FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Avram, L Ozarslan, E Assaf, Y Bar-Shir, A Cohen, Y Basser, PJ AF Avram, Liat Ozarslan, Evren Assaf, Yaniv Bar-Shir, Amnon Cohen, Yoram Basser, Peter J. TI Three-dimensional water diffusion in impermeable cylindrical tubes: theory versus experiments SO NMR IN BIOMEDICINE LA English DT Article DE q-space; diffusion; restricted; capillary; tube; orientation; diameter ID NUCLEAR-MAGNETIC-RESONANCE; FIELD-GRADIENT EXPERIMENTS; SPIN-ECHO ANALYSIS; RESTRICTED DIFFUSION; SELF-DIFFUSION; POROUS-MEDIA; EXPERIMENTAL PARAMETERS; SPHERICAL PORES; NMR-DIFFUSION; WHITE-MATTER AB Characterizing diffusion of gases and liquids within pores is important in understanding numerous transport processes and affects a wide range of practical applications. Previous measurements of the pulsed gradient stimulated echo (PGSTE) signal attenuation, E(q), of water within nerves and impermeable cylindrical microcapillary tubes showed it to be exquisitely sensitive to the orientation of the applied wave vector. q. with respect to the tube axis in the high-q regime. Here, we provide a simple three-dimensional model to explain this angular dependence by decomposing the average propagator, which describes the net displacement of water molecules, into components parallel and perpendicular to the tube wall, in which axial diffusion is free and radial diffusion is restricted. The model faithfully predicts the experimental data. not only the observed diffraction peaks in E(q) when the diffusion gradients are approximately normal to the tube wall, but their disappearance when the gradient orientation possesses a small axial component. The model also successfully predicts the dependence of E(q) oil gradient pulse duration and oil gradient strength as well as tube inner diameter. To account for the deviation front the narrow pulse approximation in the PGSTE sequence, We use Callaghan's matrix operator framework. which this study validates experimentally for the first time. We also show how to combine average propagators derived for classical one-dimensional and two-dimensional models of restricted diffusion (e.g. between plates, within cylinders) to Construct composite three-dimensional models of diffusion complex media containing pores rectangular prisms and/ or capped cylinders) having a distribution of orientations, sizes, and aspect ratios. This three-dimensional modeling framework should aid in describing diffusion in numerous biological systems and in a myriad of materials sciences applications. Copyright (C) 2008 John Wiley & Sons. Ltd. C1 [Ozarslan, Evren; Basser, Peter J.] NICHD, Sect Tissue Biophys & Biomimet, NIH, Bethesda, MD 20892 USA. [Avram, Liat; Bar-Shir, Amnon; Cohen, Yoram] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Chem, IL-69978 Tel Aviv, Israel. [Assaf, Yaniv] Tel Aviv Univ, Dept Neurobiochem, IL-69978 Tel Aviv, Israel. [Assaf, Yaniv] Tel Aviv Univ, Tel Aviv Sourasky Med Ctr, Funct Brain Imaging Unit, IL-69978 Tel Aviv, Israel. RP Basser, PJ (reprint author), NICHD, Sect Tissue Biophys & Biomimet, NIH, 13 S Dr,MSC 5772,Bldg 13,Roorn 3W16, Bethesda, MD 20892 USA. EM pjbasser@helix.nih.gov RI Ozarslan, Evren/B-4858-2013; Basser, Peter/H-5477-2011 OI Ozarslan, Evren/0000-0003-0859-1311; FU Eunice Kennedy Shtriver National Institute of Child Health and Human Development (NICHD); srael-US Bi-National Science Foundation (BSF) FX The Intramural Research Program of the Eunice Kennedy Shtriver National Institute of Child Health and Human Development (NICHD) supported P.J.B. and E.O; L.A., A.B.-S. and Y.C. were all supported, in part, by the Israel-US Bi-National Science Foundation (BSF). We thank Liz Salak for her careful editing of this manuscript. Raisa Freidlin helped prepare several figures. NR 64 TC 26 Z9 26 U1 1 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD OCT PY 2008 VL 21 IS 8 BP 888 EP 898 DI 10.1002/nbm.1277 PG 11 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 355RQ UT WOS:000259726400012 PM 18574856 ER PT J AU van den Born, E Omelchenko, MV Bekkelund, A Leihne, V Koonin, EV Dolja, VV Falnes, PO AF van den Born, Erwin Omelchenko, Marina V. Bekkelund, Anders Leihne, Vibeke Koonin, Eugene V. Dolja, Valerian V. Falnes, Pal O. TI Viral AlkB proteins repair RNA damage by oxidative demethylation SO NUCLEIC ACIDS RESEARCH LA English DT Article ID ESCHERICHIA-COLI; DNA-REPAIR; POLYNUCLEOTIDE KINASE; NUCLEOTIDE-SEQUENCE; ALKYLATION DAMAGE; ENZYME ALKB; VIRUS; BACTERIAL; METHYLATION; 3-METHYLTHYMINE AB Bacterial and mammalian AlkB proteins are iron(II)- and 2-oxoglutarate-dependent dioxygenases that reverse methylation damage, such as 1-methyladenine and 3-methylcytosine, in RNA and DNA. An AlkB-domain is encoded by the genome of numerous single-stranded, plant-infecting RNA viruses, the majority of which belong to the Flexiviridae family. Our phylogenetic analysis of AlkB sequences suggests that a single plant virus might have acquired AlkB relatively recently, followed by horizontal dissemination among other viruses via recombination. Here, we describe the first functional characterization of AlkB proteins from three plant viruses. The viral AlkB proteins efficiently reactivated methylated bacteriophage genomes when expressed in Escherichia coli, and also displayed robust, iron(II)- and 2-oxoglutarate-dependent demethylase activity in vitro. Viral AlkB proteins preferred RNA over DNA substrates, and thus represent the first AlkBs with such substrate specificity. Our results suggest a role for viral AlkBs in maintaining the integrity of the viral RNA genome through repair of deleterious methylation damage, and support the notion that AlkB-mediated RNA repair is biologically relevant. C1 [van den Born, Erwin; Bekkelund, Anders; Leihne, Vibeke; Falnes, Pal O.] Univ Oslo, Dept Mol Biosci, N-0316 Oslo, Norway. [Omelchenko, Marina V.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Dolja, Valerian V.] Oregon State Univ, Dept Bot & Plant Pathol, Ctr Genome Res & Biocomp, Corvallis, OR 97331 USA. [Falnes, Pal O.] Univ Oslo, Rikshosp, Ctr Mol Biol & Neurosci, Radiumhosp HF, N-0027 Oslo, Norway. RP Falnes, PO (reprint author), Univ Oslo, Dept Mol Biosci, POB 1041, N-0316 Oslo, Norway. EM pal.falnes@imbv.uio.no FU FRIBIOMOL; FUGE; Research Council of Norway; DHHS (National Library of Medicine); National Institutes of Health [GM053190]; BARD [IS-3784-05] FX FRIBIOMOL and FUGE programs in the Research Council of Norway (P.O.F.); DHHS (National Library of Medicine) intramural funds (M.V.O. and E. V. K.); National Institutes of Health award (GM053190 to V.V.D.) and BARD award (IS-3784-05 to V.V.D.). Funding for open access charges: NIH intramural funds. NR 46 TC 39 Z9 40 U1 0 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2008 VL 36 IS 17 BP 5451 EP 5461 DI 10.1093/nar/gkn519 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 365QZ UT WOS:000260424200003 PM 18718927 ER PT J AU Wynveen, A Lee, DJ Kornyshev, AA Leikin, S AF Wynveen, Aaron Lee, Dominic J. Kornyshev, Alexei A. Leikin, Sergey TI Helical coherence of DNA in crystals and solution SO NUCLEIC ACIDS RESEARCH LA English DT Article ID B-DNA; DINUCLEOTIDE STEPS; SEQUENCE; RECOGNITION; PARAMETERS; AGGREGATION; FLEXIBILITY; STACKING; GEOMETRY; DATABASE AB The twist, rise, slide, shift, tilt and roll between adjoining base pairs in DNA depend on the identity of the bases. The resulting dependence of the double helix conformation on the nucleotide sequence is important for DNA recognition by proteins, packaging and maintenance of genetic material, and other interactions involving DNA. This dependence, however, is obscured by poorly understood variations in the stacking geometry of the same adjoining base pairs within different sequence contexts. In this article, we approach the problem of sequence-dependent DNA conformation by statistical analysis of X-ray and NMR structures of DNA oligomers. We evaluate the corresponding helical coherence length-a cumulative parameter quantifying sequence-dependent deviations from the ideal double helix geometry. We find, e. g. that the solution structure of synthetic oligomers is characterized by 100-200A coherence length, which is similar to -150 angstrom coherence length of natural, salmon-sperm DNA. Packing of oligomers in crystals dramatically alters their helical coherence. The coherence length increases to 800-1200 angstrom, consistent with its theoretically predicted role in interactions between DNA at close separations. C1 [Wynveen, Aaron] Univ Dusseldorf, Inst Theoret Phys Weiche Mat 2, D-40225 Dusseldorf, Germany. [Wynveen, Aaron; Lee, Dominic J.; Kornyshev, Alexei A.] Univ London Imperial Coll Sci Technol & Med, Dept Chem, Fac Nat Sci, London SW7 2AZ, England. [Lee, Dominic J.] Max Planck Inst Phys Komplexer Syst, D-01187 Dresden, Germany. [Leikin, Sergey] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Phys Biochem, NIH, DHHS, Bethesda, MD 20892 USA. RP Wynveen, A (reprint author), Univ Dusseldorf, Inst Theoret Phys Weiche Mat 2, Univ Str 1, D-40225 Dusseldorf, Germany. EM awynveen@googlemail.com; leikins@mail.nih.gov RI Leikin, Sergey/A-5518-2008; Kornyshev, Alexei/C-3404-2008 OI Leikin, Sergey/0000-0001-7095-0739; FU Alexander von Humboldt foundation; Engineering and Physical Sciences Research Council [GR/S31068/01]; Royal Society; Liverhulme Trust; Intramural Research Program; National Institute of Child Health and Human Development; National Institutes of Health FX This work was supported by a fellowship from the Alexander von Humboldt foundation (A.W.). It was funded by the Engineering and Physical Sciences Research Council (GR/S31068/01, A.A.K and D.J.L.), the Royal Society (A.A.K. and A.W.), the Liverhulme Trust (F/07058/AE, A.A.K.), and the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health (S.L.). Funding for Open Access publication charge: Intramural Research Program, NICHD, NR 55 TC 29 Z9 29 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2008 VL 36 IS 17 BP 5540 EP 5551 DI 10.1093/nar/gkn514 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 365QZ UT WOS:000260424200009 PM 18755709 ER PT J AU Frith, MC Park, Y Sheetlin, SL Spouge, JL AF Frith, Martin C. Park, Yonil Sheetlin, Sergey L. Spouge, John L. TI The whole alignment and nothing but the alignment: the problem of spurious alignment flanks SO NUCLEIC ACIDS RESEARCH LA English DT Article ID SEQUENCE ALIGNMENT; HUMAN GENOME; PROTEINS; DATABASE; BIOLOGY; MOUSE; DNA AB Pairwise sequence alignment is a ubiquitous tool for inferring the evolution and function of DNA, RNA and protein sequences. It is therefore essential to identify alignments arising by chance alone, i.e. spurious alignments. On one hand, if an entire alignment is spurious, statistical techniques for identifying and eliminating it are well known. On the other hand, if only a part of the alignment is spurious, elimination is much more problematic. In practice, even the sizes and frequencies of spurious subalignments remain unknown. This article shows that some common scoring schemes tend to overextend alignments and generate spurious alignment flanks up to hundreds of base pairs/amino acids in length. In the UCSC genome database, e.g. spurious flanks probably comprise >18% of the human-fugu genome alignment. To evaluate the possibility that chance alone generated a particular flank on a particular pairwise alignment, we provide a simple 'overalignment' P-value. The overalignment P-value can identify spurious alignment flanks, thereby eliminating potentially misleading inferences about evolution and function. Moreover, by explicitly demonstrating the tradeoff between over- and under-alignment, our methods guide the rational choice of scoring schemes for various alignment tasks. C1 [Park, Yonil; Sheetlin, Sergey L.; Spouge, John L.] Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. [Frith, Martin C.] Natl Inst Adv Ind Sci & Technol, Computat Biol Res Ctr, Tokyo 1350064, Japan. RP Spouge, JL (reprint author), Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM spouge@ncbi.nlm.nih.gov RI Park, Yonil/E-6075-2010; OI Frith, Martin/0000-0003-0998-2859 FU National Library of Medicine; National Institutes of Health FX Intramural Research Program of the National Library of Medicine at the National Institutes of Health partially. Funding for open access charge: NLM, NIH. NR 27 TC 11 Z9 11 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 EI 1362-4962 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2008 VL 36 IS 18 BP 5863 EP 5871 DI 10.1093/nar/gkn579 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 361UP UT WOS:000260152900013 PM 18796526 ER PT J AU Ahmad, S Keskin, O Sarai, A Nussinov, R AF Ahmad, Shandar Keskin, Ozlem Sarai, Akinori Nussinov, Ruth TI Protein-DNA interactions: structural, thermodynamic and clustering patterns of conserved residues in DNA-binding proteins SO NUCLEIC ACIDS RESEARCH LA English DT Article ID HOT-SPOTS; PREDICTION; SITES; RECOGNITION; INTERFACES; NONADDITIVITY; ADDITIVITY; COMPLEXES; SEQUENCE; AFFINITY AB Amino acid residues, which play important roles in protein function, are often conserved. Here, we analyze thermodynamic and structural data of protein-DNA interactions to explore a relationship between free energy, sequence conservation and structural cooperativity. We observe that the most stabilizing residues or putative hotspots are those which occur as clusters of conserved residues. The higher packing density of the clusters and available experimental thermodynamic data of mutations suggest cooperativity between conserved residues in the clusters. Conserved singlets contribute to the stability of protein-DNA complexes to a lesser extent. We also analyze structural features of conserved residues and their clusters and examine their role in identifying DNA-binding sites. We show that about half of the observed conserved residue clusters are in the interface with the DNA, which could be identified from their amino acid composition; whereas the remaining clusters are at the protein-protein or protein-ligand interface, or embedded in the structural scaffolds. In protein-protein interfaces, conserved residues are highly correlated with experimental residue hotspots, contributing dominantly and often cooperatively to the stability of protein-protein complexes. Overall, the conservation patterns of the stabilizing residues in DNA-binding proteins also highlight the significance of clustering as compared to single residue conservation. C1 [Sarai, Akinori] Kyushu Inst Technol, Dept Biosci & Bioinformat, Fukuoka 8208502, Japan. [Ahmad, Shandar] Natl Inst Biomed Innovat, Osaka 5670085, Japan. [Ahmad, Shandar] Osaka Univ, Grad Sch Frontier Biosci, Suita, Osaka 565, Japan. [Keskin, Ozlem] Koc Univ, Ctr Computat Biol & Bioinformat, Coll Engn, TR-34450 Rumeli Feneri Yolu, Sariyer, Turkey. [Nussinov, Ruth] NCI, SAIC, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Sarai, A (reprint author), Kyushu Inst Technol, Dept Biosci & Bioinformat, Fukuoka 8208502, Japan. EM sarai@bio.kyutech.ac.jp OI Ahmad, Shandar/0000-0002-7287-305X FU National Cancer Institute; National Institutes of Health [NO1-CO-12400]; Center for Cancer Research; Ministry of Education, Culture, Sports, Science and Technology of Japan [16014219, 16041235] 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 NO1-CO-12400. This research was supported (in part) by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This research was also funded by Grants-in-Aid for Scientific Research 16014219 and 16041235 to A. S. from the Ministry of Education, Culture, Sports, Science and Technology of Japan. NR 36 TC 42 Z9 45 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2008 VL 36 IS 18 BP 5922 EP 5932 DI 10.1093/nar/gkn573 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 361UP UT WOS:000260152900018 PM 18801847 ER PT J AU Gomez-Rodriguez, J Washington, V Cheng, J Dutra, A Pak, E Liu, PT McVicar, DW Schwartzberg, PL AF Gomez-Rodriguez, Julio Washington, Valance Cheng, Jun Dutra, Amalia Pak, Evgenia Liu, Pentao McVicar, Daniel W. Schwartzberg, Pamela L. TI Advantages of q-PCR as a method of screening for gene targeting in mammalian cells using conventional and whole BAC-based constructs SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EMBRYONIC STEM-CELLS; BACTERIAL ARTIFICIAL CHROMOSOMES; POLYMERASE-CHAIN-REACTION; HOMOLOGOUS RECOMBINATION; MOUSE GENOME; ES CELLS; GENERATION; INSERTION; VECTORS; MICE AB We evaluate here the use of real-time quantitative PCR (q-PCR) as a method for screening for homologous recombinants generated in mammalian cells from either conventional gene-targeting constructs or whole BAC-based constructs. Using gene-targeted events at different loci, we show that q-PCR is a highly sensitive and accurate method for screening for conventional gene targeting that can reduce the number of clones requiring follow-up screening by Southern blotting. We further compared q-PCR to fluorescent in situ hybridization (FISH) for the detection of gene-targeting events using full-length BAC-based constructs designed to introduce mutations either into one gene or simultaneously into two adjacent genes. We find that although BAC-based constructs appeared to have high rates of homologous recombination when evaluated by FISH, screening by FISH was prone to false positives that were detected by q-PCR. Our results demonstrate the utility of q-PCR as a screening tool for gene targeting and further highlight potential problems with the use of whole BAC-based constructs for homologous recombination. C1 [Gomez-Rodriguez, Julio; Cheng, Jun; Dutra, Amalia; Pak, Evgenia; Schwartzberg, Pamela L.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Washington, Valance; McVicar, Daniel W.] NCI, Canc & Inflammat Program, Frederick, MD 21702 USA. [Liu, Pentao] Wellcome Trust Sanger Inst, Cambridge CB10 1HH, England. RP Schwartzberg, PL (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM pams@mail.nih.gov RI McVicar, Daniel/G-1970-2015 FU National Institutes of Health; National Human Genome Research Institute; National Cancer Institute FX The authors would like to thank L. Garrett and A. Kimmel for helpful comments.; Intramural Research Program of the National Institutes of Health, National Human Genome Research Institute and National Cancer Institute. Wellcome Trust (P. L.). Funding for open access charge: Intramural Research Program of the National Institutes of Health. NR 32 TC 7 Z9 8 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD OCT PY 2008 VL 36 IS 18 AR e117 DI 10.1093/nar/gkn523 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 361UP UT WOS:000260152900031 PM 18710883 ER PT J AU Beck, J Ferrucci, L Sun, K Fried, LP Varadhan, R Walston, J Guralnik, JM Semba, RD AF Beck, Justine Ferrucci, Luigi Sun, Kai Fried, Linda P. Varadhan, Ravi Walston, Jeremy Guralnik, Jack M. Semba, Richard D. TI Circulating oxidized low-density lipoproteins are associated with overweight, obesity, and low serum carotenoids in older community-dwelling women SO NUTRITION LA English DT Article DE body mass index; carotenoids; low-density lipoproteins; obesity; oxidative stress ID CORONARY-ARTERY-DISEASE; MEDITERRANEAN DIET; OXIDATIVE STRESS; LDL OXIDATION; HEART-DISEASE; WEIGHT-LOSS; METABOLIC-SYNDROME; ABDOMINAL OBESITY; BODY-COMPOSITION; VITAMIN-E AB Objective: The objective of this study was to determine whether total serum carotenoids, alpha-tocopherol, selenium, and obesity were independently associated with oxidized low-density lipoproteins (ox-LDLs) in moderately to severely disabled older women living in the community. Methods: Serum ox-LDLs, carotenoids, alpha-tocopherol, and selenium were measured in a population-based sample of 543 moderately to severely disabled women >= 65 y in the Women's Health and Aging Study I in Baltimore, Maryland. Results: Total serum carotenoids, smoking, overweight (body mass index 25-29.9 kg/m(2)), and obesity (body mass index >= 30 mg/kg(2)) were significantly associated with the ox-LDL/LDL cholesterol ratio after adjusting for age, C-reactive protein, and chronic diseases. alpha-Tocopherol and selenium were not significantly associated with the ox-LDL/LDL cholesterol ratio. Conclusion: Older women who are overweight or obese or who have low total serum carotenoids are more likely to have higher lipoprotein oxidation. Weight reduction in overweight/obese women and increased intake of carotenoid-rich foods may potentially reduce lipoprotein oxidation. (C) 2008 Elsevier Inc. All rights reserved. C1 [Beck, Justine; Sun, Kai; Fried, Linda P.; Varadhan, Ravi; Walston, Jeremy; Semba, Richard D.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Ferrucci, Luigi] NIA, Clin Res Branch, Longitudinal Studies Sect, Baltimore, MD 21224 USA. [Guralnik, Jack M.] NIA, Epidemiol Demog & Biometry Branch, Bethesda, MD 20892 USA. RP Semba, RD (reprint author), Johns Hopkins Med Inst, Baltimore, MD 21205 USA. EM rdsemba@jhmi.edu FU National Institute on Aging [R01 AG027012, AG11703-01A1, N01-AG12112]; National Institutes of Health/National Center for Research Resources, Out Patient Department-Guard Clinical Research Center [RR00722, R01 A141956] FX This work was supported by National Institute on Aging grants R01 AG027012 and AG11703-01A1; National Institutes of Health/National Center for Research Resources, Out Patient Department-Guard Clinical Research Center grants RR00722 and R01 A141956; National Institute on Aging contract N01-AG12112; and the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 41 TC 8 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0899-9007 J9 NUTRITION JI Nutrition PD OCT PY 2008 VL 24 IS 10 BP 964 EP 968 DI 10.1016/j.nut.2008.04.006 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 352ZF UT WOS:000259535200006 PM 18585897 ER PT J AU Adler-Wailes, DC Guiney, EL Koo, J Yanovski, JA AF Adler-Wailes, Diane C. Guiney, Evan L. Koo, Jashin Yanovski, Jack A. TI Effects of ritonavir on adipocyte gene expression: Evidence for a stress-related response SO OBESITY LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; HIV PROTEASE INHIBITORS; INSULIN-RESISTANCE; FRAGMENTATION FACTOR; OXIDATIVE STRESS; ADIPOSE-TISSUE; FACTOR-ALPHA; OBESITY; LIPOLYSIS; DEATH AB To understand the molecular mechanisms underlying the development of dyslipidemia and lipodystrophy that occurs after administration of aspartic acid protease inhibitors, we examined transcriptional profiles using cDNA microarrays in 3T3-L1 adipocytes exposed to 10 mu mol/l ritonavir for 2-21 days. The expression levels of similar to 12,000 transcripts were assessed using the MgU74Av2 mouse microarray chip. Ritonavir altered gene expression of inflammatory cytokines, stress response genes localized to endoplasmic reticulum, oxidative stress genes, apoptosis-related genes, and expression of genes involved in cell adhesion and extracellular matrix remodeling. Microarray analysis also identified a novel gene downregulated by ritonavir, Cidea, whose expression levels may affect free-fatty acid metabolism. These changes suggest a unique, stress-related pattern in adipocytes induced by chronic exposure to the protease inhibitor, ritonavir. C1 [Adler-Wailes, Diane C.; Guiney, Evan L.; Koo, Jashin; Yanovski, Jack A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, Unit Growth & Obes, Program Dev Endocrinol & Genet,NIH, Bethesda, MD USA. RP Yanovski, JA (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Dept Hlth & Human Serv, Unit Growth & Obes, Program Dev Endocrinol & Genet,NIH, Bethesda, MD USA. EM jy15i@nih.gov OI Yanovski, Jack/0000-0001-8542-1637 FU National Institutes of Health; National Institute of Child Health and Human Development [Z01-HD-000641]; , National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health, grant Z01-HD-000641 from the National Institute of Child Health and Human Development, National Institutes of Health (to J.A.Y.). J.A.Y. is a commissioned Officer in the United States Public Health Service. NR 41 TC 14 Z9 14 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD OCT PY 2008 VL 16 IS 10 BP 2379 EP 2387 DI 10.1038/oby.2008.350 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 354OR UT WOS:000259649400029 PM 18719645 ER PT J AU Alexander, JM Leveno, KJ Rouse, D Landon, MB Gilbert, SA Spong, CY Varner, MW Caritis, SN Harper, M Wapner, RJ Sorokin, Y Miodovnik, M O'Sullivan, MJ Sibai, BM Langer, O Gabbe, SG AF Alexander, James M. Leveno, Kenneth J. Rouse, Dwight Landon, Mark B. Gilbert, Sharon A. Spong, Catherine Y. Varner, Michael W. Caritis, Steve N. Harper, Margaret Wapner, Ronald J. Sorokin, Yoram Miodovnik, Menachem O'Sullivan, Mary J. Sibai, Baha M. Langer, Oded Gabbe, Steven G. CA Eunice Kennedy Shriver Natl Inst C TI Cesarean delivery for the second twin SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID PERINATAL-MORTALITY; MANAGEMENT; MORBIDITY; SECTION; DEATH AB OBJECTIVE: To examine maternal and infant outcomes after a vaginal delivery of twin A and a cesarean delivery of twin B, and to identify whether the second twin experienced increased short-term morbidity as part of a combined route of delivery. METHODS: Between January 1, 1999, and December 31, 2000, a prospective cohort study of all cesarean deliveries was conducted at 13 university centers. This secondary analysis was limited to women with twin gestations who experienced labor and underwent cesarean delivery. We compared outcomes of the second twin in women who had vaginal delivery of the first twin and a cesarean delivery of the second twin to those who had cesarean delivery of both twins. RESULTS: One thousand twenty-eight twin pregnancies experienced labor and underwent cesarean delivery; 179 (17%) had a combined vaginal/cesarean delivery. Gestational age at delivery was 34.6 weeks in both groups (P=.97). The rupture of membranes to delivery interval was longer in the combined group (3.2 compared with 2.3 hours, P<.001). Endometritis and culture-proven sepsis in the second twin were more common in the combined group, respectively (n=24, odds ratio 1.6, 95% confidence interval, 1.0-2.7; n=15, odds ratio 1.8, 95% confidence interval, 1.0-3.4). These differences were not significant after logistic regression analysis. There were no statistically significant differences in an arterial cord pH of less than 7.0, Apgar score less than or equal to 3 at 5 minutes, seizures, grade III or IV intraventricular hemorrhage, hypoxic ischemic encephalopathy, or neonatal death. CONCLUSION: Combined twin delivery may be associated with endometritis and neonatal sepsis when compared with a twin delivery where both are delivered by cesarean in twin pregnancies experiencing labor. More serious neonatal sequelae, including hypoxic ischemic encephalopathy and death, were not affected by the route of delivery of the second twin. C1 Univ Texas SW Med Ctr Dallas, Dept Obstet, Dallas, TX 75235 USA. Univ Texas SW Med Ctr Dallas, Dept Gynecol, Dallas, TX 75235 USA. Univ Alabama, Birmingham, AL USA. Ohio State Univ, Columbus, OH 43210 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. NICHHD, Bethesda, MD 20892 USA. Univ Utah, Dept Obstet, Salt Lake City, UT USA. Univ Utah, Dept Gynecol, Salt Lake City, UT USA. Univ Chicago, Chicago, IL 60637 USA. Univ Pittsburgh, Pittsburgh, PA USA. Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. Thomas Jefferson Univ, Philadelphia, PA 19107 USA. Wayne State Univ, Detroit, MI USA. Univ Cincinnati, Cincinnati, OH USA. Univ Miami, Miami, FL USA. Univ Tennessee, Memphis, TN USA. Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. Vanderbilt Univ, Nashville, TN USA. RP Alexander, JM (reprint author), Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, 5323 Harry Hines Blvd, Dallas, TX 75235 USA. EM alexander@utsouthwestern.edu RI Varner, Michael/K-9890-2013 OI caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973 FU National Institute of Child Health and Human Development [HD21410, HD21414, HD27860, HD27861, HD27869, HD27905, HD27915, HD27917, HD34116, HD34122, HD34136, HD34208, HD34210, HD36801] FX Supported by grants from the National Institute of Child Health and Human Development (HD21410, HD21414, HD27860, HD27861, HD27869, HD27905, HD27915, HD27917, HD34116, HD34122, HD34136, HD34208, HD34210, and HD36801). NR 10 TC 15 Z9 15 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD OCT PY 2008 VL 112 IS 4 BP 748 EP 752 DI 10.1097/AOG.0b013e318187ccb2 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 356GW UT WOS:000259767700003 PM 18827115 ER PT J AU Kreyling, J Beierkuhnlein, C Ellis, L Jentsch, A AF Kreyling, Juergen Beierkuhnlein, Carl Ellis, Laura Jentsch, Anke TI Invasibility of grassland and heath communities exposed to extreme weather events - additive effects of diversity resistance and fluctuating physical environment SO OIKOS LA English DT Article ID SPECIES RICHNESS; PLANT-COMMUNITIES; CLIMATE-CHANGE; INVASION; BIODIVERSITY; PRODUCTIVITY; PATTERNS; COMPETITION; CALIFORNIA; INVADERS AB Understanding the resistance of plant communities to invasion is urgent in times of changes in the physical environment due to climate change and changes in the resident communities due to biodiversity loss. Here, we test the interaction between repeated drought or heavy rainfall events and functional diversity of grassland and heath communities on invasibility, measured as the number of plant individuals invading from the matrix vegetation. Invasibility of experimental plant communities was influenced by extreme weather events, although no change in above-ground productivity of the resident communities was observed. Drought decreased invasibility while heavy rainfall increased invasibility, a pattern that is consistent with the fluctuating resource hypothesis. Higher community diversity generally decreased invasibility, which can be explained by a combination of the fluctuating resource hypothesis and niche theory. The effects of the physical environment (extreme weather events) and diversity resistance (community composition) were additive, as they were independent from each other. Differences in the composition of invading species sets were found, and Indicator Species Analysis revealed several invading species with significant affinity to one particular extreme weather event or community composition. This finding supports niche theory and contradicts neutral species assembly. Our data supports theories which predict decreased resistance of plant communities due to both increased climate variability and biodiversity loss. The effects of these two factors, however, appear to be independent from each other. C1 [Kreyling, Juergen; Jentsch, Anke] UFZ Helmholtz Ctr Environm Res, D-04318 Leipzig, Germany. [Kreyling, Juergen; Jentsch, Anke] Univ Bayreuth, DE-95440 Bayreuth, Germany. [Ellis, Laura] NIH, Bethesda, MD 20892 USA. [Beierkuhnlein, Carl] Univ Bayreuth, BayCEER, DE-95440 Bayreuth, Germany. RP Kreyling, J (reprint author), UFZ Helmholtz Ctr Environm Res, Permoserstr 15, D-04318 Leipzig, Germany. EM juergen.kreyling@uni-bayreuth.de RI Kreyling, Juergen/E-8178-2012 OI Kreyling, Juergen/0000-0001-8489-7289 NR 53 TC 23 Z9 24 U1 7 U2 47 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0030-1299 J9 OIKOS JI Oikos PD OCT PY 2008 VL 117 IS 10 BP 1542 EP 1554 DI 10.1111/j.0030-1299.2008.16653.x PG 13 WC Ecology SC Environmental Sciences & Ecology GA 350KQ UT WOS:000259351700012 ER PT J AU Mazan-Mamczarz, K Hagner, PR Corl, S Srikantan, S Wood, WH Becker, KG Gorospe, M Keene, JD Levenson, AS Gartenhaus, RB AF Mazan-Mamczarz, K. Hagner, P. R. Corl, S. Srikantan, S. Wood, W. H. Becker, K. G. Gorospe, M. Keene, J. D. Levenson, A. S. Gartenhaus, R. B. TI Post-transcriptional gene regulation by HuR promotes a more tumorigenic phenotype SO ONCOGENE LA English DT Article DE post-transcriptional operon; MCT-1 oncogene; TSP1; HuR; RNA-binding protein; tumor angiogenesis ID BINDING PROTEIN HUR; MESSENGER-RNA STABILITY; RIBONUCLEOPROTEIN COMPLEXES; TRANSLATIONAL REPRESSION; TUMOR ANGIOGENESIS; EXPRESSION; CELLS; RICH; CANCER; REGION AB In a breast tumor xenograft model, the MCT-1 oncogene increases the in vivo tumorgenicity of MCF7 cells by promoting angiogenesis and inhibiting apoptosis. Increases in the tumor microvascular density are accompanied by a strong reduction in the levels of the angiogenesis inhibitor thrombospondin-1 (TSP1), but the mechanisms underlying this process are unknown. We show that TSP1 expression is controlled, at least in part, by post-transcriptional events. Using RNA interference to knock down the expression of the RNA-binding protein HuR in MCF7 cells as well as HuR overexpression, we demonstrate that HuR plays an important role in translation of the TSP1 mRNA. Furthermore, employing the RIP-Chip assay yielded 595 transcripts with significantly altered binding to HuR in the more tumorigenic breast cancer clones compared with the weakly tumorigenic clones. These mRNAs clustered in several pathways implicated in the transformed phenotype, such as the RAS pathway (involved in mitogenesis), the PI3K pathway (evasion of apoptosis) and pathways mediating angiogenesis and the cellular response to hypoxia. These findings demonstrate for the first time that global changes in HuR-bound mRNAs are implicated in the evolution to a more tumorigenic phenotype in an in vivo tumor model and underscore the role of global mRNA-protein interactions toward tumor progression. C1 [Mazan-Mamczarz, K.; Hagner, P. R.; Corl, S.; Gartenhaus, R. B.] Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, Baltimore, MD 21201 USA. [Srikantan, S.; Gorospe, M.] NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. [Wood, W. H.; Becker, K. G.] NIA, Gene Express & Genom Unit, NIH, Baltimore, MD 21224 USA. [Keene, J. D.] Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC USA. [Levenson, A. S.] Northwestern Univ, Dept Urol, Feinberg Sch Med, Chicago, IL 60611 USA. [Levenson, A. S.] Robert H Lurie Comprehens Canc Ctr, Chicago, IL USA. RP Gartenhaus, RB (reprint author), Univ Maryland, Marlene & Stewart Greenebaum Canc Ctr, 9-011 BRB,655 W Baltimore St,22 S Greene St, Baltimore, MD 21201 USA. EM rgartenhaus@som.umaryland.edu OI srikantan, subramanya/0000-0003-1810-6519; Becker, Kevin/0000-0002-6794-6656 FU National Institute on Aging Intramural Research Program; NIH FX We thank Dr Y Zhang for assistance with the statistical analysis of the RIP-Chip array data and Dr J Hasday for technical support. A Merit Review Award from the Department of Veterans Affairs to RBG supported this work. MG and SS were supported by the National Institute on Aging Intramural Research Program, NIH. NR 49 TC 77 Z9 77 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT PY 2008 VL 27 IS 47 BP 6151 EP 6163 DI 10.1038/onc.2008.215 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 360UJ UT WOS:000260083100008 PM 18641687 ER PT J AU Klein, R Knudtson, MD Klein, BEK Wong, TY Cotch, MF Liu, K Cheng, CY Burke, GL Saad, MF Jacobs, DR Sharrett, AR AF Klein, Ronald Knudtson, Michael D. Klein, Barbara E. K. Wong, Tien Y. Cotch, Mary Frances Liu, Kiang Cheng, Ching Y. Burke, Gregory L. Saad, Mohammed F. Jacobs, David R., Jr. Sharrett, A. Richey TI Inflammation, complement factor H, and age-related macular degeneration - The Multi-Ethnic Study of Atherosclerosis SO OPHTHALMOLOGY LA English DT Article ID CHLAMYDIA-PNEUMONIAE INFECTION; C-REACTIVE PROTEIN; BEAVER DAM EYE; BLUE-MOUNTAINS-EYE; RISK-FACTORS; CARDIOVASCULAR-DISEASE; ENDOTHELIAL DYSFUNCTION; 5-YEAR INCIDENCE; MEDICATION USE; UNITED-STATES AB Objective: To describe the relationship of systemic inflammatory disease, complement factor H (CFH) Y402H (1277T -> C) genotype status and age-related macular degeneration (AMD) prevalence in a multiethnic population of whites, blacks, Hispanics, and Chinese. Design: Population-based, cross-sectional study. Participants: We included 5887 persons aged 45 to 84 years with gradable AMD. Methods: Digital fundus photographs were used to measure AMD. Two years earlier, biomarkers of inflammation were measured and history of inflammatory disease and use of anti inflammatory agents obtained. Main Outcome Measure: Prevalence of AMD. Results: While controlling for age, gender, race/ethnicity, and study site, there were no associations between systemic inflammatory factors and AMD severity. Higher levels of high-sensitivity C-reactive protein (odds ratio [OR] per standard deviation [SD] increase in natural log [In] units, 2.34; 95% confidence interval [CI], 1.33-4.13) and interleukin-6 (OR per SD in In, 2.06; 95% CI, 1.21-3.49) were associated with geographic atrophy but not other AMD end points. History of periodontal disease (OR, 1.68; 95% CI, 1.14-2.47) was related to increased retinal pigment. A history of arthritis was associated with soft distinct drusen (OR, 1.24; 95% CI, 1.06-1.46). A history of oral steroid use was related to large drusen (OR, 2.13; 95% CI, 1.14-3.97) and soft distinct drusen (OR, 1.76; 95% CI, 1.00-3.10) and history of cyclooxygenase 2 inhibitor use were associated with large drusen (OR, 1.50; 95% CI, 1.10-2.04), soft indistinct drusen (OR, 1.84; 95% CI, 1.09-3.10), and large drusen area (OR, 1.66; 95% CI, 1.02-2.71). Whites, blacks, and Hispanics with CFH Y402H CC variant genotype had the highest frequency of early AMD compared with those with wild TT genotype. The frequency of CFH did explain some of the difference in AMD prevalence between Chinese and Hispanics compared with whites, but did not explain the difference in prevalence between whites and blacks. Conclusions: This study confirmed associations of the Y402H CFH gene variant with AMD in nonwhite populations, but neither explained the lack of association between inflammatory factors and AMD in the cohort nor the basis for the observed differences in AMD prevalence across ethnic groups. C1 [Klein, Ronald; Knudtson, Michael D.; Klein, Barbara E. K.] Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Health, Madison, WI 53726 USA. [Wong, Tien Y.] Univ Melbourne, Ctr Eye Res, Melbourne, Vic, Australia. [Wong, Tien Y.] Natl Univ Singapore, Singapore Eye Res Inst, Singapore 117548, Singapore. [Cotch, Mary Frances] NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. [Liu, Kiang] Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL USA. [Cheng, Ching Y.; Sharrett, A. Richey] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Cheng, Ching Y.] NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. [Cheng, Ching Y.] Taipei Vet Gen Hosp, Taipei, Taiwan. [Cheng, Ching Y.] Natl Yang Ming Univ, Dept Ophthalmol, Taipei 112, Taiwan. [Burke, Gregory L.] Wake Forest Univ, Dept Publ Hlth Sci, Wake Forest, NC USA. [Saad, Mohammed F.] Stony Brook Med Sch, Dept Prevent Med, Stony Brook, NY USA. [Jacobs, David R., Jr.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. [Jacobs, David R., Jr.] Univ Oslo, Dept Nutr, Oslo, Norway. RP Klein, R (reprint author), Univ Wisconsin, Dept Ophthalmol & Visual Sci, Sch Med & Publ Health, 610 N Walnut Street,450 WARE, Madison, WI 53726 USA. EM kleinr@epi.ophth.wisc.edu RI Cheng, Ching-Yu/K-7017-2013; OI Cheng, Ching-Yu/0000-0003-0655-885X; Cotch, Mary Frances/0000-0002-2046-4350; Klein, Ronald/0000-0002-4428-6237 FU National Heart, Lung, and Blood Institute [N01-HC-95159, N01-HC-95165, N01-HC-95169]; NIH [HL69979-03] FX The authors do not have any conflicts of interest related to the article.; Supported by contracts N01-HC-95159 through N01-HC-95165 and N01-HC-95169 from the National Heart, Lung, and Blood Institute. Additional support was provided by NIH grant HL69979-03 (Klein R and Won, TY). A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org. NR 54 TC 48 Z9 52 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 EI 1549-4713 J9 OPHTHALMOLOGY JI Ophthalmology PD OCT PY 2008 VL 115 IS 10 BP 1742 EP 1749 DI 10.1016/j.ophtha.2008.03.021 PG 8 WC Ophthalmology SC Ophthalmology GA 357NJ UT WOS:000259852200015 PM 18538409 ER PT J AU Ludlow, CL Adler, CH Berke, GS Bielamowicz, SA Blitzer, A Bressman, SB Hallett, M Jinnah, HA Juergens, U Martin, SB Perlmutter, JS Sapienza, C Singleton, A Tanner, CM Woodson, GE AF Ludlow, Christy L. Adler, Charles H. Berke, Gerald S. Bielamowicz, Steven A. Blitzer, Andrew Bressman, Susan B. Hallett, Mark Jinnah, H. A. Juergens, Uwe Martin, Sandra B. Perlmutter, Joel S. Sapienza, Christine Singleton, Andrew Tanner, Caroline M. Woodson, Gayle E. TI Research priorities in spasmodic dysphonia SO OTOLARYNGOLOGY-HEAD AND NECK SURGERY LA English DT Review ID FOCAL HAND DYSTONIA; ADDUCTOR DENERVATION-REINNERVATION; IDIOPATHIC TORSION DYSTONIA; BOTULINUM TOXIN INJECTIONS; MUSCULAR TENSION DYSPHONIA; LARYNGEAL NERVE RESECTION; ESSENTIAL VOICE TREMOR; SPASTIC DYSPHONIA; WRITERS CRAMP; GENERALIZED DYSTONIA AB OBJECTIVE: To identify research priorities to increase understanding of the pathogenesis, diagnosis, and improved treatment of spasmodic dysphonia. STUDY DESIGN AND SETTING: A multidisciplinary working group was formed that included both scientists and clinicians from multiple disciplines (otolaryngology, neurology, speech pathology, genetics, and neuroscience) to review currently available information on spasmodic dysphonia and to identify research priorities. RESULTS: Operational definitions for spasmodic dysphonia at different levels of certainty were recommended for diagnosis and recommendations made for a multicenter multidisciplinary validation study. CONCLUSIONS: The highest priority is to characterize the disorder and identify risk factors that may contribute to its onset. Future research should compare and contrast spasmodic dysphonia with other forms of focal dystonia. Development of animal models is recommended to explore hypotheses related to pathogenesis. Improved understanding of the pathophysiology of spasmodic dysphonia should provide the basis for developing new treatment options and exploratory clinical trials. SIGNIFICANCE: This document should foster future research to improve the care of patients with this chronic debilitating voice and speech disorder by otolaryngology, neurology, and speech pathology. (C) 2008 American Academy of Otolaryngology-Head and Neck Surgery Foundation. All rights reserved. C1 [Ludlow, Christy L.; Martin, Sandra B.] NINDS, Laryngeal & Speech Sect, Clin Neurosci Program, NIH, Bethesda, MD 20892 USA. [Adler, Charles H.] Mayo Clin, Dept Neurol, Scottsdale, AZ USA. [Berke, Gerald S.] Univ Calif Los Angeles, David Geffen Sch Med, Div Head & Neck Surg, Los Angeles, CA 90095 USA. [Bielamowicz, Steven A.] George Washington Univ, Med Fac Associates, Div Otolaryngol Head & Neck Surg, Washington, DC USA. [Blitzer, Andrew] Columbia Univ, Coll Phys & Surg, Dept Otolaryngol Head & Neck Surg, New York, NY USA. [Blitzer, Andrew] Columbia Univ, Coll Phys & Surg, New York Ctr Voice & Swallowing Disorders, New York, NY USA. [Bressman, Susan B.] Beth Israel Deaconess Med Ctr, Dept Neurol, New York, NY 10003 USA. [Bressman, Susan B.] Albert Einstein Coll Med, New York, NY USA. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Jinnah, H. A.] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21218 USA. [Juergens, Uwe] German Primate Ctr, Dept Neurobiol, Gottingen, Germany. [Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Neurobiol, St Louis, MO 63110 USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA. [Perlmutter, Joel S.] Washington Univ, Sch Med, Dept Phys Therapy, St Louis, MO 63110 USA. [Sapienza, Christine] Univ Florida, Dept Commun Sci & Disorders, Gainesville, FL USA. [Sapienza, Christine] Brain Rehabil Res Ctr, Gainesville, FL USA. [Singleton, Andrew] NIA, Mol Genet Unit, NIH, Bethesda, MD 20892 USA. [Tanner, Caroline M.] Parkinsons Inst, Sunnyvale, CA USA. [Woodson, Gayle E.] So Illinois Univ, Sch Med, Div Otolaryngol, Springfield, IL USA. RP Ludlow, CL (reprint author), NINDS, Laryngeal & Speech Sect, Clin Neurosci Program, NIH, Bldg 10,Room 5D38,MSC 1416,10 Ctr Dr, Bethesda, MD 20892 USA. RI Singleton, Andrew/C-3010-2009; OI Woodson, Gayle/0000-0002-0315-5329; Ludlow, Christy/0000-0002-2015-6171 FU Allergan; Merz; Elan; Solstice; National Institutes of Health; National Institute of Neurological Disorders and Stroke; National Spasmodic Dysphonia Association; Movement Disorder Society; National Institute on Deafness and Other Communication Disorders FX Charles Adler is a consultant for Allergan and has research funding from Allergan, Merz, and Elan; Andrew Blitzer received research support from Allergan, Solstice, and Metz and is a consultant to Allergan and Solstice and receives royalty income. Support for the Workshop was from the Office of Rare Diseases of the National Institutes of Health, the National Institute of Neurological Disorders and Stroke, the National Spasmodic Dysphonia Association, the Movement Disorder Society, the National Institute on Deafness and Other Communication Disorders, and the Intramural Research Program of the National Institute of Neurological Disorders and Stroke. NR 83 TC 35 Z9 37 U1 0 U2 4 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0194-5998 EI 1097-6817 J9 OTOLARYNG HEAD NECK JI Otolaryngol. Head Neck Surg. PD OCT PY 2008 VL 139 IS 4 BP 495 EP 505 DI 10.1016/j.otohns.2008.05.624 PG 11 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 356GR UT WOS:000259767200004 PM 18922334 ER PT J AU Kleta, R Gahl, WA AF Kleta, Robert Gahl, William A. TI Cystinosis: insights into an adult lysosomal storage disorder SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 [Kleta, Robert] UCL, London, England. [Gahl, William A.] Natl Inst Hlth, Maryland, MD USA. 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 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD OCT PY 2008 VL 23 IS 10 BP 1911 EP 1912 PG 2 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 344CH UT WOS:000258902600054 ER PT J AU Rovner, AJ Miller, RS AF Rovner, Alisha J. Miller, Ryan S. TI Vitamin D deficiency and insufficiency in children with osteopenia or osteoporosis SO PEDIATRICS LA English DT Letter C1 [Rovner, Alisha J.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent, Bethesda, MD 20892 USA. [Miller, Ryan S.] Johns Hopkins Univ, Sch Med, Div Metab, Baltimore, MD 21287 USA. [Miller, Ryan S.] Johns Hopkins Univ, Sch Med, Div Pediat Endocrinol, Baltimore, MD 21287 USA. RP Rovner, AJ (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent, Bethesda, MD 20892 USA. NR 5 TC 8 Z9 8 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2008 VL 122 IS 4 BP 907 EP 908 DI 10.1542/peds.2008-1743 PG 5 WC Pediatrics SC Pediatrics GA 356YD UT WOS:000259812600036 PM 18829822 ER PT J AU Raju, TNK Bock, R Alexander, D AF Raju, Tonse N. K. Bock, Robert Alexander, Duane TI Renaming of the National Institute of Child Health and Human Development in honor of Mrs Eunice Kennedy Shriver SO PEDIATRICS LA English DT Editorial Material AB "I am delighted to approve the legislation authorizing the creation of a National Institute of Child Health and Human Development.... The future health of our Nation rests on the care of our children and the development of our knowledge of the medical and biological sciences.... Research in recent years has established beyond question that adult behavior, intelligence, and motivation are established by the experience and patterns of response developed in the formative years of life...". C1 [Raju, Tonse N. K.; Bock, Robert; Alexander, Duane] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Bethesda, MD USA. RP Raju, TNK (reprint author), 6100 Execut Blvd,Room 4B03, Bethesda, MD 20892 USA. EM rajut@mail.nih.gov NR 5 TC 1 Z9 1 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2008 VL 122 IS 4 BP E948 EP E949 DI 10.1542/peds.2008-1678 PG 2 WC Pediatrics SC Pediatrics GA 356YD UT WOS:000259812600065 PM 18794195 ER PT J AU Shankaran, S Pappas, A Laptook, AR McDonald, SA Ehrenkranz, RA Tyson, JE Walsh, M Goldberg, RN Higgins, RD Das, A AF Shankaran, Seetha Pappas, Athina Laptook, Abbott R. McDonald, Scott A. Ehrenkranz, Richard A. Tyson, Jon E. Walsh, Michelle Goldberg, Ronald N. Higgins, Rosemary D. Das, Abhik CA NICHD Neonatal Res Network TI Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy SO PEDIATRICS LA English DT Article DE hypoxic-ischemic encephalopathy; whole-body hypothermia; safety; effectiveness ID MILD THERAPEUTIC HYPOTHERMIA; PERINATAL ASPHYXIA; MODERATE HYPOTHERMIA; SYSTEMIC HYPOTHERMIA; TERM INFANTS; NEWBORN AB BACKGROUND. Whole-body hypothermia reduced the frequency of death or moderate/severe disabilities in neonates with hypoxic-ischemic encephalopathy in a randomized, controlled multicenter trial. OBJECTIVE. Our goal was to evaluate outcomes of safety and effectiveness of hypothermia in infants up to 18 to 22 months of age. DESIGN/METHODS. A priori outcomes were evaluated between hypothermia (n = 102) and control (n = 106) groups. RESULTS. Encephalopathy attributable to causes other than hypoxia-ischemia at birth was not noted. Inotropic support (hypothermia, 59% of infants; control, 56% of infants) was similar during the 72-hour study intervention period in both groups. Need for blood transfusions (hypothermia, 24%; control, 24%), platelet transfusions (hypothermia, 20%; control, 12%), and volume expanders (hypothermia, 54%; control, 49%) was similar in the 2 groups. Among infants with persistent pulmonary hypertension (hypothermia, 25%; control, 22%), nitric-oxide use (hypothermia, 68%; control, 57%) and placement on extracorporeal membrane oxygenation (hypothermia, 4%; control, 9%) was similar between the 2 groups. Non-central nervous system organ dysfunctions occurred with similar frequency in the hypothermia (74%) and control (73%) groups. Rehospitalization occurred among 27% of the infants in the hypothermia group and 42% of infants in the control group. At 18 months, the hypothermia group had 24 deaths, 19 severe disabilities, and 2 moderate disabilities, whereas the control group had 38 deaths, 25 severe disabilities, and 1 moderate disability. Growth parameters were similar between survivors. No adverse outcomes were noted among infants receiving hypothermia with transient reduction of temperature below a target of 33.5 degrees C at initiation of cooling. There was a trend in reduction of frequency of all outcomes in the hypothermia group compared with the control group in both moderate and severe encephalopathy categories. CONCLUSIONS. Although not powered to test these secondary outcomes, whole-body hypothermia in infants with encephalopathy was safe and was associated with a consistent trend for decreasing frequency of each of the components of disability. C1 [Shankaran, Seetha; Pappas, Athina] Wayne State Univ, Sch Med, Dept Pediat, Detroit, MI 48201 USA. [Laptook, Abbott R.] Women & Infants Hosp Rhode Isl, Dept Pediat, Providence, RI 02908 USA. [McDonald, Scott A.; Das, Abhik] RTI Int, Dept Stat & Epidemiol, Res Triangle Pk, NC USA. [Ehrenkranz, Richard A.] Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. [Tyson, Jon E.] Univ Texas Houston, Sch Med, Dept Pediat, Houston, TX USA. [Walsh, Michelle] Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. [Goldberg, Ronald N.] Duke Univ, Dept Pediat, Durham, NC 27706 USA. [Higgins, Rosemary D.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Rockville, MD USA. RP Shankaran, S (reprint author), Childrens Hosp Michigan, 3901 Beaubien Blvd, Detroit, MI 48201 USA. EM sshankar@med.wayne.edu RI Myers , Gary /I-4901-2013 OI Myers , Gary /0000-0003-4317-015X FU NICHD [U10 HD34216, U10 HD27853, U10 HD27871, U10 HD40461, U10 HD40689, U10 HD27856, U10 HD27904, U10 HD40498, U10 HD40521, U01 HD36790, U10 HD21385, U10 HD27880, U10 HD27851, U10 HD 21373]; National Center for Research Resources [M01 RR 08084, M01 RR 00125, M01 RR 00750, M01 RR 00070, M01 RR 0039-43, M01RR 00039, 5 M01 RR00044] FX This work was supported in part by NICHD grants U10 HD34216, U10 HD27853, U10 HD27871, U10 HD40461, U10 HD40689, U10 HD27856, U10 HD27904, U10 HD40498, U10 HD40521, U01 HD36790, U10 HD21385, U10 HD27880, U10 HD27851, and U10 HD 21373 and GCRCs (General Clinical Research Center) grants from the National Center for Research Resources M01 RR 08084, M01 RR 00125, M01 RR 00750, M01 RR 00070, M01 RR 0039-43, M01RR 00039, and 5 M01 RR00044. NR 29 TC 75 Z9 79 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2008 VL 122 IS 4 BP E791 EP E798 DI 10.1542/peds.2008-0456 PG 8 WC Pediatrics SC Pediatrics GA 356YD UT WOS:000259812600043 PM 18829776 ER PT J AU Fein, SB Grummer-Strawn, LM Raju, TNK AF Fein, Sara B. Grummer-Strawn, Laurence M. Raju, Tonse N. K. TI Infant feeding and care practices in the United States: Results from the Infant Feeding Practices Study II SO PEDIATRICS LA English DT Editorial Material C1 [Fein, Sara B.] US FDA, Ctr Food Safety & Appl Nutr, College Pk, MD 20740 USA. [Grummer-Strawn, Laurence M.] Ctr Dis Control & Prevent, Div Nutr Phys Act & Obes, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, Bethesda, MD USA. RP Fein, SB (reprint author), US FDA, Ctr Food Safety & Appl Nutr, 5100 Paint Branch Pkwy,HFS 020, College Pk, MD 20740 USA. EM sara.fein@fda.hhs.gov NR 13 TC 26 Z9 26 U1 0 U2 9 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2008 VL 122 SU S BP S25 EP S27 DI 10.1542/peds.2008-1315b PG 3 WC Pediatrics SC Pediatrics GA 357CB UT WOS:000259822800001 PM 18829827 ER PT J AU Hauck, FR Signore, C Fein, SB Raju, TNK AF Hauck, Fern R. Signore, Caroline Fein, Sara B. Raju, Tonse N. K. TI Infant sleeping arrangements and practices during the first year of life SO PEDIATRICS LA English DT Article DE sleep; sudden infant death syndrome; SIDS; suffocation; infant mortality; risk reduction; health campaigns; breastfeeding ID DEATH-SYNDROME; UNITED-STATES; POSITION; RISK; ENVIRONMENT AB OBJECTIVES. Our goal was to examine the sleeping arrangements for infants from birth to 1 year of age and to assess the association between such arrangements and maternal characteristics. METHODS. Responses to the 3-, 6-, 9-, and 12-month questionnaires from the Infant Feeding Practices Study II were analyzed to assess sleep arrangements, including bed sharing, the latter defined as mother ever ( in a given time frame) slept with the infant on the same sleeping surface for nighttime sleep. Women were also asked about the reasons for bed sharing or not bed sharing. RESULT Approximately 2300 women responded at 3 months, and 1800 at 12 months. At 3 months, 85% of the infants slept in the same room as their mother, and at 12 months that rate was 29%. At 3 months, 26% of the mothers did not use the recommended supine position for their infant's nighttime sleep. The rate of noncompliance increased to 29% by 6 months and 36% by 12 months. The bed-sharing rates were 42% at 2 weeks, 34% at 3 months, and 27% at 12 months. Approximately two thirds of those who bed shared with their infant also shared the bed with their husband or partner, and 5% to 15% shared it with other children. The major reasons for bed sharing were to calm a fussy infant, facilitate breastfeeding, and help the infant and/ or mother sleep better. The major reasons for not lying down with the infant were safety concerns. Non-Hispanic black mothers were more likely than non-Hispanic white mothers to use nonsupine infant sleep positions and to bed share. CONCLUSIONS. More than one third of the women in this cohort were noncompliant with safe-sleeping guidelines when their infant was 3 months old. Health care providers need to advise parents of current recommendations and discuss the risks and benefits of their choices for infant sleeping practices. C1 [Hauck, Fern R.] Univ Virginia, Dept Family Med, Sch Med, Charlottesville, VA 22908 USA. [Hauck, Fern R.] Univ Virginia, Dept Publ Hlth Sci, Sch Med, Charlottesville, VA 22908 USA. [Signore, Caroline; Raju, Tonse N. K.