distinct antigen-specific T-cell populations, and examined the possibility that two distinct vaccines could be used concomitantly. Using recombinant poxvirus and yeast vaccines, we compared the T-cell populations induced by these two platforms in terms of serum cytokine response, T-cell gene expression, T-cell receptor phenotype, antigen-specific cytokine expression, T-cell avidity, and T-cell antigen-specific tumor cell lysis. These studies demonstrate for the first time that vaccination with a recombinant poxvirus platform (rV/F-CEA/TRICOM) or a heat-killed yeast vaccine platform (yeast-CEA) elicits T-cell populations with both shared and unique phenotypic and functional characteristics. Furthermore, both the antigen and the vector play a role in the induction of distinct T-cell populations. In this study, we demonstrate that concurrent administration of two vaccines targeting the same antigen induces a more diverse T-cell population that leads to enhanced antitumor efficacy. These studies provide the rationale for future clinical studies investigating concurrent administration of vaccine platforms targeting a single antigen to enhance the antigen-specific immune response. C1 [Boehm, Amanda L.; Higgins, Jack; Schlom, Jeffrey; Hodge, James W.] NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Franzusoff, Alex] GlobeImmune Inc, Louisville, CO 80027 USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09,MSC 1750, Bethesda, MD 20892 USA. EM js141c@nih.gov; jh241d@nih.gov RI Hodge, James/D-5518-2015 OI Hodge, James/0000-0001-5282-3154 FU Intramural NIH HHS [Z01 BC010661-03] NR 41 TC 28 Z9 28 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD MAR PY 2010 VL 59 IS 3 BP 397 EP 408 DI 10.1007/s00262-009-0759-7 PG 12 WC Oncology; Immunology SC Oncology; Immunology GA 537GM UT WOS:000273101200006 PM 19756595 ER PT J AU Cook, JA Choudhuri, R DeGraff, W Gamson, J Mitchell, JB AF Cook, John A. Choudhuri, Rajani DeGraff, William Gamson, Janet Mitchell, James B. TI Halofuginone enhances the radiation sensitivity of human tumor cell lines SO CANCER LETTERS LA English DT Article DE Radiation sensitizer; TGF-beta; Halofuginone; Fibrosis ID TGF-BETA; HEPATOCELLULAR-CARCINOMA; H2AX PHOSPHORYLATION; HISTONE H2AX; CANCER CELLS; DNA-DAMAGE; GROWTH; INHIBITION; THERAPY; INJURY AB Transforming growth factor beta (TGF-beta) is implicated in radiation-induced fibrosis of normal tissues in patients receiving radiotherapy. Inhibiting the TGF-beta signaling pathway by various means has been shown to reduce radiation-induced fibrosis in pre-clinical studies. The present study evaluated the effects of interfering with the TGE-beta signaling pathway on the radiosensitivity of selected human tumor cell lines using the plant-derived alkaloid, halofuginone. Halofuginone treatment inhibited cell growth, halted cell cycle progression, decreased radiation-induced DNA damage repair, and decreased TGF-beta receptor II protein levels, leading to increased cellular radiosensitization. These data further support the goal of manipulating the TGE-beta pathway to achieve a positive increase in the therapeutic gain in clinical radiotherapy. Published by Elsevier Ireland Ltd. C1 [Cook, John A.; Choudhuri, Rajani; DeGraff, William; Gamson, Janet; Mitchell, James B.] NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Mitchell, JB (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, Bldg 10,Room B3-B69, Bethesda, MD 20892 USA. EM jbm@helix.nih.gov FU Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH FX This research was supported by the Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH. NR 35 TC 7 Z9 13 U1 2 U2 6 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD MAR 1 PY 2010 VL 289 IS 1 BP 119 EP 126 DI 10.1016/j.canlet.2009.08.009 PG 8 WC Oncology SC Oncology GA 578EI UT WOS:000276275900014 PM 19713035 ER PT J AU Satia, JA Barlow, J Armstrong-Brown, J Watters, JL AF Satia, Jessie A. Barlow, Jameta Armstrong-Brown, Janelle Watters, Joanne L. TI Qualitative Study to Explore Prospect Theory and Message Framing and Diet and Cancer Prevention-Related Issues Among African American Adolescents SO CANCER NURSING LA English DT Article DE Adolescents; African Americans; Cancer prevention; Diet; Interventions; Message framing; Nutrition; Prospect Theory ID CORONARY-HEART-DISEASE; GAIN-FRAMED MESSAGES; PHYSICAL-ACTIVITY; VEGETABLE CONSUMPTION; SEDENTARY BEHAVIOR; LIFE-STYLE; RISK; FRUIT; PERCEPTIONS; NUTRITION AB Background: There is a dearth of knowledge regarding factors that may motivate African American adolescents to consume healthier diets. Objective: To develop and test cancer prevention messages based on Prospect Theory on motivation to improve dietary intake in African American adolescents and to explore other salient factors that may inform dietary intervention design and implementation in this population. Methods: Semistructured in-person qualitative interviews were conducted with 13 African American male and female adolescents, aged 12 to 16 years, in North Carolina. Prospect Theory and message framing were used to guide the design of the 4 sets of diet-related messages related to cancer prevention: short-term, gain-framed; long-term, gain-framed; short-term, loss-framed; and long-term, loss-framed messages. Data were also collected on demographic, behavioral, and psychological factors; usual health behaviors; and preferences for intervention delivery. Results: Most respondents found the gain-framed, short-term messages most salient for both fruits/vegetables (8 [61.5%]) and fat consumption (7 [53.8%]). For fat consumption only, 2 (15.4%) found the loss-framed, short-term messages pertinent; none found the loss-framed, long-term messages relevant for either dietary variable. All indicated interest in participating in a dietary intervention/education program; most preferred the Internet as a channel for intervention delivery. Participants expressed diverse views regarding knowledge, attitudes, and beliefs regarding healthy eating. Conclusion: The gain-framed, short-term messages were most salient for motivating the majority of respondents to consume a healthy diet and most expressed a strong interest in participating in programs about diet and nutrition, with the Internet as the preferred communication channel. Implications for Practice: Researchers conducting dietary interventions and education initiatives and medical professionals who counsel African American adolescents should consider using Prospect Theory as a theoretical framework, should focus on gain-framed, short-term messages regarding cancer prevention, and should use the Internet for data collection and intervention and information delivery. C1 [Satia, Jessie A.] Univ N Carolina, Dept Nutr, Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Satia, Jessie A.] Univ N Carolina, Dept Epidemiol, Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. [Satia, Jessie A.] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Barlow, Jameta] Duke Univ, Duke Ctr Clin Hlth Policy Res, Durham, NC USA. [Armstrong-Brown, Janelle] Univ N Carolina, Gillings Sch Global Publ Hlth, Dept Hlth Behav & Hlth Educ, Chapel Hill, NC 27599 USA. [Watters, Joanne L.] NCI, Nutr Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Satia, JA (reprint author), Univ N Carolina, Dept Nutr, Sch Global Publ Hlth, Chapel Hill, NC 27599 USA. EM jsatia@unc.edu FU National Institutes of Health, Department of Health and Human Services [U01CA114629]; [K22CA096556]; [DK056350] FX This study was funded by grants K22CA096556, DK056350, and Carolina Community Network grant no. U01CA114629 from the National Institutes of Health, Department of Health and Human Services. NR 48 TC 5 Z9 5 U1 3 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0162-220X J9 CANCER NURS JI Cancer Nurs. PD MAR-APR PY 2010 VL 33 IS 2 BP 102 EP 109 DI 10.1097/NCC.0b013e3181be5e8a PG 8 WC Oncology; Nursing SC Oncology; Nursing GA 568XY UT WOS:000275560700004 PM 20142738 ER PT J AU Bevans, M Castro, K Prince, P Shelburne, N Prachenko, O Loscalzo, M Soeken, K Zabora, J AF Bevans, Margaret Castro, Kathleen Prince, Patricia Shelburne, Nonniekaye Prachenko, Olena Loscalzo, Matthew Soeken, Karen Zabora, James TI An Individualized Dyadic Problem-Solving Education Intervention for Patients and Family Caregivers During Allogeneic Hematopoietic Stem Cell Transplantation A Feasibility Study SO CANCER NURSING LA English DT Article DE Caregivers; Coping skills; Education; Hematopoietic stem cell transplant; Oncology; Problem-solving ID BONE-MARROW-TRANSPLANTATION; CANCER-PATIENTS; PROSTATE-CANCER; PSYCHOSOCIAL INTERVENTIONS; UNIPOLAR DEPRESSION; THERAPY; CARE; ADAPTATION; DISTRESS; EFFICACY AB Background: Allogeneic hematopoietic stem cell transplantation (HSCT) generates multiple problems that vary in complexity and create significant distress for both patients and their caregivers. Interventions that address patient and family caregiver distress during allogeneic hematopoietic stem cell transplantation ( HSCT) have not been tested. Objective: To evaluate the feasibility of conducting an individualized dyadic problem-solving education (PSE) intervention during HSCT and estimate a preliminary effect size on problem-solving skills and distress. Methods: The PSE intervention consisted of 4 sessions of the Prepared Family Caregiver PSE model. Data were collected with an interventionist log, subject interviews and standardized questionnaires. Results: Of the 34 adult dyads screened, 24 were ineligible primarily because of being non-English-speaking (n = 11) and inconsistent caregivers (n = 10). Ten dyads (n = 20) were enrolled, and 8 dyads (n = 16) completed the intervention. Of the 31 sessions, 29 were completed (94%). Worsening patient condition was the primary reason for sessions to be incomplete. Patients attended 90% of the sessions; caregivers attended 74%. Reasons for missed sessions included patient symptom distress and limited caregiver availability. Dyads reported being very satisfied (mean, 4.8 [SD, 1.8]; range, 1-5), stating "an opportunity to talk'' and "creative thinking'' were most beneficial. Conclusion: Results suggest that dyads can participate in PSE during HSCT and view it as beneficial. Participants identified the active process of solving problems as helpful. Implications for Practice: Targeted interventions that promote effective, meaningful behaviors are needed to guide patients and caregivers through HSCT. Future research recommendations include testing a version of PSE with fewer sessions, including spousal and nonspousal caregivers and those who are non-English speaking. C1 [Bevans, Margaret; Castro, Kathleen; Prince, Patricia; Shelburne, Nonniekaye; Prachenko, Olena] NIH, Bethesda, MD 20892 USA. [Loscalzo, Matthew] City Hope Natl Med Ctr, Duarte, CA USA. [Zabora, James] Natl Catholic Sch Social Serv, Washington, DC USA. [Soeken, Karen] Univ Maryland, Sch Nursing, Baltimore, MD 21201 USA. RP Bevans, M (reprint author), 5061 Durham Rd W, Columbia, MD 21044 USA. EM mbevans@cc.nih.gov FU National Institutes of Health, Clinical Center FX This study was funded by the Intramural Research Program of the National Institutes of Health, Clinical Center. NR 53 TC 10 Z9 10 U1 3 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0162-220X J9 CANCER NURS JI Cancer Nurs. PD MAR-APR PY 2010 VL 33 IS 2 BP E24 EP E32 DI 10.1097/NCC.0b013e3181be5e6d PG 9 WC Oncology; Nursing SC Oncology; Nursing GA 568XY UT WOS:000275560700015 PM 20142739 ER PT J AU Neuhouser, ML Till, C Kristal, A Goodman, P Hoque, A Platz, EA Hsing, AW Albanes, D Parnes, HL Pollak, M AF Neuhouser, Marian L. Till, Cathee Kristal, Alan Goodman, Phyllis Hoque, Ashraful Platz, Elizabeth A. Hsing, Ann W. Albanes, Demetrius Parnes, Howard L. Pollak, Michael TI Finasteride Modifies the Relation between Serum C-Peptide and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial SO CANCER PREVENTION RESEARCH LA English DT Article ID BODY-MASS INDEX; GROWTH-FACTOR-I; MIDDLE-AGED MEN; INSULIN-RESISTANCE; BREAST-CANCER; METABOLIC SYNDROME; GENETIC ASSOCIATION; CELL-PROLIFERATION; GLUCOSE-TOLERANCE; SUPPLEMENT USE AB Hyperinsulinemia and obesity-related metabolic disturbances are common and have been associated with increased cancer risk and poor prognosis. To investigate this issue in relation to prostate cancer, we conducted a nested case-control study within the Prostate Cancer Prevention Trial (PCPT), a randomized, placebo-controlled trial testing finasteride versus placebo for primary prevention of prostate cancer. Cases (n = 1,803) and controls (n = 1,797) were matched on age, PCPT treatment arm, and family history of prostate cancer; controls included all eligible non-whites. Baseline bloods were assayed for serum C-peptide (marker of insulin secretion) and leptin (an adipokine) using ELISA. All outcomes were biopsy determined. Logistic regression calculated odds ratios (OR) for total prostate cancer and polytomous logistic regression calculated ORs for low-grade (Gleason <7) and high-grade (Gleason >7) disease. Results were stratified by PCPT treatment arm for C-peptide. For men on placebo, higher versus lower serum C-peptide was associated with a nearly 2-fold increased risk of high-grade prostate cancer (Gleason >7; multivariate-adjusted OR, 1.88; 95% confidence interval, 1.19-2.97; P(trend) = 0.004). When C-peptide was modeled as a continuous variable, every unit increase in log(C-peptide) resulted in a 39% increased risk of high-grade disease (P = 0.01). In contrast, there was no significant relationship between C-peptide and high-grade prostate cancer among men receiving finasteride. Leptin was not independently associated with high-grade prostate cancer. In conclusion, these results support findings from other observational studies that high serum C-peptide and insulin resistance, but not leptin, are associated with increased risk of high-grade prostate cancer. Our novel finding is that the C-peptide-associated risk was attenuated by use of finasteride. Cancer Prev Res; 3(3); 279-89. (C) 2010 AACR. C1 [Neuhouser, Marian L.; Till, Cathee; Kristal, Alan; Goodman, Phyllis] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. [Kristal, Alan] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA. [Hoque, Ashraful] Univ Texas MD Anderson Canc Ctr, Dept Clin Canc Prevent, Houston, TX 77030 USA. [Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Hsing, Ann W.; Albanes, Demetrius] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Parnes, Howard L.] NCI, Prostate & Urol Canc Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Pollak, Michael] McGill Univ, Dept Med, Montreal, PQ, Canada. [Pollak, Michael] McGill Univ, Dept Oncol, Montreal, PQ, Canada. RP Neuhouser, ML (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1100 Fairview Ave N,M4-B402, Seattle, WA 98109 USA. EM mneuhous@fhcrc.org RI Albanes, Demetrius/B-9749-2015; OI Kristal, Alan/0000-0002-7329-1617 FU National Cancer Institute at the NIH; U.S. Department of Health and Human Services [P01 CA108964] FX National Cancer Institute at the NIH, U.S. Department of Health and Human Services (P01 CA108964). NR 75 TC 14 Z9 15 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2010 VL 3 IS 3 BP 279 EP 289 DI 10.1158/1940-6207.CAPR-09-0188 PG 11 WC Oncology SC Oncology GA 563UG UT WOS:000275159800005 PM 20179296 ER PT J AU Camalier, CE Young, MR Bobe, G Perella, CM Colburn, NH Beck, GR AF Camalier, Corinne E. Young, Matthew R. Bobe, Gerd Perella, Christine M. Colburn, Nancy H. Beck, George R., Jr. TI Elevated Phosphate Activates N-ras and Promotes Cell Transformation and Skin Tumorigenesis SO CANCER PREVENTION RESEARCH LA English DT Article ID INHIBITED 3T3 CELLS; INORGANIC-PHOSPHATE; PARATHYROID-HORMONE; OSTEOBLAST CELLS; HIGH PHOSPHORUS; SERUM CONCENTRATION; TUMOR PROGRESSION; GENE-EXPRESSION; JB6 CELLS; OSTEOPONTIN AB Recent results suggest a paradigm shift from viewing inorganic phosphate as a passive requirement for basic cell functions to an active regulator of cell behavior. We have previously shown that elevated concentrations of phosphate increased cell proliferation and expression of protumorigenic genes such as Fra1 and osteopontin in a preosteoblast cell line. Therefore, we hypothesized that elevated phosphate concentrations would promote cell transformation in vitro and tumorigenesis in vivo. Supplementation of medium with phosphate increased anchorage-independent transformation and proliferation of BALB/c mouse JB6 epidermal cells, activation of N-ras, ERK1/2, and activator protein-1, and increased gene expression of Fra-1, COX-2, and osteopontin in a dose-dependent manner. These in vitro results led to the hypothesis that varying the levels of dietary inorganic phosphate would alter tumorigenesis in the mouse model of skin carcinogenesis. Female FVB/N mice were treated with 7,12-dimethylbenz (a) anthracene/12-O-tetradecanoylphorbol-13-acetate and fed high-or low-phosphate diets (1.2% versus 0.2% of the diet) for 19 weeks. The high-phosphate diet increased skin papilloma number by similar to 50% without changing feed intake and body weights. High dietary phosphate increased serum concentrations of phosphate, parathyroid hormone, and osteopontin and decreased serum concentrations of calcium. Thus, we conclude that elevated phosphate promotes cell transformation and skin tumorigenesis partly by increasing the availability of phosphate for activation of N-ras and its downstream targets, which defines reducing dietary phosphate as a novel target for chemoprevention. Cancer Prev Res; 3(3); 359-70. (C) 2010 AACR. C1 [Camalier, Corinne E.; Beck, George R., Jr.] Emory Univ, Sch Med, Dept Med, Div Endocrinol Metab & Lipids, Atlanta, GA 30322 USA. [Young, Matthew R.; Bobe, Gerd; Colburn, Nancy H.] NCI, Gene Regulat Sect, Frederick, MD 21701 USA. [Camalier, Corinne E.; Beck, George R., Jr.] NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21701 USA. [Perella, Christine M.] NCI, Lab Anim Sci Program, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. [Bobe, Gerd] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, Bethesda, MD 20892 USA. RP Beck, GR (reprint author), Emory Univ, Sch Med, Dept Med, Div Endocrinol Metab & Lipids, 101 Woodruff Circle,WMRB 1026, Atlanta, GA 30322 USA. EM george.beck@emory.edu FU NIH/National Cancer Institute [CA136059]; NIH/NIAMS [AR056090]; Emory University Research Committee; National Cancer Institute, NIH FX G. R. Beck, Jr. and C. E. Camalier are supported in part by grants from the NIH/National Cancer Institute (CA136059), NIH/NIAMS (AR056090), Emory University Research Committee grant, and M. R. Young, G. Bobe, C. M. Perella, and N.H. Colburn supported by federal funds from the National Cancer Institute, NIH. NR 63 TC 25 Z9 26 U1 2 U2 10 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2010 VL 3 IS 3 BP 359 EP 370 DI 10.1158/1940-6207.CAPR-09-0068 PG 12 WC Oncology SC Oncology GA 563UG UT WOS:000275159800013 PM 20145188 ER PT J AU McCormick, DL Rao, KVN Johnson, WD Bosland, MC Lubet, RA Steele, VE AF McCormick, David L. Rao, K. V. N. Johnson, William D. Bosland, Maarten C. Lubet, Ronald A. Steele, Vernon E. TI Null Activity of Selenium and Vitamin E as Cancer Chemopreventive Agents in the Rat Prostate SO CANCER PREVENTION RESEARCH LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; SYRIAN GOLDEN-HAMSTERS; METHYL-N-NITROSOUREA; PREVENTION TRIAL; SERUM SELENIUM; INTRAEPITHELIAL NEOPLASIA; GLUTATHIONE PEROXIDASE; BIOLOGICAL-MATERIALS; DIETARY SELENIUM; RISK AB To evaluate the potential efficacy of selenium and vitamin E as inhibitors of prostate carcinogenesis, four chemoprevention studies using a common protocol were done in a rat model of androgen-dependent prostate cancer. After stimulation of prostate epithelial cell proliferation by a sequential regimen of cyproterone acetate followed by testosterone propionate, male Wistar-Unilever rats received a single i.v. injection of N-methyl-N-nitrosourea (MNU) followed by chronic androgen stimulation via subcutaneous implantation of testosterone pellets. At 1 week post-MNU, groups of carcinogen-treated rats (39-44/group) were fed either a basal diet or a basal diet supplemented with L-selenomethionine (3 or 1.5 mg/kg diet; study 1), DL-alpha-tocopherol (vitamin E, 4,000 or 2,000 mg/kg diet; study 2), L-selenomethionine + vitamin E (3 + 2,000 mg/kg diet or 3 + 500 mg/kg diet; study 3), or selenized yeast (target selenium levels of 9 or 3 mg/kg diet; study 4). Each chemoprevention study was terminated at 13 months post-MNU, and prostate cancer incidence was determined by histopathologic evaluation. No statistically significant reductions in prostate cancer incidence were identified in any group receiving dietary supplementation with selenium and/or vitamin E. These data do not support the hypotheses that selenium and vitamin E are potent cancer chemopreventive agents in the prostate, and when considered with the recent clinical data reported in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), show the predictive nature of this animal model for human prostate cancer chemoprevention. Cancer Prev Res; 3(3); 381-92. (C) 2010 AACR. C1 [McCormick, David L.; Rao, K. V. N.; Johnson, William D.] IIT, Res Inst, Life Sci Grp, Chicago, IL 60616 USA. [Bosland, Maarten C.] NYU, Sch Med, Nelson Inst Environm Med, New York, NY USA. [Lubet, Ronald A.; Steele, Vernon E.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP McCormick, DL (reprint author), IIT, Res Inst, Life Sci Grp, 10 W 35th St, Chicago, IL 60616 USA. EM dmccormick@iitri.org FU Division of Cancer Prevention, National Cancer Institute, Department of Health and Human Services [N01-CN-35566-02, N01-CN-95113, N01-CN-65120]; NIH [P30-ES-00260, P30-CA-16087] FX Research supported by contracts N01-CN-35566-02, N01-CN-95113, and N01-CN-65120 from the Division of Cancer Prevention, National Cancer Institute, Department of Health and Human Services, and by NIH center grants P30-ES-00260 and P30-CA-16087. NR 51 TC 21 Z9 24 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1940-6207 J9 CANCER PREV RES JI Cancer Prev. Res. PD MAR PY 2010 VL 3 IS 3 BP 381 EP 392 DI 10.1158/1940-6207.CAPR-09-0176 PG 12 WC Oncology SC Oncology GA 563UG UT WOS:000275159800015 PM 20145190 ER PT J AU Safaeian, M Schiffman, M Gage, J Castle, PE Solomon, D Wheeler, CM AF Safaeian, Mahboobeh Schiffman, Mark Gage, Julia Castle, Philip E. Solomon, Diane Wheeler, Cosette M. TI Comment re: Detection of Cervical Precancer by HPV Genotype Response SO CANCER RESEARCH LA English DT Letter C1 [Safaeian, Mahboobeh; Schiffman, Mark; Gage, Julia; Castle, Philip E.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Solomon, Diane] NCI, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Wheeler, Cosette M.] Univ New Mexico, Sch Med, Dept Mol Genet & Microbiol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. [Wheeler, Cosette M.] Univ New Mexico, Sch Med, Dept Obstet & Gynecol, Hlth Sci Ctr, Albuquerque, NM 87131 USA. RP Safaeian, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NR 2 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 MAR 1 PY 2010 VL 70 IS 5 BP 2137 EP 2137 DI 10.1158/0008-5472.CAN-09-3750 PG 1 WC Oncology SC Oncology GA 607FZ UT WOS:000278485800042 ER PT J AU Kosaka, N Ogawa, M Paik, DS Paik, CH Choyke, PL Kobayashi, H AF Kosaka, Nobuyuki Ogawa, Mikako Paik, David S. Paik, Chang H. Choyke, Peter L. Kobayashi, Hisataka TI Semiquantitative assessment of the microdistribution of fluorescence-labeled monoclonal antibody in small peritoneal disseminations of ovarian cancer SO CANCER SCIENCE LA English DT Article ID BINDING-SITE BARRIER; SOLID TUMORS; MODELING ANALYSIS; RADIOIMMUNOTHERAPY; THERAPY; PENETRATION; RESISTANCE; LYMPHOMA; DELIVERY AB Uniform antibody microdistribution throughout tumor nodules is crucial for antibody-targeted therapy, because non-uniform microdistribution leads to suboptimal therapeutic effect, a commonly observed limitation of therapeutic antibodies. Herein, we evaluated the microdistribution of different doses of intraperitoneally injected fluorescence-labeled full-antibody trastuzumab (15, 50, and 150 mu g) and its Fab fragment (trastuzumab-Fab: 15 and 50 mu g) in a mouse model of ovarian cancer with peritoneal disseminated tumor. A semiquantitative approach (central/peripheral accumulation ratio; C/P ratio) was developed using in situ fluorescence microscopy. Furthermore, we compared the microdistribution of intact trastuzumab with a mixed injection of trastuzumab and trastuzumab-Fab or serial injections of trastuzumab using in situ multicolor fluorescence microscopy. Fluorescence images after the administration of 15 or 50 mu g trastuzumab and 15 mu g trastuzumab-Fab demonstrated antibody accumulation in the tumor periphery, whereas administration of 150 mu g trastuzumab and 50 mu g trastuzumab-Fab showed relatively uniform accumulation throughout the tumor nodule. Using serial injections (19-h interval) of trastuzumab-rhodamine green and carboxytetramethylrhodamine (TAMRA), it was observed that the latterly injected trastuzumab-TAMRA was distributed more centrally than trastuzumab-rhodamine green injected first, whereas no difference was observed in the control mixed-injection group. Moreover, the mixed injection of trastuzumab and trastuzumab-Fab showed that trastuzumab-Fab distributed more centrally than the same amount of co-injected trastuzumab. Our results suggest that the strategies of increasing dose and using Fab fragments can be used to achieve a uniform antibody distribution within peritoneal disseminated nodules after intraperitoneal injection. Furthermore, serial-injection and mixed-injection strategies can modify antibody microdistribution within tumors and have the potential for preferential delivery of anticancer drugs to either the tumor periphery or its center. (Cancer Sci 2010; 101: 820-825) C1 [Kosaka, Nobuyuki; Ogawa, Mikako; Paik, David S.; Choyke, Peter L.; Kobayashi, Hisataka] NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. [Paik, Chang H.] NIH, Dept Nucl Med, Warren Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. EM kobayash@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 25 TC 13 Z9 13 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1347-9032 J9 CANCER SCI JI Cancer Sci. PD MAR PY 2010 VL 101 IS 3 BP 820 EP 825 DI 10.1111/j.1349-7006.2009.01423.x PG 6 WC Oncology SC Oncology GA 556VQ UT WOS:000274621800036 PM 19961490 ER PT J AU Zabirnyk, O Liu, W Khalil, S Sharma, A Phang, JM AF Zabirnyk, Olga Liu, Wei Khalil, Shadi Sharma, Anit Phang, James M. TI Oxidized low-density lipoproteins upregulate proline oxidase to initiate ROS-dependent autophagy SO CARCINOGENESIS LA English DT Article ID ACTIVATED-RECEPTOR-GAMMA; SMOOTH-MUSCLE-CELLS; OXIDATIVE STRESS; COLORECTAL-CANCER; LIGAND ACTIVATION; TUMOR-SUPPRESSOR; CYCLE PROTEINS; APOPTOSIS; ATHEROSCLEROSIS; EXPRESSION AB Epidemiological studies showed that high levels of oxidized low-density lipoproteins (oxLDLs) are associated with increased cancer risk. We examined the direct effect of physiologic concentrations oxLDL on cancer cells. OxLDLs were cytotoxic and activate both apoptosis and autophagy. OxLDLs have ligands for peroxisome proliferator-activated receptor gamma and upregulated proline oxidase (POX) through this nuclear receptor. We identified 7-ketocholesterol (7KC) as a main component responsible for the latter. To elucidate the role of POX in oxLDL-mediated cytotoxicity, we knocked down POX via small interfering RNA and found that this (i) further reduced viability of cancer cells treated with oxLDL; (ii) decreased oxLDL-associated reactive oxygen species generation; (iii) decreased autophagy measured via beclin-1 protein level and light-chain 3 protein (LC3)-I into LC3-II conversion. Using POX-expressing cell model, we established that single POX overexpression was sufficient to activate autophagy. Thus, it led to autophagosomes accumulation and increased conversion of LC3-I into LC3-II. Moreover, beclin-1 gene expression was directly dependent on POX catalytic activity, namely the generation of POX-dependent superoxide. We conclude that POX is critical in the cellular response to the noxious effects of oxLDL by activating protective autophagy. C1 [Zabirnyk, Olga] NCI, Metab & Canc Susceptibil Sect, Comparat Carcinogenesis Lab, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Zabirnyk, O (reprint author), NCI, Metab & Canc Susceptibil Sect, Comparat Carcinogenesis Lab, Ctr Canc Res,NIH, Bldg 538,Room 144, Frederick, MD 21702 USA. EM olga_zabirnyk@yahoo.com; phangj@mail.nih.gov RI liu, wei /E-7340-2012 FU National Institutes of Health; National Cancer Institute; Center for Cancer Research FX Intramural Research Program of the National Institutes of Health; National Cancer Institute; Center for Cancer Research. NR 52 TC 31 Z9 36 U1 1 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAR PY 2010 VL 31 IS 3 BP 446 EP 454 DI 10.1093/carcin/bgp299 PG 9 WC Oncology SC Oncology GA 564VE UT WOS:000275245200017 PM 19942609 ER PT J AU Dossus, L Kaaks, R Canzian, F Albanes, D Berndt, SI Boeing, H Buring, J Chanock, SJ Clavel-Chapelon, F Feigelson, HS Gaziano, JM Giovannucci, E Gonzalez, C Haiman, CA Hallmans, G Hankinson, SE Hayes, RB Henderson, BE Hoover, RN Hunter, DJ Khaw, KT Kolonel, LN Kraft, P Ma, J Le Marchand, L Lund, E Peeters, PHM Stampfer, M Stram, DO Thomas, G Thun, MJ Tjonneland, A Trichopoulos, D Tumino, R Riboli, E Virtamo, J Weinstein, SJ Yeager, M Ziegler, RG Cox, DG AF Dossus, Laure Kaaks, Rudolf Canzian, Federico Albanes, Demetrius Berndt, Sonja I. Boeing, Heiner Buring, Julie Chanock, Stephen J. Clavel-Chapelon, Francoise Feigelson, Heather Spencer Gaziano, John M. Giovannucci, Edward Gonzalez, Carlos Haiman, Christopher A. Hallmans, Goran Hankinson, Susan E. Hayes, Richard B. Henderson, Brian E. Hoover, Robert N. Hunter, David J. Khaw, Kay-Tee Kolonel, Laurence N. Kraft, Peter Ma, Jing Le Marchand, Loic Lund, Eiliv Peeters, Petra H. M. Stampfer, Meir Stram, Dan O. Thomas, Gilles Thun, Michael J. Tjonneland, Anne Trichopoulos, Dimitrios Tumino, Rosario Riboli, Elio Virtamo, Jarmo Weinstein, Stephanie J. Yeager, Meredith Ziegler, Regina G. Cox, David G. TI PTGS2 and IL6 genetic variation and risk of breast and prostate cancer: results from the Breast and Prostate Cancer Cohort Consortium (BPC3) SO CARCINOGENESIS LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; BASE-LINE CHARACTERISTICS; SINGLE-NUCLEOTIDE POLYMORPHISMS; GROWTH-FACTOR-I; COX-2 GENE; CHRONIC INFLAMMATION; INTERLEUKIN-6 GENE; DNA-DAMAGE; ASSOCIATION; CYCLOOXYGENASE-2 AB Genes involved in the inflammation pathway have been associated with cancer risk. Genetic variants in the interleukin-6 (IL6) and prostaglandin-endoperoxide synthase-2 (PTGS2, encoding for the COX-2 enzyme) genes, in particular, have been related to several cancer types, including breast and prostate cancers. We conducted a study within the Breast and Prostate Cancer Cohort Consortium to examine the association between IL6 and PTGS2 polymorphisms and breast and prostate cancer risk. Twenty-seven polymorphisms, selected by pairwise tagging, were genotyped on 6292 breast cancer cases and 8135 matched controls and 8008 prostate cancer cases and 8604 matched controls. The large sample sizes and comprehensive single nucleotide polymorphism tagging in this study gave us excellent power to detect modest effects for common variants. After adjustment for multiple testing, none of the associations examined remained statistically significant at P = 0.01. In analyses not adjusted for multiple testing, one IL6 polymorphism (rs6949149) was marginally associated with breast cancer risk (TT versus GG, odds ratios (OR): 1.32; 99% confidence intervals (CI): 1.00-1.74, P(trend) = 0.003) and two were marginally associated with prostate cancer risk (rs6969502-AA versus rs6969502-GG, OR: 0.87, 99% CI: 0.75-1.02; P(trend) = 0.002 and rs7805828-AA versus rs7805828-GG, OR: 1.11, 99% CI: 0.99-1.26; P(trend) = 0.007). An increase in breast cancer risk was observed for the PTGS2 polymorphism rs7550380 (TT versus GG, OR: 1.38, 99% CI: 1.04-1.83). No association was observed between PTGS2 polymorphisms and prostate cancer risk. In conclusion, common genetic variation in these two genes might play at best a limited role in breast and prostate cancers. C1 [Dossus, Laure; Kaaks, Rudolf; Canzian, Federico] German Canc Res Ctr, Div Canc Epidemiol, D-69120 Heidelberg, Germany. [Albanes, Demetrius; Berndt, Sonja I.; Chanock, Stephen J.; Hoover, Robert N.; Weinstein, Stephanie J.; Ziegler, Regina G.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Boeing, Heiner; Hayes, Richard B.; Thomas, Gilles; Yeager, Meredith] German Inst Human Nutr, Dept Epidemiol, D-14558 Postdam Rehbruecke, Nuthetal, Germany. [Buring, Julie] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Med,Div Prevent Med, Boston, MA 02215 USA. [Clavel-Chapelon, Francoise] Inst Gustave Roussy, F-94805 Villejuif, France. [Clavel-Chapelon, Francoise] INSERM, ERI 20, EA 4045, F-94805 Villejuif, France. [Feigelson, Heather Spencer; Thun, Michael J.] Amer Canc Soc, Dept Epidemiol, Atlanta, GA 30303 USA. [Feigelson, Heather Spencer] Kaiser Permanente, Denver, CO 80237 USA. [Gaziano, John M.] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Aging,Dept Med, Boston, MA 02215 USA. [Giovannucci, Edward] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02215 USA. [Giovannucci, Edward; Hankinson, Susan E.; Ma, Jing; Stampfer, Meir] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02215 USA. [Giovannucci, Edward; Stampfer, Meir; Trichopoulos, Dimitrios] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Gonzalez, Carlos] Catalan Inst Oncol ICO Idibell ISCIII RETICC, Unit Nutr Environm & Canc, Barcelona 08907, Spain. [Haiman, Christopher A.; Henderson, Brian E.; Stram, Dan O.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Hallmans, Goran] Umea Univ, Dept Publ Hlth & Clin Med, S-90187 Umea, Sweden. [Hayes, Richard B.] NYU, Sch Med, Dept Environm Med, Div Epidemiol, New York, NY 10012 USA. [Hunter, David J.; Kraft, Peter] Harvard Univ, Sch Publ Hlth, Program Mol & Genet Epidemiol, Dept Epidemiol, Boston, MA 02215 USA. [Khaw, Kay-Tee; Le Marchand, Loic] Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge CB1 8RN, England. [Kolonel, Laurence N.] Univ Hawaii, Canc Res Ctr, Program Epidemiol, Honolulu, HI 96822 USA. [Lund, Eiliv] Univ Tromso, Inst Community Med, N-9037 Tromso, Norway. [Peeters, Petra H. M.] Univ Med Ctr, Julius Ctr Hlth Sci & Primary Care, NL-3508 GA Utrecht, Netherlands. [Thomas, Gilles] Ctr Leon Berard, INSERM, U590, F-69373 Lyon, France. [Tjonneland, Anne] Danish Canc Soc, Inst Canc Epidemiol, DK-2100 Copenhagen, Denmark. [Trichopoulos, Dimitrios] Hellen Hlth Fdn, Athens 11527, Greece. [Tumino, Rosario] Canc Registry Azienda Osped Civile MP Arezzo, I-97100 Ragusa, Italy. [Riboli, Elio] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London W2 1PG, England. [Virtamo, Jarmo] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, FI-00271 Helsinki, Finland. [Yeager, Meredith] NCI, Core Genotyping Facil, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Dossus, L (reprint author), German Canc Res Ctr, Div Canc Epidemiol, Neuenheimer Feld 280, D-69120 Heidelberg, Germany. EM l.dossus@dkfz.de RI Dossus, Laure/B-2875-2013; Clavel-Chapelon, Francoise/G-6733-2014; Albanes, Demetrius/B-9749-2015; Cox, David/A-2023-2009 OI Dossus, Laure/0000-0003-2716-5748; Hayes, Richard/0000-0002-0918-661X; Cox, David/0000-0002-2152-9259 FU National Cancer Institute [CA98233, CA98710, CA98216, CA98758] FX National Cancer Institute under U01 grants (CA98233, CA98710, CA98216, CA98758). NR 55 TC 39 Z9 42 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAR PY 2010 VL 31 IS 3 BP 455 EP 461 DI 10.1093/carcin/bgp307 PG 7 WC Oncology SC Oncology GA 564VE UT WOS:000275245200018 PM 19965896 ER PT J AU Mukhopadhyay, P Rajesh, M Batkai, S Patel, V Kashiwaya, Y Liaudet, L Evgenov, OV Mackie, K Hasko, G Pacher, P AF Mukhopadhyay, Partha Rajesh, Mohanraj Batkai, Sandor Patel, Vivek Kashiwaya, Yoshihiro Liaudet, Lucas Evgenov, Oleg V. Mackie, Ken Hasko, Gyoergy Pacher, Pal TI CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes SO CARDIOVASCULAR RESEARCH LA English DT Article DE Heart failure; CB1 receptor; Endocannabinoids; Rimonabant; SR141716; AM281 ID ISCHEMIA-REPERFUSION INJURY; ENDOCANNABINOID SYSTEM; ISCHEMIA/REPERFUSION INJURY; INDUCED CARDIOTOXICITY; NITRIC-OXIDE; IN-VITRO; PEROXYNITRITE; DYSFUNCTION; MICE; SUPEROXIDE AB Here we investigated the mechanisms by which cardiovascular CB1 cannabinoid receptors may modulate the cardiac dysfunction, oxidative stress, and interrelated cell death pathways associated with acute/chronic cardiomyopathy induced by the widely used anti-tumour compound doxorubicin (DOX). Both load-dependent and -independent indices of left-ventricular function were measured by the Millar pressure-volume conductance system. Mitogen-activated protein kinase (MAPK) activation, cell-death markers, and oxidative/nitrosative stress were measured by molecular biology/biochemical methods and flow cytometry. DOX induced left-ventricular dysfunction, oxidative/nitrosative stress coupled with impaired antioxidant defense, activation of MAPK (p38 and JNK), and cell death and/or fibrosis in hearts of wide-type mice (CB1+/+), and these effects were markedly attenuated in CB1 knockouts (CB1-/-). In human primary cardiomyocytes expressing CB1 receptors (demonstrated by RT-PCR, western immunoblot, and flow cytometry) DOX, likewise the CB1 receptor agonist HU210 and the endocannabinoid anandamide (AEA), induced MAPK activation and cell death. The DOX-induced MAPK activation and cell death were significantly enhanced when DOX was co-administered with CB1 agonists AEA or HU210. Remarkably, cell death and MAPK activation induced by AEA, HU210, and DOX +/- AEA/HU210 were largely attenuated by either CB1 antagonists (rimonabant and AM281) or by inhibitors of p38 and JNK MAPKs. Furthermore, AEA or HU210 in primary human cardiomyocytes triggered increased reactive oxygen species generation. CB1 activation in cardiomyocytes may amplify the reactive oxygen/nitrogen species-MAPK activation-cell death pathway in pathological conditions when the endocannabinoid synthetic or metabolic pathways are dysregulated by excessive inflammation and/or oxidative/nitrosative stress, which may contribute to the pathophysiology of various cardiovascular diseases. C1 [Mukhopadhyay, Partha; Rajesh, Mohanraj; Batkai, Sandor; Patel, Vivek; Pacher, Pal] NIAAA, Sect Oxidat Stress & Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Kashiwaya, Yoshihiro] NIAAA, Lab Metab Control, NIH, Bethesda, MD 20892 USA. [Liaudet, Lucas] Univ Hosp, Dept Intens Care Med, Lausanne, Switzerland. [Evgenov, Oleg V.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Anesthesia Crit Care & Pain Med, Boston, MA USA. [Mackie, Ken] Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA. [Hasko, Gyoergy] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. RP Pacher, P (reprint author), NIAAA, Sect Oxidat Stress & Tissue Injury, Lab Physiol Studies, NIH, 5625 Fishers Lane,MSC-9413, Bethesda, MD 20892 USA. EM pacher@mail.nih.gov RI MUKHOPADHYAY, PARTHA/G-3890-2010; Mackie, Kenneth/B-7358-2011; Batkai, Sandor/G-3889-2010; Pacher, Pal/B-6378-2008; Mackie, Ken/E-3715-2013; Batkai, Sandor/H-7983-2014; Liaudet, Lucas/E-1322-2017 OI MUKHOPADHYAY, PARTHA/0000-0002-1178-1274; Pacher, Pal/0000-0001-7036-8108; Mackie, Ken/0000-0001-8501-6199; Liaudet, Lucas/0000-0003-2670-4930 FU National Institutes of Health/NIAAA [DA11322]; Swiss National Fund for Scientific Research [PP00B-68882/1] FX This study was supported by the Intramural research program of the National Institutes of Health/NIAAA (to P. P.) and DA11322 (to K. M.), Swiss National Fund for Scientific Research Grant PP00B-68882/1 (to L. L.). NR 48 TC 71 Z9 76 U1 2 U2 10 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0008-6363 J9 CARDIOVASC RES JI Cardiovasc. Res. PD MAR 1 PY 2010 VL 85 IS 4 BP 773 EP 784 DI 10.1093/cvr/cvp369 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 555DO UT WOS:000274487900017 PM 19942623 ER PT J AU Torres, SM March, TH Carter, MM McCash, CL Seilkop, SK Poirier, MC Walker, DM Walker, VE AF Torres, Salina M. March, Thomas H. Carter, Meghan M. McCash, Consuelo L. Seilkop, Steven K. Poirier, Miriam C. Walker, Dale M. Walker, Vernon E. TI In Utero Exposure of Female CD-1 Mice to AZT and/or 3TC: I. Persistence of Microscopic Lesions in Cardiac Tissue SO CARDIOVASCULAR TOXICOLOGY LA English DT Article DE AZT; 3TC; Cardiotoxicity; Electron microscopy; Histopathology; Mitochondrial pathology; PTAH stain; Transplacental exposure; Trichrome stain; Ultrastructural pathology ID REVERSE-TRANSCRIPTASE INHIBITORS; TO-CHILD TRANSMISSION; MITOCHONDRIAL TOXICITY; PERINATAL EXPOSURE; PATAS MONKEYS; ANTIRETROVIRAL THERAPY; NUCLEOSIDE ANALOGS; DYSFUNCTION; HIV; ZIDOVUDINE AB The current study was designed to delineate temporal changes in cardiomyocytes and mitochondria at the light and electron microscopic levels in hearts of mice exposed transplacentally to commonly used nucleoside analogs (NRTIs). Pregnant CD-1 mice were given 80 mg AZT/kg, 40 mg 3TC/kg, 80 mg AZT/kg plus 40 mg 3TC/kg, or vehicle alone during the last 7 days of gestation, and hearts from female mouse pups were examined at 13 and 26 weeks postpartum for histopathological or ultrastructural changes in cross-sections of both the ventricles and the interventricular septum. Using light microscopy and special staining techniques, transplacental exposure to AZT, 3TC, or AZT/3TC was shown to induce significant histopathological changes in myofibrils; these changes were more widespread at 13 weeks than at 26 weeks postpartum. While most light microscopic lesions resolved, some became more severe between 13 and 26 weeks postpartum. Transplacental NRTI exposure also resulted in progressive drug-specific changes in the number and ultrastructural integrity of cardiac mitochondria. These light and electron microscopic findings show that a subset of changes in cardiac mitochondria and myofibrils persisted and progressed months after transplacental exposure of an animal model to NRTIs, with combined AZT/3TC exposure yielding additive effects compared with either drug alone. C1 [Torres, Salina M.; Walker, Vernon E.] Univ New Mexico, Coll Pharm, Albuquerque, NM 87131 USA. [Torres, Salina M.; March, Thomas H.; Carter, Meghan M.; McCash, Consuelo L.; Walker, Vernon E.] Lovelace Resp Res Inst, Albuquerque, NM 87108 USA. [Seilkop, Steven K.] SKS Consulting Serv, Siler City, NC 27344 USA. [Poirier, Miriam C.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Walker, Dale M.; Walker, Vernon E.] BioMosaics Inc, Burlington, VT 05405 USA. [Walker, Vernon E.] Univ Vermont, Dept Pathol, Genet Toxicol Lab, Burlington, VT 05405 USA. RP Walker, VE (reprint author), Univ Vermont, Dept Pathol, Genet Toxicol Lab, 665 Spear St, Burlington, VT 05405 USA. EM vwalker@uvm.edu FU NIH [R01 HL 72727]; National Heart, Lung, and Blood Institute FX We wish to thank Mr. Steve Randock, Ms. Cynthia Herrera, and Ms. Wendy Piper (LRRI) for technical assistance in preparing figures and the manuscript. This work was supported, in part, by NIH grants R01 HL 72727 to VEW and 1 F31 HL081928 to SMT from the National Heart, Lung, and Blood Institute. The contents of this paper are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. NR 39 TC 8 Z9 8 U1 0 U2 0 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1530-7905 J9 CARDIOVASC TOXICOL JI Cardiovasc. Toxicol. PD MAR PY 2010 VL 10 IS 1 BP 37 EP 50 DI 10.1007/s12012-010-9061-3 PG 14 WC Cardiac & Cardiovascular Systems; Toxicology SC Cardiovascular System & Cardiology; Toxicology GA 553XA UT WOS:000274398900005 PM 20101476 ER PT J AU Anderson, HV Rosenfield, KA White, CJ Ho, KKL Spertus, JA Jones, PG Tang, FM Cates, CU Jaff, MR Koroshetz, WJ Katzan, IL Hopkins, LN Rumsfeld, JS Brindis, RG AF Anderson, H. Vernon Rosenfield, Kenneth A. White, Christopher J. Ho, Kalon K. L. Spertus, John A. Jones, Philip G. Tang, Fengming Cates, Christopher U. Jaff, Michael R. Koroshetz, Walter J. Katzan, Irene L. Hopkins, L. Nelson Rumsfeld, John S. Brindis, Ralph G. TI Clinical Features and Outcomes of Carotid Artery Stenting by Clinical Expert Consensus Criteria: A Report From the CARE Registry SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Article DE peripheral vascular disease; quantitative vascular angiography; total occlusions ID RISK PATIENTS; ENDARTERECTOMY; PROTECTION; PREDICTORS AB Background: In 2007, a multispecialty society task force published a clinical expert consensus document (CECD) on carotid stenting (CAS), containing recommendations for appropriate patient selection and quality of care. The CECD also inspired creation of a large, national registry of carotid revascularization, the Carotid Artery Revascularization and Endarterectomy (CARE) registry. Our goal here was to investigate whether initial CAS procedures submitted to CARE conformed to CECD recommendations, and examine their clinical outcomes. Methods: We analyzed CAS procedures for the period January 1, 2005 through December 31, 2008. These were grouped into those that conformed to CECD recommendations [CECD(+), n = 4,636, 79.8%] and those that did not [CECD(), n = 1,168, 20.2%]. Results: The CECD(+) patients were older than CECD() patients (71.5 +/- 10.3 vs. 67.6 +/- 10.3 years, P = 0.001, respectively), and more frequently had chronic kidney disease (46.9% vs. 17.8%, P = 0.001), chronic lung disease (33.0% vs. 12.4%, P = 0.001), ejection fraction <= 0.30 (13.5% vs. 5.5%, P = 0.001) and contralateral carotid artery occlusion (12.7% vs. 4.6%, P = 0.001). Clinical outcomes at 30 days were similar, including death (1.24% vs. 0.76%, P = 0.184), stroke (5.32% vs. 5.34%, P = 0.954), and death, stroke, or MI (7.04% vs. 6.95%, P = 0.944). Conclusions: Most CAS procedures submitted to CARE conformed to CECD recommendations for patient selection. For reported data, clinical outcomes at 30 days were similar for procedures meeting and those not meeting recommendations, and were similar to outcomes reported by other large registries. These findings suggest that acceptable patient selection criteria for CAS are employed as it expands beyond investigators into more widespread clinical practice. (C) 2010 Wiley-Liss, Inc. C1 [Anderson, H. Vernon] Univ Texas Hlth Sci Ctr, Div Cardiol, Houston, TX 77030 USA. [Rosenfield, Kenneth A.] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. [White, Christopher J.] Ochsner Clin Fdn, Dept Cardiol, New Orleans, LA USA. [Ho, Kalon K. L.] Beth Israel Deaconess Med Ctr, Dept Cardiol, Boston, MA 02215 USA. [Spertus, John A.; Jones, Philip G.; Tang, Fengming] St Lukes Hosp, Mid Amer Heart Inst, Dept Cardiol, Kansas City, MO 64111 USA. [Cates, Christopher U.] Emory Univ Hosp, Dept Cardiol, Atlanta, GA 30322 USA. [Jaff, Michael R.] Massachusetts Gen Hosp, Dept Cardiol, Boston, MA 02114 USA. [Koroshetz, Walter J.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Katzan, Irene L.] Cleveland Clin, Cerebrovasc Ctr, Cleveland, OH 44106 USA. [Katzan, Irene L.] Cleveland Clin, Dept Neurol, Cleveland, OH 44106 USA. [Hopkins, L. Nelson] SUNY Buffalo, Millard Fillmore Hosp, Dept Neurosurg, Buffalo, NY 14260 USA. [Rumsfeld, John S.] Denver VA Med Ctr, Denver, CO USA. [Rumsfeld, John S.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Brindis, Ralph G.] Amer Coll Cardiol, Washington, DC USA. RP Anderson, HV (reprint author), Univ Texas Hlth Sci Ctr, Div Cardiol, 6431 Fannin,1246, Houston, TX 77030 USA. EM h.v.anderson@uth.tmc.edu RI White, Christopher/J-6686-2012 OI White, Christopher/0000-0001-8618-7539 NR 10 TC 7 Z9 7 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD MAR 1 PY 2010 VL 75 IS 4 BP 519 EP 525 DI 10.1002/ccd.22333 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 582HW UT WOS:000276588600009 PM 20088016 ER PT J AU McNeely, S Conti, C Sheikh, T Patel, H Zabludoff, S Pommier, Y Schwartz, G Tse, A AF McNeely, Samuel Conti, Chiara Sheikh, Tahir Patel, Himali Zabludoff, Sonya Pommier, Yves Schwartz, Gary Tse, Archie TI Chk1 inhibition after replicative stress activates a double strand break response mediated by ATM and DNA-dependent protein kinase SO CELL CYCLE LA English DT Article DE Chk1; ATM; DNA-PK; AZD7762; gemcitabine ID TOPOISOMERASE-I POISON; CHECKPOINT ABROGATION; SIGNALING PATHWAYS; DAMAGE RESPONSE; MRE11-RAD50-NBS1 COMPLEX; CANCER CELLS; GEMCITABINE; PHOSPHORYLATION; REPAIR; 2,2-DIFLUORODEOXYCYTIDINE AB Checkpoint kinase 1 (Chk1) regulates cell cycle checkpoints and DNA damage repair in response to genotoxic stress. Inhibition of Chk1 is an emerging strategy for potentiating the cytotoxicity of chemotherapeutic drugs. Here, we demonstrate that AZD7762, an ATP-competitive Chk1/2 inhibitor induces gamma H2AX in gemcitabine-treated cells by altering both dynamics and stability of replication forks, allowing the firing of suppressed replication origins as measured by DNA fiber combing and causing a dramatic increase in DNA breaks as measured by comet assay. Furthermore, we identify ATM and DNA-PK, rather than ATR, as the kinases mediating gamma H2AX induction, suggesting AZD7762 converts stalled forks into double strand breaks (DSBs). Consistent with DSB formation upon fork collapse, cells deficient in DSB repair by lack of BRCA2, XRCC3 or DNA-PK were selectively more sensitive to combined AZD7762 and gemcitabine. Checkpoint abrogation by AZD7762 also caused premature mitosis in gemcitabine-treated cells arrested in G(1)/early S-phase. Prevention of premature mitotic entry via Cdk1 siRNA knockdown suppressed apoptosis. These results demonstrate that chemosensitization of gemcitabine by Chk1 inhibition results from at least three cellular events, namely, activation of origin firing, destabilization of stalled replication forks and entry of cells with damaged DNA into lethal mitosis. Additionally, the current study indicates that the combination of Chk1 inhibitor and gemcitabine may be particularly effective in targeting tumors with specific DNA repair defects. C1 [McNeely, Samuel; Sheikh, Tahir; Schwartz, Gary; Tse, Archie] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Patel, Himali] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10021 USA. [Conti, Chiara; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Zabludoff, Sonya] AstraZeneca R&D Boston, Waltham, MA USA. RP Tse, A (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. EM atse@dsi.com FU AstraZeneca; NCI [5K08CA116612] FX This work was supported in part by AstraZeneca and NCI grant 5K08CA116612. We thank Dr. Irene Orlow (Memorial Sloan-Kettering Cancer Center) for assistance with the comet assay. NR 53 TC 56 Z9 58 U1 0 U2 5 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAR 1 PY 2010 VL 9 IS 5 BP 995 EP 1004 DI 10.4161/cc.9.5.10935 PG 10 WC Cell Biology SC Cell Biology GA 578QB UT WOS:000276307700034 PM 20160494 ER PT J AU Jia, YF Wu, SL Isenberg, JS Dai, SJ Sipes, JM Field, L Zeng, BX Bandle, RW Ridnour, LA Wink, DA Ramchandran, R Karger, BL Roberts, DD AF Jia, Yifeng Wu, Shiaw-Lin Isenberg, Jeff S. Dai, Shujia Sipes, John M. Field, Lyndsay Zeng, Bixi Bandle, Russell W. Ridnour, Lisa A. Wink, David A. Ramchandran, Ramani Karger, Barry L. Roberts, David D. TI Thiolutin inhibits endothelial cell adhesion by perturbing Hsp27 interactions with components of the actin and intermediate filament cytoskeleton SO CELL STRESS & CHAPERONES LA English DT Article DE Hsp27; Arp2/3; Intermediate filaments; Angiogenesis; Mass spectrometry ID SMOOTH-MUSCLE-CELLS; ALPHA-B-CRYSTALLIN; HEAT-SHOCK; FOCAL ADHESIONS; PHOSPHORYLATED HSP27; PROTEIN-KINASE; HEAT-SHOCK-PROTEIN-27; EXPRESSION; NESTIN; ANGIOGENESIS AB Thiolutin is a dithiole synthesized by Streptomyces sp. that inhibits endothelial cell adhesion and tumor growth. We show here that thiolutin potently inhibits developmental angiogenesis in zebrafish and vascular outgrowth from tissue explants in 3D cultures. Thiolutin is a potent and selective inhibitor of endothelial cell adhesion accompanied by rapid induction of HSPB1 (Hsp27) phosphorylation. The inhibitory effects of thiolutin on endothelial cell adhesion are transient, potentially due to a compensatory increase in Hsp27 protein levels. Accordingly, heat shock induction of Hsp27 limits the anti-adhesive activity of thiolutin. Thiolutin treatment results in loss of actin stress fibers, increased cortical actin as cells retract, and decreased cellular F-actin. Mass spectrometric analysis of Hsp27 binding partners following immunoaffinity purification identified several regulatory components of the actin cytoskeleton that associate with Hsp27 in a thiolutin-sensitive manner including several components of the Arp2/3 complex. Among these, ArpC1a is a direct binding partner of Hsp27. Thiolutin treatment induces peripheral localization of phosphorylated Hsp27 and Arp2/3. Hsp27 also associates with the intermediate filament components vimentin and nestin. Thiolutin treatment specifically ablates Hsp27 interaction with nestin and collapses nestin filaments. These results provide new mechanistic insights into regulation of cell adhesion and cytoskeletal dynamics by Hsp27. C1 [Jia, Yifeng; Isenberg, Jeff S.; Sipes, John M.; Field, Lyndsay; Zeng, Bixi; Bandle, Russell W.; Ramchandran, Ramani; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ramchandran, Ramani] Med Coll Wisconsin, Dept Pediat, Childrens Res Inst, Milwaukee, WI 53226 USA. [Wu, Shiaw-Lin; Dai, Shujia; Karger, Barry L.] Northeastern Univ, Barnett Inst, Boston, MA 02115 USA. [Ridnour, Lisa A.; Wink, David A.] NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bldg 10,Room 2A33,10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU NIH [GM 1584, CA 128616]; NCI; Center for Cancer Research (DDR); Barnett Institute [934] FX We thank Susan Garfield for guidance with confocal imaging. The authors acknowledge support from the Intramural Research Program of the NIH, NCI, Center for Cancer Research (DDR) and NIH grants GM 1584 (BLK) and CA 128616 (JSI). Contribution Number 934 from the Barnett Institute. NR 66 TC 22 Z9 25 U1 0 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1355-8145 J9 CELL STRESS CHAPERON JI Cell Stress Chaperones PD MAR PY 2010 VL 15 IS 2 BP 165 EP 181 DI 10.1007/s12192-009-0130-0 PG 17 WC Cell Biology SC Cell Biology GA 552KH UT WOS:000274288200004 PM 19579057 ER PT J AU Im, K Jo, HJ Mangin, JF Evans, AC Kim, SI Lee, JM AF Im, Kiho Jo, Hang Joon Mangin, Jean-Francois Evans, Alan C. Kim, Sun I. Lee, Jong-Min TI Spatial Distribution of Deep Sulcal Landmarks and Hemispherical Asymmetry on the Cortical Surface SO CEREBRAL CORTEX LA English DT Article DE brain development; cortical folding; functional lateralization; magnetic resonance imaging; sulcal pits ID AUTOMATED 3-D EXTRACTION; HUMAN BRAIN; CEREBRAL-CORTEX; STRUCTURAL ASYMMETRIES; PLANUM TEMPORALE; FOLDING PATTERNS; GENETIC-CONTROL; GENERIC MODEL; LANGUAGE; VOLUME AB The locally deepest regions of major sulci, the sulcal pits, are thought to be the first cortical folds to develop and are closely related to functional areas. We examined the spatial distribution of sulcal pits across the entire cortical region, and assessed the hemispheric asymmetry in their frequency and distribution in a large group of normal adult brains. We automatically extracted sulcal pits from magnetic resonance imaging data using surface-based methods and constructed a group map from 148 subjects. The spatial distribution of the sulcal pits was relatively invariant between individuals, showing high frequency and density in specific focal areas. The left and right sulcal pits were spatially covariant in the regions of the earliest developed sulci. The sulcal pits with great spatial invariance appear to be useful as stable anatomical landmarks. We showed the most significant asymmetry in the frequency and spatial variance of sulcal pits in the superior temporal sulcus, which might be related to the lateralization of language function to the left hemisphere, developing more consistently and strongly than for the right. Our analyses support previous empirical and theoretical studies, and provide additional insights concerning the anatomical and functional development of the brain. C1 [Im, Kiho; Kim, Sun I.; Lee, Jong-Min] Hanyang Univ, Dept Biomed Engn, Seoul 133791, South Korea. [Jo, Hang Joon] NIMH, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Mangin, Jean-Francois] CEA, I2BM, LNAO, F-91190 Gif Sur Yvette, France. [Evans, Alan C.] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ H3A 2B4, Canada. RP Lee, JM (reprint author), Hanyang Univ, Dept Biomed Engn, POB 55, Seoul 133605, South Korea. EM ljm@hanyang.ac.kr RI JO, HANG JOON/D-1775-2011 OI JO, HANG JOON/0000-0002-9180-3831 FU Korea government (MEST) [R0A-2007-000-20068-0] FX Korea Science and Engineering Foundation (KOSEF) NRL program grant funded by the Korea government (MEST) (grant number R0A-2007-000-20068-0). NR 67 TC 43 Z9 43 U1 1 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD MAR PY 2010 VL 20 IS 3 BP 602 EP 611 DI 10.1093/cercor/bhp127 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 555DU UT WOS:000274488600010 PM 19561060 ER PT J AU Gronich, N Kumar, A Zhang, YW Efimov, IR Soldatov, NM AF Gronich, Naomi Kumar, Azad Zhang, Yuwei Efimov, Igor R. Soldatov, Nikolai M. TI Molecular remodeling of ion channels, exchangers and pumps in atrial and ventricular myocytes in ischemic cardiomyopathy SO CHANNELS LA English DT Article DE ischemic cardiomyopathy; molecular profiling; atrial myocytes; ventricular myocytes; ion channels; phospholemman; Na(+),K(+)-ATPase; CLIC ID CARDIAC SODIUM-CHANNEL; HEART-FAILURE; K+ CHANNEL; POTASSIUM CHANNEL; CALCIUM-CHANNEL; GENE-EXPRESSION; MESSENGER-RNA; TISSUE DISTRIBUTION; MOUSE HEART; RAT-HEART AB existing molecular knowledge base of cardiovascular diseases is rudimentary because of lack of specific attribution to cell type and function. The aim of this study was to investigate cell-specific molecular remodeling in human atrial and ventricular myocytes associated with ischemic cardiomyopathy. Our strategy combines two technological innovations, laser-capture microdissection of identified cardiac cells in selected anatomical regions of the heart and splice microarray of a narrow catalog of the functionally most important genes regulating ion homeostasis. We focused on expression of a principal family of genes coding for ion channels, exchangers and pumps (Ce&P genes) that are involved in electrical, mechanical and signaling functions of the heart and constitute the most utilized drug targets. We found that (1) Ce&P genes remodel in a cell-specific manner: ischemic cardiomyopathy affected 63 Ce&P genes in ventricular myocytes and 12 essentially different genes in atrial myocytes. (2) Only few of the identified Ce&P genes were previously linked to human cardiac disfunctions. (3) The ischemia-affected Ce&P genes include nuclear chloride channels, adrenoceptors, cyclic nucleotide-gated channels, auxiliary subunits of Na(+), K(+) and Ca(2+) channels, and cell-surface Ce&Ps. (4) In both atrial and ventricular myocytes ischemic cardiomyopathy reduced expression of CACNG7 and induced overexpression of FXYD1, the gene crucial for Na(+) and K(+) homeostasis. Thus, our cell-specific molecular profiling defined new landmarks for correct molecular modeling of ischemic cardiomyopathy and development of underlying targeted therapies. C1 [Gronich, Naomi; Kumar, Azad; Zhang, Yuwei; Soldatov, Nikolai M.] NIA, NIH, Baltimore, MD 21224 USA. [Efimov, Igor R.] Washington Univ, St Louis, MO USA. RP Soldatov, NM (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM soldatovN@grc.nia.nih.gov RI Efimov, Igor/B-8040-2010 OI Efimov, Igor/0000-0002-1483-5039 FU National Institutes of Health, National Institute on Aging [Z01 AG000294-08]; National Heart, Lung and Blood Institute [RO1 HL085369] FX The authors thank Kevin Becker and William H. Wood (Gene Expression and Genomics Unit, NIA) for development of splice microarray slides, Heather Jordan and Weiyin Zhou (ExonHit Therapeutics) for help with splice microarray analysis, and Cardiac Transplantation Unit of the Washington University in St. Louis, MO for help with cardiac tissues. This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (Z01 AG000294-08 to Nikolai M. Soldatov) and by the National Heart, Lung and Blood Institute grant (RO1 HL085369 to Igor R. Efimov). NR 101 TC 9 Z9 10 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1933-6950 J9 CHANNELS JI Channels PD MAR-APR PY 2010 VL 4 IS 2 BP 101 EP 107 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 587IE UT WOS:000276983200007 PM 20090424 ER PT J AU Thai, KM Windisch, A Stork, D Weinzinger, A Schiesaro, A Guy, RH Timin, EN Hering, S Ecker, GF AF Thai, Khac-Minh Windisch, Andreas Stork, Daniela Weinzinger, Anna Schiesaro, Andrea Guy, Robert H. Timin, Eugen N. Hering, Steffen Ecker, Gerhard F. TI The hERG Potassium Channel and Drug Trapping: Insight from Docking Studies with Propafenone Derivatives SO CHEMMEDCHEM LA English DT Article DE docking; drug trapping; hERG; ion channels; propafenone ID QT INTERVAL PROLONGATION; K+ CHANNEL; MOLECULAR DETERMINANTS; STRUCTURAL BASIS; HOMOLOGY MODEL; INHIBITION; BLOCKERS; BINDING; BLOCKADE; CLASSIFICATION AB The inner cavity of the hERG potassium ion channel can accommodate large, structurally diverse compounds that can be trapped in the channel by closure of the activation gate. A small set of propafenone derivatives was synthesized, and both use-dependency and recovery from block were tested in order to gain insight into the behavior of these compounds with respect to trapping and non-trapping. Ligand-protein docking into homology models of the closed and open state of the hERG channel provides the first evidence for the molecular basis of drug trapping. C1 [Thai, Khac-Minh; Schiesaro, Andrea; Ecker, Gerhard F.] Univ Vienna, Dept Med Chem, Emerging Field Pharmacoinformat, A-1090 Vienna, Austria. [Windisch, Andreas; Stork, Daniela; Weinzinger, Anna; Timin, Eugen N.; Hering, Steffen] Univ Vienna, Dept Pharmacol & Toxicol, A-1090 Vienna, Austria. [Thai, Khac-Minh] Univ Med & Pharm Ho Chi Minh City, Fac Pharm, Dept Pharmaceut Chem, Ho Chi Minh City, Vietnam. [Guy, Robert H.] NCI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. RP Ecker, GF (reprint author), Univ Vienna, Dept Med Chem, Emerging Field Pharmacoinformat, Althanstr 14, A-1090 Vienna, Austria. EM gerhard.f.ecker@univie.ac.at RI Stary-Weinzinger, Anna/A-3629-2014; OI Stary-Weinzinger, Anna/0000-0002-9202-0484; Thai, Khac-Minh/0000-0002-5279-9614; Ecker, Gerhard/0000-0003-4209-6883 FU PhD program 'Molecular Drug Targets' of the University of Vienna FX Khac-Minh Thai thanks the ASEA-Uninet, the Austrian Ministry for Science and Research, and the Austrian Exchange Service 6AD for providing a PhD scholarship. This work was supported by the PhD program 'Molecular Drug Targets' of the University of Vienna. NR 46 TC 15 Z9 15 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1860-7179 EI 1860-7187 J9 CHEMMEDCHEM JI ChemMedChem PD MAR PY 2010 VL 5 IS 3 BP 436 EP 442 DI 10.1002/cmdc.200900374 PG 7 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 568KM UT WOS:000275521200013 PM 20146282 ER PT J AU Schecter, A Colacino, J Sjodin, A Needham, L Birnbaum, L AF Schecter, Arnold Colacino, Justin Sjodin, Andreas Needham, Larry Birnbaum, Linda TI Partitioning of polybrominated diphenyl ethers (PBDEs) in serum and milk from the same mothers SO CHEMOSPHERE LA English DT Article DE PBDE; Partitioning; Milk; Blood; Serum ID BROMINATED FLAME RETARDANTS; HIGH-THROUGHPUT EXTRACTION; IN-HOUSE DUST; POLYCHLORINATED-BIPHENYLS; BREAST-MILK; 2,2',4,4',5-PENTABROMODIPHENYL ETHER; DEVELOPMENTAL EXPOSURE; ADIPOSE-TISSUE; CLEANUP METHOD; BLOOD AB We and others have previously described partitioning of chemicals, including polychlorinated-p-dioxins, dibenzofurans, and biphenyls in different types of human tissues and fluids, including blood and milk. Additionally, we previously reported the blood to milk partitioning of polybrominated diphenyl ethers (PBDEs) in a group of 11 women. Partitioning is of importance in understanding the toxicokinetics of these compounds and also in clinical medicine in improving estimates of levels in different matrices including blood and milk. In this study we extend these findings, describing the levels of PBDEs detected in the serum and milk of 29 women from Texas. The median sum of the levels of the four most detected congeners (BDE 47, 99, 100, and 153) in serum was 27.8 ng g(-1) lipid (range 6.7-501.6 ng g(-1) lipid). In milk, the median sum of the levels of the same congeners was 39.7 ng g(-1) lipid (range 12.9-580.3 ng g(-1) lipid). The levels detected in breast milk in this study are similar to those we reported in 2003, where a median total PBDE level of 34 ng g-1 lipid was reported. When congener specific blood to milk partitioning ratios were calculated for BDEs 47, 99, 100, and 153, the relatively small tetrabrominated congener, BDE 47, was found in higher concentrations in milk compared to blood, while the higher molecular weight hexabrominated congener, BIDE 153, was found in approximately equal quantities in blood and milk, on a lipid normalized basis. The reason for the differential partitioning of PBDE congeners in milk and blood could be due to variation in toxicokinetics, specifically distribution based on molecular size or molecular weight. (C) 2009 Elsevier Ltd. All rights reserved. C1 [Schecter, Arnold] Univ Texas Dallas, Sch Publ Hlth, Dallas, TX 75390 USA. [Colacino, Justin] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Sjodin, Andreas; Needham, Larry] Ctr Dis Control & Prevent, Atlanta, CA USA. [Birnbaum, Linda] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Schecter, A (reprint author), Univ Texas Dallas, Sch Publ Hlth, 5323 Harry Hines,V8-112, Dallas, TX 75390 USA. EM arnold.schecter@utsouthwestern.edu RI Sjodin, Andreas/F-2464-2010; Needham, Larry/E-4930-2011 NR 35 TC 48 Z9 54 U1 3 U2 21 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0045-6535 J9 CHEMOSPHERE JI Chemosphere PD MAR PY 2010 VL 78 IS 10 BP 1279 EP 1284 DI 10.1016/j.chemosphere.2009.12.016 PG 6 WC Environmental Sciences SC Environmental Sciences & Ecology GA 571RN UT WOS:000275772600014 PM 20079522 ER PT J AU Colombo, RE Hill, SC Claypool, RJ Holland, SM Olivier, KN AF Colombo, Rhonda E. Hill, Suvimol C. Claypool, Reginald J. Holland, Steven M. Olivier, Kenneth N. TI Familial Clustering of Pulmonary Nontuberculous Mycobacterial Disease SO CHEST LA English DT Article ID AVIUM COMPLEX; INFECTION; DISORDERS AB Background: Nontuberculous mycobacteria (NTM) are environmental organisms associated with pulmonary disease without person-to-person transmission. Although genetic causes of disseminated NTM infection are well characterized, genetic causes for most human susceptibility to pulmonary NTM infection have not been determined. Methods: Family histories for relevant disease characteristics were obtained as part of an ongoing natural history study. Six families were identified in which at least two blood relatives had pulmonary NTM. A systematic review of medical records extracted data relevant to pulmonary infection and baseline demographics. Data were reconfirmed by telephone interviews. Results: Familial clustering of pulmonary NTM was proven in six families. Four of the families were white, and the majority of affected individuals were women. The average age at diagnosis was 56.4 +/- 10.7 years, the average height was 167.5 +/- 8.7 cm, and the mean BMI was 22.0 +/- 2.98 kg/m(2). Scoliosis was present in 31%. Five of 12 patients bad cystic fibrosis transmembrane conductance regulator gene variations, but none had classic cystic fibrosis. Infections were caused by both slow and rapid growing mycobacteria, including Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium abscessus, and Mycobacterium massiliense. Family members were typically infected with different species of NTM. Conclusion: We identified six familial clusters of pulmonary NTM infection, suggesting that there are genetic factors contributing to host susceptibility to pulmonary infection with NTM among some individuals with nodular bronchiectatic disease. CHEST 2010; 137(3):629-634 C1 [Colombo, Rhonda E.; Claypool, Reginald J.; Holland, Steven M.; Olivier, Kenneth N.] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. [Hill, Suvimol C.] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. RP Olivier, KN (reprint author), NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, NIH, 9000 Rockville Pike,Bldg 10,Room 11N234, Bethesda, MD 20892 USA. EM olivierk@niaid.nih.gov FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 11 TC 26 Z9 26 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD MAR PY 2010 VL 137 IS 3 BP 629 EP 634 DI 10.1378/chest.09-1173 PG 6 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 567WC UT WOS:000275477100020 PM 19858235 ER PT J AU Ryall, JG Church, JE Lynch, GS AF Ryall, James G. Church, Jarrod E. Lynch, Gordon S. TI Novel role for beta-adrenergic signalling in skeletal muscle growth, development and regeneration SO CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY LA English DT Article DE beta-adrenergic signalling; beta-adrenoceptor agonists; cancer cachexia; differentiation; muscle damage; muscle injury and repair; muscle regeneration; muscular dystrophy; myogenesis; sarcopenia ID FOXO TRANSCRIPTION FACTORS; MAMMALIAN TARGET; GENE-EXPRESSION; MESSENGER-RNA; BETA-2-ADRENERGIC RECEPTOR; FUNCTIONAL REPAIR; C2C12 MYOGENESIS; ATROPHY INVOLVE; CLENBUTEROL; RAPAMYCIN AB P>1. In adult mammals, skeletal muscle mass is maintained through a precise balance of protein synthesis and protein degradation, whereas during development cellular (not protein) turnover predominates. When protein balance is shifted towards synthesis, skeletal muscle hypertrophy ensues. In contrast, increased protein degradation leads to skeletal muscle atrophy. Insulin-like growth factor (IGF)-I is among the best documented of the growth factors and regulates skeletal muscle mass by increasing protein synthesis and decreasing protein degradation. However, an IGF-I-independent growth pathway has been identified that involves the activation of beta-adrenoceptors and subsequent skeletal muscle growth, development and hypertrophy. 2. Although the importance of beta-adrenergic signalling in the heart has been well documented and continues to receive significant attention, it is only more recently that we have started to appreciate the importance of this signalling pathway in skeletal muscle structure and function. Studies have identified an important role for beta-adrenoceptors in myogenesis and work from our laboratory has identified a novel role for beta-adrenoceptors in regulating skeletal muscle regeneration after myotoxic injury. In addition, new data suggest that beta-adrenoceptors are markedly upregulated during differentiation of C2C12 cells. 3. It is now clear that beta-adrenoceptors play an important role in regulating skeletal muscle structure and function. Importantly, a clearer understanding of the pathways regulating skeletal muscle mass may lead to the identification of novel therapeutic targets for the treatment of muscle wasting disorders, including sarcopenia, cancer cachexia and the muscular dystrophies. C1 [Ryall, James G.; Church, Jarrod E.; Lynch, Gordon S.] Univ Melbourne, Dept Physiol, Basic & Clin Myol Lab, Parkville, Vic 3052, Australia. [Ryall, James G.] NIAMSD, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. RP Lynch, GS (reprint author), Univ Melbourne, Dept Physiol, Melbourne, Vic 3010, Australia. EM gsl@unimelb.edu.au RI Lynch, Gordon/G-9553-2015 OI Lynch, Gordon/0000-0001-9220-9810 FU Australian Research Council [DP0665071, DP0772781]; National Health and Medical Research Council of Australia (NHMRC) [454561, 509313, 520034]; Muscular Dystrophy Association (Tucson, AZ, USA) [4167]; Pfizer Inc. FX The authors are grateful for research grant funding from the Australian Research Council Discovery-Project funding scheme (DP0665071, DP0772781), the National Health and Medical Research Council of Australia (NHMRC; 454561, 509313), the Muscular Dystrophy Association (Tucson, AZ, USA; 4167) and Pfizer Inc. (New York, NY, USA). JGR is supported by a Biomedical Overseas Research Fellowship from the NHMRC (520034). NR 48 TC 13 Z9 13 U1 0 U2 11 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0305-1870 J9 CLIN EXP PHARMACOL P JI Clin. Exp. Pharmacol. Physiol. PD MAR PY 2010 VL 37 IS 3 BP 397 EP 401 DI 10.1111/j.1440-1681.2009.05312.x PG 5 WC Pharmacology & Pharmacy; Physiology SC Pharmacology & Pharmacy; Physiology GA 560MY UT WOS:000274908000024 PM 19793099 ER PT J AU Wells, DK Ward, MM AF Wells, D. K. Ward, M. M. TI Nephritis and the risk of acute myocardial infarction in patients with systemic lupus erythematosus SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Article DE Systemic lupus erythematosus; myocardial infarction; cardiovascular disease; lupus nephritis ID PRIMARY ANTIPHOSPHOLIPID SYNDROME; CORONARY-ARTERY CALCIFICATION; CARDIOVASCULAR-DISEASE; VASCULAR EVENTS; ACCELERATED ATHEROSCLEROSIS; VENOUS THROMBOEMBOLISM; RHEUMATOID-ARTHRITIS; HEART-DISEASE; COHORT; WOMEN AB Background Patients with systemic lupus erythematosus (SLE) have an increased risk of acute myocardial infarction (AMI). We examined if nephritis or other clinical manifestations of SLE identified patients at increased risk. Methods In this population-based case-control study, we identified patients with SLE hospitalized with an AMI in California in 1996-2000. We compared the frequency of six manifestations of SLE (nephritis, pleuritis, hemolytic anemia, thrombocytopenia, psychosis/major depression, seizures) and of venous thrombosis/pulmonary embolism, in this group (n=535) to the frequency of these manifestations in two control groups: patients with SLE hospitalised for pulmonary disease (n=529), and patients with SLE hospitalized for gastrointestinal bleeding (n=349). Results Nephritis was present in 23.7% of patients with AMI, 11.0% of patients with pulmonary disease and 25.2% of patients with gastrointestinal bleeding. In adjusted analyses, nephritis was more common in the AMI group (odds ratio (OR) 2.85, 95% confidence interval (CI) 1.97-4.14; p<.0001) than in the pulmonary disease control group. Among women, nephritis was more common in the AMI group (OR 2.83; 95% CI 1.33-6.01; p=0.007) than in the gastrointestinal bleeding control group. Psychosis/major depression was less common among patients with AMI. Conclusions Among patients with SLE, nephritis was associated with 2.8-fold increased risk of AMI. C1 [Wells, D. K.; Ward, M. M.] NIAMSD, Intramural Res Program, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMS, NIH, IRP, Bldg 10 CRC,Room 4-1339,10 Ctr Dr,MSC 1468, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health. NR 49 TC 8 Z9 12 U1 0 U2 0 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD MAR-APR PY 2010 VL 28 IS 2 BP 223 EP 229 PG 7 WC Rheumatology SC Rheumatology GA 604UL UT WOS:000278303900010 PM 20483044 ER PT J AU Huang, H Menefee, M Edgerly, M Zhuang, S Kotz, H Poruchynsky, M Huff, LM Bates, S Fojo, T AF Huang, Hui Menefee, Michael Edgerly, Maureen Zhuang, Sen Kotz, Herb Poruchynsky, Marianne Huff, Lyn Mickley Bates, Susan Fojo, Tito TI A Phase II Clinical Trial of Ixabepilone (Ixempra; BMS-247550; NSC 710428), an Epothilone B Analog, in Patients with Metastatic Renal Cell Carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID MICROTUBULE-STABILIZING AGENTS; PREVIOUSLY TREATED PATIENTS; HIGH-DOSE INTERLEUKIN-2; HUMAN TUMOR XENOGRAFTS; BREAST-CANCER; INTERFERON ALPHA-2A; DESOXYEPOTHILONE-B; 96-HOUR PACLITAXEL; UNITED-STATES; THERAPY AB Purpose: Ixabepilone (Ixempra; BMS-247550) is an epothilone B analog and nontaxane microtubule-stabilizing compound with clinical activity in a range of solid tumors. This phase II study was conducted to assess the efficacy and safety of ixabepilone in patients with metastatic renal cell carcinoma. Experimental Design: Patients with metastatic renal cell carcinoma who had measurable disease and had not received previous cytotoxic or targeted therapy were treated with 6 mg/m(2) ixabepilone i.v. daily for 5 days every 3 weeks. Levels of Glu-terminated and acetylated tubulin, markers of microtubule stabilization, were assessed by Western blot. VHL gene mutation status was determined by sequencing. Results: Eighty-seven patients received a total of 590 cycles, with a median of 5 cycles (range, 1-29). The overall response rate was 13% (Response Evaluation Criteria in Solid Tumor). One patient had a complete response, 10 patients had partial responses, and 59 patients had stable disease. The median duration of response was 5.5 months. The median overall survival of renal cell carcinoma Motzer grade 0 and 1 patients with clear cell histology was 19.25 months. Treatment-related adverse events were primarily alopecia, gastrointestinal toxicity, neuropathy, and fatigue. Biopsies were done at baseline and after five doses of ixabepilone. Microtubule target engagement was achieved in 84.6% to 92.3% of patients evaluated. No correlation was identified between the target engagement, VHL gene mutation status, and clinical response. Conclusion: Ixabepilone can cause tumor regression in some patients with metastatic renal cell carcinoma and could be considered in combination regimens with other therapies. Clin Cancer Res; 16(5); 1634-41. (C) 2010 AACR. C1 [Huang, Hui; Menefee, Michael; Edgerly, Maureen; Zhuang, Sen; Kotz, Herb; Poruchynsky, Marianne; Huff, Lyn Mickley; Bates, Susan; Fojo, Tito] NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. [Huang, Hui] N Calif Kaiser Permanente, Dept Hematol & Oncol, Vallejo, CA USA. RP Fojo, T (reprint author), NCI, Med Oncol Branch, NIH, Bldg 10,Room 12N226,900 Rockville Pike, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov NR 43 TC 25 Z9 25 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 1 PY 2010 VL 16 IS 5 BP 1634 EP 1641 DI 10.1158/1078-0432.CCR-09-0379 PG 8 WC Oncology SC Oncology GA 607ZJ UT WOS:000278545500031 PM 20179242 ER PT J AU Robinson, ES Matulonis, UA Ivy, P Berlin, ST Tyburski, K Penson, RT Humphreys, BD AF Robinson, Emily S. Matulonis, Ursula A. Ivy, Percy Berlin, Suzanne T. Tyburski, Karin Penson, Richard T. Humphreys, Benjamin D. TI Rapid Development of Hypertension and Proteinuria with Cediranib, an Oral Vascular Endothelial Growth Factor Receptor Inhibitor SO CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID NITRIC-OXIDE SYNTHASE; BLOOD-PRESSURE; ANGIOGENESIS INHIBITOR; BREAST-CANCER; BEVACIZUMAB; TRIAL; EXPRESSION; PACLITAXEL; REGRESSION; SORAFENIB AB Background and objectives: Hypertension and proteinuria are common but poorly understood renal toxicities of vascular endothelial growth factor (VEGF) receptor signaling pathway inhibitors. In this phase II study of cediranib (AZD2171) for recurrent epithelial ovarian cancer, the time course and severity of BP changes and proteinuria were characterized. Design, setting, participants, & measurements: 46 women ages 41 to 77 years were treated with cediranib. 26% had baseline hypertension. Twice-daily BP was recorded. Urinalyses were performed every 2 weeks, and in some patients proteinuria was further quantified. Results: 31 women (67%) developed hypertension by day 3; 87% by the end of the study. 43%, developed grade >= 3 hypertension. Mean systolic BP increase over 3 days was 18 mmHg. Women above the mean age (>= 57 years) had a larger rise in systolic BP by day 3 (15.9 versus 7.0 mmHg). 14 women developed proteinuria. There was a dose response (45 versus 30 mg daily). Proteinuria also developed rapidly, with 7 of 14 women developing proteinuria within 2 weeks. Only 7 of 20 women who developed grade 3 hypertension developed proteinuria. Conclusions: Cediranib induced a rapid but variable rise in BP within 3 days of initiation in most patients. Proteinuria was common and also developed rapidly. The rapid development of hypertension suggests that acute inhibition of VEGF-dependent vasodilation might explain the BP rise with VEGF inhibitors. Clinicians must be vigilant in early detection and management of toxicities of this expanding drug class, especially in older patients. Clin J Am Soc Nephrol 5: 477-483, 2010. doi: 10.2215/CJN.08111109 C1 [Robinson, Emily S.; Humphreys, Benjamin D.] Brigham & Womens Hosp, Dept Med, Div Renal, Boston, MA 02115 USA. [Matulonis, Ursula A.; Berlin, Suzanne T.; Tyburski, Karin] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Humphreys, Benjamin D.] Dana Farber Canc Inst, Adult Survivorship Program, Boston, MA 02115 USA. [Ivy, Percy] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Penson, Richard T.] Massachusetts Gen Hosp, Dept Hematol & Oncol, Boston, MA 02114 USA. RP Robinson, ES (reprint author), Channing Labs, 3rd Floor,181 Longwood Ave, Boston, MA 02115 USA. EM Erobinson11@partners.org; bhumphreys@partners.org FU National Kidney Foundation; Madeline Franchi Ovarian Cancer Fund; Ovations for the Cure; National Institutes of Health [DK073628, UL1 RR 025758-02] FX Support for this research was provided by a National Kidney Foundation Fellowship Grant (to E.S.R.), The Madeline Franchi Ovarian Cancer Fund, Ovations for the Cure, National Institutes of Health grant DK073628 (to B.D.H.), and a pilot grant from Harvard Catalyst: National Institutes of Health grant UL1 RR 025758-02 with financial contributions from participating institutions (to B.D.H.). NR 34 TC 36 Z9 38 U1 0 U2 1 PU AMER SOC NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1555-9041 J9 CLIN J AM SOC NEPHRO JI Clin. J. Am. Soc. Nephrol. PD MAR PY 2010 VL 5 IS 3 BP 477 EP 483 DI 10.2215/CJN.08111109 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 565WB UT WOS:000275325000014 PM 20056761 ER PT J AU Voermans, NC Guillard, M Doedee, R Lammens, M Huizing, M Padberg, GW Wevers, RA van Engelen, BG Lefeber, DJ AF Voermans, N. C. Guillard, M. Doedee, R. Lammens, M. Huizing, M. Padberg, G. W. Wevers, R. A. van Engelen, B. G. Lefeber, D. J. TI Clinical features, lectin staining, and a novel GNE frameshift mutation in hereditary inclusion body myopathy SO CLINICAL NEUROPATHOLOGY LA English DT Article DE Hereditary Inclusion Body Myopathy; HIBM; distal myopathy; muscular dystrophy; sialic acid; UDP-GlcNAc 2-epimerase/ManNAc kinase; hyposialylation; PNA lectin; glycosylation ID ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; O-GLYCAN BIOSYNTHESIS; DISTAL MYOPATHY; RIMMED VACUOLES; N-ACETYLMANNOSAMINE; ACID BIOSYNTHESIS; RAT-LIVER; HYPOSIALYLATION; GLYCOPROTEINS; PURIFICATION AB We present a comprehensive report of two siblings with hereditary inclusion body myopathy (HIBM). The clinical features and histological characteristics of the muscle biopsies showed the typical pattern of predominantly distal vacuolar myopathy with quadriceps sparing. This was confirmed by muscle MRI. PNA lectin staining showed an increased signal at the sarcolemma in patient muscle sections compared to control muscle, indicating reduced sialylation of glycoconjugates. Mutation analysis revealed compound heterozygous mutations in the GNE gene, encoding the key enzyme in sialic acid synthesis UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase: a missense mutation (c.2086G > A; p.V696M) previously described in HIBM patients of Indian origin, and a novel frame shift mutation (c.1295delA; p.K432RfsX17) leading to a premature stopcodon. These findings confirmed the diagnosis of HIBM on the histological, molecular and biochemical level. C1 [Voermans, N. C.; Lammens, M.; Padberg, G. W.; Wevers, R. A.; van Engelen, B. G.; Lefeber, D. J.] Radboud Univ Nijmegen, Med Ctr, Dept Neurol, Donders Inst Brain Cognit & Behav, NL-6500 HB Nijmegen, Netherlands. [Guillard, M.; Doedee, R.; Wevers, R. A.; Lefeber, D. J.] Radboud Univ Nijmegen, Med Ctr, Lab Pediat & Neurol, NL-6500 HB Nijmegen, Netherlands. [Lammens, M.] Radboud Univ Nijmegen, Med Ctr, Dept Pathol, NL-6500 HB Nijmegen, Netherlands. [Huizing, M.] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Voermans, NC (reprint author), Radboud Univ Nijmegen, Med Ctr, Dept Neurol, Donders Inst Brain Cognit & Behav, POB 9101, NL-6500 HB Nijmegen, Netherlands. EM n.voermans@neuro.umcn.nl RI van Engelen, Baziel/D-3475-2009; lefeber, dirk/G-5063-2012; Engelen, B.G.M./H-8027-2014; Padberg, G.W.A.M./H-8079-2014; Lefeber, Dirk/A-2146-2014; Wevers, Ron/H-8116-2014; Voermans, N.C./L-4724-2015 OI Wevers, Ron/0000-0003-2278-9746; FU National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; NWO, The Netherlands Organization for Scientific Research, The Netherlands FX We are grateful to Mrs. K. Verrijp for her assistance in the staining procedures of muscle biopsies. This work was partially supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA (M. Huizing) and by the NWO, The Netherlands Organization for Scientific Research, The Netherlands (N.C. Voermans). NR 21 TC 7 Z9 7 U1 0 U2 2 PU DUSTRI-VERLAG DR KARL FEISTLE PI DEISENHOFEN-MUENCHEN PA BAHNHOFSTRASSE 9 POSTFACH 49, D-82032 DEISENHOFEN-MUENCHEN, GERMANY SN 0722-5091 J9 CLIN NEUROPATHOL JI Clin. Neuropathol. PD MAR-APR PY 2010 VL 29 IS 2 BP 71 EP 77 PG 7 WC Clinical Neurology; Pathology SC Neurosciences & Neurology; Pathology GA 572QX UT WOS:000275849000003 PM 20175955 ER PT J AU Jin, SH Lin, P Hallett, M AF Jin, Seung-Hyun Lin, Peter Hallett, Mark TI Linear and nonlinear information flow based on time-delayed mutual information method and its application to corticomuscular interaction SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE Linear and nonlinear information flow; Time-delayed mutual information; Surrogate tests; Corticomuscular interaction; Model-free connectivity measure ID SCIENTIFIC HYPOTHESIS GENERATION; MOTOR CORTEX; STATISTICAL ASSESSMENT; FINGER MOVEMENTS; CEREBRAL-CORTEX; SURROGATE DATA; HUMAN BRAIN; EEG; TASK; COHERENCE AB Objective: To propose a model-free method to show linear and nonlinear information flow based on time-delayed mutual information (TDMI) by employing uni- and bi-variate surrogate tests and to investigate whether there are contributions of the nonlinear information flow in corticomuscular (CM) interaction. Methods: Using simulated data, we tested whether our method would successfully detect the direction of information flow and identify a relationship between two simulated time series. As an experimental data application, we applied this method to investigate CM interaction during a right wrist extension task. Results: Results of simulation tests show that we can correctly detect the direction of information flow and the relationship between two time series without a prior knowledge of the dynamics of their generating systems. As experimental results, we found both linear and nonlinear information flow from contralateral sensorimotor cortex to muscle. Conclusions: Our method is a viable model-free measure of temporally varying causal interactions that is capable of distinguishing linear and nonlinear information flow. With respect to experimental application, there are both linear and nonlinear information flows in CM interaction from contralateral sensorimotor cortex to muscle, which may reflect the motor command from brain to muscle. Significance: This is the first study to show separate linear and nonlinear information flow in CM interaction. (C) 2009 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. C1 [Jin, Seung-Hyun; Lin, Peter; Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. RP Jin, SH (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 7D37,10 Ctr Dr MSC 1428, Bethesda, MD 20892 USA. EM jinse@mail.nih.gov FU NINDS, NIH; Korean Government (MOEHRD) [KRF-2006-352-H00006] FX This research was supported in part by the Intramural Research program of the NINDS, NIH. S. H. Jin was supported by a Korea Research Foundation Grant funded by the Korean Government (MOEHRD) (KRF-2006-352-H00006). The authors thank Dr. Ou Bai for use of his MATLAB scripts (http://www.engineering.vcu.edu/eegbci/bci2vr_index.html) for preprocessing of our EEG and sEMG data. NR 76 TC 25 Z9 26 U1 1 U2 7 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 EI 1872-8952 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD MAR PY 2010 VL 121 IS 3 BP 392 EP 401 DI 10.1016/j.clinph.2009.09.033 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 556AE UT WOS:000274557800020 PM 20044309 ER PT J AU Leung, E Tasker, SL Atkinson, L Vaillancourt, T Schulkin, J Schmidt, LA AF Leung, Eman Tasker, Susan L. Atkinson, Leslie Vaillancourt, Tracy Schulkin, Jay Schmidt, Louis A. TI Perceived Maternal Stress During Pregnancy and Its Relation to Infant Stress Reactivity at 2 Days and 10 Months of Postnatal Life SO CLINICAL PEDIATRICS LA English DT Article DE stress reactivity; newborns; maternal stress; pregnancy; cortisol; HPA functioning ID PITUITARY-ADRENAL AXIS; PRENATAL STRESS; CORTISOL; BEHAVIOR; CHILDREN; ANXIETY; HEALTH; BRAIN; BIRTH; RATS AB Background. Although the negative impact of maternal stress during pregnancy on stress reactivity in offspring is well documented in nonhuman animals, we know little about these relations in humans and their lasting effects. Aim. The authors examined the relation between perceived maternal stress during pregnancy and stability of infant stress reactivity across the first year of postnatal life in humans. Study design. Perceived maternal stress during pregnancy was measured in the immediate postpartum period and again at 10 months after delivery in 84 mothers and examined in relation to behavioral and neuroendocrine stress reactivity measures in their healthy, full-term infants. Outcome measures. Salivary cortisol was collected between 24 to 48 hours of postnatal life in response to a heel stick and again at 10 months of age in response to a toy removal task in the same sample of infants. Behavioral reactivity was coded from direct observation during the toy removal task. Results . Perceived maternal stress during pregnancy and neonatal cortisol reactivity each remained stable across the first 10 months of postnatal life. Maternal stress during pregnancy predicted infant cortisol reactivity at 2 days and 10 months after birth as well as behavioral reactivity at 10 months. Neonatal cortisol reactivity predicted 10-month behavioral reactivity. Conclusion . These preliminary findings suggest that maternal stress during pregnancy may negatively affect neonatal stress reactivity within 24 to 48 hours after birth, and these influences may persist through the first year of postnatal life. C1 [Schmidt, Louis A.] McMaster Univ, Dept Psychol Neurosci & Behav, Hamilton, ON L8S 4K1, Canada. [Leung, Eman; Atkinson, Leslie] Univ Toronto, Toronto, ON, Canada. [Leung, Eman; Atkinson, Leslie] Ctr Addict & Mental Hlth, Toronto, ON, Canada. [Tasker, Susan L.] Univ Victoria, Victoria, BC, Canada. [Atkinson, Leslie] Ryerson Univ, Toronto, ON, Canada. [Vaillancourt, Tracy] Univ Ottawa, Ottawa, ON, Canada. [Schulkin, Jay] Amer Coll Obstetricians & Gynecologists, Washington, DC 20024 USA. [Schulkin, Jay] NIMH, NIH, Bethesda, MD 20892 USA. [Schulkin, Jay] Georgetown Univ, Sch Med, Washington, DC USA. RP Schmidt, LA (reprint author), McMaster Univ, Dept Psychol Neurosci & Behav, Hamilton, ON L8S 4K1, Canada. EM schmidtl@mcmaster.ca RI Vaillancourt, Tracy/F-8949-2015; OI LEUNG, Eman/0000-0002-8267-1785; Atkinson, Leslie/0000-0003-1265-3298 FU Natural Sciences and Engineering Research Council (NSERC) of Canada FX This research was funded by a grant from the Natural Sciences and Engineering Research Council (NSERC) of Canada awarded to Louis A. Schmidt. NR 36 TC 10 Z9 10 U1 3 U2 12 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0009-9228 J9 CLIN PEDIATR JI Clin. Pediatr. PD MAR PY 2010 VL 49 IS 2 BP 158 EP 165 DI 10.1177/0009922809346570 PG 8 WC Pediatrics SC Pediatrics GA 544SD UT WOS:000273678700009 PM 20080522 ER PT J AU LaSala, PR Holbrook, M AF LaSala, P. Rocco Holbrook, Michael TI Tick-Borne Flaviviruses SO CLINICS IN LABORATORY MEDICINE LA English DT Article DE Flavivirus; Vector; Host; Tick-borne; Encephalitis ID HEMORRHAGIC-FEVER VIRUS; NEUTRALIZATION TESTS; SAUDI-ARABIA; LOUPING ILL; ENCEPHALITIS; INFECTION; DISEASE; MRI; TRANSMISSION; VACCINATION AB There has been a remarkable increase in tick-borne flaviviral disease incidence throughout the past 2 decades. Transmission of tick-borne viruses, like other vector-borne agents, is impacted by a very broad set of factors, both natural (eg, climate and ecology) and man-made (eg, human mobility and agricultural patterns). As our encroachment into areas of virus endemicity intensifies, and as changes in global economic and environmental conditions continue to promote the expansion of tick populations, we will undoubtedly continue to observe attendant increases in rates of disease attributable to these vector-borne pathogens. This article focuses on a some of the major tick-borne flaviviral diseases, caused in particular by tick-borne encephalitis virus, louping ill virus, Powassan virus, Kyasanur Forest disease virus, and Omsk hemorrhagic fever virus, as well as their subtypes. C1 [LaSala, P. Rocco] W Virginia Univ, Dept Pathol, Clin Microbiol Lab, Morgantown, WV 26506 USA. [Holbrook, Michael] Univ Texas Med Branch, Dept Pathol, Robert Shope Lab BSL 4, Galveston, TX 77555 USA. [Holbrook, Michael] NIAID, Integrated Res Facil, Frederick, MD 21702 USA. RP LaSala, PR (reprint author), W Virginia Univ, Dept Pathol, Clin Microbiol Lab, 2190 Hlth Sci N,POB 9203, Morgantown, WV 26506 USA. EM plasala@hsc.wvu.edu NR 36 TC 13 Z9 13 U1 3 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-2712 J9 CLIN LAB MED JI Clin. Lab. Med. PD MAR PY 2010 VL 30 IS 1 BP 221 EP + DI 10.1016/j.cll.2010.01.002 PG 16 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 618MA UT WOS:000279358200011 PM 20513549 ER PT J AU Maheu, FS Dozier, M Guyer, AE Mandell, D Peloso, E Poeth, K Jenness, J Lau, JYF Ackerman, JP Pine, DS Ernst, M AF Maheu, Francoise S. Dozier, Mary Guyer, Amanda E. Mandell, Darcy Peloso, Elizabeth Poeth, Kaitlin Jenness, Jessica Lau, Jennifer Y. F. Ackerman, John P. Pine, Daniel S. Ernst, Monique TI A preliminary study of medial temporal lobe function in youths with a history of caregiver deprivation and emotional neglect SO COGNITIVE AFFECTIVE & BEHAVIORAL NEUROSCIENCE LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; CHILDHOOD SEXUAL-ABUSE; GENERALIZED ANXIETY DISORDER; EARLY INSTITUTIONAL DEPRIVATION; PREFRONTAL CORTEX ACTIVATION; MAJOR DEPRESSIVE DISORDER; MALTREATED CHILDREN; FACIAL EXPRESSIONS; FOSTER-CARE; DEVELOPMENTAL EXAMINATION AB Previous research findings have linked caregiver deprivation and emotional neglect with sensitivity to threatening cues. The present preliminary study investigated whether dysfunctions of the medial temporal lobe could underlie these associations. Using fMRI, we measured medial temporal lobe responses to emotional faces (angry, fearful, happy, neutral) among 30 youths. Eleven of the youths had a history of caregiver deprivation and emotional neglect. Attention states (i.e., attention to anger, fear, or physical attributes, or passive viewing) were systematically manipulated. Relative to comparison youths, youths with a history of caregiver deprivation and emotional neglect showed significantly greater left amygdala and left anterior hippocampus activation during the processing of threatening information. To our knowledge, these findings are the first to demonstrate altered medial temporal lobe function during the processing of threat cues in youths with a history of caregiver deprivation and emotional neglect. C1 [Maheu, Francoise S.] CHU Ste Justine, Res Ctr, Montreal, PQ H3T 1C5, Canada. [Maheu, Francoise S.] Univ Montreal, Dept Psychiat, Fac Med, Montreal, PQ H3T 1C5, Canada. [Dozier, Mary; Peloso, Elizabeth] Univ Delaware, Newark, DE USA. [Guyer, Amanda E.; Mandell, Darcy; Poeth, Kaitlin; Jenness, Jessica; Pine, Daniel S.; Ernst, Monique] NIMH, Bethesda, MD 20892 USA. [Lau, Jennifer Y. F.] Univ Oxford, Oxford, England. [Ackerman, John P.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Maheu, FS (reprint author), CHU Ste Justine, Res Ctr, 3175 Cote Ste Catherine, Montreal, PQ H3T 1C5, Canada. EM francoise.maheu@umontreal.ca FU National Alliance for Research on Schizophrenia and Depression Young Investigator; Fonds de la Recherche en Sante du Quebec; Edna Bennett Pierce; NIMH [52135, 74374] FX The present study was supported by a National Alliance for Research on Schizophrenia and Depression Young Investigator Award and a postdoctoral fellowship from the Fonds de la Recherche en Sante du Quebec to F.S.M., by funding from Edna Bennett Pierce, by NIMH Grants 52135 and 74374 to M.D., and by the NIMH Intramural Research Program. The authors thank the anonymous reviewers for their helpful comments in revising the manuscript. Address correspondence to F.S. Maheu, Research Centre, CHU Ste-Justine and Psychiatry Department, Faculty of Medicine, University of Montreal, 3175 Cote-Ste-Catherine, Montreal, QC, H3T 1C5 Canada (e-mail: francoise.maheu@umontreal.ca). NR 101 TC 70 Z9 70 U1 13 U2 25 PU PSYCHONOMIC SOC INC PI AUSTIN PA 1710 FORTVIEW RD, AUSTIN, TX 78704 USA SN 1530-7026 J9 COGN AFFECT BEHAV NE JI Cogn. Affect. Behav. Neurosci. PD MAR PY 2010 VL 10 IS 1 SI SI BP 34 EP 49 DI 10.3758/CABN.10.1.34 PG 16 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 653DF UT WOS:000282066600004 PM 20233954 ER PT J AU Robles, AI Harris, CC AF Robles, Ana I. Harris, Curtis C. TI Clinical Outcomes and Correlates of TP53 Mutations and Cancer SO COLD SPRING HARBOR PERSPECTIVES IN BIOLOGY LA English DT Article ID P53 TUMOR-SUPPRESSOR; CELL LUNG-CANCER; HEPATOCELLULAR-CARCINOMA PATIENTS; CHRONIC LYMPHOCYTIC-LEUKEMIA; COMMON GENETIC-VARIATION; CODON 72 POLYMORPHISM; LI-FRAUMENI-SYNDROME; BREAST-CANCER; COLORECTAL-CANCER; PLASMA DNA AB The initial observation that p53 accumulation might serve as a surrogate biomarker for TP53 mutation has been the cornerstone for vast translational efforts aimed at validating its clinical use for the diagnosis, prognosis, and treatment of cancer. Early on, it was realized that accurate evaluation of p53 status and function could not be achieved through protein-expression analysis only. As our understanding of the p53 pathway has evolved and more sophisticated methods for assessment of p53 functional integrity have become available, the clinical and molecular epidemiological implications of p53 abnormalities in cancers are being revealed. They include diagnostic testing for germline p53 mutations, and the assessment of selected p53 mutations as biomarkers of carcinogen exposure and cancer risk and prognosis. Here, we describe the strengths and limitations of the most frequently used techniques for determination of p53 status in tumors, as well as the most remarkable latest findings relating to its clinical and epidemiological value. C1 [Robles, Ana I.; Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM harrisc@mail.nih.gov RI Xie, Huangming/B-2260-2012 NR 103 TC 76 Z9 78 U1 0 U2 10 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1943-0264 J9 CSH PERSPECT BIOL JI Cold Spring Harbor Perspect. Biol. PD MAR PY 2010 VL 2 IS 3 AR a001016 DI 10.1101/cshperspect.a001016 PG 15 WC Cell Biology SC Cell Biology GA 625GA UT WOS:000279881700005 PM 20300207 ER PT J AU Erickson, HS Gannot, G Tangrea, MA Chuaqui, RF Gillespie, JW Emmert-Buck, MR AF Erickson, Heidi S. Gannot, Gallya Tangrea, Michael A. Chuaqui, Rodrigo F. Gillespie, John W. Emmert-Buck, Michael R. TI High Throughput Screening of Normal and Neoplastic Tissue Samples SO COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING LA English DT Article DE Tissue; microdissection; high throughput screening; biomarker discovery; biomarker validation; technologies; review ID HUMAN PROSTATE-CANCER; LASER-CAPTURE MICRODISSECTION; POLYMERASE CHAIN-REACTION; COMPARATIVE GENOMIC HYBRIDIZATION; NUCLEOTIDE POLYMORPHISM ARRAYS; PHASE PROTEIN MICROARRAYS; PARAFFIN-EMBEDDED TISSUES; GENE-EXPRESSION ANALYSIS; HIGH-RESOLUTION ANALYSIS; MASS-SPECTROMETRY AB The capacity to rapidly and efficiently elucidate a reliable set of disease specific biomarkers is paramount to enable a future of personalized medicine. High throughput screening methods applied to human clinical samples for the discovery of diagnostic, prognostic, and therapeutic targets address this need. Although the ability to analyze either thousands of markers from one sample or one marker from thousands of samples is the current state of high throughput screening, it would be ideal to have the ability to analyze thousands of markers from thousands of samples to expedite the early discovery phase of biomarkers and their validation. This review summarizes the current state of high throughput screening of tissue specimens and discusses its applications. In addition, the rationale, difficulties, strategies, and development of new technologies to address the need for improved high throughput capabilities are discussed. C1 [Gillespie, John W.] NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. [Erickson, Heidi S.; Gannot, Gallya; Tangrea, Michael A.; Chuaqui, Rodrigo F.; Emmert-Buck, Michael R.] NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Erickson, Heidi S.; Gannot, Gallya; Tangrea, Michael A.; Chuaqui, Rodrigo F.; Emmert-Buck, Michael R.] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Erickson, Heidi S.] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Thorac Mol Pathol Lab, Houston, TX 77030 USA. [Tangrea, Michael A.] NCI, Tumor Angiogenesis Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. RP Gillespie, JW (reprint author), NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. EM jgill1230@gmail.com FU NIH; National Cancer Institute; Center for Cancer Research FX This review was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 144 TC 5 Z9 5 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1386-2073 J9 COMB CHEM HIGH T SCR JI Comb. Chem. High Throughput Screen PD MAR PY 2010 VL 13 IS 3 BP 253 EP 267 PG 15 WC Biochemical Research Methods; Chemistry, Applied; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Chemistry; Pharmacology & Pharmacy GA 568EO UT WOS:000275505200004 PM 20015016 ER PT J AU Williams, RV Ravishankar, C Zak, V Evans, F Atz, AM Border, WL Levine, J Li, JS Mahony, L Mital, S Pearson, GD Prakash, A Hsu, DT AF Williams, Richard V. Ravishankar, Chitra Zak, Victor Evans, Frank Atz, Andrew M. Border, William L. Levine, Jami Li, Jennifer S. Mahony, Lynn Mital, Seema Pearson, Gail D. Prakash, Ashwin Hsu, Daphne T. CA Pediat Heart Network Investigators TI Birth Weight and Prematurity in Infants with Single Ventricle Physiology: Pediatric Heart Network Infant Single Ventricle Trial Screened Population SO CONGENITAL HEART DISEASE LA English DT Article DE Single Ventricle Physiology; Preterm Birth; Low Birth Weight; Small for Gestational Age ID FOR-GESTATIONAL-AGE; CARDIOVASCULAR MALFORMATIONS; UNITED-STATES; RISK-FACTORS; NORWOOD PROCEDURE; GROWTH; CHILDREN; PALLIATION; MORTALITY; PATTERNS AB Objectives. Although congenital heart disease is associated with low birth weight and prematurity, there is little information about these birth outcomes in infants with single ventricle physiology. We describe the birth outcomes (i.e., gestational age and birth weight) in neonates with single ventricle physiology screened for enrollment in the Pediatric Heart Network's Infant Single Ventricle Trial, compare these outcomes with US norms, and examine the association of birth outcomes with anatomic diagnosis and race. Patients and Methods. All neonates with single ventricle physiology presenting to Infant Single Ventricle Trial centers were screened for enrollment. Demographic data and anatomic diagnoses were obtained from medical records. Results. A total of 1245 neonates with single ventricle physiology were screened at 10 centers (63 to 266 per center). Diagnoses included hypoplastic left heart syndrome in 49%, unbalanced atrioventricular septal defect in 12%, and tricuspid atresia in 9%. Preterm birth occurred in 16% of neonates with single ventricle physiology vs. 12% in normal neonates (P < .001), low birth weight (< 2.5 kg) in 18% vs. 8% in normals (P < .001), and small for gestational age (< 10th percentile by definition) in 22% vs. 10% in normals (P < .001). A genetic syndrome was reported in 8%. The percentage of preterm birth, low birth weight, and small for gestational age was similar between screened neonates with and without hypoplastic left heart syndrome. Conclusions. In this large, contemporary cohort of neonates with single ventricle physiology, rates of preterm birth, low birth weight, and small for gestational age were higher than in the general population, but similar between screened neonates with and without hypoplastic left heart syndrome. C1 [Williams, Richard V.] Univ Utah, Dept Pediat, Salt Lake City, UT USA. [Ravishankar, Chitra] Childrens Hosp Philadelphia, Dept Pediat, Philadelphia, PA 19104 USA. [Zak, Victor] New England Res Inst, Watertown, MA 02172 USA. [Evans, Frank; Pearson, Gail D.] NHLBI, NIH, Bethesda, MD 20892 USA. [Atz, Andrew M.] Med Univ S Carolina, Dept Pediat, Charleston, SC 29425 USA. [Border, William L.] Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH USA. [Levine, Jami] Childrens Hosp Boston, Dept Cardiol, Boston, MA USA. [Li, Jennifer S.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Mahony, Lynn] Univ Texas SW, Dept Pediat, Dallas, TX USA. [Mital, Seema] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada. [Prakash, Ashwin; Hsu, Daphne T.] Columbia Univ, Dept Pediat, New York, NY 10027 USA. RP Williams, RV (reprint author), Primary Childrens Med Ctr, 100 Mario Capecchi Dr, Salt Lake City, UT 84113 USA. EM richard.williams@imail.org OI Hsu, Daphne/0000-0002-2654-0430 FU National Heart, Lung, and Blood Institute [HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, HL085057]; Food Drug and Administration Office of Orphan Products Development FX Supported by U01 grants from the National Heart, Lung, and Blood Institute (HL068269, HL068270, HL068279, HL068281, HL068285, HL068292, HL068290, HL068288, and HL085057) and from the Food Drug and Administration Office of Orphan Products Development. NR 26 TC 11 Z9 11 U1 0 U2 1 PU WILEY PERIODICALS, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN STREET, MALDEN, MA 02148-529 USA SN 1747-079X J9 CONGENIT HEART DIS JI Congenit. Heart Dis. PD MAR-APR PY 2010 VL 5 IS 2 BP 96 EP 103 DI 10.1111/j.1747-0803.2009.00369.x PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 748UG UT WOS:000289417500003 PM 20412481 ER PT J AU Weiss, RD Potter, JS Provost, SE Huang, Z Jacobs, P Hasson, A Lindblad, R Connery, HS Prather, K Ling, W AF Weiss, Roger D. Potter, Jennifer Sharpe Provost, Scott E. Huang, Zhen Jacobs, Petra Hasson, Albert Lindblad, Robert Connery, Hilary Smith Prather, Kristi Ling, Walter TI A multi-site, two-phase, Prescription Opioid Addiction Treatment Study (POATS): Rationale, design, and methodology SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE Adaptive treatment research design; Buprenorphine; Opioid; Pain; Drug abuse; Counseling ID METHADONE-MAINTENANCE TREATMENT; PRIMARY-CARE; BUPRENORPHINE TREATMENT; HEROIN DEPENDENCE; SUBSTANCE USE; PAIN; DETOXIFICATION; DEPRESSION; USERS AB The National Institute on Drug Abuse Clinical Trials Network launched the Prescription Opioid Addiction Treatment Study (POATS) in response to rising rates of prescription opioid dependence and gaps in understanding the optimal course of treatment for this population. POATS employed a multi-site, two-phase adaptive, sequential treatment design to approximate clinical practice. The study took place at 10 community treatment programs around the United States. Participants included men and women age >= 18 who met Diagnostic and Statistical Manual, 4th Edition criteria for dependence upon prescription opioids, with physiologic features; those with a prominent history of heroin use (according to pre-specified criteria) were excluded. All participants received buprenorphine/naloxone (bup/nx). Phase 1 consisted of 4 weeks of bup/nx treatment, including a 14-day dose taper, with 8 weeks of follow-up. Phase 1 participants were monitored for treatment response during these 12 weeks. Those who relapsed to opioid use, as defined by pre-specified criteria, were invited to enter Phase 2; Phase 2 consisted of 12 weeks of bup/nx stabilization treatment, followed by a 4-week taper and 8 weeks of post-treatment follow-up. Participants were randomized at the beginning of Phase 1 to receive bup/nx, paired with either Standard Medical Management (SMM) or Enhanced Medical Management (EMM; defined as SMM plus individual drug counseling). Eligible participants entering Phase 2 were re-randomized to either EMM or SMM. POATS was developed to determine what benefit, if any, EMM offers over SMM in short-term and longer-term treatment paradigm. This paper describes the rationale and design of the study. (C) 2010 Elsevier Inc. All rights reserved. C1 [Weiss, Roger D.; Potter, Jennifer Sharpe; Provost, Scott E.; Connery, Hilary Smith; Prather, Kristi] McLean Hosp, Div Alcohol & Drug Abuse, Belmont, MA 02478 USA. [Weiss, Roger D.; Potter, Jennifer Sharpe; Connery, Hilary Smith] Harvard Univ, Sch Med, Dept Psychiat, Cambridge, MA 02138 USA. [Weiss, Roger D.; Potter, Jennifer Sharpe; Provost, Scott E.; Hasson, Albert; Connery, Hilary Smith; Prather, Kristi; Ling, Walter] NIDA, Clin Trials Network, Bethesda, MD USA. [Potter, Jennifer Sharpe] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Huang, Zhen] Duke Clin Res Inst, Durham, NC 27705 USA. [Jacobs, Petra] NIDA, Ctr Clin Trials Network, Rockville, MD 20892 USA. [Hasson, Albert; Ling, Walter] Univ Calif Los Angeles, Integrated Subst Abuse Programs, Los Angeles, CA 90025 USA. [Lindblad, Robert] EMMES Corp, Rockville, MD 20847 USA. RP Weiss, RD (reprint author), McLean Hosp, Div Alcohol & Drug Abuse, 115 Mill St, Belmont, MA 02478 USA. EM rweiss@mclean.harvard.edu RI Potter, Jennifer/C-6720-2008 OI Potter, Jennifer/0000-0002-7250-4422 FU NIDA Clinical Trials Network [U10 DA015831, U10 DA013045, HHSN2712005220HC, K24 DA022288, K23 DA022297] FX We thank the staff and participants at the community treatment programs and regional research and training centers of the National Institute on Drug Abuse Clinical Trials Network for their involvement in this project, including Chestnut Ridge Hospital (Appalachian Tri-State Node), San Francisco General Hospital (California/Arizona Node), St. Luke's Roosevelt Hospital and Long Island Jewish Medical Center-Addiction Recovery Services (Long Island Node), Bellevue Hospital Center (New York Node), McLean Hospital (Northern New England Node), East Indiana Treatment Center (Ohio Valley Node), Adapt, Inc. (Oregon/Hawaii Node), Integrated Substance Abuse Programs (Pacific Node), Behavioral Health Service of Pickens County (Southern Consortium Node), and Providence Behavioral Health Services (Washington Node). We also thank the staff of the Clinical Coordinating Center (The EMMES Corporation, Rockville, MD) and the Data and Statistics Center (The Duke Clinical Research Institute, Durham, NC), and the staff of the Center for the Clinical Trials Network at the National Institute on Drug Abuse (Rockville, MD) for their work on this project; This work was supported by NIDA Clinical Trials Network Grants U10 DA015831 (RDW, Northern New England Node); and U10 DA013045 (WL, Pacific Node); NIDA Contract HHSN2712005220HC (Duke Clinical Research Institute); and NIDA Grants K24 DA022288 (RDW) and K23 DA022297 (JSP). Some NIDA personnel were involved in the study and in the authorship of this paper. NR 37 TC 33 Z9 33 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD MAR PY 2010 VL 31 IS 2 BP 189 EP 199 DI 10.1016/j.cct.2010.01.003 PG 11 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 576FJ UT WOS:000276129400011 PM 20116457 ER PT J AU Suarez, RO Golby, A Whalen, S Sato, S Theodore, WH Kufta, CV Devinsky, O Balish, M Bromfield, EB AF Suarez, Ralph O. Golby, Alexandra Whalen, Stephen Sato, Susumu Theodore, William H. Kufta, Conrad V. Devinsky, Orrin Balish, Marshall Bromfield, Edward B. TI Contributions to singing ability by the posterior portion of the superior temporal gyrus of the non-language-dominant hemisphere: First evidence from subdural cortical stimulation, Wada testing, and fMRI SO CORTEX LA English DT Article DE Singing laterality; Cortical stimulation; fMRI; Wada test; Music ability ID FUNCTIONAL MRI; BROCAS AREA; MUSIC; PERCEPTION; LATERALIZATION; BRAIN; SPEAKING; CORTEX; SYNTAX; AMUSIA AB Introduction: Although the substrates that mediate singing abilities in the human brain are not well understood, invasive brain mapping techniques used for clinical decision making such as intracranial electro-cortical testing and Wada testing offer a rare opportunity to examine music-related function in a select group of subjects, affording exceptional spatial and temporal specificity. Methods: We studied eight patients with medically refractory epilepsy undergoing indwelling subdural electrode seizure focus localization. All patients underwent Wada testing for language lateralization. Functional assessment of language and music tasks was done by electrode grid cortical stimulation. One patient was also tested non-invasively with functional magnetic resonance imaging (fMRI). Functional organization of singing ability compared to language ability was determined based on four regions-of-interest (ROIs): left and right inferior frontal gyrus (IFG), and left and right posterior superior temporal gyrus (pSTG). Results: In some subjects, electrical stimulation of dominant pSTG can interfere with speech and not singing, whereas stimulation of non-dominant pSTG area can interfere with singing and not speech. Stimulation of the dominant IFG tends to interfere with both musical and language expression, while non-dominant IFG stimulation was often observed to cause no interference with either task; and finally, that stimulation of areas adjacent to but not within non-dominant pSTG typically does not affect either ability. Functional fMRI mappings of one subject revealed similar music/language dissociation with respect to activation asymmetry within the ROIs. Conclusion: Despite inherent limitations with respect to strictly research objectives, invasive clinical techniques offer a rare opportunity to probe musical and language cognitive processes of the brain in a select group of patients. (c) 2009 Elsevier Srl. All rights reserved. C1 [Suarez, Ralph O.; Golby, Alexandra; Whalen, Stephen] Harvard Univ, Dept Neurosurg, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Suarez, Ralph O.; Golby, Alexandra] Harvard Univ, Dept Radiol, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Bromfield, Edward B.] Harvard Univ, Dept Neurol, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. [Sato, Susumu; Theodore, William H.; Kufta, Conrad V.; Devinsky, Orrin; Balish, Marshall; Bromfield, Edward B.] NINDS, Natl Inst Hlth, Bethesda, MD 20892 USA. [Kufta, Conrad V.] Hanger Orthoped Grp, Bethesda, MD USA. [Devinsky, Orrin] NYU, Dept Neurol, New York, NY 10016 USA. [Balish, Marshall] Washington VA Med Ctr, Dept Neurol, Washington, DC USA. RP Suarez, RO (reprint author), Harvard Univ, Dept Neurosurg, Sch Med, Brigham & Womens Hosp, Room CA-138,75 Francis St, Boston, MA 02115 USA. EM rosuarez@bwh.harvard.edu OI Devinsky, Orrin/0000-0003-0044-4632 FU National Institutes of Health (NIH) [NINDS, K08-NS048063-02, NIBIB, T32-EB002177, NCRR, U41-RR019703, 3U41RR019703-03S1] FX The subjects' motivation and cooperation made this study possible. Drs. Paul Fedio, Christine Cox, and Aaron Nelson performed neuropsychological testing and assisted with intracarotid amytal testing. Ms. Kathleen Kelley, Ms. Patricia Reeves, Mr. Robert Long, and Mr. Hugh Malek provided invaluable assistance with EEG and video recording. Mr. Joseph Bucolo ably assisted with technical aspects of stimulation. We also gratefully acknowledge Drs. Tracey Milligan and Joseph Madsen for their excellent medical and surgical care of patient 8. Partial support for this research was provided by National Institutes of Health (NIH) grants: NINDS, K08-NS048063-02 (AJG); NIBIB, T32-EB002177 (ROS); NCRR, U41-RR019703 (AJG) and 3U41RR019703-03S1 (ROS). The authors would like to dedicate this article in loving memory of our respected colleague and dear friend, Dr. Edward Bromfield. NR 46 TC 13 Z9 14 U1 2 U2 11 PU ELSEVIER MASSON PI MILANO PA VIA PALEOCAPA 7, 20121 MILANO, ITALY SN 0010-9452 J9 CORTEX JI Cortex PD MAR PY 2010 VL 46 IS 3 BP 343 EP 353 DI 10.1016/j.cortex.2009.04.010 PG 11 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 563PZ UT WOS:000275146500008 PM 19570530 ER PT J AU Berra, L Cressoni, M Bassi, GL Kolobow, T Panigada, M Zanella, A AF Berra, Lorenzo Cressoni, Massimo Li Bassi, Gianluigi Kolobow, Theodor Panigada, Mauro Zanella, Alberto CA Gravity VAP Network TI Continuous lateral rotation therapy to prevent ventilator-associated pneumonia: The neglected effects of gravity on pathogenesis of ventilator-associated pneumonia SO CRITICAL CARE MEDICINE LA English DT Letter C1 [Berra, Lorenzo] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Cressoni, Massimo; Panigada, Mauro] Fdn IRCCS Policlin, Milan, Italy. [Li Bassi, Gianluigi] Hosp Clin Barcelona, Barcelona, Spain. [Kolobow, Theodor] NIH, Bethesda, MD 20892 USA. [Zanella, Alberto] Osped San Gerardo, Monza, Italy. RP Berra, L (reprint author), Massachusetts Gen Hosp, Boston, MA 02114 USA. RI Cressoni, Massimo/B-7315-2017; Panigada, Mauro/K-4650-2014; OI Cressoni, Massimo/0000-0002-0089-2905; Panigada, Mauro/0000-0003-4841-9794; zanella, Alberto/0000-0002-2967-2527 NR 3 TC 0 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD MAR PY 2010 VL 38 IS 3 BP 1018 EP 1019 DI 10.1097/CCM.0b013e3181cc40fc PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 565CI UT WOS:000275266200070 PM 20168183 ER PT J AU Lamuraglia, M Bridal, SL Santin, M Izzi, G Rixe, O Paradiso, A Lucidarme, O AF Lamuraglia, Michele Bridal, S. Lori Santin, Mathieu Izzi, Gianni Rixe, Olivier Paradiso, Angelo Lucidarme, Olivier TI Clinical relevance of contrast-enhanced ultrasound in monitoring anti-angiogenic therapy of cancer: Current status and perspectives SO CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY LA English DT Review DE Angiogenesis; Monitoring anti-angiogenesis treatment; Contrast-enhanced ultrasound (CEUS); Contrast agent ID GASTROINTESTINAL STROMAL TUMORS; ENDOTHELIAL GROWTH-FACTOR; ISOLATED LIMB PERFUSION; BLOOD-FLOW; ANTIANGIOGENIC THERAPY; COMPUTED-TOMOGRAPHY; DOPPLER ULTRASOUND; TISSUE PERFUSION; SOLID TUMORS; AGENTS AB Angiogenesis regulation is one of the newest fronts in the fight against cancer. Anti-angiogenic therapy is based on inhibiting factors required to solicit vessel formation thus cutting-off the tumor's supply of nutriments and oxygen. Initial vascular response is followed by formation of necrosis. Volumetric regression occurs more tardively. Effective monitoring of this new therapeutic approach thus requires imaging techniques that can detect early microvascular changes. A number of clinical studies provide evidence that contrast-enhanced ultrasound (CEUS) can provide early indication of tumor response to anti-angiogenic therapy. More sophisticated imaging and analysis techniques for CEUS and contrast agents targeted for adhesion to anti-angiogenic markers have also demonstrated promise in animal model studies. This review underlines the relevance of CEUS for anti-angiogenic therapy monitoring by summarizing the current clinical results, emerging CEUS techniques and preclinical data. (C) 2009 Elsevier Ireland Ltd. All rights reserved. C1 [Lamuraglia, Michele] Univ Paris 06, Lab Imagerie Parametr, CNRS, UMR 7623, F-75006 Paris, France. [Lamuraglia, Michele; Izzi, Gianni; Paradiso, Angelo] Natl Canc Inst Bari Giovanni Paolo II, I-70126 Bari, Italy. [Lamuraglia, Michele; Lucidarme, Olivier] Hop La Pitie Salpetriere, Serv Radiol Polyvalente Diagnost & Intervent, F-75651 Paris, France. [Rixe, Olivier] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Lamuraglia, M (reprint author), Univ Paris 06, Lab Imagerie Parametr, CNRS, UMR 7623, 15 Rue Ecole Med, F-75006 Paris, France. EM michele.lamuraglia@gmail.com OI Bridal, S. Lori/0000-0001-5053-5423 FU Martine Midy Foundation FX Authors acknowledge financial support from the Martine Midy Foundation, in particular for the fellowship of M. Lamuraglia. NR 49 TC 41 Z9 43 U1 0 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1040-8428 J9 CRIT REV ONCOL HEMAT JI Crit. Rev. Oncol./Hematol. PD MAR PY 2010 VL 73 IS 3 BP 202 EP 212 DI 10.1016/j.critrevonc.2009.06.001 PG 11 WC Oncology; Hematology SC Oncology; Hematology GA 561QH UT WOS:000274993000003 PM 19546008 ER PT J AU Favoni, RE Pattarozzi, A Lo Casto, M Barbieri, F Gatti, M Paleari, L Bajetto, A Porcile, C Gaudino, G Mutti, L Corte, G Florio, T AF Favoni, R. E. Pattarozzi, A. Lo Casto, M. Barbieri, F. Gatti, M. Paleari, L. Bajetto, A. Porcile, C. Gaudino, G. Mutti, L. Corte, G. Florio, T. TI Gefitinib Targets EGFR Dimerization and ERK1/2 Phosphorylation to Inhibit Pleural Mesothelioma Cell Proliferation SO CURRENT CANCER DRUG TARGETS LA English DT Review DE Human malignant pleural mesothelioma cells; EGFR targeting; Gefitinib; preclinical chemotherapy ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; HUMAN-MALIGNANT MESOTHELIOMA; ZD1839 IRESSA; IMATINIB MESYLATE; ZD-1839 IRESSA; OVARIAN-CANCER; LINES; THERAPY; TRANSACTIVATION AB Altered EGFR activity is a causal factor for human tumor development, including malignant pleural mesotheliomas. The aim of the present study was the evaluation of the effects of Gefitinib on EGF-induced mesothelioma cell proliferation and the intracellular mechanisms involved. Cell proliferation, DNA synthesis and apoptosis were measured by MTT, thymidine incorporation and FACS analysis; EGFR, ERK1/2 and Akt expression and phosphorylation by Western blot, whereas receptor sites were analyzed by binding studies. Gefitinib inhibited EGF-induced proliferation in two mesothelioma cell lines, derived from pleural effusion (IST-Mes2) or tumor biopsy (ZL55). The treatment with Gefitinib induced cell cycle arrest in both cell lines, while apoptosis was observed only for high concentrations and prolonged drug exposure. EGF-dependent mesothelioma cell proliferation was mediated by EGFR and ERK1/2 phosphorylation, while Akt was not affected. Gefitinib inhibited both EGFR and ERK1/2 activation, being maximal at drug concentrations that induce cytostatic effects, suggesting that the proapoptotic activity of Gefitinib is independent from EGFR inhibition. Gefitinib treatment increased EGFR Bmax, possibly through membrane stabilization of inactive receptor dimers that we show to be induced by the drug also in the absence of EGF. EGFR activation of ERK1/2 represents a key pathway for pleural mesothelioma cell proliferation. Low concentrations of Gefitinib cause mesothelioma cell cycle arrest through the blockade of EGFR activity while high concentrations induce apoptosis. Finally, we propose that the formation of inactive EGFR dimers may contribute to the antitumoral activity of Gefitinib. C1 [Favoni, R. E.; Corte, G.] Ist Nazl Ric Canc, Natl Canc Inst, Dept Translat Oncol, Gene Transfer Lab, I-16132 Genoa, Italy. [Lo Casto, M.] Ist Nazl Ric Canc, Natl Canc Inst, Dept Translat Oncol, Mol Oncol & Angiogenesis Lab, I-16132 Genoa, Italy. [Paleari, L.] Ist Nazl Ric Canc, Natl Canc Inst, Lung Canc Unit, Dept Adv Diagnost Technol, I-16132 Genoa, Italy. [Pattarozzi, A.; Barbieri, F.; Gatti, M.; Bajetto, A.; Porcile, C.; Corte, G.; Florio, T.] Univ Genoa, Pharmacol Sect, Dept Oncol Biol & Genet, I-16132 Genoa, Italy. [Gaudino, G.] Univ Piemonte Orientale, DISCAFF Dept, I-28100 Novara, Italy. [Gaudino, G.] Univ Piemonte Orientale, DFBC Ctr, I-28100 Novara, Italy. [Mutti, L.] Vercelli Hosp, Dept Gen Med, I-13100 Vercelli, Italy. [Mutti, L.] Vercelli Hosp, Lab Clin Oncol, I-13100 Vercelli, Italy. RP Favoni, RE (reprint author), Ist Nazl Ric Canc, Lab Trasferimento Genico, Dept Oncol Traslaz, IST Nord, B3,Rm18,Largo Rosanna Benzi 10, I-16132 Genoa, Italy. EM roberto.favoni@istge.it RI Florio, Tullio/A-2211-2012; Barbieri, Federica/L-8753-2015; OI Florio, Tullio/0000-0002-2394-996X; Barbieri, Federica/0000-0001-8988-6896; Monica, Gatti/0000-0002-2016-0285 NR 45 TC 11 Z9 11 U1 1 U2 4 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1568-0096 J9 CURR CANCER DRUG TAR JI Curr. Cancer Drug Targets PD MAR PY 2010 VL 10 IS 2 BP 176 EP 191 PG 16 WC Oncology SC Oncology GA 579YB UT WOS:000276412300006 PM 20088784 ER PT J AU Guha, R Gilbert, K Fox, G Pierce, M Wild, D Yuan, HP AF Guha, Rajarshi Gilbert, Kevin Fox, Geoffrey Pierce, Marlon Wild, David Yuan, Huapeng TI Advances in Cheminformatics Methodologies and Infrastructure to Support the Data Mining of Large, Heterogeneous Chemical Datasets SO CURRENT COMPUTER-AIDED DRUG DESIGN LA English DT Article DE Cheminformatics; web-service; WSDL; distributed; QSAR; diversity; cancer; malaria ID STRUCTURE-ACTIVITY LANDSCAPE; WEB SERVICE INFRASTRUCTURE; PLASMODIUM-FALCIPARUM; MOLECULAR DIVERSITY; ACTIVITY CLIFFS; SEMANTIC WEB; E-SCIENCE; MODELS; IDENTIFICATION; DATABASES AB In recent years, there has been an explosion in the availability of publicly accessible chemical information, including chemical structures of small molecules, structure-derived properties and associated biological activities in a variety of assays. These data sources present us with a significant opportunity to develop and apply computational tools to extract and understand the underlying structure-activity relationships. Furthermore, by integrating chemical data sources with biological information (protein structure, gene expression and so on), we can attempt to build up a holistic view of the effects of small molecules in biological systems. Equally important is the ability for non-experts to access and utilize state of the art cheminformatics method and models. In this review we present recent developments in cheminformatics methodologies and infrastructure that provide a robust, distributed approach to mining large and complex chemical datasets. In the area of methodology development, we highlight recent work on characterizing structure-activity landscapes, Quantitative Structure Activity Relationship (QSAR) model domain applicability and the use of chemical similarity in text mining. In the area of infrastructure, we discuss a distributed web services framework that allows easy deployment and uniform access to computational (statistics, cheminformatics and computational chemistry) methods, data and models. We also discuss the development of PubChem derived databases and highlight techniques that allow us to scale the infrastructure to extremely large compound collections, by use of distributed processing on Grids. Given that the above work is applicable to arbitrary types of cheminformatics problems, we also present some case studies related to virtual screening for anti-malarials and predictions of anti-cancer activity. C1 [Guha, Rajarshi] NIH, Chem Genom Ctr, Rockville, MD 20850 USA. [Guha, Rajarshi; Gilbert, Kevin; Fox, Geoffrey; Wild, David] Indiana Univ, Sch Informat, Bloomington, IN 47408 USA. [Fox, Geoffrey; Pierce, Marlon; Yuan, Huapeng] Indiana Univ, Community Grids Labs, Bloomington, IN 47408 USA. RP Guha, R (reprint author), NIH, Chem Genom Ctr, Rockville, MD 20850 USA. EM guhar@mail.nih.gov RI Wild, David/B-1741-2009; OI Pierce, Marlon/0000-0002-9582-5712 NR 79 TC 16 Z9 16 U1 3 U2 15 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1573-4099 EI 1875-6697 J9 CURR COMPUT-AID DRUG JI Curr. Comput.-Aided Drug Des. PD MAR PY 2010 VL 6 IS 1 BP 50 EP 67 PG 18 WC Chemistry, Medicinal; Computer Science, Interdisciplinary Applications SC Pharmacology & Pharmacy; Computer Science GA 563QZ UT WOS:000275149800004 PM 20370695 ER PT J AU Yoon, V Fridkis-Hareli, M Munisamy, S Lee, J Anastasiades, D Stevceva, L AF Yoon, V. Fridkis-Hareli, M. Munisamy, S. Lee, J. Anastasiades, D. Stevceva, L. TI The GP120 Molecule of HIV-1 and its Interaction with T Cells SO CURRENT MEDICINAL CHEMISTRY LA English DT Review DE Gp120; HIV; CD4+; CD8+; CTLs; viral escape; anergy; apoptosis ID IMMUNODEFICIENCY-VIRUS TYPE-1; NECROSIS-FACTOR-ALPHA; BLOOD MONONUCLEAR-CELLS; CD4 CROSS-LINKING; ENVELOPE GLYCOPROTEIN; DISEASE PROGRESSION; IMMUNE-RESPONSES; FAS ANTIGEN; INFECTED INDIVIDUALS; LYMPHOCYTE RESPONSES AB The gp120 molecule of HIV-1 is a glycoprotein that is part of the outer layer of the virus. It presents itself as viral membrane spikes consisting of 3 molecules of gp120 linked together and anchored to the membrane by gp41 protein. Gp120 is essential for viral infection as it facilitates HIV entry into the host cell and this is its best-known and most researched role in HIV infection. However, it is becoming increasingly evident that gp120 might also be facilitating viral persistence and continuing HIV infection by influencing the T cell immune response to the virus. Several mechanisms might be involved in this process of which gp120 binding to the CD4 receptor of T cells is the best known and most important interaction as it facilitates viral entry into the CD4+ cells and their depletion, a hallmark of the HIV infection. Gp120 is shed from the viral membrane and accumulates in lymphoid tissues in significant amounts. Here, it can induce apoptosis and severely alter the immune response to the virus by dampening the antiviral CTL response thus impeding the clearance of HIV. The effects of gp120 and how it interacts and influences T cell immune response to the virus is an important topic and this review aims to summarize what has been published so far in hopes of providing guidance for future work in this area. C1 [Stevceva, L.] NIAID, Virol Branch, Dept Microbiol & Infect Dis, NIH, Bethesda, MD 20892 USA. [Anastasiades, D.] Columbia Univ, Dept Biochem & Mol Biophys, New York, NY USA. [Munisamy, S.; Lee, J.] Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, Cambridge CB2 0SP, England. [Fridkis-Hareli, M.] ME Biotechnol Consulting, Sudbury, MA USA. [Yoon, V.] Massachusetts Gen Hosp E, Partners AIDS Res Ctr & Infect Dis Med, Charlestown, MA 02129 USA. RP Stevceva, L (reprint author), NIAID, Virol Branch, Dept Microbiol & Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lstevceva@yahoo.com NR 86 TC 10 Z9 10 U1 2 U2 14 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 0929-8673 J9 CURR MED CHEM JI Curr. Med. Chem. PD MAR PY 2010 VL 17 IS 8 BP 741 EP 749 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 549DR UT WOS:000274024900003 PM 20088758 ER PT J AU Klatt, NR Brenchley, JM AF Klatt, Nichole R. Brenchley, Jason M. TI Th17 cell dynamics in HIV infection SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE HIV; immune activation; microbial translocation; T cell; Th17 ID CD4(+) T-CELLS; IMMUNODEFICIENCY VIRUS-INFECTION; SYSTEMIC-LUPUS-ERYTHEMATOSUS; INFLAMMATORY-BOWEL-DISEASE; SOOTY MANGABEYS; SIV INFECTION; HOST-DEFENSE; MYCOBACTERIUM-TUBERCULOSIS; MICROBIAL TRANSLOCATION; CROHNS-DISEASE AB Purpose of review Th17 cells are a newly identified subtype of CD4(+) T cells that respond to bacterial and fungal antigens and are important in mucosal immunology. Because HIV infection results in loss of CD4(+) T cells as well as disruption to the gastrointestinal tract that causes microbial translocation and immune activation, Th17 cells potentially play an important role in HIV pathogenesis. Here we examine the relationship between Th17 cells and HIV disease pathogenesis. Recent findings Th17 cells are preferentially lost from the gastrointestinal tract of HIV-infected individuals, which is not entirely due to direct infection, as Th17 cells can be infected in vivo, but are not preferentially infected. Long-term highly active antiretroviral therapy (HAART) can result in restoration of Th17 cells in the gastrointestinal, which may be associated with better disease prognosis. Furthermore, other cells, such as V delta 1 T cells, can make IL-17 in vivo during HIV infection and may contribute to antibacterial immunity after loss of Th17 cells. Summary Recent studies have improved our understanding of the role for Th17 cells during HIV infection; however, more studies are needed to discern better the detrimental consequences of loss of Th17 cells during HIV infection. C1 [Brenchley, Jason M.] NIAID, Immunopathogenesis Unit, Mol Microbiol Lab, NIH,VSV, Bethesda, MD 20892 USA. RP Brenchley, JM (reprint author), NIAID, Immunopathogenesis Unit, Mol Microbiol Lab, NIH,VSV, 9000 Rockville Pike,Bldg 4,Room 307, Bethesda, MD 20892 USA. EM jbrenchl@niaid.nih.gov FU NIAID, NIH FX J.M.B. and N.R.K. are funded by the intramural research program, NIAID, NIH. The authors disclose no competing interests. NR 76 TC 56 Z9 56 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAR PY 2010 VL 5 IS 2 BP 135 EP 140 DI 10.1097/COH.0b013e3283364846 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 828NB UT WOS:000295507100005 PM 20543590 ER PT J AU Cecchinato, V Franchini, G AF Cecchinato, Valentina Franchini, Genoveffa TI Th17 cells in pathogenic simian immunodeficiency virus infection of macaques SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE gut; simian immunodeficiency virus; Th17 ID SIV INFECTION; T-CELLS; DEPLETION; IL-23; GUT AB Purpose of review We discuss studies on a subset of CD4(+)T cells, designated Th17, and their role in the pathogenesis of human and simian acquired immune deficiency, caused by infection with HIV and simian immunodeficiency virus (SIV), respectively. Most of the Th17 cells are lost within 2 weeks from infection at mucosal sites of SIV-infected macaques and are not replenished over time. Comparison of simian pathogenic and nonpathogenic models of SIV infection suggests that Th17 cells contribute to the pathogenesis of AIDS. Recent findings Th17 cells, a recently identified subset of T helper cells, play a major role in both inducing autoimmune disorders and fencing off extracellular pathogens. Several groups have reported that the number of Th17 cells is decreased in the gut of HIV-infected and SIV-infected hosts. The loss of Th17 cells from the mucosal compartment has been associated with the dissemination of Salmonella typhimurium that is normally contained locally by the host immune system. It is believed that microbial translocation sustains immune activation in HIV infection and contributes to AIDS. Summary Understanding the mechanisms that lead to disruption of mucosal integrity, viral spread, and chronic immune activation is of crucial importance for the design of efficient vaccines and therapeutic intervention for HIV. C1 [Cecchinato, Valentina] Inst Biomed Res, Bellinzona, Switzerland. [Franchini, Genoveffa] NCI, Anim Models & Retroviral Vaccine Sect, NIH, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), 9000 Rockville Pike,Bldg 41,Room D-804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov FU Intramural NIH HHS [Z01 BC005688-17] NR 17 TC 19 Z9 19 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAR PY 2010 VL 5 IS 2 BP 141 EP 145 DI 10.1097/COH.0b013e32833653ec PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 828NB UT WOS:000295507100006 PM 20543591 ER PT J AU Milner, JD Sandler, NG Douek, DC AF Milner, Joshua D. Sandler, Netanya G. Douek, Daniel C. TI Th17 cells, Job's syndrome and HIV: opportunities for bacterial and fungal infections SO CURRENT OPINION IN HIV AND AIDS LA English DT Article DE HIV; hyper IgE syndrome; Job's syndrome; STAT3; Th17 ID HYPER-IGE SYNDROME; HYPERIMMUNOGLOBULIN-E SYNDROME; CHRONIC VIRAL-INFECTION; STAPHYLOCOCCUS-AUREUS INFECTIONS; FOLLICULAR-HELPER-CELLS; T-CELLS; DISEASES SOCIETY; EPITHELIAL-CELLS; STAT3 MUTATIONS; RISK-FACTORS AB Purpose of review Patients with hyper IgE syndrome (HIES) share with HIV patients a predisposition to infections, including candidiasis in autosomal dominant HIES (AD-HIES) and molluscum contagiosum and other viral infections in other disorders of elevated IgE with infectious predilections. This review highlights the underlying pathogenesis of these diseases and their relevance to HIV infection. Recent findings Patients with mutations in STAT3, who lack Th17 cells, develop AD-HIES, whereas other disorders of elevated IgE may be caused by mutations in Tyk2 or DOCK8, the latter of which is associated with decreased expansion of CD8 more so than CD4 T cells. Recent studies on patients with recurrent mucocutaneous candidiasis have led to the discovery of mutations in CARD9 and DECTIN-1, genes key to the production of the Th17-driving cytokines IL-1 beta, IL-6, and IL-23. Studies of the peripheral blood of HIV-positive patients have shown a decreased Th17:Th1 ratio, and Th17 cells were preferentially depleted from the gastrointestinal tract within weeks of simian immunodeficiency virus infection in rhesus macaques. Summary The consequences of inadequate Th17 production in primary immunodeficiency syndromes illustrate the role of Th17 cells in controlling pathogens to which HIV-positive individuals are susceptible. Further understanding of the pathogenesis of opportunistic disease in HIV infection will probably require exploring the role of Th17 cells. C1 [Sandler, Netanya G.; Douek, Daniel C.] NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Milner, Joshua D.] NIAID, Allerg Inflammat Unit, Lab Allerg Dis, Vaccine Res Ctr,NIH, Bethesda, MD 20892 USA. 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 OI Utay, Netanya/0000-0002-6407-8670 FU National Institutes of Health, National Institute of Allergy and Infectious Diseases FX The present work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infectious Diseases. NR 67 TC 23 Z9 23 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1746-630X J9 CURR OPIN HIV AIDS JI Curr. Opin. HIV AIDS PD MAR PY 2010 VL 5 IS 2 BP 179 EP 183 DI 10.1097/COH.0b013e328335ed3e PG 5 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 828NB UT WOS:000295507100012 PM 20543597 ER PT J AU Wang, MY Monticone, RE Lakatta, EG AF Wang, Mingyi Monticone, Robert E. Lakatta, Edward G. TI Arterial aging: a journey into subclinical arterial disease SO CURRENT OPINION IN NEPHROLOGY AND HYPERTENSION LA English DT Review DE angiotensin II; arterial aging; arterial disease ID SMOOTH-MUSCLE-CELLS; VASCULAR ENDOTHELIAL DYSFUNCTION; CROSS-LINK BREAKER; FACTOR-KAPPA-B; ANGIOTENSIN-II; OXIDATIVE STRESS; HYPERTENSIVE-RATS; MATRIX METALLOPROTEINASE-2; PROGENITOR CELLS; MMP-2 ACTIVITY AB Purpose of review Age-associated arterial alterations in cells, matrix, and biomolecules are the foundation for the initiation and progression of cardiovascular diseases in older persons. This review focuses on the latest advances on the intertwining of aging and disease within the arterial wall at the cell and molecular levels. Recent findings Endothelial dysfunction, vascular smooth muscle cell (VSMC) proliferation/invasion/secretion, matrix fragmentation, collagenization and glycation are characteristics of an age-associated arterial phenotype that creates a microenvironment enriched with reactive oxygen species (ROS) for the pathogenesis of arterial disease. This niche creates an age-associated arterial secretory phenotype (AAASP), which is orchestrated by the concerted effects of numerous age-modified angiotensin II signaling molecules. Most of these biomolecular, cell, and matrix modifications that constitute the AAASP can be elicited by experimental hypertension or atherosclerosis at a younger age. The arterial AAASP also shares features of a senescence-associated secretory phenotype (SASP) identified in other mesenchymocytes, that is, fibroblasts. Summary A subclinical AAASP evolves during aging. Targeting this subclinical AAASP may reduce the incidence and progression of the quintessential age-associated arterial diseases, that is, hypertension and atherosclerosis. C1 [Wang, Mingyi; Monticone, Robert E.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Cardiovasc Sci Lab, Intramural Res Program, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM lakattae@grc.nia.nih.gov FU National Institute on Aging, National Institutes of Health FX Funding: This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 62 TC 75 Z9 79 U1 2 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1062-4821 J9 CURR OPIN NEPHROL HY JI Curr. Opin. Nephrol. Hypertens. PD MAR PY 2010 VL 19 IS 2 BP 201 EP 207 DI 10.1097/MNH.0b013e3283361c0b PG 7 WC Urology & Nephrology; Peripheral Vascular Disease SC Urology & Nephrology; Cardiovascular System & Cardiology GA 562OU UT WOS:000275062900013 PM 20040868 ER PT J AU Bechlioulis, A Naka, KK Calis, KA Makrigiannakis, A Michalis, L Kalantaridou, SN AF Bechlioulis, Aris Naka, Katerina K. Calis, Karim A. Makrigiannakis, Antonis Michalis, Lampros Kalantaridou, Sophia N. TI Cardiovascular Effects of Endogenous Estrogen and Hormone Therapy SO CURRENT VASCULAR PHARMACOLOGY LA English DT Article DE Atherosclerosis; hormone therapy; menopause; vascular endothelium; estrogen; estrogen receptor polymorphisms ID CORONARY-ARTERY-DISEASE; C-REACTIVE PROTEIN; HEALTHY POSTMENOPAUSAL WOMEN; RANDOMIZED CONTROLLED-TRIAL; ENDOTHELIAL PROGENITOR CELLS; CONJUGATED EQUINE ESTROGENS; ALPHA GENE POLYMORPHISMS; NITRIC-OXIDE SYNTHASE; ESTROGEN/PROGESTIN INTERVENTIONS PEPI; DENSITY-LIPOPROTEIN CHOLESTEROL AB The incidence of cardiovascular disease is low in healthy premenopausal women and increases with age especially after the menopause; this difference has been attributed to the loss of endogenous estrogen. Atherosclerosis is a chronic inflammatory condition of the vascular wall that may result in an acute clinical event by inducing plaque rupture/erosion leading to thrombosis. A growing body of evidence suggests that the spectrum of the effects of estrogen on vascular pathophysiology is complex and may depend largely on the state of vascular pathology. In relatively healthy vessels, estrogen prevents the development and progression of atherosclerotic lesions, while in the presence of established atherosclerotic plaques, estrogen fails to inhibit the progression of atherosclerosis or may even trigger cardiovascular events. The mechanisms responsible for this are not yet fully elucidated. It is possible that postmenopausal estrogen/progestogen therapy may be beneficial in perimenopausal and early menopausal women prior to atherosclerotic plaque formation, but it may not prevent progression of atherosclerotic plaques and acute cardiovascular events in older women with cardiovascular risk factors or women with established atherosclerosis. Various formulations, doses and routes of hormone therapy administration as well as the genetic background of women should also be taken into account when considering the benefit-to-risk ratio of hormone therapy use. C1 [Naka, Katerina K.; Michalis, Lampros] Univ Ioannina, Sch Med, Dept Cardiol, GR-45110 Ioannina, Greece. [Bechlioulis, Aris; Naka, Katerina K.; Michalis, Lampros; Kalantaridou, Sophia N.] Univ Ioannina, Michaelid Cardiac Ctr, GR-45110 Ioannina, Greece. [Calis, Karim A.] NIH, Clin Res Ctr, Bethesda, MD 20892 USA. [Makrigiannakis, Antonis] Univ Crete, Sch Med, Dept Obstet & Gynaecol, Iraklion, Greece. [Kalantaridou, Sophia N.] Univ Ioannina, Sch Med, Dept Obstet & Gynaecol, GR-45110 Ioannina, Greece. RP Michalis, L (reprint author), Univ Ioannina, Sch Med, Dept Cardiol, Univ Campus, GR-45110 Ioannina, Greece. EM lmihalis@cc.uoi.gr RI Bechlioulis, Aris/D-4814-2011 NR 142 TC 9 Z9 9 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 1570-1611 J9 CURR VASC PHARMACOL JI Current Vascular Pharmacology PD MAR PY 2010 VL 8 IS 2 BP 249 EP 258 PG 10 WC Pharmacology & Pharmacy; Peripheral Vascular Disease SC Pharmacology & Pharmacy; Cardiovascular System & Cardiology GA 563WS UT WOS:000275167500008 PM 19485910 ER PT J AU Dagur, PK Tatlici, G Gourley, M Samsel, L Raghavachari, N Liu, PC Liu, DL Mccoy, JP AF Dagur, Pradeep Kumar Tatlici, Gulnaz Gourley, Mark Samsel, Leigh Raghavachari, Nalini Liu, Poching Liu, Delong McCoy, J. Philip, Jr. TI CD146+T Lymphocytes Are Increased in Both the Peripheral Circulation and in the Synovial Effusions of Patients with Various Musculoskeletal Diseases and Display Pro-inflammatory Gene Profiles SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Article DE T cells; CD146; synovial effusion; arthritis ID JUVENILE IDIOPATHIC ARTHRITIS; RHEUMATOID-ARTHRITIS; T-CELLS; ADHESION MOLECULES; ENDOTHELIAL-CELLS; ANTIGEN; EXPRESSION; RECEPTOR; SUBSET; BLOOD AB Twenty-eight synovial effusions (SE) were obtained from 24 patients, paired samples of peripheral blood (PB) from 10 of these patients, and PB from 36 healthy individuals for analysis of CD146 on T-lymphocytes by flow cytometry. CD146+ or CD146 T-lymphocytes were sorted from three SE to study gene expression profiles and selected genes revalidated using QPCR assays. We found more CD3+CD146+ and CD4+CD146+ T-lymphocytes in PB from patients compared with PB of healthy individuals (4.71% +/- 2.48% vs. 2.53% +/- 1.08%, P = 0.028) and (6.29% +/- 2.74% vs. 2.41% +/- 0.96%, P = 0.0017), respectively, whereas CD8+CD146+ T-Iymphocytes were not significantly different (2.55% +/- 1.65% vs. 3.18% +/- 2.59%, P = 0.5008). SE displayed CD146 staining on 16.32% +/- 6.06% of CD3+ cells. This expression was skewed toward CD4+ T-lymphocytes, with CD146 present on 24.06% +/- 8.20% of the CD4+ T-lymphocytes compared with 6.19% +/- 5.22% of the CD8+ T-lymphocytes. CD146 on CD3+, CD4+ and CD8+ T-lymphocytes in SE was significantly higher compared with PB in patients (P<0.0001, P<0.0001 and P = 0.0036, respectively). Gene expression profiles of sorted CD146+CD4+CD3+ vs. CD146-CD4+CD3+ T-lymphocytes (n = 2) and CD2+CD146+ vs. CD2+CD 146 (n = 1) from SE, displayed increased CD146, LAIR2, CXCL13, CD109, IL6ST, IL6R, TNFRsf18, and TNFRsf4 genes, whereas decreased CCR7, CCL5, and cytotoxicity-associated genes including granzymes b, h, and k, perforin were found with the CD146- T-lymphocytes. By QPCR higher mRNA expression of CXCL13, CD146 and CD109 was also noted in the CD146+ subset, compared with the CD146- subset, in PB of healthy individuals and in PB and SE from patients. Our study establishes increased CD146+ T-lymphocytes in diseases with joint effusions, and demonstrates pro-inflammatory gene profiles in these cells. Published 2009 Wiley-Liss, Inc. C1 [McCoy, J. Philip, Jr.] NHLBI, NIH, Flow Cytometry Core Facil, Bethesda, MD 20892 USA. [Gourley, Mark] NIAMSD, Bethesda, MD 20892 USA. [Raghavachari, Nalini; Liu, Poching] NHLBI, Genom Core Facil, Bethesda, MD 20892 USA. [Liu, Delong] NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. RP Mccoy, JP (reprint author), NHLBI, NIH, Flow Cytometry Core Facil, 10 Ctr Dr,MSC 1357,Bldg 10,Rm 8C103D, Bethesda, MD 20892 USA. EM mccoyjp@nhlbi.nih.gov FU Intramural Research Programs; National Heart, Lung, and Blood Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health) FX Grant sponsors: Intramural Research Programs, National Heart, Lung, and Blood Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases (National Institutes of Health). NR 27 TC 13 Z9 14 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD MAR PY 2010 VL 78B IS 2 BP 88 EP 95 DI 10.1002/cyto.b.20502 PG 8 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 578BE UT WOS:000276267500003 PM 19834966 ER PT J AU Rich, BA Holroyd, T Carver, FW Onelio, LM Mendoza, JK Cornwell, BR Fox, NA Pine, DS Coppola, R Leibenluft, E AF Rich, Brendan A. Holroyd, Tom Carver, Frederick W. Onelio, Laura M. Mendoza, Jennifer K. Cornwell, Brian R. Fox, Nathan A. Pine, Daniel S. Coppola, Richard Leibenluft, Ellen TI A PRELIMINARY STUDY OF THE NEURAL MECHANISMS OF FRUSTRATION IN PEDIATRIC BIPOLAR DISORDER USING MAGNETOENCEPHALOGRAPHY SO DEPRESSION AND ANXIETY LA English DT Article DE irritability; attention; neuroimaging; anterior cingulate cortex; parietal lobe; theta ID MAJOR DEPRESSIVE DISORDER; FRONTAL MIDLINE THETA; SPATIALLY-FILTERED MAGNETOENCEPHALOGRAPHY; EVENT-RELATED SYNCHRONIZATION; ROSTRAL ANTERIOR CINGULATE; SUBCORTICAL BRAIN-REGIONS; RESPONSE-INHIBITION; PREFRONTAL CORTEX; GO/NOGO TASK; BEHAVIORAL-RESPONSES AB Background: Irritability is prevalent and impairing in pediatric bipolar disorder (BD) but has been minimally studied using neuroimaging techniques We used magnetoencephalograpby (MEG) to study theta band oscillations in the anterior cingulate cortex (ACC) during frustration in BD youth. ACC theta power is associated with attention to emotional stimuli, and the A CC may mediate responses to frustrating stimuli. Methods: We used the affective Posner task, an attention paradigm that uses rigged feedback to induce frustration, to compare 20 medicated BD youth (14.9 +/- 2.0 years; 45% male) and 20 healthy controls (14.7 +/- 1.7 years; 45% male). AIEG measured neuronal activity after negative and positive feedback; we also compared groups on reaction time, response accuracy, and self-reported affect Patients met strict DSM-IV BD criteria and were euthymic Controls bad no psychiatric history. Results: BD youth reported more negative affective responses than controls. After negative feedback, BD subject, relative to controls, displayed greater theta power in the right ACC and bilateral parietal lobe. After positive feedback, BD subjects displayed lower theta power in the left A CC than did controls. Correlations between MEG, behavior, and affect were nonsignificant. Conclusion: In this first MEG study of BD youth, BD youth displayed patterns of theta oscillations in the A CC and parietal lobe in response to frustration-inducing negative feedback that differed from healthy controls. These data suggest that BD youth may display heightened processing of negative feedback and exaggerated self-monitoring after frustrating emotional stimuli Future studies are needed with unmedicated bipolar youth, and comparison ADHD and anxiety groups. Depression and Anxiety 27:276-286, 2010. (C) 2009 Wiley-Liss, Inc. C1 [Rich, Brendan A.] Catholic Univ Amer, Dept Psychol, Washington, DC 20064 USA. [Holroyd, Tom; Carver, Frederick W.; Coppola, Richard] NIMH, MEG Core Facil, Bethesda, MD 20892 USA. [Onelio, Laura M.; Mendoza, Jennifer K.; Cornwell, Brian R.; Pine, Daniel S.; Leibenluft, Ellen] NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Fox, Nathan A.] Univ Maryland, Child Dev Lab, College Pk, MD 20742 USA. RP Rich, BA (reprint author), Catholic Univ Amer, Dept Psychol, 4001 Harewood Rd NE,327 OBoyle Hall, Washington, DC 20064 USA. EM richb@cua.edu FU Intramural Research Program of the NIH; NIMH FX This research was supported by the Intramural Research Program of the NIH, NIMH. This funding organization was not involved in research aspects, such as study design and conduct, data collection, analysis, or interpretation, nor manuscript preparation or approval. We acknowledge the subjects and families of patients and controls whose participation enabled this research. We also thank the staff of the Section on Bipolar Spectrum Disorders at the NIMH. NR 120 TC 15 Z9 15 U1 6 U2 9 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1091-4269 J9 DEPRESS ANXIETY JI Depress. Anxiety PD MAR PY 2010 VL 27 IS 3 BP 276 EP 286 DI 10.1002/da.20649 PG 11 WC Psychology, Clinical; Psychiatry; Psychology SC Psychology; Psychiatry GA 563BU UT WOS:000275101400008 PM 20037920 ER PT J AU Bornstein, MH Arterberry, ME AF Bornstein, Marc H. Arterberry, Martha E. TI The Development of Object Categorization in Young Children: Hierarchical Inclusiveness, Age, Perceptual Attribute, and Group Versus Individual Analyses SO DEVELOPMENTAL PSYCHOLOGY LA English DT Article DE categorization; sequential touching; toddlers ID BASIC-LEVEL; INFANTS CATEGORIZATION; DEPENDENT CATEGORIZATION; INDUCTIVE INFERENCE; SEMANTIC MEMORY; FOLK BIOLOGY; SCALE ERRORS; REAL OBJECTS; SIMILARITY; KNOWLEDGE AB Multiple levels of category inclusiveness in 4 object domains (animals, vehicles, fruit, and furniture) were examined using a sequential touching procedure and assessed in both individual and group analyses in eighty 12-, 18-, 24-, and 30-month-olds. The roles of stimulus discriminability and child motor development, fatigue, and actions were also investigated. More inclusive levels of categorization systematically emerged before less inclusive levels, and a consistent advantage for categorizing high versus low perceptual contrasts was found. Group and individual analyses generally converged, but individual analyses added information about child categorization over group analyses. The development of object categorization in young children is discussed in light of efficiency of processing and similarity-differentiation theories. C1 [Bornstein, Marc H.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurosci, NIH, Publ Hlth Serv, Bethesda, MD 20892 USA. [Arterberry, Martha E.] Colby Coll, Waterville, ME 04901 USA. RP Bornstein, MH (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Program Dev Neurosci, NIH, Publ Hlth Serv, Rockledge 1,Suite 8030,6705 Rockledge Dr,MSC 7971, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov FU Intramural NIH HHS [ZIA HD001119-22, Z01 HD001119-20] NR 137 TC 20 Z9 21 U1 6 U2 10 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0012-1649 J9 DEV PSYCHOL JI Dev. Psychol. PD MAR PY 2010 VL 46 IS 2 BP 350 EP 365 DI 10.1037/a0018411 PG 16 WC Psychology, Developmental SC Psychology GA 566PQ UT WOS:000275385400005 PM 20210495 ER PT J AU Um, JH Park, SJ Kang, H Yang, ST Foretz, M McBurney, MW Kim, MK Viollet, B Chung, JH AF Um, Jee-Hyun Park, Sung-Jun Kang, Hyeog Yang, Shutong Foretz, Marc McBurney, Michael W. Kim, Myung K. Viollet, Benoit Chung, Jay H. TI AMP-Activated Protein Kinase-Deficient Mice Are Resistant to the Metabolic Effects of Resveratrol SO DIABETES LA English DT Article ID SKELETAL-MUSCLE; LIFE-SPAN; MITOCHONDRIAL BIOGENESIS; DIETARY RESTRICTION; INSULIN-RESISTANCE; RAT-LIVER; C-ELEGANS; SIRT1; EXERCISE; PGC-1-ALPHA AB OBJECTIVE-Resveratrol, a natural polyphenolic compound that is found in grapes and red wine, increases metabolic rate, insulin sensitivity, mitochondrial biogenesis, and physical endurance and reduces fat accumulation in mice. Although it is thought that resveratrol targets Sirt1, this is controversial because resveratrol also activates 5' AMP-activated protein kinase (AMPK), which also regulates insulin sensitivity and mitochondrial biogenesis. Here, we use mice deficient in AMPK alpha 1 or -alpha 2 to determine whether the metabolic effects of resveratrol are mediated by AMPK. RESEARCH DESIGN AND METHODS-Mice deficient in the catalytic subunit of AMPK (alpha 1 or alpha 2) and wild-type mice were fed a high-fat diet or high-fat diet supplemented with resveratrol for 13 weeks. Body weight was recorded biweekly and metabolic parameters were measured. We also used mouse embryonic fibroblasts deficient in AMPK to study the role of AMPK in resveratrol-mediated effects in vitro. RESULTS-Resveratrol increased the metabolic rate and reduced fat mass in wild-type mice but not in AMPK alpha 1(-/-) mice. In the absence of either AMPK alpha 1 or -alpha 2, resveratrol failed to increase insulin sensitivity, glucose tolerance, mitochondrial biogenesis, and physical endurance. Consistent with this, the expression of genes important for mitochondrial biogenesis was not induced by resveratrol in AMPK-deficient mice. In addition, resveratrol increased the NAD-to-NADH ratio in an AMPK-dependent manner, which may explain how resveratrol may activate Sirt1 indirectly. CONCLUSIONS-We conclude that AMPK, which was thought to be an off-target hit of resveratrol, is the central target for the metabolic effects of resveratrol. Diabetes 59:554-563, 2010 C1 [Um, Jee-Hyun; Park, Sung-Jun; Kang, Hyeog; Yang, Shutong; Kim, Myung K.; Chung, Jay H.] NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. [Foretz, Marc; Viollet, Benoit] Univ Paris 05, CNRS, UMR 8104, Inst Cochin, Paris, France. [Foretz, Marc; Viollet, Benoit] Natl Sante & Rech Med, Paris, France. [McBurney, Michael W.] Ottawa Hlth Res Inst, Ctr Canc Therapeut, Ottawa, ON, Canada. RP Chung, JH (reprint author), NHLBI, Lab Biochem Genet, NIH, Bldg 10, Bethesda, MD 20892 USA. EM chungj@nhlbi.nih.gov FU Intramural Research Program; National Heart, Lung, and Blood Institute; National Institutes of Health; European Union [LSHM-CT2004-005272] FX This work was supported by the Intramural Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, and by the European Union FP6 Program (EXGENESIS Integrated Project LSHM-CT2004-005272).; No potential conflicts of interest relevant to this article were reported.; We thank Dalton Saunders for his assistance with animal management. NR 52 TC 312 Z9 322 U1 4 U2 40 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAR PY 2010 VL 59 IS 3 BP 554 EP 563 DI 10.2337/db09-0482 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 568YQ UT WOS:000275562900002 PM 19934007 ER PT J AU Cowie, CC Rust, KF Byrd-Holt, DD Gregg, EW Ford, ES Geiss, LS Bainbridge, KE Fradkin, JE AF Cowie, Catherine C. Rust, Keith F. Byrd-Holt, Danita D. Gregg, Edward W. Ford, Earl S. Geiss, Linda S. Bainbridge, Kathleen E. Fradkin, Judith E. TI Prevalence of Diabetes and High Risk for Diabetes Using A1C Criteria in the US Population in 1988-2006 SO DIABETES CARE LA English DT Article AB OBJECTIVE - We examined prevalences of previously diagnosed diabetes and undiagnosed diabetes and high risk for diabetes using recently Suggested A1C criteria in the U.S. during 2003-2006. We compared these prevalences to those in earlier surveys and those using glucose criteria. RESEARCH DESIGN AND METHODS - in 2003-2006, the National Health and Nutrition Examination Survey included a probability sample of 14,611 individuals aged >= 12 years. Participants were classified on glycemic status by interview for diagnosed diabetes and by A1C, fasting, and 2-h glucose challenge values measured in subsamples. RESULTS - Using A1C criteria, the crude prevalence of total diabetes in adults aged >= 20 years was 9.6% (20.4 million), of which 19.0% was undiagnosed (7.8% diagnosed, 1.8% undiagnosed Using A1C >= 6.5%). Another 3.5% of adults (7.4 million) were at high risk for diabetes (A1C 6.0 to <6.5%). Prevalences were disproportionately high in the elderly. Age-/sex-standardized prevalence was more than two Limes higher in non-Hispanic blacks and Mexican Americans versus non-Hispanic whites for diagnosed, undiagnosed, and total diabetes (P < 0.003); standardized prevalence at high risk for diabetes was more than two times higher in non-Hispanic blacks Versus non-Hispanic whites and Mexican Americans (P < 0.00001. Since 1988-1994, diagnosed diabetes generally increased, while the percent of diabetes that was undiagnosed and the percent at high risk of diabetes generally decreased. Using A1C Criteria, prevalences of undiagnosed diabetes and high risk of diabetes were one-third that and one-tenth that, respectively, using glucose criteria. CONCLUSIONS - Although A1C detects much lower prevalences than glucose criteria, hyperglycemic conditions remain high in the U.S., and elderly and minority groups are disproportionately affected. C1 [Cowie, Catherine C.; Fradkin, Judith E.] NIDDK, NIH, Bethesda, MD 20892 USA. [Rust, Keith F.] WESTAT Corp, Rockville, MD 20850 USA. [Byrd-Holt, Danita D.; Bainbridge, Kathleen E.] Social & Sci Syst, Silver Spring, MD USA. [Gregg, Edward W.; Geiss, Linda S.] Ctr Dis Control & Prevent, Div Diabet Translat, Atlanta, GA USA. [Ford, Earl S.] Ctr Dis Control & Prevent, Div Adult & Community Hlth, Atlanta, GA USA. RP Cowie, CC (reprint author), NIDDK, NIH, Bethesda, MD 20892 USA. EM cowie@nih.gov NR 14 TC 290 Z9 295 U1 0 U2 7 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD MAR PY 2010 VL 33 IS 3 BP 562 EP 568 DI 10.2337/dc09-1524 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 568YO UT WOS:000275562700021 PM 20067953 ER PT J AU Menjoge, AR Kannan, RM Tomalia, DA AF Menjoge, Anupa R. Kannan, Rangaramanujam M. Tomalia, Donald A. TI Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications SO DRUG DISCOVERY TODAY LA English DT Review ID POLYAMIDOAMINE PAMAM DENDRIMERS; MAGNETIC RESONANCE LYMPHANGIOGRAPHY; CACO-2 CELL MONOLAYERS; MR CONTRAST AGENT; IN-VITRO; POLY(AMIDOAMINE) DENDRIMERS; SURFACE MODIFICATION; BIOLOGICAL EVALUATION; STARBURST DENDRIMERS; STEALTH DENDRIMERS AB Dendrimers are members of a versatile fourth new class of polymer, architecture (i.e. dendritic polymers after traditional linear crosslinked, and branched types) [1]. Typically, dendrimers are used as well-defined scaffolding or nanocontainers to conjugate, complex or encapsulate therapeutic drugs or imaging moieties. As a delivery vector, the dendrimer conjugate linker or spacer chemistry plays a crucial part in determining optimum drug delivery to disease sites by conserving active drug efficacy while influencing appropriate release patterns. This review focuses oil several crucial issues related to those dendrimer features, namely the role of dendrimers as nanoscaffolding and nanocontainers, crucial principles that might be invoked for improving dendrimer cytotoxicity properties, understanding dendrimer cellular transport mechanisms and the exciting role of dendrimers as high-contrast MRI imaging agents. The review concludes with a brief survey of translational efforts from research and development phases to clinical trials that are actively emerging. C1 [Tomalia, Donald A.] Cent Michigan Univ, Dept Chem, Natl Dendrimer & Nanotechnol Ctr, Mt Pleasant, MI 48859 USA. [Menjoge, Anupa R.; Kannan, Rangaramanujam M.] Wayne State Univ, Dept Chem Engn & Mat Sci & Biomed Engn, Detroit, MI 48202 USA. [Menjoge, Anupa R.; Kannan, Rangaramanujam M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NICHD, NIH,DHHS, Detroit, MI 48201 USA. RP Tomalia, DA (reprint author), Cent Michigan Univ, Dept Chem, Natl Dendrimer & Nanotechnol Ctr, Mt Pleasant, MI 48859 USA. EM rkannan@eng.wayne.edu; donald.tomalia@cmich.edu FU Intramural NIH HHS NR 114 TC 374 Z9 381 U1 19 U2 203 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD MAR PY 2010 VL 15 IS 5-6 BP 171 EP 185 DI 10.1016/j.drudis.2010.01.009 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 573IU UT WOS:000275906900003 PM 20116448 ER PT J AU Hoelbl, A Schuster, C Kovacic, B Zhu, BM Wickre, M Hoelzl, MA Fajmann, S Grebien, F Warsch, W Stengl, G Hennighausen, L Poli, V Beug, H Moriggl, R Sexl, V AF Hoelbl, Andrea Schuster, Christian Kovacic, Boris Zhu, Bingmei Wickre, Mark Hoelzl, Maria A. Fajmann, Sabine Grebien, Florian Warsch, Wolfgang Stengl, Gabriele Hennighausen, Lothar Poli, Valeria Beug, Hartmut Moriggl, Richard Sexl, Veronika TI Stat5 is indispensable for the maintenance of bcr/abl-positive leukaemia SO EMBO MOLECULAR MEDICINE LA English DT Article DE Bcr/Abl; leukaemia; leukaemic stem cells; Stat5 ID HEMATOPOIETIC STEM-CELLS; CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; DNA-BINDING ACTIVITY; BCR-ABL; MYELOPROLIFERATIVE DISORDERS; TYROSINE KINASE; CONSTITUTIVE ACTIVATION; BLAST-CRISIS; LYMPHOPROLIFERATIVE DISEASE AB Tumourigenesis caused by the Bcr/Abl oncoprotein is a multi-step process proceeding from initial to tumour-maintaining events and finally results in a complex tumour-supporting network. A key to successful cancer therapy is the identification of critical functional nodes in an oncogenic network required for disease maintenance. So far, the transcription factors Stat3 and Stat5a/b have been implicated in bcr/abl-induced initial transformation. However, to qualify as a potential drug target, a signalling pathway must be required for the maintenance of the leukaemic state. Data on the roles of Stat3 or Stat5a/b in leukaemia maintenance are elusive. Here, we show that both, Stat3 and Stat5 are necessary for initial transformation. However, Stat5- but not Stat3-deletion induces G(0)/G(1) cell cycle arrest and apoptosis of imatinib-sensitive and imatinib-resistant stable leukaemic cells in vitro. Accordingly, Stat5-abrogation led to effective elimination of myeloid and lymphoid leukaemia maintenance in vivo. Hence, we identified Stat5 as a vulnerable point in the oncogenic network downstream of Bcr/Abl representing a case of non-oncogene addiction (NOA). C1 [Hoelbl, Andrea; Schuster, Christian; Hoelzl, Maria A.; Fajmann, Sabine; Warsch, Wolfgang; Sexl, Veronika] MUV, Inst Pharmacol, Ctr Biomol Med & Pharmacol, Vienna, Austria. [Kovacic, Boris; Stengl, Gabriele; Beug, Hartmut] Res Inst Mol Pathol IMP, Vienna, Austria. [Zhu, Bingmei; Wickre, Mark; Hennighausen, Lothar] NIH, Bethesda, MD 20892 USA. [Grebien, Florian] MUV, MFPL, Vienna, Austria. [Poli, Valeria] Univ Turin, Ctr Mol Biotechnol, Turin, Italy. [Moriggl, Richard] Ludwig Boltzmann Inst Canc Res, Vienna, Austria. RP Sexl, V (reprint author), MUV, Inst Pharmacol, Ctr Biomol Med & Pharmacol, Vienna, Austria. EM veronika.sexl@meduniwien.ac.at RI Poli, Valeria/A-9215-2012; Kovacic, Boris/J-1871-2016; OI Poli, Valeria/0000-0002-3739-3966; Kovacic, Boris/0000-0002-1148-4149; Hoelbl-Kovacic, Andrea/0000-0001-6219-8794; Grebien, Florian/0000-0003-4289-2281; Moriggl, Richard/0000-0003-0918-9463 FU Austrian Research fund [FWF-SFB-28]; Vienna Science and Technology Fund [WWTF-LS07-037]; GEN-AU-program DRAGON FX We are deeply indebted to M. Freissmuth, M. Busslinger, P. Valent, O. Hantschel, G. Superti-Furga and T. Decker for continuous discussion and scientific input. We also thank M. Mayerhofer for providing the Bcr/Ablp210T315I mutant. This work was made possible by financial support from the Austrian Research fund (FWF-SFB-28), the Vienna Science and Technology Fund (WWTF-LS07-037) and the GEN-AU-program DRAGON. NR 69 TC 108 Z9 115 U1 1 U2 14 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1757-4676 J9 EMBO MOL MED JI EMBO Mol. Med. PD MAR PY 2010 VL 2 IS 3 BP 98 EP 110 DI 10.1002/emmm.201000062 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 572IN UT WOS:000275822700004 PM 20201032 ER PT J AU Risi, GF Bloom, ME Hoe, NP Arminio, T Carlson, P Powers, T Feldmann, H Wilson, D AF Risi, George F. Bloom, Marshall E. Hoe, Nancy P. Arminio, Thomas Carlson, Paul Powers, Tamara Feldmann, Heinz Wilson, Deborah TI Preparing a Community Hospital to Manage Work-related Exposures to Infectious Agents in BioSafety Level 3 and 4 Laboratories SO EMERGING INFECTIOUS DISEASES LA English DT Article ID IMPORTED LASSA FEVER; EBOLA-VIRUS; HEMORRHAGIC-FEVER; BIOTERRORISM; GERMANY; PATIENT; RISK AB Construction of new BioSafety Level (BSL) 3 and 4 laboratories has raised concerns regarding provision of care to exposed workers because of healthcare worker (HCW) unfamiliarity with precautions required. When the National Institutes of Health began construction of a new BSL-4 laboratory in Hamilton, Montana, USA, in 2005, they contracted with St. Patrick Hospital in Missoula, Montana, for care of those exposed. A care and isolation unit is described. We developed a training program for HCWs that emphasized the optimal use of barrier precautions and used pathogen-specific modules and simulations with mannequins and fluorescent liquids that represented infectious body fluids. The facility and training led to increased willingness among HCWs to care for patients with all types of communicable diseases. This model may be useful for other hospitals, whether they support a BSL-4 facility, are in the proximity of a BSL-3 facility, or are interested in upgrading their facilities to prepare for exotic and novel infectious diseases. C1 [Powers, Tamara] St Patricks Hosp, Missoula, MT USA. [Powers, Tamara] Hlth Sci Ctr, Missoula, MT USA. [Risi, George F.; Hoe, Nancy P.; Arminio, Thomas; Carlson, Paul; Wilson, Deborah] NIH, Bethesda, MD 20892 USA. [Bloom, Marshall E.; Feldmann, Heinz] NIAID, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Risi, GF (reprint author), 614 W Spruce St, Missoula, MT 59802 USA. EM grisi@mail.nih.gov FU NIH Division of Occupational Health and Safety; NIAID Division of Intramural Research FX This work was supported by the NIH Division of Occupational Health and Safety (G.R., N.H., T.A., P.C., D.W.), and the NIAID Division of Intramural Research (M.B., H.F.). NR 33 TC 6 Z9 6 U1 1 U2 14 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAR PY 2010 VL 16 IS 3 BP 373 EP 378 DI 10.3201/eid1603.091485 PG 6 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 566WR UT WOS:000275404700001 PM 20202409 ER PT J AU Aguilera, G Chen, J Liu, Y AF Aguilera, Greti Chen, Jun Liu, Ying TI Epigenetic regulation of hypothalamic-pituitary adrenal axis and corticotrophin releasing hormone transcription by early life stress SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Aguilera, Greti; Chen, Jun; Liu, Ying] NICHHD, PDEGEN, Sect Endocrine Physiol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S253 EP S253 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742600251 ER PT J AU Al-Attas, O Al-Daghri, N Alokail, M Bamakhramah, A Sabico, S Huang, T McTernan, P Kumar, S AF Al-Attas, Omar Al-Daghri, Nasser Alokail, Majed Bamakhramah, Ahmed Sabico, Shaun Huang, Terry McTernan, Philip Kumar, Sudhesh TI Telomere length and childhood obesity among Arab youth SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Al-Attas, Omar; Al-Daghri, Nasser; Alokail, Majed; Bamakhramah, Ahmed; Sabico, Shaun] King Saud Univ, Dept Biochem, Riyadh, KSA, Saudi Arabia. [Huang, Terry] Eunice Kennedy Shriver Natl Inst, Child Hlth & Human Dev, Bethesda, MD USA. [McTernan, Philip; Kumar, Sudhesh] Univ Warwick, Diabet & Metab Unit, Coventry CV4 7AL, W Midlands, England. RI Al-Daghri, Nasser/G-7736-2011; Al-okail, Majed/E-5565-2016 OI Al-okail, Majed/0000-0001-8147-3499 NR 0 TC 0 Z9 0 U1 0 U2 4 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S619 EP S619 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742601807 ER PT J AU Cheng, SY AF Cheng, Sheue-yann TI Regulation of metastasis in follicular carcinoma of the thyroid: Insights from a mouse model SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Cheng, Sheue-yann] NCI, LMB, CCR, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S277 EP S277 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742600351 ER PT J AU Gainer, H AF Gainer, Harold TI Recent progress in understanding the regulation of the cell-specific expression of oxytocin and vasopressin genes in the hypothalamus SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Gainer, Harold] NINDS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S256 EP S256 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742600260 ER PT J AU Gorden, P AF Gorden, Phillip TI The application of adipokine biology to the treatment of human disease SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Gorden, Phillip] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S224 EP S224 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742600125 ER PT J AU Hanyu, O Fuda, H Higashi, Y Endo, M Nakae, H Kohjitani, A Miida, T Aizawa, Y Strott, CA AF Hanyu, Osamu Fuda, Hirotoshi Higashi, Yuko Endo, Motohiro Nakae, Hanako Kohjitani, Atsushi Miida, Takashi Aizawa, Yoshifusa Strott, Charles A. TI Cholesterol sulfate regulation of profilaggrin expression: Studies involving sirna for SULT2B1B and ROR alpha in primary cultures of normal human epidermal keratinocytes SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Hanyu, Osamu; Aizawa, Yoshifusa] Niigata Univ, Grad Sch Med & Dent Sci, Dept Homeostat Regulat & Dev, Div Endocrinol & Metab, Niigata, Japan. [Miida, Takashi] Juntendo Univ, Sch Med, Dept Clin Lab Med, Tokyo 113, Japan. [Fuda, Hirotoshi; Higashi, Yuko; Endo, Motohiro; Nakae, Hanako; Kohjitani, Atsushi; Strott, Charles A.] NICHHD, Sect Steroid Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S545 EP S546 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742601509 ER PT J AU Kimura, S AF Kimura, Shioko TI Stem cells in thyroid carcinomas SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S317 EP S317 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742600514 ER PT J AU Kino, T Hurt, DE Ichijo, T Nader, N Chrousos, GP AF Kino, Tomoshige Hurt, Darrell E. Ichijo, Takamasa Nader, Nancy Chrousos, George P. TI Non-coding RNA Gas5 is a growth arrest/starvation-associated repressor of the glucocorticoid receptor SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Kino, Tomoshige; Ichijo, Takamasa; Nader, Nancy] Eunice Kennedy Shirver Natl Inst Child Hlth & Hum, Program Reprod & Adult Endocrinol, Bethesda, MD USA. [Hurt, Darrell E.] NIAID, Bioinformat & Sci IT Program, Off Technol Informat Syst, Bethesda, MD 20892 USA. [Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, GR-11527 Athens, Greece. NR 0 TC 0 Z9 0 U1 1 U2 3 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S544 EP S544 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742601503 ER PT J AU Korach, K AF Korach, Kenneth TI Estrogen receptor insensitivity: Consequences in endocrine physiology SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Korach, Kenneth] Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC 27709 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S263 EP S263 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742600291 ER PT J AU Marx, SJ AF Marx, Stephen J. TI Multiple endocrine neoplasia type 1 (MEN1) SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Marx, Stephen J.] NIDDK, Metab Dis Branch, NIH, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 1 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S211 EP S211 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742600073 ER PT J AU Mercado-Asis, LB Lim-Uy, SW Galia, AM Mamba, LAE Sia-Atanacio, AY Chu, AL Lorenzo, ZG Padua, MLM Macaballug, AG Fonte, JS Robles, JF Pacak, K AF Mercado-Asis, Leilani B. Lim-Uy, Stefanie W. Galia, Analyza M. Mamba, Lucy Anne E. Sia-Atanacio, Aileen Y. Chu, Albert L. Lorenzo, Zarina G. Padua, Ma. Louella M. Macaballug, Aurora G. Fonte, Jay S. Robles, Jeremyjones F. Pacak, Karel TI Clinical, hormonal, and genetic profile of filipino patients with suspected pheochromocytoma (preliminary report) SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Mercado-Asis, Leilani B.; Lim-Uy, Stefanie W.; Galia, Analyza M.; Mamba, Lucy Anne E.; Sia-Atanacio, Aileen Y.; Chu, Albert L.; Lorenzo, Zarina G.; Padua, Ma. Louella M.; Macaballug, Aurora G.; Fonte, Jay S.; Robles, Jeremyjones F.] Univ Santo Tomas Hosp, Sect Endocrinol & Metab, Manila, Philippines. [Fonte, Jay S.; Robles, Jeremyjones F.; Pacak, Karel] NICHHD, Reprod & Adult Endocrinol Program, Sect Med Neuroendocrinol, Natl Inst Hlth, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S634 EP S634 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742601867 ER PT J AU Merke, DP AF Merke, Deborah P. TI New aspects of congenital adrenal hyperplasia SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Merke, Deborah P.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S307 EP S307 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742600480 ER PT J AU Nieman, LK AF Nieman, Lynnette K. TI Diagnostic challenges and medical treatment of Cushing's disease SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Nieman, Lynnette K.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S209 EP S209 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742600066 ER PT J AU Shamay, A Feuermann, Y Klover, P Yamaji, D Robinson, GW Hennighausen, L AF Shamay, Avi Feuermann, Yonatan Klover, Peter Yamaji, D. Robinson, G. W. Hennighausen, Lothar TI Expression of micro RNA 21 in mammary stem cells is controlled by cytokine-STAT5 signaling SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Shamay, Avi] Agr Res Org, Volcani Ctr, Inst Anim Sci, IL-50250 Bet Dagan, Israel. [Shamay, Avi; Feuermann, Yonatan; Klover, Peter; Yamaji, D.; Robinson, G. W.; Hennighausen, Lothar] Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S623 EP S623 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742601824 ER PT J AU Sue, M Nakamura, H Kawashima, A Ishido, Y Wu, H Akama, T Tanigawa, K Kohn, LD Suzuki, K AF Sue, Mariko Nakamura, Hanna Kawashima, Akira Ishido, Yuko Wu, Huhehasi Akama, Takeshi Tanigawa, Kazunari Kohn, Leonard D. Suzuki, Koichi TI The effect of anti-thyroid drugs on sodium-iodide-symporter (NIS) expression in rat thyroid FRTL-5 cells SO ENDOCRINE JOURNAL LA English DT Meeting Abstract C1 [Sue, Mariko; Kawashima, Akira; Ishido, Yuko; Wu, Huhehasi; Akama, Takeshi; Tanigawa, Kazunari; Suzuki, Koichi] Natl Inst Infect Dis, Leoprosy Res Ctr, Lab Mol Diagnost, Tokyo, Japan. [Sue, Mariko; Nakamura, Hanna] Toho Univ, Sch Med, Dept Internal Med Omori, Div Diabet Metab & Endocrinol, Tokyo, Japan. [Nakamura, Hanna; Kohn, Leonard D.; Suzuki, Koichi] NIDDK, Cell Regulat Sect, Metab Dis Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JAPAN ENDOCRINE SOC PI KYOTO PA 75 YANAGINOBANBA NISHIIRU-MASUYA-CHO, SANJOU-DORI, NAKAGYOU-KU, KYOTO, 604-8111, JAPAN SN 0918-8959 J9 ENDOCR J JI Endocr. J. PD MAR PY 2010 VL 57 SU 2 BP S480 EP S480 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 623LV UT WOS:000279742601243 ER PT J AU Dahiya, N Morin, PJ AF Dahiya, Neetu Morin, Patrice J. TI MicroRNAs in ovarian carcinomas SO ENDOCRINE-RELATED CANCER LA English DT Review ID CHRONIC LYMPHOCYTIC-LEUKEMIA; TARGET MESSENGER-RNAS; TUMOR-SUPPRESSOR; HUMAN CANCER; EXPRESSION PROFILES; CELL-PROLIFERATION; GENE-EXPRESSION; DOWN-REGULATION; NUCLEAR EXPORT; MIRNA TARGETS AB The molecular mechanisms involved in epithelial ovarian cancer initiation and progression are just beginning to be elucidated. In particular, it has become evident that microRNAs (miRNAs or miRs), a class of molecules that post-transcriptionally regulate gene expression, play a major role in ovarian tumorigenesis. Several microRNA profiling studies have identified changes in microRNA patterns that take place during ovarian cancer development. While most deregulated microRNAs are down-regulated in cancer, and may therefore act as tumor suppressors, others are elevated and may represent novel oncogenes in this disease. A number of microRNAs identified as aberrantly expressed in ovarian carcinoma have been shown to have important functional roles in cancer development and may therefore represent targets for therapy. In addition, some of the microRNA patterns may have prognostic significance. The identification of functional targets represents a major hurdle in our understanding of microRNA function in ovarian carcinoma, but significant progress is being made. It is hoped that a better understanding of the microRNA expression and roles in ovarian cancer may provide new avenues for the detection, diagnosis, and therapy of this deadly disease. C1 [Dahiya, Neetu; Morin, Patrice J.] NIA, Lab Cellular & Mol Biol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Morin, Patrice J.] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21287 USA. RP Morin, PJ (reprint author), NIA, Lab Cellular & Mol Biol, NIH, Biomed Res Ctr, 251 Bayview Blvd,Suite 100,Room 6C228, Baltimore, MD 21224 USA. EM morinp@mail.nih.gov RI Dahiya, Neetu/E-5208-2011 FU National Institutes of Health, National Institute on Aging FX This work was supported entirely by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 93 TC 48 Z9 51 U1 1 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD MAR PY 2010 VL 17 IS 1 BP F77 EP F89 DI 10.1677/ERC-09-0203 PG 13 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 570HJ UT WOS:000275663100033 PM 19903743 ER PT J AU Liu, Y Coello, AG Grinevich, V Aguilera, G AF Liu, Ying Coello, Ana G. Grinevich, Valery Aguilera, Greti TI Involvement of Transducer of Regulated cAMP Response Element-Binding Protein Activity on Corticotropin Releasing Hormone Transcription SO ENDOCRINOLOGY LA English DT Article ID MEDIATED GENE-EXPRESSION; HYPOTHALAMIC CELL-LINE; IN-VIVO; STRESS; CREB; KINASE; ACTIVATION; COACTIVATORS; RECEPTORS; PHOSPHORYLATION AB We have recently shown that phospho-cAMP response element-binding protein ( CREB) is essential but not sufficient for activation of CRH transcription, suggesting the requirement of a coactivator. Here, we test the hypothesis that the CREB coactivator, transducer of regulated CREB activity (TORC), is required for activation of CRH transcription, using the cell line 4B and primary cultures of hypothalamic neurons. Immunohistochemistry and Western blot experiments in 4B cells revealed time-dependent nuclear translocation of TORC1, TORC 2, and TORC3 by forskolin [ but not by the phorbol ester, phorbol 12-myristate 13-acetate (PMA)] in a concentration-dependent manner. In reporter gene assays, cotransfection of TORC1 or TORC2 potentiated the stimulatory effect of forskolin on CRH promoter activity but had no effect in cells treated with PMA. Knockout of endogenous TORC using silencing RNA markedly inhibited forskolin-activated CRH promoter activity in 4B cells, as well as the induction of endogenous CRH primary transcript by forskolin in primary neuronal cultures. Coimmunoprecipitation and chromatin immunoprecipitation experiments in 4B cells revealed association of CREB and TORC in the nucleus, and recruitment of TORC2 by the CRH promoter, after 20-min incubation with forskolin. These studies demonstrate a correlation between nuclear translocation of TORC with association to the CRH promoter and activation of CRH transcription. The data suggest that TORC is required for transcriptional activation of the CRH promoter by acting as a CREB coactivator. In addition, cytoplasmic retention of TORC during PMA treatment is likely to explain the failure of phorbolesters to activate CRH transcription in spite of efficiently phosphorylating CREB. ( Endocrinology 151: 1109-1118, 2010) C1 [Liu, Ying; Coello, Ana G.; Aguilera, Greti] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Endocrine Physiol, Program Dev Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. [Grinevich, Valery] Max Planck Inst Med Res, Dept Mol Neurobiol, D-69120 Heidelberg, Germany. RP Aguilera, G (reprint author), NICHHD, Sect Endocrine Physiol, Dev Endocrinol Branch, NIH, Bldg 10,CRC,Room 1E-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM greti_aguilera@nih.gov FU Intramural Research program of the National Institutes of Health/National Institute of Child Health and Human Development FX We thank Dr. Marc Montminy (Salk Institute, La Jolla, CA) for providing the expression vectors for TORC1 and TORC2.; Address all correspondence and requests for reprints to: Greti Aguilera, M. D, Section on Endocrine Physiology, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health Building 10, CRC, Room 1E-3330, 10 Center Drive, Bethesda, Maryland 20892. E-mail: greti_aguilera@nih.gov.; This work was supported by the Intramural Research program of the National Institutes of Health/National Institute of Child Health and Human Development.; Disclosure Summary: The authors have nothing to disclose. NR 32 TC 28 Z9 29 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2010 VL 151 IS 3 BP 1109 EP 1118 DI 10.1210/en.2009-0963 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 558AF UT WOS:000274711600031 PM 20080871 ER PT J AU Schecter, A Haffner, D Colacino, J Patel, K Papke, O Opel, M Birnbaum, L AF Schecter, Arnold Haffner, Darrah Colacino, Justin Patel, Keyur Paepke, Olaf Opel, Matthias Birnbaum, Linda TI Polybrominated Diphenyl Ethers (PBDEs) and Hexabromocyclodecane (HBCD) in Composite US Food Samples SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE dietary intake; food; HBCD; PBDE; United States ID BROMINATED FLAME RETARDANTS; TETRABROMOBISPHENOL-A TBBPA; POLYCHLORINATED-BIPHENYLS; UNITED-STATES; MARKET-BASKET; ADIPOSE-TISSUE; HUMAN EXPOSURE; DIETARY-INTAKE; HOUSE-DUST; TEMPORAL TREND AB OBJECTIVES: This study was designed to update previous U.S. market basket surveys of levels and polybrominated diphenyl ether (PBDE) dietary intake calculations. This study also quantifies hexabromocyclododecane (HBCD) levels in U.S.-purchased foods for the first time and estimates U.S. dietary intake of HBCD. This is part of a larger market basket study reported in two companion articles, of current levels of certain persistent organic pollutants (POPs) PBDEs, HBCD, perfluorinated compounds, polychlorinated biphenyls, and pesticides in composite food samples collected in 2008-2009. METHODS: In this study, we measured concentrations of 24 PBDE congeners and total HBCD in composite samples of 31 food types (310 samples). U.S. dietary intake of PBDEs and HBCD was estimated referencing the most current U.S. Department of Agriculture loss-adjusted food availability report. RESULTS: Total PBDE concentrations in food varied by food type, ranging from 12 pg/g wet weight (ww) in whole milk to 1,545 pg/g ww in canned sardines and 6,211 pg/g ww in butter. Total HBCD concentrations also varied substantially within and among food groups, ranging from 23 pg/g in canned beef chili to 593 pg/g in canned sardines. HBCD was not detected in any dairy samples. Dietary intake of all PBDE congeners measured was estimated to be 50 ng/day, mostly from dairy consumption but also from meat and fish. HBCD intake was estimated at 16 ng/day, primarily from meat consumption. CONCLUSION: PBDEs and HBCDs currently contaminate some food purchased in the United States, although PBDE intake estimated in this study is lower than reported in our previous market basket surveys. HBCD is in food at higher levels than expected based on previously reported levels in milk and blood compared with PBDE levels and is comparable to European levels. C1 [Schecter, Arnold; Patel, Keyur] Univ Texas Dallas, Sch Publ Hlth, Dallas, TX 75390 USA. [Haffner, Darrah] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Colacino, Justin] Univ Michigan, Sch Publ Hlth, Ann Arbor, MI 48109 USA. [Paepke, Olaf; Opel, Matthias] Eurofins, Hamburg, Germany. [Birnbaum, Linda] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Schecter, A (reprint author), Univ Texas Dallas, Sch Publ Hlth, 6011 Harry Hines, Dallas, TX 75390 USA. EM arnold.schecter@utsouthwestern.edu FU Gustavus and Louise Pfeiffer Research Foundation FX We acknowledge the Gustavus and Louise Pfeiffer Research Foundation for their generous funding of this research. NR 59 TC 80 Z9 82 U1 4 U2 58 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAR PY 2010 VL 118 IS 3 BP 357 EP 362 DI 10.1289/ehp.0901345 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 567LX UT WOS:000275449500026 PM 20064778 ER PT J AU D'Aloisio, AA Baird, DD DeRoo, LA Sandler, DP AF D'Aloisio, Aimee A. Baird, Donna D. DeRoo, Lisa A. Sandler, Dale P. TI Association of Intrauterine and Early-Life Exposures with Diagnosis of Uterine Leiomyomata by 35 Years of Age in the Sister Study SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE diabetes mellitus; diethylstilbestrol; early life; leiomyoma; phytoestrogens; pregnancy; prenatal exposure delayed effects; socioeconomic factors; soy formula ID PHYTOESTROGEN GENISTEIN; IMPRINTED GENES; REPRODUCTIVE FACTORS; NEONATAL EXPOSURE; INFANT FORMULA; RISK; EXPRESSION; WOMEN; MICE; FIBROIDS AB BACKGROUND: Early-life exposures to hormonally active compounds and other factors may affect later response to estrogen or progesterone and hence may influence development of uterine leiomyomata (fibroids). OBJECTIVES: We evaluated associations of in utero and early-life exposures, including soy formula, with self-report of physician-diagnosed fibroids by 35 years of age. METHODS: Our study included 19,972 non-Hispanic white women who were 35-59 years of age when they enrolled in the Sister Study in 2003-2007. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) using log-binomial regression models for fibroid associations with adjustment for participant's age and education, maternal age at participant's birth, birth order, and childhood family income. RESULTS: Greater risk of early fibroid diagnosis was associated with soy formula during infancy (RR = 1.25; 95% CI, 0.97-1.61), maternal prepregnancy diabetes (RR = 2.05; 95% CI, 1.16-3.63), low childhood socioeconomic status (RR = 1.28; 95% CI, 1.01-1.63), and gestational age at birth (RR = 1.64; 95% CI, 1.27-2.13, for being born at least 1 month early). In utero diethylstilbestrol (DES) exposure was also associated with early fibroid diagnosis (RR = 1.42; 95% CI, 1.13-1.80), but this association was driven by women reporting probable rather than definite exposure. CONCLUSIONS: There are plausible biological pathways by which these early-life factors could promote fibroid pathogenesis. This is the first epidemiologic study to evaluate such exposures, with the exception of in utero DES, in relation to fibroid risk, and replication of findings in other populations is needed. C1 [D'Aloisio, Aimee A.; Baird, Donna D.; DeRoo, Lisa A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP D'Aloisio, AA (reprint author), NIEHS, Epidemiol Branch, NIH, US Dept HHS, POB 12233,Mail Drop A3-05,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM daloisio@niehs.nih.gov RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Sandler, Dale/0000-0002-6776-0018 FU Intramural Research Program of the National Institutes of Health; National Institute of Environmental Health Sciences [Z01 ES04400509] FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences (Z01 ES04400509). NR 34 TC 44 Z9 46 U1 1 U2 9 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAR PY 2010 VL 118 IS 3 BP 375 EP 381 DI 10.1289/ehp.0901423 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 567LX UT WOS:000275449500029 PM 20194067 ER PT J AU Birnbaum, LS AF Birnbaum, Linda S. TI TSCA Reform Under Way in Congress SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 [Birnbaum, Linda S.] NIEHS, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. [Birnbaum, Linda S.] NTP, NIH, US Dept HHS, Res Triangle Pk, NC USA. RP Birnbaum, LS (reprint author), NIEHS, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM birnbaumls@niehs.nih.gov NR 0 TC 2 Z9 2 U1 0 U2 2 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAR PY 2010 VL 118 IS 3 BP A106 EP A106 DI 10.1289/ehp.1001917 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 567LX UT WOS:000275449500001 PM 20197245 ER PT J AU Zavitsanou, A Malliori, M Sypsa, V Petrodaskalaki, M Psichogiou, M Rokka, C Giannopoulos, A Kalapothaki, V Whitby, D Hatzakis, A AF Zavitsanou, A. Malliori, M. Sypsa, V. Petrodaskalaki, M. Psichogiou, M. Rokka, C. Giannopoulos, A. Kalapothaki, V. Whitby, D. Hatzakis, A. TI Seroepidemiology of human herpesvirus 8 (HHV-8) infection in injecting drug users SO EPIDEMIOLOGY AND INFECTION LA English DT Article DE HHV-8; injecting drug users (IDUs); risk factors; seroepidemiology ID HIV-1-INFECTED PREGNANT-WOMEN; HUMAN-IMMUNODEFICIENCY-VIRUS; KAPOSIS-SARCOMA; SEXUAL TRANSMISSION; DNA-SEQUENCES; HERPESVIRUS-INFECTION; RISK-FACTORS; SEROPREVALENCE; AIDS; BLOOD AB A cross-sectional study was carried out in injecting drug users (IDUs) from Greece to assess the seroprevalence of human herpesvirus 8 (HHV-8) and to identify potentially associated risk factors. A total of 288 IDUs were tested for K8.1 antibodies to HHV-8 lytic antigen. Associations between HHV-8 serostatus and potential risk factors were examined Using univariate and multivarlate logistic regression analysis. Seroprevalence of HHV-8 was 24.3% (95% CI 19.5-29.7), increasing with age from 19.4% in those aged <30 years to 52.9% in those aged >= 40 years (P for trend = 0.003). No statistically significant associations between HHV-8-positive status and gender, educational level, age at first drug injection, needle sharing, number of imprisonments, complications from drug overdose, HIV and HCV were observed. In the multivariate logistic regression analysis, older age (>= 40 vs. <40 years, OR 3.30, 95 % CI 1.14-9.56) and report of septicaemia/abscess (yes vs. no, OR 1.80, 95% CI 1.01-3.18) were each independently associated with higher HHV-8 seroprevalence. HHV-8 is highly prevalent in the IDU Population in Greece. The independent association between HHV-8 and reported abscess or septicaemia supports the hypothesis that poor hygiene conditions in the setting of drug injection may contribute to HHV-8 transmission. C1 [Zavitsanou, A.; Sypsa, V.; Petrodaskalaki, M.; Psichogiou, M.; Rokka, C.; Kalapothaki, V.; Hatzakis, A.] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, GR-11527 Athens, Greece. [Malliori, M.] Univ Athens, Sch Med, Eginit Hosp, Dept Psychiat, GR-11527 Athens, Greece. [Giannopoulos, A.] Univ Athens, Sch Med, Laiko Gen Hosp, Dept Surg 1, GR-11527 Athens, Greece. [Whitby, D.] NCI, Viral Oncol Sect, AIDS & Canc Virus Program, SAIC Frederick, Frederick, MD 21701 USA. RP Hatzakis, A (reprint author), Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, 75 Mikras Asias St, GR-11527 Athens, Greece. EM ahatzak@med.uoa.gr FU Hellenic Scientific Society for AIDS and Sexually Transmitted Diseases FX This project was funded by the Hellenic Scientific Society for AIDS and Sexually Transmitted Diseases. NR 39 TC 3 Z9 3 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0950-2688 J9 EPIDEMIOL INFECT JI Epidemiol. Infect. PD MAR PY 2010 VL 138 IS 3 BP 403 EP 408 DI 10.1017/S0950268809990628 PG 6 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 560CD UT WOS:000274878500014 PM 19698211 ER PT J AU Botello-Harbaum, M Schroeder, JR Collins, CC Moolchan, ET AF Botello-Harbaum, Maria Schroeder, Jennifer R. Collins, Charles C. Moolchan, Eric T. TI NICOTINE REPLACEMENT THERAPY USE AMONG ADOLESCENT SMOKERS SEEKING CESSATION TREATMENT SO ETHNICITY & DISEASE LA English DT Article DE Nicotine Dependence; Adolescents; Nicotine Replacement Therapy; Treatment; Health Disparities ID AMERICAN TEENAGE SMOKERS; DISPARITIES; DEPENDENCE; HEALTH; PATCH AB Objective: To examine the correlates of prior nicotine replacement therapy (NRT) in an urban sample of adolescent smokers seeking smoking cessation treatment. Design: Adolescents were recruited via radio, TV and print advertisements for participation in treatment studies. Participants completed a structured interview using a prescreeningquestionnaire. Setting: Data were collected via a telephone interview by trained research personnel. Participants: A sample (N=1879) cessation treatment-seeking volunteer boys (38.2%) and girls (61.8%) aged 12 to 17 years, from a diverse ethnic background residing in the Baltimore, Maryland metropolitan area. Interventions: No interventions were used in this observational study. Main Outcome Measures: Use of NRT in adolescents stratified by age, Fagerstrom Test of Nicotine Dependence (FTND), and race/ethnicity. Results: The sample had a mean FIND score of 5.7 (SD = 2.2). About 41% smoked 11 to 20 cigarettes per day. Adolescent smokers who had used NRT were statistically but only marginally older than those who had not (15.9 vs 15.7 years; t-test= 2.60, P=0.01). FTND score, a measure of nicotine dependence, was higher among those who had used NRT (6.0 vs 5.6; t-test= 3.37, P=.001). African American adolescents were less likely to have used NRT than their European American counterparts (33.0% vs 61.2%; chi(2)=16.09, P<.003). After stepwise logistic regression analyses, age, FIND and race/ethnicity remained predictors of NRT use. Conclusion: Our results show differences in NRT use patterns based on age, FTND, and race! ethnicity. European American youths are more likely than their 'other' counterparts to use NRT, after adjusting for age and smoking severity, whereas, African American youth are less likely than their 'other' counterparts to use NRT. These findings suggest racial/ethnic disparities in accessing smoking cessation modalities among adolescents. Further research is needed to fully elucidate factors contributing to these differences in order to facilitate increased smoking cessation rates among all adolescents. (Ethn Dis. 2010;20:180-184) C1 [Botello-Harbaum, Maria] NICHHD, NIH, Intramural Res Program, Bethesda, MD USA. [Schroeder, Jennifer R.; Collins, Charles C.; Moolchan, Eric T.] Natl Inst Drug Abuse, NIH, Intramural Res Program, Bethesda, MD USA. RP Moolchan, ET (reprint author), Alkermes Inc, Clin Sci, 88 Sidney St, Cambridge, MA 02139 USA. EM eric.moolchan@alkermes.com FU National Institute on Drug Abuse; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Health Resources and Services Administration FX This research was supported by the Intramural Research Program of the National Institute on Drug Abuse, the Eunice Kennedy Shriver National Institute of Child Health and Human Development Intramural Research Program, and the Health Resources and Services Administration. We are grateful for the recruitment contributions of NOVA Research and the Matthews Media Group. NR 23 TC 8 Z9 8 U1 1 U2 2 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD SPR PY 2010 VL 20 IS 2 BP 180 EP 184 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 598EJ UT WOS:000277815700016 PM 20503900 ER PT J AU Walitza, S Wendland, JR Gruenblatt, E Warnke, A Sontag, TA Tucha, O Lange, KW AF Walitza, Susanne Wendland, Jens R. Gruenblatt, Edna Warnke, Andreas Sontag, Thomas A. Tucha, Oliver Lange, Klaus W. TI Genetics of early-onset obsessive-compulsive disorder SO EUROPEAN CHILD & ADOLESCENT PSYCHIATRY LA English DT Review DE Obsessive-compulsive disorder; Serotonin; Glutamate transporter gene; Early onset; Brain-derived neurotrophic factor ID 5-HT2A PROMOTER POLYMORPHISM; SEROTONIN TRANSPORTER; TRANSMISSION DISEQUILIBRIUM; PSYCHIATRIC-DISORDERS; PEDIATRIC PROBANDS; FAMILY; ASSOCIATION; ADOLESCENTS; CHILDREN; LINKAGE AB Obsessive-compulsive disorder (OCD) is characterized by recurrent, intrusive and disturbing thoughts as well as by repetitive stereotypic behaviors. Epidemiological data are similar in children and adults, i.e., between 1 and 3% of the general population suffer from OCD. Children with OCD are often seriously impaired in their development. OCD, especially of early onset, has been shown to be familial. Several candidate genes of predominantly neurotransmitter systems have been analyzed and a total of three genome-wide linkage scans have been performed until now. Analyses of candidate genes in linkage regions have not provided evidence for their involvement in OCD, with the exception of the glutamate transporter gene SLC1A1 on 9p24. Genome-wide association analyses are in progress and the results will promote further independent replication studies. The consideration of subtypes regarding age of onset, symptom dimensions and/or comorbid disorders is needed. C1 [Walitza, Susanne; Gruenblatt, Edna] Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland. [Wendland, Jens R.] NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. [Warnke, Andreas] Univ Wurzburg, Dept Child & Adolescent Psychiat & Psychotherapy, Wurzburg, Germany. [Sontag, Thomas A.; Lange, Klaus W.] Univ Regensburg, Dept Expt Psychol, Regensburg, Germany. [Tucha, Oliver] Univ Groningen, Dept Psychol, NL-9712 TS Groningen, Netherlands. RP Walitza, S (reprint author), Univ Zurich, Dept Child & Adolescent Psychiat, Zurich, Switzerland. EM susanne.walitza@kjpdzh.ch RI Wendland, Jens/A-1809-2012; Grunblatt, Edna/A-6762-2016; OI Grunblatt, Edna/0000-0001-8505-7265; Walitza, Susanne/0000-0002-8161-8683 NR 59 TC 36 Z9 37 U1 7 U2 22 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1018-8827 J9 EUR CHILD ADOLES PSY JI Eur. Child Adolesc. Psych. PD MAR PY 2010 VL 19 IS 3 SI SI BP 227 EP 235 DI 10.1007/s00787-010-0087-7 PG 9 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 569WE UT WOS:000275632700005 PM 20213231 ER PT J AU Scuteri, A Najjar, SS Orru', M Usala, G Piras, MG Ferrucci, L Cao, A Schlessinger, D Uda, M Lakatta, EG AF Scuteri, Angelo Najjar, Samer S. Orru', Marco Usala, Gianluca Piras, Maria Grazia Ferrucci, Luigi Cao, Antonio Schlessinger, David Uda, Manuela Lakatta, Edward G. TI The central arterial burden of the metabolic syndrome is similar in men and women: the SardiNIA Study SO EUROPEAN HEART JOURNAL LA English DT Article DE Metabolic syndrome; Ageing; Gender; Arterial stiffness; Carotid IMT ID EARLY CAROTID ATHEROSCLEROSIS; CARDIOVASCULAR-DISEASE; RISK-FACTOR; STIFFNESS; ADULTS; HEALTH; AGE AB We evaluated whether specific clusters of metabolic syndrome (MetS) components differentially impact on arterial structure and function, and whether the impact is similar in men and in women. Components of the MetS and arterial properties were assessed in 6148 subjects, aged 14-102 in a cluster of four towns in Sardinia, Italy. MetS was defined in accordance with the ATP III criteria. Age groups were classified as: < 35, 35-49, 50-64, and >= 65 years. Systolic blood pressure (BP), diastolic BP, pulse pressure, common carotid artery (CCA) diameter, intima-media thickness, distensibility, strain, stiffness index, wall stress, and aortic pulse wave velocity were measured. Common carotid artery plaque was defined as focal encroachment of the arterial wall and CCA calcification as acoustic shadowing. In any age group, subjects with MetS presented thicker, stiffer or less distensible, and wider large arteries than controls. The arterial burden of MetS increased as the number of altered MetS components increased. However, not all MetS components were associated with the same changes in arterial properties. In fact, specific clusters of MetS components, i.e. any combination of altered glucose tolerance, elevated BP, and elevated triglycerides (with or without abdominal obesity), dramatically increased age-associated arterial changes. The impact of MetS on arterial function was similar in men and women. MetS accelerates age-associated arterial changes, even in older persons. However, not all the clusters of MetS components render the same burden on arterial structure and function. C1 [Scuteri, Angelo; Najjar, Samer S.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. [Scuteri, Angelo; Orru', Marco; Usala, Gianluca; Piras, Maria Grazia; Cao, Antonio; Uda, Manuela] Cittadella Univ Monserrato, CNR, INN, I-09042 Cagliari, Italy. [Ferrucci, Luigi] NIA, Longitudinal Study Sect, NIH, Baltimore, MD 21224 USA. [Schlessinger, David] NIA, Genet Lab, NIH, Baltimore, MD 21224 USA. RP Scuteri, A (reprint author), IRCCS, INRCA, UO Geriatria, Via Cassia 1167, I-00189 Rome, Italy. EM angeloelefante@interfree.it OI piras, maria grazia/0000-0001-9004-0900 FU NIA [NO1-AG-1-2109] FX The SardiNIA team was supported by Contract NO1-AG-1-2109 from the NIA. NR 24 TC 39 Z9 40 U1 3 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD MAR PY 2010 VL 31 IS 5 BP 602 EP 613 DI 10.1093/eurheartj/ehp491 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 564UA UT WOS:000275241900020 PM 19942601 ER PT J AU Yang, HP Brinton, LA Platz, EA Lissowska, J Lacey, JV Sherman, ME Peplonska, B Garcia-Closas, M AF Yang, Hannah P. Brinton, Louise A. Platz, Elizabeth A. Lissowska, Jolanta Lacey, James V., Jr. Sherman, Mark E. Peplonska, Beata Garcia-Closas, Montserrat TI Active and passive cigarette smoking and the risk of endometrial cancer in Poland SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE Endometrial cancer; Active smoking; Passive smoking ID NONSMOKING WOMEN; BREAST-CANCER; LUNG-CANCER; TOBACCO; 2-HYDROXYESTRONE; POPULATION; ESTRADIOL; EXPOSURE; ESTROGEN; STATES AB Background: Epidemiological studies have consistently reported that active cigarette smoking is inversely associated with endometrial cancer risk. However, dose-response relationships with quantitative measures of active smoking or passive smoking remain less clear. Methods: Data on lifetime active and passive smoking were collected for 551 endometrial cancer cases and 1925 controls in a population-based case-control study conducted during 2001-2003 in Poland (Warsaw and Lodz). Results: Compared with never active smokers, active current (odds Ratio (OR) = 0.51, 95% Confidence Interval (CI): 0.39, 0.68) and former smokers (OR = 0.60, 95% CI: 0.45, 0.80) were at a statistically significantly decreased risk. We did not observe statistically significant inverse dose-response relationships with increasing exposure with duration and cumulative measures. However, there was some indication that the highest category of number of years (OR = 0.35, 95% CI: 0.23-0.55), intensity (OR = 0.41, 95% CI: 0.24-0.69), and dose (OR = 0.38, 95% CI: 0.24-0.60) of smoking among current smokers had the greatest inverse association compared to never smokers. Our data did not support the presence of an inverse association with passive smoking among never active smokers (OR = 0.92; 95% CI: 0.65, 1.29). Conclusion: Our results support that long-term and heavy smoking among current smokers strongly influence endometrial cancer risk. Published by Elsevier Ltd. C1 [Yang, Hannah P.; Brinton, Louise A.; Lissowska, Jolanta; Lacey, James V., Jr.; Sherman, Mark E.; Garcia-Closas, Montserrat] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. [Yang, Hannah P.; Platz, Elizabeth A.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Lissowska, Jolanta] M Sklodowska Curie Mem Canc Ctr, Dept Canc Epidemiol & Prevent, Warsaw, Poland. [Lissowska, Jolanta] Inst Oncol, Warsaw, Poland. [Peplonska, Beata] Nofer Inst Occupat Med, Dept Occupat & Environm Epidemiol, Lodz, Poland. RP Yang, HP (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS-5034A, Rockville, MD 20852 USA. EM yanghan@mail.nih.gov RI Peplonska, Beata/F-6004-2010; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Lissowska, Jolanta/0000-0003-2695-5799 FU National Cancer Institute, National Institutes of Health FX The authors would like to thank Neonila Szeszenia-Dabrowska of the Nofer Institute of Occupational medicine (Lodz, Poland) and Witold Zatonski of the M. Sklodowska-Curie institute of Oncology and Cancer Centre (Warsaw, Poland) for their contribution to the Polish Endometrial Cancer Study. Pei Chao and Michael Stagner (IMS, Silver Spring, MD, USA) have been invaluable to the management of the study. This work would not be possible without the dedicated efforts of the physicians, nurses, interviewers and study participants. This research was supported by funds from the intramural programme of the National Cancer Institute, National Institutes of Health. NR 30 TC 12 Z9 12 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD MAR PY 2010 VL 46 IS 4 BP 690 EP 696 DI 10.1016/j.ejca.2009.11.015 PG 7 WC Oncology SC Oncology GA 569KE UT WOS:000275594500012 PM 20036529 ER PT J AU van Cruijsen, H Voest, EE Punt, CJA Hoekman, K Witteveen, PO Meijerink, MR Puchalski, TA Robertson, J Saunders, O Jurgensmeier, JM van Herpen, CML Giaccone, G AF van Cruijsen, Hester Voest, Emile E. Punt, Cornelis J. A. Hoekman, Klaas Witteveen, Petronella O. Meijerink, Martijn R. Puchalski, Thomas A. Robertson, Jane Saunders, Owain Jurgensmeier, Juliane M. van Herpen, Carla M. L. Giaccone, Giuseppe TI Phase I evaluation of cediranib, a selective VEGFR signalling inhibitor, in combination with gefitinib in patients with advanced tumours SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE VEGFR-1; VEGFR-2; VEGFR-3; EGFR; Angiogenesis inhibitors; Clinical trial; Phase I ID ENDOTHELIAL GROWTH-FACTOR; CELL LUNG-CANCER; TYROSINE KINASE INHIBITOR; FACTOR RECEPTOR; SOLID TUMORS; TRIAL; CARCINOMA; BEVACIZUMAB; SUNITINIB; ERLOTINIB AB Aim: Cediranib is a highly potent inhibitor of vascular endothelial growth factor receptor (VEGFR) signalling. Preclinical and clinical data suggest that inhibition of the VEGFR and epidermal growth factor receptor (EGFR) pathways may be synergistic. Combination treatment with cediranib and gefitinib, an EGFR signalling inhibitor, was evaluated in patients with advanced solid tumours. Patients and methods: Ninety patients received treatment in this four-part, open-label study (NCT00502060). The patients received once-daily oral doses of cediranib (20-45 mg) and gefitinib 250 mg (part A1; n = 16) or 500 mg (part B1; n = 44). A cohort expansion phase investigated the potential pharmacokinetic interaction of cediranib 30 mg with gefitinib 250 mg (part A2; n = 15) or 500 mg (part B2; n = 15). The primary objective was to assess the safety and tolerability of cediranib with gefitinib. Secondary assessments included pharmacokinetics, efficacy and pharmacodynamics. Results: Combination treatment was generally well tolerated; the protocol-defined maximum-tolerated dose of cediranib was 30 mg/day with gefitinib 250 mg/day (part Al) and cediranib 45 mg/day was the maximum dose investigated with gefitinib 500 mg/day (part B1). The most common adverse events were diarrhoea (84 [93%]), anorexia (63 [70%]) and fatigue (60 [67%]). Cediranib pharmacokinetic parameters were not substantially different when given alone or in combination with gefitinib. Gefitinib pharmacokinetic parameters were similar to those seen previously with gefitinib monotherapy. Efficacy results included eight (9%) confirmed partial responses (6 renal; 1 lung; 1 osteosarcoma) and 38 (42%) patients with stable disease. Pharmacodynamic assessments demonstrated changes in levels of VEGF and soluble VEGFR-2 following treatment. Conclusions: Combination treatment was generally well tolerated and showed encouraging antitumour activity in patients with advanced solid tumours. These results merit further exploration. (C) 2009 Elsevier Ltd. All rights reserved. C1 [van Cruijsen, Hester; Hoekman, Klaas; Giaccone, Giuseppe] Vrije Univ Amsterdam, Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Meijerink, Martijn R.] Vrije Univ Amsterdam, Med Ctr, Dept Radiol, Amsterdam, Netherlands. [Voest, Emile E.; Witteveen, Petronella O.] Univ Med Ctr Utrecht, Dept Med Oncol, Utrecht, Netherlands. [Punt, Cornelis J. A.; van Herpen, Carla M. L.] Radboud Univ Nijmegen, Med Ctr, Dept Med Oncol, NL-6525 ED Nijmegen, Netherlands. [Puchalski, Thomas A.] AstraZeneca, Wilmington, DE USA. [Robertson, Jane; Saunders, Owain; Jurgensmeier, Juliane M.] AstraZeneca, Macclesfield, Cheshire, England. RP Giaccone, G (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bldg 10,Room 12N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Juergensmeier, Juliane/I-4117-2013; Herpen, Carla/N-3576-2014; Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Meijerink, Martijn/0000-0002-1500-7294 FU AstraZeneca FX This study, including editorial assistance provided by Dr. Jen Lewis of Mudskipper Bioscience, was supported financially by AstraZeneca. NR 42 TC 34 Z9 34 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD MAR PY 2010 VL 46 IS 5 BP 901 EP 911 DI 10.1016/j.ejca.2009.12.023 PG 11 WC Oncology SC Oncology GA 584MJ UT WOS:000276755800017 PM 20061136 ER PT J AU Nacci, C Addabbo, F Tarquinio, M De Benedictis, L Carratu, MR Quon, MJ Montagnani, M AF Nacci, C. Addabbo, F. Tarquinio, M. De Benedictis, L. Carratu, M. R. Quon, M. J. Montagnani, M. TI Globular and full-length adiponectin differentially modulate overexpression of cyclo-oxygenase 2 in endothelium SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Meeting Abstract C1 [Nacci, C.; Addabbo, F.; Tarquinio, M.; De Benedictis, L.; Carratu, M. R.; Montagnani, M.] Dept Pharmacol & Human Physiol, Bari, Italy. [Quon, M. J.] NIH, NCCAM, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD MAR PY 2010 VL 40 SU 1 BP 9 EP 9 PG 1 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 552BF UT WOS:000274260200026 ER PT J AU Brock, KE Graubard, BI Fraser, DR Weinstein, SJ Stolzenberg-Solomon, RZ Lim, U Tangrea, JA Virtamo, J Ke, L Snyder, K Albanes, D AF Brock, K. E. Graubard, B. I. Fraser, D. R. Weinstein, S. J. Stolzenberg-Solomon, R. Z. Lim, U. Tangrea, J. A. Virtamo, J. Ke, L. Snyder, K. Albanes, D. TI Predictors of vitamin D biochemical status in a large sample of middle-aged male smokers in Finland SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE vitamin D (25(OH) D) status; predictors of vitamin D deficiency; vitamin D intake; fish intake; physical activity; BMI ID YOUNG FINNISH MEN; 25-HYDROXYVITAMIN D; SERUM-LEVELS; D DEFICIENCY; CANCER-RISK; PROSTATE-CANCER; SUBSEQUENT RISK; D INSUFFICIENCY; BONE TURNOVER; POPULATION AB Background/Objectives: As vitamin D deficiency is considered to be more common in regions with little solar ultraviolet (UV) light in winter, the aim of this study was to analyze predictors of vitamin D status by season within a large sample of male smokers from Finland, a country where there is negligible solar UV light in winter. Subjects/Methods: Vitamin D ( measured by 25-hydroxyvitamin D (25(OH) D) nmol/l) and other serum constituents were assayed. Measured anthropometry, and self-reported dietary intake and physical activity (PA) were obtained and analyzed using stepwise multiple linear and logistic regression in 2271 middle-aged Finnish male smokers. Results: In all, 27% of the population in winter and 17% in summer had serum 25( OH) D levels of <25 nmol/l, respectively. In summer, in multiple logistic regression analyses with adjustment for confounding and other predictors, high vitamin D intake ( odds ratios ( OR) 3.6; 95% confidence interval (CI) 1.5-8.5), some leisure time PA ( OR 2.0; 95% CI 1.3-3.1) and having a body mass index (BMI) of >= 21 kg/m(2) compared with <21 kg/m(2) ( OR 2.6; 95% CI 1.3-5.0), were associated with 25(OH) D >= 25 nmol/l. In winter, additional modifiable factors were occupational PA ( OR 1.6; 95% CI 1.1-2.5) and high fish ( OR 3.1; 95% CI 1.7-6.2) or poultry consumption ( OR 1.7; 95% CI 1.2-2.5). Predictors from linear regression analyses of continuous levels of 25( OH) D were similar to the logistic regression analyses of 25( OH) D >= 25 nmol/l. Conclusion: In this Finnish sample more vitamin D intake, PA and having a BMI of >= 21 may have important modifiable roles in maintaining an adequate vitamin D status. European Journal of Clinical Nutrition ( 2010) 64, 280-288; doi:10.1038/ejcn.2009.137; published online 6 January 2010 C1 [Brock, K. E.] Univ Sydney, Fac Hlth Sci, Sydney, NSW 2141, Australia. [Graubard, B. I.; Weinstein, S. J.; Stolzenberg-Solomon, R. Z.; Albanes, D.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Fraser, D. R.] Univ Sydney, Fac Vet Sci, Sch Anim Sci, Sydney, NSW 2141, Australia. [Lim, U.] Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. [Tangrea, J. A.] NCI, Canc Prevent Div, NIH, DHHS, Bethesda, MD 20892 USA. [Virtamo, J.] Natl Inst Hlth & Welf, Dept Chron Dis Prevent, Helsinki, Finland. [Ke, L.] George Inst, Dept Res & Dev, Beijing, Peoples R China. [Snyder, K.] Informat Management Serv Inc, Silver Spring, MD USA. RP Brock, KE (reprint author), Univ Sydney, Fac Hlth Sci, Room G204,POB 170 Lidcombe 1825,East St,Lidcombe, Sydney, NSW 2141, Australia. EM Kaye.Brock@Sydney.edu.au RI Albanes, Demetrius/B-9749-2015; Osborne, Nicholas/N-4915-2015 OI Osborne, Nicholas/0000-0002-6700-2284 FU NIH; National Cancer Institute, Department of Health and Human Services [N01-CN-45165, N01-RC-45035, N01-RC-37004] FX This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. In addition, this research was supported by the US Public Health Service contracts N01-CN-45165, N01-RC-45035 and N01-RC-37004 from the National Cancer Institute, Department of Health and Human Services. All authors reviewed the final paper before submission. NR 50 TC 25 Z9 25 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD MAR PY 2010 VL 64 IS 3 BP 280 EP 288 DI 10.1038/ejcn.2009.137 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 563WX UT WOS:000275168400008 PM 20051977 ER PT J AU Avery, CL Mills, KT Chambless, LE Chang, PP Folsom, AR Mosley, TH Ni, HY Rosamond, WD Wagenknecht, L Wood, J Heiss, G AF Avery, Christy L. Mills, Katherine T. Chambless, Lloyd E. Chang, Patricia P. Folsom, Aaron R. Mosley, Thomas H. Ni, Hanyu Rosamond, Wayne D. Wagenknecht, Lynne Wood, Joy Heiss, Gerardo TI Long-term association between self-reported signs and symptoms and heart failure hospitalizations: the Atherosclerosis Risk In Communities (ARIC) Study SO EUROPEAN JOURNAL OF HEART FAILURE LA English DT Article DE Epidemiology; Heart failure; Gothenburg score; Surveillance ID VENTRICULAR SYSTOLIC DYSFUNCTION; GENERAL-POPULATION; MEN BORN; PREVALENCE; SURVIVAL; CARE; EPIDEMIOLOGY; CONCORDANCE; VALIDATION; ROTTERDAM AB Although studies of the accuracy of heart failure (HF) classification scoring systems are available, few have examined their performance when restricted to self-reported items. We evaluated the association between a simplified version of the Gothenburg score, a validated HF score comprised of cardiac and pulmonary signs and symptoms and medication use, and incident HF hospitalizations in 15 430 Atherosclerosis Risk in Communities (ARIC) Study participants. Gothenburg scores (range: 0-3) were constructed using self-reported items obtained at study baseline (1987-89). Incident HF hospitalization over 14.7 years of follow-up was defined as the first identified hospitalization with an ICD-9 discharge code of 428 (n = 1668). Self-reported Gothenburg scores demonstrated very high agreement with the original metric comprised of self-reported and clinical measures and were directly associated with incident HF hospitalizations: [score = 1: hazard rate ratio (HRR) = 1.23 (1.07-1.42); score = 2: HRR = 2.17 (1.92-2.43); score = 3: HRR = 3.98 (3.37-4.70)]. In a population-based cohort, self-reported Gothenburg criteria items were associated with hospitalized HF over a prolonged follow-up time. The association was also consistent across groups defined by sex and race, suggesting that this simple score deserves further study as a screening tool for the identification of individuals at high risk of HF in resource-limited settings. C1 [Avery, Christy L.; Mills, Katherine T.; Rosamond, Wayne D.; Wood, Joy; Heiss, Gerardo] Univ N Carolina, Dept Epidemiol, Bank Amer Ctr, Chapel Hill, NC 27514 USA. [Chambless, Lloyd E.] Univ N Carolina, Dept Biostat, Chapel Hill, NC 27514 USA. [Chang, Patricia P.] Univ N Carolina, Dept Med, Chapel Hill, NC 27514 USA. [Folsom, Aaron R.] Univ Minnesota, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Mosley, Thomas H.] Univ Mississippi, Dept Med, Jackson, MS 39216 USA. [Ni, Hanyu] NHLBI, Bethesda, MD 20892 USA. [Wagenknecht, Lynne] Wake Forest Univ Hlth Sci, Div Publ Hlth Sci, Winston Salem, NC USA. RP Avery, CL (reprint author), Univ N Carolina, Dept Epidemiol, Bank Amer Ctr, 137 E Franklin St,Suite 306, Chapel Hill, NC 27514 USA. EM christy_avery@unc.edu FU National Heart, Lung, and Blood Institute [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022] FX This work was supported by National Heart, Lung, and Blood Institute contracts (grant numbers N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, and N01-HC-55022). NR 32 TC 9 Z9 9 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1388-9842 J9 EUR J HEART FAIL JI Eur. J. Heart Fail. PD MAR PY 2010 VL 12 IS 3 BP 232 EP 238 DI 10.1093/eurjhf/hfp203 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 558WG UT WOS:000274778600006 PM 20097681 ER PT J AU Meng, GX Strober, W AF Meng, Guangxun Strober, Warren TI New insights into the nature of autoinflammatory diseases from mice with Nlrp3 mutations SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Inflammasome; Inflammation; IL-1; Th17 ID NALP3 INFLAMMASOME; CIAS1 MUTATIONS; INTERLEUKIN-1-BETA RELEASE; P2X(7) RECEPTOR; KEY PLAYER; CELL-DEATH; T-CELLS; ACTIVATION; CASPASE-1; ATP AB Mutations in the Nlrp3 (CIAS1, cryopyrin) gene are associated with cryopyrin-associated periodic syndrome, autoinflammatory diseases characterized by excessive IL-1 production and neutrophilia in blood and tissues. Recent studies with gene-targeted mice expressing mutations homologous to those found in cryopyrin-associated periodic syndrome patients have advanced the understanding of NLRP3-associated autoinflammation. In this Viewpoint, we will discuss the mechanisms of NLRP3 inflammasome activation and its induction of Th17-cell-dominant immunologic responses. C1 [Meng, Guangxun; Strober, Warren] NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, Host Def Lab, NIH, CRC Bldg 10,Room 5W3940,10 Ctr Dr,9000 Rockville, Bethesda, MD 20892 USA. EM wstrober@niaid.nih.gov OI 孟, 广勋/0000-0002-4253-9675 FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We apologize to those authors whose work could not be cited due to space limitations. NR 35 TC 9 Z9 9 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD MAR PY 2010 VL 40 IS 3 BP 649 EP 653 DI 10.1002/eji.200940191 PG 5 WC Immunology SC Immunology GA 573SQ UT WOS:000275935600015 PM 20201022 ER PT J AU Bolinger, B Engeler, D Krebs, P Miller, S Firner, S Hoffmann, M Palmer, DC Restifo, NP Tian, YH Clavien, PA Ludewig, B AF Bolinger, Beatrice Engeler, Daniel Krebs, Philippe Miller, Simone Firner, Sonja Hoffmann, Matthias Palmer, Douglas C. Restifo, Nicholas P. Tian, Yinghua Clavien, Pierre-Alain Ludewig, Burkhard TI IFN-gamma-receptor signaling ameliorates transplant vasculopathy through attenuation of CD8(+) T-cell-mediated injury of vascular endothelial cells SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE Chronic rejection; CTL; IFN-gamma-receptor; PD-L1; Transplantation; Vascular endothelial cells ID CARDIAC ALLOGRAFT VASCULOPATHY; CORONARY-ARTERY-DISEASE; VERSUS-HOST-DISEASE; INTERFERON-GAMMA; MOUSE HEARTS; DENDRITIC CELLS; IMMUNOLOGICAL IGNORANCE; MONOCLONAL-ANTIBODY; ANTIVIRAL IMMUNITY; GRAFT-REJECTION AB Occlusive transplant vasculopathy (TV) is the major cause for chronic graft rejection. Since endothelial cells (EC) are the first graft cells encountered by activated host lymphocytes, it is important to delineate the molecular mechanisms that coordinate the interaction of EC with activated T cells. Here, the interaction of CD8(+) T cells with Ag-presenting EC in vivo was examined using a transgenic heart transplantation model with beta-galactosidase (beta-gal) expression exclusively in EC (Tie2-LacZ hearts). We found that priming with beta-gal peptide-loaded DC failed to generate a strong systemic IFN-gamma response, but elicited pronounced TV in both IFN-gamma receptor (IFNGR)-competent, and ifngr(-/-) Tie2-LacZ hearts. In contrast, stimulation of EC-specific CD8(+) T cells with beta-gal-recombinant mouse cytomegalovirus (MCMV-LacZ) in recipients of ifngr(+/+) Tie2-LacZ hearts did not precipitate significant TV. However, MCMV-LacZ infection of recipients of ifngr(-/-) Tie2-LacZ hearts led to massive activation of beta-gal-specific CD8 T cells, and led to development of fulminant TV. Further analyses revealed that the strong systemic IFN-gamma "storm" associated with MCMV infection induced upregulation of programmed death-1 ligand 1 (PD-L1) on EC, and subsequent attenuation of programmed death-1 (PD-1)-expressing EC-specific CD8(+) T cells. Thus, IFNGR signaling in ECs activates a potent peripheral negative feedback circuit that protects vascularized grafts from occlusive TV. C1 [Hoffmann, Matthias] Hannover Med Sch, Dept Visceral Surg, D-3000 Hannover, Germany. [Palmer, Douglas C.; Restifo, Nicholas P.] NCI, NIH, Bethesda, MD 20892 USA. [Tian, Yinghua; Clavien, Pierre-Alain] Univ Zurich Hosp, Dept Visceral Surg, CH-8091 Zurich, Switzerland. [Ludewig, Burkhard] Univ Zurich, VetSuisse Fac, Zurich, Switzerland. [Bolinger, Beatrice; Engeler, Daniel; Krebs, Philippe; Miller, Simone; Firner, Sonja; Ludewig, Burkhard] Kantonal Hosp St Gallen, Inst Immunobiol, St Gallen, Switzerland. RP Ludewig, B (reprint author), Kantonsspital St Gallen, Inst Immunobiol, Rorschacherstr 95, CH-9007 St Gallen, Switzerland. EM burkhard.ludewig@kssg.ch RI Restifo, Nicholas/A-5713-2008; Palmer, Douglas/B-9454-2008; Krebs, Philippe/A-3449-2012 OI Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580; Krebs, Philippe/0000-0003-4918-6654 FU Swiss National Science Foundation; Velux Foundation; Kanton of St. Gallen FX We would like to thank Silvia Behnke, Andre Fitsche, and Karin Eugster for help with immunohistochemistry, and Luisa Cervantes-Barragan and Tobias Junt for critical reading of the manuscript. The project received support from the Swiss National Science Foundation (to B. L.), the Velux Foundation (to B. L.), and the Kanton of St. Gallen (to B. L.). NR 59 TC 11 Z9 11 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD MAR PY 2010 VL 40 IS 3 BP 733 EP 743 DI 10.1002/eji.200939706 PG 11 WC Immunology SC Immunology GA 573SQ UT WOS:000275935600026 PM 20049875 ER PT J AU Scheidemann, F Therrien, JP Vogel, J Pfutzner, W AF Scheidemann, Frank Therrien, Jean-Philippe Vogel, Jon Pfuetzner, Wolfgang TI In vivo synthesis and secretion of erythropoietin by genetically modified primary human keratinocytes grafted onto immunocompromised mice SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE erythropoietin; gene therapy; keratinocyte; selection; skin ID MULTIDRUG-RESISTANCE GENE; PRODUCT P-GLYCOPROTEIN; HEMATOPOIETIC-CELLS; SYSTEMIC DELIVERY; GROWTH-HORMONE; RENAL-FAILURE; EPIDERMAL-KERATINOCYTES; MOUSE ERYTHROPOIETIN; BICISTRONIC VECTORS; HEMOPHILIA-B AB P>Background: The skin is an easily accessible tissue with a high blood flow facilitating the distribution of secreted peptides. These features make it a very intriguing target to serve as a biofactory releasing a systemically needed factor, such as erythropoietin (EPO). Methods: To evaluate the potential of human keratinocytes (KC) to systemically synthesize EPO, EPO-transduced KC were grafted onto immunocompromised mice and EPO secretion was followed by serum ELISA. Furthermore, we assessed if topical colchicine application would select for enriched percentages of KC expressing the multi-drug resistance (MDR) gene as a selectable gene connected to the EPO gene (measured by fluorescence-activated cell sorting (FACS)-analysis) and result in enhanced EPO production (determined by ELISA). Results: Transduced KC showed stable EPO production in vivo during a 6-month observation period, pointing to engraftment of EPO-secreting KC progenitor cells. When adding colchicines the number of EPO/MDR+ KC were significantly enriched, both in skin grafts (in vivo) and in skin equivalents (in vitro). Of note, this did not result in enhanced EPO production. Rather, while EPO secretion was substantially increased in transduced KC grown as monolayers and selected with colchicine, it was reduced by more than 50% in both colchicine-treated skin grafts and skin equivalents. Conclusion: Keratinocytes carry the potential to serve as a genetically modified biofactory synthesizing human EPO. In vivo gene selection does not allow to select for increased EPO secretion, most likely because of altered secretory activity of transduced KC in the stratified, differentiated epidermis. Thus, further studies are necessary to optimize the release of EPO by genetically modified KC. C1 [Pfuetzner, Wolfgang] Univ Marburg, Dept Dermatol & Allergol, D-35037 Marburg, Germany. [Scheidemann, Frank; Pfuetzner, Wolfgang] Univ Munich, Dept Dermatol & Allergol, Munich, Germany. [Therrien, Jean-Philippe; Vogel, Jon] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Pfutzner, W (reprint author), Univ Marburg, Dept Dermatol & Allergol, Deutsch Str 9-11, D-35037 Marburg, Germany. EM wpfuetzn@med.uni-marburg.de FU DFG [Pf 344/2-2]; Canadian Institutes of Health Research (CIHR) FX This work was supported by DFG Grant No. Pf 344/2-2. J.-P. Therrien is a recipient of a postdoctoral fellowship from the Canadian Institutes of Health Research (CIHR). We thank Daniela Holler-Obrigkeit, Department of Dermatology, University of Aachen, Germany, for helpful advice optimizing culture conditions for raft cultures and Ines Nachtigall for expert technical assistance. NR 63 TC 2 Z9 2 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD MAR PY 2010 VL 19 IS 3 BP 289 EP 296 DI 10.1111/j.1600-0625.2009.00984.x PG 8 WC Dermatology SC Dermatology GA 554RL UT WOS:000274452000008 PM 19889025 ER PT J AU Pascual, I Larrayoz, IM Campos, MM Rodriguez, IR AF Pascual, Iranzu Larrayoz, Ignacio M. Campos, Maria M. Rodriguez, Ignacio R. TI Methionine sulfoxide reductase B2 is highly expressed in the retina and protects retinal pigmented epithelium cells from oxidative damage SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE retina; macula; methionine sulfoxide reductase B2; mitochondria; antioxidant ID MACULAR DEGENERATION; INDUCED INFLAMMATION; ANTIOXIDANT DEFENSE; KNOCKOUT MOUSE; LENS CELLS; STRESS; MSRA; GENE; OVEREXPRESSION; RESISTANCE AB Methionine sulfoxide reductase B2 (MSRB2) is a mitochondrial enzyme that converts methionine sulfoxide (R) enantiomer back to methionine. This enzyme is suspected of functioning to protect mitochondrial proteins from oxidative damage. In this study we report that the retina is one of the human tissues with highest levels of MSRB2 mRNA expression. Other tissues with high expression were heart, kidney and skeletal muscle. Overexpression of an MSRB2-GFP fusion protein increased the MSR enzymatic activity three-fold in stably transfected cultured RPE cells. This overexpression augmented the resistance of these cells to the toxicity induced by 7-ketocholesterol, tent-butyl hydroperoxide and all-trans retinoic acid. By contrast, knockdown of MSRB2 by a miRNA in stably transfected cells did not convey increased sensitivity to the oxidative stress. In the monkey retina MSRB2 localized to the ganglion cell layer (GLC), the outer plexiform layer (OPL) and the retinal pigment epithelium (RPE). MSRB2 expression is most pronounced in the OPL of the macula and foveal regions suggesting an association with the cone synaptic mitochondria. Our data suggests that MSRB2 plays an important function in protecting cones from multiple type of oxidative stress and may be critical in preserving central vision. (C) Published by Elsevier Ltd. C1 [Pascual, Iranzu; Larrayoz, Ignacio M.; Rodriguez, Ignacio R.] NEI, Mech Retinal Dis Sect, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Campos, Maria M.] NEI, Image Core Facil, NIH, Bethesda, MD 20892 USA. RP Rodriguez, IR (reprint author), NEI, Mech Retinal Dis Sect, Retinal Cell & Mol Biol Lab, NIH, 6 Ctr Dr,MSC 0608,Bldg 6,Rm 136, Bethesda, MD 20892 USA. EM pascuali@nei.nih.gov; larrayozi@nei.nih.gov; camposm@nei.nih.gov; rodriguezi@nei.nih.gov RI Larrayoz, Ignacio/I-5613-2012 OI Larrayoz, Ignacio/0000-0003-1629-152X FU Intramural NIH HHS [ZIA EY000307-15] NR 54 TC 3 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 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD MAR PY 2010 VL 90 IS 3 BP 420 EP 428 DI 10.1016/j.exer.2009.12.003 PG 9 WC Ophthalmology SC Ophthalmology GA 572QO UT WOS:000275848100008 PM 20026324 ER PT J AU Kisby, GE Kohama, SG Olivas, A Churchwell, M Doerge, D Spangler, E de Cabo, R Ingram, DK Imhof, B Bao, GB Kow, YW AF Kisby, Glen E. Kohama, Steven G. Olivas, Antoinette Churchwell, Mona Doerge, Daniel Spangler, Edward de Cabo, Rafael Ingram, Donald K. Imhof, Barry Bao, Gaobin Kow, Yoke W. TI Effect of caloric restriction on base-excision repair (BER) in the aging rat brain SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Exonuclease; Apyrimidinic/apurinic endonuclease (APE); DNA polymerase beta; DNA ligase III; Frontal/parietal cortex; 8-Oxodeoxyguanosine ID OXIDATIVE DNA-DAMAGE; SENESCENCE-ACCELERATED MICE; ALZHEIMERS-DISEASE; DIETARY RESTRICTION; MITOCHONDRIAL-DNA; GENOMIC STABILITY; AGE; STRESS; MOUSE; ENDONUCLEASE AB Apyrimidinic/apurinic endonuclease (APE) is a key protein involved in the base-excision DNA repair (BER) pathway of oxidative DNA lesions. Using a novel oligonucleotide substrate, we demonstrate that APE activity in the frontal/parietal cortex (F/PCTX), cerebellum, brainstem, midbrain and hypothalamus declined with age in rats on an ad libitum (AL) diet. In contrast, APE activity for these brain regions was similar to 1.5-3 times higher in young, caloric restricted (CR) rats. Despite continuous CR treatment in all animals since six weeks of age, APE activity in the CR group started to decline by middle-age and continued into old age. However, CR maintained APE activity at a level that was significantly higher than that in AL rats across age and in the brain regions examined. Because Western analysis of APE, DNA polymerase 0 and DNA ligase III levels in the F/PCTX of both CR and AL rats remained unchanged with age, this suggests that the increased APE activity in CR rats is the result of differential post-translational modification of APE. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kisby, Glen E.; Olivas, Antoinette] Oregon Hlth & Sci Univ, Ctr Res Occupat & Environm Toxicol, Portland, OR 97239 USA. [Kohama, Steven G.] Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Portland, OR 97239 USA. [Churchwell, Mona; Doerge, Daniel] Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. [Spangler, Edward; de Cabo, Rafael; Ingram, Donald K.] NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. [Imhof, Barry; Bao, Gaobin; Kow, Yoke W.] Emory Univ, Sch Med, Dept Radiat Oncol, Atlanta, GA 30322 USA. RP Kisby, GE (reprint author), Oregon Hlth & Sci Univ, Ctr Res Occupat & Environm Toxicol, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM kisby@ohsu.edu RI de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU NIH [CA90860]; NIEHS [PO1 ES011163, RR00163, DAMD 17-98-1-8625] FX We thank Dr. Vilhelm Bohr for his valuable comments on the manuscript. This work is supported by NIH CA90860 (YWK), NIEHS PO1 ES011163 (YWK), RR00163 (SGK) and DAMD 17-98-1-8625 (GK). NR 48 TC 10 Z9 11 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD MAR PY 2010 VL 45 IS 3 BP 208 EP 216 DI 10.1016/j.exger.2009.12.003 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 574KD UT WOS:000275987100007 PM 20005284 ER PT J AU Sun, XP Seeberger, J Alberico, T Wang, CX Wheeler, CT Schauss, AG Zou, S AF Sun, Xiaoping Seeberger, Jeanne Alberico, Thomas Wang, Chunxu Wheeler, Charles T. Schauss, Alexander G. Zou, Sige TI Acai palm fruit (Euterpe oleracea Mart.) pulp improves survival of flies on a high fat diet SO EXPERIMENTAL GERONTOLOGY LA English DT Article DE Lifespan; Aging intervention; Euterpe oleracea Mart; Phytochemical; Phosphoenolpyruvate carboxykinase; Oxidative stress ID ABSORBENCY CAPACITY ASSAY; LIFE-SPAN; SUPEROXIDE-DISMUTASE; CALORIE RESTRICTION; DROSOPHILA; ANTIOXIDANT; CANCER; BERRY; FLUORESCEIN; POLYPHENOLS AB Reducing oxidative damage is thought to be an effective aging intervention. Acai, a fruit indigenous to the Amazon, is rich in phytochemicals that possesses high anti-oxidant activities, and has anti-inflammatory, anti-cancer and anti-cardiovascular disease properties. However, little is known about its potential anti-aging properties especially at the organismal level. Here we evaluated the effect of acai pulp on modulating lifespan in Drosophila melanogaster. We found that acai supplementation at 2% in the food increased the lifespan of female flies fed a high fat diet compared to the non-supplemented control. We measured transcript changes induced by acai for age-related genes. Although transcript levels of most genes tested were not altered, acai increased the transcript level of 1(2)efl, a small heat-shock-related protein. and two detoxification genes, GstD1 and MtnA, while decreasing the transcript level of phosphoenolpyruvate carboxykinase (Pepck), a key gene involved in gluconeogenesis. Furthermore, acai increased the lifespan of oxidative stressed females caused by sod1 RNAi. This suggests that acai improves survival of flies fed a high fat diet through activation of stress response pathways and suppression of Pepck expression. Acai has the potential to antagonize the detrimental effect of fat in the diet and alleviate oxidative stress in aging. Published by Elsevier Inc. C1 [Sun, Xiaoping; Seeberger, Jeanne; Alberico, Thomas; Wang, Chunxu; Wheeler, Charles T.; Zou, Sige] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Schauss, Alexander G.] AIBMR Life Sci Inc, Puyallup, WA 98373 USA. RP Zou, S (reprint author), NIA, Lab Expt Gerontol, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM zous@grc.nia.nih.gov FU National Institute on Aging, National Institutes of Health, USA FX We thank Edward Spangler and Luc Poirier for critical reading of the manuscript and valuable comments, and thank the Natural and Medicinal Products Division of AIBMR Life Sciences, Inc. for generously providing acai samples. This work was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, USA. NR 50 TC 48 Z9 49 U1 1 U2 13 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0531-5565 J9 EXP GERONTOL JI Exp. Gerontol. PD MAR PY 2010 VL 45 IS 3 BP 243 EP 251 DI 10.1016/j.exger.2010.01.008 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 574KD UT WOS:000275987100010 PM 20080168 ER PT J AU Jacobi, A Thieme, S Lehmann, R Ugarte, F Malech, HL Koch, S Thiede, C Muller, K Bornhauser, M Ryser, M Brenner, S AF Jacobi, Angela Thieme, Sebastian Lehmann, Romy Ugarte, Fernando Malech, Harry L. Koch, Sina Thiede, Christian Mueller, Katrin Bornhaeuser, Martin Ryser, Martin Brenner, Sebastian TI Impact of CXCR4 inhibition on FLT3-ITD-positive human AML blasts SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; STEM-CELLS; PERIPHERAL-BLOOD; FLT3 MUTATIONS; FLT3-ACTIVATING MUTATIONS; HEMATOPOIETIC-CELLS; PROGENITOR CELLS; UP-REGULATION; ENGRAFTMENT AB Objective. Internal tandem duplication (ITD) mutations of the FLT3 receptor are associated with a high incidence of relapse in acute myeloid leukemia (AML). Expression of the CXCR4 receptor in FLT3-ITD-positive AML is correlated with poor outcome, and inhibition of CXCR4 was shown to sensitize AMI, blasts toward chemotherapy. The aim of this study was to evaluate the impact of FLT3-ITD on cell proliferation and CXCR4-dependent migration in human hematopoietic progenitor cells and to investigate their response to CXCR4 inhibition. Materials and Methods. We use primary blasts from patients with FLT3-ITD or FLT3 wild-type AML. In addition, human CD34(+) hematopoietic progenitor cells were transduced to >70% with retroviral vectors containing human FLT3-ITD. Results. We found that FLT3-ITD transgene overexpressing human hematopoietic progenitor cells show strongly reduced migration toward stromal-derived factor-1 in vitro and display significantly reduced bone marrow homing in nonobese diabetic severe combined immunodeficient mice. Cocultivation of FLT3-ITD-positive AML blasts or hematopoietic progenitor cells oil bone marrow stromal cells resulted in a strong proliferation advantage and increased early cobblestone area-forming cells compared to FLT3-wild-type AML blasts. Addition of the CXCR4 inhibitor AMD3100 to the coculture significantly reduced both cobblestone area-forming cells and proliferation of FLT3-ITD-positive cells, but did not affect FLT3-wild-type cells-highlighting the critical interaction between CXCR4 and FLT3-ITD. Conclusion. CXCR4 inhibition to decrease cell proliferation and to control the leukemic burden play provide a novel therapeutic strategy in patients with advanced FLT3-ITD-positive AML. (C) 2010 ISEH - Society for Hematology and Stern Cells. Published by Elsevier Inc. C1 [Jacobi, Angela; Thieme, Sebastian; Lehmann, Romy; Ugarte, Fernando; Ryser, Martin; Brenner, Sebastian] Univ Clin Carl Gustav Carus Dresden, Dept Pediat, D-01307 Dresden, Germany. [Thieme, Sebastian; Thiede, Christian; Bornhaeuser, Martin; Brenner, Sebastian] Tech Univ Dresden, DFG Res Ctr & Cluster Excellence Regenerat Therap, Dresden, Germany. [Malech, Harry L.] NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Koch, Sina; Thiede, Christian; Mueller, Katrin; Bornhaeuser, Martin] Univ Clin Carl Gustav Carus Dresden, Med Clin 1, D-01307 Dresden, Germany. RP Brenner, S (reprint author), Univ Clin Carl Gustav Carus Dresden, Dept Pediat, Bldg 21,Fetscherstr 74, D-01307 Dresden, Germany. RI Brenner, Sebastian/D-7456-2013; OI Malech, Harry/0000-0001-5874-5775 FU Deutsche Forschungsgemeinschaft (Bonn, Germany) [SFB 655] FX This work was supported by the 'Deutsche Forschungsgemeinschaft' (Bonn, Germany) (SFB 655 to CT, MB and SB) NR 27 TC 14 Z9 14 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD MAR PY 2010 VL 38 IS 3 BP 180 EP 190 DI 10.1016/j.exphem.2009.12.003 PG 11 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 566JC UT WOS:000275364900003 PM 20035824 ER PT J AU Wirth, EK Conrad, M Winterer, J Wozny, C Carlson, BA Roth, S Schmitz, D Bornkamm, GW Coppola, V Tessarollo, L Schomburg, L Kohrle, J Hatfield, DL Schweizer, U AF Wirth, Eva K. Conrad, Marcus Winterer, Jochen Wozny, Christian Carlson, Bradley A. Roth, Stephan Schmitz, Dietmar Bornkamm, Georg W. Coppola, Vincenzo Tessarollo, Lino Schomburg, Lutz Koehrle, Josef Hatfield, Dolph L. Schweizer, Ulrich TI Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration SO FASEB JOURNAL LA English DT Article DE selenium; parvalbumin; excitability; schizophrenia; gamma oscillation ID APOLIPOPROTEIN-E RECEPTOR-2; NEUROLOGICAL DYSFUNCTION; SELENIUM DEFICIENCY; BRAIN-DEVELOPMENT; TARGET TISSUES; MICE; MOUSE; GENE; SURVIVAL; SELENOCYSTEINE AB Cerebral selenium (Se) deficiency is associated with neurological phenotypes including seizures and ataxia. We wanted to define whether neurons require selenoprotein expression and which selenoproteins are most important, and explore the possible pathomechanism. Therefore, we abrogated the expression of all selenoproteins in neurons by genetic inactivation of the tRNA[Ser](Sec) gene. Cerebral expression of selenoproteins was significantly diminished in the mutants, and histological analysis revealed progressive neurodegeneration. Developing interneurons failed to specifically express parvalbumin (PV) in the mutants. Electrophysiological recordings, before overt cell death, showed normal excitatory transmission, but revealed spontaneous epileptiform activity consistent with seizures in the mutants. In developing cortical neuron cultures, the number of PV(+) neurons was reduced on combined Se and vitamin E deprivation, while other markers, such as calretinin (CR) and GAD67, remained unaffected. Because of the synergism between Se and vitamin E, we analyzed mice lacking neuronal expression of the Se-dependent enzyme glutathione peroxidase 4 (GPx4). Although the number of CR(+) interneurons remained normal in Gpx4-mutant mice, the number of PV(+) interneurons was reduced. Since these mice similarly exhibit seizures and ataxia, we conclude that GPx4 is a selenoenzyme modulating interneuron function and PV expression. Cerebral SE deficiency may thus act via reduced GPx4 expression.-Wirth, E. K., Conrad, M., Winterer, J., Wozny, C., Carlson, B. A., Roth, S., Schmitz, D., Bornkamm, G. W., Coppola, V., Tessarollo, L., Schomburg, L., Kohrle, J., Hatfield, D. L., Schweizer, U. Neuronal selenoprotein expression is required for interneuron development and prevents seizures and neurodegeneration. FASEB J. 24, 844-852 (2010). www.fasebj.org C1 [Schomburg, Lutz; Koehrle, Josef; Schweizer, Ulrich] Charite, Inst Expt Endocrinol, D-13353 Berlin, Germany. [Winterer, Jochen; Wozny, Christian; Schmitz, Dietmar] Charite, Neurosci Res Ctr, D-13353 Berlin, Germany. [Conrad, Marcus; Bornkamm, Georg W.] Helmholtz Zentrum Munchen, Inst Clin Mol Biol & Tumour Genet, Munich, Germany. [Carlson, Bradley A.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Coppola, Vincenzo; Tessarollo, Lino] NCI, Neural Dev Grp, Mouse Canc Genet Program, Frederick, MD 21701 USA. RP Schweizer, U (reprint author), Charite, Inst Expt Endocrinol, Augustenburger Pl 1, D-13353 Berlin, Germany. EM ulrich.schweizer@charite.de RI Coppola, Vincenzo/E-2917-2011; Schweizer, Ulrich/E-8105-2013; Wozny, Christian /A-1498-2015; OI Coppola, Vincenzo/0000-0001-6163-1779; Wozny, Christian /0000-0003-4220-2033; Wirth, Eva Katrin/0000-0002-0491-9941; Conrad, Marcus/0000-0003-1140-5612; Kohrle, Josef/0000-0002-9187-9078; Schweizer, Ulrich/0000-0003-1380-4780 FU Deutsche Forschungsgemeinschaft [Scho849/2-2, SFB 665/A7, Ko922/11-1]; Charite Universitatsmedizin Berlin; U.S. National Institutes of Health; National Cancer Institute; Center for Cancer Research FX The authors thank Dr. Claudia Iserhot, who performed initial physiological studies. SiJie Zhang performed some of the neuron cultures. CamK-Cre mice were generously provided by Gunther Schutz (Deutsches Krebsforschungszentrum, Heidelberg, Germany). The authors gratefully acknowledge the technical assistance of Vartiter Seher, Anita Kinne, Silke Kappler, Antje Kretschmer, and Heidi Forster. Dorette Freyer (Experimental Neurology, Charite Universitatsmedizin Berlin), initially helped with primary neuron culture. Funding for this study was provided by Deutsche Forschungsgemeinschaft Scho849/2-2, SFB 665/A7, Ko922/11-1, and Charite Universitatsmedizin Berlin and in part by the Intramural Research Program of the U.S. National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 46 TC 74 Z9 75 U1 1 U2 10 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAR PY 2010 VL 24 IS 3 BP 844 EP 852 DI 10.1096/fj.09-143974 PG 9 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 561KE UT WOS:000274974600020 PM 19890015 ER PT J AU Hoashi, T Tamaki, K Hearing, VJ AF Hoashi, Toshihiko Tamaki, Kunihiko Hearing, Vincent J. TI The secreted form of a melanocyte membrane-bound glycoprotein (Pmel17/gp100) is released by ectodomain shedding SO FASEB JOURNAL LA English DT Article DE melanosome; glycosylation; proprotein convertase ID MATRIX PROTEIN PMEL17/GP100; MONOCLONAL-ANTIBODY; MELANOSOME BIOGENESIS; ALZHEIMERS-DISEASE; PRECURSOR PROTEIN; AMYLOID FORMATION; T-LYMPHOCYTES; SILVER LOCUS; CLEAVAGE; CELLS AB Ectodomain shedding is a proteolytic mechanism by which a transmembrane protein is converted into a secreted form. Pmel17/gp100 is a melanocyte-specific membrane-bound glycoprotein that has amyloid characteristics and forms fibrillar structures in melanosomes after a complex sequence of post-translational processing and trafficking events, including cleavage by a furin-like proprotein convertase (PC). A secreted form of Pmel17 (termed sPmel17) was also thought to be released due to cleavage by a PC. We used multidisciplinary approaches to demonstrate that sPmel17 is released by ectodomain shedding at the juxtamembrane and/or intramembrane motif and to show that this is independent of cleavage by a PC. We further show that sPmel17 consists of 2 fragments linked by disulfide bonds and that the shedding is inhibited at low temperature but not by metalloproteinase inhibitors. Moreover, treatment with a phorbol ester or a calmodulin inhibitor induces Pmel17 shedding. We also refine the reactivity of HMB50 and NKI/beteb, 2 monoclonal antibodies commonly used as melanoma-specific markers. The fact that those antibodies require physically separated domains of Pmel17 sheds interesting light on its 3-dimensional conformation. We conclude that sPmel17 is released by regulated proteolytic ectodomain shedding.-Hoashi, T., Tamaki, K., Hearing, V. J. The secreted form of a melanocyte membrane-bound glycoprotein (Pmel17/gp100) is released by ectodomain shedding. FASEB J. 24, 916-930 (2010). www.fasebj.org C1 [Hoashi, Toshihiko; Hearing, Vincent J.] NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. [Hoashi, Toshihiko; Tamaki, Kunihiko] Univ Tokyo, Dept Dermatol, Fac Med, Tokyo 1138655, Japan. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Rm 2132, Bethesda, MD 20892 USA. EM thoashi-tky@umin.ac.jp; hearingv@nih.gov FU National Institutes of Health, National Cancer Institute FX We gratefully thank Dr. Michael S. Marks (University of Pennsylvania, Philadelphia, PA, USA) for kindly providing the Pmel17-i, Pmel17-l, and Pmel17-s vectors; Dr. Richard N. Sifers (Baylor College of Medicine, Houston, TX, USA) for the kind gift of hATM-pcDNA3.1; Dr. Donald F. Steiner (University of Chicago, Chicago, IL, USA) for the kind gift of pCMV-furin; Dr. Susan H. Garfield and Dr. Stephen M. Wincovitch for expert advice on confocal microscopy; and Dr. Motozo Yamashita for useful suggestions. This research was supported, in part, by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 67 TC 21 Z9 21 U1 0 U2 3 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD MAR PY 2010 VL 24 IS 3 BP 916 EP 930 DI 10.1096/fj.09-140921 PG 15 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 561KE UT WOS:000274974600027 PM 19884326 ER PT J AU Navarathna, DHMLP Harris, SD Roberts, DD Nickerson, KW AF Navarathna, Dhammika H. M. L. P. Harris, Steven D. Roberts, David D. Nickerson, Kenneth W. TI Evolutionary aspects of urea utilization by fungi SO FEMS YEAST RESEARCH LA English DT Article DE urease; urea amidolyase; DUR1,2; Ni-dependent enzymes; fusel alcohols; methylcrotonyl CoA carboxylase ID CANDIDA-ALBICANS; NUTRITIONAL CONTROL; VIRULENCE; AMIDOLYASE; CEREVISIAE; GROWTH; MUTANT; BIOTIN; MODEL; FORM AB The higher fungi exhibit a dichotomy with regard to urea utilization. The hemiascomycetes use urea amidolyase (DUR1,2), whereas all other higher fungi use the nickel-containing urease. Urea amidolyase is an energy-dependent biotin-containing enzyme. It likely arose before the Euascomycete/Hemiascomycete divergence c. 350 million years ago by insertion of an unknown gene into one copy of a duplicated methylcrotonyl CoA carboxylase (MccA). The dichotomy between urease and urea amidolyase coincides precisely with that for the Ni/Co transporter (Nic1p), which is present in the higher fungi that use urease and is absent in those that do not. We suggest that the selective advantage for urea amidolyase is that it allowed the hemiascomycetes to jettison all Ni(2+) - and Co(2+) - dependent metabolisms and thus to have two fewer transition metals whose concentrations need to be regulated. Also, the absence of MccA in the hemiascomycetes coincides with and may explain their production of fusel alcohols. C1 [Navarathna, Dhammika H. M. L. P.; Nickerson, Kenneth W.] Univ Nebraska, Sch Biol Sci, Lincoln, NE 68588 USA. [Navarathna, Dhammika H. M. L. P.; Roberts, David D.] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Harris, Steven D.] Univ Nebraska, Dept Plant Pathol, Lincoln, NE 68588 USA. RP Nickerson, KW (reprint author), Univ Nebraska, Sch Biol Sci, Lincoln, NE 68588 USA. EM knickerson1@unl.edu RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU University of Nebraska; John C. and Nettie V. David Memorial Trust Fund; Ann L. Kelsall and the Farnesol and Candida albicans Research Fund; University of Nebraska Foundation; NIH, NCI, Center for Cancer Research FX We thank Donald G. Ahearn, Vadim Gladyshev, and anonymous reviewer #2 for helpful suggestions and discussions. This work was supported by the University of Nebraska Tobacco Settlement Biomedical Research Enhancement Fund, the John C. and Nettie V. David Memorial Trust Fund, Ann L. Kelsall and the Farnesol and Candida albicans Research Fund, University of Nebraska Foundation, and the Intramural Research Program of the NIH, NCI, Center for Cancer Research (DDR). NR 29 TC 19 Z9 19 U1 2 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1567-1356 J9 FEMS YEAST RES JI FEMS Yeast Res. PD MAR PY 2010 VL 10 IS 2 BP 209 EP 213 DI 10.1111/j.1567-1364.2010.00602.x PG 5 WC Biotechnology & Applied Microbiology; Microbiology; Mycology SC Biotechnology & Applied Microbiology; Microbiology; Mycology GA 552VE UT WOS:000274320900009 PM 20100286 ER PT J AU Baechler, MF Groth, AT Nesti, LJ Martin, BD AF Baechler, Martin F. Groth, Adam T. Nesti, Leon J. Martin, Barry D. TI Soft Tissue Management of War Wounds to the Foot and Ankle SO FOOT AND ANKLE CLINICS LA English DT Article DE War; Foot; Ankle; Flap; Reconstruction; Microsurgery ID OPERATION IRAQI-FREEDOM; THIGH PERFORATOR FLAP; BREVIS MUSCLE FLAP; MICROSURGICAL RECONSTRUCTION; EXTERNAL FIXATION; ENDURING FREEDOM; OPEN FRACTURES; DISTAL LEG; SURAL FLAP; THERAPY AB Reconstruction of the war-wounded foot and ankle is a challenging process requiring endurance, patience, diligence, and many harrowing decisions for the patient and surgeon. These decisions involve reconciling the difficult balance between expectations and feasibility. The reconstructive process does not end with the successful healing of a flap. Indeed, the surgeon must counsel the patient that flap coverage is but one small component of the reconstruction process. Multiple procedures may be necessary before the patient reaches maximum function. Overtime, the patient and the surgeon may consider revisions of a flap to improve shoe wear and weight-bearing of the reconstructed foot and ankle. Also of high importance is the availability of a skilled orthotist for custom fitting of braces and shoe wear in the post-reconstructive period. Ultimately, the patient is the final judge of the outcome of foot and ankle reconstruction. It is not a rare occurrence that the patient and surgeon agree at some point during reconstructive efforts that an amputation is the best option. C1 [Baechler, Martin F.] Walter Reed Army Med Ctr, Dept Orthopaed & Rehabil, Washington, DC 20307 USA. [Baechler, Martin F.; Martin, Barry D.] Uniformed Serv Univ Hlth Sci, Dept Surg, Bethesda, MD 20814 USA. [Groth, Adam T.] Tripler Army Med Ctr, Dept Surg, Orthopaed Surg Serv, Honolulu, HI 96859 USA. [Nesti, Leon J.] McDonald Army Community Hosp, Dept Surg, Orthopaed Surg Serv, Ft Eustis, VA 23604 USA. [Nesti, Leon J.] NIAMSD, NIH, Bethesda, MD 20892 USA. [Martin, Barry D.] Walter Reed Army Med Ctr, Dept Surg, Integrated Plast Surg Serv, Washington, DC 20307 USA. RP Baechler, MF (reprint author), Walter Reed Army Med Ctr, Dept Orthopaed & Rehabil, 6900 Georgia Ave NW, Washington, DC 20307 USA. EM martin.baechler@us.army.mil RI Groth, Adam/P-9366-2016 OI Groth, Adam/0000-0003-2475-6200 FU NIAAA NIH HHS [F30 AA005516-01, F30 AA005516-02, F30 AA005516-03] NR 67 TC 15 Z9 18 U1 0 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1083-7515 J9 FOOT ANKLE CLIN JI Foot Ankle Clin. PD MAR PY 2010 VL 15 IS 1 BP 113 EP 138 DI 10.1016/j.fcl.2009.10.006 PG 26 WC Orthopedics SC Orthopedics GA 745TK UT WOS:000289189200008 PM 20189120 ER PT J AU Zhu, WH Dahut, WL AF Zhu, Wenhui Dahut, William L. TI Tumor angiogenesis as an early marker of long-term prostate cancer mortality SO FUTURE ONCOLOGY LA English DT Editorial Material DE angiogenesis; microvessel density; prostate cancer; prostate cancer-specific mortality ID CELLS PREDICT SURVIVAL; BEAM RADIATION-THERAPY; RADICAL PROSTATECTOMY; MICROVESSEL DENSITY; PATHOLOGICAL STAGE; PRETREATMENT NOMOGRAM; PSA VELOCITY; ANTIGEN ERA; RECURRENCE; BRACHYTHERAPY AB Evaluation of: Mucci LA, Powolny A, Giovanni E et al.: Prospective study of prostate tumor angiogenesis and cancer-specific mortality in the health professionals follow-up study. J. Clin. Oncol. 27, 5627-5633 (2009). Most prostate cancer patients are diagnosed with localized disease, Long-term prostate cancer mortality is low, and many patients have been overtreated. Better prediction tools are needed to distinguish clinically insignificant, low-risk prostate cancers from lethal diseases. Tumor microvessel density, a marker of angiogenesis, has been shown to be related to the development of prostate cancer metastasis and even mortality. Mucci et al. found that morphologic characteristics of tumor microvessels, such as vessel size and irregularity, from prostatectomy specimen may be better than microvessel density as indicators of active angiogenesis, cancer aggressiveness and metastatic potential, and potentially prostate cancer-specific mortality. Prognostic tools combining angiogenesis biomarkers and clinical features led to marked improvement in the prediction of lethal prostate cancer. If these results are confirmed with studies from prostate biopsy samples, this novel prognosis tool will be of significant importance to guide clinical decision-making for localized prostate cancer, C1 [Zhu, Wenhui; Dahut, William L.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Dahut, WL (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, 10 Ctr Dr,Room 12N226, Bethesda, MD 20892 USA. EM zhuwen@mail.nih.gov; dahutw@mail.nih.gov NR 38 TC 2 Z9 2 U1 0 U2 0 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 EI 1744-8301 J9 FUTURE ONCOL JI Future Oncol. PD MAR PY 2010 VL 6 IS 3 BP 341 EP 345 DI 10.2217/FON.09.177 PG 5 WC Oncology SC Oncology GA 571NQ UT WOS:000275759700006 PM 20222790 ER PT J AU Kucherlapati, MH Lee, K Nguyen, AA Clark, AB Hou, H Rosulek, A Li, H Yang, K Fan, KH Lipkin, M Bronson, RT Jelicks, L Kunkel, TA Kucherlapati, R Edelmann, W AF Kucherlapati, Melanie Lee, Kyeryoung Nguyen, Andrew A. Clark, Alan B. Hou, Harry, Jr. Rosulek, Andrew Li, Hua Yang, Kan Fan, Kunhua Lipkin, Martin Bronson, Roderick T. Jelicks, Linda Kunkel, Thomas A. Kucherlapati, Raju Edelmann, Winfried TI An Msh2 Conditional Knockout Mouse for Studying Intestinal Cancer and Testing Anticancer Agents SO GASTROENTEROLOGY LA English DT Article DE Mismatch Repair; Msh2; Tumorigenesis; Chemotherapy ID DNA MISMATCH REPAIR; NONPOLYPOSIS COLORECTAL-CANCER; MICROSATELLITE-INSTABILITY; GASTROINTESTINAL-TRACT; APC MUTATIONS; COLON-CANCER; MICE; INACTIVATION; TUMORS; DEFICIENCY AB BACKGROUND & AIMS: Mutations in the DNA mismatch repair (MMR) gene MSH2 cause Lynch syndromes I and II and sporadic colorectal cancers. Msh2(null) mice predominantly develop lymphoma and do not accurately recapitulate the colorectal cancer phenotype. METHODS: We generated and examined mice with a conditional Msh2 disruption (Msh2(LoxP)), permitting tissue-specific gene inactivation. ECMsh2(LoxP/LoxP) mice carried an EIIa-Cre transgene, and VCMsh2(LoxP/LoxP) mice carried a Villin-Cre transgene. We combined the VCMsh2(LoxP) allele with either Msh2(Delta 7null) (VCMsh2(LoxP/null)) or Msh2(G674D) mutations (VCMsh2(LoxP/G674D)) to create allelic phase mutants. These mice were given cisplatin or 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX), and their tumors were measured by magnetic resonance imaging. RESULTS: Embryonic fibroblasts from ECMsh2(LoxP/LoxP) mice do not express MSH2 and are MMR deficient. Reverse transcription, polymerase chain reaction, and immunohistochemistry from VCMsh2(LoxP/LoxP) mice demonstrated specific loss of Msh2 messenger RNA and protein from epithelial cells of the intestinal tract. Microsatellite instability was observed in all VCMsh2 strains and limited to the intestinal mucosa. Resulting adenomas and adenocarcinomas had somatic truncation mutations to the adenomatous polyposis coli (Apc) gene. VCMsh2(LoxP/LoxP) mice did not develop lymphoma. Comparison of allelic phase tumors revealed significant differences in multiplicity and size. When treated with cisplatin or FOLFOX, tumor size was reduced in VCMsh2(LoxP/G674D) but not VCMsh2LoxP/null tumors. The apoptotic response to FOLFOX was partially sustained in the intestinal mucosa of VCMsh2(LoxP/G674D) animals. CONCLUSIONS: Msh2(LoxP/LoxP) mice in combination with appropriate Cre recombinase transgenes have excellent potential for preclinical modeling of Lynch syndrome, MMR-deficient tumors of other tissue types, and use in drug development. C1 [Kucherlapati, Melanie] Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Genet, Boston, MA 02115 USA. [Lee, Kyeryoung; Hou, Harry, Jr.; Edelmann, Winfried] Albert Einstein Coll Med, Dept Cell Biol, Bronx, NY 10467 USA. [Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Mol Genet Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Clark, Alan B.; Kunkel, Thomas A.] NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Li, Hua; Jelicks, Linda] Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10467 USA. [Yang, Kan; Fan, Kunhua; Lipkin, Martin] Cornell Univ, Weill Med Ctr, Dept Med Gastroenterol, Strang Canc Res Lab, New York, NY 10021 USA. [Bronson, Roderick T.] Tufts Univ, Sch Med, Dept Pathol, Boston, MA 02111 USA. [Bronson, Roderick T.] Tufts Univ, Sch Vet Med, Dept Pathol, Boston, MA 02111 USA. RP Kucherlapati, MH (reprint author), Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Genet, Boston, MA 02115 USA. EM mkucherlapati@partners.org; edelmann@aecom.yu.edu FU NIH [ES11040, CA084301, CA76329, CA93484]; Division of Intramural Research of the NIH, NIEHS [Z01 ES065089]; [CA13330] FX Supported by NIH grants ES11040 (to R. K.), CA084301 (to R. K.), CA76329 (to W. E.), and CA93484 (to W. E.); Center grant CA13330 (to Albert Einstein College of Medicine); and Project Z01 ES065089, Division of Intramural Research of the NIH, NIEHS (to T. A. K.). NR 37 TC 29 Z9 30 U1 0 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2010 VL 138 IS 3 BP 993 EP U243 DI 10.1053/j.gastro.2009.11.009 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 563EF UT WOS:000275109900030 PM 19931261 ER PT J AU Sakiani, S Koh, C Heller, T AF Sakiani, Sasan Koh, Christopher Heller, Theo TI Glowing in the Dark: Not Always a Bad Thing SO GASTROENTEROLOGY LA English DT Editorial Material ID FOCAL NODULAR HYPERPLASIA C1 [Sakiani, Sasan; Koh, Christopher; Heller, Theo] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. RP Sakiani, S (reprint author), NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. FU Intramural NIH HHS [ZIA DK054514-03] NR 3 TC 0 Z9 0 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD MAR PY 2010 VL 138 IS 3 BP E8 EP U536 DI 10.1053/j.gastro.2009.05.065 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 563EF UT WOS:000275109900056 PM 20123140 ER PT J AU Galter, D Pernold, K Yoshitake, T Lindqvist, E Hoffer, B Kehr, J Larsson, NG Olson, L AF Galter, D. Pernold, K. Yoshitake, T. Lindqvist, E. Hoffer, B. Kehr, J. Larsson, N. -G. Olson, L. TI MitoPark mice mirror the slow progression of key symptoms and L-DOPA response in Parkinson's disease SO GENES BRAIN AND BEHAVIOR LA English DT Article DE Cre-loxP system; HPLC; mitochondria; striatum; substantia nigra; tissue-specific knock-out mice ID GROUND REACTION FORCES; COMPENSATORY ADJUSTMENTS; TYROSINE-HYDROXYLASE; ACID DECARBOXYLASE; MESSENGER-RNA; IMPAIRMENTS; NEURONS; RATS; MITOCHONDRIA; TRANSPORTER AB The MitoPark mouse, in which the mitochondrial transcription factor Tfam is selectively removed in midbrain dopamine (DA) neurons, is a genetic model for Parkinson's disease (PD) that replicates the slow and progressive development of key symptoms. To further validate this model, we have extended both behavioral and biochemical analyses in these animals. We found that vertical movements decline earlier and faster than horizontal movements, possibly modeling the early occurrence of axial, postural instability in PD. L-DOPA induces different locomotor responses depending on the age: in young MitoPark mice the L-DOPA-induced motor activation is small; middle-aged MitoPark mice respond in a dose-dependent manner to L-DOPA, whereas aged MitoPark mice display a double-peaked locomotor response to a high dose of L-DOPA that includes an intermittent period of very low motor activity, similar to the 'on-off' phenomenon in PD. To correlate behavior with biochemical data, we analyzed monoamine levels in three different brain areas that are highly innervated by the DA system: striatum, anterior cortex and olfactory bulb. DA levels declined earlier and faster in striatum than in cortex; only at the latest time-point analyzed, DA levels were found to be significantly lower than control levels in the olfactory bulb. Interestingly, the ratio between homovanillic acid (HVA) and DA differed between regions over time. In striatum and olfactory bulb, the ratio increased steeply indicating increased DA turnover. In contrast, the ratio decreased over time in cortex, revealing important differences between DA cells in substantia nigra and the ventral tegmental area. C1 [Hoffer, B.] NIDA, NIH, Baltimore, MD USA. [Yoshitake, T.; Kehr, J.] Dept Physiol & Pharmacol, Baltimore, MD USA. [Larsson, N. -G.] Karolinska Inst, Dept Lab Med, S-17177 Stockholm, Sweden. [Larsson, N. -G.] Max Planck Inst Biol Aging, Cologne, Germany. RP Galter, D (reprint author), Karolinska Inst, Dept Neurosci, Retzius Vag 8,B2 4, S-17177 Stockholm, Sweden. EM dagmar.galter@ki.se RI Galter, Dagmar/C-4826-2011 OI Galter, Dagmar/0000-0001-6485-6244 FU Swedish Research Council; Swedish Brain Foundation and Hallstens Forskningsstiftelse; Swedish Parkinson Foundation; Swedish Brain Power; Michael J. Fox Foundation; Karolinska Institutet Funds FX This study was supported by the Swedish Research Council, the Swedish Brain Foundation and Hallstens Forskningsstiftelse, The Swedish Parkinson Foundation, Swedish Brain Power, the Michael J. Fox Foundation and Karolinska Institutet Funds. Conflict of interest statement: N- G. L. and L. O. are co-owners of a company owning commercial rights to the MitoPark mice. NR 23 TC 29 Z9 29 U1 2 U2 6 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1601-1848 J9 GENES BRAIN BEHAV JI Genes Brain Behav. PD MAR PY 2010 VL 9 IS 2 BP 173 EP 181 DI 10.1111/j.1601-183X.2009.00542.x PG 9 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 568JX UT WOS:000275519700003 PM 20002202 ER PT J AU Knutsen, T Padilla-Nash, HM Wangsa, D Barenboim-Stapleton, L Camps, J McNeil, N Difilippantonio, MJ Ried, T AF Knutsen, Turid Padilla-Nash, Hesed M. Wangsa, Danny Barenboim-Stapleton, Linda Camps, Jordi McNeil, Nicole Difilippantonio, Michael J. Ried, Thomas TI Definitive Molecular Cytogenetic Characterization of 15 Colorectal Cancer Cell Lines SO GENES CHROMOSOMES & CANCER LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; GENE AMPLIFICATION; CHROMOSOMAL-ABERRATIONS; TELOMERE CAPTURE; INSTABILITY; TRANSLOCATIONS; TUMORS; BREAK; MECHANISMS; EVOLUTION AB In defining the genetic profiles in cancer, cytogenetically aberrant cell lines derived from primary tumors are important tools for the study of carcinogenesis. Here, we present the results of a comprehensive investigation of 15 established colorectal cancer cell lines using spectral karyotyping (SKY), fluorescence in situ hybridization, and comparative genomic hybridization (CGH). Detailed karyotypic analysis by SKY on five of the lines (P53HCT116, T84, NCI-H508, NCI-H716, and SK-CO-I) is described here for the first time. The five lines with karyotypes in the diploid range and that are characterized by defects in DNA mismatch repair had a mean of 4.8 chromosomal abnormalities per line, whereas the 10 aneuploid lines exhibited complex karyotypes and a mean of 30 chromosomal abnormalities. Of the 150 clonal translocations, only eight were balanced and none were recurrent among the lines. We also reviewed the karyotypes of 345 cases of adenocarcinoma of the large intestine listed in the Mitelman Database of Chromosome Aberrations in Cancer. The types of abnormalities observed in the cell lines reflected those seen in primary tumors: there were no recurrent translocations in either tumors or cell lines; isochromosomes were the most common recurrent abnormalities; and breakpoints occurred most frequently at the centromeric/pericentromeric and telomere regions. Of the genomic imbalances detected by array CGH, 87% correlated with chromosome aberrations observed in the SKY studies. The fact that chromosome abnormalities predominantly result in copy number changes rather than specific chromosome or gene fusions suggests that this may be the major mechanism leading to carcinogenesis in colorectal cancer. Published 2009 Wiley-Liss, Inc.dagger C1 [Knutsen, Turid; Padilla-Nash, Hesed M.; Wangsa, Danny; Barenboim-Stapleton, Linda; Camps, Jordi; McNeil, Nicole; Difilippantonio, Michael J.; Ried, Thomas] NCI, Sect Canc Genom, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Knutsen, T (reprint author), NCI, Sect Canc Genom, Genet Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM knutsent@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX Supported by: Intramural Research program of the NIH, National Cancer Institute, Center for Cancer Research. NR 42 TC 18 Z9 18 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1045-2257 J9 GENE CHROMOSOME CANC JI Gene Chromosomes Cancer PD MAR PY 2010 VL 49 IS 3 BP 204 EP 223 DI 10.1002/gcc.20730 PG 20 WC Oncology; Genetics & Heredity SC Oncology; Genetics & Heredity GA 547ZT UT WOS:000273929200002 PM 19927377 ER PT J AU Miller, HI AF Miller, Henry I. TI Tempering Regulation with Common Sense SO GENETIC ENGINEERING & BIOTECHNOLOGY NEWS LA English DT Editorial Material C1 Stanford Univ, Hoover Inst, Stanford, CA 94305 USA. [Miller, Henry I.] NIH, Bethesda, MD USA. [Miller, Henry I.] US FDA, Rockville, MD 20857 USA. RP Miller, HI (reprint author), Stanford Univ, Hoover Inst, Stanford, CA 94305 USA. EM henry.miller@stanford.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1935-472X J9 GENET ENG BIOTECHN N JI Genet. Eng. Biotechnol. News PD MAR 1 PY 2010 VL 30 IS 5 BP 6 EP 7 PG 2 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 668LF UT WOS:000283270000003 ER PT J AU Narlikar, L Sakabe, NJ Blanski, AA Arimura, FE Westlund, JM Nobrega, MA Ovcharenko, I AF Narlikar, Leelavati Sakabe, Noboru J. Blanski, Alexander A. Arimura, Fabio E. Westlund, John M. Nobrega, Marcelo A. Ovcharenko, Ivan TI Genome-wide discovery of human heart enhancers SO GENOME RESEARCH LA English DT Article ID CONSERVED NONCODING SEQUENCES; CIS-REGULATORY MODULES; SERUM RESPONSE FACTOR; GENE-EXPRESSION; TRANSCRIPTION FACTORS; BINDING-SITE; ZEBRAFISH; IDENTIFICATION; MUSCLE; CLUSTERS AB The various organogenic programs deployed during embryonic development rely on the precise expression of a multitude of genes in time and space. Identifying the cis-regulatory elements responsible for this tightly orchestrated regulation of gene expression is an essential step in understanding the genetic pathways involved in development. We describe a strategy to systematically identify tissue-specific cis-regulatory elements that share combinations of sequence motifs. Using heart development as an experimental framework, we employed a combination of Gibbs sampling and linear regression to build a classifier that identifies heart enhancers based on the presence and/or absence of various sequence features, including known and putative transcription factor (TF) binding specificities. In distinguishing heart enhancers from a large pool of random noncoding sequences, the performance of our classifier is vastly superior to four commonly used methods, with an accuracy reaching 92% in cross-validation. Furthermore, most of the binding specificities learned by our method resemble the specificities of TFs widely recognized as key players in heart development and differentiation, such as SRF, MEF2, ETS1, SMAD, and GATA. Using our classifier as a predictor, a genome-wide scan identified over 40,000 novel human heart enhancers. Although the classifier used no gene expression information, these novel enhancers are strongly associated with genes expressed in the heart. Finally, in vivo tests of our predictions in mouse and zebrafish achieved a validation rate of 62%, significantly higher than what is expected by chance. These results support the existence of underlying cis-regulatory codes dictating tissue-specific transcription in mammalian genomes and validate our enhancer classifier strategy as a method to uncover these regulatory codes. C1 [Sakabe, Noboru J.; Blanski, Alexander A.; Arimura, Fabio E.; Westlund, John M.; Nobrega, Marcelo A.] Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. [Narlikar, Leelavati; Ovcharenko, Ivan] NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Nobrega, MA (reprint author), Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. EM nobrega@uchicago.edu; ovcharei@ncbi.nlm.nih.gov RI Sakabe, Noboru/A-8708-2009 FU NIH; National Library of Medicine [HL088393, HG004428] FX We thank Ryan Vo for helping us compile the set of known heart enhancers, Andrew McCallion for providing the tol2- EGFP plasmid, and Robert Ho for generously sharing his zebrafish facility and injection bays with us. This research was supported by the Intramural Research Program of the NIH, National Library of Medicine (I. O.), and by grants HL088393 and HG004428 (M. A. N). NR 67 TC 72 Z9 74 U1 1 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD MAR PY 2010 VL 20 IS 3 BP 381 EP 392 DI 10.1101/gr.098657.109 PG 12 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 563JJ UT WOS:000275124600010 PM 20075146 ER PT J AU Saadat, L Dupree, JL Kilkus, J Han, XL Traka, M Proia, RL Dawson, G Popko, B AF Saadat, Laleh Dupree, Jeffrey L. Kilkus, John Han, Xianlin Traka, Maria Proia, Richard L. Dawson, Glyn Popko, Brian TI Absence of Oligodendroglial Glucosylceramide Synthesis does not Result in CNS Myelin Abnormalities or Alter the Dysmyelinating Phenotype of CGT-Deficient Mice SO GLIA LA English DT Article DE oligodendrocyte; glycolipids; mouse models ID MULTIDIMENSIONAL MASS-SPECTROMETRY; SHOTGUN LIPIDOMICS; GLYCOSPHINGOLIPID SYNTHESIS; GLYCOPROTEIN MAG; RAT-BRAIN; GANGLIOSIDES; CERAMIDE; EXPRESSION; SYNTHASE; FRACTION AB To examine the function of glycosphingolipids (GSLs) in oligodendrocytes, the myelinating cells of the central nervous system (CNS), mice were generated that lack oligodendroglial expression of UDP-glucose ceramide glucosyltransferase (encoded by Ugcg). These mice (Ugcg(flox/flox);Cnp/Cre) did not show any apparent clinical phenotype, their total brain and myelin extracts had normal GSL content, including ganglioside composition, and myelin abnormalities were not detected in their CNS. These data indicate that the elimination of gangliosides from oligodendrocytes is not detrimental to myelination. These mice were also used to asses the potential compensatory effect of hydroxyl fatty acid glucosylceramide (HFA-GlcCer) accumulation in UDP-galactose:ceramide galactosyltransferase (encoded by Cgt, also known as Ugt8a) deficient mice. At postnatal day 18, the phenotypic characteristics of the Ugcg(flox/flox);Cnp/Cre;Cgt(-/-) mutants, including the degree of hypomyelination, were surprisingly similar to that of Cgt(-/-) mice, suggesting that the accumulation of HFA-GlcCer in Qgt(-/-) mice does not modify their phenotype. These studies demonstrate that abundant, structurally intact myelin can form in the absence of glycolipids, which normally represent over 20% of the dry weight of myelin. (C) 2009 Wiley-Liss, Inc. C1 [Saadat, Laleh; Traka, Maria; Popko, Brian] Univ Chicago, Dept Neurol, Jack Miller Ctr Peripheral Neuropathy, Chicago, IL 60637 USA. [Dupree, Jeffrey L.] Virginia Commonwealth Univ, Dept Anat & Neurobiol, Richmond, VA USA. [Kilkus, John; Dawson, Glyn] Univ Chicago, Dept Pediat, Chicago, IL 60637 USA. [Han, Xianlin] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. [Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. RP Popko, B (reprint author), 5841 S Maryland Ave,MC2030, Chicago, IL 60637 USA. EM bpopko@uchicago.edu RI Proia, Richard/A-7908-2012 FU National Institutes of Health [NS027336, NS036866]; National Multiple Sclerosis Society postdoctoral fellowship award; VCU Department of Anatomy and Neurobiology Microscopy Facility; NIH-NINDS [5P30NS047463]; NIA [AG23168] FX Grant sponsor: National Institutes of Health; Grant numbers: NS027336 (to B.P.) and NS036866 (to G.D.); Grant sponsor: National Multiple Sclerosis Society postdoctoral fellowship award (to M.T.). Grant sponsor: VCU Department of Anatomy and Neurobiology Microscopy Facility (where microscopy was performed), supported in part with funding from an NIH-NINDS Center core grant; Grant number: 5P30NS047463. Grant sponsor: Washington University School of Medicine, supported in part, with funding from an NIA grant (where mass spectrometric analysis was performed); Grant number: NIA AG23168. NR 38 TC 24 Z9 25 U1 1 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0894-1491 J9 GLIA JI Glia PD MAR PY 2010 VL 58 IS 4 BP 391 EP 398 DI 10.1002/glia.20930 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 550YZ UT WOS:000274172500002 PM 19705459 ER PT J AU Kurochkina, N Yardeni, T Huizing, M AF Kurochkina, Natalya Yardeni, Tal Huizing, Marjan TI Molecular modeling of the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase and predictions of structural effects of mutations associated with HIBM and sialuria SO GLYCOBIOLOGY LA English DT Article DE GNE; MNK; homology model; missense mutation; protein structure; sialic acid ID INCLUSION-BODY MYOPATHY; ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; ATP-DEPENDENT GLUCOKINASE; SIALIC-ACID BIOSYNTHESIS; HELIX-HELIX INTERFACES; RIMMED VACUOLES DMRV; DISTAL MYOPATHY; N-ACETYLGLUCOSAMINE; GNE GENE; CRYSTAL-STRUCTURE AB The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK), encoded by the GNE gene, catalyzes the first two committed, rate-limiting steps in the biosynthesis of N-acetylneuraminic acid (sialic acid). GNE/MNK is feedback inhibited by binding of the downstream product, CMP-sialic acid in its allosteric site. GNE mutations can result in two human disorders, hereditary inclusion body myopathy (HIBM) or sialuria. So far, no active site geometry predictions or conformational transitions involved with function are available for mammalian GNE/MNK. The N-terminal GNE domain is homologous to various prokaryotic 2-epimerases, some of which have solved crystallographic structures. The C-terminal MNK domain belongs to the sugar kinases superfamily; its crystallographic structure is solved at 2.84 angstrom and three-dimensional structures have also been reported for several other kinases. In this work, we employed available structural data of GNE/MNK homologs to model the active sites of human GNE/MNK and identify critical amino acid residues responsible for interactions with substrates. In addition, we modeled effects of GNE/MNK missense mutations associated with HIBM or sialuria on helix arrangement, substrate binding, and enzyme action. We found that all reported mutations are associated with the active sites or secondary structure interfaces of GNE/MNK. The Persian-Jewish HIBM founder mutation p.M712T is located at the interface alpha 4 alpha 10 and likely affects GlcNAc, Mg(2+), and ATP binding. This work contributes to further understanding of GNE/MNK function and ligand binding, which may assist future studies for therapeutic options that target misfolded GNE/MNK in HIBM and/or sialuria. C1 [Kurochkina, Natalya] Sch Theoret Modeling, Dept Biophys, Chevy Chase, MD 20825 USA. [Yardeni, Tal; Huizing, Marjan] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Yardeni, Tal] Tel Aviv Univ, Sackler Sch Med, Grad Partner Program, Tel Aviv, Israel. RP Kurochkina, N (reprint author), Sch Theoret Modeling, Dept Biophys, Chevy Chase, MD 20825 USA. EM info@schtm.org FU National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA; Research Funds of The School of Theoretical Modeling, Chevy Chase, MD, USA FX The Intramural Research programs of the National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA and Research Funds of The School of Theoretical Modeling, Chevy Chase, MD, USA. NR 61 TC 10 Z9 11 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD MAR PY 2010 VL 20 IS 3 BP 322 EP 337 DI 10.1093/glycob/cwp176 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 553CC UT WOS:000274341300006 PM 19917666 ER PT J AU Trimble, EL Denicoff, AM Abrams, JS AF Trimble, Edward L. Denicoff, Andrea M. Abrams, Jeffrey S. TI Strengthening accrual to cancer clinical trials SO GYNECOLOGIC ONCOLOGY LA English DT Editorial Material ID BARRIERS; IMPACT C1 [Trimble, Edward L.; Denicoff, Andrea M.; Abrams, Jeffrey S.] NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. RP Trimble, EL (reprint author), 6130 Execut Blvd,Suite 7025,MSC 7436, Bethesda, MD 20892 USA. EM tt6m@nih.gov NR 11 TC 2 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 BP 291 EP 292 DI 10.1016/j.ygyno.2010.01.015 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 566HF UT WOS:000275360000001 PM 20152512 ER PT J AU Bosquet, JG Terstriep, SA Cliby, WA Brown-Jones, M Kaur, JS Podratz, KC Keeney, GL AF Bosquet, Jesus Gonzalez Terstriep, Shelby A. Cliby, William A. Brown-Jones, Monica Kaur, Judith S. Podratz, Karl C. Keeney, Gary L. TI The impact of multi-modal therapy on survival for uterine carcinosarcomas SO GYNECOLOGIC ONCOLOGY LA English DT Article DE Carcinosarcomas; Treatment outcomes; FIGO staging ID MIXED MULLERIAN TUMORS; GYNECOLOGIC-ONCOLOGY-GROUP; PHASE-III TRIAL; FEMALE GENITAL-TRACT; PROGNOSTIC-FACTORS; ENDOMETRIAL CANCER; MESODERMAL TUMORS; HISTOLOGIC TYPES; STAGE-I; UTERUS AB Objectives. To investigate treatment outcomes of patients with carcinosarcoma of the uterus and to identify parameters predictive of survival. Secondary objectives included (a) the assessment of treatment failures as a function Of histologic subtypes and (b) the impact of the new FIGO staging classification system, Methods. This is a retrospective outcomes analysis of 121 patients diagnosed with primary carcinosarcoma of the uterus. Clinical, surgical and pathological data were reviewed and patients were classified according to the new 2009 FIGO staging system for endometrial carcinoma. Survivorship curves were evaluated with the log-rank test and associations between events and variables with Cox proportional hazards model. Results. in the multivariate analyses for disease-specific survival (DSS) and disease-free Survival (DFS), the only independent factors were FIGO stage, adjuvant chemotherapy after Surgery and the presence of clear cell histology in the tumor. The 5-year DSS for stages I-II, III and IV was 59%, 22% and 9%, respectively. The administration of platin-based chemotherapy provided a significant benefit with regard to both DFS (OR = 0.28; p = 0.001) and DSS (OR = 0.35; p = 0.01). While radiotherapy (RT) appeared to control vaginal failures in all stages, pelvic RT did not impact DSS. Of importance, the epithelial component was the predominant histology in both the primary extrauterine metastases (94%) and the distant failure sites (82%). Conclusions. This highly aggressive uterine malignancy warrants comprehensive surgical staging to assess tumor dissemination followed by systemic therapy in patients with both early and advanced stage disease. Published by Elsevier Inc. C1 [Bosquet, Jesus Gonzalez] NCI, Lab Translat Genom, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Cliby, William A.; Brown-Jones, Monica; Podratz, Karl C.] Mayo Clin, Dept Obstet & Gynecol, Div Gynecol Oncol, Rochester, MN 55905 USA. [Keeney, Gary L.] Mayo Clin, Dept Anat Pathol, Rochester, MN 55905 USA. RP Bosquet, JG (reprint author), Adv Technol Ctr, Lab Translat Genom, 8717 Grovemont Circle, Gaithersburg, MD 20877 USA. EM gonzalej@mail.nih.gov NR 33 TC 36 Z9 36 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 BP 419 EP 423 DI 10.1016/j.ygyno.2009.10.053 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 566HF UT WOS:000275360000027 ER PT J AU Kuo, DYS Blank, SV Christos, PJ Kim, M Caputo, TA Pothuri, B Hershman, D Goldman, N Ivy, PS Runowicz, CD Muggia, F Goldberg, GL Einstein, MH AF Kuo, Dennis Yi-Shin Blank, Stephanie V. Christos, Paul J. Kim, Mimi Caputo, Thomas A. Pothuri, Bhavana Hershman, Dawn Goldman, Noah Ivy, Percy S. Runowicz, Carolyn D. Muggia, Franco Goldberg, Gary L. Einstein, Mark H. TI Paclitaxel plus oxaliplatin for recurrent or metastatic cervical cancer: A New York Cancer Consortium Study SO GYNECOLOGIC ONCOLOGY LA English DT Article; Proceedings Paper CT 40th Annual Meeting on Womens Cancer CY FEB 05-08, 2009 CL San Antonio, TX DE Recurrent cervical cancel; Paclitaxel; Oxaliplatin; Response; Toxicity ID GYNECOLOGIC-ONCOLOGY-GROUP; CELL LUNG-CANCER; PHASE-II; CARCINOMA; CISPLATIN; CHEMOTHERAPY; PLATINUM AB Objective. Survival in women with recurrent or metastatic cervical cancer remains poor. More effective and less toxic regimens are needed. Cisplatin is an effective radiosensitizer, but its single agent activity ill recurrent cervical cancer, especially after prior cisplatin exposure, is disappointing, with a response rate of only 13%. Oxaliplatin has preclinical activity in cisplatin-resistant tumors and may have synergic activity when combined with paclitaxel. Our objective is to determine the efficacy and toxicity of paclitaxel and oxaliplatin in patients with recurrent or metastatic cervical cancer. Methods. patients with histologic confirmation of primary metastatic or recurrent cervical cancer not amenable to surgical management were eligible. Treatment consisted of paclitaxel 175 mg/m(2) IV and oxaliplatin 130 mg/m(2) IV every 21 days. The primary endpoints were toxicity, recorded every cycle, and response, determined by RECIST criteria and were assessed every 9 weeks, with Subsequent confirmation as required. Sample size determinations were made using a Simon's two-stage design with a projected overall response proportion of 13% with cisplatin alone. Survival rates were calculated with Kaplan-Meier methods. Results. Of the 35 patients enrolled, 32 were evaluable. The median age was 56 (27-78): 30 had had prior-radiation (23 concomitant with cisplatin). Patients completed a mean of 4.2 cycles (1-11). There were 2 complete and 5 Partial responses for a total response rate of 7/32 (22%: 95% CI: 9.3%-40.0%). Eight patients had stable disease For an overall clinical benefit rate of 15/32 (47%; 95% Cl: 29.1%-65.3%). The mean time to best response was 13.5 weeks (95% Cl: 10.6, 16.4). The mean progression-free Survival was 21 weeks (95% Cl: 14.7, 27.2) and mean overall Survival was 52 weeks (95% CI: 39.4, 64.8). A total of 135 cycles were administered. There were 28 (20.1%) grade 3/4 hematologic toxicities and 46 (34.1%) grade 3/4 non-hematologic toxicities, which were predominantly sensory neuropathy. There were 13 treatment delays, 4 dose reductions, and no treatment-related deaths. Conclusions. The combination of paclitaxel and oxaliplatin is an effective regimen in patients with recurrent or persistent cervical cancer including a majority previously exposed to cisplatin. Further study and comparison with other platinum-based regimens is warranted. (C) 2009 Elsevier Inc. All rights reserved. C1 [Kuo, Dennis Yi-Shin; Goldberg, Gary L.; Einstein, Mark H.] Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10461 USA. [Blank, Stephanie V.; Pothuri, Bhavana; Muggia, Franco] NYU, Sch Med, New York, NY 10003 USA. [Christos, Paul J.; Caputo, Thomas A.] New York Presbyterian Hosp, Weill Cornell Med Coll, New York, NY USA. [Hershman, Dawn] Columbia Univ, New York Presbyterian Hosp, New York, NY 10027 USA. [Goldman, Noah] Beth Israel Deaconess Med Ctr, New York, NY 10003 USA. [Ivy, Percy S.] NCI, CTEP, Bethesda, MD 20892 USA. [Runowicz, Carolyn D.] Univ Connecticut, Ctr Hlth, Storrs, CT 06269 USA. RP Kuo, DYS (reprint author), Montefiore Med Ctr, Albert Einstein Coll Med, 1695 Eastchester Rd Suite 601, Bronx, NY 10461 USA. EM dykuo@montefiore.org OI Muggia, Franco/0000-0003-0703-9146 FU NCI NIH HHS [N01 CM062204, N01-CM62204, N01CM62204] NR 21 TC 7 Z9 11 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 BP 442 EP 446 DI 10.1016/j.ygyno.2009.10.082 PG 5 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 566HF UT WOS:000275360000031 PM 19931137 ER PT J AU Dewdney, S Kizer, N Babb, S Rimmel, B Andaya, A Ali, S O'Malley, D Mannel, R Darcy, K DiSilvestro, P Lele, S Pearl, M Brinton, L Goodfellow, P AF Dewdney, S. Kizer, N. Babb, S. Rimmel, B. Andaya, A. Ali, S. O'Malley, D. Mannel, R. Darcy, K. DiSilvestro, P. Lele, S. Pearl, M. Brinton, L. Goodfellow, P. TI Uterine serous carcinoma: Increased familial risk for pancreatic cancer and other Lynch-associated malignancies SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Dewdney, S.; Kizer, N.; Babb, S.; Rimmel, B.; Goodfellow, P.] Washington Univ, Sch Med, St Louis, MO USA. [Andaya, A.; Brinton, L.] Natl Inst Hlth, Bethesda, MD USA. [O'Malley, D.] Ohio State Univ, Columbus, OH 43210 USA. [Mannel, R.] Univ Oklahoma, Oklahoma City, OK USA. [Lele, S.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Ali, S.; Darcy, K.] GOG Stat & Data Ctr, Buffalo, NY USA. [DiSilvestro, P.] Womens & Infants, Providence, RI USA. [Pearl, M.] Suny Downstate Med Ctr, St James, NY USA. RI Brinton, Louise/G-7486-2015; OMalley, David/E-3789-2011 OI Brinton, Louise/0000-0003-3853-8562; NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 14 BP S8 EP S9 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000016 ER PT J AU Kim, K Tosca, P Rudge, T Peggins, J Broadt, T Wang, M Harris, R Aurigemma, R Curiel, D Alvarez, R AF Kim, K. Tosca, P. Rudge, T. Peggins, J. Broadt, T. Wang, M. Harris, R. Aurigemma, R. Curiel, D. Alvarez, R. TI Identifying the safety profile of Ad5/3-Delta 24, a novel infectivity-enhanced conditionally replicative adenovirus, in anticipation of a phase I clinical trial in patients with ovarian cancer SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Kim, K.; Curiel, D.; Alvarez, R.] Univ Alabama, Birmingham, AL USA. [Tosca, P.; Peggins, J.; Aurigemma, R.] Natl Canc Inst, Bethesda, MD USA. [Rudge, T.] Battelle Biomed Res Ctr, W Jefferson, OH USA. [Broadt, T.] Sci Applicat Int Corp, Washington, DC USA. [Wang, M.; Harris, R.] Sci Applicat Int Corp, Philadelphia, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 390 BP S150 EP S151 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000378 ER PT J AU Kimball, K Barnes, M Wang, M Siegal, G Wang, W Harris, R Aurigemma, R Preuss, M Alvarez, R AF Kimball, K. Barnes, M. Wang, M. Siegal, G. Wang, W. Harris, R. Aurigemma, R. Preuss, M. Alvarez, R. TI Phase I study of a tropism-modified, conditionally replicative adenovirus (CRAd) for recurrent gynecologic malignancies SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Kimball, K.; Barnes, M.; Wang, M.; Siegal, G.; Wang, W.; Preuss, M.; Alvarez, R.] Univ Alabama, Birmingham, AL USA. [Harris, R.] Sci Applicat Int Corp, Philadelphia, PA USA. [Aurigemma, R.] Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 282 BP S111 EP S112 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000275 ER PT J AU Lu, K Chen, L Lynch, H Munsell, M Cornelison, T Boyd-Rogers, S Rubin, M Daniels, M Loose, D Broaddus, R AF Lu, K. Chen, L. Lynch, H. Munsell, M. Cornelison, T. Boyd-Rogers, S. Rubin, M. Daniels, M. Loose, D. Broaddus, R. TI A prospective, multicenter randomized study of oral contraceptive versus Depo-Provera for the prevention of endometrial cancer in women with Lynch syndrome SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Lu, K.; Munsell, M.; Boyd-Rogers, S.; Daniels, M.; Broaddus, R.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Chen, L.; Rubin, M.] UCSF, Ctr Comprehens Canc, San Francisco, CA USA. [Lynch, H.] Creighton Univ, Sch Med, Omaha, NE 68178 USA. [Cornelison, T.] Natl Canc Inst, Bethesda, MD USA. [Loose, D.] Univ Texas Houston, Sch Med, Houston, TX USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 6 BP S4 EP S5 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000008 ER PT J AU Mannel, R Brady, M Kohn, E Hanjani, P Hiura, M Lee, R De Geest, K Cohn, D Monk, B Michael, H AF Mannel, R. Brady, M. Kohn, E. Hanjani, P. Hiura, M. Lee, R. De Geest, K. Cohn, D. Monk, B. Michael, H. TI GOG 175: A Randomized phase III trial of IV carboplatin (AUC 6) and paclitaxel 175 mg/m(2) Q 21 days x 3 courses plus low-dose paclitaxel 40 mg/m(2)/wk versus IV carboplatin (AUC 6) and paclitaxel 175 mg/m(2) Q 21 days x 3 courses plus observation in patients with early-stage ovarian carcinoma SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Mannel, R.] Univ Oklahoma, Oklahoma City, OK USA. [Brady, M.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Kohn, E.] Natl Canc Inst, Bethesda, MD USA. [Hanjani, P.] Abington Mem Hosp, Rosenfeld Canc Ctr, Abington, PA 19001 USA. [Hiura, M.] Shikoku Canc Ctr, Matsuyama, Ehime, Japan. [Lee, R.] Southwest Gynecol Oncol Associates Inc, Lakewood, WA USA. [De Geest, K.] Univ Iowa, Iowa City, IA USA. [Cohn, D.] Ohio State Univ, Columbus, OH 43210 USA. [Monk, B.] Univ Calif Irvine, Orange, CA 92668 USA. [Michael, H.] Indiana Univ, Sch Med, Indianapolis, IN 46204 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 1 BP S2 EP S2 DI 10.1016/j.ygyno.2009.12.013 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000003 ER PT J AU Mathews, C Tenney, M Moxley, K Stoner, J Smith, K Nicolas, W Wang, S Gold, M Landrum, L Walker, J AF Mathews, C. Tenney, M. Moxley, K. Stoner, J. Smith, K. Nicolas, W. Wang, S. Gold, M. Landrum, L. Walker, J. TI Tubal ligation and cervical cancer risk SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Smith, K.; Walker, J.] Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. [Nicolas, W.] Natl Canc Inst, Bethesda, MD USA. [Gold, M.] Vanderbilt Univ, Nashville, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 91 BP S36 EP S37 PG 2 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000086 ER PT J AU Mok, S Birrer, M Donninger, H Hao, K Ozbun, L Samini, G Vathepadiekal, V Berkowitz, R Bonome, T Wong, K AF Mok, S. Birrer, M. Donninger, H. Hao, K. Ozbun, L. Samini, G. Vathepadiekal, V. Berkowitz, R. Bonome, T. Wong, K. TI A gene signature predictive for outcome in advanced ovarian cancer identifies a novel survival factor: Microfibril-associated glycoprotein 2 SO GYNECOLOGIC ONCOLOGY LA English DT Meeting Abstract C1 [Mok, S.; Wong, K.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Birrer, M.; Vathepadiekal, V.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Donninger, H.; Ozbun, L.; Samini, G.; Bonome, T.] NCI, Bethesda, MD 20892 USA. [Hao, K.] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Berkowitz, R.] Dana Farber Brigham & Womens Canc Ctr, Boston, MA 02115 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0090-8258 J9 GYNECOL ONCOL JI Gynecol. Oncol. PD MAR PY 2010 VL 116 IS 3 SU 1 MA 426 BP S164 EP S164 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 594LA UT WOS:000277538000413 ER PT J AU Pittaluga, S Jaffe, ES AF Pittaluga, Stefania Jaffe, Elaine S. TI T-cell/histiocyte-rich large B-cell lymphoma SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Editorial Material ID PREDOMINANT HODGKINS-DISEASE; DISTINCT CLINICOPATHOLOGICAL ENTITY; DIFFERENTIAL-DIAGNOSIS; FOLLICULAR LYMPHOMA; HISTIOCYTE-RICH; IMMUNOGLOBULIN; EXPRESSION; PU.1; REARRANGEMENTS; POPULATIONS C1 [Pittaluga, Stefania; Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD USA. RP Pittaluga, S (reprint author), NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD USA. EM elainejaffe@nih.gov OI Jaffe, Elaine/0000-0003-4632-0301 NR 39 TC 13 Z9 13 U1 0 U2 2 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD MAR PY 2010 VL 95 IS 3 BP 352 EP 356 DI 10.3324/haematol.2009.016931 PG 5 WC Hematology SC Hematology GA 578KK UT WOS:000276292100003 PM 20207840 ER PT J AU Sloand, EM Olnes, MJ Weinstein, B Wu, C Maciejewski, J Scheinberg, P Young, NS AF Sloand, Elaine M. Olnes, Matthew J. Weinstein, Barbara Wu, Colin Maciejewski, Jaroslaw Scheinberg, Phillip Young, Neal S. TI Long-term follow-up of patients with moderate aplastic anemia and pure red cell aplasia treated with daclizumab SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE interleukin-2 receptors; immunosuppression; T-regulatory cells; marrow failure ID REGULATORY T-CELLS; RECEPTOR ANTIBODY DACLIZUMAB; RENAL-TRANSPLANTATION; MYELODYSPLASTIC SYNDROME; MULTIPLE-SCLEROSIS; ACUTE REJECTION; HOST-DISEASE; CYCLOSPORINE; INDUCTION; THERAPY AB Background Pure red cell aplasia and moderate aplastic anemia are marrow failure states with an immune pathogenesis. Previously, we described short-term improvements in blood counts in two pilot studies treating moderate aplastic anemia (mAA) and pure red cell aplasia (PRCA) patients with daclizumab, a humanized monoclonal antibody to the interleukin-2 receptor; we now report our long-term experience with a larger cohort of patients. Design and Methods After a median follow-up period of 4.8 years, 19 of 45 (42%) evaluable mAA patients and 10 of 26 (38%) patients with PRCA responded by three months and 2 additional m-AA patients responded by six months following administration of the drug. Results Seven of 28 (25%) mAA patients achieved long-term packed red blood cell PRBC transfusion independence, and all PRCA responders achieved long-term transfusion PRBC transfusion independence. Conclusions Red cell transfusion-independence prior to treatment in mAA patients predicted response. The only significant adverse treatment-related events were transient rashes and arthralgias. Daclizumab is safe and effective, and produces lengthy remissions in patients with PRCA and mAA. C1 [Sloand, Elaine M.; Olnes, Matthew J.; Weinstein, Barbara; Wu, Colin; Maciejewski, Jaroslaw; Scheinberg, Phillip; Young, Neal S.] NHLBI, Bethesda, MD 20892 USA. RP Sloand, EM (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM sloande@nih.gov OI Scheinberg, Phillip/0000-0002-9047-4538 NR 28 TC 14 Z9 18 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD MAR PY 2010 VL 95 IS 3 BP 382 EP 387 DI 10.3324/haematol.2009.013557 PG 6 WC Hematology SC Hematology GA 578KK UT WOS:000276292100009 PM 20207845 ER PT J AU Lamant, L Pileri, S Sabattini, E Brugieres, L Jaffe, ES Delsol, G AF Lamant, Laurence Pileri, Stefano Sabattini, Elena Brugieres, Laurence Jaffe, Elaine S. Delsol, Georges TI Cutaneous presentation of ALK-positive anaplastic large cell lymphoma following insect bites: evidence for an association in five cases SO HAEMATOLOGICA-THE HEMATOLOGY JOURNAL LA English DT Article DE ALK-positive ALCL; NPM-ALK; skin involvement ID BARR-VIRUS INFECTION; MOSQUITO BITES; BORRELIA-BURGDORFERI; HYPERSENSITIVITY; KINASE; PATIENT; FUSION; SKIN; INFILTRATION; EXPRESSION AB Background Skin involvement is frequent in ALK-positive anaplastic large cell lymphomas. The role of an insect bite as a triggering event has been postulated but not well documented. Design and Methods We retrospectively investigated five cases of ALK-positive anaplastic large cell lymphoma who presented with skin lesions occurring after an insect bite. Biopsies were immunostained with antibodies against CD30, ALK, T- and B-cell antigens. Results Persistent skin lesions developed after solitary insect bites in three patients and after multiple bites in two. Regional lymphadenopathy developed within weeks after the bite in three cases. In four cases the correct diagnosis was delayed due to misinterpretation of the findings as a reactive infiltrate in the skin (n=2) or lymph nodes (n=2); all cases subsequently showed small numbers of cells with nuclear and cytoplasmic staining for ALK. The final diagnoses were lymphohistiocytic variant (n=3) and composite common/small cell type (n=2) anaplastic large cell lymphoma. The patients were treated and three were alive at the last follow-up. Two patients died, one of pneumonia and the other of disseminated disease. Conclusions In these cases the sequence of events between the insect bites and the occurrence of both skin lesions and satellite lymphadenopathy suggest a direct relationship between the bite and the presentation with anaplastic large cell lymphoma. We postulate that insect bite-associated antigens could result in an influx of T lymphocytes, some bearing the t(2,5). The subsequent release of cytokines at the site of the bite could act as a 'second hit', eliciting activation of the latter cells, which would then express the oncogenic NPM-ALK protein and undergo uncontrolled proliferation. C1 [Jaffe, Elaine S.] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Lamant, Laurence; Delsol, Georges] Univ Toulouse 3, Toulouse, France. [Lamant, Laurence; Delsol, Georges] Fac Med Toulouse, INSERM, Ctr Physiopathol Toulouse Purpan, U 563, F-31073 Toulouse, France. [Lamant, Laurence; Delsol, Georges] CHU Purpan, Anat Pathol Lab, Toulouse, France. [Pileri, Stefano; Sabattini, Elena] Univ Bologna, Unit Haematopathol, Dept Haematol & Oncol Sci L & A Seragnoli, Policlin S Orsola, Bologna, Italy. [Brugieres, Laurence] Inst Gustave Roussy, Dept Pediat Oncol, Villejuif, France. RP Jaffe, ES (reprint author), NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res,NIH, Bldg 10,Room 2B 42 10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. EM elainejaffe@nih.gov OI Jaffe, Elaine/0000-0003-4632-0301 FU A.I.R.C. (Milan); Center for Cancer Research, National Cancer Institute; Institut National du Cancer (PAIR lymphomes) FX Funding: this work was partly supported by A.I.R.C. (Milan), by the intramural research program of the Center for Cancer Research, National Cancer Institute and by the Programme d'Action Integree de Recherche sur les Lymphomes, Institut National du Cancer (PAIR lymphomes). NR 31 TC 20 Z9 20 U1 0 U2 0 PU FERRATA STORTI FOUNDATION PI PAVIA PA VIA GIUSEPPE BELLI 4, 27100 PAVIA, ITALY SN 0390-6078 J9 HAEMATOL-HEMATOL J JI Haematol-Hematol. J. PD MAR PY 2010 VL 95 IS 3 BP 449 EP 455 DI 10.3324/haematol.2009.015024 PG 7 WC Hematology SC Hematology GA 578KK UT WOS:000276292100017 PM 19951975 ER PT J AU Hoots, K AF Hoots, K. TI A commentary on variant Creutzfeld-Jacob disease SO HAEMOPHILIA LA English DT Editorial Material C1 NHLBI, Div Blood Dis & Resources, NIH, Bethesda, MD 20892 USA. RP Hoots, K (reprint author), NHLBI, Div Blood Dis & Resources, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1351-8216 J9 HAEMOPHILIA JI Haemophilia PD MAR PY 2010 VL 16 IS 2 BP 238 EP 239 DI 10.1111/j.1365-2516.2010.02234.x PG 2 WC Hematology SC Hematology GA 560YI UT WOS:000274941200003 PM 20487441 ER PT J AU Friedmann, T AF Friedmann, Theodore TI How Close Are We to Gene Doping? SO HASTINGS CENTER REPORT LA English DT Article ID THERAPY; IMMUNODEFICIENCY C1 [Friedmann, Theodore] Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. [Friedmann, Theodore] NIH, Recombinant DNA Advisory Comm, Off Biotechnol Activ, Bethesda, MD USA. RP Friedmann, T (reprint author), Univ Calif San Diego, Sch Med, San Diego, CA 92103 USA. NR 10 TC 9 Z9 9 U1 1 U2 14 PU HASTINGS CENTER PI BRIARCLIFF MANOR PA 255 ELM ROAD, BRIARCLIFF MANOR, NY 10510 USA SN 0093-0334 J9 HASTINGS CENT REP JI Hastings Cent. Rep. PD MAR-APR PY 2010 VL 40 IS 2 BP 20 EP 22 PG 3 WC Ethics; Health Care Sciences & Services; Medical Ethics; Social Sciences, Biomedical SC Social Sciences - Other Topics; Health Care Sciences & Services; Medical Ethics; Biomedical Social Sciences GA 574MD UT WOS:000275992600014 PM 20391845 ER PT J AU Lonsdorf, AS Becker, MR Stockfleth, E Schakel, K Ulrich, C AF Lonsdorf, A. S. Becker, M. R. Stockfleth, E. Schaekel, K. Ulrich, C. TI Primary and secondary prevention of skin cancer in organ transplant recipients SO HAUTARZT LA German DT Article DE Organ transplantation; Immunosuppression; mTOR-Inhibitor; Skin cancer; Actinic keratosis ID TOPICAL PHOTODYNAMIC THERAPY; SQUAMOUS-CELL CARCINOMA; ACTINIC KERATOSES; 5-PERCENT IMIQUIMOD; CONTROLLED TRIAL; RISK-FACTORS; DNA-DAMAGE; IMMUNOSUPPRESSION; DISEASE; KIDNEY AB Skin cancer constitutes the most frequently reported post-transplant malignancy in solid organ transplant recipients (OTR) worldwide. Whereas the risk for malignant melanoma is only moderately increased, non-melanoma skin cancers (NMSC) seem to thrive on chronic immunosuppression and account for up to 95% of post-transplant cutaneous malignancies. Compared to the general population cutaneous squamous cell carcinoma (SCC) and actinic keratoses (AK) characteristically show even higher incidences than basal cell carcinoma (BCC) and act as an indicator for the development of multiple primary cutaneous neoplasias and locally recurrent cancers (field cancerization). Early diagnosis and therapy of pre-malignant cutaneous lesions is crucial for the secondary prophylaxis of further invasive and highly aggressive skin cancers. High quality interdisciplinary care and prophylactic modalities, including consistent and sufficient UV protection, topical immunmodulatory therapies of UV-damaged skin areas, retinoid chemoprevention as well as tapering immunosuppressive treatment or the selection of immunosuppressants with proposed antiangiogenic properties like mTor-inhibitors may help to reduce the multiplicity of subsequent primary skin cancers in high-risk patients. Apart from the continuous need for educational intervention of OTR in the primary prophylaxis of post-transplant skin cancers, dermatologic care occupies a central position within the field of transplantation medicine in terms of pre- and post-transplanation dermatologic evaluation and therapy as well as the implication of timely and effective secondary preventive approaches in the management of this high-risk patient population. C1 [Lonsdorf, A. S.; Schaekel, K.] Hauttumorzentrum, Univ Hautklin, D-69115 Heidelberg, Germany. [Becker, M. R.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. [Stockfleth, E.; Ulrich, C.] Charite, Klin Dermatol Venerol & Allergol, D-13353 Berlin, Germany. RP Lonsdorf, AS (reprint author), Hauttumorzentrum, Univ Hautklin, Vossstr 2, D-69115 Heidelberg, Germany. EM anke.lonsdorf@med.uni-heidelberg.de NR 32 TC 5 Z9 5 U1 1 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0017-8470 J9 HAUTARZT JI Hautarzt PD MAR PY 2010 VL 61 IS 3 BP 195 EP + DI 10.1007/s00105-009-1858-2 PG 10 WC Dermatology SC Dermatology GA 566VL UT WOS:000275401200007 PM 20177652 ER PT J AU Drori-Herishanu, L Lodish, M Verma, S Bimpaki, E Keil, MF Horvath, A Stratakis, CA AF Drori-Herishanu, L. Lodish, M. Verma, S. Bimpaki, E. Keil, M. F. Horvath, A. Stratakis, C. A. TI The Growth Hormone Receptor (GHR) Polymorphism in Growth-retarded Children with Cushing Disease: Lack of Association with Growth and Measures of the Somatotropic Axis SO HORMONE AND METABOLIC RESEARCH LA English DT Article DE Cushing syndrome; cortisol; pituitary gland; growth hormone receptor; genetics ID GESTATIONAL-AGE CHILDREN; FULL-LENGTH ISOFORMS; INCREASED RESPONSIVENESS; REPLACEMENT THERAPY; DEFICIENT ADULTS; TURNER SYNDROME; SHORT STATURE; FINAL HEIGHT; EXON-3; DELETION AB Pediatric Cushing disease (CD) often presents with short stature, but we have observed significant inter-individual variability in the growth delay caused by endogenous hypercortisolism. Glucocorticoids cause growth retardation by affecting the growth hormone (GH) - insulin-like growth factor-1 (IGF 1) somatotropic axis, but also other, GH-independent sites. Recently, the GH receptor (GHR) gene was found to have a common polymorphism (P) that leads to a deletion (d3) or retention of exon 3. In this study, we tested the hypothesis that the GH receptor polymorphism (GHR-P) maybe one of the significant variants that determines the degree of growth delay among patients with CD. GHR genotyping was performed on 56 children with newly diagnosed CD (24 females, 32 males, mean age of 12.9 +/- 3.3 years) who were followed at our institution between the years 1997-2007. Correlation analysis included genotype, measures of growth and the somatotropic axis, and anthropometrics. Within the group, 31 (12 girls, 19 boys) expressed the full length GHR allele, 10 (4 girls, 6 boys) were d3-GHR homozygotes and 15 (7 girls, 8 boys) were d3-GHR heterozygotes. No significant differences were found between the GHR genotypes and patient's height and/or growth velocity, or any other measures that we evaluated. The presence of a well-studied and common GHR polymorphism does not appear to be responsible for the variability of growth delay observed in patients with Cushing disease. C1 NIH, Sect Endocrinol & Genet, Program Dev Endocrinol & Genet, Bethesda, MD 20892 USA. NIH, Pediat Endocrinol Interinst Training Program, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHD, Sect Endocrinol & Genet, Director Pediat Endocrinol Training Program, DEB,NIH, Bldg 10 CRC,Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU United States National Institutes of Health, National Institute of Child Health & Human Development (NICHD) [Z01-HD-000642-04] FX The described studies were supported by the United States National Institutes of Health, National Institute of Child Health & Human Development (NICHD) intramural project Z01-HD-000642-04 to C.A. Stratakis. NR 30 TC 2 Z9 2 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0018-5043 J9 HORM METAB RES JI Horm. Metab. Res. PD MAR PY 2010 VL 42 IS 3 BP 194 EP 197 DI 10.1055/s-0029-1242744 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 568CY UT WOS:000275500600007 PM 20013551 ER PT J AU Franceschini, N Voruganti, VS Haack, K Almasy, L Laston, S Goring, HHH Umans, JG Lee, ET Best, LG Fabsitz, RR MacCluer, JW Howard, BV North, KE Cole, SA AF Franceschini, Nora Voruganti, V. Saroja Haack, Karin Almasy, Laura Laston, Sandy Goering, Harald H. H. Umans, Jason G. Lee, Elisa T. Best, Lyle G. Fabsitz, Richard R. MacCluer, Jean W. Howard, Barbara V. North, Kari E. Cole, Shelley A. TI The association of the MYH9 gene and kidney outcomes in American Indians: the Strong Heart Family Study SO HUMAN GENETICS LA English DT Article ID TYPE-2 DIABETES-MELLITUS; STAGE RENAL-DISEASE; AFRICAN-AMERICANS; LINKAGE DISEQUILIBRIUM; CARDIOVASCULAR-DISEASE; RISK; POLYMORPHISMS; ALBUMINURIA; COMMITTEE AB Chronic kidney disease (CKD) is an important public health problem in American Indian populations. Recent research has identified associations of polymorphisms in the myosin heavy chain type II isoform A (MYH9) gene with hypertensive CKD in African-Americans. Whether these associations are also present among American Indian individuals is unknown. To evaluate the role of genetic polymorphisms in the MYH9 gene on kidney disease in American Indians, we genotyped 25 SNPs in the MYH9 gene region in 1,119 comparatively unrelated individuals. Four SNPs failed, and one SNP was monomorphic. We inferred haplotypes using seven SNPs within the region of the previously described E haplotype using Phase v2.1. We studied the association between 20 MYH9 SNPs with kidney function (estimated glomerular filtration rate, eGFR) and CKD (eGFR < 60 ml/min/1.73 m(2) or renal replacement therapy or kidney transplant) using age-, sex- and center-adjusted models and measured genotyped within the variance component models. MYH9 SNPs were not significantly associated with kidney traits in additive or recessive genetic adjusted models. MYH9 haplotypes were also not significantly associated with kidney outcomes. In conclusion, common variants in MYH9 polymorphisms may not confer an increased risk of CKD in American Indian populations. Identification of the actual functional genetic variation responsible for the associations seen in African-Americans will likely help to clarify the lack of replication of this gene in our population of American Indians. C1 [Franceschini, Nora; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27514 USA. [Voruganti, V. Saroja; Haack, Karin; Almasy, Laura; Laston, Sandy; Goering, Harald H. H.; MacCluer, Jean W.; Cole, Shelley A.] SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. [Umans, Jason G.] Georgetown Univ, Med Ctr, Div Nephrol & Hypertens, Washington, DC 20007 USA. [Lee, Elisa T.] Univ Oklahoma, Hlth Sci Ctr, Ctr Amer Indian Hlth Res, Coll Publ Hlth, Oklahoma City, OK USA. [Best, Lyle G.] Missouri Breaks Ind Res Inc, Timber Lake, SD USA. [Fabsitz, Richard R.] NHLBI, Div Cardiovasc Sci, Bethesda, MD 20892 USA. [Umans, Jason G.; Howard, Barbara V.; North, Kari E.] MedStar Res Inst, Washington, DC USA. [North, Kari E.] Univ N Carolina, Ctr Genome Sci, Chapel Hill, NC USA. RP Franceschini, N (reprint author), Univ N Carolina, Dept Epidemiol, 137 E Franklin St,Suite 306 CB 8050, Chapel Hill, NC 27514 USA. EM noraf@unc.edu FU National Heart, Lung, and Blood Institute, Bethesda, MD [U01-HL65520, U01-HL41642, U01-HL41652, U01-HL41654, U01-HL65521]; National Institutes of Health [MH59490] FX This work was supported by grants U01-HL65520, U01-HL41642, U01-HL41652, U01-HL41654, and U01-HL65521 from the National Heart, Lung, and Blood Institute, Bethesda, MD. Development of SOLAR was supported by National Institutes of Health grant MH59490. NR 22 TC 13 Z9 13 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD MAR PY 2010 VL 127 IS 3 BP 295 EP 301 DI 10.1007/s00439-009-0769-8 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 554TE UT WOS:000274456500003 PM 19921264 ER PT J AU Hehr, U Pineda-Alvarez, DE Uyanik, G Hu, P Zhou, N Hehr, A Schell-Apacik, C Altus, C Daumer-Haas, C Meiner, A Steuernagel, P Roessler, E Winkler, J Muenke, M AF Hehr, Ute Pineda-Alvarez, Daniel E. Uyanik, Goekhan Hu, Ping Zhou, Nan Hehr, Andreas Schell-Apacik, Chayim Altus, Carola Daumer-Haas, Cornelia Meiner, Annechristin Steuernagel, Peter Roessler, Erich Winkler, Juergen Muenke, Maximilian TI Heterozygous mutations in SIX3 and SHH are associated with schizencephaly and further expand the clinical spectrum of holoprosencephaly SO HUMAN GENETICS LA English DT Article ID SONIC HEDGEHOG GENE; GERMLINE MUTATIONS; EMX2; POPULATION; FEATURES AB Schizencephaly (SCH) is a clinically and etiologically heterogeneous cerebral malformation presenting as unilateral or bilateral hemispheric cleft with direct connection between the inner and outer liquor spaces. The SCH cleft is usually lined by gray matter, which appears polymicrogyric implying an associated impairment of neuronal migration. The majority of SCH patients are sporadic, but familial SCH has been described. An initial report of heterozygous mutations in the homeobox gene EMX2 could not be confirmed in 52 patients investigated in this study in agreement with two independent SCH patient cohorts published previously. SCH frequently occurs with additional cerebral malformations like hypoplasia or aplasia of the septum pellucidum or optic nerve, suggesting the involvement of genes important for the establishment of midline forebrain structures. We therefore considered holoprosencephaly (HPE)-associated genes as potential SCH candidates and report for the first time heterozygous mutations in SIX3 and SHH in a total of three unrelated patients and one fetus with SCH; one of them without obvious associated malformations of midline forebrain structures. Three of these mutations have previously been reported in independent patients with HPE. SIX3 acts directly upstream of SHH, and the SHH pathway is a key regulator of ventral forebrain patterning. Our data indicate that in a subset of patients SCH may develop as one aspect of a more complex malformation of the ventral forebrain, directly result from mutations in the SHH pathway and hence be considered as yet another feature of the broad phenotypic spectrum of holoprosencephaly. C1 [Hehr, Ute; Hehr, Andreas] Univ Klinikum D3, Ctr Human Genet, D-93053 Regensburg, Germany. [Hehr, Ute] Univ Regensburg, Dept Human Genet, Regensburg, Germany. [Pineda-Alvarez, Daniel E.; Hu, Ping; Zhou, Nan; Roessler, Erich; Muenke, Maximilian] NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. [Uyanik, Goekhan] Univ Regensburg, Dept Neurol, Regensburg, Germany. [Schell-Apacik, Chayim] Univ Munich, Inst Social Pediat & Adolescent Med, Munich, Germany. [Daumer-Haas, Cornelia] Prenatal Med Munich, Munich, Germany. [Steuernagel, Peter] Klinikum Oldenburg, Dept Clin Genet & Cytogenet, Oldenburg, Germany. [Winkler, Juergen] Univ Hosp Erlangen, Div Mol Neurol, Erlangen, Germany. RP Hehr, U (reprint author), Univ Klinikum D3, Ctr Human Genet, Franz Josef Strauss Allee 11, D-93053 Regensburg, Germany. EM ute.hehr@humangenetik-regensburg.de FU Intramural NIH HHS [ZIA HG000209-10] NR 30 TC 14 Z9 16 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-6717 J9 HUM GENET JI Hum. Genet. PD MAR PY 2010 VL 127 IS 5 BP 555 EP 561 DI 10.1007/s00439-010-0797-4 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 583HP UT WOS:000276665000008 PM 20157829 ER PT J AU Traherne, JA Martin, M Ward, R Ohashi, M Pellett, F Gladman, D Middleton, D Carrington, M Trowsdale, J AF Traherne, James A. Martin, Maureen Ward, Rosemary Ohashi, Maki Pellett, Fawnda Gladman, Dafna Middleton, Derek Carrington, Mary Trowsdale, John TI Mechanisms of copy number variation and hybrid gene formation in the KIR immune gene complex SO HUMAN MOLECULAR GENETICS LA English DT Article ID IMMUNOGLOBULIN-LIKE RECEPTOR; SYSTEMIC-LUPUS-ERYTHEMATOSUS; HUMAN GENOME; ALLELIC POLYMORPHISM; STRUCTURAL VARIATION; HAPLOTYPES CONTAIN; CELL-RECEPTOR; HUMAN HISTORY; FINE-SCALE; NK CELLS AB The fine-scale structure of the majority of copy number variation (CNV) regions remains unknown. The killer immunoglobulin receptor (KIR) gene complex exhibits significant CNV. The evolutionary plasticity of the KIRs and their broad biomedical relevance makes it important to understand how these immune receptors evolve. In this paper, we describe haplotype re-arrangement creating novel loci at the KIR complex. We completely sequenced, after fosmid cloning, two rare contracted haplotypes. Evidence of frequent hybrid KIR genes in samples from many populations suggested that re-arrangements may be frequent and selectively advantageous. We propose mechanisms for formation of novel hybrid KIR genes, facilitated by protrusive non-B DNA structures at transposon recombination sites. The heightened propensity to generate novel hybrid KIR receptors may provide a proactive evolutionary measure, to militate against pathogen evasion or subversion. We propose that CNV in KIR is an evolutionary strategy, which KIR typing for disease association must take into account. C1 [Traherne, James A.; Ward, Rosemary; Ohashi, Maki; Trowsdale, John] Univ Cambridge, Dept Pathol, Div Immunol, Cambridge CB2 1QP, England. [Martin, Maureen; Carrington, Mary] SAIC Frederick Inc, Expt Immunol Lab, Canc & Inflammat Program, NCI Frederick, Frederick, MD 21702 USA. [Martin, Maureen; Carrington, Mary] MIT & Harvard, Ragon Inst MGH, Boston, MA 02129 USA. [Middleton, Derek] Univ Liverpool, Liverpool Univ Hosp, Liverpool L69 3BX, Merseyside, England. [Middleton, Derek] Univ Liverpool, Sch Infect & Host Def, Liverpool L69 3BX, Merseyside, England. [Pellett, Fawnda; Gladman, Dafna] Toronto Western Res Inst, Toronto, ON M5T 2S8, Canada. RP Traherne, JA (reprint author), Univ Cambridge, Dept Pathol, Div Immunol, Tennis Court Rd, Cambridge CB2 1QP, England. EM jat51@cam.ac.uk FU MRC; National Cancer Institute; National Institutes of Health [HHSN261200800001E] FX This work was supported by the MRC (www. mrc. ac. uk). This project has been funded in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government. This Research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. NR 53 TC 46 Z9 46 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 1 PY 2010 VL 19 IS 5 BP 737 EP 751 DI 10.1093/hmg/ddp538 PG 15 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 553CD UT WOS:000274341400001 PM 19959527 ER PT J AU Rhee, DB Wang, YS Mizesko, M Zhou, F Haneline, L Liu, Y AF Rhee, David B. Wang, Yisong Mizesko, Melissa Zhou, Fang Haneline, Laura Liu, Yie TI FANCC suppresses short telomere-initiated telomere sister chromatid exchange SO HUMAN MOLECULAR GENETICS LA English DT Article ID ABERRANT HOMOLOGOUS RECOMBINATION; DNA-DAMAGE RESPONSE; STEM-CELLS; REPOPULATING ABILITY; DEFICIENT MOUSE; ALT CELLS; ANEMIA; MICE; LENGTH; REPAIR AB Telomere shortening has been linked to rare human disorders that present with bone marrow failure including Fanconi anemia (FA). FANCC is one of the most commonly mutated FA genes in FA patients and the FANCC subtype tends to have a relatively early onset of bone marrow failure and hematologic malignancies. Here, we studied the role of Fancc in telomere length regulation in mice. Deletion of Fancc (Fancc(-/-)) did not affect telomerase activity, telomere length or telomeric end-capping in a mouse strain possessing intrinsically long telomeres. However, ablation of Fancc did exacerbate telomere attrition when murine bone marrow cells experienced high cell turnover after serial transplantation. When Fancc(-/-) mice were crossed into a telomerase reverse transcriptase heterozygous or null background (Tert(+/-) or Tert(-/-)) with short telomeres, Fancc deficiency led to an increase in the incidence of telomere sister chromatid exchange. In contrast, these phenotypes were not observed in Tert mutant mice with long telomeres. Our data indicate that Fancc deficiency accelerates telomere shortening during high turnover of hematopoietic cells and promotes telomere recombination initiated by short telomeres. C1 [Mizesko, Melissa; Haneline, Laura] Indiana Univ, Sch Med, Dept Pediat, Herman B Wells Ctr, Indianapolis, IN 46202 USA. [Mizesko, Melissa; Haneline, Laura] Indiana Univ, Sch Med, Dept Microbiol & Immunol, Herman B Wells Ctr, Indianapolis, IN 46202 USA. [Rhee, David B.; Zhou, Fang; Liu, Yie] NIA, Lab Mol Gerontol, NIH, Biomed Res Ctr, Baltimore, MD 21224 USA. [Wang, Yisong] Oak Ridge Natl Lab, Biosci Div, Oak Ridge, TN USA. RP Haneline, L (reprint author), Indiana Univ, Sch Med, Dept Pediat, Herman B Wells Ctr, R4-476,1044 W Walnut St, Indianapolis, IN 46202 USA. EM lhanelin@iupui.edu; liuyie@mail.nih.gov FU Intramural Research Program of the NIA; National Institutes of Health; U. S. Public Health Services [R01 HL077175, P30 CA82709, T32 DK07519]; Riley Children's Foundation FX This study was supported by the Intramural Research Program of the NIA, National Institutes of Health (Y. L.), U. S. Public Health Services Grants R01 HL077175 (L. H.), P30 CA82709 (L. H.), T32 DK07519 (M. M.) and the Riley Children's Foundation (L. H.). NR 54 TC 17 Z9 18 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD MAR 1 PY 2010 VL 19 IS 5 BP 879 EP 887 DI 10.1093/hmg/ddp556 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 553CD UT WOS:000274341400012 PM 20022886 ER PT J AU Tom, SE Cooper, R Kuh, D Guralnik, JM Hardy, R Power, C AF Tom, Sarah E. Cooper, Rachel Kuh, Diana Guralnik, Jack M. Hardy, Rebecca Power, Chris TI Fetal environment and early age at natural menopause in a British birth cohort study SO HUMAN REPRODUCTION LA English DT Article DE menopause; fetal environment; birth cohort; birthweight; fetal growth ID CAUSE-SPECIFIC MORTALITY; SYSTOLIC BLOOD-PRESSURE; LIFE-STYLE FACTORS; INTRAUTERINE GROWTH; GESTATIONAL-AGE; HEART-DISEASE; RISK-FACTORS; SWEDISH MEN; WOMEN; WEIGHT AB Early life development may influence the timing of natural menopause through association with size of the initial follicle pool or early follicular loss. This study examines the relationships of birthweight, gestational age and birthweight standardized by gestational age with early menopause in the 1958 British birth cohort study. Study participants were over 2900 women with data on birthweight, gestational age (obtained at birth), menopausal status at age 44-45 years and potential confounding factors. Logistic regression was used to study relationships of birthweight, gestational age and birthweight standardized by gestational age with post-menopausal status by 44-45 years, with and without adjustments for confounding factors. There was a U-shaped association between birthweight and menopausal status at 44-45 years: women at either extremes of birthweight (< 2.5 and >= 4.0 kg) had increased odds of post-menopausal status compared with those weighing 3.0-3.49 kg [odds ratio (OR) = 1.91, 95% confidence interval (CI) 1.08, 3.38; 1.81, 95% CI 1.11, 2.97, respectively]. Women with higher birthweight standardized by gestational age (which indicates faster fetal growth rate) also had increased odds of being post-menopausal by 44-45 years (OR for fastest quarter versus second fastest quarter = 1.80; 95% CI 1.16, 2.81). These associations persisted after adjustment for socioeconomic position at birth, adult smoking status and use of oral contraceptives. These findings suggest that variations in fetal environment may be associated with the timing of menopause. Given that extremes of birthweight and higher birthweight standardized by gestational age were associated with earlier age at menopause, mechanisms related to these characteristics that also regulate ovarian function should be investigated further. C1 [Tom, Sarah E.] Grp Hlth Res Inst, Seattle, WA 98101 USA. [Cooper, Rachel; Kuh, Diana; Hardy, Rebecca] MRC, Unit Lifelong Hlth & Ageing, London WC1B 5JU, England. [Guralnik, Jack M.