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Pregnancy & Perinatol Branch, NIH, US Dept HHS, Bethesda, MD USA. [Fein, Sara B.] US FDA, Ctr Food Safety & Appl Nutr, US Dept HHS, College Pk, MD USA. RP Hauck, FR (reprint author), Univ Virginia, Dept Family Med, Sch Med, POB 800729, Charlottesville, VA 22908 USA. EM frh8e@virginia.edu FU Food and Drug Administration; Centers for Disease Control and Prevention; Office of Women's Health; National Institutes of Health; Maternal and Child Health Bureau in the US Department of Health and Human Services FX This study was funded by the Food and Drug Administration, Centers for Disease Control and Prevention, Office of Women's Health, National Institutes of Health, and Maternal and Child Health Bureau in the US Department of Health and Human Services. NR 25 TC 39 Z9 40 U1 3 U2 8 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD OCT PY 2008 VL 122 SU S BP S113 EP S120 DI 10.1542/peds.2008-1315o PG 8 WC Pediatrics SC Pediatrics GA 357CB UT WOS:000259822800014 PM 18829826 ER PT J AU Limdi, NA Beasley, TM Crowley, MR Goldstein, JA Rieder, MJ Flockhart, DA Arnett, DK Acton, RT Liu, NJ AF Limdi, Nita A. Beasley, T. Mark Crowley, Michael R. Goldstein, Joyce A. Rieder, Mark J. Flockhart, David A. Arnett, Donna K. Acton, Ronald T. Liu, Nianjun TI VKORC1 polymorphisms, haplotypes and haplotype groups on warfarin dose among African-Americans and European-Americans SO PHARMACOGENOMICS LA English DT Article DE African-Americans; cohort study; CYP2C9; European-Americans; pharmacogenetics; VKORC1 haplotypes; warfarin ID K EPOXIDE REDUCTASE; CYTOCHROME P4502C9; INTERINDIVIDUAL VARIABILITY; CYP2C9 GENOTYPES; ANTICOAGULATION STATUS; COMPLEX SUBUNIT-1; DOSING REGIMEN; MAINTENANCE; REQUIREMENT; POPULATION AB Background: Although the influence of VKORC1 and CYP2C9 polymorphisms on warfarin response has been studied, variability in dose explained by CYP2C9 and VKORC1 is lower among African-Americans compared with European-Americans. This has lead investigators to hypothesize that assessment of VKORC1 haplotypes may help capture a greater proportion of the variability in dose for this under-represented group. However, the inadequate representation of African-Americans and the assessment of a few VKORC1 polymorphisms have hindered this effort. Methods: To determine if VKORC1 haplotypes or haplotype groups explain a higher variability in warfarin dose, we comprehensively assessed VKORC1 polymorphisms in 273 African-Americans and 302 European-Americans. The influence of VKORC1 polymorphisms, race-specific haplotypes and haplotype groups on warfarin dose was evaluated in race-stratified multivariable analyses after accounting for CYP2C9 (*2, *3, *5, *6 and *11) and clinical covariates. Results: VKORC1 explained 18% (30% with CYP2C9) variability in warfarin dose among European-Americans and 5% (8% with CYP2C9) among African-Americans. Four common haplotypes in European-Americans and twelve in African-Americans were identified. In each race VKORC1 haplotypes emerged into two groups: low-dose (Group A) and high-dose (Group 13). African-Americans had a lower frequency of Group A haplotype (10.6%) compared with European-Americans (35%, p < 0.0001). The variability in dose explained by VKORC1 haplotype or haplotype groups was similar to that of a single informative polymorphism. Conclusions: Our findings support the use of CYP2C9, VKORC1 polymorphisms (rs9934438 or rs9923231) and clinical covariates to predict warfarin dose in both African- and European-Americans. A uniform set of common polymorphisms in CYP2C9 and VKORC1, and limited clinical covariates can be used to improve warfarin dose prediction for a racially diverse population. C1 [Limdi, Nita A.] Univ Alabama, Dept Neurol, Birmingham, AL 35294 USA. [Beasley, T. Mark; Liu, Nianjun] Univ Alabama, Dept Biostat, Sect Stat Genet, Birmingham, AL 35294 USA. [Crowley, Michael R.] Univ Alabama, Dept Genet, Birmingham, AL 35294 USA. [Goldstein, Joyce A.] NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC USA. [Rieder, Mark J.] Univ Washington, Dept Genome Sci, Washington, DC USA. [Flockhart, David A.] Indiana Univ, Sch Med, Div Clin Pharmacol, Bloomington, IN 47405 USA. [Arnett, Donna K.] Univ Alabama, Dept Epidemiol, Birmingham, AL USA. [Acton, Ronald T.] Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. RP Limdi, NA (reprint author), Univ Alabama, Dept Neurol, 1719 6th Ave S,CIRC 312, Birmingham, AL 35294 USA. EM nlimdi@uab.edu RI Goldstein, Joyce/A-6681-2012 FU National Institute of Neurological Disorders and Stroke [K23NS45598-01]; Intramural Research Program of the NIH; National Institute of Environmental Health Sciences FX Supported in part by a grant from the National Institute of Neurological Disorders and Stroke (Grant Number: K23NS45598-01) and in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. NR 49 TC 63 Z9 64 U1 0 U2 1 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD OCT PY 2008 VL 9 IS 10 BP 1445 EP 1458 DI 10.2217/14622416.9.10.1445 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 374BC UT WOS:000261016200015 PM 18855533 ER PT J AU Vanover, KE Betz, AJ Weber, SM Bibbiani, F Kielaite, A Weiner, DM Davis, RE Chase, TN Salamone, JD AF Vanover, Kimberly E. Betz, Adrienne J. Weber, Suzanne M. Bibbiani, Francesco Kielaite, Aiste Weiner, David M. Davis, Robert E. Chase, Thomas N. Salamone, John D. TI A 5-HT(2A) receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE serotonin; 5-HT(2A); Parkinson's disease; rodent; primate; animal model; dyskinesia; tremor ID TREMULOUS JAW MOVEMENTS; DOPA-INDUCED DYSKINESIAS; PARKINSONS-DISEASE; SUBCELLULAR-DISTRIBUTION; ATYPICAL ANTIPSYCHOTICS; ANTIPARKINSONIAN DRUGS; MOTOR COMPLICATIONS; CLOZAPINE; NEURONS; 5-HYDROXYTRYPTAMINE(2A) AB A potent 5-hydroxytryptamine (5-HT)(2A) receptor inverse agonist and antagonist, ACP-103 [N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1. active:salt)], was evaluated for its ability to reduce the primary motor symptom of tremor using tacrine-induced tremulous jaw movements in rats, which is an animal model of parkinsonian tremor. Furthermore, ACP-103 was evaluated for its ability to reduce levodopa-induced dyskinesias in monkeys rendered parkinsonian with MPTP [1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine]. ACP-103 reduced tacrine-induced tremulous jaw movements in rats. In addition, ACP-103 administered in combination with levodopa caused a dose-related reduction in dyskinesias in monkeys. These data suggest that ACP-103 may have the potential to reduce tremor and levodopa-induced dyskinesias in Parkinson's disease. (c) 2008 Elsevier Inc. All rights reserved. C1 [Betz, Adrienne J.; Weber, Suzanne M.; Salamone, John D.] Univ Connecticut, Dept Psychol, Storrs, CT 06269 USA. [Vanover, Kimberly E.; Weiner, David M.; Davis, Robert E.] ACADIA Pharmaceut Inc, San Diego, CA USA. [Bibbiani, Francesco; Kielaite, Aiste; Chase, Thomas N.] NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Salamone, JD (reprint author), Univ Connecticut, Dept Psychol, Storrs, CT 06269 USA. EM john.salamone@uconn.edu RI Salamone, John/H-8165-2015 OI Salamone, John/0000-0001-6435-9635 FU United States NIH/NINDS FX This research was partially supported by a grant to JDS from the United States NIH/NINDS. NR 57 TC 35 Z9 36 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD OCT PY 2008 VL 90 IS 4 BP 540 EP 544 DI 10.1016/j.pbb.2008.04.010 PG 5 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 339ZM UT WOS:000258615800006 PM 18534670 ER PT J AU Jinsmaa, Y Marczak, ED Balboni, G Salvadori, S Lazarus, LH AF Jinsmaa, Yunden Marczak, Ewa D. Balboni, Gianfranco Salvadori, Severo Lazarus, Lawrence H. TI Inhibition of the development of morphine tolerance by a potent dual mu-/delta-opioid antagonist, H-Dmt-Tic-Lys-NH-CH(2)-Ph SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE H-Dmt-Tic-Lys-NH-CH(2)-Ph; antinociception; tolerance; spinal; dual mu-/delta-opioid antagonist ID RECEPTOR KNOCKOUT MICE; C-TERMINUS; PHYSICAL-DEPENDENCE; MEDIATED ANALGESIA; OPIATE RECEPTOR; DELTA-AGONISTS; SPINAL-CORD; HETERODIMERIZATION; ANTINOCICEPTION; PHARMACOPHORE AB Three analogues of the dual mu-/delta-antagonist, H-Dmt-Tic-R-NH-CH(2)-Ph (R = 1, Lys-Z; 2, Lys-Ac: 3, Lys) were examined in vivo: I and 2 exhibited weak bioactivity, while 3 injected intracerebroventricularly was a potent dual antagonist for morphine- and deltorphin C-induced antinociception comparable to naltrindole (delta-antagonist), but 93% as effective as naloxone (nonspecific opioid receptor antagonist) and 4% as active as CTOR mu p antagonist. Subcutaneous or oral administration of 3 antagonized morphine-induced antinociception indicating passage across epithelial and blood-brain barriers. Mice pretreated with 3 before morphine did not develop morphine tolerance indicative of a potential clinical role to inhibit development of drug tolerance. (c) Published by Elsevier Inc. C1 [Jinsmaa, Yunden; Marczak, Ewa D.; Lazarus, Lawrence H.] NIEHS, Med Chem Grp, Inst Pharmacol, Res Triangle Pk, NC 27709 USA. [Balboni, Gianfranco] Univ Cagliari, Dept Toxicol, I-09126 Cagliari, Italy. [Salvadori, Severo] Univ Ferrara, Dept Pharmaceut Sci, I-44100 Ferrara, Italy. [Salvadori, Severo] Univ Ferrara, Ctr Biotechnol, I-44100 Ferrara, Italy. RP Marczak, ED (reprint author), NIEHS, Med Chem Grp, Inst Pharmacol, MD C304,POB 12233,111 S TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM marczake@niehs.nih.gov FU Intramural Research Program of the NIH; NIEHS; University of Cagliari [PRIN 200]; University of Ferrara [PRIN 2004] FX This work was supported in part by the Intramural Research Program of the NIH and NIEHS, and in part by the University of Cagliari (PRIN 2004) and University of Ferrara (PRIN 2004). The authors appreciate the expertise and assistance of the library staff and the Comparative Medicine Branch at NIEHS. NR 38 TC 6 Z9 6 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD OCT PY 2008 VL 90 IS 4 BP 651 EP 657 DI 10.1016/j.pbb.2008.05.008 PG 7 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 339ZM UT WOS:000258615800021 PM 18571706 ER PT J AU Kaikunte, S Lai, Z Tewari, N Chichester, C Romero, R Padbury, J Sharma, S AF Kaikunte, S. Lai, Z. Tewari, N. Chichester, C. Romero, R. Padbury, J. Sharma, S. TI In Vitro and In Vivo Evidence for Lack of Endovascular Remodeling by Third Trimester Trophoblasts SO PLACENTA LA English DT Article DE Trophoblast invasion; Endothelial cells; Angiogenesis; Three-dimensional co-culture system; Capillary tube formation; VEGF C and VEGF R2; E-cadherin ID GROWTH-FACTOR RECEPTOR-2; SPIRAL ARTERIES; 1ST TRIMESTER; PREECLAMPSIA; EXPRESSION; CELLS; PREGNANCY; INVASION; VEGF; CYTOTROPHOBLASTS AB The placental-decidual interaction through invading trophoblasts determines whether a physiological transformation of the uterine spiral arteries is established or not. Trophoblast-orchestrated artery remodeling is central to normal placentation. Dysregulated uteroplacental interaction and vascular remodeling are thought to be associated with the molecular events underlying the pathology of late pregnancy anomalies including preeclampsia. Although the exact gestational age at which trophoblast invasion ceases is not known, it remains unclear whether late pregnancy trophoblasts retain the ability to transform the uterine arteries. Here, we have developed a dual cell, in vitro culture system that mimics the vascular remodeling events during normal pregnancy. We demonstrate that first and third trimester trophoblasts respond differentially to interactive signals from endothelial cells when cultured on matrigel. Term primary trophoblasts of immortalized third trimester extravillous TCL1 trophoblasts not only fail to respond to signals from endothelial cells but also inhibit endothelial cell tube formation. In contrast, HTR8 cells, representing a first trimester trophoblast cell line with invasive properties, undergo spontaneous migration and synchronize with the endothelial cells in a capillary network. This disparity in behavior was confirmed in vivo using a matrigel plug assay. Poor expression of VEGF C and VEGF receptors coupled with high E-cadherin expression by term primary trophoblasts and TCL1 cells contributed to their restricted interactive and migratory properties. We further show that the kinase activity of VEGF R2 is essential for proactive crosstalk by HTR8 cells. This unique behavior of first trimester trophoblasts in the presence of endothelial cells offers a potential approach to study cell-cell interactions and to decipher modulatory components in the serum samples from adverse pregnancy outcomes. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Kaikunte, S.; Lai, Z.; Tewari, N.; Padbury, J.; Sharma, S.] Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02905 USA. [Chichester, C.] Univ Rhode Isl, Sch Pharm, Dept Biomed & Pharmaceut Sci, Kingston, RI 02881 USA. [Romero, R.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Perinatol Res Branch, NIH, DHHS, Bethesda, MD USA. RP Sharma, S (reprint author), Brown Univ, Women & Infants Hosp, Dept Pediat, 101 Dudley St, Providence, RI 02905 USA. EM ssharma@wihri.org FU NIH [P20RR018728]; NICHD [WSU05056, N01-HD-2-3342]; NIEHS [P42ES013660] FX This work was supported in part by an NIH grant P20RR018728, a Subcontract WSU05056 under NICHD Contract #N01-HD-2-3342 (Intramural Research Program of NICHD, NIH), and Superfund Basic Research Program Award (P42ES013660) from the NIEHS. NR 35 TC 5 Z9 8 U1 0 U2 1 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD OCT PY 2008 VL 29 IS 10 BP 871 EP 878 DI 10.1016/j.placenta.2008.07.009 PG 8 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 358AZ UT WOS:000259890000006 PM 18775564 ER PT J AU Zhang, MY Zimmermann, S Fischer, R Schillberg, S AF Zhang, M. -Y. Zimmermann, S. Fischer, R. Schillberg, S. TI Generation and evaluation of movement protein-specific single-chain antibodies for delaying symptoms of Tomato spotted wilt virus infection in tobacco SO PLANT PATHOLOGY LA English DT Article DE disease resistance; phage display; recombinant antibodies; tospovirus; transgenic plants ID MOSAIC-VIRUS; TRANSGENIC PLANTS; NICOTIANA-TABACUM; ESCHERICHIA-COLI; COAT-PROTEIN; MEDIATED RESISTANCE; FV-ANTIBODY; IN-VITRO; EXPRESSION; FRAGMENTS AB This study investigated whether single-chain antibodies (scFvs) specific for a viral movement protein could accumulate in the plant cell cytosol and restrict viral systemic infection in plants. Nine chicken scFv fragments against the Tomato spotted wilt virus (TSWV) movement protein (NS(M)) were isolated by phage display. Soluble scFvs were produced in bacteria and the NS(M) binding activity of purified scFvs was confirmed. The nine scFv genes were cloned into a plant expression vector enabling recombinant protein accumulation in the plant cell cytosol. Immunoblot analysis demonstrated that two of the nine chicken scFvs accumulated to high levels (5.9 and 8.0% of total soluble protein). Bioassays of viral infection using transgenic tobacco plants producing NS(M)-specific chicken scFvs showed delayed symptom development when compared to non-transgenic control plants, indicating that expression of antibodies recognizing the TSWV movement protein is a potential strategy for generating resistant plants. C1 [Zhang, M. -Y.; Zimmermann, S.; Fischer, R.] Rhein Westfal TH Aachen, Inst Mol Biotechnol Biol 7, D-52074 Aachen, Germany. [Fischer, R.; Schillberg, S.] IME, Fraunhofer Inst Mol Biol & Angew Oekol, D-52074 Aachen, Germany. RP Zhang, MY (reprint author), NCI, CCR, CCRNP, NIH, Bldg 469,Room 131,POB B,Miller Dr, Frederick, MD 21702 USA. EM stefan.schillberg@ime.fraunhofer.de RI Schillberg, Stefan/I-5449-2013 OI Schillberg, Stefan/0000-0002-1896-4575 FU European Commission [FAIR1-CT95-0905] FX This work was supported in part by the European Commission (FAIR1-CT95-0905). We would like to thank Dr Neil Emans for critical reading of the manuscript, Dr Flora Schuster, Dr Dagmar Weier and Dr Jurgen Drossard for technical assistance and Professor Rob Goldbach, Dr Marcel Prins and Dr Richard Kormelink for helpful discussions throughout the project. NR 34 TC 10 Z9 10 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0032-0862 J9 PLANT PATHOL JI Plant Pathol. PD OCT PY 2008 VL 57 IS 5 BP 854 EP 860 DI 10.1111/j.1365-3059.2008.01863.x PG 7 WC Agronomy; Plant Sciences SC Agriculture; Plant Sciences GA 350LM UT WOS:000259354000007 ER PT J AU Hazkani-Covo, E Covo, S AF Hazkani-Covo, Einat Covo, Shay TI Numt-Mediated Double-Strand Break Repair Mitigates Deletions during Primate Genome Evolution SO PLOS GENETICS LA English DT Article ID DNA-POLYMERASE-MU; HUMAN MITOCHONDRIAL PSEUDOGENES; HUMAN SEGMENTAL DUPLICATIONS; VIRUS VECTOR INTEGRATION; MAMMALIAN-CELLS; IONIZING-RADIATION; HOMOLOGOUS RECOMBINATION; V(D)J RECOMBINATION; BROKEN CHROMOSOMES; CHIMPANZEE GENOME AB Non-homologous end joining (NHEJ) is the major mechanism of double-strand break repair (DSBR) in mammalian cells. NHEJ has traditionally been inferred from experimental systems involving induced double strand breaks (DSBs). Whether or not the spectrum of repair events observed in experimental NHEJ reflects the repair of natural breaks by NHEJ during chromosomal evolution is an unresolved issue. In primate phylogeny, nuclear DNA sequences of mitochondrial origin, numts, are inserted into naturally occurring chromosomal breaks via NHEJ. Thus, numt integration sites harbor evidence for the mechanisms that act on the genome over evolutionary timescales. We have identified 35 and 55 lineage-specific numts in the human and chimpanzee genomes, respectively, using the rhesus monkey genome as an outgroup. One hundred and fifty two numt-chromosome fusion points were classified based on their repair patterns. Repair involving microhomology and repair leading to nucleotide additions were detected. These repair patterns are within the experimentally determined spectrum of classical NHEJ, suggesting that information from experimental systems is representative of broader genetic loci and end configurations. However, in incompatible DSBR events, small deletions always occur, whereas in 54% of numt integration events examined, no deletions were detected. Numts show a statistically significant reduction in deletion frequency, even in comparison to DSBR involving filler DNA. Therefore, numts show a unique mechanism of integration via NHEJ. Since the deletion frequency during numt insertion is low, native overhangs of chromosome breaks are preserved, allowing us to determine that 24% of the analyzed breaks are cohesive with overhangs of up to 11 bases. These data represent, to the best of our knowledge, the most comprehensive description of the structure of naturally occurring DSBs. We suggest a model in which the sealing of DSBs by numts, and probably by other filler DNA, prevents nuclear processing of DSBs that could result in deleterious repair. C1 [Hazkani-Covo, Einat] Natl Evolutionary Synth Ctr, Durham, NC USA. [Covo, Shay] Natl Inst Environm Hlth Sci, Mol Genet Lab, Chromosome Stabil Sect, NIH, Res Triangle Pk, NC USA. RP Hazkani-Covo, E (reprint author), Natl Evolutionary Synth Ctr, Durham, NC USA. EM einat@duke.edu FU National Evolutionary Synthesis Center (NESCent); NSF [EF-0423641]; National Institute of Environmental Health Sciences (NIH) FX Research support was from National Evolutionary Synthesis Center (NESCent), NSF #EF-0423641 (to EH-C) and National Institute of Environmental Health Sciences (NIH) intramural research funds (to SC). NR 77 TC 42 Z9 43 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2008 VL 4 IS 10 AR e1000237 DI 10.1371/journal.pgen.1000237 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 380QS UT WOS:000261480900032 PM 18949041 ER PT J AU Landry, J Sharov, AA Piao, YL Sharova, LV Xiao, H Southon, E Matta, J Tessarollo, L Zhang, YE Ko, MSH Kuehn, MR Yamaguchi, TP Wu, C AF Landry, Joseph Sharov, Alexei A. Piao, Yulan Sharova, Lioudmila V. Xiao, Hua Southon, Eileen Matta, Jennifer Tessarollo, Lino Zhang, Ying E. Ko, Minoru S. H. Kuehn, Michael R. Yamaguchi, Terry P. Wu, Carl TI Essential Role of Chromatin Remodeling Protein Bptf in Early Mouse Embryos and Embryonic Stem Cells SO PLOS GENETICS LA English DT Article ID ANTERIOR-POSTERIOR POLARITY; PRIMITIVE STREAK FORMATION; GROWTH-FACTOR-BETA; VISCERAL ENDODERM; PREIMPLANTATION DEVELOPMENT; TRANSCRIPTION FACTOR; TARGETED DISRUPTION; GENE-EXPRESSION; AXIS FORMATION; GENOME-WIDE AB We have characterized the biological functions of the chromatin remodeling protein Bptf ( Bromodomain PHD-finger Transcription Factor), the largest subunit of NURF ( Nucleosome Remodeling Factor) in a mammal. Bptf mutants manifest growth defects at the post-implantation stage and are reabsorbed by E8.5. Histological analyses of lineage markers show that Bptf(-/-) embryos implant but fail to establish a functional distal visceral endoderm. Microarray analysis at early stages of differentiation has identified Bptf-dependent gene targets including homeobox transcriptions factors and genes essential for the development of ectoderm, mesoderm, and both definitive and visceral endoderm. Differentiation of Bptf(-/-) embryonic stem cell lines into embryoid bodies revealed its requirement for development of mesoderm, endoderm, and ectoderm tissue lineages, and uncovered many genes whose activation or repression are Bptf-dependent. We also provide functional and physical links between the Bptf-containing NURF complex and the Smad transcription factors. These results suggest that Bptf may co-regulate some gene targets of this pathway, which is essential for establishment of the visceral endoderm. We conclude that Bptf likely regulates genes and signaling pathways essential for the development of key tissues of the early mouse embryo. C1 [Landry, Joseph; Xiao, Hua; Wu, Carl] NCI, Lab Biochem & Mol Cell Biol, NIH, Bethesda, MD 20892 USA. [Sharov, Alexei A.; Piao, Yulan; Sharova, Lioudmila V.; Ko, Minoru S. H.] NIA, Dev Genom & Aging Sect, NIH, Baltimore, MD 21224 USA. [Southon, Eileen; Tessarollo, Lino] NCI, Mouse Canc Genet Program, NIH, Frederick, MD 21701 USA. [Matta, Jennifer] NCI, Lab Anim Sci Program, SAIC Frederick, Frederick, MD 21701 USA. [Zhang, Ying E.] NCI, Cellular & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Kuehn, Michael R.] NCI, Lab Protein Dynam & Signaling, NIH, Frederick, MD 21701 USA. [Yamaguchi, Terry P.] NCI, Canc & Dev Biol Lab, NIH, Frederick, MD 21701 USA. RP Landry, J (reprint author), NCI, Lab Biochem & Mol Cell Biol, NIH, Bethesda, MD 20892 USA. EM landrjos@mail.nih.gov; carlwu@helix.nih.gov RI Ko, Minoru/B-7969-2009; Kuehn, Michael/A-4573-2014; Zhang, Ying/G-3657-2015 OI Ko, Minoru/0000-0002-3530-3015; Kuehn, Michael/0000-0002-7703-9160; Zhang, Ying/0000-0003-2753-7601 FU American Cancer Society [PF-05-122-01-DDC]; National Institutes of Health [N01-CO-12400]; National Cancer Institute FX This work was supported by American Cancer Society postdoctoral fellowship PF-05-122-01-DDC to JL, and National Institutes of Health intramural research grants to LT, YEZ, MSHK, MRK, TPY, and CW. This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 71 TC 60 Z9 61 U1 1 U2 10 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2008 VL 4 IS 10 AR e1000241 DI 10.1371/journal.pgen.1000241 PG 18 WC Genetics & Heredity SC Genetics & Heredity GA 380QS UT WOS:000261480900036 PM 18974875 ER PT J AU Takahashi, Y Dulev, S Liu, XP Hiller, NJ Zhao, XL Strunnikov, A AF Takahashi, Yoshimitsu Dulev, Stanimir Liu, Xianpeng Hiller, Natalie Jasmin Zhao, Xiaolan Strunnikov, Alexander TI Cooperation of Sumoylated Chromosomal Proteins in rDNA Maintenance SO PLOS GENETICS LA English DT Article ID SACCHAROMYCES-CEREVISIAE; TOPOISOMERASE-II; CONJUGATING ENZYME; SUMO LIGASE; DNA-REPAIR; REPLICATION FORKS; RIBOSOMAL-RNA; IN-VIVO; S-PHASE; YEAST AB SUMO is a posttranslational modifier that can modulate protein activities, interactions, and localizations. As the GFP-Smt3p fusion protein has a preference for subnucleolar localization, especially when deconjugation is impaired, the nucleolar role of SUMO can be the key to its biological functions. Using conditional triple SUMO E3 mutants, we show that defects in sumoylation impair rDNA maintenance, i.e., the rDNA segregation is defective and the rDNA copy number decreases in these mutants. Upon characterization of sumoylated proteins involved in rDNA maintenance, we established that Top1p and Top2p, which are sumoylated by Siz1p/Siz2p, most likely collaborate with substrates of Mms21p to maintain rDNA integrity. Cohesin and condensin subunits, which both play important roles in rDNA stability and structures, are potential substrates of Mms21, as their sumoylation depends on Mms21p, but not Siz1p and Siz2p. In addition, binding of cohesin and condensin to rDNA is altered in the mms21-CH E3-deficient mutant. C1 [Takahashi, Yoshimitsu; Dulev, Stanimir; Strunnikov, Alexander] NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. [Dulev, Stanimir] Paisij Hilendarski Univ Plovdiv, BG-4000 Plovdiv, Bulgaria. [Liu, Xianpeng; Zhao, Xiaolan] Mem Sloan Kettering Canc Ctr, Dept Mol Biol, New York, NY USA. [Hiller, Natalie Jasmin] Rockefeller Univ, New York, NY 10021 USA. RP Takahashi, Y (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM strunnik@mail.nih.gov OI Zhao, Xiaolan/0000-0002-8302-6905; Strunnikov, Alexander/0000-0002-9058-2256 FU National Institute of Child Health and Human Development; NIH [GM080670]; Fulbright Enterprise FX This work was supported by the Intramural Research program of the National Institute of Child Health and Human Development, YT is a recipient of the NIH Research Training Award. SD is in the Graduate Partnerships Program of NIH. NH was supported by a Fulbright Enterprise Scholarship. XZ acknowledges the support of NIH grant GM080670. NR 63 TC 36 Z9 37 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD OCT PY 2008 VL 4 IS 10 AR e1000215 DI 10.1371/journal.pgen.1000215 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 380QS UT WOS:000261480900010 PM 18846224 ER PT J AU Young, NS Ioannidis, JPA Al-Ubaydi, O AF Young, Neal S. Ioannidis, John P. A. Al-Ubaydi, Omar TI Why Current Publication Practices May Distort Science SO PLOS MEDICINE LA English DT Editorial Material ID CLINICAL-RESEARCH; IMPACT FACTOR; WINNERS CURSE; PUBLISHED RESEARCH; RANDOMIZED-TRIALS; MEDICAL JOURNALS; BIAS; TRANSLATION; AUCTIONS; BEHAVIOR AB The current system of publication in biomedical research provides a distorted view of the reality of scientific data that are generated in the laboratory and clinic. This system can be studied by applying principles from the field of economics. The "winner's curse," a more general statement of publication bias, suggests that the small proportion of results chosen for publication are unrepresentative of scientists' repeated samplings of the real world. The self-correcting mechanism in science is retarded by the extreme imbalance between the abundance of supply (the output of basic science laboratories and clinical investigations) and the increasingly limited venues for publication (journals with sufficiently high impact). This system would be expected intrinsically to lead to the misallocation of resources. The scarcity of available outlets is artificial, based on the costs of printing in an electronic age and a belief that selectivity is equivalent to quality. Science is subject to great uncertainty: we cannot be confident now which efforts will ultimately yield worthwhile achievements. However, the current system abdicates to a small number of intermediates an authoritative prescience to anticipate a highly unpredictable future. In considering society's expectations and our own goals as scientists, we believe that there is a moral imperative to reconsider how scientific data are judged and disseminated. C1 [Young, Neal S.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Ioannidis, John P. A.] Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. [Ioannidis, John P. A.] Fdn Res & Technol Hellas, Ioannina, Greece. [Ioannidis, John P. A.] Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. [Al-Ubaydi, Omar] George Mason Univ, Dept Econ, Fairfax, VA 22030 USA. [Al-Ubaydi, Omar] George Mason Univ, Mercatus Ctr, Fairfax, VA 22030 USA. RP Young, NS (reprint author), NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM youngns@mail.nih.gov RI Ioannidis, John/G-9836-2011 NR 55 TC 173 Z9 180 U1 5 U2 52 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD OCT PY 2008 VL 5 IS 10 BP 1418 EP 1422 DI 10.1371/journal.pmed.0050201 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 365QY UT WOS:000260424100003 PM 18844432 ER PT J AU Viboud, C Miller, M AF Viboud, Cecile Miller, Mark TI Health Benefits of Universal Influenza Vaccination Strategy SO PLOS MEDICINE LA English DT Editorial Material ID MORTALITY; US; SENIORS C1 [Viboud, Cecile; Miller, Mark] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Viboud, C (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM viboudc@mail.nih.gov NR 12 TC 3 Z9 3 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD OCT PY 2008 VL 5 IS 10 BP 1423 EP 1425 DI 10.1371/journal.pmed.0050216 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 365QY UT WOS:000260424100004 PM 18959475 ER PT J AU Kuller, LH Tracy, R Belloso, W De Wit, S Drummond, F Lane, HC Ledergerber, B Lundgren, J Neuhaus, J Nixon, D Paton, NI Neaton, JD AF Kuller, Lewis H. Tracy, Russell Belloso, Waldo De Wit, Stephane Drummond, Fraser Lane, H. Clifford Ledergerber, Bruno Lundgren, Jens Neuhaus, Jacqueline Nixon, Daniel Paton, Nicholas I. Neaton, James D. CA INSIGHT SMART Study Grp TI Inflammatory and Coagulation Biomarkers and Mortality in Patients with HIV Infection SO PLOS MEDICINE LA English DT Article ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; LOGISTIC-REGRESSION ANALYSIS; ANTIRETROVIRAL THERAPY; CARDIOVASCULAR HEALTH; RISK-FACTORS; MYOCARDIAL-INFARCTION; ENDOTHELIAL FUNCTION; ACTIVATION MARKERS; IMMUNE ACTIVATION AB Background In the Strategies for Management of Anti-Retroviral Therapy trial, all-cause mortality was higher for participants randomized to intermittent, CD4-guided antiretroviral treatment (ART) (drug conservation [DC]) than continuous ART (viral suppression [VS]). We hypothesized that increased HIV-RNA levels following ART interruption induced activation of tissue factor pathways, thrombosis, and fibrinolysis. Methods and Findings Stored samples were used to measure six biomarkers: high sensitivity C-reactive protein (hsCRP), interleukin-6 (IL-6), amyloid A, amyloid P, D-dimer, and prothrombin fragment 1+2. Two studies were conducted: (1) a nested case-control study for studying biomarker associations with mortality, and (2) a study to compare DC and VS participants for biomarker changes. For (1), markers were determined at study entry and before death (latest level) for 85 deaths and for two controls (n = 170) matched on country, age, sex, and date of randomization. Odds ratios (ORs) were estimated with logistic regression. For each biomarker, each of the three upper quartiles was compared to the lowest quartile. For (2), the biomarkers were assessed for 249 DC and 250 VS participants at study entry and 1 mo following randomization. Higher levels of hsCRP, IL-6, and D-dimer at study entry were significantly associated with an increased risk of all-cause mortality. Unadjusted ORs (highest versus lowest quartile) were 2.0 (95% confidence interval [CI], 1.0-4.1; p = 0.05), 8.3 (95% CI, 3.3-20.8; p < 0.0001), and 12.4 (95% CI, 4.2-37.0; p < 0.0001), respectively. Associations were significant after adjustment, when the DC and VS groups were analyzed separately, and when latest levels were assessed. IL-6 and D-dimer increased at 1 mo by 30% and 16% in the DC group and by 0% and 5% in the VS group (p < 0.0001 for treatment difference for both biomarkers); increases in the DC group were related to HIV-RNA levels at 1 mo (p, 0.0001). In an expanded case-control analysis (four controls per case), the OR (DC/VS) for mortality was reduced from 1.8 (95% CI, 1.1-3.1; p = 0.02) to 1.5 (95% CI, 0.8-2.8) and 1.4 (95% CI, 0.8-2.5) after adjustment for latest levels of IL-6 and D-dimer, respectively. Conclusions IL-6 and D-dimer were strongly related to all-cause mortality. Interrupting ART may further increase the risk of death by raising IL-6 and D-dimer levels. Therapies that reduce the inflammatory response to HIV and decrease IL-6 and D-dimer levels may warrant investigation. Trial Registration: ClinicalTrials. gov (NCT00027352). C1 [Neuhaus, Jacqueline; Neaton, James D.] Univ Minnesota, Minneapolis, MN 55455 USA. [Kuller, Lewis H.] Univ Pittsburgh, Pittsburgh, PA USA. [Tracy, Russell] Univ Vermont, Burlington, VT USA. [Belloso, Waldo] Hosp Italiano Buenos Aires, Buenos Aires, DF, Argentina. [De Wit, Stephane] St Pierre Hosp, Brussels, Belgium. [Drummond, Fraser] Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. [Lane, H. Clifford] NIAID, NIH, Bethesda, MD 20892 USA. [Ledergerber, Bruno] Univ Zurich Hosp, CH-8091 Zurich, Switzerland. [Lundgren, Jens] Univ Copenhagen, Copenhagen, Denmark. [Nixon, Daniel] Virginia Commonwealth Univ, Richmond, VA USA. [Paton, Nicholas I.] MRC, Clin Trials Unit, London, England. RP Neaton, JD (reprint author), Univ Minnesota, Minneapolis, MN 55455 USA. EM jim@ccbr.umn.edu RI Infektiologie, USZ/A-6921-2011; Ledergerber, Bruno/B-5656-2009; OI Ledergerber, Bruno/0000-0002-6881-4401; Lundgren, Jens/0000-0001-8901-7850 FU NIAID; NIH [U01AI042170, U01AI46362] FX Support provided by: NIAID, NIH grants U01AI042170 and U01AI46362. Role of the Funding Source: The trial was funded by the National Institute of Allergy and Infectious Disease (NIAID) and NIAID approved the study design of SMART. One person (HCL) from NIAID contributed to the preparation of this paper. Other staff members from NIAID who are on the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT) Executive Committee participated in the review of the design of this study and the paper. The funding source had no role in data collection, data analysis, or the decision to publish the results. NR 42 TC 342 Z9 346 U1 0 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD OCT PY 2008 VL 5 IS 10 BP 1496 EP 1508 DI 10.1371/journal.pmed.0050203 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 365QY UT WOS:000260424100014 PM 18942885 ER PT J AU van Raalten, TR Ramsey, NF Duyn, J Jansma, JM AF van Raalten, Tamar R. Ramsey, Nick F. Duyn, Jeff Jansma, Johan M. TI Practice Induces Function-Specific Changes in Brain Activity SO PLOS ONE LA English DT Article ID VERBAL WORKING-MEMORY; DUAL-TASK INTERFERENCE; EVENT-RELATED FMRI; SHORT-TERM-MEMORY; PREFRONTAL CORTEX; INDIVIDUAL-DIFFERENCES; CORTICAL ACTIVITY; COGNITIVE TASK; MRI; PERFORMANCE AB Background: Practice can have a profound effect on performance and brain activity, especially if a task can be automated. Tasks that allow for automatization typically involve repeated encoding of information that is paired with a constant response. Much remains unknown about the effects of practice on encoding and response selection in an automated task. Methodology: To investigate function-specific effects of automatization we employed a variant of a Sternberg task with optimized separation of activity associated with encoding and response selection by means of m-sequences. This optimized randomized event-related design allows for model free measurement of BOLD signals over the course of practice. Brain activity was measured at six consecutive runs of practice and compared to brain activity in a novel task. Principal Findings: Prompt reductions were found in the entire cortical network involved in encoding after a single run of practice. Changes in the network associated with response selection were less robust and were present only after the third run of practice. Conclusions/Significance: This study shows that automatization causes heterogeneous decreases in brain activity across functional regions that do not strictly track performance improvement. This suggests that cognitive performance is supported by a dynamic allocation of multiple resources in a distributed network. Our findings may bear importance in understanding the role of automatization in complex cognitive performance, as increased encoding efficiency in early stages of practice possibly increases the capacity to otherwise interfering information. C1 [van Raalten, Tamar R.; Ramsey, Nick F.] Univ Med Ctr Utrecht, Dept Neurol & Neurosurg, Rudolf Magnus Inst Neurosci, Utrecht, Netherlands. [van Raalten, Tamar R.] Univ Med Ctr Utrecht, Dept Child & Adolescent Psychiat, Rudolf Magnus Inst Neurosci, Utrecht, Netherlands. [Duyn, Jeff] NIH, NINDS, Lab Mol Funct Imag, Bethesda, MD USA. [Jansma, Johan M.] NIH, NIMH, Sect Neuroimag Mood & Anxiety Disorders, Bethesda, MD USA. RP van Raalten, TR (reprint author), Univ Med Ctr Utrecht, Dept Neurol & Neurosurg, Rudolf Magnus Inst Neurosci, Utrecht, Netherlands. EM t.vanraalten@umcutrecht.nl RI Duyn, Jozef/F-2483-2010; OI Lauwereyns, Jan/0000-0003-0551-2550 FU Netherlands Organisation for Scientific Research; Utrecht University [016.036.401]; Organisation for Scientific Research [R-95-405]; Foundation de Drie Lichten in the Netherlands; NIH, NINDS FX This research was sponsored by Netherlands Organisation for Scientific Research and Utrecht University, Grant 016.036.401, Netherlands, Organisation for Scientific Research Travel Grant R-95-405 and by Foundation de Drie Lichten in the Netherlands. This research was supported (in part) by the Intramural Research Program of the NIH, NINDS. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 49 TC 9 Z9 9 U1 1 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 OCT 1 PY 2008 VL 3 IS 10 AR e3270 DI 10.1371/journal.pone.0003270 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 427RU UT WOS:000264797200001 PM 18827897 ER PT J AU Forsell, MNE Dey, B Morner, A Svehla, K O'dell, S Hogerkorp, CM Voss, G Thorstensson, R Shaw, GM Mascola, JR Hedestam, GBK Wyatt, RT AF Forsell, Mattias N. E. Dey, Barna Moerner, Andreas Svehla, Krisha O'dell, Sijy Hoegerkorp, Carl-Magnus Voss, Gerald Thorstensson, Rigmor Shaw, George M. Mascola, John R. Hedestam, Gunilla B. Karlsson Wyatt, Richard T. TI B Cell Recognition of the Conserved HIV-1 Co-Receptor Binding Site Is Altered by Endogenous Primate CD4 SO PLOS PATHOGENS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEIN COMPLEX; NEUTRALIZING ANTIBODIES; GP120 GLYCOPROTEINS; SOLUBLE CD4; VACCINE; IMMUNOGENICITY; RESPONSES; RECEPTOR; TRIMERS AB The surface HIV-1 exterior envelope glycoprotein, gp120, binds to CD4 on the target cell surface to induce the coreceptor binding site on gp120 as the initial step in the entry process. The binding site is comprised of a highly conserved region on the gp120 core, as well as elements of the third variable region (V3). Antibodies against the co-receptor binding site are abundantly elicited during natural infection of humans, but the mechanism of elicitation has remained undefined. In this study, we investigate the requirements for elicitation of co-receptor binding site antibodies by inoculating rabbits, monkeys and human-CD4 transgenic (huCD4) rabbits with envelope glycoprotein (Env) trimers possessing high affinity for primate CD4. A cross-species comparison of the antibody responses showed that similar HIV-1 neutralization breadth was elicited by Env trimers in monkeys relative to wild-type (WT) rabbits. In contrast, antibodies against the co-receptor site on gp120 were elicited only in monkeys and huCD4 rabbits, but not in the WT rabbits. This was supported by the detection of high-titer co-receptor antibodies in all sera from a set derived from human volunteers inoculated with recombinant gp120. These findings strongly suggest that complexes between Env and (high-affinity) primate CD4 formed in vivo are responsible for the elicitation of the co-receptor-site-directed antibodies. They also imply that the naive B cell receptor repertoire does not recognize the gp120 co-receptor site in the absence of CD4 and illustrate that conformational stabilization, imparted by primary receptor interaction, can alter the immunogenicity of a type 1 viral membrane protein. C1 [Forsell, Mattias N. E.; Dey, Barna; Svehla, Krisha; O'dell, Sijy; Hoegerkorp, Carl-Magnus; Mascola, John R.; Wyatt, Richard T.] NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. [Forsell, Mattias N. E.; Hedestam, Gunilla B. Karlsson] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. [Forsell, Mattias N. E.; Moerner, Andreas; Thorstensson, Rigmor; Hedestam, Gunilla B. Karlsson] Swedish Inst Infect Dis Control, Solna, Sweden. [Voss, Gerald] GlaxoSmithKline Biol, Rixensart, Belgium. [Shaw, George M.] Univ Alabama, Birmingham, AL USA. RP Forsell, MNE (reprint author), NIH, Vaccine Res Ctr, Bldg 10, Bethesda, MD 20892 USA. EM richardwyatt@nih.gov OI Morner, Andreas/0000-0002-3654-1728 FU Swedish International Development Agency (Sida)/Department of Research Cooperation (SAREC); National Institute of Allergy and Infectious Diseases; National Institutes of Allergies and Infectious Diseases intramural research program; International AIDS Vaccine Initiative; Bill and Melinda Gates Foundation FX This study was supported by a grant from Swedish International Development Agency (Sida)/Department of Research Cooperation (SAREC) (GBKH and RT) and by the National Institute of Allergy and Infectious Diseases, National Institutes of Allergies and Infectious Diseases intramural research program (RTW and JRM), the International AIDS Vaccine Initiative (GBKH and RTW) and the Bill and Melinda Gates Foundation (GMS, JRM, RTW). NR 41 TC 46 Z9 46 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7366 J9 PLOS PATHOG JI PLoS Pathog. PD OCT PY 2008 VL 4 IS 10 AR e1000171 DI 10.1371/journal.ppat.1000171 PG 12 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 380QU UT WOS:000261481100005 PM 18833294 ER PT J AU Paukner, A Suomi, SJ AF Paukner, Annika Suomi, Stephen J. TI Sex differences in play behavior in juvenile tufted capuchin monkeys (Cebus apella) SO PRIMATES LA English DT Article DE Capuchin monkey; Cebus apella; Social play; Nonsocial play; Motor training hypothesis ID RHESUS-MONKEYS; EVOLUTION; BIRTH AB According to the motor training hypothesis, play behavior in juvenile primates improves motor skills that are required in later adult life. Sex differences in juvenile play behavior can therefore be expected when adult animals assume distinct sexually dimorphic roles. Tufted capuchin monkeys show sexually dimorphic levels of physical antagonism in both inter- and intra-group encounters. Accordingly, it can be predicted that juvenile capuchins also show sex differences in social play behavior. To test this hypothesis, the play behavior of nine juvenile and two infant capuchins was examined. As predicted, juvenile males showed significantly higher levels of social play (wrestle, chase) than juvenile females, but no differences were found in nonsocial play (arboreal, object). Levels of infant play behavior were comparable to that of juveniles. These results lend support to the motor training hypothesis and highlight the need for more detailed investigations of individual differences in play behavior. C1 [Paukner, Annika; Suomi, Stephen J.] NICHHD, Comparat Ethol Lab, NIH, Anim Ctr, Poolesville, MD 20837 USA. RP Paukner, A (reprint author), NICHHD, Comparat Ethol Lab, NIH, Anim Ctr, POB 529, Poolesville, MD 20837 USA. EM pauknera@mail.nih.gov FU Division of Intramural Research, NICHD FX This study was supported by funds from the Division of Intramural Research, NICHD. This research complied with the Animal Welfare Institute of Child Health and Human Development Animal Care and Use Committee. NR 15 TC 10 Z9 13 U1 0 U2 16 PU SPRINGER TOKYO PI TOKYO PA 1-11-11 KUDAN-KITA, CHIYODA-KU, TOKYO, 102-0073, JAPAN SN 0032-8332 J9 PRIMATES JI Primates PD OCT PY 2008 VL 49 IS 4 BP 288 EP 291 DI 10.1007/s10329-008-0095-0 PG 4 WC Zoology SC Zoology GA 364EM UT WOS:000260319000008 PM 18668302 ER PT J AU Ullah, H Scappini, EL Moon, AF Williams, LV Armstrong, DL Pedersen, LC AF Ullah, Hemayet Scappini, Erica Louise Moon, Andrea Florence Williams, Latanya Veronica Armstrong, David Lee Pedersen, Lars Christian TI Structure of a signal transduction regulator, RACK1, from Arabidopsis thaliana SO PROTEIN SCIENCE LA English DT Article DE RACK1; protein signaling; scaffolding protein; WD40; propeller; protein-protein interaction; drought ID PROTEIN BETA-SUBUNIT; WD-REPEAT PROTEINS; CRYSTAL-STRUCTURE; KINASE-C; DEVELOPMENTAL PROCESSES; SCAFFOLD PROTEINS; NIH 3T3-CELLS; ABSCISIC-ACID; SRC ACTIVITY; RECEPTOR AB The receptor for activated C-kinase 1 (RACK1) is a highly conserved WD40 repeat scaffold protein found in a wide range of eukaryotic species from Chlamydymonas to plants and humans. In tissues of higher mammals, RACK1 is ubiquitously expressed and has been implicated in diverse signaling pathways involving neuropathology, cellular stress, protein translation, and developmental processes. RACK1 has established itself as a scaffold protein through physical interaction with a myriad of signaling proteins ranging from kinases, phosphatases, ion channels, membrane receptors, G proteins, IP3 receptor, and with widely conserved structural proteins associated with the ribosome. In the plant Arabidopsis thaliana, RACK1A is implicated in diverse developmental and environmental stress pathways. Despite the functional conservation of RACK1-mediated protein-protein interaction-regulated signaling modes, the structural basis of such interactions is largely unknown. Here we present the first crystal structure of a RACK1 protein, RACK1 isoform A from Arabidobsis thaliana, at 2.4 angstrom resolution, as a C-terminal fusion of the maltose binding protein. The structure implicates highly conserved surface residues that could play critical roles in protein-protein interactions and reveals the surface location of proposed post-transcriptionally modified residues. The availability of this structure provides a structural basis for dissecting RACK1-mediated cellular signaling mechanisms in both plants and animals. C1 [Moon, Andrea Florence; Pedersen, Lars Christian] Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC USA. [Ullah, Hemayet; Williams, Latanya Veronica] Howard Univ, Dept Biol, Washington, DC 20059 USA. [Scappini, Erica Louise; Armstrong, David Lee] Natl Inst Environm Hlth Sci, Neurobiol Lab, NIH, Res Triangle Pk, NC USA. RP Pedersen, LC (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, 111 TW Alexander Dr,MD F3-09, Res Triangle Pk, NC USA. EM pederse2@niehs.nih.gov FU NIH; National Institute of Environmental Health Sciences [1Z01ES080043-20]; National Science Foundation RIG FX We thank Drs. L. G. Pedersen and N. Martin for critical reading of the manuscript. This work is supported in part by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 number 1Z01ES080043-20) and by the National Science Foundation RIG grant (H. U.). NR 62 TC 55 Z9 59 U1 2 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD OCT PY 2008 VL 17 IS 10 BP 1771 EP 1780 DI 10.1110/ps.035121.108 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351CK UT WOS:000259401900014 PM 18715992 ER PT J AU Yaffe, E Fishelovitch, D Wolfson, HJ Halperin, D Nussinov, R AF Yaffe, Eitan Fishelovitch, Dan Wolfson, Haim J. Halperin, Dan Nussinov, Ruth TI MolAxis: Efficient and accurate identification of channels in macromolecules SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE molecular dynamics; cytochome P450 3A4 CYP3A4; large pore channels; adenosine triphosphate binding cassette; transmembrane; medial axis ID MOLECULAR-DYNAMICS SIMULATION; HUMAN CYTOCHROME-P450 3A4; X-RAY CRYSTALLOGRAPHY; BINDING-SITES; ACTIVE-SITE; CRYSTAL-STRUCTURE; MECHANISM; CAVITIES; PROTEINS; POCKETS AB Channels and cavities play important roles in macromolecular functions, serving as access/exit routes for substrates/products, cofactor and drug binding, catalytic sites, and ligand/protein. In addition, channels formed by transmembrane (TM) proteins serve as transporters and ion channels. MolAxis is a new sensitive and fast tool for the identification and classification of channels and cavities of various sizes and shapes in macromolecules. MolAxis constructs corridors, which are pathways that represent probable routes taken by small molecules passing through channels. The outer medial axis of the molecule is the collection of points that have more than one closest atom. It is composed of two-dimensional surface patches and can be seen as a skeleton of the complement of the molecule. We have implemented in MolAxis a novel algorithm that uses state-of-the-art computational geometry techniques to approximate and scan a useful subset of the outer medial axis, thereby reducing the dimension of the problem and consequently rendering the algorithm extremely efficient. MolAxis is designed to identify channels that connect buried cavities to the outside of macromolecules and to identify TM channels in proteins. We apply MolAxis to enzyme cavities and TM proteins. We further utilize MolAxis to monitor channel dimensions along Molecular Dynamics trajectories of a human Cytochrome P450. MolAxis constructs high quality corridors for snapshots at picosecond time-scale intervals substantiating the gating mechanism in the 2e substrate access channel. We compare our results with previous tools in terms Of accuracy, performance and underlying theoretical guarantees of finding the desired pathways. MolAxis is available on line as a web-server and as a standalone easy-to-use program (http://bioinfo3d.cs.tau.ac.il/MoLAxis/). C1 [Yaffe, Eitan; Wolfson, Haim J.; Halperin, Dan] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Fishelovitch, Dan; Nussinov, Ruth] Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI Frederick Bldg 469,Rm 151, Frederick, MD 21702 USA. EM danha@post.tau.ac.il; ruthn@ncifcrf.gov RI Wolfson, Haim/A-1837-2011; OI Yaffe, Eitan/0000-0002-2896-3349 FU IST Programme of the EU as Shared-cost RTD (FET Open) Project [IST-006413]; Israel Science Foundation [236/06]; National Cancer Institute, National Institutes of Health [N01-CO-12400]; Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research FX Grant sponsor IST Programme of the EU as Shared-cost RTD (FET Open) Project; Grant number: IST-006413; Grant sponsor: Israel Science Foundation; Grant number 236/06; Grant sponsor: National Cancer Institute, National Institutes of Health; Grant number: N01-CO-12400; Grant sponsors: Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 48 TC 66 Z9 66 U1 1 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-3585 J9 PROTEINS JI Proteins PD OCT PY 2008 VL 73 IS 1 BP 72 EP 86 DI 10.1002/prot.22052 PG 15 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 347BR UT WOS:000259114500009 PM 18393395 ER PT J AU Whiteley, G AF Whiteley, Gordon TI Bringing diagnostic technologies to the clinical laboratory: Rigor, regulation, and reality SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Review DE Biomarker development; FDA filing ID SERUM PROTEOMIC PATTERNS; OVARIAN-CANCER; PROSTATE-CANCER; BREAST-CANCER; BIOMARKER DISCOVERY; PLATFORM; REPRODUCIBILITY; RECOMMENDATIONS; VALIDATION; MARKERS AB With the numerous reports of new technologies and biomarkers reported in the literature, it may be surprising that there are not an equal number of new products available to the clinical diagnostic laboratory. Powerful potential tools such as protein microarrays and MS patterns have been extensively published yet commercialization and acceptance of these technologies has yet to happen. The reasons for this are a combination of industry risk avoidance, academic focus on discovery, and a lack of appreciation for the high standards and regulation that surrounds the clinical diagnostic laboratory. The development and validation of a new technology or biomarker ensures that a test is reproducible, controllable, and has a defined accuracy and clinical predictive result but this information is only obtained through somewhat mundane but necessary experimental work. The use of design of experiment principles helps to define material parameters to ensure performance. The organization and documentation of this work through a quality system is both mandated and practical. All of this must be done before a test can reach the market with the safety and effectiveness review of regulatory agencies. C1 NCI, Clin Prote Reference Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Whiteley, G (reprint author), NCI, Clin Prote Reference Lab, Adv Technol Program, SAIC Frederick Inc, POB B, Frederick, MD 21702 USA. EM whiteleyg@ncifcrf.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400]; 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 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 US Government. This Research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 36 TC 6 Z9 6 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD OCT PY 2008 VL 2 IS 10-11 BP 1378 EP 1385 DI 10.1002/prca.200780170 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 362PG UT WOS:000260209000002 PM 19325937 ER PT J AU Xu, X Veenstra, TD AF Xu, Xia Veenstra, Timothy D. TI Analysis of biofluids for biomarker research SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Review DE Biomarkers; 2-D DIGE; 2-D PAGE; Mass spectrometry; Quantitative proteomics ID HUMAN PLASMA PROTEOME; MASS-SPECTROMETRY; SYSTEMS BIOLOGY; SERUM; PROTEINS; DEPLETION; FRACTIONATION; DISCOVERY; STRATEGIES; COMPLEXES AB While many of the developments made in high-throughput proteomics were originally applied to procaryotic and simple eucaryotic organisms, the analysis of biofluids became increasingly important as the prospect of using proteomics to discover novel biomarkers became realized. Biofluids have represented a unique challenge to proteomics as they are often present only in small amounts and, particularly in the cases of serum and plasma, can have protein concentration ranges that differ by ten orders of magnitude. While the discovery of authentic, clinically useful biomarkers in the proteomics era has been lacking, there have been a number of significant developments in the ability to more comprehensively characterize biofluid proteomes. The rapid pace of these developments suggest that the eventual discovery of clinically validate biomarkers using proteomic technologies still has a bright future. C1 [Xu, Xia; Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Veenstra, TD (reprint author), NCI, Lab Prote & Analyt Technol, SAIC Frederick Inc, POB B, Frederick, MD 21701 USA. EM veenstra@ncifcrf.gov FU National Cancer Institute, National Institutes of Health [NO1-CO-12400] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract (NO1-CO-12400). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the United States Government. NR 34 TC 6 Z9 6 U1 1 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD OCT PY 2008 VL 2 IS 10-11 BP 1403 EP 1412 DI 10.1002/prca.200780173 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 362PG UT WOS:000260209000004 PM 21136789 ER PT J AU Hewitt, SM Takikita, M Abedi-Ardekani, B Kris, Y Bexfield, K Braunschweig, T Chung, JY AF Hewitt, Stephen M. Takikita, Mikiko Abedi-Ardekani, Behnoush Kris, Ylaya Bexfield, Kathryn Braunschweig, Till Chung, Joon-Yong TI Validation of proteomic-based discovery with tissue microarrays SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Review DE Antibody; Biomarker; Pathology; Tissue microarray ID PHASE PROTEIN MICROARRAYS; EXPRESSION; CANCER; IMMUNOHISTOCHEMISTRY; ACTIVATION; BIOMARKERS; CARCINOMA; SPECIMENS; COLON AB Proteomics is routinely utilized for biomarker discovery above and beyond its general use in basic science. Multiple platforms provide a robust pipeline of candidates that require verification and validation as biomarkers of disease. Within the field of oncology, tissue biomarkers are in high demand as tools of diagnosis, prognosis and prediction of response to therapy. By examining the proteome, rather than the transcriptome, there is the potential to directly interrogate the drug targets and define biomarkers at the most proximate level. Toward these ends, the tissue microarray has become a common platform for verification of results and validation of clinically relevant biomarkers. Immunohistochemistry remains the most common analytical method applied to TMA and provides a direct channel toward clinical application. The TMA stands at the crossroads of proteomics and pathology, combining formalin-fixed paraffin-embedded tissue as an analyte and IHC as a method of assay. C1 [Hewitt, Stephen M.; Takikita, Mikiko; Abedi-Ardekani, Behnoush; Kris, Ylaya; Bexfield, Kathryn; Braunschweig, Till; Chung, Joon-Yong] Natl Canc Inst, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD USA. RP Hewitt, SM (reprint author), Adv Technol Ctr, TARP Lab, MSC 4605, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov RI Abedi-Ardekani, Behnoush/O-7829-2016; OI Abedi-Ardekani, Behnoush/0000-0002-0980-0587; Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 31 TC 9 Z9 9 U1 0 U2 4 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD OCT PY 2008 VL 2 IS 10-11 BP 1460 EP 1466 DI 10.1002/prca.200800003 PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 362PG UT WOS:000260209000009 PM 21136794 ER PT J AU Chung, JY Lee, SJ Kris, Y Braunschweig, T Traicoff, JL Hewitt, SM AF Chung, Joon-Yong Lee, Seo-Jin Kris, Ylaya Braunschweig, Till Traicoff, June L. Hewitt, Stephen M. TI A well-based reverse-phase protein array applicable to extracts from formalin-fixed paraffin-embedded tissue SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Article DE Formalin fixed; Laser capture microdissection; Paraffin embedded tissue; Protein extraction; Reverse-phase protein array; Tissue lysate ID GENE-EXPRESSION; MASS-SPECTROMETRY; MICROARRAYS; SECTIONS AB Proteomic analysis of formalin-fixed paraffin-embedded (FFPE) tissue offers significant diagnostic utility but is complicated due to the high level of covalently crosslinked proteins arising from formalin fixation. To address these challenges, we developed a reliable protein extraction method for FFPE tissue, based on heat-induced antigen retrieval within a pressure cooker. The protein extraction yield from archival FFPE tissue section is approximately 90% of that recovered from frozen tissue. This method demonstrates preservation of immunoreactivity and recovery of full-length proteins by Western blotting. Additionally, we developed a well-based RP protein array platform utilizing an electrochemfluminescence detection system. Protein samples derived from FFPE tissue by means of laser capture dissection, with as few as 500 shots demonstrate measurable signal differences for different proteins. The lysates coated to the array plate, remain stable over 1 month at room temperature. Theses data suggest that this new protein-profiling platform coupled with the protein extraction method can be used for molecular profiling analysis in FFPE tissue, and contribute to the validation and development of biomarkers in clinical studies. C1 [Chung, Joon-Yong; Kris, Ylaya; Braunschweig, Till; Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Lee, Seo-Jin] NCI, Extracellular Matrix Pathol Sect, Vasc Biol Fac, NIH, Bethesda, MD 20892 USA. [Lee, Seo-Jin] NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. [Braunschweig, Till] Univ Aachen, Rhein Westfal TH Aachen, Inst Pathol, D-5100 Aachen, Germany. [Traicoff, June L.] Sci Applicat Int Corp, Mclean, VA 22102 USA. RP Hewitt, SM (reprint author), Adv Technol Ctr, TARP Lab, MSC 4605, Bethesda, MD 20892 USA. EM genejock@helix.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU NIH, National Cancer Institute, Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 25 TC 37 Z9 37 U1 0 U2 6 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD OCT PY 2008 VL 2 IS 10-11 BP 1539 EP 1547 DI 10.1002/prca.200800005 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 362PG UT WOS:000260209000016 PM 21136801 ER PT J AU Crowley, JJ Lipsky, RH Lucki, I Berrettini, WH AF Crowley, James J. Lipsky, Robert H. Lucki, Irwin Berrettini, Wade H. TI Variation in the genes encoding vesicular monoamine transporter 2 and beta-1 adrenergic receptor and antidepressant treatment outcome SO PSYCHIATRIC GENETICS LA English DT Article DE ADRB1; antidepressant; depression; pharmacogenetic; SLC18A2; Sequenced Treatment Alternatives to Relieve Depression ID STAR-ASTERISK-D; ASSOCIATION; CITALOPRAM AB The identification of genetic variants regulating antidepressant response would allow for more individualized, rational, and successful drug treatments. We previously identified a region of mouse chromosome 19 that strongly influences citalopram response in an antidepressant model, the tail suspension test By virtue of their location in this loci, expression in brain, and involvement in monoamine neurotransmission, we nominated SLC18A2 (encoding vesicular monoamine transporter 2, a.k.a. VMAT2) and ADRB1 (encoding beta-1 adrenergic receptor) as candidate genes for a human pharmacogenetic study. This study tested for an association between SLC18A2 and ADRB1 and treatment outcome in 873 major depressive disorder patients treated with the antidepressant citalopram in the Sequenced Treatment Alternatives to Relieve Depression study. Haplotype-tagging single nucleotide polymorphisms (four in SLC18A2 and two in ADRB1) were chosen to detect the common genetic variation. We failed to detect any significant association between treatment outcome and genotypes or allele frequencies at any of the markers studied. We did, however, detect ethnic differences in the allele frequencies of five out of six markers. These data do not rule out the possible involvement of SLC18A2 or ADRB1 in antidepressant treatment response as these genes may contribute a small effect size or interact epistatically with other genes. Psychiatr Genet 18:248-251 (C) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Berrettini, Wade H.] Univ Penn, Sch Med, Ctr Neurobiol & Behav, Dept Psychiat, Philadelphia, PA 19104 USA. [Lipsky, Robert H.] NIAAA, Mol Genet Sect, Neurogenet Lab, NIH,DHHS, Rockville, MD 20852 USA. RP Berrettini, WH (reprint author), Univ Penn, Sch Med, Ctr Neurobiol & Behav, Dept Psychiat, Translat Res Bldg,125 S 31st St, Philadelphia, PA 19104 USA. EM wadeb@mail.med.upenn.edu OI Crowley, James/0000-0001-9051-1557; Lipsky, Robert/0000-0001-7753-1473 FU IV Drug Abuse Treatment Research [5T32DA007241-15] FX This research was supported by the Fellowship in IV Drug Abuse Treatment Research (Charles P. O'Brien, PI, 5T32DA007241-15) to JJC. NR 8 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8829 J9 PSYCHIAT GENET JI Psychiatr. Genet. PD OCT PY 2008 VL 18 IS 5 BP 248 EP 251 DI 10.1097/YPG.0b013e3283052ff7 PG 4 WC Genetics & Heredity; Neurosciences SC Genetics & Heredity; Neurosciences & Neurology GA 380NZ UT WOS:000261473700005 PM 18797399 ER PT J AU Williams, RM Zincke, NL Turner, RO Davis, JL Davis, KM Schwartz, MD Johnson, L Kerner, JF Taylor, KL AF Williams, Randi M. Zincke, Nicole L. Turner, Ralph O. Davis, Jackson L. Davis, Kimberly M. Schwartz, Marc D. Johnson, Lenora Kerner, Jon F. Taylor, Kathryn L. TI Prostate cancer screening and shared decision-making preferences among African-American members of the Prince Hall Masons SO PSYCHO-ONCOLOGY LA English DT Article DE shared decision making; African American (AA) men; prostate cancer screening ID RANDOMIZED CONTROLLED-TRIAL; PHYSICIAN-PATIENT DISCUSSIONS; MEDICAL-CARE; ANTIGEN TEST; INFORMED-CONSENT; MEN KNOW; KNOWLEDGE; INVOLVEMENT; COMMUNITY; OUTCOMES AB Objectives: Shared decision making (SDM) is recommended as one method to assist men in informed decision about prostate cancer screening (PCS). SDM preferences for PCS have not been evaluated among African-American (AA) men. Given AA men's increased risk and the uncertainity surrounding screening, it is critical to determine how to assist AA men in making an informed decision. We assessed the extent to which a sample of AA men wished to engage in SDM regarding PCS and the demographic and psychological characteristics el associated with SDM preferences. Methods: Participants completed a telephone interview that covered demographic and medical information, SDM preferences, PCS knowledge, decisional conflict, and satisfaction with previous screening decisions. Subjects included 286 AA men aged 40-70, who were members of a Masonic organization. Results: Fifty-seven percent preferred SDM, 36% preferred to make their own decision, and 7% wanted their doctor to decide. A higher level of education and older age were associated with preferring SDM (p < 0.05), while men with greater PCS knowledge were more likely to prefer to make the decision independently (p < 0.05). Conclusions: Results suggest that physicians need to be prepared to discuss PCS with their patients. Further, more attention may be needed to engage younger, less educated, and less knowledgeable men as they may be less likely to discuss PCS. This understanding of AA men's preferences for PCS decisions helps to clarify the issues that health professionals need to consider when attempting to assist AA men in making a PCS decision. Copyright (c) 2008 John Wiley & Sons, Ltd. C1 [Williams, Randi M.; Davis, Kimberly M.; Schwartz, Marc D.; Taylor, Kathryn L.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20007 USA. [Zincke, Nicole L.] Westat Res Corp, Rockville, MD USA. [Turner, Ralph O.; Davis, Jackson L.] Most Worshipful Prince Hall Grand Lodge, Washington, DC USA. [Johnson, Lenora; Kerner, Jon F.] NCI, Bethesda, MD 20892 USA. RP Taylor, KL (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Oncol, 3300 Whitehaven St NW,Suite 4100, Washington, DC 20007 USA. EM taylorkl@georgetown.edu OI Kerner, Jon/0000-0002-8792-3830 FU Centers for Disease Control [TS290]; National Cancer Institute [K07 CA72645] FX Abstract presented at the American Society of Preventive Oncology, Annual Conference 2006. Funded by the Centers for Disease Control (#TS290) and the National Cancer Institute (K07 CA72645). All authors who contributed to this paper have disclosed all financial and personal relationships between themselves and no conflicts of interest exist. NR 54 TC 11 Z9 11 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD OCT PY 2008 VL 17 IS 10 BP 1006 EP 1013 DI 10.1002/pon.1318 PG 8 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 364QU UT WOS:000260351000006 PM 18203246 ER PT J AU Norcross, M Poonam, M Enoch, AJ Karlsson, RM Brigman, JL Cameron, HA Harvey-White, J Holmes, A AF Norcross, Maxine Poonam, Mathur Enoch, Abigail J. Karlsson, Rose-Marie Brigman, Jonathan L. Cameron, Heather A. Harvey-White, Judith Holmes, Andrew TI Effects of adolescent fluoxetine treatment on fear-, anxiety- or stress-related behaviors in C57BL/6J or BALB/cJ mice SO PSYCHOPHARMACOLOGY LA English DT Article DE fluoxetine; SSRI; antidepressant; mouse; anxiety; fear; depression; stress; development; serotonin ID NEONATAL CLOMIPRAMINE TREATMENT; SEROTONIN REUPTAKE INHIBITORS; EARLY-LIFE BLOCKADE; KNOCK-OUT MICE; ANIMAL-MODELS; MOUSE STRAINS; ADULT-RATS; DEPRESSION; TRANSPORTER; EXPOSURE AB Rationale 5-Hydroxytryptamine (5-HT, serotonin) plays a major role in brain ontogeny. Disruption of 5-HT during early postnatal development produces lasting changes in rodent 'emotion-related' behaviors. Adverse effects of treatment with serotonin reuptake inhibitor (SRI) antidepressants have been reported in human adolescents. However, the long-term effects of chronic SRI treatment during adolescence in rodents remain unclear. Objectives The objectives of the study are to assess the effects of fluoxetine treatment throughout the adolescent period in measures of fear-, anxiety- and stress-related endpoints in drug-free adults and to examine these effects in two genetic strains of mice differing in baseline stress- and anxiety-related behaviors and sensitivity to SRIs. Materials and methods C57BL/6J and BALB/cJ mice received one of two fluoxetine doses for 4 weeks during adolescence (3-7 weeks old). A separate group of C57BL/6J and BALB/cJ mice received fluoxetine for 4 weeks during adulthood (8-12 weeks old). After a 3-week washout period, mice were tested for anxiety-like behaviors (novel open field, elevated plus-maze), fear conditioning and extinction, and stress-related responses to forced swim, as well as serotonin brain levels. Results Adolescent fluoxetine treatment did not increase adult measures of anxiety-, fear- or stress-related behaviors, or brain serotonin levels. The same duration of treatment in adulthood also had no effects on these measures when tested after a 3-week washout period. Conclusions In clear contrast with emotion-related abnormalities caused by preadolescent fluoxetine treatment or genetic inactivation of fluoxetine's pharmacological target, the 5-HT transporter, fluoxetine treatment throughout mouse adolescence did not produce detectable, lasting abnormalities in either "high" or "low anxiety" inbred mouse strains. C1 [Norcross, Maxine; Poonam, Mathur; Enoch, Abigail J.; Brigman, Jonathan L.; Holmes, Andrew] NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. [Karlsson, Rose-Marie] NIH, Lab Translat & Clin Studies, Inst Alcohol Abuse & Alcoholism, Bethesda, MD 20892 USA. [Karlsson, Rose-Marie] Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. [Cameron, Heather A.] NIMH, Unit Neuroplast, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. [Harvey-White, Judith] NIAAA, Lab Physiol Studies, NIH, Rockville, MD 20852 USA. RP Holmes, A (reprint author), NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, 5625 Fishers Lane,Room 2N09, Rockville, MD 20852 USA. EM holmesan@mail.nih.gov RI Cameron, Heather/E-6221-2011; Brigman, Jonathan/O-4978-2016; OI Cameron, Heather/0000-0002-3245-5777; Enoch, Abigail/0000-0002-3183-0010 FU National Institute of Alcohol Abuse and Alcoholism [Z01-AA000411]; National Institute on Mental Health [Z01-MH002784] FX The research is supported by the Intramural Research Program of the National Institute of Alcohol Abuse and Alcoholism (Z01-AA000411) and National Institute on Mental Health (Z01-MH002784). The authors declare no financial conflicts of interest. NR 57 TC 53 Z9 55 U1 0 U2 13 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD OCT PY 2008 VL 200 IS 3 BP 413 EP 424 DI 10.1007/s00213-008-1215-7 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 349CX UT WOS:000259257500010 PM 18594797 ER PT J AU Thompson, RL Bandera, EV Burley, VJ Cade, JE Forman, D Freudenheim, JL Greenwood, D Jacobs, DR Kalliecharan, RV Kushi, LH McCullough, ML Miles, LM Moore, DF Moreton, JA Rastogi, T Wiseman, MJ AF Thompson, R. L. Bandera, E. V. Burley, V. J. Cade, J. E. Forman, D. Freudenheim, J. L. Greenwood, D. Jacobs, D. R. Kalliecharan, R. V. Kushi, L. H. McCullough, M. L. Miles, L. M. Moore, D. F. Moreton, J. A. Rastogi, T. Wiseman, M. J. TI Reproducibility of systematic literature reviews on food, nutrition, physical activity and endometrial cancer SO PUBLIC HEALTH NUTRITION LA English DT Article DE systematic literature review; endometrial carcinoma; diet; epidemiological studies; reproducibility ID METAANALYSIS; RISK AB Objective: Despite the increasing dependence on systematic reviews to summarise the literatuer and to issue public health recommendations, the formal assessment of the reliability of conclusions emerging from systematic reviews has received little attention. The main goal of the present study was to evaluate whether two independent centres, in two continents, draw similar conclusions regarding the association of food, nutrtition and physical activity and endometrial cancer, when provided with the same general instructions and with similar resources. Design: The assessment of reproducibility concentrated on four main areas: (1) paper search and selection; (2) assignment of study design; (3) inclusion of 'key' papers; and (4) individual studies selected for meta-analysis and the summary risk estimate obtained. Results: In total 310 relevant papers were identified, 166 (54%) were included by both centres. Of the remaining 144 papers, 72 (50%) were retrieved in the searches of one centre and not the other (54 in centre A, 18 in centre B) and 72 were retrieved in both searches but regarded as relevant by only one of the centres (52 in centre A, 20 in centre B). Of papers included by both centres, 80% were allocated the same study desing. Agreement for inclusion of cohort-type and case-control studies was about 63% compared with 50% or less for ecological and case series studies. The agreement for inclusion of 138 'key' papers was 87%. Summary risk estimates from meta-analyses were similar. Conclusions: Transparency of process and explicit detailed procedures are necessary parts of a systematic review and crucial for the reader to interpret its findings. C1 [Thompson, R. L.; Wiseman, M. J.] Univ Southampton, Inst Human Nutr, Southampton, Hants, England. [Bandera, E. V.; Moore, D. F.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. [Burley, V. J.; Cade, J. E.; Forman, D.; Greenwood, D.; Kalliecharan, R. V.; Moreton, J. A.] Univ Leeds, Ctr Biostat & Epidemiol, Leeds, W Yorkshire, England. [Freudenheim, J. L.] Univ Buffalo, Dept Social & Prevent Med, Sch Publ Hlth & Hlth Profess, Buffalo, NY 14222 USA. [Jacobs, D. R.] Univ Minnesota, Sch Publ Hlth, Div Epidemiol, Minneapolis, MN 55455 USA. [Kushi, L. H.] Kaiser Permanente, Div Res, Oakland, CA USA. [McCullough, M. L.] Amer Canc Soc, Atlanta, GA 30329 USA. [Miles, L. M.; Wiseman, M. J.] World Canc Res Fund Int, London, England. [Moore, D. F.] Univ Med & Dent New Jersey, Sch Publ Hlth, New Brunswick, NJ USA. [Rastogi, T.] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Thompson, RL (reprint author), British Nutr Fdn, High Holborn House,52-54 High Holborn, London WC1V 6RQ, England. EM r.thompson@nutrition.org.uk RI Greenwood, Darren/C-3220-2008; Bandera, Elisa/M-4169-2014; Cade, Janet/G-4250-2016; OI Greenwood, Darren/0000-0001-7035-3096; Bandera, Elisa/0000-0002-8789-2755; Cade, Janet/0000-0003-3421-0121; Kushi, Lawrence/0000-0001-9136-1175; Burley, Victoria/0000-0003-0282-2932 FU WCRF/AICR FX This work was funded by WCRF/AICR. We also wish to acknowledge the contribution of other team members and research staff of the SLR centres, and of members of the Secretariat and Methodology Task Force of the WCRF/AICR expert report. NR 18 TC 5 Z9 5 U1 1 U2 6 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 EI 1475-2727 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD OCT PY 2008 VL 11 IS 10 BP 1006 EP 1014 DI 10.1017/S1368980007001334 PG 9 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA 356TJ UT WOS:000259800200005 PM 18053295 ER PT J AU Cassatt, DR Kaminski, JM Hatchett, RJ DiCarlo, AL Benjamin, JM Maidment, BW AF Cassatt, David R. Kaminski, Joseph M. Hatchett, Richard J. DiCarlo, Andrea L. Benjamin, Jessica M. Maidment, Bert W. TI Medical countermeasures against nuclear threats: Radionuclide decorporation agents SO RADIATION RESEARCH LA English DT Article ID SELF-ASSEMBLED MONOLAYERS; CHELATING-AGENTS; MESOPOROUS SUPPORTS; HEAVY-METALS; INJECTED PU-238; D-PENICILLAMINE; DFO-HOPO; THERAPY; DTPA; RATS AB Exposure to radionuclides disseminated by a radiological dispersion device or deposited as fallout after a nuclear power plant accident or detonation of an improvised nuclear device could result in internal contamination of a significant number of individuals. Internalized radionuclides may cause both acute and chronic radiation injury and increase an individual's risk of developing cancer. This damage and risk can be mitigated by the use of decorporation agents that reduce internal contamination. Unfortunately, most effective agents decorporate only a limited range of radionuclides, and some are formulated in ways that would make administration in mass casualty situations challenging. There is a need for new radionuclide decorporation agents, reformulations of existing agents, and/or expansion of the labeled indications for existing treatments. Researchers developing novel or improved decorporation agents should also understand the regulatory pathway for these products. This workshop, the first in nearly half a century to focus exclusively on radionuclide decorporation, brought together researchers and scientific administrators from academia, government and industry as well as senior regulatory affairs officers and U.S. Food and Drug Administration personnel. Meeting participants reviewed recent progress in the development of decorporation agents and contemplated the future of the field. (C) 2008 by Radiation Research Society. C1 [Cassatt, David R.; Kaminski, Joseph M.; Hatchett, Richard J.; DiCarlo, Andrea L.; Benjamin, Jessica M.; Maidment, Bert W.] NIAID, DAIT, NIH, Bethesda, MD 20892 USA. RP Cassatt, DR (reprint author), NIAID, DAIT, NIH, 6610 Rockledge Dr,Room 4014, Bethesda, MD 20892 USA. EM cassattd@niaid.nih.gov FU NIH; NIAID FX The authors wish to thank conference participants for their contributions to the discussion, especially those researchers who made up the expert panel (see Table 1) and assisted with the preparation of this report. This conference was supported by NIH. The authors also wish to thank Dr. Narayani Ramakrishnan (NIAID) for her critical review of this manuscript. NR 47 TC 45 Z9 45 U1 0 U2 5 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD OCT PY 2008 VL 170 IS 4 BP 540 EP 548 DI 10.1667/RR1485.1 PG 9 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 355CJ UT WOS:000259686300015 PM 19024661 ER PT J AU Greathouse, KL Cook, JD Lin, K Davis, BJ Berry, TD Bredfeldt, TG Walker, CL AF Greathouse, K. L. Cook, J. D. Lin, K. Davis, B. J. Berry, T. D. Bredfeldt, T. G. Walker, C. L. TI Identification of Uterine Leiomyoma Genes Developmentally Reprogrammed by Neonatal Exposure to Diethylstilbestrol SO REPRODUCTIVE SCIENCES LA English DT Article DE Uterine leiomyoma; developmental reprogramming; diethylstilbestrol; gene expression ID TYPE-2 IODOTHYRONINE DEIODINASE; BONE MORPHOGENETIC PROTEIN-3; CALBINDIN-D-9K MESSENGER-RNA; RAT UTERUS; IN-UTERO; MATRIX METALLOPROTEINASES; EXPRESSION; ESTROGEN; CANCER; ADENOCARCINOMA AB Environmental exposures during development can alter susceptibility later in life to adult diseases including uterine leiomyoma, a phenomenon termed developmental reprogramming. The goal of this study was to identify genes developmentally reprogrammed by diethylstilbestrol (DES) and aberrantly expressed in leiomyomas. Transcriptional profiling identified 171 genes differentially expressed in leiomyomas relative to normal myometrium, Of which 6/18 genes with putative estrogen responsive elements and confirmed to be estrogen-responsive in neonatal uteri were reprogrammed by neonatal DES exposure. Calbindin D9k and Dio2, normally induced by estrogen, exhibited elevated expression in DES-exposed animals during both phases of the estrus cycle. Gdf10, CarS, Gria2, and Mmp3, genes normally repressed by estrogen, exhibited elevated expression in DES-exposed animals during the proliferative phase, when estrogen is highest. These data demonstrate that neonatal DES exposure causes reprogramming of estrogen-responsive genes expressed in uterine leiomyomas, leading to over-expression of these genes in the myometrium of exposed animals prior to the onset of tumorigenesis. C1 [Greathouse, K. L.; Lin, K.; Berry, T. D.; Bredfeldt, T. G.; Walker, C. L.] MD Anderson Canc Ctr, Sci Pk Res Div, Dept Carcinogenesis, Smithville, TX USA. [Cook, J. D.] Dana Farber Canc Inst, Boston, MA USA. [Davis, B. J.] Millennium Pharmaceut Inc, Cambridge, MA USA. [Davis, B. J.] NIEHS, Res Triangle Pk, NC USA. RP Walker, CL (reprint author), 1808 Pk Rd 1C,POB 389, Smithville, TX 78957 USA. EM cwalker@odin.mdacc.tmc.edu FU National Institutes of Health [HD046282]; NIEHS [ES008263, ES007784] FX This work was done at the MD Anderson Cancer Center, Science Park Research Division, Smithville, TX. This work was supported by National Institutes of Health Grants HD046282 and NIEHS Grants ES008263 and ES007784. NR 53 TC 30 Z9 30 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 EI 1933-7205 J9 REPROD SCI JI Reprod. Sci. PD OCT PY 2008 VL 15 IS 8 BP 765 EP 778 DI 10.1177/1933719108322440 PG 14 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 366TM UT WOS:000260506300004 PM 19017814 ER PT J AU Skelley, SL Goldberg, TE Egan, MF Weinberger, DR Gold, JM AF Skelley, Shayna L. Goldberg, Terry E. Egan, Michael F. Weinberger, Daniel R. Gold, James M. TI Verbal and visual memory: Characterizing the clinical and intermediate phenotype in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Memory; Learning; Cognition; Genetics; Verbal; Visual; Episodic; Family; Phenotype; Endophenotype; Wechsler Memory Scale; Recall; Savings; Retention ID COGNITIVE DEFICITS; 1ST-DEGREE RELATIVES; DECLARATIVE MEMORY; ADULT RELATIVES; METAANALYSIS; SIBLINGS; LONG; DYSFUNCTION; MECHANISMS; PARENTS AB Background: Verbal and visual memory deficits are prominent trait markers for schizophrenia, with impairments also observed in first-degree relatives [Snitz, B.E., Macdonald, A.W., 3rd, & Carter, C.S. (2006). Cognitive deficits in unaffected first-degree relatives of schizophrenia patients: a meta-analytic review of putative endophenotypes. Schizophr Bull, 32(1), 179-194]. It remains unclear whether deficits lie in encoding or savings, and whether the deficit is heritable. Objective: To determine which features of memory performance are impaired in both patients and their healthy siblings, possibly reflecting shared genetic effects. Method: We tested episodic memory using Logical Memory (LM) and Visual Reproduction (VR) tasks of the Wechsler Memory Scale (Revised). Participants included patients with schizophrenia (n = 162), their nonpsychotic siblings (n = 146), and controls n = 205), recruited for the "CBDB/NIMH Sibling Study". We assessed immediate encoding and 30 minute and 24 hour delayed recall as well as savings scores for the "short delay" (immediate to 30 min) and "long delay" (30 min to 24 h) intervals. Results: We observed marked verbal recall deficits in both patients and siblings compared to controls for all stages (P <.0001). Only patients experienced significant verbal and visual savings deficits over short delays (p <.0001) as well as verbal deficits over long delays (p <.005). In siblings, no saving score difficulty was apparent for either measure. Conclusions: Our results confirm shared impairment in verbal learning, but not memory, for both patients and siblings, therefore marking it as a potential schizophrenia-associated intermediate phenotype. The results implicate neural systems involved in immediate encoding and stabilization of memory representations in genetic risk for schizophrenia. In contrast, visual recall and savings impairments appear to be illness, i.e. state, deficits. (c) Published by Elsevier B.V. C1 [Skelley, Shayna L.; Goldberg, Terry E.; Egan, Michael F.; Weinberger, Daniel R.] NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. [Gold, James M.] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr 701P 388, Baltimore, MD 21201 USA. RP Weinberger, DR (reprint author), NIMH, Clin Brain Disorders Branch, NIH, 10 Ctr Dr,MSC 1379, Bethesda, MD 20892 USA. EM shayna.skelley@gmail.com; goldber@nshs.edu; michael_egan@merck.com; weinberd@mail.nih.gov; jgold@mprc.umaryland.edu OI Coburn, Shayna/0000-0001-9526-3580 FU PHS HHS [95-M-0160] NR 29 TC 42 Z9 46 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD OCT PY 2008 VL 105 IS 1-3 BP 78 EP 85 DI 10.1016/j.schres.2008.05.027 PG 8 WC Psychiatry SC Psychiatry GA 367ZU UT WOS:000260591900009 PM 18617370 ER PT J AU Daumit, GL Goff, DC Meyer, JM Davis, VG Nasrallah, HA McEvoy, JP Rosenheck, R Davis, SM Hsiao, JK Stroup, TS Lieberman, JA AF Daumit, Gail L. Goff, Donald C. Meyer, Jonathan M. Davis, Vicki G. Nasrallah, Henry A. McEvoy, Joseph P. Rosenheck, Robert Davis, Sonia M. Hsiao, John K. Stroup, T. Scott Lieberman, Jeffrey A. TI Antipsychotic effects on estimated 10-year coronary heart disease risk in the CATIE schizophrenia study SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Schizophrenia; Antipsychotic; Coronary heart disease risk; Blood pressure; Cholesterol ID METABOLIC SYNDROME; MENTAL-ILLNESS; CARDIOVASCULAR RISK; WEIGHT-GAIN; MORTALITY; SMOKING; GLUCOSE; LIPIDS; TRIAL; HALOPERIDOL AB Objective: Persons with schizophrenia die earlier than the general population, in large part due to cardiovascular disease. The study objective was to examine effects of different antipsychotic treatments on estimates of 10-year coronary heart disease (CHD) risk calculated by the Framingham Heart Study formula. Method: Change in 10-year risk for CHD was compared between treatment groups in 1125 patients followed for 18 months or until treatment discontinuation in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial. Results: The covariate-adjusted mean change in 10-year CHD risk differed significantly between treatments. Olanzapine was associated with a 0.5% (SE 0.3) increase and quetiapine, a 0.3% (SE 0.3) increase; whereas risk decreased in patients treated with perphenazine, -0.5% (SE 0.3), risperidone, -0.6% (SE 0.3), and ziprasidone -0.6% (SE 0.4). The difference in 10-year CHD risk between olanzapine and risperidone was statistically significant (p=0.004). Differences in estimated 10-year CHD risk between drugs were most marked in the tertile of subjects with a baseline CHD risk of at least 10%. Among individual CHD risk factors used in the Framingham formula, only total and HDL cholesterol levels differed between treatments. Conclusions: These results indicate that the impact on 10-year CHD risk differs significantly between antipsychotic agents, with olanzapine producing the largest elevation in CHD risk of the agents studied in CATIE. (c) 2008 Elsevier B.V. All rights reserved. C1 [Daumit, Gail L.] Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21287 USA. [Goff, Donald C.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat,Freedom Trail Clin,Lindemann Mental, Boston, MA 02114 USA. [Meyer, Jonathan M.] Univ Calif San Diego, Vet Adm Med Ctr, San Diego, CA 92161 USA. [Davis, Vicki G.] Univ N Carolina, Collaborat Studies Coordinating Ctr, Dept Biostat, Coordinating Ctr 400,Bank Amer Ctr, Chapel Hill, NC 27514 USA. [Nasrallah, Henry A.] Univ Cincinnati, Dept Psychiat, Cincinnati, OH 45267 USA. [McEvoy, Joseph P.] Duke Univ, Dept Psychiat, John Umstead Hosp, Butner, NC 27509 USA. [Rosenheck, Robert] Yale Univ, Dept Psychiat, West Haven, CT 06516 USA. [Davis, Sonia M.] Quintiles Inc, Morrisville, NC 27560 USA. [Hsiao, John K.] NIMH, Adult Treatment & Prevent Intervent Res Branch, Rockville, MD 20852 USA. [Stroup, T. Scott] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. [Lieberman, Jeffrey A.] Columbia Univ, Dept Psychiat, NYS Psychiat Inst, New York, NY 10032 USA. RP Daumit, GL (reprint author), Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, 2024 E Monument St,Suite 2-500, Baltimore, MD 21287 USA. EM gdaumit@jhmi.edu; goff@psych.mgh.harvard.edu; jmmeyer@ucsd.edu; Vicki.davis@mail.cscc.unc.edu; Henry.nasrallah@uc.edu; jpmcevoy@duke.edu; Robert.rosenheck@yale.edu; Sonia.davis@quintiles.com; jh23f@nih.gov; Scott_stroup@med.unc.edu; jlieberman@pi.cpmc.columbia.edu RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU National Institute of Mental Health [1MH900001] FX The CATIE Schizophrenia Trial was supported by National Institute of Mental Health, Grant No. 1MH900001. The NIMH and study principal investigators are responsible for the design and conduct of the trial, and the primary analyses. There is no industry involvement in these activities. NR 38 TC 116 Z9 118 U1 7 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD OCT PY 2008 VL 105 IS 1-3 BP 175 EP 187 DI 10.1016/j.schres.2008.07.006 PG 13 WC Psychiatry SC Psychiatry GA 367ZU UT WOS:000260591900019 PM 18775645 ER PT J AU Baker, SG Kramer, BS AF Baker, Stuart G. Kramer, Barnett S. TI Using microarrays to study the microenvironment in tumor biology: The crucial role of statistics SO SEMINARS IN CANCER BIOLOGY LA English DT Review DE bonferroni; class prediction; cluster analysis; differential expression; false discovery rate; sample size ID GENE-EXPRESSION; CANCER; CLASSIFICATION; PREDICTION; SIGNATURE; ISSUES AB Microarrays represent a potentially powerful tool for better understanding the role of the microenvironment on tumor biology. To make the best use of microarray data and avoid incorrect or unsubstantiated conclusions, care must be taken in the statistical analysis. To illustrate the statistical issues involved we discuss three microarray studies related to the microenvironment and tumor biology involving: (i) prostatic stroma cells in cancer and non-cancer tissues; (ii) breast stroma and epithelial cells in breast cancer patients and non-cancer patients: and (iii) serum associated with wound response and stroma in cancer patients. Using these examples we critically discuss three types of analyses: differential gene expression, cluster analysis, and class prediction. We also discuss design issues. Published by Elsevier Ltd. C1 [Baker, Stuart G.] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Kramer, Barnett S.] NIH, Off Dis Prevent, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Canc Prevent Div, EPN 3131,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. EM sb16i@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 24 TC 7 Z9 7 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-579X J9 SEMIN CANCER BIOL JI Semin. Cancer Biol. PD OCT PY 2008 VL 18 IS 5 BP 305 EP 310 DI 10.1016/j.semcancer.2008.03.001 PG 6 WC Oncology SC Oncology GA 353FJ UT WOS:000259551200002 PM 18455427 ER PT J AU Patel, KV AF Patel, Kushang V. TI Epidemiology of anemia in older adults SO SEMINARS IN HEMATOLOGY LA English DT Article ID IRON-DEFICIENCY ANEMIA; NUTRITION EXAMINATION SURVEY; CHRONIC KIDNEY-DISEASE; 3RD NATIONAL-HEALTH; NURSING-HOME; HEMOGLOBIN CONCENTRATION; UNEXPLAINED ANEMIA; GASTROINTESTINAL-TRACT; UNITED-STATES; PREVALENCE AB Anemia is a common, multifactorial condition among older adults. The World Health Organization (WHO) definition of anemia (hemoglobin concentration < 12 g/dL in women and < 13 g/dL in men) is most often used in epidemiologic studies of older adults. More than 10% of community-dwelling adults age 65 years and older has WHO-defined anemia. After age 50 years, prevalence of anemia increases with advancing age and exceeds 20% in those 85 years and older. In nursing homes, anemia is present in 48% to 63% of residents. Incidence of anemia in older adults is not well characterized. Among older adults with anemia, approximately one third have evidence of iron, folate, and/or vitamin B-12 deficiency, another third have renal insufficiency and/or chronic inflammation, and the remaining third have anemia that is unexplained. Several studies demonstrate that anemia is associated with poorer survival in older adults. This review details the distribution and consequences of anemia in older adults and identifies future epidemiologic research needs. C1 [Patel, Kushang V.] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. RP Patel, KV (reprint author), 7201 Wisconsin Ave,Gateway Bldg,Suite 3C309, Bethesda, MD 20892 USA. EM patelku@mail.nih.gov FU US National Institute on Aging, National Institutes of Health FX Supported by the Intramural Research Program of the US National Institute on Aging, National Institutes of Health. NR 50 TC 78 Z9 86 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 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2008 VL 45 IS 4 BP 210 EP 217 DI 10.1053/j.seminhematol.2008.06.006 PG 8 WC Hematology SC Hematology GA 353QT UT WOS:000259584000002 PM 18809090 ER PT J AU Ferrucci, L Balducci, L AF Ferrucci, Luigi Balducci, Lodovico TI Anemia of aging: The role of chronic inflammation and cancer SO SEMINARS IN HEMATOLOGY LA English DT Article ID PLACEBO-CONTROLLED TRIAL; CELL LUNG-CANCER; PHASE-III TRIAL; DOUBLE-BLIND; DARBEPOETIN-ALPHA; HEMOGLOBIN LEVELS; OLDER PERSONS; EPOETIN-ALPHA; NECK-CANCER; RECEIVING CHEMOTHERAPY AB Aging is associated with increased incidence and prevalence of anemia, leading to a number of adverse health outcomes. These include death, functional dependence, increased risk of therapeutic complications, falls, and dementia. In approximately 30% of cases, anemia in older individuals is due to either relative or absolute erythropoietin (EPO) deficiency. Absolute EPO deficiency may be primary or secondary to declining renal function. Relative EPO deficiency is due to an age-related pro-inflammatory status that reduces the sensitivity of erythropoietic precursors to EPO. Despite this condition of EPO deficiency, the management of anemia of aging with erythropoiesis-stimulating agents (ESAs) is controversial, unless the anemia is due to renal insufficiency. The main concern related to this treatment arises from eight studies of ESAs in cancer, suggesting that ESAs may reduce patient survival in addition to increasing the risk of deep vein thrombosis. The results of these studies contrast with a host of other trials showing the safety of ESAs. The discrepancy may be explained in part by the fact that, in the trials suggesting a detrimental effect of ESAs, the goal was to obtain hemoglobin (Hb) levels higher than 12 g/dL. Because of this concern, correction of anemia in elderly individuals with relative EPO insufficiency should not be attempted outside clinical trials. C1 [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21225 USA. [Balducci, Lodovico] H Lee Moffitt Canc Ctr & Res Inst, Dept Oncol, Tampa, FL USA. [Balducci, Lodovico] H Lee Moffitt Canc Ctr & Res Inst, Dept Med, Tampa, FL USA. RP Ferrucci, L (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, 3001 S Harbor St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov FU NIA NIH HHS [Z01 AG000015-50] NR 65 TC 17 Z9 18 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 EI 1532-8686 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2008 VL 45 IS 4 BP 242 EP 249 DI 10.1053/j.seminhematol.2008.06.001 PG 8 WC Hematology SC Hematology GA 353QT UT WOS:000259584000006 PM 18809094 ER PT J AU Makipour, S Kanapuru, B Ershler, WB AF Makipour, Sasan Kanapuru, Bindu Ershler, William B. TI Unexplained anemia in the elderly SO SEMINARS IN HEMATOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; NF-KAPPA B; NURSING-HOME; HEMOGLOBIN CONCENTRATION; OLDER PERSONS; MYELODYSPLASTIC SYNDROMES; SERUM ERYTHROPOIETIN; PHYSICAL PERFORMANCE; IRON-METABOLISM; MUSCLE STRENGTH AB Among the elderly, anemia occurs with increasing frequency with each advancing decade. Unlike when anemia occurs in younger adults, the cause of anemia in the elderly is oftentimes not readily apparent or attributable to a single cause. However, this commonly observed form of anemia in the elderly (termed unexplained anemia [UA]) can generally be dissected to its root causes, which include renal insufficiency, inflammation, testosterone deficiency, and stem cell proliferative decline. Myelodysplasia (MDS) occurs commonly in this age group but can and should, for both diagnostic and therapeutic considerations, be distinguished from UA. C1 [Makipour, Sasan; Kanapuru, Bindu; Ershler, William B.] Harbor Hosp, Clin Res Branch, Intramural Res Program, NIA,NIH, Baltimore, MD 21225 USA. RP Ershler, WB (reprint author), Harbor Hosp, Clin Res Branch, Intramural Res Program, NIA,NIH, NM545,3001 S Hanover St, Baltimore, MD 21225 USA. FU National Institute on Aging, National Institutes of Health FX Supported by the Intramural Research Program, National Institute on Aging, National Institutes of Health. NR 57 TC 36 Z9 38 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0037-1963 J9 SEMIN HEMATOL JI Semin. Hematol. PD OCT PY 2008 VL 45 IS 4 BP 250 EP 254 DI 10.1053/j.seminhematol.2008.06.003 PG 5 WC Hematology SC Hematology GA 353QT UT WOS:000259584000007 PM 18809095 ER PT J AU Wickerham, DL O'Connell, MJ Costantino, JP Cronin, WM Paik, S Geyer, CE Ganz, PA Petrelli, N Momounas, EP Julian, TB Wolmark, N AF Wickerham, D. Lawrence O'Connell, Michael J. Costantino, Joseph P. Cronin, Walter M. Paik, Soonmyung Geyer, Charles E. Ganz, Patricia A. Petrelli, Nicholas Momounas, Eleftherios P. Julian, Thomas B. Wolmark, Norman TI The Half Century of Clinical Trials of the National Surgical Adjuvant Breast and Bowel Project SO SEMINARS IN ONCOLOGY LA English DT Review ID QUALITY-OF-LIFE; COMPARING TOTAL MASTECTOMY; RECEPTOR-POSITIVE TUMORS; CANCER PREVENTION TRIAL; STAR P-2 TRIAL; RANDOMIZED-TRIAL; COLON-CANCER; RADICAL-MASTECTOMY; RADIATION-THERAPY; FOLLOW-UP C1 [Wickerham, D. Lawrence; O'Connell, Michael J.; Geyer, Charles E.; Julian, Thomas B.] NSABP Operat Off, Pittsburgh, PA USA. [Costantino, Joseph P.; Cronin, Walter M.] Univ Pittsburgh, Ctr Biostat, NSABP, Pittsburgh, PA USA. [Costantino, Joseph P.; Cronin, Walter M.] Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA USA. [Paik, Soonmyung] NSABP, Div Pathol, Pittsburgh, PA USA. [Ganz, Patricia A.] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Sch Med & Publ Hlth, Los Angeles, CA 90024 USA. [Petrelli, Nicholas] Helen F Graham Canc Ctr, Newark, DE USA. [Momounas, Eleftherios P.] Aultman Hosp Canc Ctr, Canton, OH USA. [Julian, Thomas B.; Wolmark, Norman] Allegheny Gen Hosp, Dept Human Oncol, Pittsburgh, PA 15212 USA. RP Wickerham, DL (reprint author), Four Allegheny Ctr, NSABP, Pittsburgh, PA 15212 USA. EM larry.wickerham@nsabp.org FU National Cancer Institute [U10-CA37377, U10-CA69974, U10-CA69651, U10-CA12027, U24-CA114732] FX Supported in part by National Cancer Institute Grants No. U10-CA37377. U10-CA69974. U10-CA69651. U10-CA12027. and U24-CA114732. NR 34 TC 3 Z9 3 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 0093-7754 J9 SEMIN ONCOL JI Semin. Oncol. PD OCT PY 2008 VL 35 IS 5 BP 522 EP 529 DI 10.1053/j.seminoncol.2008.07.005 PG 8 WC Oncology SC Oncology GA 363AA UT WOS:000260237100007 PM 18929150 ER PT J AU Colombo, RE Olivier, KN AF Colombo, Rhonda E. Olivier, Kenneth N. TI Diagnosis and treatment of infections caused by rapidly growing mycobacteria SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE rapidly growing mycobacteria (RGM); nontuberculous mycobacteria (NTM); diagnosis; treatment ID INTRINSIC MACROLIDE RESISTANCE; LUNG-TRANSPLANT RECIPIENT; NONTUBERCULOUS MYCOBACTERIA; CYSTIC-FIBROSIS; PULMONARY INFECTION; RIBOSOMAL-RNA; ABSCESSUS INFECTION; CLINICAL-FEATURES; INTERFERON-GAMMA; GENE SEQUENCE AB Rapidly growing mycobacteria (RGM) are ubiquitous environmental organisms capable of causing a wide variety of infections in humans. The prevalence of RGM infections appears to be increasing, although exact incidence rates are unknown. Although some risk factors for pulmonary RGM infection have been determined, the specific host factors predisposing to disease in the majority of cases are not clear. Significant advances in molecular methods of mycobacterial identification have led to isolation of more varieties, changes in taxonomy, and more rapid and accurate diagnosis of RGM from clinical isolates. Despite significant advances in the field, diagnosing and treating RGM pulmonary infections remain complicated. Current guidelines are based on the most commonly encountered NTM. Their applicability to less frequent RGM isolates has not been definitively established. Treatment often requires multiple antimicrobial agents for prolonged periods of time, with varying degrees of success and significant associated morbidity. C1 [Colombo, Rhonda E.; Olivier, Kenneth N.] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Olivier, KN (reprint author), NIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike,Bldg 10,Rm 11N234, Bethesda, MD 20892 USA. EM olivierk@niaid.nih.gov FU NIAID; NIH FX This work was supported by the Intramural Research Program of the NIAID, NIH. NR 73 TC 26 Z9 27 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 J9 SEMIN RESP CRIT CARE JI Semin. Respir. Crit. Care Med. PD OCT PY 2008 VL 29 IS 5 BP 577 EP 588 DI 10.1055/s-0028-1085709 PG 12 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 353OI UT WOS:000259576900012 PM 18810691 ER PT J AU Holden, AEC Shain, RN Miller, WB Piper, JM Perdue, ST Thurman, AR Korte, JE AF Holden, Alan E. C. Shain, Rochelle N. Miller, Warren B. Piper, Jeanna M. Perdue, Sondra T. Thurman, Andrea R. Korte, Jeffrey E. TI The influence of depression on sexual risk reduction and STD infection in a controlled, randomized intervention trial SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID TRANSMITTED-DISEASE; HIV-RISK; CLINIC PATIENTS; MENTAL-HEALTH; PSYCHIATRIC-DISORDERS; MINORITY WOMEN; BEHAVIOR; SYMPTOMS; ADOLESCENTS; ADULTS AB Background: A randomized controlled trial of SAFE, a cognitive/behavioral intervention, revealed that it significantly reduces reinfection and behavioral risks among participants compared with controls. However, studies suggest that depression may moderate intervention efficacy among affected persons because of impaired information processing, failure to recognize risk, or inability to change behavior. Goal: We evaluated SAFE efficacy among depressed and non-depressed Mexican- and African American women after comparing initial risk factors by depression status. We further explored intervention effects in moderately and severely depressed women. Study Design: We stratified 477 participants (249 intervention, 228 controls) according to their depression status at baseline determined by CES-D scores. Using chi(2) and multivariate logistic regression, we evaluated differences in reinfection and behavioral risk at 6-month, 12-month, and 1-year cumulative follow-ups between groups within baseline depression strata. Results: At baseline, 74.4% of women were depressed and had significantly greater levels of behavioral risks than nondepressed women. At follow-up intervals, behavioral risks and reinfection rates were lower among intervention women compared with controls regardless of depression status. For example, at 1-year follow-up reinfection rates were 15.2% in nondepressed intervention women versus 21.4% in nondepressed controls (AOR = 0.6), and 18.6% in depressed intervention women versus 27.3% in depressed controls (AOR = 0.6). Moreover, reinfection was consistently lower among moderately and severely depressed intervention women than controls (moderately depressed: 19.3% vs. 27.2%, AOR 0.6; severely depressed: 17.9% vs. 27.5%, AOR = 0.6). Conclusions: Despite significantly greater behavioral risk among depressed women at baseline, SAFE was equally successful in reducing reinfection and high-risk behavior among depressed and nondepressed participants. C1 [Holden, Alan E. C.; Shain, Rochelle N.] Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, San Antonio, TX 78229 USA. [Miller, Warren B.] Transnatl Family Res Inst, Aptos, CA USA. [Piper, Jeanna M.] NIH, Bethesda, MD 20892 USA. [Korte, Jeffrey E.] Med Univ S Carolina, Dept Biostat Informat & Epidemiol, Bluff Estates, SC 29209 USA. RP Holden, AEC (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Obstet & Gynecol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM holden@uthscsa.edu FU National Institute of Allergy and Infectious Disease [1 U19 AI 45429, 5 U19 AI 45429] FX This project was funded by grants 1 U19 AI 45429 to 01 and 5 U19 AI 45429 to 05 from the National Institute of Allergy and Infectious Disease NR 58 TC 8 Z9 9 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD OCT PY 2008 VL 35 IS 10 BP 898 EP 904 DI 10.1097/OLQ.0b013e31817d7a33 PG 7 WC Infectious Diseases SC Infectious Diseases GA 360NB UT WOS:000260063100012 PM 18607311 ER PT J AU Baker, SG AF Baker, Stuart G. TI Two simple approaches for validating a binary surrogate endpoint using data from multiple trials SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article; Proceedings Paper CT 8th International Conference on Computational Processing of the Portuguese Language CY SEP 08-10, 2008 CL Aveiro, PORTUGAL SP Univ Aveiro, Inst Elect Telemat Engn Aveiro, Assoc Computat Linguist, Int Speech Commun Assoc, ISCA SIG-IL, Fund Cien Tecnol, Microsoft Intel, Springer, UZ Technol, DESIGNEED, Grande Hotel Curia ID CANCER AB A surrogate endpoint is an endpoint that is observed before a true endpoint and is used to draw conclusions about the effect of intervention on true endpoint. To gauge confidence in the use Of a surrogate endpoint, it must be validated. Two simple validation methods using data from multiple trials with surrogate and true endpoints are discussed: an estimation method extending previous work quad new method based on hypothesis tests. The validation methods were applied to two data sets, each involving 10 randomized trials: one for patients with early colon cancer where the true endpoint was survival status at eight,years and surrogate endpoint was cancer recurrence status at three years, and one for patients with advanced colorectal cancer where the true endpoint was survival status at 12 months and the surrogate endpoint Was cancer recurrence status at six months. The estimation method uses the surrogate endpoint in the new trial and a model relating surrogate and true endpoints in previous trials to predict the effect of intervention on true endpoint in the new trial. For validation, each trial was successively treated as the 'new' trial and a comparison was made between predicted and observed effects of intervention on true endpoint. Performance of the surrogate endpoint was good in both data sets. The hypothesis testing method involves the z-statistic for the surrogate endpoint, which is the estimated effect of intervention Oil surrogate endpoint divided by its standard error. To use this z-statistic to test a null hypothesis of no effect of intervention Oil tare endpoint, the critical value is increased above a standard level of 1.96 to a level determined by the relationships between surrogate and true endpoints in the data sets. This elevated critical value could he used for accelerated approval. C1 NCI, Biometry Res Grp, Canc Prevent Div, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, Biometry Res Grp, Canc Prevent Div, EPN 3131,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 5 TC 8 Z9 8 U1 0 U2 2 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD OCT PY 2008 VL 17 IS 5 BP 505 EP 514 DI 10.1177/0962280207081861 PG 10 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA 362SF UT WOS:000260216700006 PM 18285436 ER PT J AU Piedbois, P Croswell, JM AF Piedbois, Pascal Croswell, Jennifer Miller TI Surrogate endpoints for overall survival in advanced colorectal cancer: a clinician's perspective SO STATISTICAL METHODS IN MEDICAL RESEARCH LA English DT Article; Proceedings Paper CT 8th International Conference on Computational Processing of the Portuguese Language CY SEP 08-10, 2008 CL Aveiro, PORTUGAL SP Univ Aveiro, Inst Elect Telemat Engn Aveiro, Assoc Computat Linguist, Int Speech Commun Assoc, ISCA SIG-IL, Fund Cien Tecnol, Microsoft Intel, Springer, UZ Technol, DESIGNEED, Grande Hotel Curia ID RESPONSE RATE; FLUOROURACIL; TRIALS; METAANALYSIS; LEUCOVORIN; IRINOTECAN; THERAPIES; MARKERS AB Surrogate endpoints in oncology research and practice have garnered increasing attention over the past two decades. This activity has largely been driven by the promise surrogate endpoints appear to hold: the potential to get new therapies to seriously ill patients more rapidly. However, uncertainties abound. Even agreeing upon a definition of a "valid" surrogate endpoint has not been a straightforward exercise; this article begins by highlighting differences in how this term has been previously captured and applied, as well as laying out the basic criteria essential for its application in advanced colorectal cancer. Ideally, these elements include (but are not limited to) ease of measurement, rapid indication of treatment effect, and, most importantly, reliable and consistent prediction of the true impact of a treatment on the ultimate outcome of interest: overall survival. The strengths and weaknesses of current potential surrogate endpoints in advanced colorectal cancer, including performance status, carcinoembryonic antigen plasma level, overall response rate, time to progression, and disease-free survival, are each considered in turn. Finally, limitations of surrogate endpoints in the clinical setting, including challenges in extrapolation to new therapies, and the incomplete provision of information about potential adverse effects, are discussed. Work remains to be done between physicians and statisticians to bridge the gap between that which is statistically demonstrable and that which will be clinically useful. The term 'surrogate endpoint' was virtually unknown by most oncologists 15 years ago. A search in PubMed [http://www.ncbi.nlm.nih.gov] based on the words 'surrogate and cancer' shows that more than 2000 papers were published in medical journals in the last 20 years, with a dramatic increase of interest in the last five Years. Interestingly, the same trend is observed when the words 'surrogate and heart' are entered into PubMed, suggesting that the issue of surrogate endpoints goes beyond the field of oncology, although the frequency of discussion varies (Figure 1; note different y-axis scales for oncology and cardiology). The goal of the present paper is to discuss the main issues surrounding surrogate endpoints from a clinician's point of view, using as an example surrogate endpoints of overall survival (OS) in advanced colorectal cancer (ACC). C1 [Piedbois, Pascal] AstraZeneca, F-92844 Rueil Malmaison, France. [Croswell, Jennifer Miller] NIH, Off Dis Prevent, Off Director, Bethesda, MD 20892 USA. RP Piedbois, P (reprint author), AstraZeneca, 1 Pl Renault, F-92844 Rueil Malmaison, France. EM pascal.piedbois@astrazeneca.com NR 29 TC 9 Z9 9 U1 0 U2 3 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0962-2802 J9 STAT METHODS MED RES JI Stat. Methods Med. Res. PD OCT PY 2008 VL 17 IS 5 BP 519 EP 527 DI 10.1177/0962280207081865 PG 9 WC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Statistics & Probability SC Health Care Sciences & Services; Mathematical & Computational Biology; Medical Informatics; Mathematics GA 362SF UT WOS:000260216700008 PM 18285441 ER PT J AU Guo, WG Rao, MB AF Guo, Wenge Rao, M. Bhaskara TI On optimality of the Benjamini-Hochberg procedure for the false discovery rate SO STATISTICS & PROBABILITY LETTERS LA English DT Article ID MULTIPLE TESTING PROCEDURES AB The Benjamini-Hochberg step-up procedure controls the false discovery rate (FDR) provided the test statistics have a certain positive regression dependency. We show that this procedure controls the FDR under a weaker property and is optimal in the sense that its critical constants are uniformly greater than those of any step-up procedure with the FDR controlling property. (C) 2008 Elsevier B. V. All rights reserved. C1 [Guo, Wenge; Rao, M. Bhaskara] Univ Cincinnati, Dept Environm Hlth, Cincinnati, OH 45267 USA. RP Guo, WG (reprint author), NIEHS, Biostat Branch, POB 12233,MD A3-03111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wenge.guo@gmail.com OI Guo, Wenge/0000-0003-3777-2058 NR 16 TC 3 Z9 3 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-7152 J9 STAT PROBABIL LETT JI Stat. Probab. Lett. PD OCT 1 PY 2008 VL 78 IS 14 BP 2024 EP 2030 DI 10.1016/j.spl.2008.01.069 PG 7 WC Statistics & Probability SC Mathematics GA 357ZG UT WOS:000259885200005 ER PT J AU Gaudinski, MR Henning, EC Miracle, A Luby, M Warach, S Latour, LL AF Gaudinski, Martin R. Henning, Erica C. Miracle, Aaron Luby, Marie Warach, Steven Latour, Lawrence L. TI Establishing final infarct volume - Stroke lesion evolution past 30 days is insignificant SO STROKE LA English DT Article DE final infarct volume; fluid-attenuated inversion recovery; lesion volume evolution; magnetic resonance imaging; stroke ID ACUTE ISCHEMIC-STROKE; DIFFUSION; MRI; BRAIN; TIME; DESMOTEPLASE; THROMBOLYSIS; PERFUSION; TRIAL AB Background and Purpose-Lesion volume measured on MRI has been used as an objective surrogate marker for outcome in clinical trials. However, lesion volumes vary over time because of edema and tissue loss. This study aims to determine if lesion volumes measured at 30 and 90 days after ictus significantly differ. Methods-We performed a retrospective study of 18 patients who had acute (< 24 hours) DWI and follow-up fluid-attenuated inversion recovery imaging at 5, 30, and 90 days. Two expert readers segmented lesions and the mean volumes of both reads were used in all statistical analyses. Results-Patient age was 65.8 (SD, 13.7) years and median NIHSS at baseline was 11.5. Inter-rater variability for lesion volume measurements was 3.7 (5.8) mL. Acute DWI volume was 19.3 (17.3) mL. Fluid-attenuated inversion recovery volumes for 5, 30, and 90 days were 34.3 (23.5), 18.6 (14.0), and 15.9 (13.8) mL, respectively. These volumes differed significantly (P < 0.001). Linear regression revealed a strong correlation (r = 0.96; P < 0.001) between lesion volumes at 30 and 90 days with a slope that did not vary significantly from 1.0 (P = 0.448). Conclusions-Lesions continue to evolve between 5 and 90 days, but by 30 days lesion volume approaches final infarct volume. While clinical response is the most meaningful outcome measure, our findings suggest that lesion volumes measured at 30 days may provide a sufficient approximation for final infarct volume for use in early phase clinical trials. C1 [Gaudinski, Martin R.; Henning, Erica C.; Miracle, Aaron; Luby, Marie; Warach, Steven; Latour, Lawrence L.] Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, Stroke Branch, NIH, Bethesda, MD 20892 USA. RP Latour, LL (reprint author), Natl Inst Neurol Disorders & Stroke, Sect Stroke Diagnost & Therapeut, Stroke Branch, NIH, Bldg 10,Room B1D733,10 Ctr Dr,MSC 1063, Bethesda, MD 20892 USA. EM latourl@ninds.nih.gov RI Henning, Erica/E-8542-2010 FU National Institutes of Health; National Institute of Neurological Disorders and Stroke FX The Division of Intramural Research of the National Institutes of Health and the National Institute of Neurological Disorders and Stroke supported this research. NR 17 TC 36 Z9 37 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD OCT PY 2008 VL 39 IS 10 BP 2765 EP 2768 DI 10.1161/STROKEAHA.107.512269 PG 4 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 354OK UT WOS:000259648700016 PM 18635854 ER PT J AU Seneca, N Zoghbi, SS Skinbjerg, M Liow, JS Hong, J Sibley, DR Pike, VW Halldin, C Innis, RB AF Seneca, Nicholas Zoghbi, Sami S. Skinbjerg, Mette Liow, Jeih-San Hong, Jinsoo Sibley, David R. Pike, Victor W. Halldin, Christer Innis, Robert B. TI Occupancy of dopamine D-2/3 receptors in rat brain by endogenous dopamine measured with the agonist positron emission tomography radioligand [C-11]MNPA SO SYNAPSE LA English DT Article DE dopamine depletion; reserpine; alpha-methyl-pares-tyrosine; PET; D-2/3; receptor; [C-11]MNPA ID IN-VIVO BINDING; D-2-DOPAMINE RECEPTORS; ANTERIOR-PITUITARY; REFERENCE REGION; MONKEY BRAIN; MOUSE-BRAIN; PET; DEPLETION; SCHIZOPHRENIA; AMPHETAMINE AB Estimates of dopamine D-2/3 receptor occupancy by endogenous dopamine using positron emission tomography (PET) in animals have varied almost threefold. This variability may have been caused by incomplete depletion of dopamine or by the use of antagonist radioligands, which appear less sensitive than agonist radioligands to changes in endogenous dopamine. PET scans were performed in rats with the agonist PET radioligand [C-11]MNPA ([O-methyl-C-11]2-methoxy-N-propylnorapomorphine). [C-11]MNPA was injected as a bolus plus constant infusion to achieve steady-state concentration in the body and equilibrium receptor binding in the brain. Radioligand binding was compared at baseline and after treatment with reserpine plus a-methyl-pares-tyrosine, which cause similar to 95% depletion of endogenous dopamine. Depletion of dopamine increased radioligand binding in striatum but had little effect in cerebellum. Striatal [C-11]MNPA binding potential was 0.93 +/- 0.12 at baseline and increased to 1.99 +/- 0.25 after dopamine depletion. Occupancy of D2/3 receptors by endogenous dopamine at baseline was calculated to be similar to 53%. Striatal binding was displaceable with raclopride, but not with BP 897 (a selective D-3 compound), thus confirming the D-2 receptor specificity of [C-11]MNPA binding. Radioactivity extracted from rat brain contained only 8-10% radiometabolites and was insignificantly altered by administration of reserpine plus a-methyl-pares-tyrosine. Hence, dopamine depletion did not increase the PET measurements via an effect on radiotracer metabolism. Our in vivo estimate of dopamine's occupancy of D-2/3 receptors at baseline is higher than that previously reported using antagonist radioligands and PET, but is similar to that reported using agonist radioligands and ex vivo measurements. C1 [Seneca, Nicholas; Zoghbi, Sami S.; Skinbjerg, Mette; Liow, Jeih-San; Hong, Jinsoo; Pike, Victor W.; Innis, Robert B.] NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Seneca, Nicholas; Skinbjerg, Mette; Halldin, Christer] Karolinska Inst, Psychiat Sect, Dept Clin Neurosci, Stockholm, Sweden. [Skinbjerg, Mette; Sibley, David R.] Natl Inst Neurol Disorders & Stroke, Mol Neuropharmacol Sect, Bethesda, MD USA. RP Seneca, N (reprint author), NIMH, Mol Imaging Branch, Bldg 31,Room B2B34,MSC-2035, Bethesda, MD 20892 USA. EM nicholasseneca@mail.nih.gov FU National Institute of Mental Health [Z01-MH-002795-06] FX This research was supported in part by the Intramural Program (project #Z01-MH-002795-06) of the National Institute of Mental Health. We thank Edward Tuan and Pavitra Kannan for assistance with the ex vivo radiometabolite experiments; PMOD Technologies (Adliswil, Switzerland) for providing its image analysis and modeling software; and John Neumeyer (Mclean Hospital/Harvard Medical School) for providing an authentic sample of MNPA. NR 41 TC 16 Z9 16 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD OCT PY 2008 VL 62 IS 10 BP 756 EP 763 DI 10.1002/syn.20549 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 342GI UT WOS:000258772200005 PM 18651641 ER PT J AU Kuo, CK Tuan, RS AF Kuo, Catherine K. Tuan, Rocky S. TI Mechanoactive Tenogenic Differentiation of Human Mesenchymal Stem Cells SO TISSUE ENGINEERING PART A LA English DT Article ID SYNOVIAL JOINT FORMATION; IN-VITRO; TENDON CELLS; GENE-EXPRESSION; BONE-MARROW; OSTEOGENIC DIFFERENTIATION; MATRIX METALLOPROTEINASES; CONNECTIVE-TISSUE; WNT; REPAIR AB A mesenchymal stem cell (MSC)-seeded collagen gel under static or dynamic tension is a well-established model to study the potential of MSCs in regenerating a tendon- or ligament-like tissue. Using this model, upregulation of fibrillar collagen mRNA expression and protein production has been demonstrated in response to cyclic tensile mechanical stimulation. However, the mechanisms driving MSC tenogenesis (differentiation into tendon or ligament fibroblasts) have not been elucidated. This study investigated the mechanisms of tenogenesis of human bone marrow-derived MSCs in a dynamic, three-dimensional (3D) tissue-engineering model by investigating the effects of cyclic stretching on matrix production and gene expression of candidate tendon and ligament markers. The 3D MSC tenogenesis culture system upregulated scleraxis, but cyclic stretching was required to maintain expression of this putative tendon marker over time. Enhanced tendinous neo-tissue development demonstrated with extracellular matrix staining was largely due to changes in matrix deposition and remodeling activity under dynamic loading conditions, as evidenced by differential regulation of matrix metalloproteinases at a transcriptional level with minimal changes in collagen mRNA levels. Regulation of Wnt gene expression with cyclic stimulation suggested a similar role for Wnt4 versus Wnt5a in tenogenesis as in cartilage development. This first report of the potential involvement of matrix remodeling and Wnt signaling during tenogenesis of human MSCs in a dynamic, 3D tissue-engineering model provides insights into the mechanisms of tenogenesis in a mechanoactive environment and supports the therapeutic potential of adult stem cells. C1 [Kuo, Catherine K.; Tuan, Rocky S.] NIAMSD, NIH, Cartilage Biol & Orthoped Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, NIH, Cartilage Biol & Orthoped Branch, Dept Hlth & Human Serv, Bldg 50,Room 1523,50 S Dr,MSC 8022, Bethesda, MD 20892 USA. EM Tuanr@mail.nih.gov FU NIH; NIAMS [Z01 AR41131] FX The authors are grateful to Dr. Juan M. Taboas (National Institutes of Health) for his invaluable consultation with statistical analysis and to Dr. Paul Manner (George Washington University) for providing the human bone marrow samples. The authors would also like to acknowledge the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) Light Imaging Section for use of the microscopy facilities. This research was supported by the Intramural Research Program of the NIH, NIAMS (Z01 AR41131). NR 50 TC 129 Z9 132 U1 2 U2 30 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD OCT PY 2008 VL 14 IS 10 BP 1615 EP 1627 DI 10.1089/ten.tea.2006.0415 PG 13 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 359OS UT WOS:000259998000004 PM 18759661 ER PT J AU Ma, W Tavakoli, T Chen, S Maric, D Liu, JL O'Shaughnessy, TJ Barker, JL AF Ma, Wu Tavakoli, Tahereh Chen, Silvia Maric, Dragan Liu, Jinny L. O'Shaughnessy, Thomas J. Barker, Jeffery L. TI Reconstruction of Functional Cortical-like Tissues from Neural Stem and Progenitor Cells SO TISSUE ENGINEERING PART A LA English DT Article ID 3-DIMENSIONAL COLLAGEN GELS; PRECURSOR CELLS; DIFFERENTIATION; RAT; GROWTH; PROLIFERATION; MICROGRAVITY; BIOREACTOR; NEURONS; CULTURE AB Neural stem and progenitor cells isolated from embryonic day 13 rat cerebral cortex were immobilized in three-dimensional type I collagen gels, and then the cell-collagen constructs were transferred to rotary wall vessel bioreactors and cultured in serum-free medium containing basic fibroblast growth factor (bFGF) combined with brain-derived neurotrophic factor for up to 10 weeks. Remarkably, the collagen-entrapped cells formed a complex two-layered structure that emulated to a certain extent the cerebral cortex of the embryonic brain in architecture and functionality. The surface layer (layer I) composed primarily of proliferating neural progenitor cells (nestin(+), vimentin(+), and PCNA(+)) predominantly expressed functional neurotransmitter receptors for cholinergic and purinergic agonists while differentiating cells (TuJ1(+) and GFAP(+)) in the deeper layer (layer II) contained differentiated neurons and astrocytes and mainly responded to GABAergic and glutamatergic agonists and to veratridine, which activates voltage-dependent Na(+) channels. An active synaptic vesicle recycling was demonstrated by neuronal networks in the deeper layer using the endocytotic marker FM1-43. Cell polarization forming the characteristic two-layered structure was found to associate with the bFGF and FGF receptor signaling. These engineered functional tissue constructs have a potential use as tissue surrogates for drug screening and detection of environmental toxins, and in neural cell replacement therapy. C1 [Ma, Wu; Tavakoli, Tahereh] Amer Type Culture Collect, Stem Cell Ctr, Manassas, VA 20110 USA. [Ma, Wu; Liu, Jinny L.; O'Shaughnessy, Thomas J.] USN, Res Lab, Ctr Biomol Sci & Engn, Washington, DC 20375 USA. [Chen, Silvia] NICHHD, NIH, NASA, Ctr Tissue Culture 3D, Bethesda, MD 20892 USA. [Maric, Dragan; Barker, Jeffery L.] Natl Inst Neurol Disorders & Stroke, NIH, Neurophysiol Lab, Bethesda, MD USA. RP Ma, W (reprint author), Amer Type Culture Collect, Stem Cell Ctr, 10801 Univ Blvd, Manassas, VA 20110 USA. EM wma@atcc.org FU NASA [NRA 00-HEDS-03-136] FX This work was supported in part by NASA grant NRA 00-HEDS-03-136 to W. Ma. The opinions and assertions contained herein are the private ones of the authors and are not to be construed as official or reflecting the views of the Department of the Navy. NR 33 TC 20 Z9 20 U1 0 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1937-3341 J9 TISSUE ENG PT A JI Tissue Eng. Part A PD OCT PY 2008 VL 14 IS 10 BP 1673 EP 1686 DI 10.1089/ten.tea.2007.0357 PG 14 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Cell Biology SC Cell Biology; Biotechnology & Applied Microbiology GA 359OS UT WOS:000259998000009 PM 18601590 ER PT J AU Stout, MD Kissling, GE Suarez, FA Malarkey, DE Herbert, RA Bucher, JR AF Stout, Matthew D. Kissling, Grace E. Suarez, Fernando A. Malarkey, David E. Herbert, Ronald A. Bucher, John R. TI Influence of Helicobacter hepaticus Infection on the Chronic Toxicity and Carcinogenicity of Triethanolamine in B6C3F1 Mice SO TOXICOLOGIC PATHOLOGY LA English DT Article DE National Toxicology Program; triethanolamine; Helicobacter hepaticus; mice; hepatocellular neoplasms ID CHRONIC ACTIVE HEPATITIS; ZERO DOSE CONTROL; BODY-WEIGHT; A/JCR MICE; LIVER; TUMORIGENESIS; TOXICOLOGY; SURVIVAL; TUMORS; TESTS AB Helicobacter hepaticus (H. hepaticus) infection causes hepatitis and increased hepatocellular neoplasms in male mice; although females are also infected, liver lesions are not typically expressed. In the 1990s, B6C3F1 mice from some chronic National Toxicology Program (NTP) studies were found to be infected with H. hepaticus. In these studies, there was hepatitis in many of the males, and there were more hepatocellular neoplasms in control males compared to studies with uninfected mice. In one of these studies, increased hepatocellular neoplasms at the high doses in male and female mice exposed topically to triethanolamine (TEA) provided the only evidence of carcinogenic activity. This study was repeated in mice free of H. hepaticus. However, the NTP mouse production colony and the diet differed between studies; these differences were the result of NTP programmatic decisions. In repeat study males, although control incidences were similar between studies, exposure did not result in increased hepatocellular neoplasms. In repeat study females, the control incidence of hepatocellular neoplasms was half that observed in the initial study, and these neoplasms were increased over controls at all doses. These data suggest that in the initial study, H. hepaticus influenced the induction of hepatocellular neoplasms in males, but not in females. C1 [Stout, Matthew D.; Kissling, Grace E.; Suarez, Fernando A.; Malarkey, David E.; Herbert, Ronald A.; Bucher, John R.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Bucher, JR (reprint author), NIEHS, Natl Toxicol Program, POB 12233,MD EC 34, Res Triangle Pk, NC 27709 USA. EM bucher@niehs.nih.gov FU NIH; National Institute of Environmental Health Sciences [1 Z01 ES045004-11 BB] FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences under Research Project Number 1 Z01 ES045004-11 BB. The authors thank Drs. Richard Irwin and Ronald Melnick for critical review of this manuscript. NR 34 TC 7 Z9 7 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD OCT PY 2008 VL 36 IS 6 BP 783 EP 794 DI 10.1177/0192623308322312 PG 12 WC Pathology; Toxicology SC Pathology; Toxicology GA 463VJ UT WOS:000267460300003 PM 18812577 ER PT J AU Bolon, B Anthony, DC Butt, M Dorman, D Green, MV Little, PB Valentine, WM Weinstock, D Yan, J Sills, RC AF Bolon, Brad Anthony, Douglas C. Butt, Mark Dorman, David Green, Michael V. Little, Peter B. Valentine, William M. Weinstock, Daniel Yan, James Sills, Robert C. TI "Current Pathology Techniques" Symposium Review: Advances and Issues in Neuropathology SO TOXICOLOGIC PATHOLOGY LA English DT Review DE neuropathology; neurotoxicity; review ID CARBON-DISULFIDE NEUROTOXICITY; FUNCTIONAL OBSERVATIONAL BATTERY; MAGNETIC-RESONANCE MICROSCOPY; CEREBRAL GLUCOSE-UTILIZATION; ANIMAL PET SCANNER; DEVELOPMENTAL NEUROTOXICITY; FLUORO-JADE; PERIPHERAL-NERVE; HIGH-RESOLUTION; NEURONAL DEGENERATION AB Our understanding of the mechanisms that incite neurological diseases has progressed rapidly in recent years, mainly owing to the advent of new research instruments and our increasingly facile ability to assemble large, complex data sets acquired across several disciplines into an integrated representation of neural function at the molecular, cellular, and systemic levels. This mini-review has been designed to communicate the principal technical advances and current issues of importance in neuropathology research today in the context of our traditional neuropathology practices. Specific topics briefly addressed in this paper include correlative biology of the many facets of the nervous system; conventional and novel methods for investigating neural structure and function; theoretical and technical issues associated with investigating neuropathology end points in emerging areas of concern (developmental neurotoxicity, neurodegenerative conditions); and challenges and opportunities that will face pathologists in this field in the foreseeable future. We have organized this information in a manner that we hope will be of interest not only to professionals with a career focus in neuropathology, but also to general pathologists who occasionally face neuropathology questions. C1 [Sills, Robert C.] NIEHS, Res Triangle Pk, NC 27709 USA. [Bolon, Brad] GEMpath Inc, Longmont, CO USA. [Anthony, Douglas C.] Univ Missouri, Dept Pathol & Anat Sci, Columbia, MO USA. [Butt, Mark] Tox Path Specialists, Walkersville, MD USA. [Dorman, David] N Carolina State Univ, Coll Vet Med, Raleigh, NC USA. [Green, Michael V.] Trident Imaging, Rockville, MD USA. [Little, Peter B.] Charles River Labs, Res Triangle Pk, NC USA. [Valentine, William M.] Vanderbilt Univ, Dept Pathol, Nashville, TN USA. [Weinstock, Daniel] Sanofi Aventis, Bridgewater, NJ USA. [Yan, James] Hospira Inc, Lake Forest, IL USA. RP Sills, RC (reprint author), NIEHS, 111 TW Alexander Dr,POB 12233,MD B3-06, Res Triangle Pk, NC 27709 USA. EM sills@niehs.nih.gov OI Anthony, Douglas/0000-0002-3815-2240 FU NIH National Resource [NCRR P4105959, NCI 5R24-CA92656] FX The authors thank Dr. Gary Cockerell (Cockerell Alliances), Dr. Susan Emeigh Hart (Auxilium Pharmaceuticals Inc.), Mr. David Sandler (ILSI-HESI), and Mr. Eric Moore (ILSI-HESI) for their efforts in helping to organize the "Current Pathology Techniques" symposium. The MR imaging was performed at the Duke Center for In Vivo Microscopy, an NIH National Resource (NCRR P4105959, NCI 5R24-CA92656). NR 98 TC 10 Z9 10 U1 1 U2 4 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0192-6233 EI 1533-1601 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD OCT PY 2008 VL 36 IS 6 BP 871 EP 889 DI 10.1177/0192623308322313 PG 19 WC Pathology; Toxicology SC Pathology; Toxicology GA 463VJ UT WOS:000267460300012 ER PT J AU Hotchkiss, AK Rider, CV Blystone, CR Wilson, VS Hartig, PC Ankley, GT Foster, PM Gray, CL Gray, LE AF Hotchkiss, Andrew K. Rider, Cynthia V. Blystone, Chad R. Wilson, Vickie S. Hartig, Phillip C. Ankley, Gerald T. Foster, Paul M. Gray, Clark L. Gray, L. Earl TI Fifteen years after "Wingspread" - Environmental endocrine disrupters and human and wildlife health: Where we are today and where we need to go SO TOXICOLOGICAL SCIENCES LA English DT Review DE endocrine disruptors; androgens; estrogens; dioxins; PCBs; pharmaceuticals; mixtures; screening and multigenerational testing ID PAPER-MILL EFFLUENT; IN-UTERO EXPOSURE; ALTERS SEXUAL-DIFFERENTIATION; MINNOW PIMEPHALES-PROMELAS; ANDROGEN-RECEPTOR ANTAGONIST; RAT HERSHBERGER BIOASSAY; CATTLE FEEDLOT EFFLUENT; DOSE-RESPONSE ANALYSIS; ROACH RUTILUS-RUTILUS; REPRODUCTIVE DEVELOPMENT AB In 1991, a group of expert scientists at a Wingspread work session on endocrine-disrupting chemicals (EDCs) concluded that "Many compounds introduced into the environment by human activity are capable of disrupting the endocrine system of animals, including fish, wildlife, and humans. Endocrine disruption can be profound because of the crucial role hormones play in controlling development." Since that time, there have been numerous documented examples of adverse effects of EDCs in invertebrates, fish, wildlife, domestic animals, and humans. Hormonal systems can be disrupted by numerous different anthropogenic chemicals including antiandrogens, androgens, estrogens, AhR agonists, inhibitors of steroid hormone synthesis, antithyroid substances, and retinoid agonists. In addition, pathways and targets for endocrine disruption extend beyond the traditional estrogen/androgen/thyroid receptor-mediated reproductive and developmental systems. For example, scientists have expressed concern about the potential role of EDCs in increasing trends in early puberty in girls, obesity and type II diabetes in the United States and other populations. New concerns include complex endocrine alterations induced by mixtures of chemicals, an issue broadened due to the growing awareness that EDCs present in the environment include a variety of potent human and veterinary pharmaceutical products, personal care products, nutraceuticals and phytosterols. In this review we (1) address what have we learned about the effects of EDCs on fish, wildlife, and human health, (2) discuss representative animal studies on (anti)androgens, estrogens and 2,3,7,8-tetrachlorodibenzo-p-dioxin-like chemicals, and (3) evaluate regulatory proposals being considered for screening and testing these chemicals. C1 [Hotchkiss, Andrew K.; Rider, Cynthia V.; Blystone, Chad R.; Wilson, Vickie S.; Hartig, Phillip C.; Gray, L. Earl] US EPA, Reprod Toxicol Div, Endocrinol Branch, Natl Hlth & Environm Effects Res Lab, Res Triangle Pk, NC 27711 USA. [Hotchkiss, Andrew K.; Rider, Cynthia V.; Blystone, Chad R.] USEPA NCSU Cooperat Training Agreement CT82651201, Raleigh, NC 27695 USA. [Ankley, Gerald T.] US EPA, Midcontinent Div, Tox Effects Characterizat Res Branch, Natl Hlth & Environm Effects Res Lab, Duluth, MN 55804 USA. [Foster, Paul M.] NIEHS, Toxicol Operat Branch, NIH, Res Triangle Pk, NC 27709 USA. [Gray, Clark L.] Univ N Carolina, Dept Geog, Chapel Hill, NC 27515 USA. RP Gray, LE (reprint author), US EPA, Reprod Toxicol Div, Endocrinol Branch, Natl Hlth & Environm Effects Res Lab, MD 72, Res Triangle Pk, NC 27711 USA. EM gray.earl@epa.gov OI Wilson, Vickie/0000-0003-1661-8481 FU Intramural NIH HHS NR 179 TC 238 Z9 245 U1 15 U2 144 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2008 VL 105 IS 2 BP 235 EP 259 DI 10.1093/toxsci/kfn030 PG 25 WC Toxicology SC Toxicology GA 348JS UT WOS:000259207400002 PM 18281716 ER PT J AU Shan, W Palkar, PS Murray, IA McDevitt, EI Kennett, MJ Kang, BH Isom, HC Perdew, GH Gonzalez, FJ Peters, JM AF Shan, Weiwei Palkar, Prajakta S. Murray, Iain A. McDevitt, Emily I. Kennett, Mary J. Kang, Boo Hyon Isom, Harriet C. Perdew, Gary H. Gonzalez, Frank J. Peters, Jeffrey M. TI Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) attenuates carbon tetrachloride hepatotoxicity by downregulating proinflammatory gene expression SO TOXICOLOGICAL SCIENCES LA English DT Article DE peroxisome proliferator-activated receptors; hepatotoxicity; inflammation ID BETA/DELTA PPAR-BETA/DELTA; FACTOR-KAPPA-B; HEPATIC STELLATE CELLS; E-2 SIGNALING PATHWAYS; BETA-DEFICIENT MICE; DELTA AGONIST; COLON CARCINOGENESIS; INSULIN SENSITIVITY; TISSUE DISTRIBUTION; ENDOTHELIAL-CELLS AB Peroxisome proliferator-activated receptor (PPAR) beta/delta-null mice exhibit exacerbated hepatotoxicity in response to administration of carbon tetrachloride (CCl(4)). To determine whether ligand activation of the receptor protects against chemical toxicity in the liver, wild-type and PPAR beta/delta-null mice were administered CCl(4) with or without coadministration of the highly specific PPAR beta/delta ligand GW0742. Biomarkers of liver toxicity, including serum alanine aminotransferase (ALT) and hepatic tumor necrosis factor (TNF) alpha mRNA, were significantly higher in CCl(4)-treated PPAR beta/delta-null mice compared to wild-type mice. Hepatic expression of TNF-like weak inducer of apoptosis receptor (TWEAKr) and S100 calcium-binding protein A6 (S100A6/calcyclin), genes involved in nuclear factor kappa B signaling, was higher in the CCl(4)-treated PPAR beta/delta-null mice compared to wild-type mice. GW0742 treatment resulted in reduced serum ALT concentration and lower expression of CCl(4)-induced TNF-alpha, S100A6, monocyte chemoattractant protein-1 (MCP1), and TWEAKr in wild-type mice, and these effects were not observed in PPAR beta/delta-null mice. Expression of TNF-alpha was higher in PPAR beta/delta-null primary hepatocytes in response to interleukin-1 beta treatment compared to wild-type hepatocytes, but GW0742 did not significantly modulate TNF-alpha expression in hepatocytes from either genotype. While PPAR beta/delta-null hepatic stellate exhibited higher rates of proliferation compared to wild-type cells, GW0742 did not affect alpha-smooth muscle actin expression in these cells. Combined, these findings demonstrate that ligand activation of PPAR beta/delta protects against chemically induced hepatotoxicity by downregulating expression of proinflammatory genes. Hepatocytes and hepatic stellate cells do not appear to directly mediate the inhibitory effects of ligand activation of PPAR beta/delta in liver, suggesting the involvement of paracrine and autocrine events mediated by hepatic cells. C1 [Shan, Weiwei; Palkar, Prajakta S.; Murray, Iain A.; Kennett, Mary J.; Perdew, Gary H.; Peters, Jeffrey M.] Penn State Univ, Dept Vet & Biomed Sci, Huck Inst Life Sci, University Pk, PA 16802 USA. [Shan, Weiwei; Palkar, Prajakta S.; Murray, Iain A.; Kennett, Mary J.; Perdew, Gary H.; Peters, Jeffrey M.] Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Huck Inst Life Sci, University Pk, PA 16802 USA. [Shan, Weiwei; Peters, Jeffrey M.] Penn State Univ, Intercoll Grad Degree Program Genet, Huck Inst Life Sci, University Pk, PA 16802 USA. [McDevitt, Emily I.; Isom, Harriet C.] Penn State Coll Med, Dept Microbiol & Immunol, Hershey, PA 17033 USA. [Kang, Boo Hyon] Non Clin Pathol Res Ctr, Seoul 153801, South Korea. [Gonzalez, Frank J.] NCI, Lab Metab, Bethesda, MD 20892 USA. RP Peters, JM (reprint author), Penn State Univ, Dept Vet & Biomed Sci, Huck Inst Life Sci, University Pk, PA 16802 USA. EM jmp21@psu.edu RI Peters, Jeffrey/D-8847-2011 FU National Institutes of Health [CA124533, ES04869, CA023931]; Pennsylvania State Department of Health FX National Institutes of Health (CA124533 to J.M.P., ES04869 to G.H.P., CA023931 to H.C.I.); Tobacco Settlement funds from the Pennsylvania State Department of Health. NR 98 TC 43 Z9 46 U1 1 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2008 VL 105 IS 2 BP 418 EP 428 DI 10.1093/toxsci/kfn142 PG 11 WC Toxicology SC Toxicology GA 348JS UT WOS:000259207400018 PM 18622026 ER PT J AU Morgan, DL Flake, GP Kirby, PJ Palmer, SM AF Morgan, Daniel L. Flake, Gordon P. Kirby, Patrick J. Palmer, Scott M. TI Comments on respiratory toxicity of diacetyl in C57Bl/6 mice - Response SO TOXICOLOGICAL SCIENCES LA English DT Letter C1 [Morgan, Daniel L.; Kirby, Patrick J.] NIEHS, Mol Toxicol Lab, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. [Flake, Gordon P.] NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. [Palmer, Scott M.] Duke Univ, Med Ctr, Dept Med, Div Pulm & Crit Care Med, Durham, NC 27710 USA. RP Morgan, DL (reprint author), NIEHS, Mol Toxicol Lab, Natl Toxicol Program, MD IF-00, Res Triangle Pk, NC 27709 USA. EM morgan3@niehs.nih.gov NR 4 TC 2 Z9 2 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD OCT PY 2008 VL 105 IS 2 BP 433 EP 434 DI 10.1093/toxsci/kfn134 PG 2 WC Toxicology SC Toxicology GA 348JS UT WOS:000259207400020 ER PT J AU Masedunskas, A Weigert, R AF Masedunskas, Andrius Weigert, Roberto TI Intravital two-photon microscopy for studying the uptake and trafficking of fluorescently conjugated molecules in live rodents SO TRAFFIC LA English DT Article DE endocytosis; membrane traffic; intravital microscopy; salivary glands; two-photon microscopy ID SALIVARY-GLANDS; EXCITATION MICROSCOPY; SUBMANDIBULAR-GLANDS; CELLS; RAT; ENDOCYTOSIS; LYSOSOMES; GENERATION; SECRETION; ANIMALS AB In this study, we describe an experimental system based on intravital two-photon microscopy for studying endocytosis in live animals. The rodent submandibular glands were chosen as model organs because they can be exposed easily, imaged without compromising their function and, furthermore, they are amenable to pharmacological and genetic manipulations. We show that the fibroblasts within the stroma of the glands readily internalize systemically injected molecules such as fluorescently conjugated dextran and BSA, providing a robust model to study endocytosis. We dynamically image the trafficking of these probes from the early endosomes to the late endosomes and lysosomes while also visualizing homotypic fusion events between early endosomes. Finally, we demonstrate that pharmacological agents can be delivered specifically to the submandibular salivary glands, thus providing a powerful tool to study the molecular machinery regulating endocytosis in a physiological context. C1 [Masedunskas, Andrius; Weigert, Roberto] Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. [Masedunskas, Andrius] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. RP Weigert, R (reprint author), Natl Inst Dent & Craniofacial Res, Intracellular Membrane Trafficking Unit, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Room 303A, Bethesda, MD 20892 USA. EM weigertr@mail.nih.gov OI Masedunskas, Andrius/0000-0002-4533-5467 FU Intramural NIH HHS [Z01 DE000717-01] NR 31 TC 24 Z9 24 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1398-9219 J9 TRAFFIC JI Traffic PD OCT PY 2008 VL 9 IS 10 BP 1801 EP 1810 DI 10.1111/j.1600-0854.2008.00798.x PG 10 WC Cell Biology SC Cell Biology GA 348VK UT WOS:000259238000020 PM 18647170 ER PT J AU Shabalina, SA Koonin, EV AF Shabalina, Svetlana A. Koonin, Eugene V. TI Origins and evolution of eukaryotic RNA interference SO TRENDS IN ECOLOGY & EVOLUTION LA English DT Review ID PROVIDES ACQUIRED-RESISTANCE; TRANSPOSABLE ELEMENTS; HUMAN MICRORNAS; ARABIDOPSIS-THALIANA; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; GENE-EXPRESSION; SIRNA DESIGN; C-ELEGANS; DROSOPHILA AB Small interfering RNAs (siRNAs) and genome-encoded microRNAs (miRNAs) silence genes via complementary interactions with mRNAs. With thousands of miRNA genes identified and genome sequences of diverse eukaryotes available for comparison, the opportunity emerges for insights into the origin and evolution of RNA interference (RNAi). The miRNA repertoires of plants and animals appear to have evolved independently. However, conservation of the key proteins involved in RNAi suggests that the last common ancestor of modern eukaryotes possessed siRNA-based mechanisms. Prokaryotes have an RNAi-like defense system that is functionally analogous but not homologous to eukaryotic RNAi. The protein machinery of eukaryotic RNAi seems to have been pieced together from ancestral archaeal, bacterial and phage proteins that are involved in DNA repair and RNA processing. C1 [Shabalina, Svetlana A.; Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Shabalina, SA (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM shabalin@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gob RI Shabalina, Svetlana/N-8939-2013 OI Shabalina, Svetlana/0000-0003-2272-7473 FU Intramural Research Program of the NIH, NLM FX The number of publications on rniRNA is vast, and space limitations preclude the citation of many relevant ones. We apologize to all colleagues whose work is not cited, solely for this reason. We thank Nikolay Spiridonov for helpful discussions and critical reading of the manuscript and Yuri Merezhuk for help with the preparation of the figures. The authors' research was supported by the Intramural Research Program of the NIH, NLM NR 85 TC 148 Z9 162 U1 4 U2 48 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0169-5347 J9 TRENDS ECOL EVOL JI Trends Ecol. Evol. PD OCT PY 2008 VL 23 IS 10 BP 578 EP 587 DI 10.1016/j.tree.2008.06.005 PG 10 WC Ecology; Evolutionary Biology; Genetics & Heredity SC Environmental Sciences & Ecology; Evolutionary Biology; Genetics & Heredity GA 361RM UT WOS:000260144800010 PM 18715673 ER PT J AU Assis, R Kondrashov, AS Koonin, EV Kondrashov, FA AF Assis, Raquel Kondrashov, Alexey S. Koonin, Eugene V. Kondrashov, Fyodor A. TI Nested genes and increasing organizational complexity of metazoan genomes SO TRENDS IN GENETICS LA English DT Article ID OVERLAPPING GENES; EVOLUTION; ORIGINS; TRANSCRIPTION; PATTERNS AB The most common form of protein-coding gene overlap in eukaryotes is a simple nested structure, whereby one gene is embedded in an intron of another. Analysis of nested protein-coding genes in vertebrates, fruit flies and nematodes revealed substantially higher rates of evolutionary gains than losses. The accumulation of nested gene structures could not be attributed to any obvious functional relationships between the genes involved and represents an increase of the organizational complexity of animal genomes via a neutral process. C1 [Kondrashov, Fyodor A.] Univ Calif San Diego, Div Biol Sci, Sect Ecol Behavior & Evolut, La Jolla, CA 92093 USA. [Koonin, Eugene V.] Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. [Assis, Raquel; Kondrashov, Alexey S.] Univ Michigan, Ctr Computat Med & Biol, Ann Arbor, MI 48109 USA. [Assis, Raquel; Kondrashov, Alexey S.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. RP Kondrashov, FA (reprint author), Univ Calif San Diego, Div Biol Sci, Sect Ecol Behavior & Evolut, La Jolla, CA 92093 USA. EM fkondrashov@ucsd.edu RI Kondrashov, Fyodor Alexeevich/H-6331-2015 OI Kondrashov, Fyodor Alexeevich/0000-0001-8243-4694 FU Intramural NIH HHS [Z01 LM000073-12] NR 25 TC 22 Z9 23 U1 0 U2 4 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD OCT PY 2008 VL 24 IS 10 BP 475 EP 478 DI 10.1016/j.tig.2008.08.003 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 370IQ UT WOS:000260756300001 PM 18774620 ER PT J AU Sethupathy, P Collins, FS AF Sethupathy, Praveen Collins, Francis S. TI MicroRNA target site polymorphisms and human disease SO TRENDS IN GENETICS LA English DT Review ID GENOME-WIDE ASSOCIATION; SINGLE-NUCLEOTIDE POLYMORPHISM; DIHYDROFOLATE-REDUCTASE GENE; CANCER SUSCEPTIBILITY LOCUS; SPASTIC PARAPLEGIA TYPE-31; POSITIVE BREAST-CANCER; COLORECTAL-CANCER; BINDING-SITES; POSTTRANSCRIPTIONAL REGULATION; CONFER SUSCEPTIBILITY AB MicroRNAs (miRNAs) are important regulators of eukaryotic gene expression. They have been implicated in a broad range of biological processes, and miRNA-related genetic alterations probably underlie more human diseases than currently appreciated. Several studies have identified genetic variants in miRNA target sites that are claimed to be associated with disorders ranging from Parkinson's disease to cancer. However, careful assessment of these studies indicates that very few provide a combination of rigorous genetic and functional evidence. We therefore suggest a set of concrete recommendations to guide future investigations. Specifically, we highlight the importance of unbiased association studies and follow-up functional experiments for providing a clearer picture of the extent to which microRNA target site variations are relevant in various human diseases. C1 [Sethupathy, Praveen; Collins, Francis S.] NHGRI, Bethesda, MD 20892 USA. RP Collins, FS (reprint author), NHGRI, Bethesda, MD 20892 USA. EM francisc@mail.nih.gov NR 97 TC 183 Z9 191 U1 5 U2 21 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD OCT PY 2008 VL 24 IS 10 BP 489 EP 497 DI 10.1016/j.tig.2008.07.004 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 370IQ UT WOS:000260756300006 PM 18778868 ER PT J AU Kawasaki, BT Farrar, WL AF Kawasaki, Brian T. Farrar, William L. TI Cancer stem cells, CD200 and immunoevasion SO TRENDS IN IMMUNOLOGY LA English DT Review ID ACUTE MYELOID-LEUKEMIA; PROGNOSTIC-FACTOR; PROSTATE-CANCER; HAIR FOLLICLE; TUMOR-CELLS; MRC OX-2; MICE; IMMUNOTHERAPY; EXPRESSION; RECEPTOR AB The limited success seen in cancer immunotherapy signifies that an alternative approach is required. Advances in cancer biology have identified a biologically unique subpopulation of cells, termed cancer stem cells (CSC), that survive after conventional therapy. CSCs are the putative cancer-initiating cells responsible for tumor initiation, progression and metastasis. CSCs might be able to evade the immune system by generating a tolerogenic response facilitated by the immunosuppressive factor CD200. This article reviews the biological importance of CSCs and the potentially important role of CD200 in tumor immunology. Moreover, we discuss the prospective role CD200 plays in the ability of a CSC to escape the immune system. Future immunotherapy must consider targeting CSCs to achieve curative responses. C1 [Kawasaki, Brian T.; Farrar, William L.] NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Frederick, MD 21702 USA. RP Farrar, WL (reprint author), NCI, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Frederick, MD 21702 USA. EM farrar@mail.ncifcrf.gov FU NIH; National Cancer Institute; Center for Cancer Research; National Cancer institute, National Institutes of Health [N01-CO-12400] FX The authors thank Elaine Hurt for wonderful editing assistance. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This work has been funded in part with Federal funds from the National Cancer institute, National Institutes of Health, under Contract N01-CO-12400. The content of this paper does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations Imply endorsement by the US Government. NR 47 TC 43 Z9 46 U1 0 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD OCT PY 2008 VL 29 IS 10 BP 464 EP 468 DI 10.1016/j.it.2008.07.005 PG 5 WC Immunology SC Immunology GA 365YE UT WOS:000260445000002 PM 18775673 ER PT J AU Kim, MS Radinger, M Gilfillan, AM AF Kim, Mi-Sun Radinger, Madeleine Gilfillan, Alasdair M. TI The multiple roles of phosphoinositide 3-kinase in mast cell biology SO TRENDS IN IMMUNOLOGY LA English DT Review ID FC-EPSILON-RI; PROTEIN-TYROSINE KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; CYTOKINE PRODUCTION; REGULATORY SUBUNIT; CALCIUM MOBILIZATION; ALLERGIC RESPONSE; INDUCED SECRETION; ANTIGEN RECEPTOR; IN-VIVO AB Mast cells play a central role in the initiation of inflammatory responses associated with asthma and other allergic disorders. Receptor-mediated mast cell growth, differentiation, homing to their target tissues, survival and activation are all controlled, to varying degrees, by phosphoinositide-3-kinase (PI3K)-driven pathways. It is not fully understood how such diverse responses can be differentially regulated by PI3K. However, recent studies have provided greater insight into the mechanisms that control, and those that are controlled by, different PI3K subunit isoforms in mast cells. In this review, we discuss how PI3K influences the mast cell processes described above. Furthermore, we describe how different mast cell receptors use alternative isoforms of PI3K for these functions and discuss potential downstream targets of these isoforms. C1 [Kim, Mi-Sun; Radinger, Madeleine; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Gilfillan, AM (reprint author), NIAID, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM agilfillan@niaid.nih.gov FU NIAID; National Institues of Health FX Research in the authors' laboratory is supported by the NIAID Intramural Program with the National Institues of Health. The authors thank Michael A. Beaven LMI/NHLBI/NIH for critical review of the manuscript and the editor and the reviewers of this manuscript for helpful comments. Because of space constraints, not all pertinent, literature could be referenced in this article. This does not imply that other articles not referenced are of lesser merit. NR 92 TC 58 Z9 59 U1 1 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD OCT PY 2008 VL 29 IS 10 BP 493 EP 501 DI 10.1016/j.it.2008.07.004 PG 9 WC Immunology SC Immunology GA 365YE UT WOS:000260445000006 PM 18775670 ER PT J AU Chadwick, W Magnus, T Martin, B Keselman, A Mattson, MP Maudsley, S AF Chadwick, Wayne Magnus, Tim Martin, Bronwen Keselman, Aleksander Mattson, Mark P. Maudsley, Stuart TI Targeting TNF-alpha receptors for neurotherapeutics SO TRENDS IN NEUROSCIENCES LA English DT Review ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; BETA-PEPTIDE TOXICITY; INDUCED APOPTOSIS; BRAIN-INJURY; CELL-DEATH; HIPPOCAMPAL-NEURONS; MULTIPLE-SCLEROSIS; DIFFERENTIAL EXPRESSION C1 [Chadwick, Wayne; Keselman, Aleksander; Maudsley, Stuart] NIA, Receptor Pharmacol Unit, Neurosci Lab, Biomed Res Ctr, Baltimore, MD 21224 USA. [Magnus, Tim] Univ Hamburg, Neurol Univ Klin, ERSI, D-20246 Hamburg, Germany. [Martin, Bronwen; Mattson, Mark P.] NIA, Cellular & Mol Neurosci Lab, Neurosci Lab, Biomed Res Ctr, Baltimore, MD 21224 USA. [Martin, Bronwen] NIA, Diabet Sect, Lab Clin Invest, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Maudsley, S (reprint author), NIA, Receptor Pharmacol Unit, Neurosci Lab, Biomed Res Ctr, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM maudsleyst@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU Intramural NIH HHS [Z01 AG000318-02] NR 90 TC 32 Z9 32 U1 0 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD OCT PY 2008 VL 31 IS 10 BP 504 EP 511 DI 10.1016/j.tins.2008.07.005 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 369OH UT WOS:000260703300002 PM 18774186 ER PT J AU Than, NG Rahman, OA Magenheim, R Nagy, B Fule, T Hargitai, B Sammar, M Hupuczi, P Tarca, AL Szabo, G Kovalszky, I Meiri, H Sziller, I Rigo, J Romero, R Papp, Z AF Than, Nandor Gabor Rahman, Omar Abdul Magenheim, Rita Nagy, Balint Fule, Tibor Hargitai, Beata Sammar, Marei Hupuczi, Petronella Tarca, Adi L. Szabo, Gabor Kovalszky, Ilona Meiri, Hamutal Sziller, Istvan Rigo, Janos, Jr. Romero, Roberto Papp, Zoltan TI Placental protein 13 (galectin-13) has decreased placental expression but increased shedding and maternal serum concentrations in patients presenting with preterm pre-eclampsia and HELLP syndrome SO VIRCHOWS ARCHIV LA English DT Article DE brush border membrane; galectin; syncytiotrophoblast microparticle; trafficking; virtual microscopy ID INTRAUTERINE GROWTH RESTRICTION; ONSET PREECLAMPSIA; SPIRAL ARTERIES; PRE-ECLAMPSIA; PREGNANCY; PROTEIN; CELLS; SYNCYTIN; PP-13; GENE AB Placental protein 13 (PP13) is a galectin expressed by the syncytiotrophoblast. Women who subsequently develop preterm pre-eclampsia have low first trimester maternal serum PP13 concentrations. This study revealed that third trimester maternal serum PP13 concentration increased with gestational age in normal pregnancies (p < 0.0001), and it was significantly higher in women presenting with preterm pre-eclampsia (p = 0.02) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome (p = 0.01) than in preterm controls. Conversely, placental PP13 mRNA (p = 0.03) and protein, as well as cytoplasmic PP13 staining of the syncytiotrophoblast (p < 0.05) was decreased in these pathological pregnancies compared to controls. No differences in placental expression and serum concentrations of PP13 were found at term between patients with pre-eclampsia and control women. In contrast, the immunoreactivity of the syncytiotrophoblast microvillous membrane was stronger in both term and preterm pre-eclampsia and HELLP syndrome than in controls. Moreover, large syncytial cytoplasm protrusions, membrane blebs and shed microparticles strongly stained for PP13 in pre-eclampsia and HELLP syndrome. In conclusion, parallel to its decreased placental expression, an augmented membrane shedding of PP13 contributes to the increased third trimester maternal serum PP13 concentrations in women with preterm pre-eclampsia and HELLP syndrome. C1 [Rahman, Omar Abdul] Semmelweis Univ, Dept Med Chem Mol Biol & Pathobiochem, H-1088 Budapest, Hungary. [Magenheim, Rita] Semmelweis Univ, Dept Internal Med 1, H-1088 Budapest, Hungary. [Fule, Tibor; Hargitai, Beata; Kovalszky, Ilona] Semmelweis Univ, Dept Pathol & Expt Canc Res 1, H-1085 Budapest, Hungary. [Sammar, Marei; Meiri, Hamutal] Diagnost Technol Ltd, IL-20692 Yokneam, Israel. [Tarca, Adi L.; Romero, Roberto] Wayne State Univ, Hutzel Womens Hosp, NICHD,NIH,DHHS, Perinatol Res Branch, Detroit, MI 48201 USA. [Than, Nandor Gabor; Nagy, Balint; Hupuczi, Petronella; Szabo, Gabor; Sziller, Istvan; Rigo, Janos, Jr.; Papp, Zoltan] Semmelweis Univ, Dept Obstet & Gynecol 1, H-1088 Budapest, Hungary. RP Than, NG (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD,NIH,DHHS, Perinatol Res Branch, 3990 John R, Detroit, MI 48201 USA. EM nthan@med.wayne.edu RI Nagy, Balint/F-6943-2012; Abdul Rahman, Omar/C-6692-2013 OI Abdul Rahman, Omar/0000-0001-9655-8292 FU Hungarian Orszagos Tudomanyos Kutatasi Alapprogramok [T/046473]; European Union; Israel Chief Scientist [31851, 37324, 14128] FX This research was funded by the Hungarian Orszagos Tudomanyos Kutatasi Alapprogramok (T/046473 to N. G. T.) and by grants from the European Union (FP6, "Pregenesys-037244" to H. M. and N. G. T.) and the Israel Chief Scientist (31851, 37324, 14128 to H. M.). NR 62 TC 45 Z9 47 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0945-6317 J9 VIRCHOWS ARCH JI Virchows Arch. PD OCT PY 2008 VL 453 IS 4 BP 387 EP 400 DI 10.1007/s00428-008-0658-x PG 14 WC Pathology SC Pathology GA 352WM UT WOS:000259528100010 PM 18791734 ER PT J AU Subbiah, M Xiao, S Collins, PL Samal, SK AF Subbiah, Madhuri Xiao, Sa Collins, Peter L. Samal, Siba K. TI Complete sequence of the genome of avian paramyxovirus type 2 (strain Yucaipa) and comparison with other paramyxoviruses SO VIRUS RESEARCH LA English DT Article DE avian paramyxoviruses; APMV-2 strain yucaipa; complete genome sequence; phylogenetic analysis ID NEWCASTLE-DISEASE VIRUS; COMPLETE NUCLEOTIDE-SEQUENCE; FUSION PROTEIN; SENDAI-VIRUS; WILD BIRDS; AMINO-ACID; RESPIRATORY-DISEASE; CYNOMOLGUS MONKEYS; CLEAVAGE SITE; RNA AB The complete RNA genome sequence of avian paramyxovirus (APMV) serotype 2, strain Yucaipa isolated from chicken has been determined. With genome size of 14,904 nucleotides (nt), strain Yucaipa is consistent with the "rule of six" and is the smallest virus reported to date among the members of subfamily Paramyxovirinae. The genome contains six non-overlapping genes in the order 3'-N-P/V-M-F-HN-L-5'. The genes are flanked on either side by highly conserved transcription start and stop signals and have intergenic sequences varying in length from 3 to 23 nt. The genome contains a 55 nt leader sequence at 3' end and a 154 nt trailer sequence at 5' end. Alignment and phylogenetic analysis of the predicted amino acid sequences of strain Yucaipa proteins with the cognate proteins of viruses of all of the five genera of family Puramyxoviridae showed that APMV-2 strain Yucaipa is more closely related to APMV-6 than APMV-1. (C) 2008 Elsevier B.V. All rights reserved. C1 [Subbiah, Madhuri; Xiao, Sa; Samal, Siba K.] Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. [Collins, Peter L.] NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Samal, SK (reprint author), Univ Maryland, Virginia Maryland Reg Coll Vet Med, College Pk, MD 20742 USA. EM ssamal@umd.edu FU MAID [N01A060009]; NIH Intramural Research Program FX We thank Daniel Rockemann and all our laboratory members for their excellent technical assistance and help. We also thank Hamp Edwards for performing the electron micrograph and Ireen Dryburgh-Barry for proof reading of this manuscript. This research was supported by MAID contract no. N01A060009 (85% support) and MAID, NIH Intramural Research Program (15% support). The views expressed herein do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention the trade names, commercial practices or organizations imply endorsement by the U.S. Government. NR 54 TC 35 Z9 35 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD OCT PY 2008 VL 137 IS 1 BP 40 EP 48 DI 10.1016/j.virusres.2008.05.012 PG 9 WC Virology SC Virology GA 356BD UT WOS:000259752800005 PM 18603323 ER PT J AU Muftuoglu, M Kulikowicz, T Beck, G Lee, JW Piotrowski, J Bohr, VA AF Muftuoglu, Meltem Kulikowicz, Tomasz Beck, Gad Lee, Jae Wan Piotrowski, Jason Bohr, Vilhelm A. TI Intrinsic ssDNA annealing activity in the C-terminal region of WRN SO BIOCHEMISTRY LA English DT Article ID WERNER-SYNDROME PROTEIN; BLOOMS-SYNDROME HELICASE; OKAZAKI FRAGMENT MATURATION; SINGLE-STRANDED-DNA; FLAP ENDONUCLEASE-1; HRDC DOMAIN; EXONUCLEASE ACTIVITY; RECQ HELICASES; GAP PENALTIES; BINDING AB Werner syndrome (WS) is a rare autosomal recessive disorder in humans characterized by premature aging and genetic instability. WS is caused by mutations in the WRN gene, which encodes a member of the RecQ family of DNA helicases. Cellular and biochemical studies suggest that WRN plays roles in DNA replication, DNA repair, telomere maintenance, and homologous recombination and that WRN has multiple enzymatic activities including 3' to 5' exonuclease, 3' to 5' helicase, and ssDNA annealing. The goal of this study was to map and further characterize the ssDNA annealing activity of WRN. Enzymatic studies using truncated forms of WRN identified a C-terminal 79 amino acid region between the RQC and the HRDC domains (aa1072-1150) that is required for ssDNA annealing activity. Deletion of the region reduced or eliminated ssDNA annealing activity of the WRN protein. Furthermore, the activity appears to correlate with DNA binding and oligomerization status of the protein. C1 [Muftuoglu, Meltem; Kulikowicz, Tomasz; Beck, Gad; Lee, Jae Wan; Piotrowski, Jason; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@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 42 TC 19 Z9 19 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 30 PY 2008 VL 47 IS 39 BP 10247 EP 10254 DI 10.1021/bi800807n PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351UC UT WOS:000259450400003 PM 18771289 ER PT J AU Lardinois, OM Tomer, KB Mason, RP Deterding, LJ AF Lardinois, Olivier M. Tomer, Kenneth B. Mason, Ronald P. Deterding, Leesa J. TI Identification of protein radicals formed in the human neuroglobin - H2O2 reaction using immuno-spin trapping and mass spectrometry SO BIOCHEMISTRY LA English DT Article ID HYDROGEN-PEROXIDE; LIGAND-BINDING; GLOBIN FAMILY; NITRIC-OXIDE; OXIDATIVE STRESS; CYTOGLOBIN; OXYGEN; HEMOGLOBIN; BRAIN; METMYOGLOBIN AB Neuroglobin (Ngb) is a recently discovered protein that shows only minor sequence similarity with myoglobin and hemoglobin but conforms to the typical 3-over-3 alpha-helical fold characteristic of vertebrate globins. An intriguing feature of Ngb is its heme hexacoordination in the absence of external ligands, observed both in the ferrous and in the ferric (met) forms. In Ngb, the imidazole of a histidine residue (His-64) in the distal position, above the heme plane, provides the sixth coordination bond. In this work, a valine residue was introduced at position 64 (H64V variant) to clarify the possible role(s) of the distal residue in protecting the heme iron of Ngb from attack by strong oxidants. SDS-PAGE analyses revealed that the oxidation of the H64V variant of metNgb by H2O2 resulted in the formation of dimeric and trimeric products in contrast to the native protein. Dityrosine cross-links were shown by their fluorescence to be present in the oligomeric products. When the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) was included in the reaction mixture, nitrone adducts were detected by immuno-spin trapping. The specific location of the DMPO adducts on the H64V variant protein was determined by a mass spectrometry method that combines off-line immuno-spin trapping and chromatographic procedures. This method revealed Tyr-88 to be the site of modification by DMPO. The presence of His-64 in the wild-type protein results in the nearly complete loss of detectable radical adducts. Together, the data support the argument that wild-type Ngb is protected from attack by H2O2 by the coordinated distal His. C1 [Lardinois, Olivier M.; Mason, Ronald P.] Natl Inst Environm Hlth Sci, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. [Tomer, Kenneth B.; Deterding, Leesa J.] Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Lardinois, OM (reprint author), Natl Inst Environm Hlth Sci, Pharmacol Lab, Res Triangle Pk, NC 27709 USA. EM lardinois.olivier@gmail.com RI Tomer, Kenneth/E-8018-2013 FU National Institutes of Health; National Institute of Environmental Health Sciences FX This work has been supported by the Intramural Research Program of the National Institutes of Health and the National Institute of Environmental Health Sciences. NR 50 TC 27 Z9 29 U1 1 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 30 PY 2008 VL 47 IS 39 BP 10440 EP 10448 DI 10.1021/bi800771k PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 351UC UT WOS:000259450400022 PM 18767815 ER PT J AU De Bernardi, B Mosseri, V Rubie, H Castel, V Foot, A Ladenstein, R Laureys, G Beck-Popovic, M de Lacerda, AF Pearson, ADJ De Kraker, J Ambros, PF de Rycke, Y Conte, M Bruzzi, P Michon, J AF De Bernardi, B. Mosseri, V. Rubie, H. Castel, V. Foot, A. Ladenstein, R. Laureys, G. Beck-Popovic, M. de Lacerda, A. F. Pearson, A. D. J. De Kraker, J. Ambros, P. F. de Rycke, Y. Conte, M. Bruzzi, P. Michon, J. TI Treatment of localised resectable neuroblastoma. Results of the LNESG1 study by the SIOP Europe Neuroblastoma Group SO BRITISH JOURNAL OF CANCER LA English DT Article DE neuroblastoma; localised; MYCN gene; prognostic factors ID ITALIAN COOPERATIVE GROUP; PEDIATRIC-ONCOLOGY-GROUP; CHILDRENS-CANCER-GROUP; II NEURO-BLASTOMA; PATHOLOGY CLASSIFICATION; CHILDHOOD NEUROBLASTOMA; STAGE-IV; THERAPY; DIAGNOSIS; DISEASE AB Main objective of this study was to confirm that surgery alone is an effective and safe treatment for localised resectable neuroblastoma except stage 2 with amplified MYCN gene (MYCNA). Of 427 eligible stages 1-2 patients, 411 had normal MYCN and 16 had MYCNA. Of the 288 stage 1 patients with normal MYCN, 1 died of complications and 16 relapsed, 2 of whom died; 5-year relapse-free survival (RFS) and overall survival (OS) rates were 94.3% (95% confidence interval (CI): 91.6-97) and 98.9% (95% CI: 97.7-100), respectively. Of the 123 stage 2 patients with normal MYCN, 1 died of sepsis and 22 relapsed, 8 of whom died (RFS 82.8%, 95% CI: 76.2-89.5; OS 93.2%, 95% CI: 88.7-97.8). In stage 2, OS and RFS were worse for patients with elevated LDH and unfavourable histopathology. Of 16 children with MYCNA, 7 were stage 1 (5 relapses and 4 deaths) and 9 were stage 2 (3 relapses and 2 deaths) patients. In conclusion, surgery alone yielded excellent OS for both stage 1 and 2 neuroblastoma without MYCNA, although stage 2 patients with unfavourable histopathology and elevated LDH suffered a high number of relapses. Both stage 1 and 2 patients with MYCNA were at greater risk of relapse. C1 [De Bernardi, B.; Conte, M.] Giannina Gaslini Childrens Hosp, Dept Paediat Haematol & Oncol, I-16148 Genoa, Italy. [Mosseri, V.; de Rycke, Y.] Inst Curie, Stat Unit, Paris, France. [Rubie, H.] Hop Enfants, Dept Paediat Haematol & Oncol, Toulouse, France. [Castel, V.] Hosp Infantil Univ La Fe, Paediat Oncol Unit, Valencia, Spain. [Foot, A.] Royal Childrens Hosp, Dept Paediat, Bristol, Avon, England. [Ladenstein, R.] St Anna Childrens Hosp, Dept Paediat Oncol, Vienna, Austria. [Laureys, G.] Univ Hosp, Dept Paediat Haematol & Oncol, Ghent, Belgium. [Beck-Popovic, M.] CHU Vaudois, Dept Paediat Haematol & Oncol, Lausanne, Switzerland. [de Lacerda, A. F.] Intituto Portugues Oncol Francisco Gentil, Dept Pediat, Lisbon, Portugal. [Pearson, A. D. J.] Royal Marsden Hosp, Dept Paediat Haematol & Oncol, Sutton, Surrey, England. [De Kraker, J.] Emma Childrens Hosp, Acad Med Ctr, Dept Paediat Oncol, Amsterdam, Netherlands. [Ambros, P. F.] St Anna Childrens Hosp, Childrens Canc Res Inst, Vienna, Austria. [Bruzzi, P.] Natl Canc Inst, Clin Trials Unit, Genoa, Italy. [Michon, J.] Inst Curie, Dept Paediat, Paris, France. RP De Bernardi, B (reprint author), Giannina Gaslini Childrens Hosp, Dept Paediat Haematol & Oncol, Largo Gerolamo Gaslini 5, I-16148 Genoa, Italy. EM brunodebernardi@ospedale-gaslini.ge.it RI conte, massimo/K-2049-2016; OI conte, massimo/0000-0001-9405-7339; Bruzzi, Paolo/0000-0002-7874-2077; Castel, Victoria/0000-0002-3792-0615; Ambros, Peter F./0000-0002-5507-7211 FU Association pour la Recherche sur le Cancer; Institut Curie (Paris, France); Associazione Italiana per la Lotta al Neuroblastoma (Genova, Italy) FX We warmly thank the many physicians who provided their patients' data, Dr Emanuele SG D'Amore for his helpful suggestions, Ms Sara Calmanti and Ms Tania Caputo for their assistance with editing, and Mr Bernard Patrick for revising the English text. This study was supported, in part, by grants from the Association pour la Recherche sur le Cancer and Institut Curie (Paris, France) and the Associazione Italiana per la Lotta al Neuroblastoma (Genova, Italy). NR 28 TC 34 Z9 34 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 30 PY 2008 VL 99 IS 7 BP 1027 EP 1033 DI 10.1038/sj.bjc.6604640 PG 7 WC Oncology SC Oncology GA 355AS UT WOS:000259681600007 PM 18766186 ER PT J AU Wangsa, D Ryott, M Avall-Lundqvist, E Petersson, F Elmberger, G Luo, J Ried, T Auer, G Munck-Wikland, E AF Wangsa, D. Ryott, M. Avall-Lundqvist, E. Petersson, F. Elmberger, G. Luo, J. Ried, T. Auer, G. Munck-Wikland, E. TI Ki-67 expression predicts locoregional recurrence in stage I oral tongue carcinoma SO BRITISH JOURNAL OF CANCER LA English DT Article DE oral cancer; Ki-67; locoregional recurrence; ploidy; genomic instability ID SQUAMOUS-CELL-CARCINOMA; NECK-CANCER; PROGNOSTIC-SIGNIFICANCE; HISTOLOGIC RESPONSE; YOUNG-ADULTS; DNA-CONTENT; HEAD; MARKERS; P53; SURVIVAL AB Oral tongue squamous cell carcinoma (OTSCC) is an aggressive cancer associated with poor prognosis. Methods for determining the aggressiveness of OTSCC from analysis of the primary tumour specimen are thus highly desirable. We investigated whether genomic instability and proliferative activity (by means of Ki-67 activity) could be of clinical use for prediction of locoregional recurrence in 76 pretreatment OTSCC paraffin samples (stage I, n = 22; stage II, n = 33; stage III, n = 8; stage IV, n = 13). Eleven surgical tumour specimens were also analysed for remnants of proliferative activity after preoperative radiotherapy. Ninety-seven percent of cases (n 72) were characterised as being aneuploid as measured by means of image cytometry. Preoperative radiotherapy (50-68 Gy) resulted in significant reduction of proliferative activity in all patients for which post-treatment biopsies were available (P-value = 0.001). Proliferative activity was not associated with response to radiation in stage II patients. However, we report a significant correlation between high proliferation rates and locoregional recurrences in stage I OTSCC patients (P-value = 0.028). High-proliferative activity is thus related to an elevated risk of recurrence after surgery alone. We therefore conclude that Ki-67 expression level is a potentially useful clinical marker for predicting recurrence in surgically treated stage I OTSCC. C1 [Wangsa, D.; Petersson, F.; Elmberger, G.; Auer, G.] Karolinska Univ Hosp, Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden. [Wangsa, D.; Ried, T.] NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ryott, M.; Munck-Wikland, E.] Karolinska Univ Hosp, Dept Otorhino Laryngol Head & Neck Surg, Stockholm, Sweden. [Avall-Lundqvist, E.] Karolinska Univ Hosp, Dept Gynaecol Oncol, Radium Hemmet, Stockholm, Sweden. [Luo, J.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. RP Wangsa, D (reprint author), Karolinska Inst, Dept Pathol & Oncol, Z5 02, SE-17176 Stockholm, Sweden. EM darawalee.wangsa@ki.se RI Avall-Lundqvist, Elisabeth/C-9292-2009 FU Swedish Cancer Society (Cancerfonden); Cancer Society of Stockholm (Cancerforeningen), Laryngfonden; Karolinska Institutet FX This work was supported by the Swedish Cancer Society (Cancerfonden), the Cancer Society of Stockholm (Cancerforeningen), Laryngfonden, and Karolinska Institutet. We gratefully thank Ann Ohlssen and Margareta Waern for excellent technical assistance. We also thank Patricia Ried for high-quality editing of the paper and Kerstin Heselmeyer-Haddad for critical advice. NR 45 TC 30 Z9 32 U1 0 U2 0 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 SEP 30 PY 2008 VL 99 IS 7 BP 1121 EP 1128 DI 10.1038/sj.bjc.6604633 PG 8 WC Oncology SC Oncology GA 355AS UT WOS:000259681600020 PM 18766188 ER PT J AU Troisi, R Hoover, RN Thadhani, R Hsieh, CC Sluss, P Ballard-Barbash, R Potischman, N AF Troisi, R. Hoover, R. N. Thadhani, R. Hsieh, C-C Sluss, P. Ballard-Barbash, R. Potischman, N. TI Maternal, prenatal and perinatal characteristics and first trimester maternal serum hormone concentrations SO BRITISH JOURNAL OF CANCER LA English DT Article DE hormones; birth weight; maternal age; parity; smoking ID BREAST-CANCER; BIRTH-WEIGHT; PREGNANCY ESTRIOL; BINDING GLOBULIN; UNITED-STATES; ETHNIC-GROUPS; RISK; ESTRADIOL; AGE; PROGESTERONE AB In uncomplicated pregnancies, first trimester androgen, oestrogen and prolactin concentrations were higher in nulliparous (n = 160) than parous (n = 260) mothers. Androgens and estrogens were higher in younger than older mothers. These data are consistent with elevated hormone concentrations mediating the breast cancer protection from a first pregnancy and pregnancies occurring at younger ages. C1 [Troisi, R.; Hoover, R. N.] Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, Rockville, MD 20892 USA. [Thadhani, R.; Sluss, P.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Hsieh, C-C] Univ Massachusetts, Sch Med, Worcester, MA 01605 USA. [Ballard-Barbash, R.; Potischman, N.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Rockville, MD 20892 USA. RP Troisi, R (reprint author), Dartmouth Hitchcock Med Ctr, Room 854,7297 Rubin Bldg,1 Med Ctr Dr, Lebanon, NH 03756 USA. EM troisir@mail.nih.gov FU Divisions of Cancer Epidemiology and Genetics and Cancer Control and Population Sciences; National Cancer Institute; National Institutes of Health; US Department of Health and Human Services; HD [39223] FX The Divisions of Cancer Epidemiology and Genetics and Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, US Department of Health and Human Services provided funding for the hormone assays, data analysis and article preparation. HD 39223 provided funding for the collection of original data. NR 26 TC 22 Z9 22 U1 0 U2 0 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 SEP 30 PY 2008 VL 99 IS 7 BP 1161 EP 1164 DI 10.1038/sj.bjc.6604639 PG 4 WC Oncology SC Oncology GA 355AS UT WOS:000259681600025 PM 18766187 ER PT J AU Clements, RT Smejkal, G Sodha, NR Ivanov, AR Asara, JM Feng, J Lazarev, A Gautam, S Senthilnathan, V Khabbaz, KR Bianchi, C Sellke, FW AF Clements, Richard T. Smejkal, Gary Sodha, Neel R. Ivanov, Alexander R. Asara, John M. Feng, Jun Lazarev, Alexander Gautam, Shiva Senthilnathan, Venkatachalam Khabbaz, Kamal R. Bianchi, Cesario Sellke, Frank W. TI Pilot proteomic profile of differentially regulated proteins in right atrial appendage before and after cardiac surgery using cardioplegia and cardiopulmonary bypass SO CIRCULATION LA English DT Article; Proceedings Paper CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc DE cardioplegia; cardiopulmonary bypass; proteomics ID MYOSIN LIGHT-CHAIN; ALPHA(1)-ACID GLYCOPROTEIN; MYOCARDIAL-INFARCTION; CLINICAL IMPLICATIONS; GEL-ELECTROPHORESIS; BRIEF ISCHEMIA; PHOSPHORYLATION; CONSEQUENCES; CONTRACTION; FILAMENTS AB Background-Although highly protective, cardiac surgery using cardioplegia and cardiopulmonary bypass (CP/CPB) subjects myocardium to hypothermic reversible ischemic injury that can impair cardiac function which results in a greatly enhanced risk of mortality. Acute changes in myocardial contractile activity are likely regulated via protein modifications. We performed the following study to determine changes in the protein profile of human myocardium following CP/CPB. Methods and Results-Right atrial appendage was collected from 8 male patients pre and post-CP/CPB. Atrial tissue lysates were subjected to 2-dimensional electrophoresis, total protein staining, gel averaging, and quantitative densitometry. Ten prominent spots regulated in response to CP/CPB were identified using mass spectrometry. Two hundred twenty-five and 256 protein spots were reliably detected in 2D-gels from pre- and post-CP/CPB patients, respectively. Five unique (ie, not detected post-CP/CPB) and 17 significantly increased spots were detected pre-CP/CPB. Thirty-four unique and 25 significantly increased spots were detected in the post-CP/CPB group. Identified proteins that changed after CP/CPB included: MLC-2a, ATP-synthase delta chain and Enoyl-CoenzymeA hydratase, glutathione-s-transferase omega, alpha-1-acid-glycoprotein, and phosphatidylethanolamine-binding protein. Conclusions-Cardiac surgery results in multiple consistent changes in the human myocardial protein profile. CP/CPB modifies specific cytoskeletal, metabolic, and inflammatory proteins potentially involved in deleterious effects of CP/CPB. C1 [Clements, Richard T.; Sodha, Neel R.; Feng, Jun; Gautam, Shiva; Senthilnathan, Venkatachalam; Khabbaz, Kamal R.; Bianchi, Cesario; Sellke, Frank W.] Beth Israel Deaconess Med Ctr, Div Cardiothorac Surg, Dept Surg, Boston, MA 02215 USA. [Smejkal, Gary; Lazarev, Alexander] Pressure Biosci, Prote & Small Mol Applicat Lab, W Bridgewater Mass, MA USA. [Ivanov, Alexander R.] Harvard Univ, Sch Publ Hlth, Harvard NIEHS Ctr Environm Hlth Prote Facil, Boston, MA 02115 USA. [Asara, John M.] Beth Israel Deaconess Med Ctr, Div Signal Transduct, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. RP Sellke, FW (reprint author), Beth Israel Deaconess Med Ctr, Div Cardiothorac Surg, Dept Surg, LMOB 2A,110 Francis St, Boston, MA 02215 USA. EM fsellke@bidmc.harvard.edu RI bianchi, cesario/H-6238-2012; OI Feng, Jun/0000-0003-4762-7532 FU NHLBI NIH HHS [T32 HL076130, R01 HL069024, R01 HL046716, 5T32-HL076130-02, R01-HL69024, R01 HL046716-17, R01-HL46716] NR 33 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 30 PY 2008 VL 118 IS 14 SU 1 BP S24 EP S31 DI 10.1161/CIRCULATIONAHA.107.792747 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 354OJ UT WOS:000259648600004 PM 18824761 ER PT J AU Yang, M Kostov, Y Rasooly, A AF Yang, Minghui Kostov, Yordan Rasooly, Avraham TI Carbon nanotubes based optical immunodetection of Staphylococcal Enterotoxin B (SEB) in food SO INTERNATIONAL JOURNAL OF FOOD MICROBIOLOGY LA English DT Article DE staphylococcal enterotoxins; ELISA; carbon nanotubes; food safety ID FIELD-EFFECT TRANSISTORS; ASSAY KIT TECRA; ATOPIC-DERMATITIS; ELECTROCHEMICAL IMMUNOSENSOR; CAPILLARY-ELECTROPHORESIS; RHEUMATOID-ARTHRITIS; SUPERANTIGENS; AUREUS; TOXIN; IDENTIFICATION AB Staphylococcal enterotoxins (SEs) are a major cause of food-borne diseases. traditionally SEs assayed immunologically with ELISA. Carbon nanotubes' (CNT) unique mechanical and electronic properties combined with a large specific surface area make them attractive for biosensing. To investigate whether CNT could improve the sensitivity of ELISA assays, we developed an optical CNT immunosensor for the detection of Staphylococcal Enterotoxin B (SEB) in food. Anti-SEB antibodies were immobilized onto a CNT surface through electrostatic adsorption and then the antibody-nanotube mixture was bound onto a polycarbonate film. SEB was then detected by a "sandwich-type" ELISA assay on the polycarbonate film. The use of CNT increased the sensitivity of the immunosensor by at least 6-fold, lowering the detection limit of SEB. The CNT immunosensor was also able to detect SEB various foods. suggesting the utility of CNT for this and other optical-based immunological detection methods. Published by Elsevier B.V. C1 [Yang, Minghui; Kostov, Yordan] Univ Maryland Baltimore Cty, Ctr Adv Sensor Technol, Baltimore, MD 21250 USA. [Rasooly, Avraham] US FDA, Div Biol, Off Sci & Engn, Silver Spring, MD 20993 USA. [Rasooly, Avraham] NCI, Bethesda, MD 20892 USA. RP Rasooly, A (reprint author), NCI, NIH, 6130 Execut Blvd EPN,Room 6035A, Rockville, MD 20852 USA. EM rasoolya@mail.nih.gov NR 59 TC 28 Z9 28 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1605 J9 INT J FOOD MICROBIOL JI Int. J. Food Microbiol. PD SEP 30 PY 2008 VL 127 IS 1-2 BP 78 EP 83 DI 10.1016/j.ijfoodmicro.2008.06.012 PG 6 WC Food Science & Technology; Microbiology SC Food Science & Technology; Microbiology GA 356IG UT WOS:000259771300013 PM 18632175 ER PT J AU Melenhorst, JJ Scheinberg, P Chattopadhyay, PK Lissina, A Gostick, E Cole, DK Wooldridge, L van den Berge, HA Bornstein, E Hensel, NF Douek, DC Roederer, M Sewell, AK Barrett, AJ Price, DA AF Melenhorst, J. Joseph Scheinberg, Phillip Chattopadhyay, Pratip K. Lissina, Anna Gostick, Emma Cole, David K. Wooldridge, Linda van den Berge, Hugo A. Bornstein, Ethan Hensel, Nancy F. Douek, Daniel C. Roederer, Mario Sewell, Andrew K. Barrett, A. John Price, David A. TI Detection of low avidity CD8(+) T cell populations with coreceptor-enhanced peptide-major histocompatibility complex class I tetramers SO JOURNAL OF IMMUNOLOGICAL METHODS LA English DT Article DE peptide-major histocompatibility complex class I tetramer; polychromatic flow cytometry; T cell ID RECEPTOR RECOGNITION; EFFECTOR FUNCTION; CROSS-REACTIVITY; ANTIGEN RECEPTOR; BINDING; AFFINITY; SPECIFICITY; LYMPHOCYTES; PROLIFERATION; ACTIVATION AB The development of soluble recombinant peptide-major histocompatibility complex class I (pMHCI) molecules conjugated in multimeric form to fluorescent labels has enabled the physical quantification and characterization of antigen-specific CD8(+) T cell populations by flow cytometry. Several factors determine the binding threshold that enables visualization of cognate CD8(+) T cells with these reagents; these include the affinity of the T cell receptor (TCR) for pMHCl antigen. Here, we show that multimers constructed from peptide-human leukocyte antigen (pHLA) A*0201 monomers engineered in the heavy chain alpha 2 domain to enhance CD8 binding (K-D approximate to 85 mu M) without impacting the TCR binding platform can detect cognate CD8(+) T cells bearing low affinity TCRs that are not visible with the corresponding wildtype pHLA A*0201 multimeric complexes. Mechanistically, this effect is mediated by a disproportionate enhancement of the TCR/pMHCl association rate. In direct ex vivo applications, these coreceptor-enhanced multimers exhibit faithful cognate binding properties; concomitant increases in background staining within the non-cognate CD8(+) T cell population can be resolved phenotypically using polychromatic flow cytometry as a mixture of naive and memory cells. These findings provide the first validation of a novel approach to the physical detection of low avidity antigen-specific CD8(+) T cell populations; such coreceptor-enhanced multimeric reagents are likely to be useful in a multitude of settings for the detection of auto-immune, tumor-specific and cross-reactive CD8(+) T cells. (C) 2008 Elsevier B.V. All rights reserved. C1 [Lissina, Anna; Gostick, Emma; Cole, David K.; Wooldridge, Linda; Sewell, Andrew K.; Price, David A.] Cardiff Univ, Sch Med, Dept Med Biochem & Immunol, Cardiff CF14 4XN, S Glam, Wales. [Melenhorst, J. Joseph; Scheinberg, Phillip; Hensel, Nancy F.; Barrett, A. John] NHLBI, Hematol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Scheinberg, Phillip; Bornstein, Ethan; Douek, Daniel C.; Price, David A.] NIAID, Human Immunol Sect, Vaccine Res Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. [Chattopadhyay, Pratip K.; Roederer, Mario] NIAID, Immunotechnol Sect, Vaccine Res Ctr, Natl Inst Hlth, Bethesda, MD 20892 USA. [van den Berge, Hugo A.] Univ Warwick, Warwick Syst Biol Ctr, Coventry CU4 7AC, W Midlands, England. RP Price, DA (reprint author), Cardiff Univ, Sch Med, Dept Med Biochem & Immunol, Cardiff CF14 4XN, S Glam, Wales. EM priced6@cardiff.ac.uk RI Chattopadhyay, Pratip/B-9227-2008; Cole, David/C-8387-2012; Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Cole, David/0000-0003-0028-9396; Sewell, Andrew/0000-0003-3194-3135; Scheinberg, Phillip/0000-0002-9047-4538; Chattopadhyay, Pratip/0000-0002-5457-9666 FU Intramural Research Program of the National Institutes of Health; Vaccine Research Center; National Institute of Allergy and Infectious Diseases; National Heart, Lung and Blood Institute; Medical Research Council (UK) Senior Clinical Fellow; Wellcome Trust (UK) Clinical Intermediate Fellow FX This work was supported by the Intramural Research Program of the National Institutes of Health, Vaccine Research Center, National Institute of Allergy and Infectious Diseases and the National Heart, Lung and Blood Institute. DAP is a Medical Research Council (UK) Senior Clinical Fellow. LW is a Wellcome Trust (UK) Clinical Intermediate Fellow. NR 37 TC 20 Z9 20 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-1759 J9 J IMMUNOL METHODS JI J. Immunol. Methods PD SEP 30 PY 2008 VL 338 IS 1-2 BP 31 EP 39 DI 10.1016/j.jim.2008.07.008 PG 9 WC Biochemical Research Methods; Immunology SC Biochemistry & Molecular Biology; Immunology GA 357ER UT WOS:000259829600005 PM 18675271 ER PT J AU Booth, BW Mack, DL Androutsellis-Theotokis, A McKay, RDG Boulanger, CA Smith, GH AF Booth, Brian W. Mack, David L. Androutsellis-Theotokis, Andreas McKay, Ronald D. G. Boulanger, Corinne A. Smith, Gilbert H. TI The mammary microenvironment alters the differentiation repertoire of neural stem cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE transplantation; niche; plasticity; trans-differentiation; regeneration ID IN-VIVO; EPITHELIAL-CELLS; GLAND; MORPHOGENESIS; RECEPTOR AB A fundamental issue in stem cell biology is whether adult somatic stem cells are capable of accessing alternate tissue sites and continue functioning as stem cells in the new microenvironment. To address this issue relative to neurogenic stem cells in the mouse mammary gland microenvironment, we mixed wild-type mammary epithelial cells (MECs) with bona fide neural stem cells (NSCs) isolated from WAP-Cre/Rosa26R mice and inoculated them into cleared fat pads of immunocompromised females. Hosts were bred 6-8 weeks later and examined postinvolution. This allowed for mammary tissue growth, transient activation of the WAP-Cre gene, recombination, and constitutive expression of LacZ. The NSCs and their progeny contributed to mammary epithelial growth during ductal morphogenesis, and the Rosa26-LacZ reporter gene was activated by WAP-Cre expression during pregnancy. Some NSC-derived LacZ(+) cells expressed mammary-specific functions, including milk protein synthesis, whereas others adopted myoepithelial cell fates. Thus, NSCs and their progeny enter mammary epithelium specific niches and adopt the function of similarly endowed mammary cells. This result supports the conclusion that tissue-specific signals emanating from the stroma and from the differentiated somatic cells of the mouse mammary gland can redirect the NSCs to produce cellular progeny committed to MEC fates. C1 [Smith, Gilbert H.] NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Androutsellis-Theotokis, Andreas; McKay, Ronald D. G.] NIH, Mol Biol Lab, NINDS, Bethesda, MD 20892 USA. RP Smith, GH (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, 9000 Rockville Pike,Bldg 37,Room 1106, Bethesda, MD 20892 USA. EM gs4d@nih.gov FU intramural research program of the Center for Cancer Research; National Cancer Institute FX The intramural research program of the Center for Cancer Research, National Cancer Institute supported all aspects of the research presented here, with the exception of the isolation and propagation of the neural stem cells. NR 16 TC 78 Z9 81 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 30 PY 2008 VL 105 IS 39 BP 14891 EP 14896 DI 10.1073/pnas.0803214105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 386WW UT WOS:000261914300014 PM 18809919 ER PT J AU Dreher, JC Meyer-Lindenberg, A Kohn, P Berman, KF AF Dreher, Jean-Claude Meyer-Lindenberg, Andreas Kohn, Philip Berman, Karen Faith TI Age-related changes in midbrain dopaminergic regulation of the human reward system SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aging; dopamine; fMRI; PET; reinforcement ID INTRACRANIAL SELF-STIMULATION; WORKING-MEMORY; HUMAN BRAIN; HEMODYNAMIC-RESPONSE; PREFRONTAL FUNCTION; PREDICTION ERRORS; NUCLEUS-ACCUMBENS; OLDER-ADULTS; PET; ANTICIPATION AB The dopamine system, which plays a crucial role in reward processing, is particularly vulnerable to aging. Significant losses over a normal lifespan have been reported for dopamine receptors and transporters, but very little is known about the neurofunctional consequences of this age-related dopaminergic decline. In animals, a substantial body of data indicates that dopamine activity in the midbrain is tightly associated with reward processing. In humans, although indirect evidence from pharmacological and clinical studies also supports such an association, there has been no direct demonstration of a link between midbrain dopamine and reward-related neural response. Moreover, there are no in vivo data for alterations in this relationship in older humans. Here, by using 6-[(18)F] FluoroDOPA (FDOPA) positron emission tomography (PET) and event-related 3T functional magnetic resonance imaging (fMRI) in the same subjects, we directly demonstrate a link between midbrain dopamine synthesis and reward-related prefrontal activity in humans, show that healthy aging induces functional alterations in the reward system, and identify an age-related change in the direction of the relationship (from a positive to a negative correlation) between midbrain dopamine synthesis and prefrontal activity. These results indicate an age-dependent dopaminergic tuning mechanism for cortical reward processing and provide system-level information about alteration of a key neural circuit in healthy aging. Taken together, our findings provide an important characterization of the interactions between midbrain dopamine function and the reward system in healthy young humans and older subjects, and identify the changes in this regulatory circuit that accompany aging. C1 [Dreher, Jean-Claude; Meyer-Lindenberg, Andreas; Kohn, Philip; Berman, Karen Faith] NIMH, Sect Integrat Neuroimaging, NIH, Bethesda, MD 20892 USA. RP Dreher, JC (reprint author), CNRS, Ctr Cognit Neurosci, Reward & Decis Making Grp, F-69675 Bron, France. EM dreher@isc.cnrs.fr; karen.berman@nih.gov RI Meyer-Lindenberg, Andreas/H-1076-2011 OI Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU National Institute of Mental Health intramural research program; Fondation pour la Recherche Medicale FX This work was supported by the National Institute of Mental Health intramural research program. J.-C. D. was also supported in part by a grant from the Fondation pour la Recherche Medicale. NR 47 TC 81 Z9 84 U1 4 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 SEP 30 PY 2008 VL 105 IS 39 BP 15106 EP 15111 DI 10.1073/pnas.0802127105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 386WW UT WOS:000261914300050 PM 18794529 ER PT J AU Hu, ZH Follmann, D Qin, J Dewar, RL Sangweni, P AF Hu, Zonghui Follmann, Dean Qin, Jing Dewar, Robin L. Sangweni, Phumelele TI A nonparametric likelihood test for detecting discordance between two measurements with application to censored viral load determinations SO STATISTICS IN MEDICINE LA English DT Article DE detection limit; likelihood ratio; maximum likelihood estimation; McNemar test; nonparametric likelihood ID IMMUNODEFICIENCY-VIRUS TYPE-1; PLASMA PREPARATION TUBES; CHI-SQUARE STATISTICS; CONCORDANCE CORRELATION; CORRELATION-COEFFICIENT; MEASURING AGREEMENT; TRANSMISSION; RELIABILITY AB Patient management frequently involves quantitative evaluation of a patient's attributes. For example, in HIV Studies, a high viral load can be a trigger to initiate or modify an antiretroviral therapy. At times, a new method of evaluation may substitute for an established one, provided that the new method does not result in different clinical decisions compared with the old method. Traditional measures of agreement between the two methods are inadequate for deciding if a new method can replace the old. Especially, when the data are censored by a detection limit, estimates of agreement can be biased unless the distribution for the censored data is correctly specified; this is usually not feasible in practice. We, propose a nonparametric likelihood test that seamlessly handles censored data. We further show that the proposed test is a generalization of the test on nominal measurement concordance to continuous measurement. An exact permutation procedure is proposed for implementing the test. Our application is an HIV study to determine whether one method of processing plasma samples can safely substitute for the ether. The plasma samples are used to determine viral load and a large portion of data are left censored due to a lower detection limit. Copyright (c) 2008 John Wiley & Sons, Ltd. C1 [Hu, Zonghui; Follmann, Dean; Qin, Jing] NIAID, Biostat Res Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Sangweni, Phumelele] 1 Mil Hosp, Project Phidisa, Pretoria, South Africa. [Dewar, Robin L.] SAIC Frederick Inc, NCI Frederick, Virus Isolat & Serol Lab, Frederick, MD 21701 USA. RP Hu, ZH (reprint author), NIAID, Biostat Res Branch, Natl Inst Hlth, 6700A Rockledge Dr, Bethesda, MD 20892 USA. EM huzo@niaid.nih.gov FU National Institutes of Health [NOI-CO-12400] FX Contract/grant sponsor: National Cancer Institute, National Institutes of Health; contract/grant number: NOI-CO-12400.; This project has been funded in whole or in part by federal funds from the National Cancer Institute, National Institute of Health, under contract NOI-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 21 TC 1 Z9 1 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 30 PY 2008 VL 27 IS 22 BP 4489 EP 4501 DI 10.1002/sim.3298 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 353EZ UT WOS:000259550200008 PM 18465838 ER PT J AU Katki, HA Blackford, A Chen, S Parmigiani, G AF Katki, Hormuzd A. Blackford, Amanda Chen, Sining Parmigiani, Giovanni TI Multiple diseases in carrier probability estimation: Accounting for surviving all cancers other than breast and ovary in BRCAPRO SO STATISTICS IN MEDICINE LA English DT Article DE Mendelian models; competing risks; risk assessment; Mendelian mutation prediction models; BRCA1; BRCA2; MMRpro ID MUTATION CARRIERS; GERMLINE MUTATIONS; PREDICTION MODELS; FAMILY-HISTORY; UNITED-STATES; KIN-COHORT; RISK; TESTS; SUSCEPTIBILITY AB Mendelian models can predict who carries an inherited deleterious mutation of known disease genes based on family history. For example, the BRCAPRO model is commonly used to identify families who carry mutations of BRCA1 and BRCA2, based on familial breast and ovarian cancers. These models incorporate the age of diagnosis of diseases in relatives and current age or age of death. We develop a rigorous foundation for handling multiple diseases with censoring. We prove that any disease unrelated to mutations can be excluded from the model, unless it is sufficiently common and dependent on a mutation-related disease time. Furthermore, if a family member has a disease with higher probability density among mutation carriers, but the model does not account for it, then the carrier probability is deflated. However, even if a family only has diseases the model accounts for, if the model excludes a mutation-related disease, then the carrier probability will be inflated. In light of these results, we extend BRCAPRO to account for surviving all non-breast/ovary cancers as a sin le outcome. The extension also enables BRCAPRO to extract more useful information from male relatives. Using 1500 families from the Cancer Genetics Network, accounting for surviving other cancers improves BRCAPRO's concordance index from 0.758 to 0.762 (p=0.046), improves its positive predictive value from 35 to 39 per cent (P<10(-6)) without impacting its negative predictive value, and improves its overall calibration, although calibration slightly worsens for those with carrier probability <10 per cent. Copyright (c) 2008 John Wiley & Sons, Ltd. C1 [Katki, Hormuzd A.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. [Blackford, Amanda; Chen, Sining; Parmigiani, Giovanni] Johns Hopkins Univ, Dept Oncol, Baltimore, MD USA. [Chen, Sining] Johns Hopkins Univ, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. [Chen, Sining; Parmigiani, Giovanni] Johns Hopkins Univ, Dept Biostat, Baltimore, MD 21205 USA. [Parmigiani, Giovanni] Johns Hopkins Univ, Dept Hlth Sci Informat, Baltimore, MD 21205 USA. [Parmigiani, Giovanni] Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21205 USA. RP Katki, HA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,Roorn 8016 MSC 7244, Rockville, MD 20852 USA. EM katkih@mail.nih.gov RI Katki, Hormuzd/B-4003-2015 FU NIH; NCI [R01CA105090-01A1, P50CA62924, P50CA88843, 5P30 CA06973-39] FX Contract/grant sponsor: NIH, National Cancer Institute; Contract/-grant sponsor: NCI contract/grant numbers: R01CA105090-01A1, P50CA62924, P50CA88843, 5P30 CA06973-39 NR 34 TC 9 Z9 9 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD SEP 30 PY 2008 VL 27 IS 22 BP 4532 EP 4548 DI 10.1002/sim.3302 PG 17 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 353EZ UT WOS:000259550200011 PM 18407567 ER PT J AU Miyagi, E Schwartzkopff, F Plishka, R Buckler-White, A Clouse, KA Strebel, K AF Miyagi, Eri Schwartzkopff, Franziska Plishka, Ronald Buckler-White, Alicia Clouse, Kathleen A. Strebel, Klaus TI APOBEC3G-independent reduction in virion infectivity during long-term HIV-1 replication in terminally differentiated macrophages SO VIROLOGY LA English DT Article DE APOBEC3G; macrophages; HIV-1; Vif ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIVIRAL ACTIVITY; VIF PROTEIN; TYPE-1 VIF; HUMAN APOBEC3G; VIRAL-RNA; ANTI-HIV-1 ACTIVITY; DEAMINASE ACTIVITY; ENZYME APOBEC3G; T-LYMPHOCYTES AB APCBEC3G (APO3G) is a cellular cytidine deaminase with potent antiviral activity. In the case of HIV, the antiviral activity of APO3G is counteracted by the viral Vif protein. Monocyte-derived macrophages (MDM) are terminally differentiated, non-dividing cells Susceptible to HIV infection. Human MDM are known to express APO3G and HIV replication in these cells is dependent oil Vif. Here we analyzed the Correlation between HIV-1 replication and APO3G expression in MDM. Replication of wild type HIV-1 induced a gradual 4-5-fold reduction in APO3G expression. The efficiency of APO3G downregulation correlated with the efficiency of virus replication. Interestingly, despite downregulation of APO3G, the relative infectivity of viruses rapidly declined during the Course of infection and was already reduced similar to 90% prior to peak virus production. Cell-free virus preparations showed increased levels of a 41 kDa MA-CA processing intermediate. Sequence analysis around the MA-CA cleavage site and the protease and LTR regions did not reveal deaminase-induced hypermutation of the viral genome, suggesting that APO3G activity is not responsible for the incomplete Gag processing. Thus, the loss of infectivity of HIV-1 viruses produced from long-term infected primary macrophages is due to an APO3G-independent mechanism. Published by Elsevier Inc. C1 [Miyagi, Eri; Strebel, Klaus] NIAID, Mol Microbiol Lab, Viral Biochem Sect, NIH, Bethesda, MD 20892 USA. [Schwartzkopff, Franziska; Clouse, Kathleen A.] US FDA, Ctr Drug Evaluat & Res, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIAID, Mol Microbiol Lab, Viral Biochem Sect, NIH, 4-312,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. EM kstrebel@nih.gov FU NIH Intramural AIDS Targeted Antiviral Program; Intramural Research Program of the NIH, NIAID FX We acknowledge Ritu Goila-Gaur, Sandra Kao, Mohammad Khan, Sandrine Opi, and Hiroaki Takeuchi for helpful discussions throughout this study and Karen Fields, Linda Tiffany, Carla Lankford, and Mark Paciga for help with macrophage Culture. We are grateful to Robert Gorelick and Michael Malim for providing valuable antibodies and we thank John Kappes for the TZM-bl indicator cell line. The latter reagent was obtained through the NIH AIDS Research and Reference Reagent Program. This work was supported by a Grant from the NIH Intramural AIDS Targeted Antiviral Program to K.S. and by the Intramural Research Program of the NIH, NIAID. NR 47 TC 8 Z9 8 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 30 PY 2008 VL 379 IS 2 BP 266 EP 274 DI 10.1016/j.virol.2008.06.033 PG 9 WC Virology SC Virology GA 353ES UT WOS:000259549500011 PM 18675436 ER PT J AU Greil, CS Vorberg, IM Ward, AE Meade-White, KD Harris, DA Priola, SA AF Greil, Christopher S. Vorberg, Ina M. Ward, Anne E. Meade-White, Kimberly D. Harris, David A. Priola, Suzette A. TI Acute cellular uptake of abnormal prion protein is cell type and scrapie-strain independent SO VIROLOGY LA English DT Article DE protein aggregation; PrP; PrP-res; PrP-sen; prion; scrapie; transmissible spongiform encephalopathy; TSE ID CULTURED-CELLS; NEUROBLASTOMA-CELLS; RESISTANT STATE; TRANSGENIC MICE; INFECTED CELLS; IN-VITRO; PRP-RES; LINES; AGENT; ACCUMULATION AB Transmissible spongiform encephalopathies (TSEs) are fatal neurodegenerative diseases that include Creutzfeldt-Jakob disease, bovine spongiform encephalopathy and sheep scrapie. Although one of the earliest events during TSE infection is the cellular uptake of protease resistant prion protein (PrP-res), this process is poorly understood due to the difficulty of clearly distinguishing input PrP-res from either PrP-res or protease-sensitive PrP (PrP-sen) made by the cell. Using PrP-res tagged with a unique antibody epitope, we examined PrP-res uptake in neuronal and fibroblast cells exposed to three different mouse scrapie strains. Pi-P-res uptake was rapid and independent of scrapie strain, cell type, or cellular PrP expression, but occurred in only a subset of cells and was influenced by PrP-res preparation and aggregate size. Our results suggest that Pi-P-res aggregate size, the PrP-res microenvironment, and/or host cell-specific factors can all influence whether or not a cell takes up PrP-res following exposure to TSE infectivity. (C) 2008 Elsevier Inc. All rights reserved. C1 [Greil, Christopher S.; Ward, Anne E.; Meade-White, Kimberly D.; Priola, Suzette A.] NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, Hamilton, MT 59840 USA. [Greil, Christopher S.] Univ Montana, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA. [Vorberg, Ina M.] Tech Univ Munich, Inst Virol, D-81675 Munich, Germany. [Harris, David A.] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. RP Priola, SA (reprint author), NIAID, Rocky Mt Labs, Persistent Viral Dis Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM spriola@niaid.nih.gov FU University of Montana Department of Biomedical and Pharmaceutical Sciences Neuroscience program; NIH, National Institute of Allergy and Infectious Diseases [1-Z01-AI000752-12]; NIH [R01 NS040975] FX We wish to thank Anita Mora and Gary Hettrick for their technical support and Dr. Byron Caughey, Dr. Sonja Best, and Dr. Kristin McNally for critical reading of the manuscript. This research was supported in part by the University of Montana Department of Biomedical and Pharmaceutical Sciences Neuroscience program and the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (Project #1-Z01-AI000752-12). Construction of Tg (WT-E1) mice was supported by NIH grant R01 NS040975. All animals were treated in accordance with the regulations and guidelines of the Animal Care and Use Committee of the Rocky Mountain Laboratories and the National Institutes of Health. NR 42 TC 26 Z9 27 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 30 PY 2008 VL 379 IS 2 BP 284 EP 293 DI 10.1016/j.virol.2008.07.006 PG 10 WC Virology SC Virology GA 353ES UT WOS:000259549500013 PM 18692214 ER PT J AU Meade, KG Gormley, E O'Farrelly, C Park, SD Costello, E Keane, J Zhao, YD MacHugh, DE AF Meade, Kieran G. Gormley, Eamonn O'Farrelly, Cliona Park, Stephen D. Costello, Eamon Keane, Joseph Zhao, Yingdong MacHugh, David E. TI Antigen stimulation of peripheral blood mononuclear cells from Mycobacterium bovis infected cattle yields evidence for a novel gene expression program SO BMC GENOMICS LA English DT Article ID TOLL-LIKE RECEPTORS; AVIUM SUBSP-PARATUBERCULOSIS; IMMUNE-RESPONSES; IN-VITRO; MACROPHAGE RESPONSES; INTERFERON-GAMMA; HOST RESPONSES; TUBERCULOSIS; MICROARRAY; DISEASE AB Background: Bovine tuberculosis (BTB) caused by Mycobacterium bovis continues to cause substantial losses to global agriculture and has significant repercussions for human health. The advent of high throughput genomics has facilitated large scale gene expression analyses that present a novel opportunity for revealing the molecular mechanisms underlying mycobacterial infection. Using this approach, we have previously shown that innate immune genes in peripheral blood mononuclear cells (PBMC) from BTB-infected animals are repressed in vivo in the absence of exogenous antigen stimulation. In the present study, we hypothesized that the PBMC from BTB-infected cattle would display a distinct gene expression program resulting from exposure to M. bovis. A functional genomics approach was used to examine the immune response of BTB-infected (n = 6) and healthy control (n = 6) cattle to stimulation with bovine tuberculin (purified protein derivative-PPD-b) in vitro. PBMC were harvested before, and at 3 h and 12 h post in vitro stimulation with bovine tuberculin. Gene expression changes were catalogued within each group using a reference hybridization design and a targeted immunospecific cDNA microarray platform (BOTL-5) with 4,800 spot features representing 1,391 genes. Results: 250 gene spot features were significantly differentially expressed in BTB-infected animals at 3 h post-stimulation contrasting with only 88 gene spot features in the non-infected control animals (P <= 0.05). At 12 h post-stimulation, 56 and 80 gene spot features were differentially expressed in both groups respectively. The results provided evidence of a proinflammatory gene expression profile in PBMC from BTB-infected animals in response to antigen stimulation. Furthermore, a common panel of eighteen genes, including transcription factors were significantly expressed in opposite directions in both groups. Real-time quantitative reverse transcription PCR (qRT-PCR) demonstrated that many innate immune genes, including components of the TLR pathway and cytokines were differentially expressed in BTB-infected (n = 8) versus control animals (n = 8) after stimulation with bovine tuberculin. Conclusion: The PBMC from BTB-infected animals exhibit different transcriptional profiles compared with PBMC from healthy control animals in response to M. bovis antigen stimulation, providing evidence of a novel gene expression program due to M. bovis exposure. C1 [Park, Stephen D.; MacHugh, David E.] Univ Coll Dublin, Coll Life Sci, Sch Agr Food Sci & Vet Med, Anim Genom Lab, Dublin 4, Ireland. [Meade, Kieran G.; O'Farrelly, Cliona] Univ Dublin Trinity Coll, Sch Biochem & Immunol, Comparat Immunol Grp, Dublin 2, Ireland. [Gormley, Eamonn] Univ Coll Dublin, Coll Life Sci, Sch Agr Food Sci & Vet Med, TB Diagnost & Immunol Res Ctr, Dublin 4, Ireland. [Costello, Eamon] Cent Vet Res Lab, Celbridge, Kildare, Ireland. [Keane, Joseph] Univ Ireland Trinity Coll, St James Hosp, Sch Med, Dublin 8, Ireland. [Zhao, Yingdong] NCI, Computat & Syst Biol Grp, Biometr Res Branch, Rockville, MD USA. [MacHugh, David E.] Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland. RP MacHugh, DE (reprint author), Univ Coll Dublin, Coll Life Sci, Sch Agr Food Sci & Vet Med, Anim Genom Lab, Dublin 4, Ireland. EM kieran.meade@tcd.ie; egormley@ucd.ie; cliona.ofarrelly@tcd.ie; stephen.park@ucd.ie; eamonn.costello@agriculture.gov.ie; jkeane@stjames.ie; zhaoy@ctep.nci.nih.gov; david.machugh@ucd.ie RI Meade, Kieran/K-7562-2015; OI Gormley, Eamonn/0000-0003-3900-0393; Keane, Joseph/0000-0001-5313-385X; MacHugh, David/0000-0002-8112-4704 FU Science Foundation Ireland [SFI/01/F.1/B028] FX We would like to thank the staff at the UCD Lyons Research Farm for assistance with cattle blood sampling and Grace O'Gorman, Mairead Doyle, and Tara Fitzsimons for technical assistance and advice. We also thank Prof. Paul Coussens of the MSU Centre for Animal Functional Genomics for provision of BOTL-5 microarrays. This work was supported by an Investigator Grant from Science Foundation Ireland (Grant No: SFI/01/F.1/B028). NR 64 TC 9 Z9 10 U1 0 U2 1 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 SEP 29 PY 2008 VL 9 AR 447 DI 10.1186/1471-2164-9-447 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 362BO UT WOS:000260173400002 PM 18823559 ER PT J AU Yoshimura, T Oppenheim, JJ AF Yoshimura, Teizo Oppenheim, Joost J. TI Chemerin reveals its chimeric nature SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HUMAN CHEMOKINE RECEPTOR; RESOLVIN E1; IN-VIVO; L-CCR; EXPRESSION; CELLS; ACTIVATION; ANAPHYLATOXIN; NEUTROPHILS; CASCADES AB Chemerin is a proinflammatory plasma protein that binds to the GPCR ChemR23/CMKLR1 on macrophages and plasmacytoid dendritic cells, and promotes chemotaxis. An orphan GPCR, CCRL2, has now been identified as an additional receptor for chemerin, providing a unique mechanism by which chemerin enhances inflammation. Furthermore, because recent data shows that chemerin-derived peptides possess antiinflammatory properties, chemerin may be involved in both the initiation and resolution of inflammation. C1 [Yoshimura, Teizo; Oppenheim, Joost J.] NCI, Ctr Canc Res, Canc & Inflammat Program, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Yoshimura, T (reprint author), NCI, Ctr Canc Res, Canc & Inflammat Program, Mol Immunoregulat Lab, Frederick, MD 21702 USA. EM yoshimut@mail.nih.gov NR 29 TC 52 Z9 60 U1 0 U2 4 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD SEP 29 PY 2008 VL 205 IS 10 BP 2187 EP 2190 DI 10.1084/jem.20081736 PG 4 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 354RM UT WOS:000259656700002 PM 18809717 ER PT J AU Maciuk, A Moaddel, R Haginaka, J Wainer, IW AF Maciuk, Alexandre Moaddel, Ruin Haginaka, Jun Wainer, Irving W. TI Screening of tobacco smoke condensate for nicotinic acetylcholine receptor ligands using cellular membrane affinity chromatography columns and missing peak chromatography SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article; Proceedings Paper CT 12th Meeting on Recent Developments in Pharmaceutical Analysis (RDPA 2007) CY SEP 23-26, 2007 CL Elba, ITALY DE natural products screening; alpha(3)beta(4) nicotinic receptor; affinity chromatography; nicotine derivatives; tobacco smoke fingerprinting; drug discovery ID PERFORMANCE LIQUID-CHROMATOGRAPHY; ONLINE BIOCHEMICAL DETECTION; IMMOBILIZED P-GLYCOPROTEIN; MASS-SPECTROMETRY; NATURAL-PRODUCTS; STATIONARY PHASES; COUPLED ONLINE; INHIBITORS; EXTRACTS; ASSAY AB This manuscript reports an approach to the screening of natural product extracts for compounds which are active at membrane-bound receptors, ion channels and transporters. The technique is based upon cellular membrane affinity chromatography (CMAC) columns created through the immobilization of cellular membrane fragments on liquid chromatography stationary phases. In this study a CMAC(nAChR(+)) column was created out of membranes from a transfected cell line expressing the alpha(3)beta(4) neuronal nicotinic acetylcholine receptor (nAChR) and the column was used to screen tobacco smoke condensates. A strategy involving parallel screening with a CMAC column created from a non-transfected form of the same cell line, CMAC(nAChR(-)) was adopted. The condensate was chromatographed on both columns, timed fractions collected and concentrated. Each fraction was analyzed on a C(18) column in order to establish a chromatographic fingerprint of each fraction and a differential elution profile of each compound. Comparison of the elution profiles from the CMAC(nAChR(+)) and CMAC(nAChR(-)) columns identified patterns that could be associated with high affinity ligands and with low-affinity/non-binding compounds. Known strong ligands ((S)-nicotine, (R,S)-anatabine, N'-nitrosonomicotine), weak ligands ((R,S)-nomicotine, anabasine) as well as known non-ligands (N-methyl-gamma-oxo-3-pyridinebutanamide, (1'S,2'S)-nicotine 1'-oxide) have been identified in the complex extract. The results demonstrate that CMAC-based screens can be used in the identification of compounds within natural product extracts that bind to membrane-based targets. (C) 2007 Elsevier B.V. All rights reserved. C1 [Maciuk, Alexandre; Moaddel, Ruin; Wainer, Irving W.] NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. [Haginaka, Jun] Mukogawa Womens Univ, Nishinomiya, Hyogo 6638179, Japan. RP Wainer, IW (reprint author), NIA, Gerontol Res Ctr, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Wainerir@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000295-06] NR 34 TC 18 Z9 19 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 SEP 29 PY 2008 VL 48 IS 2 BP 238 EP 246 DI 10.1016/j.jpba.2007.11.024 PG 9 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 353HF UT WOS:000259556100002 PM 18187282 ER PT J AU Peoples, MC Phillips, TM Karnes, HT AF Peoples, Michael C. Phillips, Terry M. Karnes, H. Thomas TI Demonstration of a direct capture immunoaffinity separation for C-reactive protein using a capillary-based microfluidic device SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article; Proceedings Paper CT 12th Meeting on Recent Developments in Pharmaceutical Analysis (RDPA 2007) CY SEP 23-26, 2007 CL Elba, ITALY DE C-reactive protein (CRP); biomarker; inflammation; cardiovascular disease; immunoaffinity; microfluidic separation ID CARDIOVASCULAR-DISEASE; ASSAY SYSTEM; CHROMATOGRAPHY; IMMUNOASSAYS; MICROCHIP; BEADS; AMPLIFICATION; SENSITIVITY; ANTIGEN; MARKERS AB C-reactive protein (CRP), a biomarker of inflammation and cardiovascular disease (CVD) risk assessment, was selected as a model antigen to demonstrate a direct labeling/direct capture immunoaffinity separation. The miniaturized device for immunoaffinity chromatography was constructed from two syringe pumps, a gradient mixing microchip, micro-injector with 250nL capillary injection loop, a capillary column, and a diode laser-induced fluorescence detector fitted with a fused-silica capillary flow cell. Monoclonal anti-CRP was biotinylated and attached to 5.0 mu m streptavidin-coated silica beads to make the solid support for separation columns. CRP in simulated serum matrix was fluorescently labeled in a one-step reaction and directly injected onto the immunoaffinity capillary. The purified antigen was then eluted in an acid gradient and measured. The antibody binding of CRP was evaluated in two physiological buffers, phosphate buffered saline (PBS) and Dulbecco's PBS (DPBS). A quadratic calibration model produced % relative errors of - 15.9 to 12.6 for CRP concentration levels ranging from 0.47 to 95.0 mu g/mL. The accuracy (% difference from nominal) and precision (% relative standard deviation) of replicate injections were within 17.0%. The limit of detection was 57.2 ng/mL and chromatographic run times were less than 10 min. The instrument design is simple, and potentially portable, while the assay procedure may be modified for other clinically relevant markers by changing the capture antibody. (C) 2007 Elsevier B.V. All rights reserved. C1 [Peoples, Michael C.; Karnes, H. Thomas] Virginia Commonwealth Univ, Med Ctr, Dept Pharmaceut, Richmond, VA 23298 USA. [Phillips, Terry M.] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 28092 USA. RP Karnes, HT (reprint author), Virginia Commonwealth Univ, Med Ctr, Dept Pharmaceut, POB 980533, Richmond, VA 23298 USA. EM tom.karnes@vcu.edu NR 23 TC 8 Z9 8 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD SEP 29 PY 2008 VL 48 IS 2 SI SI BP 376 EP 382 DI 10.1016/j.jpba.2007.11.036 PG 7 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 353HF UT WOS:000259556100019 PM 18178356 ER PT J AU Kim, YS Seo, DW Kong, SK Lee, JH Lee, ES Stetler-Stevenson, M Stetler-Stevenson, WG AF Kim, Young-Sik Seo, Dong-Wan Kong, Su-Kang Lee, Ju-Han Lee, Eung-Seok Stetler-Stevenson, Maryalice Stetler-Stevenson, William G. TI TIMP1 induces CD44 expression and the activation and nuclear translocation of SHP1 during the late centrocyte/post-germinal center B cell differentiation SO CANCER LETTERS LA English DT Article DE TIMP1; CD44; SHP1; Hodgkin lymphoma ID TYROSINE-PHOSPHATASE SHP-1; EPSTEIN-BARR-VIRUS; TISSUE INHIBITOR; GROWTH-FACTOR; LYMPHOPROLIFERATIVE DISORDERS; METALLOPROTEINASES-1 TIMP-1; TUMOR INVASION; MYELOMA CELLS; LYMPHOMAS; MIGRATION AB Tissue inhibitor of metalloproteinase-1 (TIMP1) is a survival factor of germinal center (GC) B cells, and its over-expression is correlated with aggressive B cell lymphomas and classical Hodgkin lymphomas. We previously demonstrated that TIMP1 down-regulates B-cell receptor and BCL6, and activates interleukins-6,-10 (ILs)/signal transducer and activator of transcription-3 (STAT3) signaling in GC B cells. The activation of ILs/STAT3 signaling can amplify CD44 function, and vice versa, and induce protein-tyrosine phosphatase SHP1 activity by a negative feedback mechanism. Here, we show that TIMP1 up-regulates cell surface CD44 (standard and variants 3 and 7-10) and induces the activity and nuclear localization of SHP1 in an Epstein Barr virus (EBV)-negative Burkitt lymphoma cell line, the neoplastic counterpart of GC centroblasts. These results suggest that TIMP1 functions as a differentiating and survival factor of GC B cells by modulating CD44 and SHP1 in the late centrocyte/post-GC stage, regardless of EBV infection. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Kim, Young-Sik; Kong, Su-Kang; Lee, Ju-Han; Lee, Eung-Seok] Korea Univ, Ansan Hosp, Dept Pathol, Ansan 425707, South Korea. [Seo, Dong-Wan] Kangwon Natl Univ, Dept Mol Biosci, Sch Biosci & Biotechnol, Chunchon 200701, South Korea. [Stetler-Stevenson, Maryalice] NCI, Hematopathol Sect, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. [Stetler-Stevenson, William G.] NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Kim, YS (reprint author), Korea Univ, Ansan Hosp, Dept Pathol, 516 Gojan 1 Dong, Ansan 425707, South Korea. EM apysk@korea.ac.kr RI Stetler-Stevenson, William/H-6956-2012; OI Stetler-Stevenson, William/0000-0002-5500-5808; Seo, Dong-Wan/0000-0003-4971-834X FU Intramural NIH HHS [ZIA SC009179-22] NR 38 TC 9 Z9 10 U1 0 U2 1 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 SEP 28 PY 2008 VL 269 IS 1 BP 37 EP 45 DI 10.1016/j.canlet.2008.04.020 PG 9 WC Oncology SC Oncology GA 357LK UT WOS:000259847100005 PM 18502033 ER PT J AU Hoffmann, CJ Subramanian, AK Cameron, AM Engels, EA AF Hoffmann, Christopher J. Subramanian, Aruna K. Cameron, Andrew M. Engels, Eric A. TI Incidence and risk factors for hepatocellular carcinoma after solid organ transplantation SO TRANSPLANTATION LA English DT Article DE solid organ transplantation; hepatocellular carcinoma; immunosuppression; hepatitis C virus; hepatitis B virus ID LIVER-TRANSPLANTATION; HEPATITIS-C; CANCER INCIDENCE; UNITED-STATES; RECIPIENTS; RECURRENCE; INFECTION; PEOPLE AB Background. Solid organ transplant recipients commonly are infected with hepatitis viruses, are immunosuppressed, and have other potential hepatocellular carcinoma (HCC) risk factors. Methods. We studied de novo HCC incidence arising after transplant using U.S. registry data (223,660 recipients, 1987-2005). We used proportional hazards regression to identify HCC risk factors and calculated standardized incidence ratios (SIRs) to compare HCC risk with that in the general population. Results. Based on 74 cases reported by transplant centers to the registry, HCC incidence was 6.5 per 100,000 person-years among kidney, heart, and lung (non-liver) recipients and 25 per 100,000 person-years among liver recipients. Hepatocellular carcinoma incidence among non-liver recipients was independently associated with hepatitis B Surface antigenemia (hazard ratio [HR] 9.7, 95% confidence interval [CI] 2.8-33), hepatitis C virus (HCV) infection (HR 6.9, 95% CI 2.5-19), and diabetes mellitus (HR 2.8,95% CI 1.2-6.6). Among liver recipients, HCC incidence was associated with advancing age (P < 0.001), male sex (FIR 4.6, 95% CI 1.4-16), HCV infection (HR 3.1, 95% Cl 1.3-7.2), and diabetes mellitus (HR 2.7, 95% CI 1.2-6.2). Among non-liver recipients, overall HCC incidence was similar to the general population (SIR 0.8) but elevated among those with HCV (3.4) or hepatitis 13 surface antigenemia (6.5). Hepatocellular carcinoma incidence among liver transplant recipients was elevated overall (SIR 3.4) and especially among those with HCV (5.0) or diabetes mellitus (6.2). Conclusions. Hepatocellular carcinoma incidence is elevated among liver transplant recipients and subsets of non-liver recipients. These risk factors indicate the need for improved control of viral hepatitis after solid organ transplantation. C1 [Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, Rockville, MD 20892 USA. [Hoffmann, Christopher J.; Subramanian, Aruna K.; Engels, Eric A.] Johns Hopkins Univ, Sch Med, Dept Med, Div Infect Dis, Baltimore, MD 21205 USA. [Cameron, Andrew M.] Johns Hopkins Univ, Sch Med, Dept Surg, Div Transplantat, Baltimore, MD 21205 USA. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, Infect & Immunoepidemiol Branch, 6120 Execut Blvd,EPS 7076, Rockville, MD 20892 USA. EM engelse@exchange.nih.gov OI Hoffmann, Christopher/0000-0002-9422-0519 FU National Institutes of Health [DK074348]; National Cancer Institute FX This work was supported by National Institutes of Health DK074348 (C.J.H.) and the Intramural Research Program of the National Cancer Institute (E.A.E.). NR 27 TC 32 Z9 35 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD SEP 27 PY 2008 VL 86 IS 6 BP 784 EP 790 DI 10.1097/TP.0b013e3181837761 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 353US UT WOS:000259594600007 PM 18813102 ER PT J AU Kommineni, VK Nagineni, CN William, A Detrick, B Hooks, JJ AF Kommineni, Vijay K. Nagineni, Chandrasekharam N. William, Abitha Detrick, Barbara Hooks, John J. TI IFN-gamma acts as anti-angiogenic cytokine in the human cornea by regulating the expression of VEGF-A and sVEGF-R1 SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE IFN-gamma; VEGF-A; sVEGF-R1; cornea; fibroblasts; corneal neovascularization; inflammation; IL-1; TNF-alpha ID ENDOTHELIAL GROWTH-FACTOR; PIGMENT EPITHELIAL-CELLS; OCULAR NEOVASCULARIZATION; IN-VIVO; INHIBITION; RECEPTOR; DEXAMETHASONE; BETA AB Inflammatory processes within the cornea are known to be associated with corneal neovascularization (CN). We examined the effects of inflammatory mediators on the expression of angiogenic factors by corneal cells. TNF-alpha and IL-1 induced VEGF-A secretion by corneal fibroblasts (HCRF) and this was inhibited significantly by IFN-gamma. Constitutively secreted VEGF-A by corneal epithelial cells (HCE) was not affected by these cytokines. Moreover, sVEGF-R1(sFlt-1) secretion by HCRF was stimulated significantly by IFN-gamma. JAK-STAT pathway inhibitor reversed the effects of IFN-gamma on VEGF-A and sFlt-1 secretion by HCRF. RT-PCR analysis showed that IFN-gamma influences the expression of VEGF-A and sFlt-1 by affecting their mRNA level. IFN-gamma inhibited TGF-beta induced VEGF-A secretion but not sVEGF-R1 secretion. This is the first report demonstrating the inhibitory and stimulatory effects of IFN-gamma on VEGF-A and sFlt-1 secretion, respectively. Our results suggest that IFN-gamma acts as an anti-angiogenic cyrokine in the human cornea. Published by Elsevier Inc. C1 [Kommineni, Vijay K.; Nagineni, Chandrasekharam N.; William, Abitha; Hooks, John J.] NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Detrick, Barbara] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. RP Hooks, JJ (reprint author), NEI, Immunol Lab, NIH, Bldg 7,Room 200,7 Mem Dr, Bethesda, MD 20892 USA. EM hooksj@nei.nih.gov FU National Eye Institute, National Institutes of Health FX This research was supported (in part) by the Intramural Research Program of the National Eye Institute, National Institutes of Health. NR 24 TC 18 Z9 21 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 26 PY 2008 VL 374 IS 3 BP 479 EP 484 DI 10.1016/j.bbrc.2008.07.042 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 346ZT UT WOS:000259108800015 PM 18639520 ER PT J AU Cheadle, C Nesterova, M Watkins, T Barnes, KC Hall, JC Rosen, A Becker, KG Cho-Chung, YS AF Cheadle, Chris Nesterova, Maria Watkins, Tonya Barnes, Kathleen C. Hall, John C. Rosen, Antony Becker, Kevin G. Cho-Chung, Yoon S. TI Regulatory subunits of PKA define an axis of cellular proliferation/differentiation in ovarian cancer cells SO BMC MEDICAL GENOMICS LA English DT Article ID PROTEIN-KINASE-A; RI-ALPHA SUBUNIT; GENE-EXPRESSION SIGNATURES; ACTIVATED RECEPTOR-GAMMA; PROBE LEVEL DATA; CYCLIC-AMP; ANTISENSE INHIBITION; PROSTATE-CANCER; BREAST CANCERS; SET ENRICHMENT AB Background: The regulatory subunit of cAMP-dependent protein kinase (PKA) exists in two isoforms, RI and RII, which distinguish the PKA isozymes, type I (PKA-I) and type II (PKA-II). Evidence obtained from a variety of different experimental approaches has shown that the relative levels of type I and type II PKA in cells can play a major role in determining the balance between cell growth and differentiation. In order to characterize the effect of PKA type I and type II regulatory subunits on gene transcription at a global level, the PKA regulatory subunit genes for RI alpha and RII beta were stably transfected into cells of the ovarian cancer cell line (OVCAR8). Results: RI alpha transfected cells exhibit hyper-proliferative growth and RII beta transfected cells revert to a relatively quiescent state. Profiling by microarray revealed equally profound changes in gene expression between RI alpha, RII beta, and parental OVCAR cells. Genes specifically up-regulated in RI alpha cells were highly enriched for pathways involved in cell growth while genes up-regulated in RII beta cells were enriched for pathways involved in differentiation. A large group of genes (similar to 3600) was regulated along an axis of proliferation/differentiation between RI alpha, parental, and RII beta cells. RI alpha/wt and RII beta/wt gene regulation was shown by two separate and distinct gene set analytical methods to be strongly cross-correlated with a generic model of cellular differentiation. Conclusion: Overexpression of PKA regulatory subunits in an ovarian cancer cell line dramatically influences the cell phenotype. The proliferation phenotype is strongly correlated with recently identified clinical biomarkers predictive of poor prognosis in ovarian cancer suggesting a possible pivotal role for PKA regulation in disease progression. C1 [Cheadle, Chris; Nesterova, Maria; Cho-Chung, Yoon S.] NCI, Cellular Biochem Sect, Bethesda, MD 20892 USA. [Hall, John C.; Rosen, Antony] Johns Hopkins Univ, Div Rheumatol, Baltimore, MD USA. [Barnes, Kathleen C.] Johns Hopkins Univ, Div Clin Immunol & Allergy, Baltimore, MD USA. [Becker, Kevin G.] NIA, Gene Express & Genom Unit, Baltimore, MD 21224 USA. RP Cheadle, C (reprint author), NCI, Cellular Biochem Sect, Bethesda, MD 20892 USA. EM ccheadl1@jhmi.edu; nesterom@mail.nih.gov; twatkin2@jhem.jhmi.edu; kbarnes@jhmi.edu; jhal1@jhmi.edu; arosen@jhmi.edu; beckerk@grc.nia.nih.gov; chochuny@mail.nih.gov FU NIH; National Institute on Aging; Mary Beryl Patch Turnbull Scholar FX This research was supported (in part) by the Intramural Research Program of the NIH, National Institute on Aging (KGB). KCB was supported in part by the Mary Beryl Patch Turnbull Scholar Program. NR 58 TC 23 Z9 23 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1755-8794 J9 BMC MED GENOMICS JI BMC Med. Genomics PD SEP 26 PY 2008 VL 1 AR 43 DI 10.1186/1755-8794-1-43 PG 14 WC Genetics & Heredity SC Genetics & Heredity GA 531XB UT WOS:000272705400001 PM 18822129 ER PT J AU Szczesny, B Tann, AW Longley, MJ Copeland, WC Mitra, S AF Szczesny, Bartosz Tann, Anne W. Longley, Matthew J. Copeland, William C. Mitra, Sankar TI Long patch base excision repair in mammalian mitochondrial Genomes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-POLYMERASE-GAMMA; OXIDATIVE DAMAGE; ABASIC SITES; HUMAN-CELLS; IDENTIFICATION; NUCLEAR; ENDONUCLEASE; BINDING; URACIL; PURIFICATION AB The mitochondrial genome is highly susceptible to damage by reactive oxygen species (ROS) generated endogenously as a by-product of respiration. ROS-induced DNA lesions, including oxidized bases, abasic (AP) sites, and oxidized AP sites, cause DNA strand breaks and are repaired via the base excision repair (BER) pathway in both the nucleus and mitochondria. Repair of damaged bases and AP sites involving 1-nucleotide incorporation, named single nucleotide (SN)-BER, was observed with mitochondrial and nuclear extracts. During SN-BER, the 5'-phosphodeoxyribose (dRP) moiety, generated by AP-endonuclease (APE1), is removed by the lyase activity of DNA polymerase gamma (pol gamma) and polymerase beta in the mitochondria and nucleus, respectively. However, the repair of oxidized deoxyribose fragments at the 5' terminus after strand break would require 5'-exo/endonuclease activity that is provided by the flap endonuclease (FEN-1) in the nucleus, resulting in multinucleotide repair patch (long patch (LP)-BER). Here we show the presence of a 5'-exo/endonuclease in the mitochondrial extracts of mouse and human cells that is involved in the repair of a lyase-resistant AP site analog via multinucleotide incorporation, upstream and downstream to the lesion site. We conclude that LP-BER also occurs in the mitochondria requiring the 5'-exo/endonuclease and pol gamma with 3'-exonuclease activity. Although a FEN-1 antibody cross-reacting species was detected in the mitochondria, it was absent in the LP-BER-proficient APE1 immunocomplex isolated from the mitochondrial extract that contains APE1, pol gamma, and DNA ligase 3. The LP-BER activity was marginally affected in FEN-1-depleted mitochondrial extracts, further supporting the involvement of an unidentified 5'-exo/endonuclease in mitochondrial LP-BER. C1 [Szczesny, Bartosz; Tann, Anne W.; Mitra, Sankar] Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. [Longley, Matthew J.; Copeland, William C.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Mitra, S (reprint author), Univ Texas Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. EM samitra@utmb.edu RI Szczesny, Bartosz/D-1026-2012 FU National Institutes of Health; United States Public Health Service [P01 AG10514, R01 CA53791] FX This work was supported, in whole or in part, by National Institutes of Health intramural research funds (to W. C. C.). This work was also supported by United States Public Health Service Grants P01 AG10514 and R01 CA53791 (to S. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 37 TC 84 Z9 86 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 SEP 26 PY 2008 VL 283 IS 39 BP 26349 EP 26356 DI 10.1074/jbc.M803491200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 350GV UT WOS:000259341600008 PM 18635552 ER PT J AU Oshima, Y Akiyama, T Hikita, A Iwasawa, M Nagase, Y Nakamura, M Wakeyama, H Kawamura, N Ikeda, T Chung, U Hennighausen, L Kawaguchi, H Nakamura, K Tanaka, S AF Oshima, Yasushi Akiyama, Toru Hikita, Atsuhiko Iwasawa, Mitsuyasu Nagase, Yuichi Nakamura, Masaki Wakeyama, Hidetoshi Kawamura, Naohiro Ikeda, Toshiyuki Chung, Ung-il Hennighausen, Lothar Kawaguchi, Hiroshi Nakamura, Kozo Tanaka, Sakae TI Pivotal role of Bcl-2 family proteins in the regulation of chondrocyte apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HORMONE-RELATED PEPTIDE; AVIAN GROWTH-PLATE; CELL-DEATH; ENDOCHONDRAL OSSIFICATION; CONDITIONAL DELETION; EXTRACELLULAR-MATRIX; X GENE; BNIP3; MICE; EXPRESSION AB During endochondral ossification, chondrocytes undergo hypertrophic differentiation and die by apoptosis. The level of inorganic phosphate (P(i)) elevates at the site of cartilage mineralization, and when chondrocytes were treated with P(i), they underwent rapid apoptosis. Gene silencing of the proapoptotic Bcl-2 homology 3-only molecule bnip3 significantly suppressed P(i)-induced apoptosis. Conversely, overexpression of Bcl-xL suppressed, and its knockdown promoted, the apoptosis of chondrocytes. Bnip3 was associated with Bcl-xL in chondrocytes stimulated with Pi. Bcl-xL was expressed uniformly in the growth plate chondrocytes, whereas Bnip3 expression was exclusively localized in the hypertrophic chondrocytes. Finally, we generated chondrocyte-specific bcl-x knock-out mice using the Cre-loxP recombination system, and we provided evidence that the hypertrophic chondrocyte layer was shortened in those mice because of an increased apoptosis of prehypertrophic and hypertrophic chondrocytes, with the mice afflicted with dwarfism as a result. These results suggest the pivotal role of Bcl-2 family members in the regulation of chondrocyte apoptosis. C1 [Oshima, Yasushi; Akiyama, Toru; Iwasawa, Mitsuyasu; Nagase, Yuichi; Nakamura, Masaki; Wakeyama, Hidetoshi; Kawamura, Naohiro; Ikeda, Toshiyuki; Kawaguchi, Hiroshi; Nakamura, Kozo; Tanaka, Sakae] Univ Tokyo, Fac Med, Dept Orthopaed Surg, Bunkyo Ku, Tokyo 1130033, Japan. [Hikita, Atsuhiko] Sagamihara Hosp, Natl Hosp Org, Clin Res Ctr, Dept Pathomech, Kanagawa 2288522, Japan. [Chung, Ung-il] Univ Tokyo, Ctr Dis Biol & Integrat Med, Bunkyo Ku, Tokyo 1130033, Japan. [Hennighausen, Lothar] NIH, Lab Genet & Physiol, Bethesda, MD 20892 USA. RP Tanaka, S (reprint author), Univ Tokyo, Fac Med, Dept Orthopaed Surg, Bunkyo Ku, Hongo 7-3-1, Tokyo 1130033, Japan. EM TANAKAS-ORT@h.u-tokyo.ac.jp OI Akiyama, Toru/0000-0001-9493-4768 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan; Ministry of Health, Labor, and Welfare 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 grants-in-aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and health science research grants from the Ministry of Health, Labor, and Welfare of Japan (to S. T.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 46 TC 21 Z9 26 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 SEP 26 PY 2008 VL 283 IS 39 BP 26499 EP 26508 DI 10.1074/jbc.M800933200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 350GV UT WOS:000259341600026 PM 18632667 ER PT J AU Vaughan, CK Mollapour, M Smith, JR Truman, A Hu, B Good, VM Panaretou, B Neckers, L Clarke, PA Workman, P Piper, PW Prodrornou, C Pearl, LH AF Vaughan, Cara K. Mollapour, Mehdi Smith, Jennifer R. Truman, Andrew Hu, Bin Good, Valerie M. Panaretou, Barry Neckers, Len Clarke, Paul A. Workman, Paul Piper, Peter W. Prodrornou, Chrisostolmos Pearl, Laurence H. TI Hsp90-dependent activation of protein kinases is regulated by chaperone-targeted dephosphorylation of Cdc37 SO MOLECULAR CELL LA English DT Article ID HSP90 ATPASE ACTIVITY; HIGH-AFFINITY BINDING; MOLECULAR CHAPERONE; TPR DOMAIN; EIF2-ALPHA KINASE; CO-CHAPERONE; PHOSPHORYLATION; PHOSPHATASE; RECEPTOR; COMPLEX AB Activation of protein kinase clients by the Hsp90 system is mediated by the cochaperone protein Cdc37. Cdc37 requires phosphorylation at Serl 3, but little is known about the regulation of this essential posttranslational modification. We show that Serl 3 of uncomplexed Cdc37 is phosphorylated in vivo, as well as in binary complex with a kinase (C-K), or in ternary complex with Hsp90 and kinase (H-C-K). Whereas pSerl 3-Cdc37 in the H-C-K complex is resistant to nonspecific phosphatases, it is efficiently dephosphorylated by the chaperone-targeted protein phosphatase 5 (PP5/Pptl), which does not affect isolated Cdc37. We show that Cdc37 and PP5/Pptl associate in Hsp90 complexes in yeast and in human tumor cells, and that PP5/Pptl regulates phosphorylation of Ser13-Cdc37 in vivo, directly affecting activation of protein kinase clients by Hsp90-Cdc37. These data reveal a cyclic regulatory mechanism for Cdc37, in which its constitutive phosphorylation is reversed by targeted dephosphorylation in Hsp90 complexes. C1 [Vaughan, Cara K.; Good, Valerie M.; Prodrornou, Chrisostolmos; Pearl, Laurence H.] Inst Canc Res, Chester Beatty Labs, Sect Struct Biol, London SW3 6JB, England. [Mollapour, Mehdi; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Smith, Jennifer R.; Clarke, Paul A.; Workman, Paul] Inst Canc Res, Haddow & McElwain Labs, Canc Res UK Ctr Canc Therapeut, Sutton SM2 5NG, Surrey, England. [Truman, Andrew] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. [Hu, Bin; Panaretou, Barry] Kings Coll London, Div Pharmaceut Sci, London SE1 9NN, England. [Piper, Peter W.] Univ Sheffield, Dept Mol Biol & Biotechnol, Sheffield S10 2TN, S Yorkshire, England. RP Pearl, LH (reprint author), Inst Canc Res, Chester Beatty Labs, Sect Struct Biol, 237 Fulham Rd, London SW3 6JB, England. EM laurence.pearl@icr.ac.uk OI Pearl, Laurence/0000-0002-6910-1809; Clarke, Paul/0000-0001-9342-1290; Prodromou, Chrisostomos/0000-0003-4320-1147 FU Cancer Research UK Programme [C309/A8274, C28248/A9058] FX We are grateful to David Barford and Jing Yang for PP5 constructs, Stefan Millson for the Hsp90 alpha clone, and Marco Siderius for Cdc37 yeast strains. This work was supported by a Wellcome Trust Programme Grant (L.H.P.), the Intramural Research Program of the National Institutes of Health, National Cancer Institute (L.N.), Cancer Research UK Programme Grant C309/A8274 (P.W.), and Project Grant C28248/A9058 (P.W.P.). J.S. was a recipient of a studentship from the Institute of Cancer Research. NR 45 TC 80 Z9 81 U1 1 U2 6 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 SEP 26 PY 2008 VL 31 IS 6 BP 886 EP 895 DI 10.1016/j.molcel.2008.07.021 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 355PU UT WOS:000259721600012 PM 18922470 ER PT J AU Yamashita, M Fatyol, K Jin, CY Wang, XC Liu, ZG Zhang, YE AF Yamashita, Motozo Fatyol, Karoly Jin, Chaoyang Wang, Xiangchun Liu, Zhenggang Zhang, Ying E. TI TRAF6 mediates Smad-independent activation of JNK and p38 by TGF-beta SO MOLECULAR CELL LA English DT Article ID GROWTH-FACTOR-BETA; SIGNALING PATHWAYS; IN-VIVO; APOPTOSIS; TAK1; RECEPTORS; KINASE; INHIBITOR; RESPONSES; FAMILY AB In many physiological and disease processes, TGF-beta usurps branches of MAP kinase pathways in conjunction with Smads to induce apoptosis and epithelial-to-mesenchymal transition, but the detailed mechanism of how a MAP kinase cascade is activated by TGF-beta receptors is not clear. We report here that TRAFIS is specifically required for the Smad-independent activation of JNK and p38, and its carboxyl TRAF homology domain physically interacts with TGF-beta receptors. TGF-beta induces K63-linked ubiquitination of TRAF6 and promotes association between TRAF6 and TAKII. Our results indicate that TGF-beta activates JNK and p38 through a mechanism similar to that operating in the interleukin-1 beta/Tolllike receptor pathway. C1 [Yamashita, Motozo; Fatyol, Karoly; Jin, Chaoyang; Wang, Xiangchun; Zhang, Ying E.] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. [Liu, Zhenggang] NCI, Cell & Canc Biol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. RP Zhang, YE (reprint author), NCI, Cellular & Mol Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM yingz@helix.nih.gov RI Zhang, Ying/G-3657-2015 OI Zhang, Ying/0000-0003-2753-7601 FU Intramural NIH HHS [Z01 BC010419-08] NR 30 TC 241 Z9 251 U1 0 U2 16 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 SEP 26 PY 2008 VL 31 IS 6 BP 918 EP 924 DI 10.1016/j.molcel.2008.09.002 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 355PU UT WOS:000259721600015 PM 18922473 ER PT J AU Izzotti, A D'Agostini, F Balansky, R Degan, P Pennisi, TM Steele, VE De Flora, S AF Izzotti, Alberto D'Agostini, Francesco Balansky, Roumen Degan, Paolo Pennisi, Tanya M. Steele, Vernon E. De Flora, Silvio TI Exposure of mice to cigarette smoke and/or light causes DNA alterations in heart and aorta SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE environmental cigarette smoke; UV-containing light; oxidatively damaged DNA; DNA adducts; heart; aorta ID CHEMOPREVENTIVE AGENTS; POTENT CARCINOGENICITY; HALOGEN LAMPS; HAIRLESS MICE; TOBACCO-SMOKE; ADDUCTS; ATHEROSCLEROSIS; DAMAGE; LUNG; RATS AB Cigarette smoke (CS) is a major risk factor for cardiovascular diseases, cancer, and other chronic degenerative diseases. W-containing light is the most ubiquitous DNA-damaging agent existing in nature, but its possible role in cardiovascular diseases had never been suspected before, although it is known that mortality for cardiovascular diseases is increased during periods with high temperature and solar irradiation. We evaluated whether exposure of Swiss CD-1 mice to environmental CS (ECS) and UV-C-covered halogen quartz lamps, either individually or in combination, can cause DNA damage in heart and aorta cells. Nucleotide alterations were evaluated by P-32 postlabeling methods and by HPLC-electrochemical detection. The whole-body exposure of mice to ECS considerably increased the levels of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo) and of bulky DNA adducts in both heart and aorta. Surprisingly, even exposure to a light that simulated solar irradiation induced oxidatively generated damage in both tissues. The genotoxic effects of UV light in internal organs is tentatively amenable to formation of unidentified long-lived mutagenic products in the skin of irradiated mice. Nucleotide alterations were even more pronounced when the mice were exposed to smoke and/or light during the first 5 weeks of life rather than during adulthood for an equivalent period of time. Although the pathogenetic meaning is uncertain, DNA damage in heart and aorta may tentatively be related to cardiomyopathies and to the atherogenesis process, respectively. (C) 2008 Elsevier B.V. All rights reserved. C1 [Izzotti, Alberto; D'Agostini, Francesco; Balansky, Roumen; Pennisi, Tanya M.; De Flora, Silvio] Univ Genoa, Dept Hlth Sci, Genoa, Italy. [Balansky, Roumen] Natl Oncol Ctr, Sofia 1756, Bulgaria. [Degan, Paolo] Canc Res Inst IST, Genoa, Italy. [Steele, Vernon E.] NCI, Rockville, MD USA. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Genoa, Italy. EM sdf@unige.it OI izzotti, alberto/0000-0002-8588-0347 FU US National Cancer Institute [N01-CN53301]; Bulgarian Ministry of Education and Science FX This work was supported by the US National Cancer Institute contract N01-CN53301 and by the Bulgarian Ministry of Education and Science. NR 42 TC 20 Z9 20 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 EI 1873-135X J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD SEP 26 PY 2008 VL 644 IS 1-2 BP 38 EP 42 DI 10.1016/j.mrfmmm.2008.06.012 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 351KD UT WOS:000259422300006 PM 18640134 ER PT J AU Girard, H Butler, LM Villeneuve, L Millikan, RC Sinha, R Sandler, RS Guillemette, C AF Girard, Hugo Butler, Lesley M. Villeneuve, Lyne Millikan, Robert C. Sinha, Rashmi Sandler, Robert S. Guillemette, Chantal TI UGT1A1 and UGT1A9 functional variants, meat intake, and colon cancer, among Caucasians and African-Americans SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE glucuronidation; amines; colon cancer; meat; polymorphism; genetic ID UDP-GLUCURONOSYLTRANSFERASE 1A1; POLYCYCLIC AROMATIC-HYDROCARBONS; DNA ADDUCT FORMATION; HETEROCYCLIC AMINES; GENETIC POLYMORPHISMS; COLORECTAL-CANCER; CARCINOGEN DETOXIFICATION; BREAST-CANCER; CACO-2 CELLS; RISK AB Glucuronidation by the UDP-glucuronosyltransferase enzymes (UGTs) is one of the primary detoxification pathways of dietary heterocyclic amines (HCAs) and polycyclic aromatic hydrocarbons (PAHs). In a population-based case-control study of 537 cases and 866 controls, we investigated whether colon cancer was associated with genetic variations in UGT1A1 and UGT1A9 genes and we determined if those variations modify the association between colon cancer and dietary HCA and PAH exposure. We measured functional UGT1A1 polymorphisms at positions -53 (*28; A(TA)6TAA to A(TA)7TAA), -3156 (C > A), -3279 (T > G) and the UGT1A9-275(T > A) polymorphism, and found no association with colon cancer overall. However, when stratified by race, the UGT1A1-3279 GG/TG intermediate/low activity genotypes were associated with an increased risk of colon cancer (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1-2.0) in Caucasians. This finding is also supported by haplotype analyses where the UGT1A1-3279G-allele-bearing haplotype is overrepresented in case group. Overall, UGT1A1-53 and -3156 genotypes modified the association between dietary benzo(a)pyrene (BaP) and colon cancer (P for interaction = 0.02 and 0.03, respectively). The strongest association was observed for those with <7.7 ng/day BaP exposure and the low activity genotypes, for both UGT1A1 *28/*28 (OR = 1.8, 95% CI = 1.1-2.9) and -3156AA (OR = 1.7, 95% CI = 1.0-3.0), compared to >= 7.7 ng/day and combined high/intermediate genotypes. These data support a hypothesis that UGTs modify the association between meat-derived PAH exposure and colon cancer by their role in the elimination of dietary carcinogens. (C) 2008 Elsevier B.V. All rights reserved. C1 [Girard, Hugo; Villeneuve, Lyne; Guillemette, Chantal] Univ Laval, Pharmacogen Lab, CHUQ Res Ctr, Quebec City, PQ G1V 4G2, Canada. [Girard, Hugo; Villeneuve, Lyne; Guillemette, Chantal] Univ Laval, Fac Pharm, Quebec City, PQ G1V 4G2, Canada. [Butler, Lesley M.] Univ Calif Davis, Div Epidemiol, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Millikan, Robert C.; Sandler, Robert S.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Sandler, Robert S.] Univ N Carolina, Dept Med, Chapel Hill, NC USA. [Sinha, Rashmi] NCI, Nutr Epidemiol Branch, Rockville, MD USA. RP Guillemette, C (reprint author), CHUL, Res Ctr, T3-48,2705 Blvd Laurier, Quebec City, PQ G1V 4G2, Canada. EM chantal.guillemette@crchul.ulaval.ca RI Guillemette, Chantal/J-6463-2012; Sinha, Rashmi/G-7446-2015; OI Sinha, Rashmi/0000-0002-2466-7462; Guillemette, Chantal/0000-0002-1113-1212 FU Canadian Institutes of Health Research (CIHR) [MOP-42392]; National Institute of Child Health and Human Development's Building Interdisciplinary Research Careers in Women's Health (BIRCWH) [5K12HD051958]; National Institutes of Health [R01 CA66635, P30 DK34987] FX This work was supported by the Canadian Institutes of Health Research (CIHR) (MOP-42392). H.G. is a recipient of a studentship award from the CIHR. Dr. Guillemette is the chair holder of the Canada Research Chair in Pharmacogenomics. Dr. Butler was supported by National Institute of Child Health and Human Development's Building Interdisciplinary Research Careers in Women's Health (BIRCWH) grant 5K12HD051958. This research was also supported by grants from the National Institutes of Health to Dr. Sandler, R01 CA66635 and P30 DK34987. We gratefully thank Dr. Alexandre Bureau for advice regarding the SAS analysis and Mario Harvey for critical reading of the manuscript. NR 54 TC 25 Z9 25 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD SEP 26 PY 2008 VL 644 IS 1-2 BP 56 EP 63 DI 10.1016/j.mrfmmm.2008.07.002 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 351KD UT WOS:000259422300009 PM 18675828 ER PT J AU Lescano, AR Blazes, DL Montano, SM Moran, Z Naquira, C Ramirez, E Lie, R Martin, GJ Lescano, AG Zunt, JR AF Lescano, A. Roxana Blazes, David L. Montano, Silvia M. Moran, Zoe Naquira, Cesar Ramirez, Edwin Lie, Reidar Martin, Gregory J. Lescano, Andres G. Zunt, Joseph R. TI Research Ethics Training in Peru: A Case Study SO PLOS ONE LA English DT Article AB With the rapidly increasing number of health care professionals seeking international research experience, comes an urgent need for enhanced capacity of host country institutional review boards (IRB) to review research proposals and ensure research activities are both ethical and relevant to the host country customs and needs. A successful combination of distance learning, interactive courses and expert course instructors has been applied in Peru since 2004 through collaborations between the U. S. Naval Medical Research Center Detachment, the University of Washington and the Department of Clinical Bioethics of the National Institutes of Health to provide training in ethical conduct of research to IRB members and researchers from Peru and other Latin American countries. All training activities were conducted under the auspices of the Peruvian National Institute of Health (INS), Ministry of Health. To date, 927 people from 12 different Latin American countries have participated in several of these training activities. In this article we describe our training model. C1 [Lescano, A. Roxana; Blazes, David L.; Montano, Silvia M.; Moran, Zoe; Martin, Gregory J.; Lescano, Andres G.] USN, Med Res Ctr Detachment, Lima, Peru. [Naquira, Cesar] Inst Nacl Salud, Peruvian Minist Hlth, Lima, Peru. [Ramirez, Edwin] Hosp Nacl Dos Mayo, Lima, Peru. [Lie, Reidar] Univ Washington, Dept Clin Bioeth, NIH, Seattle, WA 98195 USA. [Zunt, Joseph R.] Univ Washington, Dept Neurol, Glob Hlth & Med, Seattle, WA 98195 USA. RP Lescano, AR (reprint author), USN, Med Res Ctr Detachment, Lima, Peru. EM Roxana.Lescano@med.navy.mil RI Lescano, Andres/B-8479-2008 OI Lescano, Andres/0000-0001-9779-633X FU [847705 82000 25GB B0016]; [R21NS048838]; [AI27757]; [1D43TW007393-01] FX This work was partially supported by work unit number No. 847705 82000 25GB B0016 and by Grants number R21NS048838, AI27757 and 1D43TW007393-01, Title: Fogarty International Center Grant, AIDS Research and (CFAR) Grant and Fogarty Global Infectious Diseases Training. NR 2 TC 4 Z9 4 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 SEP 26 PY 2008 VL 3 IS 9 AR e3274 DI 10.1371/journal.pone.0003274 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422ML UT WOS:000264432300002 PM 18818763 ER PT J AU Schleinitz, N March, ME Long, EO AF Schleinitz, Nicolas March, Michael E. Long, Eric O. TI Recruitment of Activation Receptors at Inhibitory NK Cell Immune Synapses SO PLOS ONE LA English DT Article AB Natural killer (NK) cell activation receptors accumulate by an actin-dependent process at cytotoxic immune synapses where they provide synergistic signals that trigger NK cell effector functions. In contrast, NK cell inhibitory receptors, including members of the MHC class I-specific killer cell Ig-like receptor (KIR) family, accumulate at inhibitory immune synapses, block actin dynamics, and prevent actin-dependent phosphorylation of activation receptors. Therefore, one would predict inhibition of actin-dependent accumulation of activation receptors when inhibitory receptors are engaged. By confocal imaging of primary human NK cells in contact with target cells expressing physiological ligands of NK cell receptors, we show here that this prediction is incorrect. Target cells included a human cell line and transfected Drosophila insect cells that expressed ligands of NK cell activation receptors in combination with an MHC class I ligand of inhibitory KIR. The two NK cell activation receptors CD2 and 2B4 accumulated and co-localized with KIR at inhibitory immune synapses. In fact, KIR promoted CD2 and 2B4 clustering, as CD2 and 2B4 accumulated more efficiently at inhibitory synapses. In contrast, accumulation of KIR and of activation receptors at inhibitory synapses correlated with reduced density of the integrin LFA-1. These results imply that inhibitory KIR does not prevent CD2 and 2B4 signaling by blocking their accumulation at NK cell immune synapses, but by blocking their ability to signal within inhibitory synapses. C1 [Schleinitz, Nicolas; March, Michael E.; Long, Eric O.] NIH, NIAID, Lab Immunogenet, Rockville, MD USA. RP Schleinitz, N (reprint author), CHU Concept, AP HM, Serv Med Interne, Marseille, France. EM eLong@nih.gov RI Long, Eric/G-5475-2011 OI Long, Eric/0000-0002-7793-3728 FU NIAID, NIH FX This research was supported by the Intramural Research Program of the NIAID, NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 24 Z9 25 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 SEP 26 PY 2008 VL 3 IS 9 AR e3278 DI 10.1371/journal.pone.0003278 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422ML UT WOS:000264432300003 PM 18818767 ER PT J AU Yi, M Stephens, RM AF Yi, Ming Stephens, Robert M. TI SLEPR: A Sample-Level Enrichment-Based Pathway Ranking Method-Seeking Biological Themes through Pathway-Level Consistency SO PLOS ONE LA English DT Article AB Analysis of microarray and other high throughput data often involves identification of genes consistently up or down-regulated across samples as the first step in extraction of biological meaning. This gene-level paradigm can be limited as a result of valid sample fluctuations and biological complexities. In this report, we describe a novel method, SLEPR, which eliminates this limitation by relying on pathway-level consistencies. Our method first selects the sample-level differentiated genes from each individual sample, capturing genes missed by other analysis methods, ascertains the enrichment levels of associated pathways from each of those lists, and then ranks annotated pathways based on the consistency of enrichment levels of individual samples from both sample classes. As a proof of concept, we have used this method to analyze three public microarray datasets with a direct comparison with the GSEA method, one of the most popular pathway-level analysis methods in the field. We found that our method was able to reproduce the earlier observations with significant improvements in depth of coverage for validated or expected biological themes, but also produced additional insights that make biological sense. This new method extends existing analyses approaches and facilitates integration of different types of HTP data. C1 [Yi, Ming; Stephens, Robert M.] SAIC Frederick Inc, NCI Frederick, Adv Technol Program, Adv Biomed Comp Ctr, Frederick, MD USA. RP Yi, M (reprint author), SAIC Frederick Inc, NCI Frederick, Adv Technol Program, Adv Biomed Comp Ctr, Frederick, MD USA. EM bobs@ncifcrf.gov FU National Cancer Institute, National Institute of Health [N01-CO-12400] FX This work has been funded in whole or in part with Federal funds from the National Cancer Institute, National Institute of Health, under Contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government NR 58 TC 14 Z9 14 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 SEP 26 PY 2008 VL 3 IS 9 AR e3288 DI 10.1371/journal.pone.0003288 PG 17 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422ML UT WOS:000264432300010 PM 18818771 ER PT J AU Poulsen, TT Naizhen, X Poulsen, HS Linnoila, RI AF Poulsen, Thomas T. Naizhen, Xu Poulsen, Hans S. Linnoila, R. Ilona TI Acute damage by naphthalene triggers expression of the neuroendocrine marker PGP9.5 in airway epithelial cells SO TOXICOLOGY LETTERS LA English DT Article DE PGP9.5; UCHL1; Naphthalene; NNK; Lung; Neuroendocrine ID LUNG-CANCER; CIGARETTE-SMOKE; GENE-EXPRESSION; TRANSCRIPTION FACTOR; TERMINAL HYDROLASE; ENDOCRINE-CELLS; UCHL1 GENE; B-MYB; PROTEIN; P27(KIP1) AB Protein Gene Product 9.5 (PGP9.5) is highly expressed in nervous tissue. Recently PGP9.5 expression has been found to be upregulated in the pulmonary epithelium of smokers and in non-small cell lung cancer, suggesting that it also plays a role in carcinogen-inflicted lung epithelial injury and carcinogenesis. We investigated the expression of PGP9.5 in mice in response to two prominent carcinogens found in tobacco smoke: Naphthalene and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). By immunostaining, we found that PGP9.5 protein was highly expressed throughout the airway epithelium in the days immediately following a single injection of naphthalene. In contrast, 5 was exclusively confined to neurons and neuroendocrine cells in the control and NNK-exposed lungs. Furthermore, we investigated the expression of PGP9.5 mRNA in the lungs by quantitative RT-PCR (qPCR). PGP9.5 mRNA expression was highly upregulated in the days immediately following naphthalene injection and gradually returning to that of control mice 5 days after naphthalene injection. In contrast, exposure to NNK did not result in a significant increase in PGP9.5 mRNA 10 weeks after exposure. No increased expression of two other neuroendocrine markers was found in the non-neuroendocrine epithelial cells after naphthalene exposure. In contrast, immunostaining for the cell cycle regulator p27(Kip1), which has previously been associated with PGP9.5 in lung cancer cells, revealed transient downregulation of p27(Kip1) in naphthalene exposed airways compared to controls, indicating that the rise in. PGP9.5 in the airway epithelium is related to downregulation of P27(Kip1). This study is the first to specifically identify the carcinogen naphthalene as an inducer of PGP9.5 expression in non-neuroendocrine epithelium after acute lung injury and further strengthens the accumulating evidence of PGP9.5 as a central player in lung epithelial damage and early carcinogenesis. Published by Elsevier Ireland Ltd. C1 [Naizhen, Xu; Linnoila, R. Ilona] NCI, Expt Pathol Sect, CCBB, CCR,NIH, Bethesda, MD 20892 USA. [Poulsen, Thomas T.; Poulsen, Hans S.] Copenhagen Univ Hosp, Dept Radiat Biol, Finsen Ctr, Sect 6321, DK-2100 Copenhagen O, Denmark. RP Linnoila, RI (reprint author), NCI, Expt Pathol Sect, CCBB, CCR,NIH, 37 Convent Dr,Room 1056B, Bethesda, MD 20892 USA. EM il17h@nih.gov FU Intramural Research Program of the National Cancer Institute; National Institutes of Health, USA; Dagmar Marshall foundation; Civilingenior Bent Bogh & Hustru Inge Bogh's foundation; Christian & Ottilia Brorson's foundation for Young Scientists; Fhv. Dir. Leo Nielsen & Hustru Karen Margrethe Nielsens Foundation for Medical Research FX This work has been supported financially by the Intramural Research Program of the National Cancer Institute, National Institutes of Health, USA, the Dagmar Marshall foundation, Civilingenior Bent Bogh & Hustru Inge Bogh's foundation, Christian & Ottilia Brorson's foundation for Young Scientists and Fhv. Dir. Leo Nielsen & Hustru Karen Margrethe Nielsens Foundation for Medical Research. NR 50 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD SEP 26 PY 2008 VL 181 IS 2 BP 67 EP 74 DI 10.1016/j.toxlet.2008.06.872 PG 8 WC Toxicology SC Toxicology GA 362NZ UT WOS:000260205700001 PM 18687389 ER PT J AU Han, LY Wang, YL Bryant, SH AF Han, Lianyi Wang, Yanli Bryant, Stephen H. TI Developing and validating predictive decision tree models from mining chemical structural fingerprints and high-throughput screening data in PubChem SO BMC BIOINFORMATICS LA English DT Article ID AIDED DRUG DESIGN; DATA SET; CLASSIFICATION; INHIBITORS; SELECTION; HIT; CHEMOINFORMATICS; DESCRIPTORS AB Background: Recent advances in high-throughput screening (HTS) techniques and readily available compound libraries generated using combinatorial chemistry or derived from natural products enable the testing of millions of compounds in a matter of days. Due to the amount of information produced by HTS assays, it is a very challenging task to mine the HTS data for potential interest in drug development research. Computational approaches for the analysis of HTS results face great challenges due to the large quantity of information and significant amounts of erroneous data produced. Results: In this study, Decision Trees (DT) based models were developed to discriminate compound bioactivities by using their chemical structure fingerprints provided in the PubChem system http://pubchem.ncbi.nlm.nih.gov. The DT models were examined for filtering biological activity data contained in four assays deposited in the PubChem Bioassay Database including assays tested for 5HT1a agonists, antagonists, and HIV-1 RT-RNase H inhibitors. The 10-fold Cross Validation (CV) sensitivity, specificity and Matthews Correlation Coefficient (MCC) for the models are 57.2 similar to 80.5%, 97.3 similar to 99.0%, 0.4 similar to 0.5 respectively. A further evaluation was also performed for DT models built for two independent bioassays, where inhibitors for the same HIV RNase target were screened using different compound libraries, this experiment yields enrichment factor of 4.4 and 9.7. Conclusion: Our results suggest that the designed DT models can be used as a virtual screening technique as well as a complement to traditional approaches for hits selection. C1 [Han, Lianyi; Wang, Yanli; Bryant, Stephen H.] Natl Ctr Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD 20894 USA. RP Wang, YL (reprint author), Natl Ctr Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD 20894 USA. EM hanl@ncbi.nlm.nih.gov; ywang@ncbi.nlm.nih.gov; bryant@ncbi.nlm.nih.gov RI Han, Lianyi/D-1499-2009 FU Intramural Research Program of the NIH; National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. We acknowledge the editorial assistance of the NIH Fellows Editorial Board. NR 49 TC 50 Z9 55 U1 1 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD SEP 25 PY 2008 VL 9 AR 401 DI 10.1186/1471-2105-9-401 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 366NI UT WOS:000260488600001 PM 18817552 ER PT J AU Sohn, S Comeau, DC Kim, W Wilbur, WJ AF Sohn, Sunghwan Comeau, Donald C. Kim, Won Wilbur, W. John TI Abbreviation definition identification based on automatic precision estimates SO BMC BIOINFORMATICS LA English DT Article ID MEDLINE; DICTIONARY AB Background: The rapid growth of biomedical literature presents challenges for automatic text processing, and one of the challenges is abbreviation identification. The presence of unrecognized abbreviations in text hinders indexing algorithms and adversely affects information retrieval and extraction. Automatic abbreviation definition identification can help resolve these issues. However, abbreviations and their definitions identified by an automatic process are of uncertain validity. Due to the size of databases such as MEDLINE only a small fraction of abbreviation-definition pairs can be examined manually. An automatic way to estimate the accuracy of abbreviation-definition pairs extracted from text is needed. In this paper we propose an abbreviation definition identification algorithm that employs a variety of strategies to identify the most probable abbreviation definition. In addition our algorithm produces an accuracy estimate, pseudo-precision, for each strategy without using a human-judged gold standard. The pseudo-precisions determine the order in which the algorithm applies the strategies in seeking to identify the definition of an abbreviation. Results: On the Medstract corpus our algorithm produced 97% precision and 85% recall which is higher than previously reported results. We also annotated 1250 randomly selected MEDLINE records as a gold standard. On this set we achieved 96.5% precision and 83.2% recall. This compares favourably with the well known Schwartz and Hearst algorithm. Conclusion: We developed an algorithm for abbreviation identification that uses a variety of strategies to identify the most probable definition for an abbreviation and also produces an estimated accuracy of the result. This process is purely automatic. C1 [Sohn, Sunghwan; Comeau, Donald C.; Kim, Won; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Sohn, S (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM s.sohn@yahoo.com; comeau@ncbi.nlm.nih.gov; wonkim@ncbi.nlm.nih.gov; wilbur@ncbi.nlm.nih.gov FU Intramural Research Program of the NIH; National Library of Medicine FX This research was supported by the Intramural Research Program of the NIH, National Library of Medicine. NR 15 TC 26 Z9 26 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD SEP 25 PY 2008 VL 9 AR 402 DI 10.1186/1471-2105-9-402 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 366NI UT WOS:000260488600002 PM 18817555 ER PT J AU Jett, DA AF Jett, David A. TI Cholinesterase research at the National Institutes of Health, USA SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article; Proceedings Paper CT 9th International Meeting on Cholinesterases CY MAY 06-10, 2007 CL Suzhou, PEOPLES R CHINA DE Cholinesterases; National Institutes of Health; Description of research supported ID HUMAN BUTYRYLCHOLINESTERASE; NERVE AGENTS; ACETYLCHOLINESTERASE; EXPOSURE; CHLORPYRIFOS; CARBAMATE; DISEASE; ASSAY; MICE AB Presented below is a brief description of research supported by the National Institutes of Health (NIH) on cholinesterases that was discussed at the IXth International Meeting on Cholinesterases in Suzhou, China. It is a partial description of the research conducted by researchers at academic and other institutions Supported by the NIH, and by some of the researchers in NIH intramural laboratories. It does not represent a comprehensive survey of all research Supported by the NIH related to cholinesterases, but rather a brief discussion of some of the Studies discussed at the IXth International Meeting on Cholinesterases. The article describes exciting basic, translational and clinical research on therapies for neurological and other diseases. In addition, cholinesterases that may treat substance abuse are discussed, and pesticide and chemical warfare agents that inhibit cholinesterases are highlighted as part of the NIH portfolio. It is the intent of this article to share with the international community some of the research being supported by the NIH on cholinesterases that complements many of the studies being conducted elsewhere. The information was obtained only from published articles or from abstracts available to the public within the NIH CRISP database (http://crisp.cit.nih.gov/). Published by Elsevier Ireland Ltd C1 NIH, Inst Neurol Disorders & Stroke, Bethesda, MD 20892 USA. RP Jett, DA (reprint author), NIH, Inst Neurol Disorders & Stroke, 6001 Execut Blvd,NSC,Room 2177,MSC 9535, Bethesda, MD 20892 USA. EM jettd@ninds.nih.gov NR 21 TC 0 Z9 0 U1 2 U2 2 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 SEP 25 PY 2008 VL 175 IS 1-3 SI SI BP 22 EP 25 DI 10.1016/j.cbi.2008.04.021 PG 4 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 361EO UT WOS:000260110500004 PM 18550039 ER PT J AU Comoletti, D Grishaev, A Whitten, AE Taylor, P Trewhella, J AF Comoletti, Davide Grishaev, Alexander Whitten, Andrew E. Taylor, Palmer Trewhella, Jill TI Characterization of the solution structure of a neuroligin/beta-neurexin complex SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article; Proceedings Paper CT 9th International Meeting on Cholinesterases CY MAY 06-10, 2007 CL Suzhou, PEOPLES R CHINA DE Synaptic adhesion molecules; Neuroligin; Neurexin; SAXS ID CRYSTAL-STRUCTURE; BETA-NEUREXINS; LNS DOMAIN; X-RAY; AUTISM; BINDING; PROTEIN; SCATTERING; MUTATIONS; GENES AB Neuroligins are post-synaptic cell adhesion molecules that promote synaptic maturation and stabilization upon binding with pre-synaptic partners, the alpha- and beta-neurexins. Using a combination of analytical Ultracentrifugation, small angle X-ray, and neutron scattering, we have characterized the low-resolution three-dimensional Structure of the extracellular domain of the neuroligins, free in solution, and in complex with beta-neurexin. The globular extracellular domain of the neuroligins forms stable homodimers through a four-helix bundle typical of the cholinesterases and other members of the alpha/beta-hydrolase fold family. The presence of the stalk region adds to the extracellular domain of neuroligin-1 an elongated Structure, suggesting a rod-like nature of the stalk domain. Sedimentation equilibrium coupled with Solution scattering data of the beta-neurexin/neuroligin-1 complex indicated a 2:2 stoichiometry where two beta-neurexin molecules bind to a neuroligin-1 climen Deuteration of neurexin allowed us to collect neutron scattering data that, in combination with other biochemical techniques, provide a basis for optimizing the positioning of each component in a detailed computational model of the neuroligin/neurexin complex. As several Mutations of both neurexin and neuroligin genes have been linked to autism spectrum disorders and mental retardation, these new structures provide an important framework for the study of altered structure and function of these synaptic proteins. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Comoletti, Davide; Taylor, Palmer] Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmacol, La Jolla, CA 92093 USA. [Grishaev, Alexander] NIDDK, Bethesda, MD 20892 USA. [Whitten, Andrew E.] Australian Nucl Sci & Technol Org, Bragg Inst, Menai, NSW 2234, Australia. [Trewhella, Jill] Univ Sydney, Sch Mol & Microbial Biosci, Sydney, NSW 2006, Australia. [Trewhella, Jill] Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. RP Comoletti, D (reprint author), Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmacol, La Jolla, CA 92093 USA. EM dcomolet@ucsd.edu OI Trewhella, Jill/0000-0002-8555-6766 FU Intramural NIH HHS; NIEHS NIH HHS [P42 ES 10337]; NIGMS NIH HHS [R37 GM018360, R37 GM018360-37, R37 GM 18360] NR 28 TC 6 Z9 6 U1 0 U2 5 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 SEP 25 PY 2008 VL 175 IS 1-3 SI SI BP 150 EP 155 DI 10.1016/j.cbi.2008.04.040 PG 6 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 361EO UT WOS:000260110500029 PM 18550038 ER PT J AU Shafferman, A Barak, D Stein, D Kronman, C Velan, B Greig, NH Ordentlich, A AF Shafferman, Avigdor Barak, Dov Stein, Dana Kronman, Chanoch Velan, Baruch Greig, Nigel H. Ordentlich, Arie TI Flexibility versus "rigidity" of the functional architecture of AChE active center SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article; Proceedings Paper CT 9th International Meeting on Cholinesterases CY MAY 06-10, 2007 CL Suzhou, PEOPLES R CHINA DE AChE; Stereoselectivity; Mutagenesis ID TORPEDO-CALIFORNICA ACETYLCHOLINESTERASE; SUBSTRATE-SPECIFICITY; CRYSTAL-STRUCTURES; REACTION-PRODUCTS; ENZYME CATALYSIS; ANIONIC SITE; CENTER GORGE; BINDING; CHOLINESTERASES; RESIDUES AB Functional architecture of the AChE active center appears to be characterized by both Structural "rigidity", necessary to stabilize the catalytic triad as well as by flexibility in accommodating the different, high affinity AChE ligands. These seemingly conflicting structural properties of the active center are demonstrated through combination of structural methods with kinetic studies of the enzyme and its mutant derivatives with plethora of Structurally diverse ligands and in particular with series of stereoselective covalent and noncovalent AChE ligands. Thus, steric perturbation of the acyl pocket precipitates in a pronounced stereoselectivity toward methylphosphonates by disrupting the stabilizing environment of the catalytic histidine Father than through steric exclusion demonstrating the functional importance of the "rigid" environment of the catalytic machinery. The acyl pocket, the cation-binding subsite (Trp86) and the peripheral anionic subsite were also found to be directly involved in HuAChE stereoselectivity toward charged chiral phosphonates, operating through differential positioning of the ligand cationic moiety within the active center. Residue Trp86 is also a part of the "hydrophobic patch" which seems flexible enough to accommodate the structurally diverse ligands like tacrine, galanthamine and the two diastereomers of huperzine A. Also, we have recently discovered further aspects of the role of both the unique Structure and the flexibility of the "hydrophobic patch" in determining the reactivity and stereoselectivity of HuAChE toward certain carbamates including analogs of physostigmine. In these cases the ligands are accommodated mostly through hydrophobic interactions and their stereoselectivity delineates precisely the steric limits of the pocket. Hence, the HuAChE stereoselectivity provides a sensitive tool in the in depth exploration of the functional architecture of the active center. These Studies suggest that the combination of "rigidity" and flexibility within the HuAChE gorge are an essential element of its molecular design. (C) 2008 Elsevier Ireland Ltd. All Fights reserved. C1 [Shafferman, Avigdor; Stein, Dana; Kronman, Chanoch; Velan, Baruch; Ordentlich, Arie] Israel Inst Biol Res, Dept Biochem & Mol Biol, IL-74100 Ness Ziona, Israel. [Barak, Dov] Israel Inst Biol Res, Dept Organ Chem, IL-74100 Ness Ziona, Israel. [Greig, Nigel H.] NIA, Drug Design & Dev Sect, Neurosci Lab, Gerontol Res Ctr 4E02,NIH, Baltimore, MD 21224 USA. RP Shafferman, A (reprint author), Israel Inst Biol Res, Dept Biochem & Mol Biol, IL-74100 Ness Ziona, Israel. EM avigdors@iibr.gov.il FU Intramural NIH HHS [Z01 AG000311-07] NR 35 TC 9 Z9 9 U1 1 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 SEP 25 PY 2008 VL 175 IS 1-3 SI SI BP 166 EP 172 DI 10.1016/j.cbi.2008.03.013 PG 7 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 361EO UT WOS:000260110500032 PM 18471807 ER PT J AU Donohue, SR Pike, VW Finnema, SJ Truong, P Andersson, J Gulyas, B Halldin, C AF Donohue, Sean R. Pike, Victor W. Finnema, Sjoerd J. Truong, Phong Andersson, Jan Gulyas, Balazs Halldin, Christer TI Discovery and labeling of high-affinity 3,4-diarylpyrazolines as candidate radioligands for in vivo imaging of cannabinoid subtype-1 (CB(1)) receptors SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID RAT-BRAIN; LOCALIZATION; CYANIDE; DRONABINOL; ANTAGONIST; ANOREXIA; TARGETS; BINDING; VARIANT; TRACER AB Imaging of cannabinoid subtype-1 (CB(1)) receptors in vivo with positron emission tomography (PET) is likely to be important for understanding their role in neuropsychiatric disorders and for drug development. Radioligands for imaging with PET are required for this purpose. We synthesized new ligands from a 3,4-diarylpyrazoline platform of which (-)-12a ((-)-3-(4-chlorophenyl)-N'-[(4-cyanophenyl)sulfonyl]-4-phenyl-4,5-dihydro- 1H-pyrazole-1-carboxamidine) was found to have high-affinity and selectivity for binding to CB, receptors. (-)-12a and its lower affinity enantiomer ((+)-12a) were labeled with carbon-11 (t(1/2) = 20.4 min) using [(11)C]cyanide ion as labeling agent and evaluated as PET radioligands in cynomolgus monkeys. After injection of [(11)C](-)-12a, there was high uptake and retention of radioactivity across brain according to the rank order of CB, receptor densities. The distomer, [(11)C](+)-12a, failed to give a sustained CB1 receptor-specific distribution. Polar radiometabolites of [(11)C]-12a appeared moderately slowly in plasma. Radioligand [(11)C](-)-12a is promising for the study of brain CB, receptors and merits further investigation in human subjects. C1 [Donohue, Sean R.