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Power, Chris] UCL, Inst Child Hlth, MRC, Ctr Epidemiol Child Hlth, London WC1N 1EH, England. RP Tom, SE (reprint author), Grp Hlth Res Inst, 1730 Minor Aveue,Suite 1600, Seattle, WA 98101 USA. EM tom.s@ghc.org OI Cooper, Rachel/0000-0003-3370-5720 FU National Institute on Aging, National Institutes of Health; Medical Research Council [G0000934] FX S. E. T. and J. G. were funded by the Intramural Research Program at the National Institute on Aging, National Institutes of Health. R. C., D. K. and R. H. were funded by the Medical Research Council. The biomedical examination of the 1958 cohort was funded by the Medical Research Council(grant G0000934 awarded under the Health of the Public Initiative). The Great Ormond Street Hospital/UCL Institute of Child Health receives a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. The Centre for Paediatric Epidemiology and Biostatistics also benefits from the funding support from the Medical Research Council in its capacity as the MRC Centre of Epidemiology for Child Health. NR 51 TC 22 Z9 22 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD MAR PY 2010 VL 25 IS 3 BP 791 EP 798 DI 10.1093/humrep/dep451 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 555EL UT WOS:000274490700032 PM 20047935 ER PT J AU Esona, MD Foytich, K Wang, YH Shin, G Wei, G Gentsch, JR Glass, RI Jiang, BM AF Esona, Mathew D. Foytich, Kimberly Wang, Yuhuan Shin, Gary Wei, Gang Gentsch, Jon R. Glass, Roger I. Jiang, Baoming TI Molecular characterization of human rotavirus vaccine strain CDC-9 during sequential passages in Vero cells SO HUMAN VACCINES LA English DT Article DE rotavirus; rotavirus vaccine; CDC-9 ID NONSTRUCTURAL GLYCOPROTEIN NSP4; POLYMERASE CHAIN-REACTION; GROUP-A; PORCINE ROTAVIRUS; ATTENUATED VACCINE; NUCLEIC-ACID; VIRUS; GENE; IDENTIFICATION; DIARRHEA AB We have developed several candidate human rotavirus vaccine strains with common serotypes via adaptation in Vero cells, adhering to the Good Laboratory Practice (GLP) guidelines. We sequenced the entire genome of a G1P[8] strain CDC-9 in original stool and passaged materials from Vero cells and examined its genetic relatedness to the prototype human rotavirus KU and other strains. With the exception of VP3 gene which was closely related to that of strain DS-1, the culture-adapted CDC-9 strain shared moderate to high nt (range 83.4%-95.1%) and deduced aa (range 81.3%-97.9%) sequence identities with the KU and other G1P[8] strains. Alignments of the deduced aa sequences of 11 gene segments of the wild-type and culture-adapted CDC-9 showed complete sequence identity in genes encoding NSP2, NSP3, NSP4, VP1, VP2, VP3 and VP7, a single aa change in genes coding for NSP1, NSP5 and VP6 and several scattered aa changes in the VP4 gene during the passage in Vero cells. Two of the VP4 aa substitutions (385 and 388) are within sites associated with neutralization resistant mutants selected by cross-reactive monoclonal antibodies. Although some sequence changes were evident, we do not know if these changes contribute to the possible attenuation of this strain. Further testing of this vaccine strain in clinical trials is justified. C1 [Esona, Mathew D.; Foytich, Kimberly; Wang, Yuhuan; Shin, Gary; Wei, Gang; Gentsch, Jon R.; Glass, Roger I.; Jiang, Baoming] Ctr Dis Control & Prevent, Div Viral Dis, Atlanta, GA 30333 USA. [Glass, Roger I.] NIH, Fogerty Int Ctr, Bethesda, MD 20892 USA. RP Jiang, BM (reprint author), Ctr Dis Control & Prevent, Div Viral Dis, Atlanta, GA 30333 USA. EM bxj4@cdc.gov FU Cooperative Research and Development Agreement with Sanofi Pasteur, Lyon, France FX We thank Charles Humphrey for performing electron microscope analysis. This study was supported in part by a Cooperative Research and Development Agreement with Sanofi Pasteur, Lyon, France. NR 51 TC 8 Z9 9 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1554-8600 J9 HUM VACCINES JI Hum. Vaccines PD MAR PY 2010 VL 6 IS 3 BP 247 EP 253 PG 7 WC Biotechnology & Applied Microbiology; Immunology SC Biotechnology & Applied Microbiology; Immunology GA 589VZ UT WOS:000277183600011 ER PT J AU Wang, KL Cheng, HM Sung, SH Chuang, SY Li, CH Spurgeon, HA Ting, CT Najjar, SS Lakatta, EG Yin, FCP Chou, P Chen, CH AF Wang, Kang-Ling Cheng, Hao-Min Sung, Shih-Hsien Chuang, Shao-Yuan Li, Cheng-Hung Spurgeon, Harold A. Ting, Chih-Tai Najjar, Samer S. Lakatta, Edward G. Yin, Frank C. P. Chou, Pesus Chen, Chen-Huan TI Wave Reflection and Arterial Stiffness in the Prediction of 15-Year All-Cause and Cardiovascular Mortalities A Community-Based Study SO HYPERTENSION LA English DT Article DE wave reflection; pulse wave velocity; arterial stiffness; vascular aging; mortality; epidemiology ID LEFT-VENTRICULAR MASS; BLOOD-PRESSURE; AUGMENTATION INDEX; AORTIC STIFFNESS; PULSE PRESSURE; HEART-DISEASE; UPPER-LIMB; VELOCITY; EVENTS; WOMEN AB The value of increased arterial wave reflection, usually assessed by the transit time-dependent augmentation index and augmented pressure (Pa), in the prediction of cardiovascular events may have been underestimated. We investigated whether the transit time-independent measures of reflected wave magnitude predict cardiovascular outcomes independent of arterial stiffness indexed by carotid-femoral pulse wave velocity. A total of 1272 participants (47% women; mean age: 52 +/- 13 years; range: 30 to 79 years) from a community-based survey were studied. Carotid pressure waveforms derived by tonometry were decomposed into their forward wave amplitudes, backward wave amplitudes (Pb), and a reflection index (=[Pb/(forward wave amplitude + Pb)]), in addition to augmentation index, Pa, and reflected wave transit time. During a median follow-up of 15 years, 225 deaths occurred (17.6%), including 64 cardiovascular origins (5%). In univariate Cox proportional hazard regression analysis, pulse wave velocity, Pa, and Pb predicted all-cause and cardiovascular mortality in both men and women, whereas augmentation index, reflected wave transit time, and reflection index were predictive only in men. In multivariate analysis accounting for age, height, and heart rate, Pb predicted cardiovascular mortality in both men and women, whereas Pa was predictive only in men. Per 1-SD increment (6 mm Hg), Pb predicted 15-year cardiovascular mortality independent of brachial but not central pressure, pulse wave velocity, augmentation index, Pa, and conventional cardiovascular risk factors with hazard ratios of approximate to 1.60 (all P<0.05). In conclusion, Pb, a transit time-independent measure of reflected wave magnitude, predicted long-term cardiovascular mortality in men and women independent of arterial stiffness. (Hypertension. 2010; 55: 799-805.) C1 [Chen, Chen-Huan] Taipei Vet Gen Hosp, Div Cardiol, Dept Med Res & Educ, Taipei, Taiwan. [Wang, Kang-Ling; Sung, Shih-Hsien; Li, Cheng-Hung] Taipei Vet Gen Hosp, Dept Med, Taipei, Taiwan. [Chuang, Shao-Yuan] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan. [Ting, Chih-Tai] Taichung Vet Gen Hosp, Ctr Cardiovasc, Taichung, Taiwan. [Spurgeon, Harold A.; Najjar, Samer S.; Lakatta, Edward G.] NIA, Cardiovasc Sci Lab, Intramural Res Program, Baltimore, MD 21224 USA. [Yin, Frank C. P.] Washington Univ, Dept Biomed Engn, St Louis, MO USA. [Chen, Chen-Huan] Natl Yang Ming Univ, Cardiovasc Res Ctr, Taipei 112, Taiwan. [Chou, Pesus; Chen, Chen-Huan] Natl Yang Ming Univ, Dept Publ Hlth, Taipei 112, Taiwan. RP Chen, CH (reprint author), Taipei Vet Gen Hosp, Div Cardiol, Dept Med Res & Educ, 201 Sec 2,Shih Pai Rd, Taipei, Taiwan. EM chench@vghtpe.gov.tw RI Chuang, Shao-Yuan/B-3478-2011 FU National Science Council (NSC) [96-2314-B-010-035-MY3]; Taipei Veterans General Hospital [V98C1-028]; Research Foundation of Cardiovascular Medicine (Taipei, Taiwan, Republic of China) [NO1-AG-1-2118]; National Institute on Aging, National Institutes of Health FX This work was supported in part by a grant from the National Science Council (NSC 96-2314-B-010-035-MY3), an intramural grant from the Taipei Veterans General Hospital (grant V98C1-028), Grants-in-Aid from the Research Foundation of Cardiovascular Medicine (Taipei, Taiwan, Republic of China), Research and Development contract NO1-AG-1-2118, and the Intramural Research Program of the National Institute on Aging, National Institutes of Health. NR 36 TC 170 Z9 175 U1 4 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD MAR 1 PY 2010 VL 55 IS 3 BP 799 EP 805 DI 10.1161/HYPERTENSIONAHA.109.139964 PG 7 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 557GV UT WOS:000274658500032 PM 20065155 ER PT J AU Grainger, JR Hall, JA Bouladoux, N Oldenhove, G Belkaid, Y AF Grainger, John R. Hall, Jason A. Bouladoux, Nicolas Oldenhove, Guillaume Belkaid, Yasmine TI Microbe-dendritic cell dialog controls regulatory T-cell fate SO IMMUNOLOGICAL REVIEWS LA English DT Review DE dendritic cell; regulatory T cell; Foxp3+; microbe; commensal ID TOLL-LIKE RECEPTORS; TRANSCRIPTION FACTOR FOXP3; EXCRETORY-SECRETORY PRODUCTS; INTESTINAL EPITHELIAL-CELLS; INFLAMMATORY-BOWEL-DISEASE; STIMULATORY CPG MOTIFS; TRANS-RETINOIC ACID; GROWTH-FACTOR-BETA; TGF-BETA; CROHNS-DISEASE AB Each microenvironment is controlled by a specific set of regulatory elements that have to be finely and constantly tuned to maintain local homeostasis. These environments could be site specific, such as the gut environment, or induced by chronic exposure to microbes. Various populations of dendritic cells are central to the orchestration of this control. In this review, we discuss some new findings associating dendritic cells from defined compartments with the induction and control of regulatory T cells in the context of exposure to both commensal and pathogenic microbes. C1 [Grainger, John R.; Hall, Jason A.; Bouladoux, Nicolas; Oldenhove, Guillaume; Belkaid, Yasmine] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, Bethesda, MD 20894 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immunol Unit, Parasit Dis Lab, 4 Ctr Dr,B1-28, Bethesda, MD 20894 USA. EM ybelkaid@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. We apologize to those authors whose work we were unable to cite because of space limitations. NR 135 TC 27 Z9 28 U1 0 U2 2 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD MAR PY 2010 VL 234 BP 305 EP 316 PG 12 WC Immunology SC Immunology GA 559HC UT WOS:000274813200020 PM 20193027 ER PT J AU Padhan, K Varma, R AF Padhan, Kartika Varma, Rajat TI Immunological synapse: a multi-protein signalling cellular apparatus for controlling gene expression SO IMMUNOLOGY LA English DT Review DE immune synapses; signalling; signal transduction; systems biology; T-cell receptor; transcription factors (gene regulation) ID NF-KAPPA-B; CD4(+) T-CELLS; ALLERGIC AIRWAY INFLAMMATION; GLYCOGEN-SYNTHASE KINASE-3; LACKING C-FOS; TRANSCRIPTION FACTOR; NUCLEAR-LOCALIZATION; IMMUNE-RESPONSES; MICE LACKING; IN-VIVO AB P>The interaction of T cells with antigen-presenting cells is the hallmark of adaptive immunity. In vitro studies have described the formation of an immunological synapse between these cells, and intra-vital imaging has described in great detail the dynamics of these interactions. The immunological synapse has become a paradigm to study signals exchanged between the two cells. A wealth of information has been amassed regarding the localization of signalling molecules, their kinetics and the transcription factors they activate. We continue to discover mechanisms that cause receptors and signalling molecules to compartmentalize in the cell; however, the emerging challenge lies in understanding how the immunological synapse contributes to differentiation. Here, we review some of the transcription factors activated downstream of T-cell receptor signalling and discuss mechanisms by which antigen dose and affinity may influence differentiation. Antigen affinity might change the kind of transcription factors that are activated whereas antigen dose is likely to influence the temporal dynamics of the transcription factors. The immunological synapse is therefore likely to influence differentiation by modulating the trafficking of transcription factors and by promoting asymmetric cell division, an emerging concept. C1 [Padhan, Kartika; Varma, Rajat] NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Varma, R (reprint author), NIAID, Cellular & Mol Immunol Lab, NIH, 4 Ctr Dr, Bethesda, MD 20892 USA. EM varmarajat@mail.nih.gov RI Varma, Rajat/I-1209-2012 OI Varma, Rajat/0000-0001-5131-0402 NR 105 TC 13 Z9 13 U1 0 U2 4 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0019-2805 J9 IMMUNOLOGY JI Immunology PD MAR PY 2010 VL 129 IS 3 BP 322 EP 328 DI 10.1111/j.1365-2567.2009.03241.x PG 7 WC Immunology SC Immunology GA 551WF UT WOS:000274242500002 PM 20409153 ER PT J AU Paul, WE AF Paul, William E. TI What determines Th2 differentiation, in vitro and in vivo? SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Review DE IL-4; IL-13; GATA3; Th1/Th2; basophils; STAT5 ID T-CELL DIFFERENTIATION; IMMUNE-RESPONSES; INTERFERON-GAMMA; DENDRITIC CELLS; IL-4; BASOPHILS; CYTOKINE; ANTIGEN; GATA-3; TSLP AB We have known since 1991 how to induce naive CD4 T cells to differentiate in vitro into Th2 cells and, over the ensuing years, a comprehensive picture of the molecules involved in this important process has emerged. GATA3 and STAT5 are both essential for in vitro differentiation, stimulating naive cells through a process involving induction, which is T-cell receptor (TCR) dependent but interleukin (IL)-4 independent, and commitment, which is IL-4 dependent. Th2 differentiation in vivo appears more complex. GATA3 and probably STAT5 are required in vivo but, at least for certain helminth infections, the IL-4/IL-4Ra/STAT6 pathway is dispensable. The role of thymic stromal lymphopoietin and of low TCR signal strength and the participation of basophils in establishing a Th2-baising in vivo environment have achieved considerable attention. Here I discuss the major players in Th2 differentiation particularly as they may exert their effects in vivo. Immunology and Cell Biology (2010) 88, 236-239; doi: 10.1038/icb.2010.2; published online 16 February 2010 C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Paul, WE (reprint author), NIAID, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Room IIN311, Bethesda, MD 20892 USA. EM wpaul@niaid.nih.gov FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX The work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 38 TC 41 Z9 43 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD MAR-APR PY 2010 VL 88 IS 3 BP 236 EP 239 DI 10.1038/icb.2010.2 PG 4 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 575OM UT WOS:000276076800003 PM 20157328 ER PT J AU Forbes, E van Panhuys, N Min, B Le Gros, G AF Forbes, Elizabeth van Panhuys, Nicholas Min, Booki Le Gros, Graham TI Differential requirements for IL-4/STAT6 signalling in CD4 T-cell fate determination and Th2-immune effector responses SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Review DE Th2; IL-4; STAT6; differentiation; effector response ID ACTIVATED PROTEIN-KINASE; ANTIGEN-PRESENTING CELLS; TH2 IMMUNE-RESPONSES; VIVO IL-4 RESPONSES; IN-VIVO; DENDRITIC CELLS; CUTTING EDGE; NIPPOSTRONGYLUS-BRASILIENSIS; AIRWAYS HYPERREACTIVITY; EXPERIMENTAL ASTHMA AB Improved analytical tools have revealed that the development and expression of a Th2 immune response can be broken down into distinct stages with respect to the cytokine microenvironment that is required. Although IL-4 and its STAT6-signalling pathway are critical for the expression of Th2 effector immune responses in peripheral tissues such as the skin, lung and gut, IL-4 and STAT6 signalling are not required for the initial generation of IL-4-producing Th2 cells in the lymph node. This finding reveals that we have yet to identify the key cytokine or microenvironment that stimulates the development of this most intriguing CD4(+) T-helper subset and emphasises the tissue specificity and timing of IL-4/STAT6-dependent Th2 effector responses. Immunology and Cell Biology (2010) 88, 240-243; doi: 10.1038/icb.2009.101; published online 15 December 2009 C1 [Forbes, Elizabeth; Le Gros, Graham] Malaghan Inst Med Res, Wellington 6242, New Zealand. [van Panhuys, Nicholas] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Min, Booki] Lerner Res Inst, Dept Immunol, Cleveland, OH USA. RP Le Gros, G (reprint author), Malaghan Inst Med Res, POB 7060, Wellington 6242, New Zealand. EM glegros@malaghan.org.nz RI Le Gros, Graham/C-6725-2011; Forbes-Blom, Elizabeth/I-3648-2013; van Panhuys, Nicholas/E-1812-2011; OI van Panhuys, Nicholas/0000-0003-2199-852X FU Health Research Council of New Zealand; Marjorie Barclay Trust; Marsden Fund; AMI Insurance Ltd FX This research was supported by Program Grant funding from the Health Research Council of New Zealand, the Marjorie Barclay Trust, the Marsden Fund and AMI Insurance Ltd. NR 73 TC 20 Z9 22 U1 0 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD MAR-APR PY 2010 VL 88 IS 3 BP 240 EP 243 DI 10.1038/icb.2009.101 PG 4 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 575OM UT WOS:000276076800004 PM 20010912 ER PT J AU Zhu, JF AF Zhu, Jinfang TI Transcriptional regulation of Th2 cell differentiation SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Review DE T-cell differentiation; transcription factors; cytokines ID LOCUS-CONTROL REGION; CD4(+) T-CELLS; NF-KAPPA-B; ALLERGIC AIRWAY INFLAMMATION; THYMIC STROMAL LYMPHOPOIETIN; ANTIGEN-PRESENTING CELLS; HELPER TYPE-1 CELLS; IN-VIVO; IL-4 PRODUCTION; CYTOKINE PRODUCTION AB CD4 T helper 2 (Th2) cells have critical functions in immune responses against extracellular parasites and are involved in asthma and other allergic diseases. The differentiation of naive CD4 T cells into Th2 cells is initiated from T-cell receptor and cytokine-mediated signaling followed by upregulation of GATA3 and activation of signal transducer and activator of transcription 5 (STAT5), two indispensable events for this differentiation process. In this review, regulation of GATA3 expression and STAT5 activation and functions of these two transcription factors in inducing the expression of Th2 cytokines, cytokine receptors as well as epigenetic modification at Th2 cytokine locus are summarized. Furthermore, I present positive and negative regulatory networks important for Th2 cell commitment, selective growth of committed Th2 cells and suppression of alternative lineage fates. Finally, the difference between in vitro and in vivo Th2 differentiation is discussed. Immunology and Cell Biology (2010) 88, 244-249; doi: 10.1038/icb.2009.114; published online 12 January 2010 C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Zhu, JF (reprint author), NIAID, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 11N323, Bethesda, MD 20892 USA. EM jfzhu@niaid.nih.gov RI Zhu, Jinfang/B-7574-2012 FU Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA FX The work is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, USA. NR 118 TC 21 Z9 24 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0818-9641 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD MAR-APR PY 2010 VL 88 IS 3 BP 244 EP 249 DI 10.1038/icb.2009.114 PG 6 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 575OM UT WOS:000276076800005 PM 20065998 ER PT J AU Cunha, N Matsunaga, G Oliveira, P Lima, T Murad, A Araujo, AC Brigido, M Waters, M Fontes, A Silva, L Souza, G Bloch, C O'Keefe, B Saucedo, C Lewis, R Old, L Caballero, O Simpson, A Ritter, G Vianna, G Rech, E AF Cunha, Nicolau Matsunaga, Gabriela Oliveira, Paula Lima, Thaina Murad, Andre Araujo, Ana Claudia Brigido, Marcelo Waters, Michael Fontes, Aparecida Silva, Luciano Souza, Gustavo Bloch, Carlos O'Keefe, Barry Saucedo, Carrie Lewis, Randolph Old, Lloyd Caballero, Otavia Simpson, Andrew Ritter, Gerd Vianna, Giovanni Rech, Elibio TI Recombinant Proteins in Soybean Seeds Under Control of Legumes Storage Proteins Regulatory Sequences SO IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL LA English DT Meeting Abstract C1 [Cunha, Nicolau; Matsunaga, Gabriela; Oliveira, Paula; Lima, Thaina; Murad, Andre; Araujo, Ana Claudia; Silva, Luciano; Bloch, Carlos; Vianna, Giovanni; Rech, Elibio] Embrapa Genet Resources & Biotechnol, Parque Estacao Biol, BR-70770917 Brasilia, DF, Brazil. [Cunha, Nicolau; Matsunaga, Gabriela; Oliveira, Paula; Lima, Thaina; Brigido, Marcelo] Univ Brasilia, Dept Cellular Biol, BR-70910900 Brasilia, DF, Brazil. [Waters, Michael] Univ Queensland, Inst Mol Biosci, St Lucia, Qld 4072, Australia. [Waters, Michael] Univ Queensland, Sch Biomed Sci, St Lucia, Qld 4072, Australia. [Fontes, Aparecida] Ctr Cellular Therapy FMRP USP, Blood Ctr Ribeirao Preto, BR-14051140 Ribeirao Preto, SP, Brazil. [Souza, Gustavo] Waters Corp, Mass Spectrometry Applicat Res & Dev Lab, BR-06455020 Sao Paulo, Brazil. [O'Keefe, Barry; Saucedo, Carrie] NCI, Mol Targets Dev Program, Frederick, MD 21702 USA. [Lewis, Randolph] Univ Wyoming, Dept Mol Biol, Dept 3944, Laramie, WY 82071 USA. [Old, Lloyd; Caballero, Otavia; Simpson, Andrew; Ritter, Gerd] Ludwig Inst Canc Res Ltd, Mem Sloan Kettering Canc Ctr, New York Branch Human Canc Immunol, New York, NY 10065 USA. RI Brigido, Marcelo/A-1972-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1071-2690 J9 IN VITRO CELL DEV-AN JI In Vitro Cell. Dev. Biol.-Anim. PD SPR PY 2010 VL 46 SU S BP S63 EP S64 PG 2 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 695JX UT WOS:000285367500140 ER PT J AU Felek, S Muszynski, A Carlson, RW Tsang, TM Hinnebusch, BJ Krukonis, ES AF Felek, Suleyman Muszynski, Artur Carlson, Russell W. Tsang, Tiffany M. Hinnebusch, B. Joseph Krukonis, Eric S. TI Phosphoglucomutase of Yersinia pestis Is Required for Autoaggregation and Polymyxin B Resistance SO INFECTION AND IMMUNITY LA English DT Article ID GENE-ENCODING PHOSPHOMANNOMUTASE; ESCHERICHIA-COLI K-12; FUNCTIONAL-ANALYSIS; LIPOPOLYSACCHARIDE BIOSYNTHESIS; TRANSCRIPTIONAL REGULATION; ALPHA-PHOSPHOGLUCOMUTASE; CYCLIC BETA-1,2-GLUCAN; SALMONELLA-TYPHIMURIUM; PATHOGENIC YERSINIAE; BIOFILM FORMATION AB Yersinia pestis, the causative agent of plague, autoaggregates within a few minutes of cessation of shaking when grown at 28 degrees C. To identify the autoaggregation factor of Y. pestis, we performed mariner-based transposon mutagenesis. Autoaggregation-defective mutants from three different pools were identified, each with a transposon insertion at a different position within the gene encoding phosphoglucomutase (pgmA; y1258). Targeted deletion of pgmA in Y. pestis KIM5 also resulted in loss of autoaggregation. Given the previously defined role for phosphoglucomutase in antimicrobial peptide resistance in other organisms, we tested the KIM5 Delta pgmA mutant for antimicrobial peptide sensitivity. The Delta pgmA mutant displayed > 1,000-fold increased sensitivity to polymyxin B compared to the parental Y. pestis strain, KIM5. This sensitivity is not due to changes in lipopolysaccharide (LPS) since the LPSs from both Y. pestis KIM5 and the Delta pgmA mutant are identical based on a comparison of their structures by mass spectrometry ( MS), tandem MS, and nuclear magnetic resonance analyses. Furthermore, the ability of polymyxin B to neutralize LPS toxicity was identical for LPS purified from both KIM5 and the Delta pgmA mutant. Our results indicate that increased polymyxin B sensitivity of the Delta pgmA mutant is due to changes in surface structures other than LPS. Experiments with mice via the intravenous and intranasal routes did not demonstrate any virulence defect for the Delta pgmA mutant, nor was flea colonization or blockage affected. Our findings suggest that the activity of PgmA results in modification and/or elaboration of a surface component of Y. pestis responsible for autoaggregation and polymyxin B resistance. C1 [Felek, Suleyman; Krukonis, Eric S.] Univ Michigan, Sch Dent, Dept Biol & Mat Sci, Ann Arbor, MI 48109 USA. [Muszynski, Artur; Carlson, Russell W.] Univ Georgia, Complex Carbohydrate Res Ctr, Athens, GA 30602 USA. [Tsang, Tiffany M.; Krukonis, Eric S.] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Hinnebusch, B. Joseph] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT USA. RP Krukonis, ES (reprint author), Univ Michigan, Sch Dent, Dept Biol & Mat Sci, 1011 N Univ,Dent Bldg,RM 3204, Ann Arbor, MI 48109 USA. EM ekrukoni@umich.edu OI Muszynski, Artur/0000-0003-3497-9977 FU Biomedical Research Council at the University of Michigan School of Medicine; University of Michigan's Office of the Vice President for Research; Rackham School of Graduate Studies; Department of Energy [FG02-93ER20097] FX We thank Stephen Trent for helpful discussions concerning this work, Clayton Jarrett for assistance with the flea experiments, and J. Chris Fenno for critical reading of the manuscript.; This study was supported by a grant from the Biomedical Research Council at the University of Michigan School of Medicine and by grants from the University of Michigan's Office of the Vice President for Research and the Rackham School of Graduate Studies. This work was also partially supported by Department of Energy Grant FG02-93ER20097 to the Complex Carbohydrate Research Center. NR 79 TC 14 Z9 16 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2010 VL 78 IS 3 BP 1163 EP 1175 DI 10.1128/IAI.00997-09 PG 13 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 557FE UT WOS:000274654200027 PM 20028810 ER PT J AU Sutten, EL Norimine, J Beare, PA Heinzen, RA Lopez, JE Morse, K Brayton, KA Gillespie, JJ Brown, WC AF Sutten, Eric L. Norimine, Junzo Beare, Paul A. Heinzen, Robert A. Lopez, Job E. Morse, Kaitlyn Brayton, Kelly A. Gillespie, Joseph J. Brown, Wendy C. TI Anaplasma marginale Type IV Secretion System Proteins VirB2, VirB7, VirB11, and VirD4 Are Immunogenic Components of a Protective Bacterial Membrane Vaccine SO INFECTION AND IMMUNITY LA English DT Article ID T-CELL RESPONSES; AGROBACTERIUM-TUMEFACIENS VIRB7; COMPLEX TRANSPORT APPARATUS; LYMPHOCYTE RESPONSES; PERIPLASMIC SURFACE; GENE CONVERSION; OUTER MEMBRANES; MOLECULAR-BASIS; CHALLENGE; PHAGOCYTOPHILUM AB Anaplasma and related Ehrlichia spp. are important tick-borne, Gram-negative bacterial pathogens of livestock and humans that cause acute infection and disease and can persist. Immunization of cattle with an Anaplasma marginale fraction enriched in outer membranes (OM) can provide complete protection against disease and persistent infection. Serological responses of OM vaccinees to the OM proteome previously identified over 20 antigenic proteins, including three type IV secretion system (T4SS) proteins, VirB9-1, VirB9-2, and VirB10. Subsequent studies showed that these three proteins also stimulated CD4(+) T-cell responses in OM vaccinees. The T4SS, composed of a complex of proteins spanning the inner and outer membranes of certain bacteria, is an important virulence factor but is relatively unexplored as a vaccine target. The goal of this study was to determine if additional T4SS proteins are immunogenic for animals immunized with the protective OM fraction of A. marginale. T4SS proteins expressed by in vitro transcription and translation were screened for stimulating proliferation of T cells from OM vaccinees, and immunogenic proteins were expressed as recombinant proteins in Escherichia coli and their immunogenicity was verified. VirB2, a putative VirB7, VirB11, and VirD4 were immunogenic for OM vaccinees expressing several common major histocompatibility complex (MHC) class II haplotypes. VirB2 is encoded by multiple genes that share a conserved central region, and epitope mapping revealed T-cell epitopes in this region. The discovery of novel immunogenic T4SS proteins recognized by outbred individuals with common MHC haplotypes further justifies evaluating the T4SS as a potential vaccine candidate for pathogenic bacteria. C1 [Sutten, Eric L.; Norimine, Junzo; Lopez, Job E.; Morse, Kaitlyn; Brayton, Kelly A.; Brown, Wendy C.] Washington State Univ, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. [Beare, Paul A.; Heinzen, Robert A.] NIAID, Coxiella Pathogenesis Sect, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. [Lopez, Job E.] NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Gillespie, Joseph J.] Virginia Tech, Bioinformat Facil, Virginia Bioinformat Inst 0477, Blacksburg, VA 24061 USA. [Gillespie, Joseph J.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Brown, WC (reprint author), Washington State Univ, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. EM wbrown@vetmed.wsu.edu OI Morse, Kaitlyn/0000-0002-3077-2832; Gillespie, Joseph/0000-0002-5447-7264 FU National Institutes of Health (NIH) National Institutes of Allergy and Infectious Diseases (NIAID) [AI053692]; NIAID [R01AI017828, R01AI59118, HHSN266200400035C] FX We thank Shelley Whidbee, Emma Karel, and Ralph Horn for excellent technical assistance and Heather Fallquist for providing A. marginale RNA.; This research was supported by National Institutes of Health (NIH) National Institutes of Allergy and Infectious Diseases (NIAID) grant AI053692 (W. C. B.) and the Intramural Research Program at NIH, NIAID (R. A. H., P. A. B., and J. E. L.). J. J. G. acknowledges support from NIAID awards R01AI017828 and R01AI59118 to Abdu Azad (University of Maryland) and contract HHSN266200400035C to Bruno Sobral (Virginia Bioinformatics Institute at Virginia Tech). NR 75 TC 26 Z9 27 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0019-9567 EI 1098-5522 J9 INFECT IMMUN JI Infect. Immun. PD MAR PY 2010 VL 78 IS 3 BP 1314 EP 1325 DI 10.1128/IAI.01207-09 PG 12 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 557FE UT WOS:000274654200043 PM 20065028 ER PT J AU Henderson, DK Dembry, L Fishman, NO Grady, C Lundstrom, T Palmore, TN Sepkowitz, KA Weber, DJ AF Henderson, David K. Dembry, Louise Fishman, Neil O. Grady, Christine Lundstrom, Tammy Palmore, Tara N. Sepkowitz, Kent A. Weber, David J. CA Soc Healthcare Epidemiology Amer TI SHEA Guideline for Management of Healthcare Workers Who Are Infected with Hepatitis B Virus, Hepatitis C Virus, and/or Human Immunodeficiency Virus SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Review ID TO-PATIENT TRANSMISSION; HBV DNA LEVELS; HIV TRANSMISSION; PERCUTANEOUS INJURIES; SURGICAL-PROCEDURES; ORTHOPEDIC SURGEON; GLOVE PERFORATION; E-ANTIGEN; OCCUPATIONAL EXPOSURES; PUNCTURE RESISTANCE AB This guideline provides the updated recommendations of the Society for Healthcare Epidemiology of America (SHEA) regarding the management of healthcare providers who are infected with hepatitis B virus (HBV), hepatitis C virus (HCV), and/or the human immunodeficiency virus (HIV). For the reasons cited in the guideline, SHEA continues to recommend that, although some aspects of the approach to and administrative management of each of these infectious syndromes in healthcare providers are similar, separate management strategies for healthcare workers who are infected with these unrelated viruses remain appropriate. As we did in both prior iterations of this document, SHEA emphasizes the use of appropriate infection control procedures to minimize exposure of patients or providers to blood, emphasizes that transfers of blood from patients to providers and from providers to patients should be avoided, and recommends that infected healthcare providers should not be totally prohibited from participating in patient-care activities solely on the basis of a bloodborne pathogen infection. The types of procedures assessed by the panel as associated with an increased risk for provider-to-patient transmission of these pathogens are discussed in detail. For each pathogen, recommendations are graduated according to the relative viral load level of the infected provider (Tables 1 and 2). However, SHEA emphasizes that, because of the complexity of these cases, each such case will be slightly different from the next, and each should be independently considered in context. C1 [Henderson, David K.; Grady, Christine] NIH, Dept Bioeth, Ctr Clin, Bethesda, MD 20892 USA. [Dembry, Louise] Yale New Haven Med Ctr, Dept Qual Improvement Support Serv, New Haven, CT 06504 USA. [Fishman, Neil O.] Univ Penn, Sch Med, Div Infect Dis, Philadelphia, PA 19104 USA. [Lundstrom, Tammy] Providence Hosp & Med Ctr, Infect Dis Sect, Detroit, MI USA. [Palmore, Tara N.] NIH, Infect Dis Fellowship Training Program, Ctr Clin, Bethesda, MD 20892 USA. [Sepkowitz, Kent A.] Mem Sloan Kettering Canc Ctr, Infect Dis Serv, New York, NY 10021 USA. [Weber, David J.] Univ N Carolina, Div Infect Dis, Chapel Hill, NC USA. RP Henderson, DK (reprint author), NIH, Dept Bioeth, Ctr Clin, Bldg 10,Rm 6-1480,10 Ctr Dr, Bethesda, MD 20892 USA. EM dkh@nih.gov NR 157 TC 48 Z9 51 U1 0 U2 5 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X EI 1559-6834 J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD MAR PY 2010 VL 31 IS 3 BP 203 EP 232 DI 10.1086/650298 PG 30 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 549UJ UT WOS:000274079500001 PM 20088696 ER PT J AU Kato, H Jochim, RC Gomez, EA Sakoda, R Iwata, H Valenzuela, JG Hashiguchi, Y AF Kato, Hirotomo Jochim, Ryan C. Gomez, Eduardo A. Sakoda, Ryo Iwata, Hiroyuki Valenzuela, Jesus G. Hashiguchi, Yoshihisa TI A repertoire of the dominant transcripts from the salivary glands of the blood-sucking bug, Triatoma dimidiata, a vector of Chagas disease SO INFECTION GENETICS AND EVOLUTION LA English DT Article DE Triatoma dimidiata; Saliva; Transcriptome; Bioinformatics; cDNA library ID ADULT FEMALE MOSQUITO; PLATELET-AGGREGATION INHIBITOR; ANTIGENIC CROSS-REACTIVITY; BLOOD-FEEDING ARTHROPODS; RHODNIUS-PROLIXUS; RECOMBINANT EXPRESSION; SEQUENCE ALIGNMENT; ANOPHELES-GAMBIAE; BINDING PROTEIN; IDENTIFICATION AB Triatoma (T.) dimidiata is a hematophagous Hemiptera and a main vector of Chagas disease. The saliva of this and other blood-sucking insects contains potent pharmacologically active components that assist them in counteracting the host hemostatic and inflammatory systems during blood feeding. To describe the repertoire of potential bioactive salivary molecules from this insect, a number of randomly selected transcripts from the salivary gland cDNA library of T. dimidiata were sequenced and analyzed. This analysis showed that 77.5% of the isolated transcripts coded for putative secreted proteins, and 89.9% of these coded for variants of the lipocalin family proteins. The most abundant transcript was a homologue of procalin, the major allergen of T. protracta saliva, and contributed more than 50% of the transcripts coding for putative secreted proteins, suggesting that it may play an important role in the blood-feeding process. Other salivary transcripts encoding lipocalin family proteins had homology to triabin (a thrombin inhibitor), triafestin (an inhibitor of kallikrein-kinin system), pallidipin (an inhibitor of collagen-induced platelet aggregation) and others with unknown function. (C) 2009 Elsevier B.V. All rights reserved. C1 [Kato, Hirotomo; Sakoda, Ryo; Iwata, Hiroyuki] Yamaguchi Univ, Fac Agr, Dept Vet Hyg, Yamaguchi 7538515, Japan. [Jochim, Ryan C.; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Sect, Lab Malaria & Vector Res, NIH, Bethesda, MD USA. [Hashiguchi, Yoshihisa] Kochi Univ, Dept Parasitol, Kochi Med Sch, Kochi 780, Japan. RP Kato, H (reprint author), Yamaguchi Univ, Fac Agr, Dept Vet Hyg, 1677-1 Yoshida, Yamaguchi 7538515, Japan. EM katoh@yamaguchi-u.ac.jp RI Kato, Hirotomo/A-4820-2012; Jochim, Ryan/C-6756-2013 OI Kato, Hirotomo/0000-0001-5429-9536; FU Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [18256004, 18780230]; Inamori Foundation; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health FX We are grateful to Dr. Jose M.C. Ribeiro (Vector Biology Section, Laboratory of Malaria and Vector Research, NIAID, NIH, USA) for the development and training of all custom bioinformatics programs used in this research. We also thank Dr. Cesar Suarez and Mrs. Erika Sanchez (Laboratory of Medical Entomology, National Institute of Health and Tropical Medicine, Ecuador) for providing T. dimidiata. This study was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (Grant Nos. 18256004 and 18780230) and by the grant from the Inamori Foundation. Because R.C.J. and J.G.V. are government employees and part of this is a government work, the work is in the public domain in the United States. This work was supported in part by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 60 TC 17 Z9 18 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-1348 J9 INFECT GENET EVOL JI Infect. Genet. Evol. PD MAR PY 2010 VL 10 IS 2 BP 184 EP 191 DI 10.1016/j.meegid.2009.10.012 PG 8 WC Infectious Diseases SC Infectious Diseases GA 573PJ UT WOS:000275926400003 PM 19900580 ER PT J AU Goldstein, E Miller, JC O'Hagan, JJ Lipsitch, M AF Goldstein, Edward Miller, Joel C. O'Hagan, Justin J. Lipsitch, Marc TI Pre-dispensing of antivirals to high-risk individuals in an influenza pandemic SO INFLUENZA AND OTHER RESPIRATORY VIRUSES LA English DT Review DE Antivirals; high-risk individuals; influenza; pre-dispensing ID RESPIRATORY-FAILURE; OSELTAMIVIR AB We consider the net benefits of pre-dispensing antivirals to high-risk individuals during an influenza pandemic, where the measure of the benefit is the number of severe outcomes (such as deaths or hospitalizations) prevented by antivirals in the whole population. One potential benefit of pre-dispensing is that individuals to whom antivirals have been pre-dispensed may be able to initiate treatment earlier than if they had to wait to obtain and fill a prescription, reducing their risk of progression to severe disease. If this benefit exceeds the side effects of misuse for the category of individuals to whom antivirals were pre-dispensed, and if antiviral supply exceeds overall population demand (which appears relevant for several countries including US in the 2009 H1N1 pandemic), pre-dispensing a quantity of antivirals not exceeding the difference between supply and demand is always beneficial. In this study, we consider the net benefits of pre-dispensing antivirals under various scenarios, including demand exceeding supply, and derive mathematical conditions under which antiviral pre-dispensing is advantageous on balance. For individuals whose relative risk of severe outcome is high enough, such as immunosuppressed individuals (particularly children) and possibly individuals with neurological disorders, pre-dispensing is always beneficial at a given level of antiviral stockpile with modest assumptions on the relative benefit of early treatment by a pre-dispensed course, regardless of the overall population demand for antivirals during the course of an epidemic. Making additional assumptions on either the overall population demand for antivirals (which appear relevant for the 2009 H1N1 pandemic) or on the relative benefit of pre-dispensing would make pre-dispensing net beneficial with inclusion of a larger number of persons such as pregnant women and morbidly obese adults. C1 [Goldstein, Edward; Miller, Joel C.; O'Hagan, Justin J.; Lipsitch, Marc] Harvard Univ, Sch Publ Hlth, Ctr Communicable Dis Dynam, Boston, MA 02115 USA. [Miller, Joel C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Goldstein, E (reprint author), Harvard Univ, Sch Publ Hlth, Ctr Communicable Dis Dynam, 677 Huntington Ave, Boston, MA 02115 USA. EM egoldste@hsph.harvard.edu RI Miller, Joel/C-4229-2015; OI Miller, Joel/0000-0003-4426-0405; Lipsitch, Marc/0000-0003-1504-9213 FU US National Institutes of Health Models of Infectious Disease Agent Study [5U01GM076497, 1U54GM088588]; RAPIDD; Department of Homeland Security, and the Fogarty International Center; National Institutes of Health (JCM) FX We thank Richard Hatchett for helpful discussions. The MIDAS High Risk Segmentation Group (D. Wagener, R. Zimmerman, D. Lauderdale) kindly shared their the data. This work was funded by the US National Institutes of Health Models of Infectious Disease Agent Study Cooperative Agreements 5U01GM076497 and 1U54GM088588 to ML for the Harvard Center for Communicable Disease Dynamics (ML,EG,JO), and by the RAPIDD program of the Science & Technology Directorate, Department of Homeland Security, and the Fogarty International Center, National Institutes of Health (JCM). An earlier version of this paper appeared online in PLoS Currents:Influenza.31 NR 29 TC 4 Z9 4 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1750-2640 J9 INFLUENZA OTHER RESP JI Influenza Other Respir. Viruses PD MAR PY 2010 VL 4 IS 2 BP 101 EP 112 DI 10.1111/j.1750-2659.2009.00128.x PG 12 WC Infectious Diseases; Virology SC Infectious Diseases; Virology GA 554BR UT WOS:000274411000007 PM 20167050 ER PT J AU de la Lande, A Maddaluno, J Parisel, O Darden, TA Piquemal, JP AF de la Lande, A. Maddaluno, J. Parisel, O. Darden, T. A. Piquemal, J-P TI Study of the Docking of Competitive Inhibitors at a Model of Tyrosinase Active Site: Insights from Joint Broken-Symmetry/Spin-Flip DFT Computations and ELF Topological Analysis SO INTERDISCIPLINARY SCIENCES-COMPUTATIONAL LIFE SCIENCES LA English DT Article DE Density Functional Theory; Spin-Flip TD-DFT; copper; oxygenase; tyrosinase; competitive inhibition AB Following our previous study (Piquemal et al., 2003), we present here a DFT study of the inhibition of the Tyrosinase enzyme. Broken-symmetry DFT computations are supplemented with Spin-Flip TD-DFT calculations, which, for the first time, are applied to such a dicopper enzyme. The chosen biomimetic model encompasses a dioxygen molecule, two Cu(II) cations, and six imidazole rings. The docking energy of a natural substrate, namely phenolate, together with those of several inhibitor and non-inhibitor compounds, are reported and show the ability of the model to rank the most potent inhibitors in agreement with experimental data. With respect to broken-symmetry calculations, the Spin-Flip TD-DFT approach reinforces the possibility for theory to point out potent inhibitors: the need for the deprotonation of the substrates, natural or inhibitors, is now clearly established. Moreover, Electron Localization Function (ELF) topological analysis computations are used to deeply track the particular electronic distribution of the Cu-O-Cu three-center bonds involved in the enzymatic Cu2O2 metallic core (Piquemal and Pilme, 2006). It is shown that such bonds exhibit very resilient out-of-plane density expansions that play a key role in docking interactions: their 3D-orientation could be the topological electronic signature of oxygen activation within such systems. C1 [de la Lande, A.; Parisel, O.; Piquemal, J-P] UPMC Univ Paris 06, UMR 7616, Chim Theor Lab, F-75005 Paris, France. [de la Lande, A.; Parisel, O.; Piquemal, J-P] CNRS, Chim Theor Lab, UMR 7616, F-75005 Paris, France. [de la Lande, A.] Univ Calgary, Inst Biocomplex & Informat, Calgary, AB T2N 1N4, Canada. [Maddaluno, J.] Univ Rouen, CNRS, UMR 6014, Inst Rech Chim Organ Fine, F-76821 Mont St Aignan, France. [Darden, T. A.] Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Piquemal, JP (reprint author), UPMC Univ Paris 06, UMR 7616, Chim Theor Lab, Case Courrier 137,4 Pl Jussieu, F-75005 Paris, France. EM jpp@lct.jussieu.fr RI Piquemal, Jean-Philip/B-9901-2009; de la Lande, Aurelien/P-5656-2016 OI Piquemal, Jean-Philip/0000-0001-6615-9426; FU CRIHAN (Saint-Etienne-du-Rouvray, France) [2008011]; Intramural Research program of the NIH; NIEHS (USA) FX The computations were performed at CRIHAN (Saint-Etienne-du-Rouvray, France) on project 2008011, IDRIS (Orsay, France) and NIEHS (RTP, NC, USA). This research was supported by the Intramural Research program of the NIH and NIEHS (USA). The authors are deeply indebted to Dr Claude Giessner-Prettre who initiated the project. NR 52 TC 7 Z9 7 U1 1 U2 13 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1913-2751 J9 INTERDISCIP SCI JI Interdiscip. Sci. PD MAR PY 2010 VL 2 IS 1 SI SI BP 3 EP 11 DI 10.1007/s12539-010-0096-8 PG 9 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA V28VT UT WOS:000208709000002 PM 20396590 ER PT J AU Balansky, R Ganchev, G Iltcheva, M Steele, VE De Flora, S AF Balansky, Roumen Ganchev, Gancho Iltcheva, Marietta Steele, Vernon E. De Flora, Silvio TI Prevention of cigarette smoke-induced lung tumors in mice by budesonide, phenethyl isothiocyanate, and N-acetylcysteine SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE mainstream cigarette smoke; lung cancer; budesonide; phenethyl isothiocyanate; N-acetyl-L-cysteine ID CANCER CHEMOPREVENTIVE AGENTS; TOBACCO-SMOKE; INHALATION EXPOSURE; BETA-CAROTENE; END-POINTS; A/J MOUSE; MODULATION; CARCINOGENESIS; RATS; DNA AB Lung cancer is the most important cause of death among neoplastic diseases worldwide, and cigarette smoke (CS) is the major risk factor for cancer. Complementarity to avoidance of exposure to CS, chemoprevention will lower the risk of cancer in passive smokers, ex-smokers, and addicted current smokers who fait to quit smoking. Unfortunately, chemoprevention clinical trials have produced disappointing results to date and, until recently, a suitable animal model evaluating CS carcinogenicity was not available. We previously demonstrated that mainstream CS induces a potent carcinogenic response when exposure of mice starts at birth. In the present study, neonatal mice (strain H) were exposed to CS for 120 consecutive days, starting at birth. The chemopreventive agents budesonide (2.4 mg/kg diet), phenethyl isothiocyanate (PEITC, 1,000 mg/kg diet), and N-acetyl-L-cysteine (NAC, 1,000 mg/kg body weight) were administered orally according to various protocols. The experiment was stopped after 210 days. Exposure to CS resulted in a high incidence and multiplicity of benign lung tumors and in significant increases of malignant lung tumors and other histopathological alterations. All three chemopreventive agents, administered to current smokers after weaning, were quite effective in protecting both mate and female mice from CS pulmonary carcinogenicity. When given to ex-smokers after withdrawal of exposure to CS, the protective capacity of budesonide was unchanged, while PEITC lost part of its cancer chemopreventive activity. In conclusion, the proposed experimental model provides convincing evidence that it is possible to prevent CS-induced lung cancer by means of dietary and pharmacological agents. C1 [Balansky, Roumen; De Flora, Silvio] Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. [Balansky, Roumen; Ganchev, Gancho; Iltcheva, Marietta] Natl Oncol Ctr, BU-1157 Sofia, Bulgaria. [Steele, Vernon E.] NCI, Rockville, MD USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via Pastore 1, I-16132 Genoa, Italy. EM sdf@unige.it FU Bulgarian Ministry of Education and Science; U.S. National Cancer Institute [N01-CN53301] FX Grant sponsor: The Bulgarian Ministry of Education and Science;; Grant sponsor: The U.S. National Cancer Institute; Grant number: N01-CN53301 NR 42 TC 31 Z9 31 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 1 PY 2010 VL 126 IS 5 BP 1047 EP 1054 DI 10.1002/ijc.24942 PG 8 WC Oncology SC Oncology GA 547PU UT WOS:000273902300003 PM 19816928 ER PT J AU Pinheiro, AP Raney, TJ Thornton, LM Fichter, MM Berrettini, WH Goldman, D Halmi, KA Kaplan, AS Strober, M Treasure, J Woodside, DB Kaye, WH Bulik, CM AF Pinheiro, Andrea Poyastro Raney, T. J. Thornton, Laura M. Fichter, Manfred M. Berrettini, Wade H. Goldman, David Halmi, Katherine A. Kaplan, Allan S. Strober, Michael Treasure, Janet Woodside, D. Blake Kaye, Walter H. Bulik, Cynthia M. TI Sexual Functioning in Women with Eating Disorders SO INTERNATIONAL JOURNAL OF EATING DISORDERS LA English DT Article DE anorexia nervosa; eating disorders; sexual behavior; sexual dysfunction ID ANOREXIA-NERVOSA; BULIMIA-NERVOSA; STRUCTURED INTERVIEW; LONGITUDINAL DATA; BODY-IMAGE; REPRODUCTION; DYSFUNCTION; DEPRESSION; EXPERIENCE; PROFILES AB Objective: To describe sexual functioning in women with eating disorders Method: We assessed physical intimacy, libido, sexual anxiety, partner status. and sexual relationships in 242 women from the international Price Foundation Genetic Studies relative to normative data Results: Intercourse (55 3%), having a partner (52 7%). decreased sexual desire (66 9%), and increased sexual anxiety (59 2%) were common Women with restricting and purging anorexia nervosa had a higher prevalence of loss of libido than women with bulimia nervosa and eating disorder not otherwise specified (75%, 74 6%, 39%, and 45 4%, respectively) Absence of sexual relationships was associated with lower minimum lifetime body mass index (BMI) and earlier age of onset. loss of libido with lower lifetime BMI. higher interoceptive awareness and trait anxiety, and sexual anxiety with lower lifetime BMI, higher harm avoidance and ineffectiveness Sexual dysfunction in eating disorders was higher than in the normative sample Discussion: Sexual dysfunction, Is common across eating disorders subtypes Low BMI is associated with loss of libido, sexual anxiety, and avoidance of Sexual relationships (C) 2009 by Wiley Periodicals, Inc C1 [Pinheiro, Andrea Poyastro; Raney, T. J.; Thornton, Laura M.; Bulik, Cynthia M.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Fichter, Manfred M.] Univ Munich, D-80539 Munich, Germany. [Berrettini, Wade H.] Univ Penn, Ctr Neurobiol & Behav, Philadelphia, PA 19104 USA. [Goldman, David] Natl Inst Alcohol Abuse & Alcoholism, Rockville, MD USA. [Halmi, Katherine A.] Cornell Univ, Weill Med Coll, New York Presbyterian Hosp, Westchester Div, White Plains, NY USA. [Kaplan, Allan S.] Toronto Hosp, Dept Psychiat, Toronto, ON M5T 2S8, Canada. [Strober, Michael] Univ Calif Los Angeles, David Geffen Sch Med, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA. [Treasure, Janet] Kings Coll London, Inst Psychiat, London WC2R 2LS, England. [Kaye, Walter H.] Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. [Kaye, Walter H.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. [Bulik, Cynthia M.] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. RP Bulik, CM (reprint author), Univ N Carolina, Dept Psychiat, 101 Manning Dr,CB 7160, Chapel Hill, NC 27599 USA. RI Goldman, David/F-9772-2010; OI Goldman, David/0000-0002-1724-5405; Treasure, Janet/0000-0003-0871-4596 FU National Institutes of Health, Bethesda [MH66117]; Franklin Mint Endowed Chair in Eating Disorders FX Supported by MH66117 from the National Institutes of Health, Bethesda. MD Or Strober is supported in part by the Franklin Mint Endowed Chair in Eating Disorders NR 43 TC 28 Z9 30 U1 1 U2 12 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0276-3478 J9 INT J EAT DISORDER JI Int. J. Eating Disord. PD MAR PY 2010 VL 43 IS 2 BP 123 EP 129 PG 7 WC Psychology, Clinical; Nutrition & Dietetics; Psychiatry; Psychology SC Psychology; Nutrition & Dietetics; Psychiatry GA 562CD UT WOS:000275025900003 PM 19260036 ER PT J AU Jiang, LY Malpica, A Deavers, MT Guo, M Villa, LL Nuovo, G Merino, MJ Silva, EG AF Jiang, Liuyan Malpica, Anais Deavers, Michael T. Guo, Ming Villa, Luisa Lina Nuovo, Gerard Merino, Maria J. Silva, Elvio G. TI Endometrial Endometrioid Adenocarcinoma of the Uterine Corpus Involving the Cervix: Some Cases Probably Represent Independent Primaries SO INTERNATIONAL JOURNAL OF GYNECOLOGICAL PATHOLOGY LA English DT Article DE Endometrial adenocarcinoma; Endocervical adenocarcinoma; Endometrioid type; Microcystic pattern ID ENDOCERVICAL ADENOCARCINOMAS; PROGNOSTIC-SIGNIFICANCE; CARCINOMA; INVOLVEMENT; SURVIVAL; CANCER; STAGE; DISTINCTION; PATTERN; VULVA AB The majority of endometrial endometrioid adenocarcinomas involving the cervix have tumor morphology that is similar in the endometrium and the endocervix. There are, however, some cases in which the morphology of the tumor in the endocervix is different from the endometrial carcinoma, in which it is more invasive than the endometrial carcinoma, or in which invasion only occurs in the endocervix while there is no or only minimal myometrial invasion. The goal of this study was to investigate whether tumors involving the endometrium and the endocervix are similar or 2 independent primaries by hematoxylin and eosin stain, immunohistochemistry (IHC), human papillomavirus (HPV) DNA in situ hybridization, RNA reverse transcriptase in situ polymerase chain reaction (PCR) analyses to reveal HPV, and DNA clonality studies. We selected 14 cases of endometrial endometrioid adenocarcinomas involving the cervix with complete pathology material available from the years between 1968 and 2004. Immunohistochemical studies for vimentin, carcinoembryonic antigen, estrogen receptor, progesterone receptor, and p16 were performed in 12 cases; HPV DNA/RNA analyses in 4 cases; and clonality studies in 9 cases. The patients' ages ranged from 42 to 81 years (mean: 62 y). Follow-up information was obtained in 11 patients. Histologic features varied between the tumors in the endometrium and the endocervix in 8 cases, and 5 of these cases had uniform, dilated glands having a microcystic appearance in the cervix. In 6 cases, the tumors in the endometrium and the endocervix had similar histologic features. The immunohistochemical studies showed some differences between the endometrial and endocervical adenocarcinomas in 8 of the 12 cases, independent of differing or similar histologic features. HPV testing in 4 of the cases (3 with similar and 1 with different histology) yielded similar results in the endometrium and endocervix: 2 cases were negative, 1 was positive and 1 was equivocal for HPV DNA/RNA analyses. Clonality studies showed differences between the adenocarcinoma in the endometrium and the endocervix in 7 cases, including 5 cases with different histologic appearances; 2 cases had similar loss of heterozygosity patterns. In conclusion, as suggested by clonality studies, coexisting endometrial and endocervical carcinomas with different histologic features are most likely independent neoplasms. Endometrial and endocervical carcinomas that have similar appearances can represent either the same neoplasm or independent primaries. Clonality tests may help determine their relationship. IHC studies may not be helpful for synchronous endometrial and endocervical tumors, especially those of endometrioid type. It is possible that IHC identifies cell differentiation, rather than site of origin. HPV studies are important to identify endocervical tumors associated with high-risk HPV. However, endometrial tumors involving the cervix and endocervical tumors unrelated to HPV are both negative for high-risk HPV. C1 [Jiang, Liuyan; Merino, Maria J.] NCI, Dept Pathol, Bethesda, MD 20892 USA. [Malpica, Anais; Deavers, Michael T.; Guo, Ming; Silva, Elvio G.] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX USA. [Villa, Luisa Lina] Ludwig Inst Canc Res, Sao Paulo, Brazil. [Nuovo, Gerard] Ohio Univ, Dept Pathol, Columbus, OH USA. RP Silva, EG (reprint author), Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX USA. EM esilva@mdanderson.org NR 18 TC 6 Z9 6 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-1691 J9 INT J GYNECOL PATHOL JI Int. J. Gynecol. Pathol. PD MAR PY 2010 VL 29 IS 2 BP 146 EP 156 DI 10.1097/PGP.0b013e3181b8e951 PG 11 WC Obstetrics & Gynecology; Pathology SC Obstetrics & Gynecology; Pathology GA 586KN UT WOS:000276907200007 PM 20173500 ER PT J AU Bedognetti, D Zoppoli, G Sertoli, MR Zanardi, E Blandini, P Uccellini, L Boccardo, F Andreoli, GB Ghio, R Racchi, O Ferrarini, M De Maria, A AF Bedognetti, Davide Zoppoli, Gabriele Sertoli, Mario Roberto Zanardi, Elisa Blandini, Pietro Uccellini, Lorenzo Boccardo, Francesco Andreoli, Giovanni Battista Ghio, Riccardo Racchi, Omar Ferrarini, Manlio De Maria, Andrea TI Relevance of HBV/HBcAb screening in lymphoma patients treated in the Rituximab era SO INTERNATIONAL JOURNAL OF HEMATOLOGY LA English DT Letter ID HEPATITIS-B; MALIGNANT-LYMPHOMA; REACTIVATION C1 [Bedognetti, Davide; Uccellini, Lorenzo] Natl Inst Hlth, Infect Dis & Immunogenet Sect, Dept Transfus Med, Bethesda, MD 20892 USA. [Bedognetti, Davide; Sertoli, Mario Roberto; Zanardi, Elisa; Boccardo, Francesco; Racchi, Omar; Ferrarini, Manlio] Univ Genoa, Dept Oncol Biol & Genet, I-16132 Genoa, Italy. [Zoppoli, Gabriele; Blandini, Pietro; Ghio, Riccardo; De Maria, Andrea] Univ Genoa, Dept Internal Med, I-16126 Genoa, Italy. [Zoppoli, Gabriele] NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sertoli, Mario Roberto; Boccardo, Francesco; Ferrarini, Manlio; De Maria, Andrea] Natl Inst Canc Res, Dept Med Oncol, Genoa, Italy. [Andreoli, Giovanni Battista] Natl Inst Canc Res, Direz Sanit, Genoa, Italy. [Racchi, Omar] Villa Scassi Hosp, Dept Internal Med, Genoa, Italy. [De Maria, Andrea] Natl Inst Canc Res, Infect Dis Sect, Genoa, Italy. RP Bedognetti, D (reprint author), Natl Inst Hlth, Infect Dis & Immunogenet Sect, Dept Transfus Med, Bldg 10,Room 1 N-224,10 Ctr Dr, Bethesda, MD 20892 USA. EM Davide.Bedognetti@nih.gov RI Bedognetti, Davide/A-9090-2012; Zoppoli, Gabriele/B-6935-2016; de maria, andrea/F-7116-2016; OI Zoppoli, Gabriele/0000-0003-3890-5588; de maria, andrea/0000-0001-5782-333X; Bedognetti, Davide/0000-0002-5857-773X; Ferrarini, Manlio/0000-0002-6154-2570 NR 12 TC 6 Z9 7 U1 0 U2 0 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 0925-5710 J9 INT J HEMATOL JI Int. J. Hematol. PD MAR PY 2010 VL 91 IS 2 BP 342 EP 344 DI 10.1007/s12185-010-0522-z PG 3 WC Hematology SC Hematology GA 580OX UT WOS:000276459900032 PM 20191334 ER PT J AU Bertherat, E England, K AF Bertherat, E. England, K. TI What is the current situation with plague in North Africa? SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Meeting Abstract C1 [Bertherat, E.] WHO, CH-1211 Geneva, Switzerland. [England, K.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD MAR PY 2010 VL 14 SU 1 BP E374 EP E375 DI 10.1016/j.ijid.2010.02.454 PG 2 WC Infectious Diseases SC Infectious Diseases GA 578MQ UT WOS:000276298201414 ER PT J AU Brown, J AF Brown, J. TI Indexing infectious disease information into a relational database for useful queries on the World Wide Web SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Meeting Abstract C1 [Brown, J.] Natl Lib Med, Tacoma, WA USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD MAR PY 2010 VL 14 SU 1 BP E273 EP E273 DI 10.1016/j.ijid.2010.02.2093 PG 1 WC Infectious Diseases SC Infectious Diseases GA 578MQ UT WOS:000276298201182 ER PT J AU Cuellar, J AF Cuellar, J. TI Tropical Infections in Solid Organ Transplant Recipients SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Meeting Abstract C1 [Cuellar, J.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD MAR PY 2010 VL 14 SU 1 BP E328 EP E328 DI 10.1016/j.ijid.2010.02.2219 PG 1 WC Infectious Diseases SC Infectious Diseases GA 578MQ UT WOS:000276298201306 ER PT J AU Morens, D AF Morens, D. TI Historical perspective: Lessons Learned from past Pandemics SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Meeting Abstract C1 [Morens, D.] NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD MAR PY 2010 VL 14 SU 1 BP E20 EP E21 DI 10.1016/j.ijid.2010.02.1531 PG 2 WC Infectious Diseases SC Infectious Diseases GA 578MQ UT WOS:000276298200053 ER PT J AU Uhlenhaut, C McClenahan, SD Sosnovtsev, S Bok, K Kapikian, AZ Green, KY Krause, PR AF Uhlenhaut, C. McClenahan, S. D. Sosnovtsev, S. Bok, K. Kapikian, A. Z. Green, K. Y. Krause, P. R. TI Enteric virus detection and identification with a universal virus discovery assay SO INTERNATIONAL JOURNAL OF INFECTIOUS DISEASES LA English DT Meeting Abstract C1 [Uhlenhaut, C.; McClenahan, S. D.; Krause, P. R.] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. [Sosnovtsev, S.; Bok, K.; Kapikian, A. Z.] NIH, Bethesda, MD 20892 USA. [Green, K. Y.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1201-9712 J9 INT J INFECT DIS JI Int. J. Infect. Dis. PD MAR PY 2010 VL 14 SU 1 BP E188 EP E189 DI 10.1016/j.ijid.2010.02.1907 PG 2 WC Infectious Diseases SC Infectious Diseases GA 578MQ UT WOS:000276298200425 ER PT J AU Green, JG Avenevoli, S Finkelman, M Gruber, MJ Kessler, RC Merikangas, KR Sampson, NA Zaslavsky, AM AF Green, Jennifer Greif Avenevoli, Shelli Finkelman, Matthew Gruber, Michael J. Kessler, Ronald C. Merikangas, Kathleen R. Sampson, Nancy A. Zaslavsky, Alan M. TI Attention deficit hyperactivity disorder. concordance of the adolescent version of the Composite International Diagnostic Interview Version 3.0 (CIDI) with the K-SADS in the US National Comorbidity Survey Replication Adolescent (NCS-A) supplement SO INTERNATIONAL JOURNAL OF METHODS IN PSYCHIATRIC RESEARCH LA English DT Article DE attention deficit hyperactivity disorder; WHO Composite International Diagnostic Interview (CIDI); validity; National Comorbidity Survey Replication Adolescent Supplement (NCS-A) ID PERFORMANCE-TEST PERFORMANCE; DEFICIT/HYPERACTIVITY-DISORDER; RATING-SCALES; CHILDREN; ADHD; SYMPTOMS; AGREEMENT; SCHEDULE; VALIDITY; SAMPLE AB This paper evaluates the internal consistency reliability and concurrent validity of the assessment of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) attention deficit hyperactivity disorder (ADHD) in the adolescent version of the World Health Organization (WHO) Composite International Diagnostic Interview Version 3.0 (CIDI). The CIDI is a lay-administered diagnostic interview that was carried out in con unction with the US National Comorbidity Survey Adolescent Supplement,) a US nationally representative survey of 10,148 adolescents and their parents. Internal consistency reliability was evaluated using factor and item response theory analyses. Concurrent validity was evaluated against diagnoses based on blinded clinician-administered interviews. Inattention and hyperactivity-impulsivity items loaded on separate but correlated factors, with hyperactivity and impulsivity items forming a single factor in parent reports but separate factors in Youth reports. We were able to differentiate hyperactivity and impulsivity factors for parents its well by eliminating a subset who endorsed zero ADHD items from the factor analysis. Although concurrent validity was relatively weak, de-composition showed that this was due to low validity of adolescent reports. A modified CIDI diagnosis based exclusively on parent reports generated a diagnosis that had good concordance with clinical diagnoses [area tinder the curve (AUC) = 0.78]. Implications for assessing ADHD using the CIDI and the effect of different informants on measurement are discussed. Copyright (C) 2010 John Wiley & Sons, Ltd C1 [Green, Jennifer Greif; Gruber, Michael J.; Kessler, Ronald C.; Sampson, Nancy A.; Zaslavsky, Alan M.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Avenevoli, Shelli] NIMH, Div Dev Translat Res, Bethesda, MD 20892 USA. [Finkelman, Matthew] Tufts Univ, Sch Dent Med, Boston, MA 02111 USA. [Merikangas, Kathleen R.] NIMH, Intramural Res Program, Genet Epidemiol Branch, Bethesda, MD 20892 USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM Kessler@hcp.medharvard.edu FU NIMH [IZOI-MI-1070884, R13-MH066849, ROI-MHO69864, ROI-MI-1077883] FX The WMH Data Coordination Centres have received support from NIMH (IZOI-MI-1070884, R13-MH066849, ROI-MHO69864, ROI-MI-1077883), NR 41 TC 14 Z9 14 U1 5 U2 8 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1049-8931 J9 INT J METH PSYCH RES JI Int. J. Methods Psychiatr. Res. PD MAR PY 2010 VL 19 IS 1 BP 34 EP 49 DI 10.1002/mpr303 PG 16 WC Psychiatry SC Psychiatry GA 571YY UT WOS:000275793700003 PM 20191660 ER PT J AU Daly, KA Hoffman, HJ Kvaerner, KJ Kvestad, E Casselbrant, ML Homoe, P Rovers, MM AF Daly, Kathleen A. Hoffman, Howard J. Kvaerner, Kari Jorunn Kvestad, Ellen Casselbrant, Margaretha L. Homoe, Preben Rovers, Maroeska M. TI Epidemiology, natural history, and risk factors: Panel report from the Ninth International Research Conference on Otitis Media SO INTERNATIONAL JOURNAL OF PEDIATRIC OTORHINOLARYNGOLOGY LA English DT Review DE Otitis media; Epidemiology; Natural history; Risk factors ID RESPIRATORY-TRACT INFECTIONS; RANDOMIZED CONTROLLED-TRIAL; MIDDLE-EAR DISEASE; PRESCHOOL-CHILDREN; WESTERN-AUSTRALIA; YOUNG-CHILDREN; DAY-CARE; EFFUSION; SCHOOLCHILDREN; INTERVENTION AB The 2007 Recent Advances in Otitis Media Research Conference Panel Report provides an update on otitis media (OM) research published from 2003 to 2007 This report summarizes important trends in disease incidence and prevalence, describes established and newly identified risk factors for acute and chronic OM and OM with effusion, and conveys information on newly discovered genetic factors In this report, researchers have described declining rates of OM diagnosis, antibiotic prescriptions, offices visits for OM, and middle car Surgery since the licensure and routine use of pneumococcal conjugate vaccine in infants The panel report also recommends short and long term goals for current and future OM research (C) 2009 Elsevier Ireland Ltd All rights reserved. C1 [Daly, Kathleen A.] Univ Minnesota, Dept Otolaryngol, Minneapolis, MN 55435 USA. [Daly, Kathleen A.] Univ Minnesota, Div Epidemiol, Minneapolis, MN 55435 USA. [Hoffman, Howard J.] Natl Inst Deafness & Other Commun Disorders NIDCD, Epidemiol & Biostat Program, NIH, Bethesda, MD 20892 USA. [Kvaerner, Kari Jorunn] Univ Oslo, Inst Special Needs, Oslo, Norway. [Kvestad, Ellen] Norwegian Inst Publ Hlth, Div Epidemiol, Oslo, Norway. [Casselbrant, Margaretha L.] Univ Pittsburgh, Sch Med, Div Pediat Otolaryngol, Childrens Hosp, Pittsburgh, PA USA. [Homoe, Preben] Univ Copenhagen, Rigshosp, Dept Otorhinolaryngol Head & Neck Surg, DK-2100 Copenhagen, Denmark. [Rovers, Maroeska M.] Univ Med Ctr Utrecht, Julius Ctr Hlth Sci & Primary Care, NL-3508 GA Utrecht, Netherlands. RP Daly, KA (reprint author), Univ Minnesota, Dept Otolaryngol, Minneapolis, MN 55435 USA. RI Rovers, Maroeska/F-2969-2014 OI Rovers, Maroeska/0000-0002-3095-170X FU National Institute on Deafness and Other Communication Disorders (NIDCD), NIH [1R13-DC-008950-01] FX The Post-Symposium Otitis Media Research Conference was made possible through funding by The National Institute on Deafness and Other Communication Disorders (NIDCD), NIH, of conference grant: 1R13-DC-008950-01 (PI - Dr. David Lim). We gratefully acknowledge Dr. Lim for his tireless efforts in organizing and Implementing the Post-Symposium OM Research Conference, as well as the preceding 9th International Symposium on Recent Advances in Otitis Media. NR 83 TC 40 Z9 43 U1 3 U2 14 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-5876 J9 INT J PEDIATR OTORHI JI Int. J. Pediatr. Otorhinolaryngol. PD MAR PY 2010 VL 74 IS 3 BP 231 EP 240 DI 10.1016/j.ijporl.2009.09.006 PG 10 WC Otorhinolaryngology; Pediatrics SC Otorhinolaryngology; Pediatrics GA 569QF UT WOS:000275612400001 PM 19836843 ER PT J AU Darby, SC Cutter, DJ Boerma, M Constine, LS Fajardo, LF Kodama, K Mabuchi, K Marks, LB Mettler, FA Pierce, LJ Trott, KR Yeh, ETH Shore, RE AF Darby, Sarah C. Cutter, David J. Boerma, Marjan Constine, Louis S. Fajardo, Luis F. Kodama, Kazunori Mabuchi, Kiyohiko Marks, Lawrence B. Mettler, Fred A. Pierce, Lori J. Trott, Klaus R. Yeh, Edward T. H. Shore, Roy E. TI RADIATION-RELATED HEART DISEASE: CURRENT KNOWLEDGE AND FUTURE PROSPECTS SO INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS LA English DT Review ID ATOMIC-BOMB SURVIVORS; BREAST-CANCER RADIOTHERAPY; LONG-TERM SURVIVORS; HODGKINS-DISEASE; MEDIASTINAL IRRADIATION; IONIZING-RADIATION; RANDOMIZED-TRIALS; CARDIAC DAMAGE; LATE MORTALITY; RAT-HEART C1 [Darby, Sarah C.; Cutter, David J.] Clin Trial Serv Unit, Oxford OX3 7LF, England. [Boerma, Marjan] Univ Arkansas Med Sci, Dept Pharmaceut Sci, Little Rock, AR 72205 USA. [Constine, Louis S.] Univ Rochester, Med Ctr, Dept Radiat Oncol, Rochester, NY 14642 USA. [Constine, Louis S.] Univ Rochester, Med Ctr, Dept Pediat, Rochester, NY 14642 USA. [Fajardo, Luis F.] Stanford Univ, Sch Med & Vet Healthcare Syst, Dept Pathol, Palo Alto, CA 94304 USA. [Kodama, Kazunori; Shore, Roy E.] Radiat Effects Res Fdn, Hiroshima, Japan. [Mabuchi, Kiyohiko] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Marks, Lawrence B.] Univ N Carolina, Dept Radiat Oncol, Chapel Hill, NC USA. [Mettler, Fred A.] New Mexico Vet Affairs Hlth Care Syst, Radiol & Nucl Med Serv, Albuquerque, NM USA. [Pierce, Lori J.] Univ Michigan, Sch Med, Dept Radiat Oncol, Ann Arbor, MI 48109 USA. [Trott, Klaus R.] UCL, Inst Canc, London, England. [Yeh, Edward T. H.] Univ Texas MD Anderson Canc Ctr, Dept Cardiol, Houston, TX 77030 USA. RP Darby, SC (reprint author), Clin Trial Serv Unit, Richard Doll Bldg, Oxford OX3 7LF, England. EM sarah.darby@ctsu.ox.ac.uk FU Intramural NIH HHS [ZIA CP010134-18]; Medical Research Council [MC_U137686858]; NCI NIH HHS [R01 CA069579] NR 54 TC 159 Z9 170 U1 0 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0360-3016 J9 INT J RADIAT ONCOL JI Int. J. Radiat. Oncol. Biol. Phys. PD MAR 1 PY 2010 VL 76 IS 3 BP 656 EP 665 DI 10.1016/j.ijrobp.2009.09.064 PG 10 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 562RT UT WOS:000275072200002 PM 20159360 ER PT J AU Kapetanovic, IM Horn, TL Johnson, WD Cwik, MJ Detrisac, CJ McCormick, DL AF Kapetanovic, Izet M. Horn, Thomas L. Johnson, William D. Cwik, Michael J. Detrisac, Carol J. McCormick, David L. TI Murine Oncogenicity and Pharmacokinetics Studies of 9-cis-UAB30, an RXR Agonist, for Breast Cancer Chemoprevention SO INTERNATIONAL JOURNAL OF TOXICOLOGY LA English DT Article DE 9-cis-UAB30; retinoid; cancer chemopreventive agent; pharmacokinetics; oncogenicity; p53((+/-)) mouse ID RETINOIC ACID ANALOGS; 9-CIS-RETINOIC ACID; PREVENTION; 9CUAB30; BEXAROTENE; INDUCTION; REXINOIDS; TAMOXIFEN; THERAPY; ENZYMES AB The synthetic retinoic acid analog, 9-cis-UAB30 [(2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-naphthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid], is a specific ligand for the retinoid X receptor. Murine oncogenicity and pharmacokinetics studies were performed as part of the preclinical development of 9-cis-UAB30 for breast cancer chemoprevention. In the oncogenicity study, TSG-p53((+/-)) (p53 knockout) mice (25 per sex per group) received daily gavage exposure to 9-cis-UAB30 doses of 0 (control), 30, 100, or 300 mg/kg/d for 6 months. Positive controls received p-cresidine (400 mg/kg/d) for 6 months. 9-cis-UAB30 had no biologically significant effects on survival, body weight, body weight gain, clinical signs, hematology, or clinical chemistry but induced dose-related hepatomegaly in both sexes and decreased thymus weights in high-dose females. Gross and microscopic pathology provided no evidence of 9-cis-UAB30 toxicity or oncogenicity; by contrast, p-cresidine induced urinary bladder neoplasms in more than 60% of male and female mice. It was concluded that 9-cis-UAB30 is not oncogenic in p53((+/-)) mice. In the pharmacokinetics study, C57BL/6 mice received daily gavage exposure to 9-cis-UAB30 (100 or 300 mg/kg/d) for 1 or 7 days. Pharmacokinetic parameters were similar after 1 and 7 days of dosing. Dose-related peak plasma levels of 9-cis-UAB30 were seen between 0.25 and 3 hours; volume of distribution was comparable at both dose levels. Increases in area under the curve were less than proportional to dose and were associated with an increased rate of apparent clearance and decreased elimination half-life. These results suggest decreased absorption and/or possible induction of clearance mechanisms. Enzyme induction may underlie the hepatomegaly seen in mice treated with 9-cis-UAB30 for 6 months in the oncogenicity study. C1 [Horn, Thomas L.; Johnson, William D.; Cwik, Michael J.; McCormick, David L.] IIT, Res Inst, Chicago, IL 60616 USA. [Kapetanovic, Izet M.] NCI, Bethesda, MD 20892 USA. [Detrisac, Carol J.] Pathol Associates Inc, Chicago, IL USA. RP McCormick, DL (reprint author), IIT, Res Inst, 10 W 35th St, Chicago, IL 60616 USA. EM dmccormick@iitri.org FU Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute [N01-CN-43304] FX The author(s) disclosed receipt of the following financial support for the research and/or authorship of this article: contract N01-CN-43304 from the Chemopreventive Agent Development Research Group, Division of Cancer Prevention, National Cancer Institute. NR 26 TC 6 Z9 6 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1091-5818 J9 INT J TOXICOL JI Int. J. Toxicol. PD MAR PY 2010 VL 29 IS 2 BP 157 EP 164 DI 10.1177/1091581809360070 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 577XP UT WOS:000276257600002 PM 20335511 ER PT J AU Amaral, J Becerra, SP AF Amaral, Juan Becerra, S. Patricia TI Effects of Human Recombinant PEDF Protein and PEDF-Derived Peptide 34-mer on Choroidal Neovascularization SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; PIGMENT-EPITHELIUM; GENE-TRANSFER; ANTIANGIOGENIC ACTIVITY; NEUROTROPHIC ACTIVITY; MACULAR DEGENERATION; BINDING-SITE; NONINHIBITORY SERPIN; ANGIOGENIC FACTOR; TUMOR-GROWTH AB PURPOSE. Pigment epithelium-derived factor (PEDF) is a serpin with antiangiogenic properties. Previously, the authors showed that PEDF injected into the subconjunctiva reaches the choroid. Here, they examined the effects of PEDF polypeptide fragments on vessel sprouting and on choroidal neovascularization (CNV) after subconjunctival administration. METHODS. Recombinant human PEDF (rhuPEDF) was cleaved at its serpin-exposed loop by limited chymotrypsin proteolysis. Synthetic PEDF peptides 34-mer (Asp(44)-Asn(77)) and 44-mer (Val(78)-Thr(121)) were used. Ex vivo chick aortic vessel sprouting assays were performed. CNV was induced in rats by laser injury of Bruch's membrane. Daily subconjunctival injections (0.01-10 pmol/d protein) were performed for 5 days starting at day of injury or at the seventh day after injury. New vessel volumes were quantified using optical sections of choroid/RPE flat-mounts labeled with isolectin-Ib4. PEDF distribution was evaluated by immunofluorescence of choroid/RPE/retina cross-sections. RESULTS. Full-length rhuPEDF, cleaved rhuPEDF, or peptide 34-mer exhibited ex vivo antiangiogenic activity, but peptide 44-mer was inefficient. PEDF immunostaining around CNV lesions diminished after laser injury. Subconjunctival administration of rhuPEDF or 34-mer at 0.1 pmol/d decreased CNV lesion volumes by 52% and 47%, respectively, whereas those of 44-mer were similar to vehicle injections. Doses of 0.1 and 1 pmol/d rhuPEDF decreased fully developed CNV complex volumes by 45% and 50%, respectively, compared with vehicle injections. CONCLUSIONS. A functional region for the inhibition of vessel sprouting and CNV resides within the 34-mer region of PEDF. Furthermore, subconjunctival administration of optimal range dosages of rhuPEDF or 34-mer can suppress and regress rat CNV lesions, demonstrating that these agents reach the choroid/RPE complex as functionally active molecules. (Invest Ophthalmol Vis Sci. 2010;51:1318-1326) DOI:10.1167/iovs.09-4455 C1 [Amaral, Juan; Becerra, S. Patricia] NEI, Sect Prot Struct & Funct, Retinal Cell & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Becerra, SP (reprint author), NEI, Sect Prot Struct & Funct, Retinal Cell & Mol Biol Lab, NIH, Bldg 6,Room 134,6 Ctr Dr,MSC 0608, Bethesda, MD 20892 USA. EM becerrap@nei.nih.gov FU Intramural Research Program of the National Eye Institute; National Institutes of Health FX Supported by the Intramural Research Program of the National Eye Institute, National Institutes of Health. NR 55 TC 32 Z9 34 U1 0 U2 3 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD MAR PY 2010 VL 51 IS 3 BP 1318 EP 1326 DI 10.1167/iovs.09-4455 PG 9 WC Ophthalmology SC Ophthalmology GA 563VW UT WOS:000275164300013 PM 19850839 ER PT J AU Turkbey, EB McClelland, RL Kronmal, RA Burke, GL Bild, DE Tracy, RP Arai, AE Lima, JAC Bluemke, DA AF Turkbey, Evrim B. McClelland, Robyn L. Kronmal, Richard A. Burke, Gregory L. Bild, Diane E. Tracy, Russell P. Arai, Andrew E. Lima, Joao A. C. Bluemke, David A. TI The Impact of Obesity on the Left Ventricle The Multi-Ethnic Study of Atherosclerosis (MESA) SO JACC-CARDIOVASCULAR IMAGING LA English DT Article DE cardiac magnetic resonance; cardiac morphology; epidemiology; left ventricular function; obesity ID CARDIOVASCULAR MAGNETIC-RESONANCE; BODY-MASS INDEX; HEART-FAILURE; 2-DIMENSIONAL ECHOCARDIOGRAPHY; EJECTION FRACTION; RISK-FACTORS; HYPERTROPHY; ASSOCIATION; GEOMETRY; DISEASE AB OBJECTIVES The purpose of this study was to evaluate the relationship of left ventricular (LV) remodeling assessed by cardiac magnetic resonance to various measures of obesity in a large population-based study. BACKGROUND Obesity is a well-known risk factor for cardiovascular disease, yet its relationship with LV size and function is poorly understood. METHODS A total of 5,098 participants (age 45 to 84 years; 48% men) in the Multi-Ethnic Study of Atherosclerosis who were free of clinically apparent cardiovascular disease underwent cardiac magnetic resonance to assess LV size and function as well as measures of obesity, including body mass index, waist-to-hip ratio and waist circumference, and cardiovascular risk factors. Fat mass (FM) was estimated based on height-weight models derived from bioelectrical impedance studies. The associations of obesity measures with LV size and function were evaluated using linear spline regression models for body mass index and multivariable regression models for other measures of obesity; they were displayed graphically using generalized additive models. RESULTS LV mass and end-diastolic volume were positively associated with measures of obesity in both sexes after adjustment for risk factors (e. g., 5.7-g and 6.9-g increase in LV mass per 10-kg increase in FM in women and men, respectively [p < 0.001]). LV mass-to-volume ratio was positively associated with increased body mass index, waist-to-hip ratio, waist circumference, and estimated FM (e. g., 0.02-g/ml and 0.06-g/ml increase in mass-to-volume ratio per 10-kg increase in FM in women and men, respectively [p < 0.001]). The increased mass-to-volume ratio was due to a greater increase in LV mass relative to LV end-diastolic volume. All associations were stronger for men than for women. Ejection fraction showed no significant association with measures of obesity. CONCLUSIONS Obesity was associated with concentric LV remodeling without change in ejection fraction in a large, multiethnic cohort study. (J Am Coll Cardiol Img 2010; 3: 266-74) (C) 2010 by the American College of Cardiology Foundation C1 [Turkbey, Evrim B.; Bluemke, David A.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [McClelland, Robyn L.; Kronmal, Richard A.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Burke, Gregory L.] Wake Forest Univ Hlth Sci, Div Publ Hlth Sci, Winston Salem, NC USA. [Bild, Diane E.] NHLBI, Div Cardiovasc Sci, NIH, Bethesda, MD 20892 USA. [Arai, Andrew E.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Tracy, Russell P.] Univ Vermont, Dept Pathol, Colchester, VT USA. [Tracy, Russell P.] Univ Vermont, Dept Biochem, Colchester, VT USA. [Lima, Joao A. C.] Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. RP Bluemke, DA (reprint author), NIH, Ctr Clin, 9000 Rockville Pike,Bldg 10,Room 1C355, Bethesda, MD 20892 USA. EM bluemked@nih.gov OI Bluemke, David/0000-0002-8323-8086 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95169] FX This research was supported by contracts N01-HC-95159 through N01-HC-95169 from the National Heart, Lung, and Blood Institute. NR 21 TC 111 Z9 115 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1936-878X J9 JACC-CARDIOVASC IMAG JI JACC-Cardiovasc. Imag. PD MAR PY 2010 VL 3 IS 3 BP 266 EP 274 DI 10.1016/j.jcmg.2009.10.012 PG 9 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 647NS UT WOS:000281625800006 PM 20223423 ER PT J AU Osinusi, A Rasimas, JJ Bishop, R Proschan, M McLaughlin, M Murphy, A Cortez, KJ Polis, MA Masur, H Rosenstein, D Kottilil, S AF Osinusi, Anu Rasimas, Joseph J. Bishop, Rachel Proschan, Michael McLaughlin, Mary Murphy, Alison Cortez, Karoll J. Polis, Michael A. Masur, Henry Rosenstein, Donald Kottilil, Shyam TI HIV/Hepatitis C Virus-Coinfected Virologic Responders to Pegylated Interferon and Ribavirin Therapy More Frequently Incur Interferon-Related Adverse Events Than Nonresponders Do SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE adverse events; HCV; HIV; Peg-interferon alpha; psychiatric toxicity ID CHRONIC HEPATITIS-C; HUMAN-IMMUNODEFICIENCY-VIRUS; ALPHA-2A PLUS RIBAVIRIN; HIV-INFECTED PATIENTS; INDUCED DEPRESSION; MANAGEMENT; CANCER; PEGINTERFERON-ALPHA-2B; COMPLICATIONS; PREDICTION AB Background: This study aimed to assess the relationship between interferon (IFN)-related adverse effects and Hepatitis C virus (HCV) virologic response in HIV/HCV-coinfected individuals treated with pegylated interferon and ribavirin. Methods: We conducted 2 prospective, open-label trials treating HIV/HCV-coinfected individuals with pegylated interferon alpha-2b or alpha-2a and ribavirin for 48 weeks. Safety laboratories, HCV RNA, psychiatric, and ophthalmologic evaluations were performed at baseline and monthly until week 72. Results: Responders were defined as those with HCV RNA decline of >= 2-log drop from baseline and nonresponders were those who did not. Remarkably, of the 27 patients (50%) who developed psychiatric toxicities, 26 patients were responders, although only 1 of 14 virologic nonresponders experienced psychiatric toxicity. Other adverse effects, such as anemia and ophthalmologic toxicities, were also more frequent in responders compared with nonresponders. Decline in CD4(+) T-cell counts strongly correlated with HCV viral decline. Conclusions: Our study demonstrates coupling of antiviral effect and occurrence of adverse events in HIV/HCV-coinfected patients. These patients with IFN-related adverse effects need a multidisciplinary treatment approach, hence, they are more likely to achieve sustained virologic response. Future studies are needed to evaluate the factors that predict the development of IFN-alpha-dependent adverse events before therapy. C1 [Kottilil, Shyam] NIAID, Immunopathogenesis Sect, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Rasimas, Joseph J.; Rosenstein, Donald] NIMH, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Bishop, Rachel] NEI, NIH, Bethesda, MD 20892 USA. [Proschan, Michael] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Cortez, Karoll J.; Masur, Henry] NIH, Dept Crit Care Med, Clin Res Ctr, Bethesda, MD 20892 USA. [Cortez, Karoll J.; Masur, Henry] NIH, CCMD, CC, Bethesda, MD 20892 USA. RP Kottilil, S (reprint author), NIAID, Immunopathogenesis Sect, Immunoregulat Lab, NIH, Bldg 10,Room 11N204, Bethesda, MD 20892 USA. EM skottilil@niaid.nih.gov OI Polis, Michael/0000-0002-9151-2268 FU National Institutes of Health FX Supported in whole by the Intramural Research Program of the National Institutes of Health (National Institute of Allergy and Infectious Diseases, National Institute of Mental Health, and the National Eye Institute). NR 33 TC 8 Z9 8 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD MAR 1 PY 2010 VL 53 IS 3 BP 357 EP 363 DI 10.1097/QAI.0b013e3181c7a29d PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 565VX UT WOS:000275324500010 PM 20101190 ER PT J AU Limb, CJ Molloy, AT Jiradejvong, P Braun, AR AF Limb, Charles J. Molloy, Anne T. Jiradejvong, Patpong Braun, Allen R. TI Auditory Cortical Activity During Cochlear Implant-Mediated Perception of Spoken Language, Melody, and Rhythm SO JARO-JOURNAL OF THE ASSOCIATION FOR RESEARCH IN OTOLARYNGOLOGY LA English DT Article DE music; PET; neuroimaging; cochlear implant; melody; rhythm; language ID POSITRON-EMISSION-TOMOGRAPHY; NORMAL-HEARING SUBJECTS; MUSIC PERCEPTION; SPEECH; USERS; PET; CORTEX; RECOGNITION; ACTIVATION; PLASTICITY AB Despite the significant advances in language perception for cochlear implant (CI) recipients, music perception continues to be a major challenge for implant-mediated listening. Our understanding of the neural mechanisms that underlie successful implant listening remains limited. To our knowledge, this study represents the first neuroimaging investigation of music perception in CI users, with the hypothesis that CI subjects would demonstrate greater auditory cortical activation than normal hearing controls. H(2) (15)O positron emission tomography (PET) was used here to assess auditory cortical activation patterns in ten postlingually deafened CI patients and ten normal hearing control subjects. Subjects were presented with language, melody, and rhythm tasks during scanning. Our results show significant auditory cortical activation in implant subjects in comparison to control subjects for language, melody, and rhythm. The greatest activity in CI users compared to controls was seen for language tasks, which is thought to reflect both implant and neural specializations for language processing. For musical stimuli, PET scanning revealed significantly greater activation during rhythm perception in CI subjects (compared to control subjects), and the least activation during melody perception, which was the most difficult task for CI users. These results may suggest a possible relationship between auditory performance and degree of auditory cortical activation in implant recipients that deserves further study. C1 [Limb, Charles J.] Johns Hopkins Univ, Peabody Inst Mus, Baltimore, MD 21202 USA. [Limb, Charles J.; Molloy, Anne T.; Braun, Allen R.] NIDCD, NIH, Language Sect, Rockville, MD 20892 USA. [Limb, Charles J.; Jiradejvong, Patpong] Johns Hopkins Univ Hosp, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. RP Limb, CJ (reprint author), Johns Hopkins Univ, Peabody Inst Mus, Baltimore, MD 21202 USA. EM climb@jhmi.edu FU NIDCD/NIH FX This work was supported by the Division of Intramural Research of the NIDCD/NIH. NR 35 TC 15 Z9 17 U1 2 U2 11 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1525-3961 J9 JARO-J ASSOC RES OTO JI JARO PD MAR PY 2010 VL 11 IS 1 BP 133 EP 143 DI 10.1007/s10162-009-0184-9 PG 11 WC Neurosciences; Otorhinolaryngology SC Neurosciences & Neurology; Otorhinolaryngology GA 554LP UT WOS:000274436800011 PM 19662456 ER PT J AU Murray, MM Savage, C AF Murray, Margaret M. Savage, Christine TI The NIAAA BSN Nursing Education Curriculum: A Rationale and Overview SO JOURNAL OF ADDICTIONS NURSING LA English DT Editorial Material ID INTERVENTION C1 [Murray, Margaret M.] NIAAA, Bethesda, MD USA. [Savage, Christine] Univ Cincinnati, Acad Hlth Ctr, Cincinnati, OH USA. RP Murray, MM (reprint author), NIAAA, Bethesda, MD USA. NR 14 TC 7 Z9 7 U1 0 U2 0 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1088-4602 J9 J ADDICT NURS JI J. Addict. Nurs. PD MAR PY 2010 VL 21 IS 1 BP 3 EP 5 DI 10.3109/10884601003594488 PG 3 WC Substance Abuse; Nursing SC Substance Abuse; Nursing GA 569GU UT WOS:000275585400001 ER PT J AU Szefler, SJ Gergen, PJ Mitchell, H Morgan, W AF Szefler, Stanley J. Gergen, Peter J. Mitchell, Herman Morgan, Wayne TI Achieving asthma control in the inner city: Do the National Institutes of Health Asthma Guidelines really work? SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Review DE Asthma; childhood asthma; inner-city asthma; exhaled nitric oxide; asthma guidelines ID URBAN CHILDREN; MANAGEMENT; DISEASE; DISPARITIES; ADHERENCE; MORBIDITY; BELIEFS; ADULTS; TRIAL; CARE AB For children living in inner cities, asthma tends to be more frequent and severe. To characterize, understand, and treat children with asthma living in the inner city more effectively, the National Institute of Allergy and Infectious Diseases established an Inner-City Asthma Program in 1991. In addition, the revised National Asthma Education and Prevention Program Expert Panel 3 report was introduced with new concepts for asthma management that are now centered on asthma control. The purpose of this review is to highlight features of the National Institute of Allergy and Infectious Diseases Inner-City Asthma Consortium Asthma Control Evaluation study that enhance our knowledge regarding the application of the asthma guidelines and to provide a summary of lessons learned from that important study. We recognized that asthma symptoms and exacerbations are theoretically linked to underlying inflammation of airways but are not direct indicators of inflammation. Based on the observations from the Asthma Control Evaluation study, we were impressed that a systematic guidelines-based approach improved asthma control significantly over the course of the 1-year treatment period. (J Allergy Clin Immunol 2010;125:521-6.) C1 [Szefler, Stanley J.] Natl Jewish Hlth, Div Pediat Clin Pharmacol, Dept Pediat, Denver, CO 80206 USA. [Szefler, Stanley J.] Natl Jewish Hlth, Div Allergy & Immunol, Dept Pediat, Denver, CO 80206 USA. [Szefler, Stanley J.] Univ Colorado, Denver Sch Med, Boulder, CO 80309 USA. [Gergen, Peter J.] NIAID, NIH, Bethesda, MD 20892 USA. [Mitchell, Herman] Rho Inc, Chapel Hill, NC USA. [Morgan, Wayne] Univ Arizona, Coll Med, Dept Pediat, Tucson, AZ 85721 USA. RP Szefler, SJ (reprint author), Natl Jewish Hlth, Div Pediat Clin Pharmacol, Dept Pediat, 1400 Jackson St,Room J304 Molly Blank Bldg, Denver, CO 80206 USA. EM szeflers@njhealth.org FU NIH/NHLBI Childhood Management Program (CAMP); NHLBI Childhood Asthma Research and Education (CARE); NIH/NHLBI Asthma Clin Res Network (ACRN); NIH/NIAID Inner City Asthma Consortium (ICAC); GlaxoSmithKline; NJH.NHLBI Asthma Net; NEEHS/EPA Childhood Environmental Health Center; NIH/NIAID; NIH/University of Wisconsin and Novartis; Public Health Services [HR-16048, HL64288, HL 51834, AI-25496, HL081335, HL075416]; National Institutes of Health and National Center for Research Resources [1 UL1 RR025780]; Colorado Cancer, Cardiovascular, and Pulmonary Disease Program FX Companies/Organizations: S. J. Szefler is a consultant for GlaxoSmithKline, Genentech, Merck, Boehringer-Ingelheim, Novartis, Schering Plough; and has received research support from the NIH/NHLBI Childhood Management Program (CAMP), NHLBI Childhood Asthma Research and Education (CARE), NIH/NHLBI Asthma Clin Res Network (ACRN), NIH/NIAID Inner City Asthma Consortium (ICAC), GlaxoSmithKline, NJH.NHLBI Asthma Net, and NEEHS/EPA Childhood Environmental Health Center grant. P. J. Gergen declares he has no conflicts of interest. H. Mitchell has received research support from the NIH/NIAID. W. Morgan is a consultant, and is Chair for the Data Safety Monitoring Board for the Cystic Fibrosis Foundation; is a consultant and is Chair for the North American Scientific Advisory Group for the Epidemiologic Study of Cystic Fibrosis for Genentech; is a consultant for Novartis; and has received research support from the NIH/University of Wisconsin and Novartis.; Supported in part by Public Health Services research grants HR-16048, HL64288, HL 51834, AI-25496, HL081335, and HL075416; the Colorado CTSA grant 1 UL1 RR025780 from the National Institutes of Health and National Center for Research Resources; and the Colorado Cancer, Cardiovascular, and Pulmonary Disease Program. NR 27 TC 25 Z9 25 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2010 VL 125 IS 3 BP 521 EP 526 DI 10.1016/j.jaci.2010.01.025 PG 6 WC Allergy; Immunology SC Allergy; Immunology GA 573BK UT WOS:000275883200003 PM 20226288 ER PT J AU Togias, A Fenton, MJ Gergen, PJ Rotrosen, D Fauci, AS AF Togias, Alkis Fenton, Matthew J. Gergen, Peter J. Rotrosen, Daniel Fauci, Anthony S. TI Asthma in the inner city: The perspective of the National Institute of Allergy and Infectious Diseases SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Inner-city asthma; asthma research funding; cockroach allergy ID ENVIRONMENTAL INTERVENTION; CHILDREN; IMMUNOTHERAPY; MORBIDITY; RHINITIS; TRIAL; CARE AB Since 1991, the National Institute of Allergy and Infectious Diseases (NIAID) has funded four consecutive research initiatives to investigate the problem of high asthma prevalence, morbidity and mortality in poor urban communities. The multi-site studies conducted under these initiatives have identified key risk factors for asthma morbidity and novel interventions to improve asthma control. NIAID focuses its asthma and allergy programs on understanding the interaction of the immune system with allergens and infectious agents and identifying genetic and epigenetic elements that influence the immune system. A key goal in this field is to define mechanisms of immune system deviation and immune tolerance and apply this knowledge to generate improvements in asthma care and allergen immunotherapy. A related goal is to further understand the environmental, social, and immunological elements that impact on the development of inner-city asthma through in-depth characterization and longitudinal follow-up of inner-city children from the time of birth. In the past 5 years, NIH budgetary constraints have imposed many challenges for the academic research community. Despite these constraints, NIAID has maintained its support of a highly productive asthma and allergy research program. (J Allergy Clin Immunol 2010;125:540-4.) C1 [Togias, Alkis] NIAID, AAIB, DAIT, NIH, Bethesda, MD 20892 USA. RP Togias, A (reprint author), NIAID, AAIB, DAIT, NIH, 6610 Rockledge Dr, Bethesda, MD 20892 USA. EM togiasa@niaid.nih.gov NR 25 TC 33 Z9 34 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2010 VL 125 IS 3 BP 540 EP 544 DI 10.1016/j.jaci.2010.01.040 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA 573BK UT WOS:000275883200005 PM 20226290 ER PT J AU Kattan, M Kumar, R Bloomberg, GR Mitchell, HE Calatroni, A Gergen, PJ Kercsmar, CM Visness, CM Matsui, EC Steinbach, SF Szefler, SJ Sorkness, CA Morgan, WJ Teach, SJ Gan, VN AF Kattan, Meyer Kumar, Rajesh Bloomberg, Gordon R. Mitchell, Herman E. Calatroni, Agustin Gergen, Peter J. Kercsmar, Carolyn M. Visness, Cynthia M. Matsui, Elizabeth C. Steinbach, Suzanne F. Szefler, Stanley J. Sorkness, Christine A. Morgan, Wayne J. Teach, Stephen J. Gan, Vanthaya N. TI Asthma control, adiposity, and adipokines among inner-city adolescents SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Obesity; asthma; adipokines; leptin; adiponectin ID BODY-MASS INDEX; QUALITY-OF-LIFE; AIRWAY INFLAMMATION; PROSPECTIVE COHORT; EMERGENCY-DEPARTMENT; CHILDHOOD OBESITY; NONOBESE CHILDREN; INCIDENT ASTHMA; SEX-DIFFERENCES; PLASMA-PROTEIN AB Background: There is an association between adiposity and asthma prevalence, but the relationship to asthma control is unclear. Objectives: We sought to understand the relationships among adiposity, sex, and asthma control in inner-city adolescents with asthma. Methods: We prospectively followed 368 adolescents with moderate-to-severe asthma (ages 12-20 years) living in 10 urban areas for 1 year. Asthma symptoms and exacerbations were recorded, and pulmonary function and exhaled nitric oxide levels were measured every 6 weeks. Adiposity measures (body mass index [BMI] and dual-energy X-ray absorptiometric scans) were made, and blood was collected for measurement of allergy markers, adiponectin, leptin, TNF-alpha, IL-6, and C-reactive protein levels. Results: More than 60% of female subjects and 50% of male subjects were above the 85th percentile of BMI for age. Higher BMI was associated with more symptom days (R = 0.18, P = .02) and exacerbations (R = 0.18, P = .06) among female subjects only. Adiponectin was inversely related to asthma symptoms (R = 0.18, P < .05) and exacerbations (R = 0.20, P < .05) and positively with FEN/1/forced vital capacity ratio (R = 0.15, P < .05) in male subjects only independent of body size. There was no relationship between adiposity or adipokines and total IgE levels, blood eosinophil counts, and exhaled nitric oxide levels. Dual-energy X-ray absorptiometry provided little additional value in relating adiposity to asthma outcome in this population of adolescents. Conclusion: Adiposity is associated with poorer asthma control in female subjects. Adiponectin is associated with improved asthma control in male subjects. (J Allergy Clin Immunol 2010;125:584-92.) C1 [Kattan, Meyer] Columbia Univ, Med Ctr, Coll Phys & Surg, Dept Pediat Pulmonol, New York, NY 10032 USA. [Kumar, Rajesh] Childrens Mem Hosp, Div Allergy Immunol, Chicago, IL 60614 USA. [Bloomberg, Gordon R.] Washington Univ, Dept Pediat, Div Allergy Immunol & Pulm Med, St Louis, MO 63130 USA. [Mitchell, Herman E.; Calatroni, Agustin; Visness, Cynthia M.] Rho Fed Syst Div Inc, Chapel Hill, NC USA. [Gergen, Peter J.] NIAID, Div Allergy Immunol & Transplantat, Bethesda, MD 20892 USA. [Kercsmar, Carolyn M.] Cincinnati Childrens Hosp, Dept Pediat, Div Pulm Med, Ctr Med, Cincinnati, OH 45229 USA. [Matsui, Elizabeth C.] Johns Hopkins Univ, Sch Med, Dept Pediat, Div Allergy & Immunol, Baltimore, MD 21205 USA. [Steinbach, Suzanne F.] Boston Univ, Sch Med, Dept Pediat, Boston, MA 02215 USA. [Szefler, Stanley J.] Univ Colorado Hlth Sci, Denver, CO USA. [Szefler, Stanley J.] Natl Jewish Hlth, Dept Pediat, Div Allergy & Immunol, Denver, CO USA. [Szefler, Stanley J.] Natl Jewish Hlth, Dept Pediat, Div Pediat Clin Pharmacol, Denver, CO USA. [Sorkness, Christine A.] Univ Wisconsin, Sch Med & Publ Hlth, Dept Allergy Pulm & Crit Care Med, Madison, WI 53706 USA. [Sorkness, Christine A.] Univ Wisconsin, Sch Pharm, Madison, WI 53706 USA. [Teach, Stephen J.] Childrens Natl Med Ctr, Div Emergency Med, Washington, DC 20010 USA. [Morgan, Wayne J.] Univ Arizona, Coll Med, Dept Pediat, Tucson, AZ USA. [Gan, Vanthaya N.] Univ Texas SW Med Ctr Dallas, Dept Pediat, Dallas, TX 75390 USA. RP Kattan, M (reprint author), Columbia Univ, Med Ctr, Coll Phys & Surg, Dept Pediat Pulmonol, 3959 Broadway,CHC 7-701, New York, NY 10032 USA. EM mk2833@columbia.edu FU National Institute of Allergy and Infectious Diseases, National Institutes of Health [NO1-AI-25496, NO1-JAI-25482]; National Center for Research Resources, National Institutes of Health [RR00052, M01RR00533, MO1RR00071, 5UL1RR024992-02, 5M01RR020359-04]; National Heart, Lung. and Blood Institute; National Institutes of Health/National Institute of Allergy and Infectious Diseases; Sepracor; NIH/NHLBI Childhood Management Program (CAMP); NHLBI Childhood Asthma Research and Education (CARE); NIH/NHLBI Asthma Clin Res Network (ACRN); NIH/NIAID Inner City Asthma Consortium (ICAC); GlaxoSmithKline; NJH/NHLBI Asthma Net; NEEHS/EPA Childhood Environmental Health Center; Schering Plough; Sanofi; NIH/University of Wisconsin; Novartis; Baylor College of Medicine/Texas Department of State Health Services FX This project has been funded in whole or in part with Federal funds from the National Institute of Allergy and Infectious Diseases, National Institutes of Health, under contract numbers NO1-AI-25496 and NO1-JAI-25482 and from the National Center for Research Resources, National Institutes of Health, under grants RR00052, M01RR00533, MO1RR00071, 5UL1RR024992-02, and 5M01RR020359-04.; Disclosure of potential conflict of interest: J. Kumar has received research support from the National Heart, Lung. and Blood Institute; is President of the Illinois Society of Allergy, Asthma. and Immunology; and is a member of the American Thoracic Society. G. R. Bloomberg has received research support from the National Institutes of Health/National Institute of Allergy and Infectious Diseases. H. Mitchell has received research support from the National Institutes of Health/National Institute of Allergy and Infectious Diseases. C. M. Kercsmar is on the Speakers' Bureau for Merck; and has received research support from Sepracor. E. Matsui has received research support from the National Institutes of Health. S. Steinback has received research support from the National Institutes of Health/National Institute of Allergy and Infectious Diseases; and has served as an expert witness on the topic of bronchiolitis. S. J. Szefler is a Consultant for GlaxoSmithKline, Genentech, Merck, Boeringher-Ingelheim, Novartis, and Schering Plough; has received research support from the NIH/NHLBI Childhood Management Program (CAMP), NHLBI Childhood Asthma Research and Education (CARE), NIH/NHLBI Asthma Clin Res Network (ACRN), NIH/NIAID Inner City Asthma Consortium (ICAC), GlaxoSmithKline, NJH/NHLBI Asthma Net, and NEEHS/EPA Childhood Environmental Health Center Grant. C. A. Sorkness is on the Advisory Board for GlaxoSmithKline, Schering Plough, AstraZeneca, and Novartis; and has received research support from Schering Plough and Sanofi. W. J. Morgan is a consultant for, and Chair of the Data Safety Monitoring Board for the Cystic Fibrosis Foundation; is a Consultant and Chair of the North American Scientific Advisory Group for the Epidemiologic Study of Cystic Fibrosis for Genentech; is a Consultant for Novartis; has received research support from the NIH/University of Wisconsin and Novartis. S. J. Teach has received research support from Novartis; has served as an expert witness on the topics of wheezing, pneumonia, and dehydration; and is a volunteer for the NIAID Food Allergy Guidelines. V. N. Gan has received research support from Baylor College of Medicine/Texas Department of State Health Services. The other authors declare they have no conflicts of interest. NR 66 TC 101 Z9 103 U1 1 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 EI 1097-6825 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2010 VL 125 IS 3 BP 584 EP 592 DI 10.1016/j.jaci.2010.01.053 PG 9 WC Allergy; Immunology SC Allergy; Immunology GA 573BK UT WOS:000275883200012 PM 20226295 ER PT J AU Pongracic, JA O'Connor, GT Muilenberg, ML Vaughn, B Gold, DR Kattan, M Morgan, WJ Gruchalla, RS Smartt, E Mitchell, HE AF Pongracic, Jacqueline A. O'Connor, George T. Muilenberg, Michael L. Vaughn, Ben Gold, Diane R. Kattan, Meyer Morgan, Wayne J. Gruchalla, Rebecca S. Smartt, Ernestine Mitchell, Herman E. TI Differential effects of outdoor versus indoor fungal spores on asthma morbidity in inner-city children SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Article DE Asthma; inner city; airborne fungi; indoor fungi; outdoor fungi; fungal allergens; children ID RESPIRATORY SYMPTOMS; RESIDENTIAL CHARACTERISTICS; ENVIRONMENTAL INTERVENTION; ASPERGILLUS-FUMIGATUS; URBAN COMMUNITIES; HOUSE DUST; 1ST YEAR; F-I; ALLERGENS; EXPOSURE AB Background: Although sensitization to fungal allergens is prevalent in inner-city children with asthma, the relationship between fungal exposure and morbidity is poorly understood. Objective: We examined relationships between fungal sensitization, exposure, and asthma morbidity in inner-city children. Methods: Participants were 5 to 11 years old and enrolled in the Inner-City Asthma Study. This report includes the subset of children with at least 1 positive skin test (PST) response to a fungal allergen extract; for these children, indoor and outdoor airborne culturable fungi levels were measured at baseline and throughout the 2-year study. Asthma morbidity measures were collected prospectively. The primary outcome was symptom days per 2 weeks. Results: At baseline, children with a PST response to a fungal allergen extract had significantly more symptom days compared with those without a PST response to any fungal allergen extract (6.3 vs 5.7 days per 2 weeks, P = .04). During the study, increases in total fungal exposure and indoor Penicillium species exposure were associated with increases in symptom days and asthma-related unscheduled visits. Indoor exposures to total fungi and to Penicillium species were associated with significant increases in unscheduled visits, even after controlling for outdoor fungal levels. Adverse effects associated with exposure to a specific fungus were stronger among children with PST responses to that fungal allergen extract compared with those seen in children with negative skin test responses. Conclusion: Outdoor fungal exposure is primarily associated with increased asthma symptoms and increased risk of exacerbations in this population. (J Allergy Clin Immunol 2010;125:593-9.) C1 [Pongracic, Jacqueline A.] Northwestern Univ, Feinburg Sch Med, Childrens Mem Hosp, Chicago, IL 60611 USA. [O'Connor, George T.] Boston Univ, Sch Med, Boston, MA 02215 USA. [Muilenberg, Michael L.] Univ Massachusetts, Sch Publ Hlth & Hlth Sci, Amherst, MA 01003 USA. [Vaughn, Ben; Mitchell, Herman E.] Rho Inc, Chapel Hill, NC USA. [Gold, Diane R.] Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. [Kattan, Meyer] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Morgan, Wayne J.] Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA. [Gruchalla, Rebecca S.] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Smartt, Ernestine] NIAID, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Pongracic, JA (reprint author), 2300 Childrens Plaza,60, Chicago, IL 60614 USA. EM j-pongracic@northwestern.edu OI O'Connor, George/0000-0002-6476-3926 FU National Institute of Allergy and Infectious Diseases [AI/ES-39769, AI/ES-39900, AI/ES39902, AI/ES-39789, AI/ES-39901, AI/ES-39761, AI/ES-39785, AI/ES-39776]; National Institutes of Environmental Health Sciences; National Institutes of Health, Department of Health and Human Services; National Center for Research Resources, National Institutes of Health, Department of Health and Human Services [M01 RR00533]; National Institute of Allergy and Infectious Diseases and the Food Allergy Project; National Institutes of Health; US Environmental Protection Agency; Novartis FX Supported by National Institutes of Health grants AI/ES-39769, AI/ES-39900, AI/ES39902, AI/ES-39789, AI/ES-39901, AI/ES-39761, AI/ES-39785, and AI/ES-39776 from the National Institute of Allergy and Infectious Diseases and the National Institutes of Environmental Health Sciences. National Institutes of Health, Department of Health and Human Services, and by grant M01 RR00533 front the National Center for Research Resources, National Institutes of Health, Department of Health and Human Services.; Disclosure of potential conflict of interest: J. A. Pongracic receives research support front the National Institute of Allergy and Infectious Diseases and the Food Allergy Project. G. T. O'Connor is a consultant for Sepracor, Inc, and Pulmatrix, Inc. M. L. Muilenberg receives research support from the National Institutes of Health. B. Vaughn is employed by Rho, Inc. D. R. Gold receives grant support from the National Institutes of Health and the US Environmental Protection Agency. W. J. Morgan is a consultant for the Cystic Fibrosis Foundation and Genentech. Inc, and receives grant support from the National Institutes of Health. R. S. Gruchalla is a consultant for GlaxoSmithKline, receives research support front Novartis, and is on the Board of Directors for ABAI. H. E. Mitchell is employed by Rho, Inc, and receives research support from the National Institute of Allergy and Infectious Diseases and the National Institutes of Environmental Health Sciences. The rest of the authors have declared that they have no conflict of interest. NR 37 TC 46 Z9 48 U1 0 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2010 VL 125 IS 3 BP 593 EP 599 DI 10.1016/j.jaci.2009.10.036 PG 7 WC Allergy; Immunology SC Allergy; Immunology GA 573BK UT WOS:000275883200013 PM 20132971 ER PT J AU van der Kleij, H Charles, N Karimi, K Mao, YK Foster, J Janssen, L Yang, PC Kunze, W Rivera, J Bienenstock, J AF van der Kleij, Hanneke Charles, Nicolas Karimi, Khalil Mao, Yu-Kang Foster, Jane Janssen, Luke Yang, Ping Chang Kunze, Wolfgang Rivera, Juan Bienenstock, John TI Evidence for neuronal expression of functional Fc (epsilon and gamma) receptors SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID SENSORY NEURONS; ACTIVATION; CELLS; MICE; RIV C1 [van der Kleij, Hanneke; Mao, Yu-Kang; Foster, Jane; Janssen, Luke; Yang, Ping Chang; Kunze, Wolfgang; Bienenstock, John] McMaster Univ, Brain Body Inst, St Josephs Healthcare Hamilton, Hamilton, ON L8S 4L8, Canada. [van der Kleij, Hanneke; Karimi, Khalil; Mao, Yu-Kang; Foster, Jane; Janssen, Luke; Yang, Ping Chang; Kunze, Wolfgang; Bienenstock, John] McMaster Univ, Dept Pathol & Mol Med, Hamilton, ON L8S 4L8, Canada. [Charles, Nicolas; Rivera, Juan] NIAMSD, Lab Immune Cell Signaling, Natl Inst Hlth, Bethesda, MD 20892 USA. RP van der Kleij, H (reprint author), McMaster Univ, Brain Body Inst, St Josephs Healthcare Hamilton, Hamilton, ON L8S 4L8, Canada. EM bienens@mcmaster.ca RI Charles, Nicolas/P-5430-2014 OI Charles, Nicolas/0000-0002-5416-5834 FU Intramural NIH HHS [Z01 AR041101-15] NR 9 TC 23 Z9 23 U1 0 U2 5 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2010 VL 125 IS 3 BP 757 EP 760 DI 10.1016/j.jaci.2009.10.054 PG 4 WC Allergy; Immunology SC Allergy; Immunology GA 573BK UT WOS:000275883200041 PM 20132972 ER PT J AU Salo, PM Zeldin, DC AF Salo, Paeivi M. Zeldin, Darryl C. TI Cats and dogs: An attractive remedy versus atopy? Reply SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID ALLERGEN; HOMES C1 [Salo, Paeivi M.; Zeldin, Darryl C.] Natl Inst Environm Hlth Sci, Natl Inst Hlth, Res Triangle Pk, NC USA. RP Salo, PM (reprint author), Natl Inst Environm Hlth Sci, Natl Inst Hlth, Res Triangle Pk, NC USA. EM zeldin@niehs.nih.gov NR 9 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 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD MAR PY 2010 VL 125 IS 3 BP 765 EP 766 DI 10.1016/j.jaci.2009.11.012 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 573BK UT WOS:000275883200046 PM 20138349 ER PT J AU Smith, ML Shimomura, E Paul, BD Cone, EJ Darwin, WD Huestis, MA AF Smith, Michael L. Shimomura, Eric Paul, Buddha D. Cone, Edward J. Darwin, W. David Huestis, Marilyn A. TI Urinary Excretion of Ecgonine and Five Other Cocaine Metabolites Following Controlled Oral, Intravenous, Intranasal, and Smoked Administration of Cocaine SO JOURNAL OF ANALYTICAL TOXICOLOGY LA English DT Article C1 [Darwin, W. David; Huestis, Marilyn A.] NIDA, Intramural Res Program, NIH, Baltimore, MD 20892 USA. [Smith, Michael L.; Shimomura, Eric; Paul, Buddha D.] Armed Forces Inst Pathol, Div Forens Toxicol, Armed Forces Med Examiner Syst, Rockville, MD USA. [Cone, Edward J.] Johns Hopkins Sch Med, Baltimore, MD USA. RP Huestis, MA (reprint author), NIDA, Intramural Res Program, NIH, Baltimore, MD 20892 USA. EM mhuestis@intra.nida.nih.gov FU National Institutes of Health, National Institute on Drug Abuse FX The authors thank the American Registry of Pathology and the Intramural Research Program, National Institutes of Health, National Institute on Drug Abuse for support. NR 10 TC 11 Z9 12 U1 0 U2 5 PU PRESTON PUBL INC PI NILES PA 6600 W TOUHY AVE, NILES, IL 60714-4588 USA SN 0146-4760 J9 J ANAL TOXICOL JI J. Anal. Toxicol. PD MAR PY 2010 VL 34 IS 2 BP 57 EP 63 PG 7 WC Chemistry, Analytical; Toxicology SC Chemistry; Toxicology GA 580OO UT WOS:000276459000001 PM 20223096 ER PT J AU Maggio, M Lauretani, F Ceda, GP Bandinelli, S Basaria, S Paolisso, G Giumelli, C Luci, M Najjar, SS Metter, EJ Valenti, G Guralnik, J Ferrucci, L AF Maggio, Marcello Lauretani, Fulvio Ceda, Gian Paolo Bandinelli, Stefania Basaria, Shehzad Paolisso, Giuseppe Giumelli, Claudio Luci, Michele Najjar, Samer S. Metter, E. Jeffrey Valenti, Giorgio Guralnik, Jack Ferrucci, Luigi TI Estradiol and Metabolic Syndrome in Older Italian Men: The InCHIANTI Study SO JOURNAL OF ANDROLOGY LA English DT Article DE Androgen; andropause ID ENDOGENOUS SEX-HORMONES; ELDERLY-MEN; CARDIOVASCULAR-DISEASE; OBESE MEN; TESTOSTERONE; ASSOCIATION; SERUM; AGE; RISK; POPULATION AB The increasing prevalence of metabolic syndrome (MS) with age in older men has been linked with decreasing testosterone levels. Interestingly, while testosterone levels decline with age, estradiol (E2) levels remain relatively stable, resulting in a decreased testosterone:E2 ratio. Because E2 levels tend to be elevated in morbid obesity, insulin resistance, and diabetes, it is reasonable to hypothesize that high E2 levels are associated with MS in older men. We studied the relationship of total and free E2 with MS after adjustment for multiple confounders, including age, BMI, smoking, alcohol consumption, physical activity, interleukin-6 (IL-6), fasting insulin, and testosterone. Men 65 years or older (age range, 65-96; n = 452) had complete data on E2, testosterone, fasting insulin, sex hormone binding globulin, IL-6, and albumin. Concentrations of free E2 and free testosterone were calculated using the mass action equations. MS was defined according to Adult Treatment Panel III (ATP-III). Participants with MS had significantly higher serum free and total E2 (P < .001) (P = .003). After adjusting for confounders, including age, smoking, alcohol consumption, physical activity, log(IL-6), and log(insulin), participants with higher log(total E2) (odds ratio [OR], 2.31; 95% confidence interval [95% CI], 1.39-4.70; P = .02) and higher log(free E2) (OR, 2.69; 1.38-5.24; P < .001) had an increased risk of having MS. Log(free E2) (P = .04) maintained significant correlation with MS, even after further adjustment for BMI. In older men, high E2 is independently associated with MS. Whether confirmed in other studies, assessment of E2 should be also considered in older men. Whether changes in this hormonal pattern play a role in the development of MS should be further tested in longitudinal studies. C1 [Maggio, Marcello; Ceda, Gian Paolo; Giumelli, Claudio; Luci, Michele; Valenti, Giorgio] Univ Parma, Sect Geriatr, Dept Internal Med & Biomed Sci, I-43100 Parma, Italy. [Maggio, Marcello; Basaria, Shehzad; Metter, E. Jeffrey; Ferrucci, Luigi] NIA, Clin Res Branch, Baltimore, MD 21224 USA. [Najjar, Samer S.] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. [Lauretani, Fulvio] Tuscany Reg Hlth Agcy, Florence, Italy. [Bandinelli, Stefania] ASF Florence, Geriatr Rehabil Unit, Florence, Italy. [Basaria, Shehzad] Johns Hopkins Univ, Sch Med, Bayview Med Ctr, Div Endocrinol,Dept Med, Baltimore, MD USA. [Paolisso, Giuseppe] Univ Naples Federico II, Dept Geriatr Med & Metab Dis 2, I-80138 Naples, Italy. [Guralnik, Jack] NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Maggio, M (reprint author), Univ Parma, Sect Geriatr, Dept Internal Med & Biomed Sci, Via Gramsci 14, I-43100 Parma, Italy. EM marcellomaggio2001@yahoo.it; ferruccilu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016 OI Ceda, Gian Paolo/0000-0002-9648-8295; Paolisso, Giuseppe/0000-0002-2137-455X; Lauretani, Fulvio/0000-0002-5287-9972 FU Italian Ministry of Health; US National Institute on Aging [N01-AG-916413, N01-AG-821336, 263 MD 916413, 263 MD 821336] FX The InCHIANTI Study was supported as a "targeted project" (ICS 110.1/RS97.71) by the Italian Ministry of Health and, in part, by the US National Institute on Aging (contracts N01-AG-916413 and N01-AG-821336) and by the Intramural Research Program of the US National Institute on Aging (contracts 263 MD 916413 and 263 MD 821336). The funding institutes had no role in the design, methods, subject recruitment, data collection, analysis, or preparation of manuscript or in the decision to submit the manuscript for publication. NR 40 TC 24 Z9 25 U1 1 U2 1 PU AMER SOC ANDROLOGY, INC PI LAWRENCE PA C/O ALLEN PRESS, INC PO BOX 368, LAWRENCE, KS 66044 USA SN 0196-3635 EI 1939-4640 J9 J ANDROL JI J. Androl. PD MAR-APR PY 2010 VL 31 IS 2 BP 155 EP 162 DI 10.2164/jandrol.108.006098 PG 8 WC Andrology SC Endocrinology & Metabolism GA 573NH UT WOS:000275920100009 PM 19059904 ER PT J AU Moldenhauer, JS Lai, YL Schatz, M Wise, R Landon, MB Newman, RB Rouse, DJ Simhan, HN Leveno, KJ Miodovnik, M Lindheimer, MD Wapner, RJ Varner, MW O'Sullivan, MJ Conway, DL AF Moldenhauer, Julie S. Lai, Yinglei Schatz, Michael Wise, Robert Landon, Mark B. Newman, Roger B. Rouse, Dwight J. Simhan, Hyagriv N. Leveno, Kenneth J. Miodovnik, Menachem Lindheimer, Marshall D. Wapner, Ronald J. Varner, Michael W. O'Sullivan, Mary Jo Conway, Deborah L. CA Eunice Kennedy Shriver Natl Inst C TI Influence of Maternal Asthma and Asthma Severity on Newborn Morphometry SO JOURNAL OF ASTHMA LA English DT Article DE asthma; neonatal morphometry; pregnancy ID BIRTH-WEIGHT; PERINATAL OUTCOMES; HIGH-ALTITUDE; PREGNANCY; GROWTH; WOMEN AB Objective. To determine if maternal asthma or asthma severity affects newborn morphometry. Study Design. A secondary analysis was performed on data collected in a multicenter prospective observational cohort study of asthma in pregnancy. Patients enrolled included women with asthma stratified by severity of disease and controls. Asthma severity was defined according to the classification proposed by the National Asthma Education Program (NAEP) Report of the Working Group on Asthma and Pregnancy, modified to include medication requirements. Newborn morphometry measurements included birth weight (BW) and multiples of the median birth weight (BW-MOM), head circumference (HC), length (L), HC:BW ratio, and ponderal index (PI). Results. Of 2480 patients there were 828 nonasthmatic controls, 828 with mild, 775 with moderate, and 49 with severe disease. Comparing all groups, there were statistically significant differences in maternal age (p < .001), race (p = .005), parity (p = .006), prepregnancy weight (p = .028), and medical care source (p = .001), with the severe asthma group having the highest mean maternal age (25.7 years), and proportion of African Americans (71.4%), proportion of multiparous patients (63.3%), and proportion of patients receiving government assistance (85.7%). When the control group was excluded from the comparisons, differences in prepregnancy weight and medical care source were no longer significant. BW-MOM and L did not differ between groups. The HC:BW ratio increased with asthma severity (p = .029) and was increased compared to controls (p = .010). This remained significant after controlling for confounding variables (both p <.001). HC was statistically significantly different between all groups (p = .032), as well as among women with varying degrees of asthma severity (p = .013), which was not clinically significant. After covariates adjustment, HC was not significantly different among all groups (p = .228), nor the asthma groups (p = .144). Conclusion. Asthma severity is associated with an increased HC:BW ratio. Severity was not found to impact HC, BW-MOM, L, or PI independently. However, the magnitudes of the effects were too small to suggest a clinically significant effect of asthma on neonatal morphometry in this large prospectively studied sample. 0.01). White and Asian BCS reported more endoscopic examinations (58.9% versus 46.5%; P < 0.001; 61.2% versus 38.4%; P < 0.05) than the comparison population. After adjustment for demographic, socioeconomic, and health status differences, screening rates for BCS showed higher mammography use (odds ratio [OR] 1.97; 95% confidence interval [95% CI] 1.58-2.46), Pap test (OR 1.44; 95% CI 1.22-1.70), and endoscopic use (OR 1.35; 95% CI 1.16-1.58), but not higher for FOBT. Conclusions Even though BCS generally had higher cancer screening rates than women without a cancer history, racial/ethnic differences exist among the type of test received. Narrowing these differences is essential to lessen disparities. Implications for cancer survivors The need for screening guidelines for BCS remains a high priority. Survivors would benefit from the frequency of screening for all cancers post-treatment. C1 [Breslau, Erica S.; Moser, Richard P.] NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Jeffery, Diana D.] NCI, Off Canc Survivorship, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Davis, William W.] NCI, Stat Res & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [McNeel, Timothy S.] Informat Management Serv Inc, Silver Spring, MD USA. [Hawley, Sarah] Univ Michigan, Div Gen Med, Ann Arbor, MI 48109 USA. RP Breslau, ES (reprint author), NCI, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. EM breslaue@mail.nih.gov NR 62 TC 11 Z9 11 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1932-2259 J9 J CANCER SURVIV JI J. Cancer Surviv.-Res. Pract. PD MAR PY 2010 VL 4 IS 1 BP 1 EP 14 DI 10.1007/s11764-009-0102-5 PG 14 WC Oncology; Social Sciences, Biomedical SC Oncology; Biomedical Social Sciences GA 788TV UT WOS:000292468200001 PM 19882379 ER PT J AU Keteyian, SJ Pina, IL Hibner, BA Fleg, JL AF Keteyian, Steven J. Pina, Ileana L. Hibner, Brooks A. Fleg, Jerome L. TI Clinical Role of Exercise Training in the Management of Patients With Chronic Heart Failure SO JOURNAL OF CARDIOPULMONARY REHABILITATION AND PREVENTION LA English DT Review DE cardiac rehabilitation; exercise training; heart failure; HF-ACTION ID RANDOMIZED CONTROLLED-TRIAL; LEFT-VENTRICULAR DYSFUNCTION; SKELETAL-MUSCLE FUNCTION; RESISTANCE EXERCISE; HF-ACTION; PROGRAM; INTOLERANCE; REHABILITATION; PERFORMANCE; PRESCRIPTION AB Prior exercise research and the recently completed HF-ACTION (Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training) trial indicate that regular exercise represents an effective therapy in the management of patients with stable chronic heart failure (HF) due to left ventricular systolic dysfunction. This review summarizes the results from these studies and provides a guide for prescribing exercise. Regular aerobic-type exercise training improves exercise capacity; does not worsen and may, in fact, mildly improve cardiac function; and partially improves other physiological abnormalities that develop because of chronic HF (eg, autonomic and skeletal muscle function). Regular exercise is safe, improves health status, and modestly reduces (similar to 15%) combined risk for cardiovascular death or HF-related hospitalization. Even greater physiological and clinical benefits appear likely in patients with HF who adhere to a higher volume of exercise (eg, 6 MET-hr per week). The exercise regimen should include an aerobic-type activity performed at least 30 minutes, 5 or more days per week, and at an intensity approximating 55% to 80% of heart rate reserve. Resistance training should be considered for patients who first demonstrate they are able to tolerate aerobic exercise training. Common to other interventions that also rely on human behavior, long-term adherence to exercise in patients with HF remains a challenge and requires additional research to determine strategies aimed at improving compliance. Areas of needed research include identifying which patient subgroup(s) benefits the most and determination of the optimal intensity, duration, and frequency of exercise needed to maximize clinical benefits and attenuate fatigue. C1 [Keteyian, Steven J.; Hibner, Brooks A.] Henry Ford Hosp, Dept Med, Detroit, MI 48202 USA. [Pina, Ileana L.] Case Western Univ, Sch Med, Vet Adm Med Ctr, Cleveland, OH USA. [Fleg, Jerome L.] NHLBI, Div Cardiovasc Dis, Bethesda, MD 20892 USA. RP Keteyian, SJ (reprint author), Henry Ford Hosp, Dept Med, 6525 2nd Ave, Detroit, MI 48202 USA. EM sketeyi1@hfhs.org NR 67 TC 30 Z9 40 U1 1 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1932-7501 J9 J CARDIOPULM REHABIL JI J. Cardiopulm. Rehabil. Prev. PD MAR-APR PY 2010 VL 30 IS 2 BP 67 EP 76 DI 10.1097/HCR.0b013e3181d0c1c1 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 575HH UT WOS:000276057600001 PM 20216359 ER PT J AU Dikovskaya, D Li, ZY Newton, IP Davidson, I Hutchins, JRA Kalab, P Clarke, PR Nathke, IS AF Dikovskaya, Dina Li, Zhuoyu Newton, Ian P. Davidson, Iain Hutchins, James R. A. Kalab, Petr Clarke, Paul R. Naethke, Inke S. TI Microtubule assembly by the Apc protein is regulated by importin-beta-RanGTP SO JOURNAL OF CELL SCIENCE LA English DT Article DE Adenomatous polyposis coli; Importin-beta; Microtubules; Mitotic spindle ID TUMOR-SUPPRESSOR PROTEIN; POLYPOSIS-COLI PROTEIN; GUANINE-NUCLEOTIDE EXCHANGE; MITOTIC SPINDLE; CELL-MIGRATION; NUCLEAR IMPORT; IN-VITRO; BINDING; IDENTIFICATION; MITOSIS AB Mutations in the tumour suppressor Adenomatous polyposis coli (Apc) initiate most sporadic colorectal cancers. Apc is implicated in regulating microtubule (MT) dynamics in interphase and mitosis. However, little is known about the underlying mechanism or regulation of this Apc function. We identified importin-beta as a binding partner of Apc that regulates its effect on MTs. Apc binds importin-beta in vitro and in Xenopus egg extracts, and RanGTP inhibits this interaction. The armadillo-like repeat domain of importin-beta binds to the middle of Apc, where it can compete with beta-catenin. In addition, two independent sites in the C terminus of Apc bind the N-terminal region of importin-beta. Binding to importin-beta reduces the ability of Apc to assemble and bundle MTs in vitro and to promote assembly of microtubule asters in Xenopus egg extracts, but does not affect the binding of Apc to MTs or to EB1. Depletion of Apc decreases the formation of cold-stable spindles in Xenopus egg extracts. Importantly, the ability of purified Apc to rescue this phenotype was reduced when it was constitutively bound to importin-beta. Thus, importin-beta binds to Apc and negatively regulates the MT-assembly and spindle-promoting activity of Apc in a Ran-regulatable manner. C1 [Dikovskaya, Dina; Li, Zhuoyu; Newton, Ian P.; Davidson, Iain; Naethke, Inke S.] Univ Dundee, Div Cell & Dev Biol, Coll Life Sci, Dundee DD1 5EH, Scotland. [Hutchins, James R. A.; Clarke, Paul R.] Univ Dundee, Biomed Res Inst, Coll Med Dent & Nursing, Ninewells Hosp & Med Sch, Dundee DD1 9SY, Scotland. [Kalab, Petr] NCI, Bethesda, MD 20892 USA. RP Dikovskaya, D (reprint author), Univ Dundee, Div Cell & Dev Biol, Coll Life Sci, Dundee DD1 5EH, Scotland. EM d.dikovskaya@dundee.ac.uk RI Clarke, Paul/B-1684-2009; Kalab, Petr/B-2478-2009 FU Cancer Research UK FX We thank Ewan Morrison for providing the EB1 expression construct, Bill Hunter and members of the Nathke laboratory for helpful discussions, Paul Appleton for help with imaging, Holly Goodson for advice with the light scattering assay, and Alan Fairlamb for providing a spectrophotometer. This work was funded by a program grant from Cancer Research UK to I. S. N. NR 38 TC 15 Z9 15 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAR 1 PY 2010 VL 123 IS 5 BP 736 EP 746 DI 10.1242/jcs.060806 PG 11 WC Cell Biology SC Cell Biology GA 556MH UT WOS:000274594700011 PM 20144988 ER PT J AU Peters, N Perez, DE Song, MH Liu, Y Muller-Reichert, T Caron, C Kemphues, KJ O'Connell, KF AF Peters, Nathaniel Perez, Dahlia E. Song, Mi Hye Liu, Yan Mueller-Reichert, Thomas Caron, Cathy Kemphues, Kenneth J. O'Connell, Kevin F. TI Control of mitotic and meiotic centriole duplication by the Plk4-related kinase ZYG-1 SO JOURNAL OF CELL SCIENCE LA English DT Article DE Centrosome amplification; Meiosis; ZYG-1; C. elegans ID SEX-DETERMINATION GENE; CAENORHABDITIS-ELEGANS; CENTROSOME DUPLICATION; C-ELEGANS; CELL-CYCLE; PROTEIN-SYNTHESIS; DROSOPHILA SPD-2; SPERMATOGENESIS; RECRUITMENT; BIOGENESIS AB Centriole duplication is of crucial importance during both mitotic and male meiotic divisions, but it is currently not known whether this process is regulated differently during the two modes of division. In Caenorhabditis elegans, the kinase ZYG-1 plays an essential role in both mitotic and meiotic centriole duplication. We have found that the C-terminus of ZYG-1 is necessary and sufficient for targeting to centrosomes and is important for differentiating mitotic and meiotic centriole duplication. Small truncations of the C-terminus dramatically lower the level of ZYG-1 at mitotic centrosomes but have little effect on the level of ZYG-1 at meiotic centrosomes. Interestingly, truncation of ZYG-1 blocks centrosome duplication in the mitotic cycle but leads to centrosome amplification in the meiotic cycle. Meiotic centriole amplification appears to result from the overduplication of centrioles during meiosis I and leads to the formation of multipolar meiosis II spindles. The extra centrioles also disrupt spermatogenesis by inducing the formation of supernumerary fertilization-competent spermatids that contain abnormal numbers of chromosomes and centrioles. Our data reveal differences in the regulation of mitotic and meiotic centrosome duplication, particularly with regard to ZYG-1 activity, and reveal an important role for centrosomes in spermatid formation. C1 [Peters, Nathaniel; Perez, Dahlia E.; Song, Mi Hye; Liu, Yan; O'Connell, Kevin F.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Mueller-Reichert, Thomas] Max Planck Inst Mol Cell Biol & Genet MPI CBG, D-01307 Dresden, Germany. [Caron, Cathy; Kemphues, Kenneth J.] Cornell Univ, Sect Genet & Dev, Ithaca, NY 14853 USA. RP O'Connell, KF (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM kevino@intra.niddk.nih.gov OI Song, Mi Hye/0000-0001-8326-6602 FU NIH National Center for Research Resources (NCRR); Shohei Mitani and the National Bioresource Project-Japan; National Institutes Health (NIH); National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Jenny Hinshaw and Jurgen Heymann for help with electron microscopy, Nina Peel, Nicholas Miliaras, and Andy Golden for comments on the manuscript, and Catherine Kemp for technical assistance. Strains were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR), and by Shohei Mitani and the National Bioresource Project-Japan. This work was supported by the Intramural Research Program of the National Institutes Health (NIH) and by the National Institute of Diabetes and Digestive and Kidney Diseases. Deposited in PMC for release after 12 months. NR 53 TC 14 Z9 19 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD MAR 1 PY 2010 VL 123 IS 5 BP 795 EP 805 DI 10.1242/jcs.050682 PG 11 WC Cell Biology SC Cell Biology GA 556MH UT WOS:000274594700017 PM 20144993 ER PT J AU Clark, K Howe, JD Pullar, CE Green, JA Artym, VV Yamada, KM Critchley, DR AF Clark, Katherine Howe, Jonathan D. Pullar, Christine E. Green, J. Angelo Artym, Vira V. Yamada, Kenneth M. Critchley, David R. TI Tensin 2 Modulates Cell Contractility in 3D Collagen Gels Through the RhoGAP DLC1 SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE TENSIN; FIBRONECTIN MATRIX ASSEMBLY; FIBRILLAR ADHESION; COLLAGEN CONTRACTION; DLC1; RhoGAP ID FIBRONECTIN MATRIX DEPOSITION; CYTOPLASMIC DOMAIN; TYROSINE PHOSPHORYLATION; BINDING DOMAINS; FAMILY-MEMBER; PTB DOMAIN; PROTEIN; ADHESIONS; MIGRATION; IDENTIFICATION AB Cytoskeletal proteins of the tensin family couple integrins to the actin cytoskeleton. They are found in both focal adhesions and the fibrillar adhesions formed between cells and the fibronectin matrix. There are four tensin genes which encode three large (similar to 200 kDa) tensin isoforms (tensin 1, 2, 3) and one short isoform (cten). However, the subcellular localization and function of the individual isoforms is poorly understood. Using human foreskin fibroblasts (HFFs), and imaging on both fixed and live cells, we show that GFP-tensin 2 is enriched in dynamic focal adhesions at the leading edge of the cell, whereas GFP-tensin 3 translocates rearward, and is enriched in fibrillar adhesions. To investigate the possible role of tensins in cell-matrix remodeling, we used siRNAs to knockdown each tensin isoform. We discovered that tensin 2 knockdown significantly reduced the ability of HFFs to contract 31) collagen gels, whilst no effect on fibronectin fibrillogenesis was observed. This inhibition of collagen gel contraction was associated with a substantial reduction in Rho activity, and it was reversed by depletion of DLC1, a RhoGAP that binds to tensin in focal adhesions. These findings suggest that focal adhesion localized tensin 2 negatively regulates DLC1 to percent Rho-mediated actomyosin contraction and remodeling of collagen fibers. J. Cell. Biochem. 109: 808-817, 2010. (C) 2010 Wiley-Liss, Inc. C1 [Clark, Katherine; Howe, Jonathan D.; Critchley, David R.] Univ Leicester, Dept Biochem, Leicester LE1 9HN, Leics, England. [Clark, Katherine; Pullar, Christine E.] Univ Leicester, Dept Cell Physiol & Pharmacol, Leicester LE1 9HN, Leics, England. [Green, J. Angelo; Artym, Vira V.; Yamada, Kenneth M.] NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. [Artym, Vira V.] Georgetown Univ, Sch Med, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. RP Critchley, DR (reprint author), Univ Leicester, Dept Biochem, Leicester LE1 9HN, Leics, England. EM drc@le.ac.uk OI Yamada, Kenneth/0000-0003-1512-6805 FU Wellcome Trust; NIH FX Grant sponsor: Wellcome Trust and the Intramural Research Program of the NIH. NR 46 TC 21 Z9 21 U1 1 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD MAR 1 PY 2010 VL 109 IS 4 BP 808 EP 817 DI 10.1002/jcb.22460 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 568XH UT WOS:000275559000020 PM 20069572 ER PT J AU Major, JM Laughlin, GA Kritz-Silverstein, D Wingard, DL Barrett-Connor, E AF Major, Jacqueline M. Laughlin, Gail A. Kritz-Silverstein, Donna Wingard, Deborah L. Barrett-Connor, Elizabeth TI Insulin-Like Growth Factor-I and Cancer Mortality in Older Men SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID IGF-BINDING PROTEIN-3; FACTOR (IGF)-I; CIRCULATING LEVELS; PANCREATIC-CANCER; PLASMA-LEVELS; RISK; WOMEN; IGFBP-3; HORMONE; COHORT AB Context: Although numerous studies have explored the relation of IGF-I with cancer incidence, few have investigated the association between IGF-I and cancer mortality. Objective: This study examined the association of serum IGF-I levels with cancer mortality in older community-dwelling men. Design, Setting, and Participants: We conducted a prospective, population-based study of 633 men aged 50 yr and older (mean = 73) who attended a 1988-1991 research clinic visit when blood was obtained for measurement of IGF-I. Participants were followed for vital status through July 2006. Main Outcome Measure: All-cancer mortality was assessed. Results: Median IGF-I was 96 ng/ml. During the 18-yr follow-up, 368 deaths occurred; 74 (20%) were due to cancer. Cox regression analyses showed a significant quadratic association between IGF-I and all-cancer mortality (P = 0.039). Higher levels of IGF-I were associated with progressively higher risk of cancer death after adjusting for age, IGF-binding protein-1, adiposity, exercise, current smoking, and previous cancer. The adjusted risk of cancer death was statistically significant for IGF-I levels above 120 ng/ml, with magnitudes of effect ranging from 1.61 [95% confidence interval (CI) = 1.28-2.02] to 2.61 (95% CI = 1.46-4.64). For the 46% of men with IGF-I above 100 ng/ml, the risk of fatal cancer was 1.82 (95% CI = 1.11-2.96) compared to the risk with lower levels. Conclusions: Higher serum IGF-I in older men is associated with increased risk of cancer death, independent of age, adiposity, lifestyle, and cancer history. These results suggest caution in the use of IGF-I-enhancing therapies to slow the adverse effects of aging. (J Clin Endocrinol Metab 95: 1054-1059, 2010) C1 [Major, Jacqueline M.; Laughlin, Gail A.; Kritz-Silverstein, Donna; Wingard, Deborah L.; Barrett-Connor, Elizabeth] Univ Calif San Diego, Dept Family & Prevent Med, Sch Med, La Jolla, CA 92093 USA. [Major, Jacqueline M.] NCI, Div Canc, Bethesda, MD 20852 USA. RP Laughlin, GA (reprint author), Univ Calif San Diego, Dept Family & Prevent Med, Sch Med, 9500 Gilman Dr, La Jolla, CA 92093 USA. EM glaughlin@ucsd.edu FU National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Aging [AG028507, AG018339] FX This work was supported by Grant DK007386-28 from the National Institute of Diabetes and Digestive and Kidney Diseases and National Institute of Aging Grants AG028507 and AG018339. NR 32 TC 26 Z9 27 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X EI 1945-7197 J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2010 VL 95 IS 3 BP 1054 EP 1059 DI 10.1210/jc.2009-1378 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 564FA UT WOS:000275197500009 PM 20080855 ER PT J AU Bechlioulis, A Kalantaridou, SN Naka, KK Chatzikyriakidou, A Calis, KA Makrigiannakis, A Papanikolaou, O Kaponis, A Katsouras, C Georgiou, I Chrousos, GP Michalis, LK AF Bechlioulis, Aris Kalantaridou, Sophia N. Naka, Katerina K. Chatzikyriakidou, Anthoula Calis, Karim A. Makrigiannakis, Antonis Papanikolaou, Odysseas Kaponis, Apostolos Katsouras, Christos Georgiou, Ioannis Chrousos, George P. Michalis, Lampros K. TI Endothelial Function, But Not Carotid Intima-Media Thickness, Is Affected Early in Menopause and Is Associated with Severity of Hot Flushes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ESTROGEN-RECEPTOR-ALPHA; CARDIOVASCULAR RISK-FACTORS; POSTMENOPAUSAL WOMEN; GENE POLYMORPHISMS; MYOCARDIAL-INFARCTION; VASOMOTOR FUNCTION; HORMONE-THERAPY; DYSFUNCTION; DISEASE; HEART AB Context: The effect of early menopause on indices of vascular function has been little studied. Objective: The objective of the study was to investigate the effect of early menopause on indices of subclinical atherosclerosis and identify predictors of those indices in early menopausal women. Design, Setting, and Participants: This was a cross-sectional study that included 120 early menopausal women (age range 42-55 yr, <3 yr in menopause) recruited from the menopause outpatient clinic of an academic hospital and 24 age-matched premenopausal women. Main Outcome Measures: Brachial artery flow-mediated dilation (FMD) and common carotid intima-media thickness (IMT) were studied. Estrogen receptor (ER)-alpha (rs2234693 T-->C and rs9340799 A-->G) and ER beta (rs4986938 A-->G) polymorphisms were studied in menopausal women. Results: FMD was significantly lower in early menopausal women compared with controls (5.43 +/- 2.53 vs. 8.74 +/- 3.17%, P < 0.001), whereas IMT did not differ between groups (P > 0.8). Severity of hot flushes was the most important independent predictor for FMD (P < 0.001) in menopausal women. Women with moderate/severe/very severe hot flushes had impaired FMD in contrast to women with no/mild hot flushes or controls. Women with no/mild hot flushes did not differ compared with controls. Age and systolic blood pressure were the main determinants of IMT (both P = 0.004). ER polymorphisms were not associated with vascular parameters. Conclusions: Impairment of endothelial function is present in the early menopausal years, whereas carotid IMT is not affected. Severity of hot flushes is the main determinant of endothelial dysfunction in early menopausal women. The studied ER polymorphisms do not offer important information on vascular health in early menopause. (J Clin Endocrinol Metab 95: 1199-1206, 2010) C1 [Naka, Katerina K.; Katsouras, Christos; Michalis, Lampros K.] Univ Ioannina, Dept Cardiol, GR-45110 Ioannina, Greece. [Chatzikyriakidou, Anthoula; Georgiou, Ioannis] Univ Ioannina, Dept Obstet & Gynecol, Genet Unit, GR-45110 Ioannina, Greece. [Bechlioulis, Aris; Naka, Katerina K.; Katsouras, Christos; Michalis, Lampros K.] Univ Ioannina, Michaelid Cardiac Ctr, GR-45110 Ioannina, Greece. [Papanikolaou, Odysseas; Kaponis, Apostolos] Univ Hosp Ioannina, Dept Obstet & Gynecol, Ioannina 45110, Greece. [Makrigiannakis, Antonis] Univ Crete, Dept Obstet & Gynecol, Iraklion 71409, Greece. [Chrousos, George P.] Univ Athens, Dept Pediat 1, Athens 15784, Greece. [Calis, Karim A.] NIH, Dept Pharm, Clin Res Ctr, Bethesda, MD 20892 USA. RP Michalis, LK (reprint author), Univ Ioannina, Dept Cardiol, GR-45110 Ioannina, Greece. EM lmihalis@cc.uoi.gr RI Bechlioulis, Aris/D-4814-2011; OI Kaponis, Apostolos/0000-0002-4738-2582 NR 34 TC 64 Z9 66 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2010 VL 95 IS 3 BP 1199 EP 1206 DI 10.1210/jc.2009-2262 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 564FA UT WOS:000275197500027 PM 20080857 ER PT J AU Zemskova, MS Gundabolu, B Sinaii, N Chen, CC Carrasquillo, JA Whatley, M Chowdhury, I Gharib, AM Nieman, LK AF Zemskova, Marina S. Gundabolu, Bhaskar Sinaii, Ninet Chen, Clara C. Carrasquillo, Jorge A. Whatley, Millie Chowdhury, Iffat Gharib, Ahmed M. Nieman, Lynnette K. TI Utility of Various Functional and Anatomic Imaging Modalities for Detection of Ectopic Adrenocorticotropin-Secreting Tumors SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; CUSHINGS-SYNDROME; CARCINOID-TUMORS; DIFFERENTIAL-DIAGNOSIS; NEUROENDOCRINE TUMORS; F-18-DOPA PET/CT; HORMONE SYNDROME; LOCALIZATION; CORTICOTROPIN AB Context: Because ectopic ACTH-secreting (EAS) tumors are often occult, improved imaging is needed. Objective: Our objective was to evaluate the utility of [(111)In-DTPA-D-Phe]pentetreotide scintigraphy [octreotide (OCT)] imaging at 6 mCi [low OCT (LOCT)] and 18 mCi [high OCT (HOCT)], [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) and [(18)F]L-3,4-dihydroxyphenylalanine (F-DOPA)-PET scans, computed tomography (CT), and magnetic resonance imaging (MRI). Design and Setting: The study was a prospective evaluation at a clinical research center. Patients: Forty-one subjects participated, 30 (17 female) with resected EAS tumors and 11 (three female) with occult EAS, based on inferior petrosal sinus sampling results and imaging studies. Intervention: Intervention included CT and MRI of neck, chest, abdomen, LOCT (with or without HOCT) and FDG- or F-DOPA-PET without CT every 6-12 months. Main Outcome Measure: Tumor identification was the main outcome measure. Results: Most recent results were analyzed. Eighteen patients had tumor resected on the first visit; otherwise, surgery occurred 33 +/- 25 (9-99) months later. Tumor size was 1.9 +/- 1.7 (0.8-8.0) cm; 83% were intrathoracic. CT, MRI, LOCT, HOCT, FDG-PET, and F-DOPA-PET had sensitivities per patient of 93% [95% confidence interval (CI) = 79-98%], 90% (95% CI = 74-96%), 57% (95% CI = 39-73%), 50% (95% CI = 25-75%), 64% (95% CI = 35-85%), and 55% (95% CI = 28-79%) and positive predictive values (PPV) per lesion of 66, 74, 79, 89, 53, and 100%, respectively. LOCT and PET detected only lesions seen by CT/MRI; abnormal LOCT or F-DOPA-PET improved PPV of CT/MRI. By modality, the fraction of patients with one or more false-positive findings was 50% by CT, 31% by MRI, 18% by L/HOCT, and 18% by FDG-PET. Eight occult EAS patients had 64 +/- 58 (9-198) months follow-up; others had none. Conclusions: High sensitivity and PPV suggest thoracic CT/MRI plus LOCT scans for initial imaging, with lesion confirmation by two modalities. (J Clin Endocrinol Metab 95: 1207-1219, 2010) C1 [Zemskova, Marina S.; Gundabolu, Bhaskar; Chowdhury, Iffat; Nieman, Lynnette K.] NICHHD, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. [Sinaii, Ninet] NIDDKD, Biostat & Clin Epidemiol Serv, NIH, Bethesda, MD 20892 USA. [Chen, Clara C.; Carrasquillo, Jorge A.; Whatley, Millie] NIDDKD, Div Nucl Med, Radiol & Imaging Sci Dept, NIH, Bethesda, MD 20892 USA. [Gharib, Ahmed M.] NIDDKD, Dept Diagnost Radiol, NIH, Bethesda, MD 20892 USA. RP Nieman, LK (reprint author), Bldg 10,CRC,1 E,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM NiemanL@nih.gov RI Carrasquillo, Jorge/E-7120-2010; Gharib, Ahmed/O-2629-2016; OI Gharib, Ahmed/0000-0002-2476-481X; Carrasquillo, Jorge/0000-0002-8513-5734 FU Intramural Research Program in Reproductive and Adult Endocrinology; Eunice Kennedy Shriver National Institute of Child Health and Development; National Institutes of Health FX This work was supported, in part, by the Intramural Research Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health. NR 25 TC 39 Z9 43 U1 1 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2010 VL 95 IS 3 BP 1207 EP 1219 DI 10.1210/jc.2009-2282 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 564FA UT WOS:000275197500028 PM 20089611 ER PT J AU Zemel, BS Leonard, MB Kelly, A Lappe, JM Gilsanz, V Oberfield, S Mahboubi, S Shepherd, JA Hangartner, TN Frederick, MM Winer, KK Kalkwarf, HJ AF Zemel, Babette S. Leonard, Mary B. Kelly, Andrea Lappe, Joan M. Gilsanz, Vicente Oberfield, Sharon Mahboubi, Soroosh Shepherd, John A. Hangartner, Thomas N. Frederick, Margaret M. Winer, Karen K. Kalkwarf, Heidi J. TI Height Adjustment in Assessing Dual Energy X-Ray Absorptiometry Measurements of Bone Mass and Density in Children SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID MINERAL CONTENT; COMPUTED-TOMOGRAPHY; ADOLESCENT GIRLS; HEALTHY-CHILDREN; AGE; DISEASE; PUBERTY; DENSITOMETRY; ACQUISITION; CHILDHOOD AB Context: In children, bone mineral content (BMC) and bone mineral density (BMD) measurements by dual-energy x-ray absorptiometry (DXA) are affected by height status. No consensus exists on how to adjust BMC or BMD (BMC/BMD) measurements for short or tall stature. Objective: The aim of this study was to compare various methods to adjust BMC/BMD for height in healthy children. Design: Data from the Bone Mineral Density in Childhood Study (BMDCS) were used to develop adjustment methods that were validated using an independent cross-sectional sample of healthy children from the Reference Data Project (RDP). Setting: We conducted the study in five clinical centers in the United States. Participants: We included 1546 BMDCS and 650 RDP participants (7 to 17 yr of age, 50% female). Intervention: No interventions were used. Main Outcome Measures: We measured spine and whole body (WB) BMC and BMD Z-scores for age (BMC/BMD(age)), height age(BMC/BMD(height age)), height(BMC(height)), bone mineral apparent density (BMAD(age)), and height-for-age Z-score (HAZ) (BMC/BMD(haz)). Results: Spine and WB BMC/BMD(age)Z and BMAD(age)Z were positively (P < 0.005; r = 0.11 to 0.64) associated with HAZ. Spine BMD(haz) and BMC(haz)Z were not associated with HAZ; WB BMC(haz)Z was modestly associated with HAZ (r = 0.14; P = 0.0003). All other adjustment methods were negatively associated with HAZ (P = 0.005; r = -0.20 to -0.34). The deviation between adjusted and BMC/BMD(age) Z-scores was associated with age for most measures (P < 0.005) except for BMC/BMD(haz). Conclusions: Most methods to adjust BMC/BMD Z-scores for height were biased by age and/or HAZ. Adjustments using HAZ were least biased relative to HAZ and age and can be used to evaluate the effect of short or tall stature on BMC/BMD Z-scores. (J Clin Endocrinol Metab 95: 1265-1273, 2010) C1 [Zemel, Babette S.; Leonard, Mary B.; Kelly, Andrea; Mahboubi, Soroosh] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Lappe, Joan M.] Creighton Univ, Omaha, NE 68131 USA. [Gilsanz, Vicente] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Oberfield, Sharon] Columbia Univ, New York, NY 10032 USA. [Shepherd, John A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Hangartner, Thomas N.] Wright State Univ, Dayton, OH 45435 USA. [Frederick, Margaret M.] Clin Trials & Surveys Corp, Baltimore, MD 21117 USA. [Winer, Karen K.] NICHHD, Bethesda, MD 20892 USA. [Kalkwarf, Heidi J.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. RP Zemel, BS (reprint author), Childrens Hosp Philadelphia, 3535 Market St,Room 1560, Philadelphia, PA 19104 USA. EM zemel@email.chop.edu FU National Institute of Child Health and Human Development [NO1-HD-1-3228, NO1-HD-1-3329, NO1-HD-1-3330, NO1-HD-1-3331, NO1-HD-1-3332, NO1-HD-1-3333]; General Clinical Research Center [5-MO1-RR-000240]; Clinical and Translational Research Center of The Children's Hospital of Philadelphia/University of Pennsylvania [UL1-RR024134]; Research Institute of The Children's Hospital of Philadelphia FX This work was supported by the National Institute of Child Health and Human Development contracts NO1-HD-1-3228, -3329, -3330, -3331, -3332, and -3333; the General Clinical Research Center (5-MO1-RR-000240); the Clinical and Translational Research Center of The Children's Hospital of Philadelphia/University of Pennsylvania (UL1-RR024134); and the Research Institute of The Children's Hospital of Philadelphia. NR 27 TC 129 Z9 131 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD MAR PY 2010 VL 95 IS 3 BP 1265 EP 1273 DI 10.1210/jc.2009-2057 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 564FA UT WOS:000275197500034 PM 20103654 ER PT J AU Danielian, S Basile, N Rocco, C Prieto, E Rossi, J Barsotti, D Roche, PA Bernasconi, A Oleastro, M Zelazko, M Braier, J AF Danielian, Silvia Basile, Natalia Rocco, Carlos Prieto, Emma Rossi, Jorge Barsotti, Dario Roche, Paul A. Bernasconi, Andrea Oleastro, Matias Zelazko, Marta Braier, Jorge TI Novel Syntaxin 11 Gene (STX11) Mutation in Three Argentinean Patients with Hemophagocytic Lymphohistiocytosis SO JOURNAL OF CLINICAL IMMUNOLOGY LA English DT Article DE Familial hemophagocytic lymphohistiocytosis; primary immunodeficiency; syntaxin 11 gene; founder mutation ID TRANS-GOLGI NETWORK; DISEASE; CYTOTOXICITY; MUNC13-4; LINKAGE; PRF1; FHL AB Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease with major diagnostic and therapeutic difficulties, basically comprising two different conditions: primary and secondary forms. Recent advances regarding molecular diagnosis may be useful to distinguish from one another, especially in sporadic cases starting in early infancy. In this report, we evaluated three Argentinean patients with clinical suspicion of HLH, but without family history. We excluded mutations in the perforin gene but identified in the three patients a novel homozygous deletion (c. 581_584delTGCC; p.Leu194ProfsX2) in the gene-encoding syntaxin 11 (STX11), causing a premature termination codon. Each parent from the three unrelated families resulted heterozygous for this deletion confirming the diagnosis of familial hemophagocytic lymphohistiocytosis type 4. Patients shared the same single-nucleotide polymorphism profile in STX11 gene, and genotyping at ten microsatellites surrounding this gene support the presence of a single-haplotype block carrying the novel mutation. C1 [Danielian, Silvia; Basile, Natalia; Prieto, Emma; Rossi, Jorge; Bernasconi, Andrea; Oleastro, Matias; Zelazko, Marta] Hosp Pediat Juan P Garrahan, Serv Inmunol & Reumatol, Buenos Aires, DF, Argentina. [Barsotti, Dario; Braier, Jorge] Hosp Pediat Juan P Garrahan, Serv Hematol Oncol, Buenos Aires, DF, Argentina. [Roche, Paul A.] NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. [Rocco, Carlos] Hosp Pediat Juan P Garrahan, Lab Biol Celular & Retrovirus, Buenos Aires, DF, Argentina. RP Danielian, S (reprint author), Hosp Pediat Juan P Garrahan, Serv Inmunol & Reumatol, Buenos Aires, DF, Argentina. EM danielian.silvia@gmail.com FU Agencia Nacional de Promocion Cientifica y Tecnologica [21235] FX The study was supported by Agencia Nacional de Promocion Cientifica y Tecnologica (PICT2004 No. 21235). We wish to thank Veronica Goris for the expert handling of patient samples and Marianela Sanz for technical assistance in the detection of NK activity and CD107a. NR 23 TC 6 Z9 6 U1 0 U2 1 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0271-9142 J9 J CLIN IMMUNOL JI J. Clin. Immunol. PD MAR PY 2010 VL 30 IS 2 SI SI BP 330 EP 337 DI 10.1007/s10875-009-9350-4 PG 8 WC Immunology SC Immunology GA 572AP UT WOS:000275798900019 PM 19967551 ER PT J AU Kantoff, PW Schuetz, TJ Blumenstein, BA Glode, LM Bilhartz, DL Wyand, M Manson, K Panicali, DL Laus, R Schlom, J Dahut, WL Arlen, PM Gulley, JL Godfrey, WR AF Kantoff, Philip W. Schuetz, Thomas J. Blumenstein, Brent A. Glode, L. Michael Bilhartz, David L. Wyand, Michael Manson, Kelledy Panicali, Dennis L. Laus, Reiner Schlom, Jeffrey Dahut, William L. Arlen, Philip M. Gulley, James L. Godfrey, Wayne R. TI Overall Survival Analysis of a Phase II Randomized Controlled Trial of a Poxviral-Based PSA-Targeted Immunotherapy in Metastatic Castration-Resistant Prostate Cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; COSTIMULATORY MOLECULES; CLINICAL-TRIALS; ANTIGEN; THERAPY; VACCINES AB Purpose Therapeutic prostate-specific antigen (PSA)-targeted poxviral vaccines for prostate cancer have been well tolerated. PROSTVAC-VF treatment was evaluated for safety and for prolongation of progression-free survival (PFS) and overall survival (OS) in a randomized, controlled, and blinded phase II study. Patients and Methods In total, 125 patients were randomly assigned in a multicenter trial of vaccination series. Eligible patients had minimally symptomatic castration-resistant metastatic prostate cancer (mCRPC). PROSTVAC-VF comprises two recombinant viral vectors, each encoding transgenes for PSA, and three immune costimulatory molecules (B7.1, ICAM-1, and LFA-3). Vaccinia-based vector was used for priming followed by six planned fowlpox-based vector boosts. Patients were allocated (2:1) to PROSTVAC-VF plus granulocyte-macrophage colony-stimulating factor or to control empty vectors plus saline injections. Results Eighty-two patients received PROSTVAC-VF and 40 received control vectors. Patient characteristics were similar in both groups. The primary end point was PFS, which was similar in the two groups (P = .6). However, at 3 years post study, PROSTVAC-VF patients had a better OS with 25 (30%) of 82 alive versus 7 (17%) of 40 controls, longer median survival by 8.5 months (25.1 v 16.6 months for controls), an estimated hazard ratio of 0.56 (95% CI, 0.37 to 0.85), and stratified log-rank P = .0061. Conclusion PROSTVAC-VF immunotherapy was well tolerated and associated with a 44% reduction in the death rate and an 8.5-month improvement in median OS in men with mCRPC. These provocative data provide preliminary evidence of clinically meaningful benefit but need to be confirmed in a larger phase III study. J Clin Oncol 28:1099-1105. (C) 2010 by American Society of Clinical Oncology C1 [Godfrey, Wayne R.] BN Immunotherapeut, Mountain View, CA 94043 USA. Harvard Univ, Sch Med, Dana Farber Canc Inst, Boston, MA 02115 USA. Therion Biol, Cambridge, MA USA. Trial Architecture Consulting, Washington, DC USA. Univ Colorado, Aurora, CO USA. Urol Associates, Nashville, TN USA. NCI, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. RP Godfrey, WR (reprint author), BN Immunotherapeut, 2425 Garcia Ave, Mountain View, CA 94043 USA. EM wayne.godfrey@bn-it.com RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU National Cancer Institute; Center for Cancer Research; National Institutes of Health; Laboratory of Tumor Immunology and Biology FX Supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, National Institutes of Health. Additional support was provided by the Laboratory of Tumor Immunology and Biology, via the National Cancer Institute, which had a Collaborative Research and Development Agreement with Therion Biologics and currently has one with BN ImmunoTherapeutics. NR 22 TC 491 Z9 502 U1 3 U2 37 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2010 VL 28 IS 7 BP 1099 EP 1105 DI 10.1200/JCO.2009.25.0597 PG 7 WC Oncology SC Oncology GA 560HG UT WOS:000274892500006 PM 20100959 ER PT J AU Wick, W Puduvalli, VK Chamberlain, MC van den Bent, MJ Carpentier, AF Cher, LM Mason, W Weller, M Hong, S Musib, L Liepa, AM Thornton, DE Fine, HA AF Wick, Wolfgang Puduvalli, Vinay K. Chamberlain, Marc C. van den Bent, Martin J. Carpentier, Antoine F. Cher, Lawrence M. Mason, Warren Weller, Michael Hong, Shengyan Musib, Luna Liepa, Astra M. Thornton, Donald E. Fine, Howard A. TI Phase III Study of Enzastaurin Compared With Lomustine in the Treatment of Recurrent Intracranial Glioblastoma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PROTEIN-KINASE-C; ENDOTHELIAL GROWTH-FACTOR; MALIGNANT GLIOMA; BRAIN-TUMORS; TRIAL; CHEMOTHERAPY; TEMOZOLOMIDE; MULTIFORME; THERAPY; CANCER AB Purpose This phase III open-label study compared the efficacy and safety of enzastaurin versus lomustine in patients with recurrent glioblastoma (WHO grade 4). Patients and Methods Patients were randomly assigned 2:1 to receive 6-week cycles of enzastaurin 500 mg/d (1,125-mg loading dose, day 1) or lomustine (100 to 130 mg/m(2), day 1). Assuming a 45% improvement in progression-free survival (PFS), 397 patients were required to provide 80% power to achieve statistical significance at a one-sided level of .025. Results Enrollment was terminated at 266 patients (enzastaurin, n = 174; lomustine, n = 92) after a planned interim analysis for futility. Patient characteristics were balanced between arms. Median PFS (1.5 v 1.6 months; hazard ratio [HR] = 1.28; 95% CI, 0.97 to 1.70), overall survival (6.6 v 7.1 months; HR = 1.20; 95% CI, 0.88 to 1.65), and 6-month PFS rate (P = .13) did not differ significantly between enzastaurin and lomustine, respectively. Stable disease occurred in 38.5% and 35.9% of patients and objective response occurred in 2.9% and 4.3% of patients, respectively. Time to deterioration of physical and functional well-being and symptoms did not differ between arms (HR = 1.12; P = .54). Four patients discontinued enzastaurin because of drug-related serious adverse events (AEs). Eleven patients treated with enzastaurin died on study (four because of AEs; one was drug-related). All four deaths that occurred in patients receiving lomustine were disease-related. Grade 3 to 4 hematologic toxicities were significantly higher with lomustine (46 events) than with enzastaurin (one event; P <= .001). Conclusion Enzastaurin was well tolerated and had a better hematologic toxicity profile but did not have superior efficacy compared with lomustine in patients with recurrent glioblastoma. J Clin Oncol 28: 1168-1174. (C) 2010 by American Society of Clinical Oncology C1 [Wick, Wolfgang] Univ Heidelberg, Dept Neurooncol, D-69120 Heidelberg, Germany. Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ S Florida, H Lee Moffitt Canc Ctr, Tampa, FL 33682 USA. Erasmus MC, Rotterdam, Netherlands. Hop La Pitie Salpetriere, Paris, France. Princess Margaret Hosp, Toronto, ON M4X 1K9, Canada. Univ Toronto, Toronto, ON, Canada. Eli Lilly & Co, Indianapolis, IN 46285 USA. NCI, Neurooncol Branch, Bethesda, MD 20892 USA. RP Wick, W (reprint author), Univ Heidelberg, Dept Neurooncol, Neuenheimer Feld 400, D-69120 Heidelberg, Germany. EM wolfgang.wick@med.uni-heidelberg.de RI Puduvalli, Vinay/A-2411-2016 FU Eli Lilly and Company FX Supported by Eli Lilly and Company. NR 45 TC 198 Z9 201 U1 0 U2 11 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 1 PY 2010 VL 28 IS 7 BP 1168 EP 1174 DI 10.1200/JCO.2009.23.2595 PG 7 WC Oncology SC Oncology GA 560HG UT WOS:000274892500016 PM 20124186 ER PT J AU Preston, G Anderson, E Silva, C Goldberg, T Wassermann, EM AF Preston, Gilbert Anderson, Erik Silva, Claudio Goldberg, Terry Wassermann, Eric M. TI Effects of 10 Hz rTMS on the Neural Efficiency of Working Memory SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID TRANSCRANIAL MAGNETIC STIMULATION; CORTICAL OSCILLATORY ACTIVITY; LEFT PREFRONTAL CORTEX; EVENT-RELATED FMRI; AUDITORY HALLUCINATIONS; POSTERIOR PARIETAL; THETA-OSCILLATIONS; TELL US; PERFORMANCE; SCHIZOPHRENIA AB Working memory (WM) has been described as short-term retention of information that is no longer accessible in the environment, and the manipulation of this information for subsequent use in guiding behavior. WM is viewed as a cognitive process underlying higher-order cognitive functions. Evidence supports a critical role for PFC in mediating WM performance. Studies show psychomotor processing speed and accuracy account for considerable variance in neural efficiency (Ne). This study compared the relative effects of active and sham 10 Hz rTMS applied to dorsolateral prefrontal cortex (DLPFC) on indices of Ne in healthy participants performing a WM paradigm that models the association between WM load and task behavior [Sternberg, S. High-speed scanning in human memory. Science, 153, 652-654, 1966]. Previous studies identified a relationship between diminished Ne and impaired WM across a broad array of clinical disorders. In the present study, the authors predicted there would be a main effect of stimulation group (STM) on accuracy (SCR) and processing speed (RT), hence, Ne. We observed a main effect of STM for RT without an effect on SCR; even so, there was a robust effect of STMon Ne. C1 [Preston, Gilbert] Univ Utah, Sch Med, Dept Psychiat, Salt Lake City, UT 84132 USA. [Goldberg, Terry] Hillside Zucker Hosp, Glen Oaks, NY USA. [Wassermann, Eric M.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP Preston, G (reprint author), Univ Utah, Sch Med, Dept Psychiat, 30 North 1900 East, Salt Lake City, UT 84132 USA. EM gilbert.preston@hsc.utah.edu FU NARSAD Young Investigator Award; L. C. Tanner Family Foundation; Intramural NINDS; DARPA; National Science Foundation [IIS-0513692, CCF-0401498, EIA-0323604, CNS-0514485, IIS-0534628, CNS-0528201, OISE-0405402]; Department of Energy; IBM Faculty Award FX This study was supported by the NARSAD Young Investigator Award (to G. P.), the L. C. Tanner Family Foundation (to G. P.), and Intramural NINDS, DARPA (to E. W.). National Science Foundation (IIS-0513692 to C. S., CCF-0401498 to C. S., EIA-0323604 to C. S., CNS-0514485 to C. S., IIS-0534628 to C. S., CNS-0528201 to C. S., OISE-0405402 to C. S.); Department of Energy (to C. S.); IBM Faculty Award (to C. S.). NR 51 TC 11 Z9 11 U1 0 U2 10 PU M I T PRESS PI CAMBRIDGE PA 238 MAIN STREET, STE 500, CAMBRIDGE, MA 02142-1046 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD MAR PY 2010 VL 22 IS 3 BP 447 EP 456 DI 10.1162/jocn.2009.21209 PG 10 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 565QO UT WOS:000275309500004 PM 19309294 ER PT J AU Cho, CH Neuenswander, B Larock, RC AF Cho, Chul-Hee Neuenswander, Benjamin Larock, Richard C. TI Diverse Methyl Sulfone-Containing Benzo[b]thiophene Library via Iodocyclization and Palladium-Catalyzed Coupling SO JOURNAL OF COMBINATORIAL CHEMISTRY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ESTROGEN-RECEPTOR MODULATORS; SELECTIVE COX-2 INHIBITORS; CYCLOOXYGENASE-2 INHIBITORS; BIOLOGICAL EVALUATION; PROSTAGLANDIN SYNTHESIS; TUBULIN POLYMERIZATION; PARKINSONS-DISEASE; POTENT; DERIVATIVES AB Parallel solution-phase methods for the synthesis of a 72-membered benzo[b]thiophene library are reported. Medicinally interesting, drug-like, methyl sulfone-substituted benzo[b]thiophenes have been prepared by the palladium-catalyzed substitution Of 3-iodobenzo[b]thiophenes by Suzuki-Miyaura, Sonogashira, Heck, carboalkoxylation, and aminocarbonylation chemistry, The key intermediates for library generation, methyl sulfone-containing 3-iodobenzo[b]thiophenes, are readily prepared by iodocyclization and oxidation methodologies from readily available alkynes. C1 [Cho, Chul-Hee; Larock, Richard C.] Iowa State Univ, Dept Chem, Ames, IA 50011 USA. [Neuenswander, Benjamin] Univ Kansas, NIH, Ctr Excellence Chem Methodol & Lib Dev, Lawrence, KS 66047 USA. RP Larock, RC (reprint author), Iowa State Univ, Dept Chem, Ames, IA 50011 USA. EM larock@iastate.edu FU National Institute of General Medical Sciences [GM070620, GM079593]; National Institutes of Health Kansas University Chemical Methodologies and Library Development Center of Excellence [GM069663] FX We would like to thank Dr. Gerald H. Lushington of Kansas University for all calculations for the compounds. We thank the National Institute of General Medical Sciences (GM070620 and GM079593) and the National Institutes of Health Kansas University Chemical Methodologies and Library Development Center of Excellence (GM069663) for support of this research: Johnson Matthey, Inc. and Kawaken Fine Chemicals Co., Ltd. for donations of palladium catalysts and Frontier Scientific and Synthonix for donations of boronic acids. NR 58 TC 40 Z9 40 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-4766 J9 J COMB CHEM JI J. Comb. Chem. PD MAR-APR PY 2010 VL 12 IS 2 BP 278 EP 285 DI 10.1021/cc900172u PG 8 WC Chemistry, Applied; Chemistry, Medicinal; Chemistry, Multidisciplinary SC Chemistry; Pharmacology & Pharmacy GA 563VZ UT WOS:000275164600012 PM 20055500 ER PT J AU Vilar, S Karpiak, J Costanzi, S AF Vilar, Santiago Karpiak, Joel Costanzi, Stefano TI Ligand and Structure-Based Models for the Prediction of Ligand-Receptor Affinities and Virtual Screenings: Development and Application to the beta(2)-Adrenergic Receptor SO JOURNAL OF COMPUTATIONAL CHEMISTRY LA English DT Article DE docking; QSAR; CoMFA; CoMSIA; statistical analysis; G protein-coupled receptors; beta(2)-adrenergic receptor; virtual screening ID PROTEIN-COUPLED RECEPTOR; MULTIPLE LINEAR-REGRESSION; CRYSTAL-STRUCTURE; DRUG DISCOVERY; IN-SILICO; BETA-2-ADRENERGIC RECEPTOR; BIOLOGICAL-ACTIVITY; LEAD OPTIMIZATION; BINDING-SITE; 3D STRUCTURE AB In this study, we evaluated the applicability of ligand-based and structure-based models to quantitative affinity predictions and virtual screenings for ligands of the beta(2)-adrenergic receptor, a G protein-coupled receptor (GPCR). We also devised and evaluated a number of consensus models obtained through partial least square regressions, to combine the strengths of the individual components. In all cases, the bioactive conformation of each ligand was derived from molecular docking at the crystal structure of the receptor. We identified the most effective models applicable to the different scenarios, in the presence or in the absence of a training set. For ranking the affinity of closely related analogs when a training set is available, a ligand-based consensus model (LI-CM) seems to be the best choice, while the structure-based MM-GBSA score seems the best alternative in the absence of a training set. For virtual screening purposes, the structure-based MM-GBSA score was found to be the method of choice. Consensus models consistently had performances superior or close to those of the best individual components, and were endowed with a significantly increased robustness. Given multiple models with no a priori knowledge of their predictive capabilities, constructing a consensus model ensures results very close to those that the best model alone would have yielded. (C) 2009 Wiley Periodicals, Inc.* J Comput Chem 31: 707-720, 2010 C1 [Vilar, Santiago; Karpiak, Joel; Costanzi, Stefano] NIDDK, Lab Biol Modeling, NIH, DHHS, Bethesda, MD 20892 USA. RP Costanzi, S (reprint author), NIDDK, Lab Biol Modeling, NIH, DHHS, Bethesda, MD 20892 USA. EM stefanoc@mail.nih.gov RI Costanzi, Stefano/G-8990-2013; OI Costanzi, Stefano/0000-0003-3183-7332; Vilar Varela, Santiago/0000-0003-2663-4370 FU NIH, NIDDK FX This research was supported by Intramural Research Program of the NIH, NIDDK. NR 55 TC 29 Z9 29 U1 1 U2 15 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0192-8651 J9 J COMPUT CHEM JI J. Comput. Chem. PD MAR PY 2010 VL 31 IS 4 BP 707 EP 720 DI 10.1002/jcc.21346 PG 14 WC Chemistry, Multidisciplinary SC Chemistry GA 560SG UT WOS:000274922000004 PM 19569204 ER PT J AU Bechert, CJ Stern, JB AF Bechert, Charles J. Stern, Jere B. TI Basal cell carcinoma with perineural invasion: reexcision perineural invasion? SO JOURNAL OF CUTANEOUS PATHOLOGY LA English DT Article ID MALIGNANCY AB Background: Perineural invasion (PI) in basal cell and squamous cell carcinomas, especially of the head and neck, has been reported to indicate an increased morbidity. Reexcision perineural invasion (RPI), a benign mimic of tumoral perineural invasion, may present a difficult histologic differential diagnosis. Methods: We surveyed the medical literature for PI occurring in basal cell carcinomas to investigate the degree to which the reported cases occurred in reexcision specimens vs. primary biopsy specimens. Results: We found large retrospective studies of 14,120 basal cell carcinomas evaluated for PI in which 310 cases of PI were identified (2.2%), and 20 sporadic case reports of basal cell carcinomas with PI. Of 310 cases of basal cell carcinoma with PI, 196 (63%) were in reexcision specimens. Of 20 sporadic reports, 17 (85%) were in reexcision specimens. Conclusion: The high percentage of PI occurring in reexcision specimens vs. primary excisions may indicate that many of the reported cases of basal cell carcinomas with PI are actually examples of RPI. C1 [Bechert, Charles J.] Univ Texas Med Branch, Dept Pathol, Galveston, TX USA. [Stern, Jere B.] NCI, Pathol Lab, Bethesda, MD 20892 USA. [Stern, Jere B.] Dermatopathol Consultat Serv, Baltimore, MD USA. RP Bechert, CJ (reprint author), Univ Texas Med Branch, Dept Pathol, Galveston, TX USA. EM cjbecher@utmb.edu NR 16 TC 8 Z9 8 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0303-6987 J9 J CUTAN PATHOL JI J. Cutan. Pathol. PD MAR PY 2010 VL 37 IS 3 BP 376 EP 379 DI 10.1111/j.1600-0560.2009.01331.x PG 4 WC Dermatology; Pathology SC Dermatology; Pathology GA 547KX UT WOS:000273887600013 PM 19615028 ER PT J AU Katoh, A Fujihara, H Ohbuchi, T Onaka, T Young, WS Dayanithi, G Yamasaki, Y Kawata, M Suzuki, H Otsubo, H Suzuki, H Murphy, D Ueta, Y AF Katoh, Akiko Fujihara, Hiroaki Ohbuchi, Toyoaki Onaka, Tatsushi Young, W. Scott, III Dayanithi, Govindan Yamasaki, Yuka Kawata, Mitsuhiro Suzuki, Hitoshi Otsubo, Hiroki Suzuki, Hideaki Murphy, David Ueta, Yoichi TI Specific expression of an oxytocin-enhanced cyan fluorescent protein fusion transgene in the rat hypothalamus and posterior pituitary SO JOURNAL OF ENDOCRINOLOGY LA English DT Article ID SUPRAOPTIC NUCLEUS; NERVE-TERMINALS; MAGNOCELLULAR NEURONS; NEUROSECRETORY-CELLS; HORMONE NEURONS; IN-VIVO; VASOPRESSIN; RELEASE; GENE; CALCIUM AB We have generated rats bearing an oxytocin (OXT)-enhanced cyan fluorescent protein (eCFP) fusion transgene designed from a murine construct previously shown to be faithfully expressed in transgenic mice. In situ hybridisation histochemistry revealed that the Oxt-eCfp fusion gene was expressed in the supraoptic nucleus (SON) and the paraventricular nucleus (PVN) in these rats. The fluorescence emanating from eCFP was observed only in the SON, the PVN, the internal layer of the median eminence and the posterior pituitary (PP). In in vitro preparations, freshly dissociated cells from the SON and axon terminals showed clear eCFP fluorescence. Immunohistochemistry for OXT and arginine vasopressin (AVP) revealed that the eCFP fluorescence co-localises with OXT immunofluorescence, but not with AVP immunofluorescence in the SON and the PVN. Although the expression levels of the Oxt-eCfp fusion gene in the SON and the PVN showed a wide range of variations in transgenic rats, eCFP fluorescence was markedly increased in the SON and the PVN, but decreased in the PP after chronic salt loading. The expression of the Oxt gene was significantly increased in the SON and the PVN after chronic salt loading in both non-transgenic and transgenic rats. Compared with wild-type animals, euhydrated and salt-loaded male and female transgenic rats showed no significant differences in plasma osmolality, sodium concentration and OXT and AVP levels, suggesting that the fusion gene expression did not disturb any physiological processes. These results suggest that our new transgenic rats are a valuable new tool to identify OXT-producing neurones and their terminals. Journal of Endocrinology (2010) 204, 275-285 C1 [Katoh, Akiko; Fujihara, Hiroaki; Ohbuchi, Toyoaki; Suzuki, Hitoshi; Otsubo, Hiroki; Ueta, Yoichi] Univ Occupat & Environm Hlth, Dept Physiol, Yahatanishi Ku, Kitakyushu, Fukuoka 8078555, Japan. [Katoh, Akiko; Fujihara, Hiroaki; Ohbuchi, Toyoaki; Suzuki, Hitoshi; Otsubo, Hiroki; Ueta, Yoichi] Univ Occupat & Environm Hlth, Dept Otorhynolaryngol, Sch Med, Yahatanishi Ku, Kitakyushu, Fukuoka 8078555, Japan. [Onaka, Tatsushi] Jichi Med Sch, Dept Physiol, Shimotsuke, Tochigi 3290498, Japan. [Young, W. Scott, III] NIMH, Sect Neural Gene Express, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. [Dayanithi, Govindan] Acad Sci Czech Republic, Inst Expt Med, Dept Cellular Neurophysiol, EU Res Ctr Excellence, CZ-14220 Prague, Czech Republic. [Yamasaki, Yuka; Kawata, Mitsuhiro] Kyoto Prefectural Univ Med, Dept Anat & Neurobiol, Kyoto 6028566, Japan. [Murphy, David] Univ Bristol, Mol Neuroendocrinol Res Grp, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol BS1 3NY, Avon, England. RP Ueta, Y (reprint author), Univ Occupat & Environm Hlth, Dept Physiol, Yahatanishi Ku, 1-1 Iseigaoka, Kitakyushu, Fukuoka 8078555, Japan. EM yoichi@med.uoeh-u.ac.jp RI Murphy, David/C-3967-2012; Young, W Scott/A-9333-2009; Onaka, Tatsushi/I-7115-2012; Dayanithi, Govindan/H-3131-2014; Dayanithi, Govindan/F-6068-2016 OI Murphy, David/0000-0003-2946-0353; Young, W Scott/0000-0001-6614-5112; Dayanithi, Govindan/0000-0002-1009-7809; Dayanithi, Govindan/0000-0002-1009-7809 FU Biotechnology and Biological Sciences Research Council [BB/G006156/1]; Intramural NIH HHS [ZIA MH002498-20]; Medical Research Council [G0700954]; NIMH NIH HHS [Z01 MH002498, Z01-MH-002498-20] NR 37 TC 11 Z9 11 U1 2 U2 3 PU BIOSCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0022-0795 J9 J ENDOCRINOL JI J. Endocrinol. PD MAR PY 2010 VL 204 IS 3 BP 275 EP 285 DI 10.1677/JOE-09-0289 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 568ND UT WOS:000275528200006 PM 20026620 ER PT J AU Lakind, JS Birnbaum, LS AF Lakind, Judy S. Birnbaum, Linda S. TI Out of the frying pan and out of the fire: the indispensable role of exposure science in avoiding risks from replacement chemicals SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Editorial Material C1 [Lakind, Judy S.] LaKind Associates LLC, Catonsville, MD USA. [Lakind, Judy S.] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Lakind, Judy S.] Penn State Coll Med, Dept Pediat, Hershey, PA USA. [Birnbaum, Linda S.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Lakind, JS (reprint author), LaKind Associates LLC, Catonsville, MD USA. EM lakindassoc@comcast.net NR 5 TC 5 Z9 5 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD MAR-APR PY 2010 VL 20 IS 2 BP 115 EP 116 DI 10.1038/jes.2009.71 PG 2 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 557DQ UT WOS:000274649700002 PM 20160736 ER PT J AU Thomas, KW Dosemeci, M Hoppin, JA Sheldon, LS Croghan, CW Gordon, SM Jones, ML Reynolds, SJ Raymer, JH Akland, GG Lynch, CF Knott, CE Sandler, DP Blair, AE Alavanja, MC AF Thomas, Kent W. Dosemeci, Mustafa Hoppin, Jane A. Sheldon, Linda S. Croghan, Carry W. Gordon, Sydney M. Jones, Martin L. Reynolds, Stephen J. Raymer, James H. Akland, Gerald G. Lynch, Charles F. Knott, Charles E. Sandler, Dale P. Blair, Aaron E. Alavanja, Michael C. TI Urinary biomarker, dermal, and air measurement results for 2,4-D and chlorpyrifos farm applicators in the Agricultural Health Study SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE 2,4-D; chlorpyrifos; exposure measurement; farm applicator; occupational exposure; Agricultural Health Study ID 2,4-DICHLOROPHENOXYACETIC ACID; PESTICIDE APPLICATORS; HUMAN VOLUNTEERS; CUSTOM APPLICATORS; DIMETHYLAMINE SALT; EXPOSURE; CANCER; WORKERS; ABSORPTION; FORESTRY AB A subset of private pesticide applicators in the Agricultural Health Study (AHS) epidemiological cohort was monitored around the time of their agricultural use of 2,4-dichlorophenoxyacetic acid (2,4-D) and O,O-diethyl-O-3,5,6-trichloro-2-pyridyl phosphorothioate (chlorpyrifos) to assess exposure levels and potential determinants of exposure. Measurements included pre- and post-application urine samples, and patch, hand wipe, and personal air samples. Boom spray or hand spray application methods were used by applicators for 2,4-D products. Chlorpyrifos products were applied using spray applications and in-furrow application of granular products. Geometric mean (GM) values for 69 2,4-D applicators were 7.8 and 25 mg/l in pre- and post-application urine, respectively (P<0.05 for difference); 0.39mg for estimated hand loading; 2.9 mg for estimated body loading; and 0.37 mu g/m(3) for concentration in personal air. Significant correlations were found between all media for 2,4-D. GM values for 17 chlorpyrifos applicators were 11 mu g/l in both pre- and post-application urine for the 3,5,6-trichloro-2-pyridinol metabolite, 0.28 mg for body loading, and 0.49 mu g/m(3) for air concentration. Only 53% of the chlorpyrifos applicators had measurable hand loading results; their median hand loading being 0.02 mg. Factors associated with differences in 2,4-D measurements included application method and glove use, and, for hand spray applicators, use of adjuvants, equipment repair, duration of use, and contact with treated vegetation. Spray applications of liquid chlorpyrifos products were associated with higher measurements than in-furrow granular product applications. This study provides information on exposures and possible exposure determinants for several application methods commonly used by farmers in the cohort and will provide information to assess and refine exposure classification in the AHS. Results may also be of use in pesticide safety education for reducing exposures to pesticide applicators. Journal of Exposure Science and Environmental Epidemiology (2010) 20, 119-134; doi: 10.1038/jes.2009.6; published online 25 February 2009 C1 [Thomas, Kent W.; Sheldon, Linda S.; Croghan, Carry W.] US EPA, Natl Exposure Res Lab, Off Res & Dev, Res Triangle Pk, NC 27711 USA. [Dosemeci, Mustafa; Blair, Aaron E.; Alavanja, Michael C.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD USA. [Hoppin, Jane A.; Sandler, Dale P.] NIEHS, Epidemiol Branch, NIH, DHHS, Res Triangle Pk, NC 27709 USA. [Gordon, Sydney M.] Battelle Mem Inst, Columbus, OH 43201 USA. [Jones, Martin L.; Reynolds, Stephen J.] Univ Iowa, Dept Occupat & Environm Med, Iowa City, IA USA. [Raymer, James H.; Akland, Gerald G.] RTI Int, Res Triangle Pk, NC USA. [Lynch, Charles F.] Univ Iowa, Dept Epidemiol, Iowa City, IA USA. [Knott, Charles E.] Battelle Ctr Publ Hlth Res & Evaluat, Durham, NC USA. RP Thomas, KW (reprint author), US EPA, Natl Exposure Res Lab, Off Res & Dev, MD-E205-04, Res Triangle Pk, NC 27711 USA. EM thomas.kent@epa.gov OI Sandler, Dale/0000-0002-6776-0018 FU The United States Environmental Protection Agency through its Office of Research and Development [68-D99-011, 68-D99-012]; NIH, National Cancer Institute [DW-75-93912801-0, Z01-CP010119-12]; National Institute of Environmental Health Sciences [Z01-ES049030-1] FX We thank the AHS cohort members participating in this study for their considerable time and effort. Several EPA researchers, including Ross Highsmith, William Steen, Miles Okino, and Ruth Allen, provided significant contributions to the study design. Paul Jones at EPA provided statistical support and Guadalupe Chapa assisted in data analysis. Joy Herrington, Nyla Logsden-Sackett, and Patti Gillette at the AHS Field Stations in IA and NC led participant screening activities. We thank Marcia Nishioka (Battelle Memorial Institute), Robin Helburn (RTI International) and David Camann and Jackie Clothier (Southwest Research Institute) for leading sample analyses and for hand wipe method development. The United States Environmental Protection Agency through its Office of Research and Development partially funded and collaborated in the research described here under contracts 68-D99-011 to Battelle and 68-D99-012 to RTI International, and through Interagency Agreement DW-75-93912801-0 to the National Cancer Institute. It has been subjected to agency administrative review and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. This study has been supported in part by the Intramural Research Program of the NIH, National Cancer Institute (Z01-CP010119-12), and National Institute of Environmental Health Sciences (Z01-ES049030-1). NR 39 TC 31 Z9 32 U1 2 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 EI 1559-064X J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD MAR-APR PY 2010 VL 20 IS 2 BP 119 EP 134 DI 10.1038/jes.2009.6 PG 16 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 557DQ UT WOS:000274649700004 PM 19240759 ER PT J AU Bhatti, P Blair, A Bell, EM Rothman, N Lan, Q Barr, DB Needham, LL Portengen, L Figgs, LW Vermeulen, R AF Bhatti, Parveen Blair, Aaron Bell, Erin M. Rothman, Nathaniel Lan, Qing Barr, Dana B. Needham, Larry L. Portengen, Lutzen Figgs, Larry W. Vermeulen, Roel TI Predictors of 2,4-dichlorophenoxyacetic acid exposure among herbicide applicators SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE 2,4-D; biomonitoring; herbicide; exposure determinants ID PROFESSIONAL TURF APPLICATORS; HUMAN URINE; METABOLITES; PESTICIDES; MODELS AB To determine the major factors affecting the urinary levels of 2,4-dichlorophenoxyacetic acid (2,4-D) among county noxious weed applicators in Kansas, we used a regression technique that accounted for multiple days of exposure. We collected 136 12-h urine samples from 31 applicators during the course of two spraying seasons (April to August of 1994 and 1995). Using mixed-effects models, we constructed exposure models that related urinary 2,4-D measurements to weighted self-reported work activities from daily diaries collected over 5 to 7 days before the collection of the urine sample. Our primary weights were based on an earlier pharmacokinetic analysis of turf applicators; however, we examined a series of alternative weighting schemes to assess the impact of the specific weights and the number of days before urine sample collection that were considered. The derived models accounting for multiple days of exposure related to a single urine measurement seemed robust with regard to the exact weights, but less to the number of days considered; albeit the determinants from the primary model could be fitted with marginal losses of fit to the data from the other weighting schemes that considered a different numbers of days. In the primary model, the total time of all activities (spraying, mixing, other activities), spraying method, month of observation, application concentration, and wet gloves were significant determinants of urinary 2,4-D concentration and explained 16% of the between-worker variance and 23% of the within-worker variance of urinary 2,4-D levels. As a large proportion of the variance remained unexplained, further studies should be conducted to try to systematically assess other exposure determinants. Journal of Exposure Science and Environmental Epidemiology (2010) 20, 160-168; doi: 10.1038/jes.2009.14; published online 25 March 2009 C1 [Bhatti, Parveen; Blair, Aaron; Rothman, Nathaniel; Lan, Qing] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. [Bell, Erin M.] SUNY Albany, Dept Epidemiol, Sch Publ Hlth, Rensselaer, NY USA. [Barr, Dana B.; Needham, Larry L.] Ctr Dis Control & Prevent, Natl Ctr Environm Hlth, Atlanta, GA USA. [Portengen, Lutzen; Vermeulen, Roel] Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. [Figgs, Larry W.] Univ Kentucky, Dept Prevent Med & Environm Hlth, Coll Publ Hlth, Lexington, KY USA. [Vermeulen, Roel] Univ Med Ctr Utrecht, Julius Ctr, Utrecht, Netherlands. RP Bhatti, P (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7049,MSC 7238, Bethesda, MD 20892 USA. EM bhattip@mail.nih.gov RI Needham, Larry/E-4930-2011; Barr, Dana/E-6369-2011; Barr, Dana/E-2276-2013; Vermeulen, Roel/F-8037-2011 OI Vermeulen, Roel/0000-0003-4082-8163 FU Intramural NIH HHS [Z01 CP010119-12] NR 11 TC 1 Z9 1 U1 0 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD MAR-APR PY 2010 VL 20 IS 2 BP 160 EP 168 DI 10.1038/jes.2009.14 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 557DQ UT WOS:000274649700007 PM 19319162 ER PT J AU Baird, DD Saldana, TM Nepomnaschy, PA Hoppin, JA Longnecker, MP Weinberg, CR Wilcox, AJ AF Baird, Donna Day Saldana, Tina M. Nepomnaschy, Pablo A. Hoppin, Jane A. Longnecker, Matthew P. Weinberg, Clarice R. Wilcox, Allen J. TI Within-person variability in urinary phthalate metabolite concentrations: measurements from specimens after long-term frozen storage SO JOURNAL OF EXPOSURE SCIENCE AND ENVIRONMENTAL EPIDEMIOLOGY LA English DT Article DE biomarker; phthalate; reproducibility; menstrual cycle; temporal variability ID TEMPORAL VARIABILITY; PREGNANT-WOMEN; MALE-RAT; EXPOSURE; POPULATION; HEALTH; ESTERS; DEHP; MONOESTERS; CHILDREN AB Laboratory studies show that exposure to phthalates during development can cause adverse effects, especially for males. Studies in humans would be facilitated by collection of urine during pregnancy, long-term storage, and measurement of phthalate metabolites at the time that offspring health is assessed. Our aims were to measure urinary phthalate metabolites after long-term freezer storage, to use those measurements to evaluate within-woman variability over 2- and 4-week intervals, and to determine whether the phases of the menstrual cycle affect metabolite levels. Samples were selected from daily first-morning urine specimens collected by 60 women and stored frozen since 1983-1985. Three specimens per woman were selected at approximately 2-week intervals to include both follicular and luteal phase samples. Seven metabolites of five phthalates were measured by mass spectrometry. Statistical analyses were conducted with correlation, mixed model regression, and the Wilcoxon signed rank test. Creatinine-corrected urinary phthalate metabolite concentrations measured in samples after long-term storage tended to have a similar right-skewed distribution, though with somewhat higher concentrations than those reported for recently collected US samples. The concentrations of three metabolites of di(2-ethylhexyl) phthalate in the same specimen were very highly correlated (Pearson r=0.85-0.97). Reproducibility over a 4-week interval was moderate for the metabolites of diethyl phthalate and benzylbutyl phthalate (intraclass correlation coefficients, ICCs, 0.48 and 0.53, respectively), whereas five other metabolites had lower ICCs (0.21-0.37). Menstrual phase was not related to metabolite concentrations. Although the same samples have not been measured both before and after long-term storage, results suggest that the measurement of phthalate metabolites after long-term sample storage yield generally similar distributions and temporal reliability as those reported for recently collected specimens. These findings support the use of stored urine specimens collected during the relevant stage of human pregnancy to investigate the influence of phthalate exposures on later outcomes. Journal of Exposure Science and Environmental Epidemiology (2010) 20, 169-175; doi: 10.1038/jes.2009.17; published online 11 March 2009 C1 [Baird, Donna Day; Hoppin, Jane A.; Longnecker, Matthew P.; Wilcox, Allen J.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Saldana, Tina M.] Social & Sci Syst Inc, Durham, NC USA. [Nepomnaschy, Pablo A.] Simon Fraser Univ, Fac Hlth Sci, Burnaby, BC V5A 1S6, Canada. [Weinberg, Clarice R.] NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Baird, DD (reprint author), NIEHS, Epidemiol Branch, NIH, MD A3-05 NIEHS,POB 12233, Res Triangle Pk, NC 27709 USA. EM baird@niehs.nih.gov RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Longnecker, Matthew/0000-0001-6073-5322; Wilcox, Allen/0000-0002-3376-1311 FU National Institute of Environmental Health Sciences, National Institutes of Health, HHS FX The field manager of the North Carolina Early Pregnancy Study was Joy Pierce, and D. Robert McConnaughey manages the study data files. This research was funded by the intramural program at the National Institute of Environmental Health Sciences, National Institutes of Health, HHS. We thank AXYS Analytical Services Ltd from Sidney, BC Canada, for their assistance with this project including their detailed description of the analytic methods. An earlier version of the manuscript was reviewed by Drs. Freya Kamel and Yang Cao. NR 33 TC 29 Z9 29 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1559-0631 J9 J EXPO SCI ENV EPID JI J. Expo. Sci. Environ. Epidemiol. PD MAR-APR PY 2010 VL 20 IS 2 BP 169 EP 175 DI 10.1038/jes.2009.17 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 557DQ UT WOS:000274649700008 PM 19277068 ER PT J AU Takikawa, S Engle, RE Faulk, KN Emerson, SU Purcell, RH Bukh, J AF Takikawa, Shingo Engle, Ronald E. Faulk, Kristina N. Emerson, Suzanne U. Purcell, Robert H. Bukh, Jens TI Molecular evolution of GB virus B hepatitis virus during acute resolving and persistent infections in experimentally infected tamarins SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID C VIRUS; IN-VIVO; CHIMPANZEES; CLONE; PROTEIN; AGENT; REGION; STRAIN; SERUM; MODEL AB GB virus B (GBV-B) causes acute hepatitis in experimentally infected tamarins. We compared evolutionary features in acute resolving and persistent GBV-B infection. We detected no evidence of evolution in four animals with clearance during weeks 9-12, whereas three animals with clearance during weeks 13-26 had several substitutions in their polyprotein sequence. A single tamarin had long-term GBV-B viraemia; analysis of virus recovered at weeks 2, 5, 12, 20, 26, 52 and 104 demonstrated that mutations accumulated over time, Overall, the amino acid substitution rate was 3.5 x 10(-3) and 1.1 x 10(-3) substitutions per site year(-1) during weeks 1-52 and 53-104, respectively. Thus, there was a significant decrease in evolution over time, as found for hepatitis C virus. The rate of non-synonymous substitution per non-synonymous site compared with that of synonymous substitution per synonymous site decreased over time, suggesting reduction of positive selective pressure. These data demonstrate that prolonged GBV-B infection is associated with viral evolution. C1 [Takikawa, Shingo; Engle, Ronald E.; Faulk, Kristina N.; Emerson, Suzanne U.; Purcell, Robert H.; Bukh, Jens] NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Takikawa, Shingo; Engle, Ronald E.; Faulk, Kristina N.; Emerson, Suzanne U.; Purcell, Robert H.; Bukh, Jens] NIAID, Mol Hepatitis Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. [Bukh, Jens] Univ Copenhagen, Fac Hlth Sci, Dept Int Hlth Immunol & Microbiol, Copenhagen N, Denmark. [Bukh, Jens] Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen Hepatitis Program C, Hvidovre, Denmark. [Bukh, Jens] Copenhagen Univ Hosp, Clin Res Ctr, Hvidovre, Denmark. RP Bukh, J (reprint author), NIAID, Hepatitis Viruses Sect, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jbukh@niaid.nih.gov FU Lundbeck Foundation; National Institute of Allergy and Infectious Diseases, National Institutes of Health FX J. B. is the recipient of a professorship at the University of Copenhagen with external funding from the Lundbeck Foundation. This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 17 TC 13 Z9 14 U1 0 U2 0 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD MAR PY 2010 VL 91 BP 727 EP 733 DI 10.1099/vir.0.015750-0 PN 3 PG 7 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 569HM UT WOS:000275587200016 PM 19906942 ER PT J AU Bailey, D Kaiser, WJ Hollinshead, M Moffat, K Chaudhry, Y Wileman, T Sosnovtsev, SV Goodfellow, IG AF Bailey, Dalan Kaiser, William J. Hollinshead, Mike Moffat, Katy Chaudhry, Yasmin Wileman, Thomas Sosnovtsev, Stanislav V. Goodfellow, Ian G. TI Feline calicivirus p32, p39 and p30 proteins localize to the endoplasmic reticulum to initiate replication complex formation SO JOURNAL OF GENERAL VIROLOGY LA English DT Article ID MOUTH-DISEASE VIRUS; VESICULAR STOMATITIS-VIRUS; TO-GOLGI TRANSPORT; POLIOVIRUS REPLICATION; SECRETORY PATHWAY; INFECTED-CELLS; NONSTRUCTURAL POLYPROTEIN; MEMBRANE-PROTEINS; PHASE-SEPARATION; CULTURED-CELLS AB In common with other positive-strand RNA viruses, replication of feline calicivirus (FCV) results in rearrangement of intracellular membranes and production of numerous membrane-bound vesicular structures on which viral genome replication is thought to occur. In this study, bioinformatics approaches have identified three of the FCV non-structural proteins, namely p32, p39 and p30, as potential transmembrane proteins. These proteins were able to target enhanced cyan fluorescent protein to membrane fractions where they behaved as integral membrane proteins. Immunofluorescence microscopy of these proteins expressed in cells showed colocalization with endoplasmic reticulum (ER) markers. Further electron microscopy analysis of cells co-expressing FCV p39 or p30 with a horseradish peroxidase protein containing the KDEL ER retention motif demonstrated gross morphological changes to the ER. Similar reorganization patterns, especially for those produced by p30, were observed in naturally infected Crandel-Rees feline kidney cells. Together, the data demonstrate that the p32, p39 and p30 proteins of FCV locate to the ER and lead to reorganization of ER membranes. This suggests that they may play a role in the generation of FCV replication complexes and that the endoplasmic reticulum may represent the potential source of the membrane vesicles induced during FCV infection. C1 [Bailey, Dalan; Hollinshead, Mike; Chaudhry, Yasmin; Goodfellow, Ian G.] Univ London Imperial Coll Sci Technol & Med, Dept Virol, London W2 1PG, England. [Kaiser, William J.] Univ Reading, Sch Biol Sci, Reading RG6 6AJ, Berks, England. [Moffat, Katy] AFRC, Inst Anim Hlth, Guildford GU24 0NF, Surrey, England. [Wileman, Thomas] Univ E Anglia, Sch Med, Norwich NR4 7TJ, Norfolk, England. [Sosnovtsev, Stanislav V.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bailey, D (reprint author), Univ London Imperial Coll Sci Technol & Med, Dept Virol, Norfolk Pl, London W2 1PG, England. EM d.bailey@imperial.ac.uk; i.goodfellow@imperial.ac.uk OI Bailey, Dalan/0000-0002-5640-2266; Goodfellow, Ian/0000-0002-9483-510X FU Wellcome Trust FX This work was supported by funding from the Wellcome Trust. I. G. G. is a Wellcome Senior Fellow. NR 58 TC 16 Z9 18 U1 0 U2 2 PU SOC GENERAL MICROBIOLOGY PI READING PA MARLBOROUGH HOUSE, BASINGSTOKE RD, SPENCERS WOODS, READING RG7 1AG, BERKS, ENGLAND SN 0022-1317 J9 J GEN VIROL JI J. Gen. Virol. PD MAR PY 2010 VL 91 BP 739 EP 749 DI 10.1099/vir.0.016279-0 PN 3 PG 11 WC Biotechnology & Applied Microbiology; Virology SC Biotechnology & Applied Microbiology; Virology GA 569HM UT WOS:000275587200018 PM 19906938 ER EF