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Donohue, Sean R.; Finnema, Sjoerd J.; Truong, Phong; Andersson, Jan; Gulyas, Balazs; Halldin, Christer] Karolinska Hosp, Dept Clin Neurosci, Karolinska Inst, Psychiat Sect, S-17176 Stockholm, Sweden. RP Donohue, SR (reprint author), NIMH, Mol Imaging Branch, NIH, Bldg 10,Rm B3 C342, Bethesda, MD 20892 USA. EM donohues@intra.nimh.nih.gov RI Andersson, Jan/C-4093-2013; Gulyas, Balazs/F-9508-2015 FU Intramural Program of the National Institute of Mental Health [ZOI-MH-002795]; NIH-Karolinska Instituter Graduate Training Partnership in Neuroscience; University of North Carolina at Chapel Hill [NO1MH32004] FX This work was supported by the Intramural Program of the National Institute of Mental Health (project no. ZOI-MH-002795). Mr. S.R. Donohue was also supported with a studentship under the NIH-Karolinska Instituter Graduate Training Partnership in Neuroscience. We thank other members of the PET group at the Karolinska Institutet for assistance. We are grateful to Eli Lilly and Co. for the provision of 6 under a CRADA (Cooperative Research and Development Agreement) with NIMH. We thank the NIMH Psychoactive Drug Screening Program (PDSP) and Marie Wennerberg at AstraZeneca for per-forming binding assays. The PDSP is directed by Bryan L. Roth, Ph.D., with project officer Jamie Driscol (NIMH), at the University of North Carolina at Chapel Hill (contract NOIMH32004). NR 46 TC 14 Z9 15 U1 1 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 25 PY 2008 VL 51 IS 18 BP 5608 EP 5616 DI 10.1021/jm800329z PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 350HG UT WOS:000259342700015 PM 18754613 ER PT J AU Donohue, SR Krushinski, JH Pike, VW Chernet, E Phebus, L Chesterfield, AK Felder, CC Halldin, C Schaus, JM AF Donohue, Sean R. Krushinski, Joseph H. Pike, Victor W. Chernet, Eyassu Phebus, Lee Chesterfield, Amy K. Felder, Christian C. Halldin, Christer Schaus, John M. TI Synthesis, ex vivo evaluation, and radiolabeling of potent 1,5-diphenylpyrrolidin-2-one cannabinoid subtype-1 receptor ligands as candidates for in vivo imaging SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CB2 RECEPTORS; DOPAMINE D2; RAT-BRAIN; PET; TRACER; LOCALIZATION; IDENTIFICATION; RADIOSYNTHESIS; RADIOLIGANDS; RADIOTRACER AB We have reported that [methyl-(11)C] (3R,5R)-5-(3-methoxyphenyl)-3-[(R)-1-phenylethylamino]-1-(4-trifluoromethylphenyl)pyrrolidin-2-one ([(11)C]8, [(11)C]MePPEP) binds with high selectivity to cannabinoid type-l (CB(1)) receptors in monkey brain in vivo. We now describe the synthesis of 8 and four analogues, namely, the 4-fluorophenyl (16, FMePPEP), 3-fluoromethoxy (20, FMPEP), 3-fluoromethoxy-d(2) (21, FMPEP-d(2)), and 3-fluoroethoxy analogues (22, FEPEP), and report their activity in an ex vivo model designed to identify compounds suitable for use as positron emission tomography (PET) ligands. These ligands exhibited high, selective potency at CB I receptors in vitro (K(b) < 1 nM). Each ligand (30 mu g/kg, iv) was injected into rats under baseline and pretreatment conditions (3, rimonabant, 10 mg/kg, iv) and quantified at later times in frontal cortex ex vivo with liquid chromatography-mass spectrometry (LC-MS) detection. Maximal ligand uptakes were high (22.6-48.0 ng/g). Under pretreatment, maximal brain uptakes were greatly reduced (6.5 - 17.3 ng/g). Since each ligand readily entered brain and bound with high selectivity to CB 1 receptors, we then established and here describe methods for producing [(11)C]8, [(11)C] 16, and [[(18)F]20-22 in adequate activities for evaluation as candidate PET radioligands in vivo. C1 [Donohue, Sean R.; Pike, Victor W.] NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. [Donohue, Sean R.; Halldin, Christer] Karolinska Hosp, Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden. [Krushinski, Joseph H.; Chernet, Eyassu; Phebus, Lee; Chesterfield, Amy K.; Felder, Christian C.; Schaus, John M.] Eli Lilly & Co, Lilly Res Labs, Indianapolis, IN 46285 USA. RP Pike, VW (reprint author), NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. EM pikev@mail.nih.gov FU National Institutes of Health; National Institute of Mental Health (NIMH); Lilly Research Laboratories; Karolinska Institutet FX This research was supported by the Intramural Research Program of the National Institutes of Health, specifically the National Institute of Mental Health (NIMH), and also by a Cooperative Research and Development Agreement between Lilly Research Laboratories, NIMH, and the Karolinska Institutet. We are grateful to Ms. Cheryl L. Morse and Mr. Jinsoo Hong for assistance in radioligand production. We thank the NIH PET Department for 11C and 18F production. NR 42 TC 41 Z9 41 U1 0 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 25 PY 2008 VL 51 IS 18 BP 5833 EP 5842 DI 10.1021/jm800416m PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 350HG UT WOS:000259342700037 PM 18800770 ER PT J AU Dabire, KR Diabate, A Djogbenou, L Ouari, A N'Guessan, R Ouedraogo, JB Hougard, JM Chandre, F Baldet, T AF Dabire, Kounbobr Roch Diabate, Abdoulaye Djogbenou, Luc Ouari, Ali N'Guessan, Raphael Ouedraogo, Jean-Bosco Hougard, Jean-Marc Chandre, Fabrice Baldet, Thierry TI Dynamics of multiple insecticide resistance in the malaria vector Anopheles gambiae in a rice growing area in South-Western Burkina Faso SO MALARIA JOURNAL LA English DT Article ID PYRETHROID RESISTANCE; CULEX-QUINQUEFASCIATUS; INCIPIENT SPECIATION; IMPREGNATED BEDNETS; MOSQUITO VECTORS; KDR MUTATION; TREATED NETS; AFRICA; COMPLEX; EFFICACY AB Background: Insecticide resistance of the main malaria vector, Anopheles gambiae, has been reported in south-western Burkina Faso, West Africa. Cross-resistance to DDT and pyrethroids was conferred by alterations at site of action in the sodium channel, the Leu-Phe kdr mutation; resistance to organophosphates and carbamates resulted from a single point mutation in the oxyanion hole of the acetylcholinesterase enzyme designed as ace-1(R). Methods: An entomological survey was carried out during the rainy season of 2005 at Vallee du Kou, a rice growing area in south-western Burkina Faso. At the Vallee du Kou, both insecticide resistance mechanisms have been previously described in the M and S molecular forms of An. gambiae. This survey aimed i) to update the temporal dynamics and the circumsporozoite infection rate of the two molecular forms M and S of An. gambiae ii) to update the frequency of the Leu-Phe kdr mutation within these forms and finally iii) to investigate the occurrence of the ace-1(R) mutation. Mosquitoes collected by indoor residual collection and by human landing catches were counted and morphologically identified. Species and molecular forms of An. gambiae, ace-1(R) and Leu-Phe kdr mutations were determined using PCR techniques. The presence of the circumsporozoite protein of Plasmodium falciparum was determined using ELISA. Results: Anopheles gambiae populations were dominated by the M form. However the S form occurred in relative important proportion towards the end of the rainy season with a maximum peak in October at 51%. Sporozoite rates were similar in both forms. The frequency of the LeuPhe kdr mutation in the S form reached a fixation level while it is still spreading in the M form. Furthermore, the ace-1(R) mutation prevailed predominately in the S form and has just started spreading in the M form. The two mutations occurred concomitantly both in M and S populations. Conclusion: These results showed that the Vallee du Kou, a rice growing area formerly occupied mainly by M susceptible populations, is progressively colonized by S resistant populations living in sympatry with the former. As a result, the distribution pattern of insecticide resistance mutations shows the occurrence of both resistance mechanisms concomitantly in the same populations. The impact of multiple resistance mechanisms in M and S populations of An. gambiae on vector control measures against malaria transmission, such as insecticide-treated nets (ITNs) and indoor residual spraying (IRS), in this area is discussed. C1 [Dabire, Kounbobr Roch; Diabate, Abdoulaye; Ouari, Ali; Ouedraogo, Jean-Bosco] Ctr Muraz, IRSS, Bobo Dioulasso, Burkina Faso. [Diabate, Abdoulaye] NIAID, Lab Malaria Vector Res, NIH, Rockville, WA USA. [Djogbenou, Luc; Hougard, Jean-Marc; Chandre, Fabrice; Baldet, Thierry] IRD, Cotonou, Benin. [Djogbenou, Luc; N'Guessan, Raphael; Baldet, Thierry] CREC, Cotonou, Benin. [Baldet, Thierry] Cirad, UPR15, Montpellier, France. RP Dabire, KR (reprint author), Ctr Muraz, IRSS, BP 390, Bobo Dioulasso, Burkina Faso. EM dabire_roch@hotmail.com; a_diabate@hotmail.com; djogbenou@irf.fr; ouari_ali@yahoo.fr; Raphael.Nguessan@lshtm.ac.uk; jbouedraogo.irss@fasonet.bf; hougard@ird.fr; chandre@ird.fr; thierry.baldet@gmail.com OI Chandre, Fabrice/0000-0002-1994-9705 NR 37 TC 44 Z9 46 U1 0 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD SEP 25 PY 2008 VL 7 AR 188 DI 10.1186/1475-2875-7-188 PG 9 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 359UJ UT WOS:000260013300001 PM 18817564 ER PT J AU Lee, TL AF Lee, Tin-Lap TI Big data: open-source format needed to aid wiki collaboration SO NATURE LA English DT Letter C1 [Lee, Tin-Lap] NICHHD, Sect Dev Genom, Lab Clin Genom, Bethesda, MD 20892 USA. RP Lee, TL (reprint author), NICHHD, Sect Dev Genom, Lab Clin Genom, Bethesda, MD 20892 USA. EM leetl@mail.nih.gov RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 NR 1 TC 9 Z9 9 U1 4 U2 64 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 25 PY 2008 VL 455 IS 7212 BP 461 EP 461 DI 10.1038/455461c PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 351TU UT WOS:000259449600020 PM 18818632 ER PT J AU Perez, MA Tanaka, S Wise, SP Willingham, DT Cohen, LG AF Perez, Monica A. Tanaka, Satoshi Wise, Steven P. Willingham, Daniel T. Cohen, Leonardo G. TI Time-specific contribution of the supplementary motor area to intermanual transfer of procedural knowledge SO JOURNAL OF NEUROSCIENCE LA English DT Article DE motor learning; training; plasticity; motor cortex; motor control; learning and memory ID POSITRON-EMISSION-TOMOGRAPHY; SEQUENTIAL FINGER MOVEMENTS; TEMPORAL ORGANIZATION; MAGNETIC STIMULATION; MULTIPLE MOVEMENTS; NEURONAL-ACTIVITY; MACAQUE MONKEYS; CORTEX; PERFORMANCE; SKILL AB The supplementary motor area (SMA) makes a crucial contribution to intermanual transfer: the ability to use one hand to perform a skill practiced and learned with the other hand. However, the timing of this contribution relative to movement remains unknown. Here, 33 healthy volunteers performed a 12 item sequence in the serial reaction time task. During training, each participant responded to a sequence of visual cues presented at 1 Hz by pressing one of four keys with their right hand. The measure of intermanual transfer was response time (RT) during repetition of the trained sequence with the left hand, which was at rest during learning. Participants were divided into three groups, which did not differ in their learning rates or amounts. In two groups, 1 Hz repetitive transcranial magnetic stimulation nduced transient virtual lesions of the SMA during training, either 100 ms before each cue (the premovement group) or during each key press (the movement group). The third group received sham stimulation (the sham group). After training with the right hand, RTs for performance with the left (transfer) hand were longer for the premovement group than for the movement or sham groups. Thus, the most crucial contribution of SMA to intermanual transfer occurs in the interval between movements, when the memory of a previous movement plays a role in encoding specific sequences. These results provide insight into frontal lobe contributions to procedural knowledge. C1 [Perez, Monica A.; Tanaka, Satoshi; Cohen, Leonardo G.] NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. [Perez, Monica A.; Tanaka, Satoshi; Cohen, Leonardo G.] NINDS, Stroke Neurorehabil Clin, NIH, Bethesda, MD 20892 USA. [Wise, Steven P.] NIMH, Lab Syst Neurosci, NIH, Bethesda, MD 20892 USA. [Willingham, Daniel T.] Univ Virginia, Dept Psychol, Charlottesville, VA 22904 USA. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov FU the National Institutes of Health; National Institute of Neurological Disorders and Stroke; National Institute of Mental Health FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute of Neurological Disorders and Stroke, and National Institute of Mental Health. NR 40 TC 30 Z9 30 U1 1 U2 3 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 24 PY 2008 VL 28 IS 39 BP 9664 EP 9669 DI 10.1523/JNEUROSCI.3416-08.2008 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 352MG UT WOS:000259500700007 PM 18815252 ER PT J AU Chen, K Tjandra, N AF Chen, Kang Tjandra, Nico TI Extended model free approach to analyze correlation functions of multidomain proteins in the presence of motional coupling SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NMR RELAXATION DATA; MAGNETIC-RESONANCE RELAXATION; INTERDOMAIN MOBILITY; DOMAIN MOTIONS; MACROMOLECULES; DYNAMICS; SIMULATIONS; CALMODULIN; DIFFUSION; APPROXIMATION AB Interdomain motion in proteins plays an important role in biomolecular interaction. Its presence also complicates interpretation of many spectroscopy measurements. Nuclear magnetic resonance (NMR) study of domain dynamics relies on knowledge of its rotational correlation function. The extended model free (EMF) approach has been implemented to analyze coupled domain and overall motions for calmodulin, a dual-domain protein; however, the validity of EMF treatment in coupled motion has not been tested. We performed stochastic simulations on a dual-vector system employing two simple restraints to drive hydrodynamics and domain coupling: (1) both unitary vectors diffuse randomly on the surface of a sphere and (2) vectors are correlated through user-defined intervector potential. The resulting correlation curve can be adequately fit with either a single- or double-exponential decay function. The latter is consistent with the EMF treatment. The derived order parameters S-2 range from about 0.4 to 1, while the motion separation, the ratio of overall and domain motion time scales (tau(m)/tau(s)) ranges from 1 to 4. A complete overlap between time scales occurs when S-2 is less than 0.4, and the correlation function effectively behaves as a single-exponential. The S-2 values are consistent with theoretical predictions from the given potential function, differing by no more than 0.03, suggesting EMF to be a generally valid approach. In addition, from the dependence of S-2 on tau(m)/tau(s) obtained from simulation, we found a cosine potential, favoring extended conformers, as opposed to the normally assumed cone potential, reached a better agreement to experimental data. C1 [Chen, Kang; Tjandra, Nico] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov FU Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute FX We thank Attila Szabo for many helpful discussions and James Gruschus for careful reading of the manuscript. This work was supported by the Intramural Research Program of the NIH, National Heart, Lung, and Blood Institute. NR 26 TC 20 Z9 20 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 24 PY 2008 VL 130 IS 38 BP 12745 EP 12751 DI 10.1021/ja803557t PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 349QG UT WOS:000259295400057 PM 18761455 ER PT J AU Adams, J Fantner, GE Fisher, LW Hansma, PK AF Adams, J. Fantner, G. E. Fisher, L. W. Hansma, P. K. TI Molecular energy dissipation in nanoscale networks of dentin matrix protein 1 is strongly dependent on ion valence SO NANOTECHNOLOGY LA English DT Article ID FORCE SPECTROSCOPY; SACRIFICIAL BONDS; SIBLING PROTEINS; HIDDEN LENGTH; IN-VITRO; FRACTURE; OSTEOPONTIN; EXPRESSION; BIOMINERALIZATION; DEFORMATION AB The fracture resistance of biomineralized tissues such as bone, dentin, and abalone is greatly enhanced through the nanoscale interactions of stiff inorganic mineral components with soft organic adhesive components. A proper understanding of the interactions that occur within the organic component, and between the organic and inorganic components, is therefore critical for a complete understanding of the mechanics of these tissues. In this paper, we use atomic force microscope (AFM) force spectroscopy and dynamic force spectroscopy to explore the effect of ionic interactions within a nanoscale system consisting of networks of dentin matrix protein 1 (DMP1) ( a component of both bone and dentin organic matrix), a mica surface and an AFM tip. We find that DMP1 is capable of dissipating large amounts of energy through an ion-mediated mechanism, and that the effectiveness increases with increasing ion valence. C1 [Adams, J.; Fantner, G. E.; Hansma, P. K.] Univ Calif Santa Barbara, Dept Phys, Santa Barbara, CA 93106 USA. [Fisher, L. W.] NIDCR, Craniofacial & Skeletal Dis Branch, NIH, DHHS, Bethesda, MD 20892 USA. RP Adams, J (reprint author), Univ Calif Santa Barbara, Dept Phys, Broida Hall, Santa Barbara, CA 93106 USA. EM adams@physics.ucsb.edu; fantner@physics.ucsb.edu; lfisher@dir.nidcr.nih.gov; prasant@physics.ucsb.edu RI Fantner, Georg/F-7392-2011 FU Intramural NIH HHS [Z01 DE000074-35]; NIGMS NIH HHS [R01 GM065354, R01 GM065354-05, R01 GM065354-06] NR 38 TC 18 Z9 18 U1 1 U2 11 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0957-4484 EI 1361-6528 J9 NANOTECHNOLOGY JI Nanotechnology PD SEP 24 PY 2008 VL 19 IS 38 AR 384008 DI 10.1088/0957-4484/19/38/384008 PG 7 WC Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied SC Science & Technology - Other Topics; Materials Science; Physics GA 336SU UT WOS:000258385700009 PM 18843380 ER PT J AU Chatterjee, DK Sitaraman, K Baptista, C Hartley, J Hill, TM Munroe, DJ AF Chatterjee, Deb K. Sitaraman, Kalavathy Baptista, Cassio Hartley, James Hill, Thomas M. Munroe, David J. TI Protein Microarray On-Demand: A Novel Protein Microarray System SO PLOS ONE LA English DT Article AB We describe a novel, simple and low-cost protein microarray strategy wherein the microarrays are generated by printing expression ready plasmid DNAs onto slides that can be converted into protein arrays on-demand. The printed expression plasmids serve dual purposes as they not only direct the synthesis of the protein of interest; they also serve to capture the newly synthesized proteins through a high affinity DNA-protein interaction. To accomplish this we have exploited the high-affinity binding (similar to 3-7 x 10(-13) M) of E. coli Tus protein to Ter, a 20 bp DNA sequence involved in the regulation of E. coli DNA replication. In our system, each protein of interest is synthesized as a Tus fusion protein and each expression construct directing the protein synthesis contains embedded Ter DNA sequence. The embedded Ter sequence functions as a capture reagent for the newly synthesized Tus fusion protein. This "all DNA'' microarray can be converted to a protein microarray on-demand without need for any additional capture reagent.. C1 [Chatterjee, Deb K.; Sitaraman, Kalavathy; Hartley, James] NCI, Prot Express Lab, SAIC Frederick Inc, Frederick, MD USA. [Baptista, Cassio] NCI, Lab Mol Technol, SAIC Frederick Inc, Frederick, MD USA. [Chatterjee, Deb K.; Sitaraman, Kalavathy; Baptista, Cassio; Hartley, James; Munroe, David J.] NCI, Advanced Technol Program, SAIC Frederick Inc, Frederick, MD USA. [Hill, Thomas M.] Univ North Dakota, Sch Med & Hlth Sci, Dept Microbiol & Immunol, Grand Forks, ND USA. RP Chatterjee, DK (reprint author), NCI, Prot Express Lab, SAIC Frederick Inc, Frederick, MD USA. EM chatterjee@mail.ncifcrf.gov FU National Cancer Institute, National Institutes of Health [N01-CO-12400] FX This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. NR 13 TC 14 Z9 15 U1 1 U2 6 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 24 PY 2008 VL 3 IS 9 AR e3265 DI 10.1371/journal.pone.0003265 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422MG UT WOS:000264431800005 PM 18813342 ER PT J AU DiNapoli, JM Murphy, BR Collins, PL Bukreyev, A AF DiNapoli, Joshua M. Murphy, Brian R. Collins, Peter L. Bukreyev, Alexander TI Impairment of the CD8+T cell response in lungs following infection with human respiratory syncytial virus is specific to the anatomical site rather than the virus, antigen, or route of infection SO VIROLOGY JOURNAL LA English DT Article ID CYTOTOXIC T-CELLS; RECOMBINANT VACCINIA VIRUS; M2 PROTEIN; MICE; IMMUNIZATION; RESISTANCE; RSV; RECOGNITION; LYMPHOCYTES; EXPRESSION AB Background: A subset of the virus-specific CD8+ cytotoxic T lymphocytes (CTL) isolated from the lungs of mice infected with human respiratory syncytial virus (RSV) is impaired in the ability to secrete interferon gamma (IFN gamma), a measure of functionality. It was suggested that the impairment specifically suppressed the host cellular immune response, a finding that could help explain the ability of RSV to re-infect throughout life. Results: To determine whether this effect is dependent on the virus, the route of infection, or the type of infection ( respiratory, disseminated, or localized dermal), we compared the CTL responses in mice following intranasal ( IN) infection with RSV or influenza virus or IN or intradermal ( ID) infection with vaccinia virus expressing an RSV CTL antigen. The impairment was observed in the lungs after IN infection with RSV, influenza or vaccinia virus, and after a localized ID infection with vaccinia virus. In contrast, we observed a much higher percentage of IFN gamma secreting CD8+ lymphocytes in the spleens of infected mice in every case. Conclusion: The decreased functionality of CD8+ CTL is specific to the lungs and is not dependent on the specific virus, viral antigen, or route of infection. C1 [DiNapoli, Joshua M.; Murphy, Brian R.; Collins, Peter L.; Bukreyev, Alexander] NIAID, NIH, Infect Dis Lab, Bethesda, MD 20892 USA. RP Bukreyev, A (reprint author), NIAID, NIH, Infect Dis Lab, 50 South Dr,Room 6505, Bethesda, MD 20892 USA. EM dinapolij@niaid.nih.gov; bmurphy@niaid.nih.gov; pcollins@niaid.nih.gov; abukreyev@nih.gov FU National Institute of Allergy and Infectious Diseases FX We thank Lijuan Yang for excellent technical assistance. This study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. NR 25 TC 14 Z9 15 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD SEP 24 PY 2008 VL 5 AR 105 DI 10.1186/1743-422X-5-105 PG 8 WC Virology SC Virology GA 360BD UT WOS:000260031100001 PM 18816384 ER PT J AU Jain, A Karadag, A Fisher, LW Fedarko, NS AF Jain, Alka Karadag, Abdullah Fisher, Larry W. Fedarko, Neat S. TI Structural requirements for bone sialoprotein binding and modulation of matrix metal loproteinase-2 SO BIOCHEMISTRY LA English DT Article ID LINKED GLYCOPROTEINS SIBLINGS; COMPLEMENT-MEDIATED ATTACK; CYSTEINE SWITCH; GELATINASE-A; GENE FAMILY; OSTEOPONTIN; INTEGRIN; PROTEINS; LIGAND; CANCER AB Bone sialoprotein (BSP) has been shown to induce limited gelatinase activity in latent matrix metalloproteinase-2 (MMP-2) without removal of the propeptide and to restore enzymatic activity to MMP-2 previously inhibited by tissue inhibitor of matrix metalloproteinase-2 (TIMP2). The current study identifies structural domains in human BSP and MMP-2 that contribute to these interactions. The 26 amino acid domain encoded by exon 4 of BSP is shown by a series of binding and activity assays to be involved in the displacement of MMP-2's propeptide from the active site and thereby inducing the protease activity. Binding assays in con unction with enzyme activity assays demonstrate that both amino- and carboxyterminal domains of BSP contribute to restoration of activity to TIMP2-inhibited MMP-2, while the MMP-2 hemopexin domain is not required for reactivation. C1 [Jain, Alka; Fedarko, Neat S.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21224 USA. [Karadag, Abdullah; Fisher, Larry W.] Natl Inst Dental & Craniofacial Res, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Dept Med, Baltimore, MD 21224 USA. RP Fedarko, NS (reprint author), Johns Hopkins Univ, Sch Med, Room 5A-64 JHAAC,5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM ndarko@jhmi.edu FU National Institutes of Health [CA113865]; Division of Intramural Research, National Institute of Dental; Craniofacial Research Intramural Research Program, National Institutes of Health, Department of Health and Human Services FX This research was supported in part by National Institutes of Health Grant CA113865 (N.S.F.) and by the Division of Intramural Research, National Institute of Dental and Craniofacial Research Intramural Research Program, National Institutes of Health, Department of Health and Human Services (L.W.F.). NR 28 TC 7 Z9 7 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 SEP 23 PY 2008 VL 47 IS 38 BP 10162 EP 10170 DI 10.1021/bi801068p PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 349GA UT WOS:000259268100024 PM 18729384 ER PT J AU Bonham, VL Ramos, EM AF Bonham, Vence L. Ramos, Erin M. TI Unravelling the contributions of social, environmental and genetic factors to health differences SO CANADIAN MEDICAL ASSOCIATION JOURNAL LA English DT Editorial Material ID SOCIOECONOMIC-STATUS; PROSPECTIVE COHORT; GENOME ERA; RACE; DISPARITIES; ETHNICITY C1 [Bonham, Vence L.] NHGRI, Social & Behav Res Branch, Div Intramural Res, NIH, Bethesda, MD 20892 USA. [Ramos, Erin M.] NHGRI, Off Populat Genom, NIH, Bethesda, MD 20892 USA. RP Bonham, VL (reprint author), NHGRI, Social & Behav Res Branch, Div Intramural Res, NIH, 31 Ctr Dr,Rm B1B55, Bethesda, MD 20892 USA. EM bonhamv@mail.nih.gov FU Intramural NIH HHS NR 17 TC 0 Z9 0 U1 1 U2 2 PU CMA-CANADIAN MEDICAL ASSOC PI OTTAWA PA 1867 ALTA VISTA DR, OTTAWA, ONTARIO K1G 3Y6, CANADA SN 0820-3946 J9 CAN MED ASSOC J JI Can. Med. Assoc. J. PD SEP 23 PY 2008 VL 179 IS 7 BP 629 EP 630 DI 10.1503/cmaj.080669 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 348AW UT WOS:000259184200003 PM 18809886 ER PT J AU Legiewicz, M Badorrek, CS Turner, KB Fabris, D Hamm, TE Rekosh, D Hammarskjold, ML Le Grice, SFJ AF Legiewicz, Michal Badorrek, Christopher S. Turner, Kevin B. Fabris, Daniele Hamm, Tiffany E. Rekosh, David Hammarskjold, Marie-Louise Le Grice, Stuart F. J. TI Resistance to RevM10 inhibition reflects a conformational switch in the HIV-1 Rev response element SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemical footprinting; HIV RNA evolution; mass spectrometry; Rev/RRE interaction ID HUMAN-IMMUNODEFICIENCY-VIRUS; TARGET SEQUENCE; TYPE-1 REV; RNA-BINDING; TRANS-ACTIVATOR; MESSENGER-RNA; ALPHA-HELIX; I REX; PROTEIN; GENE AB Nuclear export of certain HIV-1 mRNAs requires an interaction between the viral Rev protein and the Rev response element (RRE), a structured element located in the Env region of its RNA genome. This interaction is an attractive target for both drug design and gene therapy, exemplified by RevM10, a transdominant negative protein that, when introduced into host cells, disrupts viral mRNA export. However, two silent G->A mutations in the RRE (RRE61) confer RevM10 resistance, which prompted us to examine RRE structure using a novel chemical probing strategy. Variations in region III/IV/V of mutant RNAs suggest a stepwise rearrangement to RevM10 resistance. Mass spectrometry was used to directly assess Rev "loading" onto RRE and its variants, indicating that this is unaffected by RNA structural changes. Similarity in chemical footprints with mutant protein implicates additional host factors in RevM10 resistance. C1 [Legiewicz, Michal; Badorrek, Christopher S.; Le Grice, Stuart F. J.] NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Turner, Kevin B.; Fabris, Daniele] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. [Hamm, Tiffany E.; Rekosh, David; Hammarskjold, Marie-Louise] Univ Virginia, Myles Thayler Ctr AIDS & Human Retrovirus Res, Charlottesville, VA 22908 USA. [Hamm, Tiffany E.; Rekosh, David; Hammarskjold, Marie-Louise] Univ Virginia, Dept Microbiol, Charlottesville, VA 22908 USA. RP Le Grice, SFJ (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM slegrice@ncifcrf.gov FU National Institutes of Health; National Institutes of Health [A1054335, A1068501, GM643208]; University of Virginia FX This work is supported by the intramural research program of the National Institutes of Health (S.F.J.L.G.); National Institutes of Health Grants A1054335 (to D.R.), A1068501 (to M.-L.H.), and GM643208 (to D.F.); and the Myles H. Thaler and Charles Ross, Jr. Eminent Scholar Professorships at the (to D.R. and M.-L.H). NR 37 TC 32 Z9 32 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 23 PY 2008 VL 105 IS 38 BP 14365 EP 14370 DI 10.1073/pnas.0804461105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 353TY UT WOS:000259592400027 PM 18776047 ER PT J AU Ahn, BH Kim, HS Song, SW Lee, IH Liu, J Vassilopoulos, A Deng, CX Finkel, T AF Ahn, Bong-Hyun Kim, Hyun-Seok Song, Shiwei Lee, In Hye Liu, Jie Vassilopoulos, Athanassios Deng, Chu-Xia Finkel, Toren TI A role for the mitochondrial deacetylase Sirt3 in regulating energy homeostasis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE acetylation; sirtuins; complex I; electron transport ID SACCHAROMYCES-CEREVISIAE; CALORIE RESTRICTION; LYSINE ACETYLATION; DEPENDENT DEACETYLASE; LIFE-SPAN; HOMOLOG; PROTEOMICS; SIRTUINS; COMPLEX; STRESS AB Here, we demonstrate a role for the mitochondrial NAD-dependent deacetylase Sirt3 in the maintenance of basal ATP levels and as a regulator of mitochondrial electron transport. We note that Sirt3(-/-) mouse embryonic fibroblasts have a reduction in basal ATP levels. Reconstitution with wild-type but not a deacetylase-deficient form of Sirt3 restored ATP levels in these cells. Furthermore in wild-type mice, the resting level of ATP correlates with organ-specific Sirt3 protein expression. Remarkably, in mice lacking Sirt3, basal levels of ATP in the heart, kidney, and liver were reduced >50%. We further demonstrate that mitochondrial protein acetylation is markedly elevated in Sirt3(-/-) tissues. In addition, in the absence of Sirt3, multiple components of Complex I of the electron transport chain demonstrate increased acetylation. Sirt3 can also physically interact with at least one of the known subunits of Complex 1, the 39-kDa protein NDUFA9. Functional studies demonstrate that mitochondria from Sirt3(-/-) animals display a selective inhibition of Complex I activity. Furthermore, incubation of exogenous Sirt3 with mitochondria can augment Complex I activity. These results implicate protein acetylation as an important regulator of Complex I activity and demonstrate that Sirt3 functions in vivo to regulate and maintain basal ATP levels. C1 [Kim, Hyun-Seok; Vassilopoulos, Athanassios; Deng, Chu-Xia] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Ahn, Bong-Hyun; Song, Shiwei; Lee, In Hye; Liu, Jie; Finkel, Toren] NHLBI, Translat Med Branch, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDKD, Genet Dev & Dis Branch, NIH, Bldg 10,Room 9N105, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016 FU National Institutes of Health Intramural; Ellison Medical Foundation FX We are grateful to I. Rovira for help with manuscript preparation. We thank B. Schwer, M. Hirschey, and E. Verdin (University of California at San Francisco, CA) for the gift of Sirt3 antibody. This work was supported by National Institutes of Health Intramural funds (to C.D. and T.F.) and a grant from the Ellison Medical Foundation (to T.F.). NR 26 TC 479 Z9 498 U1 5 U2 39 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 SEP 23 PY 2008 VL 105 IS 38 BP 14447 EP 14452 DI 10.1073/pnas.0803790105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 353TY UT WOS:000259592400041 PM 18794531 ER PT J AU Bustamante, VH Martinez, LC Santana, FJ Knodler, LA Steele-Mortimer, O Puente, JL AF Bustamante, Victor H. Martinez, Luary C. Santana, Francisco J. Knodler, Leigh A. Steele-Mortimer, Olivia Puente, Jose L. TI HilD-mediated transcriptional cross-talk between SPI-1 and SPI-2 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE H-NS; OmpR; microbial pathogenesis; transcriptional regulation; salmonella ID ENTERICA SEROVAR TYPHIMURIUM; PATHOGENICITY ISLAND 2; PROTEIN H-NS; III SECRETION SYSTEM; ESCHERICHIA-COLI K-12; LATERAL GENE-TRANSFER; SALMONELLA-ENTERICA; INFECTIOUS ENTEROCOLITIS; ENVIRONMENTAL-REGULATION; EFFECTOR PROTEINS AB The acquisition of new genetic traits by horizontal gene transfer and their incorporation into preexisting regulatory networks have been essential events in the evolution of bacterial pathogens. An example of successful assimilation of virulence traits is Salmonella enterica, which acquired, at distinct evolutionary times, Salmonella pathogenicity island 1 (SPI-1), required for efficient invasion of the intestinal epithelium and intestinal disease, and SPI-2, essential for Salmonella replication and survival within macrophages and the progression of a systemic infection. A positive regulatory cascade mainly composed of HilD, HilA, and InvF, encoded in SPI-1, controls the expression of SPI-1 genes, whereas the two-component regulatory system SsrA/B, encoded in SPI-2, controls expression of SPI-2 genes. In this study, we report a previously undescribed transcriptional cross-talk between SPI-1 and SPI-2, where the SPI-1-encoded regulator Hill) is essential for the activation of both the SPI-1 and SPI-2 regulons but at different times during the stationary phase of growth in Luria-Bertani medium. Our data indicate that HilD counteracts the H-NS-mediated repression exerted on the OmpR-dependent activation of the ssrAB operon by specifically interacting with its regulatory region. In contrast, HilD is not required for SPI-2 regulon expression under the in vitro growth conditions that are thought to resemble the intracellular environment. Our results suggest that two independent SPI-2 activation pathways evolved to take advantage of the SPI-2-encoded information at different niches and, in consequence, in response to different growth conditions. C1 [Bustamante, Victor H.; Martinez, Luary C.; Santana, Francisco J.; Puente, Jose L.] Univ Nacl Autonoma Mexico, Inst Biotechnol, Dept Mol Microbiol, Cuernavaca 62210, Morelos, Mexico. [Puente, Jose L.] NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. RP Puente, JL (reprint author), Univ Nacl Autonoma Mexico, Inst Biotechnol, Dept Mol Microbiol, Ave Univ 2001,Colonia Chamilpa, Cuernavaca 62210, Morelos, Mexico. EM puente@ibt.unam.mx FU Consejo Nacional de Ciencia y Tecnologia (CONACYT) [42918Q, 169380]; Howard Hughes Medical Institute [75301-565101]; Direccion General de Asuntos del Personal Academico (DGAPA) [IN227306-3]; Intramural Research Program of the National Institute of Allergy and Infectious Diseases; National Institutes of Health FX We thank A. Vazquez and M. Fernandez-Mora for excellent technical assistance, L.J. Kenney for anti-SsrB and anti-OmpR antibodies, and S. Miller and F. Heffron for providing Salmonella strains. This work was supported by grants from Consejo Nacional de Ciencia y Tecnologia (CONACYT) (42918Q) (to J.L.P.) and the Howard Hughes Medical Institute (75301-565101) (to J.L.P) and from Direccion General de Asuntos del Personal Academico (DGAPA) (IN227306-3) (to V.H.B). L.C.M. is supported by a predoctoral fellowship from CONACYT (No. 169380). L.A.K. and O.S.M. were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 57 TC 61 Z9 66 U1 1 U2 12 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 23 PY 2008 VL 105 IS 38 BP 14591 EP 14596 DI 10.1073/pnas.0801205105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 353TY UT WOS:000259592400066 PM 18799744 ER PT J AU Gentile, S Martin, N Scappini, E Williams, J Erxleben, C Armstrong, DL AF Gentile, Saverio Martin, Negin Scappini, Erica Williams, Jason Erxleben, Christian Armstrong, David L. TI The human ERG1 channel polymorphism, K897T, creates a phosphorylation site that inhibits channel activity SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Kv11.1; LQT; Akt protein kinase; phosphatidylinositol 3-kinase; thyroid hormone ID LONG QT SYNDROME; POTASSIUM CHANNEL; CARDIAC-ARRHYTHMIA; THYROID-HORMONE; PLASMA-MEMBRANE; PROTEIN-KINASE; K+ CHANNELS; KCNH2 HERG; RECEPTOR; IDENTIFICATION AB Single-nucleotide polymorphisms (SNPs) in the human ether-a-go-go-related gene 1, hERG1, are associated with cardiac arrhythmias. The Kv11.1 channels encoded by hERG1 are also essential for rhythmic excitability of the pituitary, where they are regulated by thyroid hormone through a signal transduction cascade involving the phosphatidylinositol 3-kinase (PI3K) and the Ser/Thr-directed protein phosphatase, PP5. Here, we show that the hERG1 polymorphism at codon 897, which is read as a Thr instead of a Lys, creates a phosphorylation site for the Akt protein kinase on the Kv11.1 channel protein. Consequently, hormonal signaling through the PI3K signaling cascade, which normally stimulates K897 channels through PP5-mediated dephosphorylation, inhibits T897 channels through Akt-mediated phosphorylation. Thus, hormonal regulation of Kv11.1 in humans with the T897 polymorphism is predicted to prolong the QT interval of cardiac myocytes. A systematic bioinformatics search for SNIPS in human ion channel genes identified 15 additional candidates for such "phosphorylopathies," which are predicted to create or destroy putative phosphorylation sites. Changes in protein phosphorylation might represent a general mechanism for the interaction of genetic variation and environment on human health. C1 [Gentile, Saverio; Martin, Negin; Scappini, Erica; Williams, Jason; Erxleben, Christian; Armstrong, David L.] NIEHS, Environm Biol Program, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Armstrong, DL (reprint author), NIEHS, Environm Biol Program, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM armstro3@niehs.nih.gov OI Martin, Negin/0000-0003-3166-8989 FU National Institutes of Health [Z01-ES080043] FX We are grateful to Peter Smutko for assistance in completing the database search and to John O'Bryan for Akt constructs. This work was supported by the National Institutes of Health Intramural Research Program at National Institute of Environmental Health Sciences through Grant Z01-ES080043. NR 37 TC 23 Z9 23 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 23 PY 2008 VL 105 IS 38 BP 14704 EP 14708 DI 10.1073/pnas.0802250105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 353TY UT WOS:000259592400085 PM 18791070 ER PT J AU Koshiol, J Gridley, G Engels, EA McMaster, ML Landgren, O AF Koshiol, Jill Gridley, Gloria Engels, Eric A. McMaster, Mary L. Landgren, Ola TI Chronic immune stimulation and subsequent Waldenstrom macroglobulinemia SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID NON-HODGKIN-LYMPHOMA; UNDETERMINED SIGNIFICANCE; MONOCLONAL GAMMOPATHY; AUTOIMMUNE-DISEASE; INCIDENCE-PATTERNS; UNITED-STATES; RISK; FAMILY; SUSCEPTIBILITY; GENE AB Background: Certain autoimmune and infectious conditions are associated with increased risks of subtypes of non-Hodgkin lymphoma. A few previous studies suggest that chronic inflammation may particularly elevate risk of the distinct non-Hodgkin lymphoma subtype Waldenstrom macroglobulinemia (WM). Methods: We assessed WM risk in relation to a variety of chronic immune stimulatory conditions in 4 million US veterans. We identified 361 patients with WM with up to 27 years of follow-up. Using time-dependent Poisson regression, we estimated rate ratios (RRs) and 95% confidence intervals (CIs) for WM risk in relation to history of autoimmune diseases that typically have autoantibodies (with systemic or organ involvement) or do not have autoantibodies, infections, and allergies. All the models were adjusted for attained age, calendar year, race, number of hospital visits, and latency between study entry and exit. Results: The age-standardized incidence of WM was 0.34 per 100 000 person-years. Risk of WM was elevated in individuals with any previous autoimmune condition (RR, 2.23; 95% CI, 1.68-2.97), autoantibodies with systemic involvement (2.50; 1.55-4.02), or autoantibodies with organ involvement (2.30; 1.57-3.37). Risks of WM were also increased with hepatitis (RR, 3.39; 95% CI, 1.38-8.30), human immunodeficiency virus (12.05; 2.83-51.46), and rickettsiosis (3.35; 1.38-8.14). Conclusions: In the largest investigation of WM risk factors to date, we found a 2- to 3-fold elevated risk of WM in persons with a personal history of autoimmune diseases with autoantibodies and notably elevated risks associated with hepatitis, human immunodeficiency virus, and rickettsiosis. These findings provide novel insights into the still unknown etiology of WM. C1 [Koshiol, Jill] NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, Bethesda, MD 20892 USA. [Koshiol, Jill; Gridley, Gloria; Engels, Eric A.; McMaster, Mary L.; Landgren, Ola] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Koshiol, J (reprint author), NCI, Genet Epidemiol Branch, 6120 Execut Blvd,EPS 7003,MSC 7236, Bethesda, MD 20892 USA. EM koshiolj@mail.nih.go FU Intramural Research Program of the National Cancer Institute; National Institutes of Health FX This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health. NR 41 TC 23 Z9 25 U1 0 U2 0 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 SEP 22 PY 2008 VL 168 IS 17 BP 1903 EP 1909 DI 10.1001/archinternmed.2008.4 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 350ZP UT WOS:000259393000010 PM 18809818 ER PT J AU Ma, W Tavakoli, T Derby, E Serebryakova, Y Rao, MS Mattson, MP AF Ma, Wu Tavakoli, Tara Derby, Eric Serebryakova, Yevgeniya Rao, Mahendra S. Mattson, Mark P. TI Cell-extracellular matrix interactions regulate neural differentiation of human embryonic stem cells SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article ID IN-VITRO; INTEGRINS; LAMININ; NICHE; SPECIFICATION; PRECURSORS; MIGRATION; ROSETTES; CD29 AB Background: Interactions of cells with the extracellular matrix (ECM) are critical for the establishment and maintenance of stem cell self-renewal and differentiation. However, the ECM is a complex mixture of matrix molecules; little is known about the role of ECM components in human embryonic stem cell (hESC) differentiation into neural progenitors and neurons. Results: A reproducible protocol was used to generate highly homogenous neural progenitors or a mixed population of neural progenitors and neurons from hESCs. This defined adherent culture system allowed us to examine the effect of ECM molecules on neural differentiation of hESCs. hESC-derived differentiating embryoid bodies were plated on Poly-D-Lysine (PDL), PDL/fibronectin, PDL/laminin, type I collagen and Matrigel, and cultured in neural differentiation medium. We found that the five substrates instructed neural progenitors followed by neuronal differentiation to differing degrees. Glia did not appear until 4 weeks later. Neural progenitor and neuronal generation and neurite outgrowth were significantly greater on laminin and laminin-rich Matrigel substrates than on other 3 substrates. Laminin stimulated hESC-derived neural progenitor expansion and neurite outgrowth in a dose-dependent manner. The laminin-induced neural progenitor expansion was partially blocked by the antibody against integrin alpha 6 or beta 1 subunit. Conclusion: We defined laminin as a key ECM molecule to enhance neural progenitor generation, expansion and differentiation into neurons from hESCs. The cell-laminin interactions involve alpha 6 beta 1 integrin receptors implicating a possible role of laminin/alpha 6 beta 1 integrin signaling in directed neural differentiation of hESCs. Since laminin acts in concert with other ECM molecules in vivo, evaluating cellular responses to the composition of the ECM is essential to clarify further the role of cell-matrix interactions in neural derivation of hESCs. C1 [Ma, Wu; Tavakoli, Tara; Derby, Eric; Serebryakova, Yevgeniya] ATCC, Stem Cell Ctr, Manassas, VA USA. [Rao, Mahendra S.] Invitrogen, Stem Cells & Regenerat Med Res, Carlsbad, CA USA. [Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. RP Ma, W (reprint author), ATCC, Stem Cell Ctr, Manassas, VA USA. EM wma@atcc.org; ttavakoli@atcc.org; ederby@atcc.org; jserebryakova@atcc.org; mahendra.rao@invitrogen.com; mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU NIH/National Institute on Aging [N01AG40002] FX This work was supported by contract grant N01AG40002 from NIH/National Institute on Aging. NR 24 TC 101 Z9 106 U1 5 U2 34 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD SEP 22 PY 2008 VL 8 AR 90 DI 10.1186/1471-213X-8-90 PG 13 WC Developmental Biology SC Developmental Biology GA 368OR UT WOS:000260632100001 PM 18808690 ER PT J AU Kahn, RA Bruford, E Inoue, H Logsdon, JM Nie, ZZ Premont, RT Randazzo, PA Satake, M Theibert, AB Zapp, ML Cassel, D AF Kahn, Richard A. Bruford, Elspeth Inoue, Hiroki Logsdon, John M. Nie, Zhongzhen Premont, Richard T. Randazzo, Paul A. Satake, Masanobu Theibert, Anne B. Zapp, Maria L. Cassel, Dan TI Consensus nomenclature for the human ArfGAP domain-containing proteins SO JOURNAL OF CELL BIOLOGY LA English DT Review ID GTPASE-ACTIVATING PROTEIN; ACTIN CYTOSKELETON; MEMBRANE CURVATURE; GIT FAMILY; GOLGI; COMPLEX; GAP; LOCALIZATION; REGULATORS; CLATHRIN AB At the FASEB summer research conference on "Arf Family GTPases", held in Il Ciocco, Italy in June, 2007, it became evident to researchers that our understanding of the family of Arf GTPase activating proteins (ArfGAPs) has grown exponentially in recent years. A common nomenclature for these genes and proteins will facilitate discovery of biological functions and possible connections to pathogenesis. Nearly 100 researchers were contacted to generate a consensus nomenclature for human ArfGAPs. This article describes the resulting consensus nomenclature and provides a brief description of each of the 10 subfamilies of 31 human genes encoding proteins containing the ArfGAP domain. C1 [Kahn, Richard A.] Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. [Bruford, Elspeth] EMBL, EBI, HUGO Gene Nomenclature Comm, Cambridge CB10 1SA, England. [Inoue, Hiroki; Randazzo, Paul A.] NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. [Logsdon, John M.] Univ Iowa, Dept Biol, Roy J Carver Ctr Comparat Genom, Iowa City, IA 52242 USA. [Nie, Zhongzhen] Med Coll Georgia, Dept Pathol, Augusta, GA 30912 USA. [Premont, Richard T.] Duke Univ, Sch Med, Dept Med, Div Gastroenterol, Durham, NC 27710 USA. [Satake, Masanobu] Tohoku Univ, Dept Mol Immunol, Inst Dev Aging & Canc, Sendai, Miyagi 9808575, Japan. [Theibert, Anne B.] Univ Alabama, Dept Neurobiol, Birmingham, AL 35294 USA. [Theibert, Anne B.] Univ Alabama, Dept Cell Biol, Birmingham, AL 35294 USA. [Zapp, Maria L.] Univ Massachusetts, Sch Med, Program Mol Med, Worcester, MA 01605 USA. [Zapp, Maria L.] Univ Massachusetts, Sch Med, Ctr AIDS Res, Worcester, MA 01605 USA. [Cassel, Dan] Technion Israel Inst Technol, Dept Biol, IL-32000 Haifa, Israel. RP Kahn, RA (reprint author), Emory Univ, Sch Med, Dept Biochem, Atlanta, GA 30322 USA. EM rkahn@emory.edu RI Logsdon, John/B-7812-2009; OI Bruford, Elspeth/0000-0002-8380-5247; Premont, Richard/0000-0002-8053-5026 FU National Institutes of Health [GM67226, GM68029, GM59989, DA016347, AI-043208]; American Heart Association [0655454U]; Israel Science Foundation [448/04] FX This work was performed with support from extramural grants (GM67226, GM68029, R. A. Kahn; National Institutes of Health GM59989, DA016347, R. T. Premont; AI-043208, M. L. Zapp) and that from the Intramural Program ( P. A. Randazzo, H. Inoue) of the National Institutes of Health, Department of Health and Human Services as well as the American Heart Association (0655454U, R. T. Premont), and a grant from the Israel Science Foundation 448/04 (D. Cassel). NR 27 TC 63 Z9 63 U1 0 U2 3 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 SEP 22 PY 2008 VL 182 IS 6 BP 1039 EP 1044 DI 10.1083/jcb.200806041 PG 6 WC Cell Biology SC Cell Biology GA 351CW UT WOS:000259403100003 PM 18809720 ER PT J AU Szefler, S Mitchell, H Sorkness, CA Gergen, PJ O'Connor, GT Morgan, WJ Kattan, M Pongracic, JA Teach, SJ Bloomberg, GR Eggleston, PA Gruchalla, RS Kercsmar, CM Liu, AH Wildfire, JJ Curry, MD Busse, WW AF Szefler, Stanley J. Mitchell, Herman Sorkness, Christine A. Gergen, Peter J. O'Connor, George T. Morgan, Wayne J. Kattan, Meyer Pongracic, Jacqueline A. Teach, Stephen J. Bloomberg, Gordon R. Eggleston, Peyton A. Gruchalla, Rebecca S. Kercsmar, Carolyn M. Liu, Andrew H. Wildfire, Jeremy J. Curry, Matthew D. Busse, William W. TI Management of asthma based on exhaled nitric oxide in addition to guideline-based treatment for inner-city adolescents and young adults: a randomised controlled trial SO LANCET LA English DT Article ID DOSE-RESPONSE RELATIONSHIP; SCHOOL-AGE-CHILDREN; CHILDHOOD ASTHMA; DIFFICULT ASTHMA; THERAPY; INFLAMMATION; MONTELUKAST; PREVALENCE; MORBIDITY; STEROIDS AB Background Preliminary evidence is equivocal about the role of exhaled nitric oxide (NO) in clinical asthma management. We aimed to assess whether measurement of exhaled NO, as a biomarker of airway inflammation, could increase the effectiveness of asthma treatment, when used as an adjunct to clinical care based on asthma guidelines for inner-city adolescents and young adults. Methods We did a randomised, double-blind, parallel-group trial at ten centres in the USA. We screened 780 inner-city patients, aged 12-20 years, who had persistent asthma. All patients completed a run-in period of 3 weeks on a regimen based on standard treatment. 546 eligible participants who adhered to treatment during this run-in period were then randomly assigned to 46 weeks of either standard treatment, based on the guidelines of the National Asthma Education and Prevention Program (NAEPP), or standard treatment modified on the basis of measurements of fraction of exhaled NO. The primary outcome was the number of days with asthma symptoms. We analysed patients on an intention-to-treat basis. This trial is registered with clinicaltrials.gov, number NCT00114413. Findings During the 46-week treatment period, the mean number of days with asthma symptoms did not differ between the treatment groups (1.93 [95% Cl 1.74 to 2.11] in the NO monitoring group vs 1.89 [1.71 to 2.07] in the control group; difference 0.04 [-0.22 to 0.29], p=0.780). Other symptoms, pulmonary function, and asthma exacerbations did not differ between groups. Patients in the NO monitoring group received higher doses of inhaled corticosteroids (difference 119 mu g per day, 95% CI 49 to 189, p=0-001) than controls. Adverse events did not differ between treatment groups (p> 0 . 1 for all adverse events). Interpretation Conventional asthma management resulted in good control of symptoms in most participants. The addition of fraction of exhaled NO as an indicator of control of asthma resulted in higher doses of inhaled corticosteroids, without clinically important improvements in symptomatic asthma control. Funding US National Institute of Allergy and Infectious Diseases, US National Institutes of Health. C1 [Szefler, Stanley J.; Liu, Andrew H.] Natl Jewish Hlth, Dept Pediat, Denver, CO 80206 USA. [Mitchell, Herman; Wildfire, Jeremy J.; Curry, Matthew D.] Rho, Chapel Hill, NC USA. [Sorkness, Christine A.; Busse, William W.] Univ Wisconsin, Madison, WI USA. [Gergen, Peter J.] NIAID, Bethesda, MD 20892 USA. [O'Connor, George T.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Morgan, Wayne J.] Univ Arizona, Coll Med, Tucson, AZ USA. [Kattan, Meyer] Columbia Univ, New York, NY USA. [Pongracic, Jacqueline A.] Childrens Mem Hosp, Chicago, IL 60614 USA. [Teach, Stephen J.] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Bloomberg, Gordon R.] Washington Univ, St Louis, MO USA. [Eggleston, Peyton A.] Johns Hopkins Univ, Baltimore, MD USA. [Gruchalla, Rebecca S.] Univ Texas Dallas, SW Med Ctr, Dallas, TX USA. [Kercsmar, Carolyn M.] Case Western Reserve Univ, Sch Med, Cleveland, OH USA. RP Szefler, S (reprint author), Natl Jewish Hlth, Dept Pediat, 1400 Jackson St,Room J313, Denver, CO 80206 USA. EM szeflers@njc.org OI O'Connor, George/0000-0002-6476-3926 FU Division of Allergy, Immunology, and Transplantation at the US National Institute of Allergy and Infectious Diseases; National Institutes of Health [NO1-AI-25496, NO1-Al-25482, M01 RR00533]; National Center for Research Resources FX The study was funded by the Division of Allergy, Immunology, and Transplantation at the US National Institute of Allergy and Infectious Diseases, National Institutes of Health, under Contracts number NO1-AI-25496 and NO1-Al-25482, and by the National Center for Research Resources, National Institutes of Health, under grant M01 RR00533. GlaxoSmithKline donated study drugs and Lincoln Diagnostics donated skin-testing materials. We thank all study staff and consultants, study participants, and their families. NR 38 TC 252 Z9 260 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD SEP 20 PY 2008 VL 372 IS 9643 BP 1065 EP 1072 DI 10.1016/S0140-6736(08)61448-8 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 354OI UT WOS:000259648500033 PM 18805335 ER PT J AU Wolf, L Yang, Y Wawrousek, E Cvekl, A AF Wolf, Louise Yang, Ying Wawrousek, Eric Cvekl, Ales TI Transcriptional regulation of mouse alpha A-crystallin gene in a 148kb Cryaa BAC and its derivates SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article ID HEAT-SHOCK-PROTEIN; B-CRYSTALLIN; EPIGENETIC MECHANISMS; CONGENITAL CATARACT; TRANSGENIC MICE; CELL-DEATH; LENS; MUTATION; EXPRESSION; EYE AB Background: alpha A-crystallin is highly expressed in the embryonic, neonatal and adult mouse lens. Previously, we identified two novel distal control regions, DCR1 and DCR3. DCR1 was required for transgenic expression of enhanced green fluorescent protein, EGFP, in lens epithelium, whereas DCR3 was active during "late" stages of lens primary fiber cell differentiation. However, the onset of transgenic EGFP expression was delayed by 12-24 hours, compared to the expression of the endogenous Cryaa gene. Results: Here, we used bacterial artificial chromosome (BAC) and standard transgenic approaches to examine temporal and spatial regulation of the mouse Cryaa gene. Two BAC transgenes, with EGFP insertions into the third coding exon of Cryaa gene, were created: the intact alpha A-crystallin 148 kb BAC (alpha A-BAC) and alpha A-BAC(Delta DCR3), which lacks approximately 1.0 kb of genomic DNA including DCR3. Expression of EGFP in the majority of both BAC transgenics nearly recapitulated the endogenous expression pattern of the Cryaa gene in lens, but not outside of the lens. The number of cells expressing alpha A-crystallin in the lens pit was higher compared to the number of cells expressing EGFP. Next, we generated additional lines using a 15 kb fragment of alpha A-crystallin locus derived from alpha A-BAC(Delta DCR3), 15 kb Cryaa/EGFP. A 15 kb region of Cryaa/EGFP supported the expression pattern of EGFP also in the lens pit. However, co-localization studies of alpha A-crystallin and EGFP indicated that the number of cells that showed transgenic expression was higher compared to cells expressing alpha A-crystallin in the lens pit. Conclusion: We conclude that a 148 kb alpha A-BAC likely contains all of the regulatory regions required for alpha A-crystallin expression in the lens, but not in retina, spleen and thymus. In addition, while the 15 kb Cryaa/EGFP region also supported the expression of EGFP in the lens pit, expression in regions such as the hindbrain, indicate that additional genomic regions may play modulatory functions in regulating extralenticular alpha A-crystallin expression. Finally, deletion of DCR3 in either alpha A-BAC(Delta DCR3) or Cryaa (15 kb) transgenic mice result in EGFP expression patterns that are consistent with DCR's previously established role as a distal enhancer active in "late" primary lens fiber cells. C1 [Wolf, Louise; Yang, Ying; Cvekl, Ales] Albert Einstein Coll Med, Dept Ophthalmol, Bronx, NY 10461 USA. [Wolf, Louise; Yang, Ying; Cvekl, Ales] Albert Einstein Coll Med, Dept Visual Sci, Bronx, NY 10461 USA. [Wolf, Louise; Yang, Ying; Cvekl, Ales] Albert Einstein Coll Med, Dept Mol Genet, Bronx, NY 10461 USA. [Wawrousek, Eric] NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Cvekl, A (reprint author), Albert Einstein Coll Med, Dept Ophthalmol, Bronx, NY 10461 USA. EM lwolf@aecom.yu.edu; yyang@aecom.yu.edu; WawrousekE@NEI.NIH.GOV; cvekl@aecom.yu.edu RI Cvekl, Ales/B-2427-2013 FU NIH [EY014237]; Irma T. Hirschl Career Scientist Award FX We would like to thank Drs. Nathaniel Heintz, Neal Copeland and Jim Lauderdale for reagents and protocols. We would like also to thank the AECOM Core DNA Sequencing, Analytical Imaging, Histotechnology and Comparative Pathology and Transgenic facilities as well as the NEI Transgenic facility. This research is supported by NIH grant EY014237 to AC. AC is a recipient of the Irma T. Hirschl Career Scientist Award. NR 40 TC 9 Z9 9 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD SEP 19 PY 2008 VL 8 AR 88 DI 10.1186/1471-213X-8-88 PG 13 WC Developmental Biology SC Developmental Biology GA 361KL UT WOS:000260126400002 PM 18803847 ER PT J AU Belkaid, Y Oldenhove, G AF Belkaid, Yasmine Oldenhove, Guillaume TI Tuning microenvironments: Induction of regulatory T cells by dendritic cells SO IMMUNITY LA English DT Review ID TRANSCRIPTION FACTOR FOXP3; MESENTERIC LYMPH-NODES; TRANS-RETINOIC ACID; GROWTH-FACTOR-BETA; TGF-BETA; IMMUNE-RESPONSES; IFN-GAMMA; ORAL TOLERANCE; LAMINA-PROPRIA; IN-VITRO AB The body requires the generation of regulatory T (Treg) cells to preserve its integrity. Each microenvironment is controlled by a specific set of regulatory elements that have to be finefrly 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 or tumors. Various populations of dendritic cells (DCs) are central to the orchestration of this control. In this review, we will discuss some new findings associating DCs from defined compartments with the induction of antigen-specific Treg cells. C1 [Belkaid, Yasmine; Oldenhove, Guillaume] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, Bethesda, MD 20894 USA. RP Belkaid, Y (reprint author), NIAID, Mucosal Immunol Unit, Parasit Dis Lab, 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, and National Institutes of Health. We apologize to those authors whose work we were unable to cite because of space limitations. NR 117 TC 170 Z9 176 U1 0 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD SEP 19 PY 2008 VL 29 IS 3 BP 362 EP 371 DI 10.1016/j.immuni.2008.08.005 PG 10 WC Immunology SC Immunology GA 355KX UT WOS:000259708900005 PM 18799144 ER PT J AU Goubier, A Dubois, B Gheit, H Joubert, G Villard-Truc, F Asselin-Paturel, C Trinchieri, G Kaiserlian, D AF Goubier, Anne Dubois, Bertrand Gheit, Hanane Joubert, Grgoire Villard-Truc, Florence Asselin-Paturel, Carine Trinchieri, Giorgio Kaiserlian, Dominique TI Plasmacytoid dendritic cells mediate oral tolerance SO IMMUNITY LA English DT Article ID REGULATORY T-CELLS; DRAINING LYMPH-NODES; IIFN-PRODUCING CELLS; IN-VIVO; INDOLEAMINE 2,3-DIOXYGENASE; PERIPHERAL TOLERANCE; IMMUNE-RESPONSES; PEYERS-PATCHES; RETINOIC-ACID; TGF-BETA AB Oral tolerance prevents oral sensitization to dietary antigens (Ags), including proteins and haptens, and development of delayed-type hypersensitivity (DTH) responses. We showed here that plasmacytoid dendritic cells (pDCs) prevented oral T cell priming and were responsible for systemic tolerance to CD4(+) and CD8(+) T cell-mediated DTH responses induced by Ag feeding. Systemic depletion of pDCs prevented induction of tolerance by antigen feeding. Transfer of oral Ag-loaded liver pDCs to naive recipient mice induced Ag-specific suppression of CD4(+) and CD8(+) T cell responses to protein and hapten, respectively. Liver is a site of oral Ag presentation, and pDCs appeared to induce anergy or deletion of Ag-specific T cells in the liver relatively rapidly via a CD4(+) T cell-independent mechanism. These data demonstrate that oral tolerance relies on Ag presentation by pDC to T cells and suggest that pDC could represent a key therapeutic target for intestinal and systemic inflammatory diseases. C1 [Goubier, Anne; Dubois, Bertrand; Gheit, Hanane; Joubert, Grgoire; Kaiserlian, Dominique] INSERM, U851, F-69007 Lyon, France. [Goubier, Anne; Dubois, Bertrand; Gheit, Hanane; Joubert, Grgoire; Kaiserlian, Dominique] Univ Lyon 1, IFR128, F-69622 Villeurbanne, France. [Villard-Truc, Florence] Hop Edouard Herriot, Hosp Civils Lyon, Serv Gastroenterol Pediat, F-69003 Lyon, France. [Asselin-Paturel, Carine; Trinchieri, Giorgio] Schering Plough Lab Immunol Res, F-69570 Dardilly, France. [Trinchieri, Giorgio] NCI, Ctr Canc Res, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Kaiserlian, D (reprint author), INSERM, U851, 21 Ave Tony Garnier, F-69007 Lyon, France. EM kaiserlian@cervi-lyon.inserm.fr RI KAISERLIAN, Dominique/G-3325-2013; Dubois, Bertrand/D-4446-2013 FU INSERM (poste d'accueil); Fondation pour la Recherche Medicale; Academie de Medecine FX We are grateful to Dr. Amine Boulheddi and Pr. Thierry Roger from Ecole Nationale Veterinaire de Lyon, Unite d'Anatomie, Marcy l'Etoile, for their expertise and skilful assistance in performing portocaval injections. We thank Pierre-Yves Durand and Jean-Benoit Le Luduec for their expert technical assistance. We would also like to thank the staff of the Plateau de Biologie Experimentale de la Souris (PBES) of Ecole Normale Superieure de Lyon for breeding and maintaining mouse strains and Chantal Bella from the flow cytometry facility of IFR-128 Biosciences Gerland-Lyon Sud for cell sorting. Anne Goubier was supported by grants from INSERM (poste d'accueil), Fondation pour la Recherche Medicale, and Academie de Medecine. NR 44 TC 201 Z9 205 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD SEP 19 PY 2008 VL 29 IS 3 BP 464 EP 475 DI 10.1016/j.immuni.2008.06.017 PG 12 WC Immunology SC Immunology GA 355KX UT WOS:000259708900016 PM 18789731 ER PT J AU Suzuki, M Lee, DY Inyamah, N Stadtman, TC Tjandra, N AF Suzuki, Motoshi Lee, Duck-Yeon Inyamah, Nwakaego Stadtman, Thressa C. Tjandra, Nico TI Solution NMR structure of selenium-binding protein from Methanococcus vannielii SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SELD GENE-PRODUCT; ESCHERICHIA-COLI; ORIENTED MACROMOLECULES; HIGH-SENSITIVITY; C-13; SPECTROSCOPY; METABOLISM; ENHANCEMENT; COUPLINGS; SYSTEM AB Selenium is an important nutrient. The lack of selenium will suppress expression of various enzymes that will lead to cell abnormality and diseases. However, high concentrations of free selenium are toxic to the cell because it adversely affects numerous cell metabolic pathways. In Methanonoccus vannielii, selenium transport in the cell is established by the selenium-binding protein, SeBP. SeBP sequesters selenium during transport, thus regulating the level of free selenium in the cell, and delivers it specifically to the selenophosphate synthase enzyme. In solution, SeBP is an oligomer of 8.8-kDa subunits. It is a symmetric pentamer. The solution structure of SeBP was determined by NMR spectroscopy. Each subunit of SeBP is composed of an alpha-helix on top of a 4-stranded twisted beta-sheet. The stability of the five subunits stems mainly from hydrophobic interactions and supplemented by hydrogen bond interactions. The loop containing Cys(59) has been shown to be important for selenium binding, is flexible, and adopts multiple conformations. However, the cysteine accessibility is restricted in the structure, reducing the possibility of the binding of free selenium readily. Therefore, a different selenium precursor or other factors might be needed to facilitate opening of this loop to expose Cys(59) for selenium binding. C1 [Suzuki, Motoshi; Tjandra, Nico] NIH, Lab Mol Biophys, Bethesda, MD 20892 USA. [Lee, Duck-Yeon; Inyamah, Nwakaego; Stadtman, Thressa C.] NHLBI, NIH, Biochem Lab, Bethesda, MD 20892 USA. RP Stadtman, TC (reprint author), 50 South Dr,Bldg 50,Rm 3503,MSC-8012, Bethesda, MD 20892 USA. EM stadtmat@nhlbi.nih.gov; tjandran@nhlbi.nih.gov FU Intramural Research Program of the NHLBI; National Institutes of Health FX This work was supported, in whole or in part, by the Intramural Research Program of the NHLBI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 36 TC 8 Z9 8 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 19 PY 2008 VL 283 IS 38 BP 25936 EP 25943 DI 10.1074/jbc.M803773200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 348GX UT WOS:000259200100021 PM 18650445 ER PT J AU Marcellino, D Ferre, S Casado, V Cortes, A Le Foll, B Mazzola, C Drago, F Saur, O Stark, H Soriano, A Barnes, C Goldberg, SR Lluis, C Fuxe, K Franco, R AF Marcellino, Daniel Ferre, Sergi Casado, Vicent Cortes, Antonio Le Foll, Bernard Mazzola, Carmen Drago, Filippo Saur, Oliver Stark, Holger Soriano, Aroa Barnes, Chanel Goldberg, Steven R. Lluis, Carme Fuxe, Kjell Franco, Rafael TI Identification of dopamine D-1-D-3 receptor heteromers - Indications for a role of synergistic D-1-D-3 receptor interactions in the striatum SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MEDIUM SPINY NEURONS; LOCOMOTOR-ACTIVITY; CELL-MEMBRANE; D-2 RECEPTORS; MICE; D1; RAT; 7-OH-DPAT; GENE; NEUROTRANSMISSION AB The function of dopamine D-3 receptors present in the striatum has remained elusive. In the present study evidence is provided for the existence of dopamine D-1-D-3 receptor heteromers and for an intramembrane D-1-D-3 receptor cross-talk in living cells and in the striatum. The formation of D-1-D-3 receptor heteromers was demonstrated by fluorescence resonance energy transfer and bioluminescence resonance energy transfer techniques in transfected mammalian cells. In membrane preparations from these cells, a synergistic D-1-D-3 intramembrane receptor-receptor interaction was observed, by which D3 receptor stimulation enhances D-1 receptor agonist affinity, indicating that the D-1-D-3 intramembrane receptor-receptor interaction is a biochemical characteristic of the D-1-D-3 receptor heteromer. The same biochemical characteristic was also observed in membrane preparations from brain striatum, demonstrating the striatal co-localization and heteromerization of D-1 and D-3 receptors. According to the synergistic D-1-D-3 intramembrane receptor-receptor interaction, experiments in reserpinized mice showed that D-3 receptor stimulation potentiates D-1 receptor-mediated behavioral effects by a different mechanism than D-2 receptor stimulation. The present study shows that a main functional significance of the D3 receptor is to obtain a stronger dopaminergic response in the striatal neurons that co-express the two receptors. C1 [Marcellino, Daniel; Fuxe, Kjell] Karolinska Inst, Dept Neurosci, Stockholm 17177, Sweden. [Ferre, Sergi; Barnes, Chanel; Goldberg, Steven R.] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. [Casado, Vicent; Cortes, Antonio; Soriano, Aroa; Lluis, Carme; Franco, Rafael] Univ Barcelona, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain. [Casado, Vicent; Cortes, Antonio; Soriano, Aroa; Lluis, Carme; Franco, Rafael] Univ Barcelona, Inst Invest Biomed August Pi i Sunyer, E-08028 Barcelona, Spain. [Le Foll, Bernard] Univ Toronto, Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON M5S 2S1, Canada. [Mazzola, Carmen; Drago, Filippo] Univ Catania, Sch Med, Dept Expt & Clin Pharmacol, I-95125 Catania, Italy. [Saur, Oliver; Stark, Holger] Univ Frankfurt, Inst Chem Pharmacol, D-60438 Frankfurt, Germany. RP Ferre, S (reprint author), Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, Dept Hlth & Human Serv, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM sferre@intra.nida.nih.gov RI Stark, Holger/A-4235-2009; Ferre, Sergi/K-6115-2014; Le Foll, Bernard/K-2952-2014; Franco, Rafael/C-3694-2015; Soriano, Aroa/J-9105-2016; Fachbereich14, Dekanat/C-8553-2015; Casado, Vicent/K-1660-2014; OI Stark, Holger/0000-0003-0642-0180; Ferre, Sergi/0000-0002-1747-1779; Le Foll, Bernard/0000-0002-6406-4973; Franco, Rafael/0000-0003-2549-4919; Soriano, Aroa/0000-0001-9659-1471; Marcellino, Daniel/0000-0002-4618-7267; Casado, Vicent/0000-0002-1764-3825; Drago, Filippo/0000-0003-2887-5223 FU National Institute on Drug Abuse; Ministerio de Ciencia y Tecnologia [SAF2006-00170] FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program, National Institute on Drug Abuse, Dept. of Health and Human Services. This work was also supported by the Ministerio de Ciencia y Tecnologia (Grants SAF2006-00170). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 43 TC 104 Z9 105 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 SEP 19 PY 2008 VL 283 IS 38 BP 26016 EP 26025 DI 10.1074/jbc.M710349200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 348GX UT WOS:000259200100030 PM 18644790 ER PT J AU Zou, GZ de Leeuw, E Lubkowski, J Lu, WY AF Zou, Guozhang de Leeuw, Erik Lubkowski, Jacek Lu, Wuyuan TI Molecular determinants for the interaction of human neutrophil alpha defensin 1 with its propeptide SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE defensin; HNP; antimicrobial peptide; propeptide; electrostatic interaction ID NEUTROPHIL ALPHA-DEFENSINS; ANTIMICROBIAL PEPTIDES; PANETH CELLS; CHEMICAL LIGATION; SMALL-INTESTINE; HOST-DEFENSE; PROTEIN; ACTIVATION; MEMBRANES; FORCES AB Human neutrophil alpha-defensins (HNPs) are cationic antimicrobial peptides that are synthesized in vivo as inactive precursors (proHNPs). Activation requires proteolytic excision of their anionic N-terminal inhibitory pro peptide. The pro peptide of proHNP1 also interacts specifically with and inhibits the antimicrobial activity of HNP1 inter-molecularly. In the light of the opposite net charges segregated in proHNP1, functional inhibition of the C-terminal defensin domain by its propeptide is generally thought to be of electrostatic nature. Using a battery of analogs of the propeptide and of proHNP1, we identified residues in the propeptide region important for HNP1 binding and inhibition. Only three anionic residues in the propeptide, Glu(15), Asp(20) and Glu(23), were modestly important for interactions with HNP1. By contrast, the hydrophobic residues in the central part of the propeptide, and the conserved hydrophobic motif Val(24)Val(25)Val(26)Leu(28) in particular, were critical for HNP1 binding and inhibition. Neutralization of all negative charges in the propeptide only partially activated the bactericidal activity of proHNP1. Our data indicate that hydrophobic forces have a dominant role in mediating the interactions between HNP1 and its propeptide - a finding largely contrasting the commonly held view that the interactions are of an electrostatic nature. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Zou, Guozhang; de Leeuw, Erik; Lu, Wuyuan] Univ Maryland, Sch Med, Inst Human Virol, Baltimore, MD 21201 USA. [Zou, Guozhang; de Leeuw, Erik; Lu, Wuyuan] Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. [Lubkowski, Jacek] NCI, Macromol Assembly Struct & Cell Signaling Sect, NIH, Frederick, MD 21702 USA. RP Lu, WY (reprint author), Univ Maryland, Sch Med, Inst Human Virol, 725 W Lombard St, Baltimore, MD 21201 USA. EM wlu@ihv.umaryland.edu RI Lu, Wuyuan/B-2268-2010 FU National Institutes of Health [AI072732, AI061482] FX We thank Drs Jing Li and Marzena Pazgier of IHV for useful discussion. This research was supported by National Institutes of Health grants AI072732 and AI061482 (to W.L.). NR 41 TC 12 Z9 14 U1 0 U2 4 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 SEP 19 PY 2008 VL 381 IS 5 BP 1281 EP 1291 DI 10.1016/j.jmb.2008.06.066 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 347VJ UT WOS:000259169100016 PM 18616948 ER PT J AU Slobounov, S Hallett, M Cao, C Newell, K AF Slobounov, Semyon Hallett, Mark Cao, Cheng Newell, Karl TI Modulation of cortical activity as a result of voluntary postural sway direction: An EEG study SO NEUROSCIENCE LETTERS LA English DT Article DE human; postural control; electroencephalography ID EVOKED CEREBRAL POTENTIALS; BALANCE; DESYNCHRONIZATION; MOVEMENT; HUMANS AB There is increasing evidence demonstrating the role of the cerebral cortex in human postural control. Modulation of EEG both in voltage and frequency domains has been observed preceding and following self-paced postural movements and those induced by external perturbations. The current study set out to provide additional evidence regarding the role of cerebral cortex in human postural control by specifically examining modulation of EEG as a function of postural sway direction. Twelve neurologically normal subjects were instructed to produce self-paced voluntary postural sways in the anterior-posterior (AP) and medial-lateral (ML) directions. The center of pressure dynamics and EEG both in voltage and frequency domains were extracted by averaging and Morlet wavelet techniques, respectively. The amplitude of movement-related cortical potentials (MRCP) was significantly higher preceding ML sways. Also, time-frequency wavelet coefficients (TF) indicated differential modulation of EEG within alpha, beta and gamma bands as a function of voluntary postural sway direction. Thus, ML sway appear to be more difficult and energy demanding tasks than the AP sway as reflected in differential modulation of EEG. These results are discussed within the conceptual framework of differential patterns of brain activation as a result of postural task complexity. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Slobounov, Semyon; Cao, Cheng; Newell, Karl] Penn State Univ, Dept Kinesiol, University Pk, PA 16802 USA. [Slobounov, Semyon; Hallett, Mark] NINDS, Natl Inst Hlth, Bethesda, MD 20824 USA. RP Slobounov, S (reprint author), Penn State Univ, Dept Kinesiol, 19 Recreat Bldg, University Pk, PA 16802 USA. EM sms18@psu.edu FU NIH [R01 NS056227-01A2]; NINDS FX This research was supported in part by NIH grant R01 NS056227-01A2 and the NINDS Intramural Program. We thank Alessander Danna dos Santos for his help in postural data collection and preliminary analysis. NR 28 TC 22 Z9 23 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 19 PY 2008 VL 442 IS 3 BP 309 EP 313 DI 10.1016/j.neulet.2008.07.021 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 347ZO UT WOS:000259180700030 PM 18639613 ER PT J AU Grieder, NC Caussinus, E Parker, DS Cadigan, K Affolter, M Luschnig, S AF Grieder, Nicole C. Caussinus, Emmanuel Parker, David S. Cadigan, Kenneth Affolter, Markus Luschnig, Stefan TI gamma COP Is Required for Apical Protein Secretion and Epithelial Morphogenesis in Drosophila melanogaster SO PLOS ONE LA English DT Article AB Background: There is increasing evidence that tissue-specific modifications of basic cellular functions play an important role in development and disease. To identify the functions of COPI coatomer-mediated membrane trafficking in Drosophila development, we were aiming to create loss-of-function mutations in the gamma COP gene, which encodes a subunit of the COPI coatomer complex. Principal Findings: We found that gamma COP is essential for the viability of the Drosophila embryo. In the absence of zygotic gamma COP activity, embryos die late in embryogenesis and display pronounced defects in morphogenesis of the embryonic epidermis and of tracheal tubes. The coordinated cell rearrangements and cell shape changes during tracheal tube morphogenesis critically depend on apical secretion of certain proteins. Investigation of tracheal morphogenesis in gamma COP loss-of-function mutants revealed that several key proteins required for tracheal morphogenesis are not properly secreted into the apical lumen. As a consequence, gamma COP mutants show defects in cell rearrangements during branch elongation, in tube dilation, as well as in tube fusion. We present genetic evidence that a specific subset of the tracheal defects in gamma COP mutants is due to the reduced secretion of the Zona Pellucida protein Piopio. Thus, we identified a critical target protein of COPI-dependent secretion in epithelial tube morphogenesis. Conclusions/Significance: These studies highlight the role of COPI coatomer-mediated vesicle trafficking in both general and tissue-specific secretion in a multicellular organism. Although COPI coatomer is generally required for protein secretion, we show that the phenotypic effect of gamma COP mutations is surprisingly specific. Importantly, we attribute a distinct aspect of the gamma COP phenotype to the effect on a specific key target protein. C1 [Grieder, Nicole C.; Caussinus, Emmanuel; Affolter, Markus] Biozentrum Univ Basel, Abt Zellbiol, Basel, Switzerland. [Parker, David S.; Cadigan, Kenneth] Univ Michigan, Dept Mol, Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Luschnig, Stefan] Univ Zurich, Inst Zool, CH-8006 Zurich, Switzerland. RP Grieder, NC (reprint author), NICHD, NIH, Bethesda, MD USA. EM nicole.grieder@unibas.ch RI Luschnig, Stefan/A-7253-2010; OI Luschnig, Stefan/0000-0002-0634-3368; Cadigan, Ken/0000-0003-2431-1703; Affolter, Markus/0000-0002-5171-0016 FU Kantons Basel-Stadt; Basel-Land; German Research Foundation; The Swiss National Science Foundation; EMBO [fellowship]; FEBS [fellowship]; Treubel-Fonds, Basel; NIH [RO1 GM082994] FX This work was supported by grants from the Kantons Basel-Stadt and Basel-Land (MA), the German Research Foundation (SL), The Swiss National Science Foundation, an EMBO long term fellowship (EC), a FEBS fellowship (EC), the Treubel-Fonds, Basel (NCG) and the NIH grant RO1 GM082994 (KC). NR 55 TC 26 Z9 27 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 SEP 19 PY 2008 VL 3 IS 9 AR e3241 DI 10.1371/journal.pone.0003241 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422LF UT WOS:000264428600001 PM 18802472 ER PT J AU Megati, S Garcia-Hand, D Cappello, S Roopchand, V Masood, A Xu, R Luckay, A Chong, SY Rosati, M Sackitey, S Weiner, DB Felber, BK Pavlakis, GN Israel, ZR Smith, LR Eldridge, JH Sidhu, MK Egan, MA AF Megati, Shakuntala Garcia-Hand, Dorys Cappello, Sarah Roopchand, Vidia Masood, Amjed Xu, Rong Luckay, Amara Chong, Siew-Yen Rosati, Margherita Sackitey, Solomon Weiner, David B. Felber, Barbara K. Pavlakis, George N. Israel, Zimra R. Smith, Larry R. Eldridge, John H. Sidhu, Maninder K. Egan, Michael A. TI Modifying the HIV-1 env gp160 gene to improve pDNA vaccine-elicited cell-mediated immune responses SO VACCINE LA English DT Article DE plasmid DNA vaccine; cell-mediated immunity; HIV-1; mice ID PLASMID DNA VACCINE; INTRACELLULAR TARGETING STRATEGIES; REV-INDEPENDENT EXPRESSION; SIMIAN RETROVIRUS TYPE-1; CYTOTOXIC T-LYMPHOCYTES; B SURFACE-ANTIGEN; I CLINICAL-TRIAL; PHASE-I; RHESUS-MONKEYS; HIV-1-INFECTED PATIENTS AB Plasmid DNA (pDNA) vaccines are effective at eliciting immune responses in a wide variety of animal model systems, however, pDNA vaccines have generally been incapable of inducing robust immune responses in clinical trials. Therefore, to identify means to improve pDNA vaccine performance, we compared various post-transcriptional and post-translational genetic modifications for their ability to improve antigen-specific CMI responses. Mice vaccinated using a sub-optimal 100 mcg dose of a pDNA encoding an unmodified primary isolate HIV-1(6101) env gp160 failed to demonstrate measurable env-specific CMI responses. In contrast, significant env-specific CMI responses were seen in mice immunized with pDNA expression vectors encoding env genes modified by RNA optimization or codon optimization. Further modification of the RNA optimized env gp160 gene by the addition of (i) a simian retrovirus type 1 constitutive RNA transport element; (ii) a murine intracisternal A-particle derived RNA transport element; (iii) a tissue plasminogen activator protein signal leader sequences; (iv) a beta-catenin derived ubiquitination target sequence: or (v) a monocyte chemotactic protein-3 derived signal sequence failed to further improve the induction of env-specific CMI responses. Therefore, modification of the env gp160 gene by RNA or codon optimization alone is necessary for high-level rev-independent expression and results in robust env-specific CMI responses in immunized mice. Importantly, further modification(s) of the env gene to alter cellular localization OF increase proteolytic processing failed to result in increased env-specific immune responses. These results have important implications for the design and development of an efficacious vaccine for the prevention of HIV-1 infection. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Megati, Shakuntala; Garcia-Hand, Dorys; Cappello, Sarah; Roopchand, Vidia; Masood, Amjed; Xu, Rong; Luckay, Amara; Chong, Siew-Yen; Sackitey, Solomon; Israel, Zimra R.; Smith, Larry R.; Eldridge, John H.; Sidhu, Maninder K.; Egan, Michael A.] Wyeth Vaccines Res, Pearl River, NY 10965 USA. [Rosati, Margherita; Felber, Barbara K.; Pavlakis, George N.] NCI, Frederick, MD 21702 USA. [Weiner, David B.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Egan, MA (reprint author), Wyeth Vaccines Res, 401 N Middletown Rd,Bldg 180-216-10, Pearl River, NY 10965 USA. EM eganm@wyeth.com RI Weiner, David/H-8579-2014 FU National Institutes of Health [NIH/NIAID HVDDT N01-AI-05397] FX This work was supported by a HIV-1 Vaccine Design and Development Team contract NIH/NIAID HVDDT N01-AI-05397 from the National Institutes of Health. NR 89 TC 13 Z9 14 U1 0 U2 6 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 SEP 19 PY 2008 VL 26 IS 40 SI SI BP 5083 EP 5094 DI 10.1016/j.vaccine.2008.03.092 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 356TE UT WOS:000259799700004 PM 18485543 ER PT J AU Rosati, M Valentin, A Jalah, R Patel, V von Gegerfelt, A Bergamaschi, C Alicea, C Weiss, D Treece, J Pal, R Markham, PD Marques, ETA August, JT Khan, A Draghia-Akli, R Felber, BK Pavlakis, GN AF Rosati, Margherita Valentin, Antonio Jalah, Rashmi Patel, Vainav von Gegerfelt, Agneta Bergamaschi, Cristina Alicea, Candido Weiss, Deborah Treece, Jim Pal, Ranajit Markham, Phillip D. Marques, Ernesto T. A. August, J. Thomas Khan, Amir Draghia-Akli, Ruxandra Felber, Barbara K. Pavlakis, George N. TI Increased immune responses in rhesus macaques by DNA vaccination combined with electroporation SO VACCINE LA English DT Article DE HIV; SIV; DNA vaccine; electroporation; intramuscular injection; rhesus macaque; immune response; central memory; effector memory; T cell subset ID IMMUNODEFICIENCY VIRUS SIVMAC251; IN-VIVO; GENE-TRANSFER; HIV VACCINES; II COMPARTMENT; PLASMID DNA; EXPRESSION; DELIVERY; GAG; DECREASE AB We used optimized DNA expression vectors to compare two gene delivery methodologies in rhesus macaques, namely direct DNA injection and in vivo adaptive constant-current electroporation via the intramuscular route. The use of in vivo electroporation increased levels of gene expression and immune responses. We used an optimized HIV gag expression plasmid to show the development of new cellular immune responses in SIV-infected animals controlling viremia. Furthermore, after vaccination with SIV expression plasmids the recall responses to the SIV antigens were very high, indicating that DNA is a strong boost in the presence of antiretroviral treatment in SIV-infected animals. There was substantial animal-to-animal variability in DNA expression, revealed by plasma measurements of IL-15 produced by co-injected IL-15 DNA. IL-15 expression levels correlated with peak immune responses. Electroporation led to an expansion of antigen-specific CD4+ and CD8+ T cells of both central and effector memory phenotype. These results indicate that improved gene delivery and expression by electroporation dramatically increases immunogenicity of DNA vaccines. Electroporation is thus an important method to improve the effectiveness of DNA vaccination. Published by Elsevier Ltd. C1 [Rosati, Margherita; Valentin, Antonio; Patel, Vainav; von Gegerfelt, Agneta; Bergamaschi, Cristina; Pavlakis, George N.] NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Jalah, Rashmi; Alicea, Candido; Felber, Barbara K.] NCI, Human Retrovirus Pathogenesis Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. [Weiss, Deborah; Treece, Jim; Pal, Ranajit; Markham, Phillip D.] Adv BioSci Labs Inc, Kensington, MD 20895 USA. [Marques, Ernesto T. A.; August, J. Thomas] Johns Hopkins Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. [Khan, Amir; Draghia-Akli, Ruxandra] Immune Therapeut Div Inc, VGX Pharmaceut, The Woodlands, TX 77381 USA. RP Pavlakis, GN (reprint author), NCI, Human Retrovirus Sect, Vaccine Branch, Ctr Canc Res, Frederick, MD 21702 USA. EM pavlakis@ncifcrf.gov RI Saude Publica, Inct/J-9544-2013; Marques, Ernesto/L-4514-2013; Marques, Ernesto/L-4967-2013 OI Marques, Ernesto/0000-0003-3826-9358; Marques, Ernesto/0000-0003-3826-9358 FU NAID/NIH FX We thank P. Roth for technical support, N. Miller, NAID/NIH for Support with macaques, S. Orndorff and the staff at Advanced BioScience Laboratories, Kensington, for their expert help. We thank T. Jones for editorial assistance. NR 36 TC 65 Z9 68 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 SEP 19 PY 2008 VL 26 IS 40 SI SI BP 5223 EP 5229 DI 10.1016/j.vaccine.2008.03.090 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 356TE UT WOS:000259799700024 PM 18468743 ER PT J AU Zhu, Y Li, H Miller, DJ Wang, ZY Xuan, JH Clarke, R Hoffman, EP Wang, Y AF Zhu, Yitan Li, Huai Miller, David J. Wang, Zuyi Xuan, Jianhua Clarke, Robert Hoffman, Eric P. Wang, Yue TI caBIG (TM) VISDA: Modeling, visualization, and discovery for cluster analysis of genomic data SO BMC BIOINFORMATICS LA English DT Article ID GENE-EXPRESSION DATA; HIGH-DIMENSIONAL DATA; MICROARRAY DATA; MOLECULAR CLASSIFICATION; MIXTURE MODEL; PATTERNS; ALGORITHM; CANCER; SPACES; CRITERIA AB Background: The main limitations of most existing clustering methods used in genomic data analysis include heuristic or random algorithm initialization, the potential of finding poor local optima, the lack of cluster number detection, an inability to incorporate prior/expert knowledge, black-box and non-adaptive designs, in addition to the curse of dimensionality and the discernment of uninformative, uninteresting cluster structure associated with confounding variables. Results: In an effort to partially address these limitations, we develop the VIsual Statistical Data Analyzer (VISDA) for cluster modeling, visualization, and discovery in genomic data. VISDA performs progressive, coarse-to-fine ( divisive) hierarchical clustering and visualization, supported by hierarchical mixture modeling, supervised/unsupervised informative gene selection, supervised/unsupervised data visualization, and user/prior knowledge guidance, to discover hidden clusters within complex, high-dimensional genomic data. The hierarchical visualization and clustering scheme of VISDA uses multiple local visualization subspaces (one at each node of the hierarchy) and consequent subspace data modeling to reveal both global and local cluster structures in a "divide and conquer" scenario. Multiple projection methods, each sensitive to a distinct type of clustering tendency, are used for data visualization, which increases the likelihood that cluster structures of interest are revealed. Initialization of the full dimensional model is based on first learning models with user/prior knowledge guidance on data projected into the low-dimensional visualization spaces. Model order selection for the high dimensional data is accomplished by Bayesian theoretic criteria and user justification applied via the hierarchy of low-dimensional visualization subspaces. Based on its complementary building blocks and flexible functionality, VISDA is generally applicable for gene clustering, sample clustering, and phenotype clustering (wherein phenotype labels for samples are known), albeit with minor algorithm modifications customized to each of these tasks. Conclusion: VISDA achieved robust and superior clustering accuracy, compared with several benchmark clustering schemes. The model order selection scheme in VISDA was shown to be effective for high dimensional genomic data clustering. On muscular dystrophy data and muscle regeneration data, VISDA identified biologically relevant co-expressed gene clusters. VISDA also captured the pathological relationships among different phenotypes revealed at the molecular level, through phenotype clustering on muscular dystrophy data and multi-category cancer data. C1 [Zhu, Yitan; Li, Huai; Wang, Zuyi; Xuan, Jianhua; Wang, Yue] Virginia Polytech Inst & State Univ, Dept Elect & Comp Engn, Arlington, VA 22203 USA. [Li, Huai] NIA, Bioinformat Unit, RRB, NIH, Baltimore, MD 21224 USA. [Miller, David J.] Penn State Univ, Dept Elect Engn, University Pk, PA 16802 USA. [Wang, Zuyi; Hoffman, Eric P.] Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. [Clarke, Robert] Georgetown Univ, Dept Oncol Physiol & Biophys, Washington, DC 20007 USA. [Clarke, Robert] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. RP Wang, Y (reprint author), Virginia Polytech Inst & State Univ, Dept Elect & Comp Engn, Arlington, VA 22203 USA. EM yitanzhu@vt.edu; huai.li@gmail.com; millerdj@ee.psu.edu; ZWang@cnmcresearch.org; xuan@vt.edu; clarker@georgetown.edu; EHoffman@cnmcresearch.org; yuewang@vt.edu RI Clarke, Robert/A-6485-2008 OI Clarke, Robert/0000-0002-9278-0854 FU National Institutes of Health [CA109872, NS29525, CA096483, EB000830]; caBIG(TM) FX The authors want to thank Bai Zhang, Guoqiang Yu, and Yibin Dong for help in software implementation and experiment. This work is supported by the National Institutes of Health under Grants CA109872, NS29525, CA096483, EB000830 and caBIG (TM). NR 64 TC 6 Z9 6 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD SEP 18 PY 2008 VL 9 AR 383 DI 10.1186/1471-2105-9-383 PG 18 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 360SZ UT WOS:000260079400001 PM 18801195 ER PT J AU Suh, HC Leeanansaksiri, W Ji, M Klarmann, KD Renn, K Gooya, J Smith, D McNiece, I Lugthart, S Valk, PJM Delwel, R Keller, JR AF Suh, H. C. Leeanansaksiri, W. Ji, M. Klarmann, K. D. Renn, K. Gooya, J. Smith, D. McNiece, I. Lugthart, S. Valk, P. J. M. Delwel, R. Keller, J. R. TI Id1 immortalizes hematopoietic progenitors in vitro and promotes a myeloproliferative disease in vivo SO ONCOGENE LA English DT Article DE Id1; myeloproliferative disease; leukemia; therapeutic target; prevention ID ACUTE MYELOID-LEUKEMIA; LOOP-HELIX PROTEINS; CELL-DEVELOPMENT; TRANSGENIC MICE; STEM-CELLS; TRANSCRIPTION FACTORS; BONE-MARROW; C/EBP-ALPHA; EXPRESSION; DIFFERENTIATION AB Id1 is frequently overexpressed in many cancer cells, but the functional significance of these findings is not known. To determine if Id1 could contribute to the development of hematopoietic malignancy, we reconstituted mice with hematopoietic cells overexpressing Id1. We showed for the first time that deregulated expression of Id1 leads to a myeloproliferative disease in mice, and immortalizes myeloid progenitors in vitro. In human cells, we demonstrate that Id genes are expressed in human acute myelogenous leukemia cells, and that knock down of Id1 expression inhibits leukemic cell line growth, suggesting that Id1 is required for leukemic cell proliferation. These findings established a causal relationship between Id1 overexpression and hematologic malignancy. Thus, deregulated expression of Id1 may contribute to the initiation of myeloid malignancy, and Id1 may represent a potential therapeutic target for early stage intervention in the treatment of hematopoietic malignancy. C1 [Suh, H. C.; Leeanansaksiri, W.; Ji, M.; Klarmann, K. D.; Renn, K.; Gooya, J.; Keller, J. R.] NCI, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Suh, H. C.; Leeanansaksiri, W.; Ji, M.; Klarmann, K. D.; Renn, K.; Gooya, J.; Keller, J. R.] NCI, Canc Res Ctr, Frederick, MD 21702 USA. [Smith, D.; McNiece, I.] Sidney Kimmel Comprehens Canc Ctr, Div Hematol Malignancies, Baltimore, MD USA. [Lugthart, S.; Valk, P. J. M.; Delwel, R.] Erasmus Univ, Med Ctr, Dept Hematol, Rotterdam, Netherlands. RP Keller, JR (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Bldg 560,Room 12-03, Frederick, MD 21702 USA. EM kellerj@ncifcrf.gov RI Ji, Ming/C-2795-2011 FU National Cancer Institute; National Institutes of Health [NO1-CO-12400]; Intramural Research Program of NIH; Center for Cancer Research; Regional Oncology Research Center [5 P30 CA06973] FX We gratefully acknowledge the technical support of Steve Stull, Kathleen Noer, Roberta Matthai and Samantha Bauchiero. We also thank Dr Nancy Colburn, Dr Sandra Ruscetti and Dr Kristbjorn Gudmundsson for their critical review of this article. This project has been funded, in part, with Federal funds from the National Cancer Institute, National Institutes of Health, under contract number NO1-CO-12400. This research was supported, in part, by the Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. Clinical specimens were provided by the Sidney Kimmel Cancer Center at Johns Hopkins Tumor and Cell Procurement Bank, supported by the Regional Oncology Research Center Grant no. 5 P30 CA06973. NR 49 TC 24 Z9 25 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 SEP 18 PY 2008 VL 27 IS 42 BP 5612 EP 5623 DI 10.1038/onc.2008.175 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 349KX UT WOS:000259280800007 PM 18542061 ER PT J AU Wijdeven, MA Wijtmans, R van den Berg, RJF Noorduin, W Schoemaker, HE Sonke, T van Delft, FL Blaauw, RH Fitch, RW Spande, TF Daly, JW Rutjes, FPJT AF Wijdeven, Marloes A. Wijtmans, Roel van den Berg, Rutger J. F. Noorduin, Wim Schoemaker, Hans E. Sonke, Theo van Delft, Floris L. Blaauw, Richard H. Fitch, Richard W. Spande, Thomas F. Daly, John W. Rutjes, Floris P. J. T. TI N,N-Acetals as N-acyliminium ion precursors: Synthesis and absolute stereochemistry of epiquinamide SO ORGANIC LETTERS LA English DT Article ID ASYMMETRIC-SYNTHESIS; (+)-EPIQUINAMIDE; CHEMISTRY; 223G AB A stereoselective synthesis of (+)-epiquinamide is presented in combination with determination of the absolute configuration of the natural product. Key steps in the sequence involved chemoenzymatic formation of an enantiomerically pure cyanohydrin, reductive cyclization to the corresponding cyclic N,N-acetal, and subsequent conversion into a suitable N-acyliminium ion precursor to enable construction of the second ring. C1 [Wijdeven, Marloes A.; Wijtmans, Roel; van den Berg, Rutger J. F.; Noorduin, Wim; van Delft, Floris L.; Rutjes, Floris P. J. T.] Radboud Univ Nijmegen, Inst Mol & Mat, NL-6525 ED Nijmegen, Netherlands. [Schoemaker, Hans E.; Sonke, Theo] DSM Pharma Chem Adv Synth Catalysis & Dev, NL-6160 MD Geleen, Netherlands. [Blaauw, Richard H.] Chiralix BV, NL-6503 CB Nijmegen, Netherlands. [Fitch, Richard W.] Indiana State Univ, Dept Chem, Terre Haute, IN 47809 USA. [Spande, Thomas F.; Daly, John W.] NIDDK, Bioorgan Chem Lab, Natl Inst Hlth, HHS, Bethesda, MD 20892 USA. RP Rutjes, FPJT (reprint author), Radboud Univ Nijmegen, Inst Mol & Mat, Toernooiveld 1, NL-6525 ED Nijmegen, Netherlands. EM f.rutjes@science.ru.nl RI van Delft, Floris/D-4524-2012; Rutjes, Floris/E-1711-2012 OI Rutjes, Floris/0000-0003-1538-3852 FU ACTS-NWO FX This research is performed as part of the IBOS Program (Integration of Biosynthesis & Organic Synthesis) of ACTS-NWO. C. van den Broek (DSM Pharma Chemicals) is kindly acknowledged for assistance with the large scale HNL experiments. NR 17 TC 33 Z9 33 U1 0 U2 10 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 SEP 18 PY 2008 VL 10 IS 18 BP 4001 EP 4003 DI 10.1021/ol801490m PG 3 WC Chemistry, Organic SC Chemistry GA 348FY UT WOS:000259197600018 PM 18702495 ER PT J AU Natanson, C Lurie, P Wolfe, SM AF Natanson, Charles Lurie, Peter Wolfe, Sidney M. TI Hemoglobin-based blood substitutes and risk of myocardial infarction and death - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID ORTHOPEDIC-SURGERY; HEMOSPAN(R); SAFETY; TRIAL C1 [Natanson, Charles] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Lurie, Peter; Wolfe, Sidney M.] Publ Citizen, Hlth Res Grp, Washington, DC USA. RP Natanson, C (reprint author), NIH, Ctr Clin, Dept Crit Care Med, Bldg 10, Bethesda, MD 20892 USA. EM cnatanson@cc.nih.gov NR 7 TC 1 Z9 1 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 17 PY 2008 VL 300 IS 11 BP 1298 EP 1299 DI 10.1001/jama.300.11.1298 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 348ST UT WOS:000259231100021 ER PT J AU Natanson, C AF Natanson, Charles TI Incomplete financial disclosure in a study of cell-free hemoglobin-based blood substitutes and risks of myocardial infarction and death SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 [Natanson, Charles] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Natanson, C (reprint author), NIH, Ctr Clin, Dept Crit Care Med, Bldg 10, Bethesda, MD 20892 USA. EM cnatanson@cc.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 17 PY 2008 VL 300 IS 11 BP 1300 EP 1300 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 348ST UT WOS:000259231100023 ER PT J AU Nygaard, I Barber, MD Burgio, KL Kenton, K Meikle, S Schaffer, J Spino, C Whitehead, WE Wu, J Brody, DJ AF Nygaard, Ingrid Barber, Matthew D. Burgio, Kathryn L. Kenton, Kimberly Meikle, Susan Schaffer, Joseph Spino, Cathie Whitehead, William E. Wu, Jennifer Brody, Debra J. CA Pelvic Floor Disorders Network TI Prevalence of symptomatic pelvic floor disorders in US women SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID QUALITY-OF-LIFE; NUTRITION EXAMINATION SURVEY; FEMALE URINARY-INCONTINENCE; PAD-WEIGHING TESTS; FECAL INCONTINENCE; ORGAN PROLAPSE; GENITAL PROLAPSE; ANAL INCONTINENCE; SEVERITY INDEX; RISK-FACTORS AB Context Pelvic floor disorders ( urinary incontinence, fecal incontinence, and pelvic organ prolapse) affect many women. No national prevalence estimates derived from the same population- based sample exists for multiple pelvic floor disorders in women in the United States. Objective To provide national prevalence estimates of symptomatic pelvic floor disorders in US women. Design, Setting, and Participants A cross- sectional analysis of 1961 nonpregnant women ( >= 20 years) who participated in the 2005- 2006 National Health and Nutrition Examination Survey, a nationally representative survey of the US noninstitutionalized population. Women were interviewed in their homes and then underwent standardized physical examinations in a mobile examination center. Urinary incontinence ( score of >= 3 on a validated incontinence severity index, constituting moderate to severe leakage), fecal incontinence ( at least monthly leakage of solid, liquid, or mucous stool), and pelvic organ prolapse ( seeing/ feeling a bulge in or outside the vagina) symptoms were assessed. Main Outcome Measures Weighted prevalence estimates of urinary incontinence, fecal incontinence, and pelvic organ prolapse symptoms. Results The weighted prevalence of at least 1 pelvic floor disorder was 23.7% ( 95% confidence interval [ CI], 21.2%- 26.2%), with 15.7% of women ( 95% CI, 13.2%-18.2%) experiencing urinary incontinence, 9.0% of women ( 95% CI, 7.3%- 10.7%) experiencing fecal incontinence, and 2.9% of women ( 95% CI, 2.1%- 3.7%) experiencing pelvic organ prolapse. The proportion of women reporting at least 1 disorder increased incrementally with age, ranging from 9.7% ( 95% CI, 7.8%- 11.7%) in women between ages 20 and 39 years to 49.7% ( 95% CI, 40.3%- 59.1%) in those aged 80 years or older ( P <. 001), and parity ( 12.8% [ 95% CI, 9.0%- 16.6%], 18.4% [ 95% CI, 12.9%- 23.9%], 24.6% [ 95% CI, 19.5%- 29.8%], and 32.4% [ 95% CI, 27.8%-37.1%] for 0, 1, 2, and 3 or more deliveries, respectively; P <. 001). Overweight and obese women were more likely to report at least 1 pelvic floor disorder than normal weight women ( 26.3% [ 95% CI, 21.7%- 30.9%], 30.4% [ 95% CI, 25.8%- 35.0%], and 15.1% [ 95% CI, 11.6%- 18.7%], respectively; P <. 001). We detected no differences in prevalence by racial/ ethnic group. Conclusion Pelvic floor disorders affect a substantial proportion of women and increase with age. C1 [Nygaard, Ingrid] Univ Utah, Sch Med, Dept Obstet & Gynecol, Salt Lake City, UT 84132 USA. [Barber, Matthew D.] Obstet Gynecol & Womens Hlth Inst, Cleveland, OH USA. [Barber, Matthew D.] Cleveland Clin, Cleveland, OH 44106 USA. [Burgio, Kathryn L.] Univ Alabama, Dept Med, Birmingham, AL 35294 USA. [Burgio, Kathryn L.] Dept Vet Affairs, Birmingham, AL USA. [Kenton, Kimberly] Loyola Univ, Stritch Sch Med, Dept Obstet & Gynecol, Maywood, IL 60153 USA. [Kenton, Kimberly] Loyola Univ, Stritch Sch Med, Dept Urol, Maywood, IL 60153 USA. [Meikle, Susan] NICHHD, Bethesda, MD 20892 USA. [Schaffer, Joseph] Univ Texas SW Med Ctr Dallas, Dept Obstet & Gynecol, Dallas, TX 75390 USA. [Spino, Cathie] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Whitehead, William E.] Univ N Carolina, Sch Med, Dept Internal Med, Chapel Hill, NC USA. [Wu, Jennifer] Duke Univ, Sch Med, Dept Obstet & Gynecol, Durham, NC USA. [Brody, Debra J.] Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Nygaard, I (reprint author), Univ Utah, Sch Med, Dept Obstet & Gynecol, 30 N 1900 E, Salt Lake City, UT 84132 USA. EM ingrid.nygaard@hsc.utah.edu FU Eunice Kennedy Shriver NICHD [U01 HD41249, U10 HD41268, U10 HD41248, U10 HD41250, U10 HD41261, U10 HD41263, U10 HD41269, U10 HD41267, U10 HD54136, U10 HD54214, U10 HD54215]; National Institute of Diabetes and Digestive and Kidney Diseases; National Institutes of Health Office of Research on Women's Health FX This work was supported by grants U01 HD41249, U10 HD41268, U10 HD41248, U10 HD41250, U10 HD41261, U10 HD41263, U10 HD41269, U10 HD41267, U10 HD54136, U10 HD54214, and U10 HD54215 from the Eunice Kennedy Shriver NICHD and funding from the National Institute of Diabetes and Digestive and Kidney Diseases and the National Institutes of Health Office of Research on Women's Health. NR 42 TC 494 Z9 510 U1 2 U2 18 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 17 PY 2008 VL 300 IS 11 BP 1311 EP 1316 DI 10.1001/jama.300.11.1311 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 348ST UT WOS:000259231100026 PM 18799443 ER PT J AU Butman, JA Linehan, WM Lonser, RR AF Butman, John A. Linehan, W. Marston Lonser, Russell R. TI Neurologic manifestations of von Hippel-Lindau disease SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ENDOLYMPHATIC SAC TUMORS; CENTRAL-NERVOUS-SYSTEM; GROWTH-FACTOR RECEPTOR; MORBID HEARING-LOSS; SUPPRESSOR GENE; NATURAL-HISTORY; SURGICAL-MANAGEMENT; GERMLINE MUTATIONS; INHIBITOR SU5416; SPINAL-CORD AB von Hippel-Lindau disease ( VHL) is an autosomal- dominant neoplasia syndrome that is the result of a germline mutation of the VHL tumor suppressor gene on the short arm of chromosome 3. Patients with VHL are predisposed to develop lesions of the central nervous system and viscera. Central nervous system lesions include hemangioblastomas ( the most common tumor in VHL) and endolymphatic sac tumors ( ELSTs). Visceral manifestations include renal carcinomas and cysts, pancreatic neuroendocrine tumors and cysts, pheochromocytomas, and cystadenomas of the reproductive adnexal organs. Despite their benign pathology, hemangioblastomas and ELSTs are a frequent cause of morbidity and mortality in patients with VHL. Recent molecular biologic investigations into these VHL- associated central nervous system lesions provide new insight into their origin and development. Emerging data from serial imaging and clinical surveillance protocols provide insight into the natural history of these lesions. Because of the dissimilar pathobiology and clinical course between hemangioblastomas and ELSTs, the optimal management strategies for these neurologic manifestations of VHL are very different. C1 [Lonser, Russell R.] Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. [Butman, John A.] NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. [Linehan, W. Marston] NCI, Urol Oncol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Lonser, RR (reprint author), Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, NIH, 10 Center Dr,Bldg 10,Room 5D37, Bethesda, MD 20892 USA. EM lonserr@ninds.nih.gov RI Butman, John/A-2694-2008; OI Butman, John/0000-0002-1547-9195 FU Intramural Research Program of the Clinical Center; National Institute of Neurologic Disorders and Stroke; National Cancer Institute at the National Institutes of Health. FX This research was supported by the Intramural Research Program of the Clinical Center, the National Institute of Neurologic Disorders and Stroke, and the National Cancer Institute at the National Institutes of Health. NR 55 TC 33 Z9 35 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD SEP 17 PY 2008 VL 300 IS 11 BP 1334 EP 1342 DI 10.1001/jama.300.11.1334 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 348ST UT WOS:000259231100029 PM 18799446 ER PT J AU Liu, PY Vikis, HG Wang, DL Lu, Y Wang, Y Schwartz, AG Pinney, SM Yang, P de Andrade, M Petersen, GM Wiest, JS Fain, PR Gazdar, A Gaba, C Rothschild, H Mandal, D Coons, T Lee, JW Kupert, E Seminara, D Minna, J Bailey-Wilson, JE Wu, XF Spitz, MR Eisen, T Houlston, RS Amos, CI Anderson, MW You, M AF Liu, Pengyuan Vikis, Haris G. Wang, Daolong Lu, Yan Wang, Yian Schwartz, Ann G. Pinney, Susan M. Yang, Ping de Andrade, Mariza Petersen, Gloria M. Wiest, Jonathan S. Fain, Pamela R. Gazdar, Adi Gaba, Colette Rothschild, Henry Mandal, Diptasri Coons, Teresa Lee, Juwon Kupert, Elena Seminara, Daniela Minna, John Bailey-Wilson, Joan E. Wu, Xifeng Spitz, Margaret R. Eisen, Timothy Houlston, Richard S. Amos, Christopher I. Anderson, Marshall W. You, Ming TI Familial aggregation of common sequence variants on 15q24-25.1 in lung cancer SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID GENOME-WIDE ASSOCIATION; RECEPTOR SUBUNIT GENES; MENDELIAN INHERITANCE; SUSCEPTIBILITY LOCUS; NICOTINE DEPENDENCE; DISEQUILIBRIUM; APOPTOSIS; TESTS; SNPS; MAPS AB Three recent genome-wide association studies identified associations between markers in the chromosomal region 15q24-25.1 and the risk of lung cancer. We conducted a genome-wide association analysis to investigate associations between single-nucleotide polymorphisms (SNPs) and the risk of lung cancer, in which we used blood DNA from 194 case patients with familial lung cancer and 219 cancer-free control subjects. We identified associations between common sequence variants at 15q24-25.1 (that spanned LOC123688 [a hypothetical gene], PSMA4, CHRNA3, CHRNA5, and CHRNB4) and lung cancer. The risk of lung cancer was more than fivefold higher among those subjects who had both a family history of lung cancer and two copies of high-risk alleles rs8034191 (odds ratio [OR] = 7.20, 95% confidence interval [CI] = 2.21 to 23.37) or rs1051730 (OR = 5.67, CI = 2.21 to 14.60, both of which were located in the 15q24-25.1 locus, than among control subjects. Thus, further research to elucidate causal variants in the 15q24-25.1 locus that are associated with lung cancer is warranted. C1 [You, Ming] Washington Univ, Dept Surg, St Louis, MO 63110 USA. [You, Ming] Washington Univ, Alvin J Siteman Canc Ctr, St Louis, MO 63110 USA. [Schwartz, Ann G.] Karmanos Canc Inst, Detroit, MI USA. [Pinney, Susan M.] Univ Cincinnati, Cincinnati, OH USA. [Yang, Ping; de Andrade, Mariza; Petersen, Gloria M.; Seminara, Daniela] Mayo Clin, Rochester, MN USA. [Wiest, Jonathan S.] NCI, Bethesda, MD 20892 USA. [Fain, Pamela R.] Univ Colorado, Denver, CO 80202 USA. [Gazdar, Adi; Minna, John] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Gaba, Colette] Univ Toledo, Coll Med, Toledo, OH 43606 USA. [Rothschild, Henry; Mandal, Diptasri] Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. [Coons, Teresa] Saccomanno Res Inst, Grand Junction, CO USA. [Bailey-Wilson, Joan E.] NHGRI, Baltimore, MD USA. [Wu, Xifeng; Spitz, Margaret R.; Amos, Christopher I.] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA. [Eisen, Timothy] Univ Cambridge, Dept Oncol, Cambridge CB2 2RE, England. [Houlston, Richard S.] Inst Canc Res, Sect Canc Genet, Sutton SM2 5NG, Surrey, England. RP You, M (reprint author), Washington Univ, Dept Surg, 660 Euclid Ave,Box 8109, St Louis, MO 63110 USA. EM youm@wudosis.wustl.edu OI Bailey-Wilson, Joan/0000-0002-9153-2920; Houlston, Richard/0000-0002-5268-0242 FU National Institutes of Health (NIH) [U01CA76293]; Genetic Epidemiology of Lung Cancer Consortium [R01CA058554, R01CA093643, R01CA099147, R01CA099187, R01ES012063, R01 ES013340, R03CA77118, R01CA80127, P30ES 06096, P50CA70907]; Specialized Program of Re search Excellence [N01HG65404, N01-PC35145, P30CA22453, R01CA63700, DE-FGB-95ER62060, R01CA55769, R01CA121197, R01CA133996]; Mayo Clinic intramural research funds; Department of Defense VITAL grant; National Cancer Institute; National Human Genome Research Institute FX This work was supported in part by the following: National Institutes of Health (NIH) grants U01CA76293 (Genetic Epidemiology of Lung Cancer Consortium), R01CA058554, R01CA093643, R01CA099147, R01CA099187, R01ES012063, R01 ES013340, R03CA77118, R01CA80127, P30ES 06096, P50CA70907 (Specialized Program of Re search Excellence), N01HG65404, N01-PC35145, P30CA22453, R01CA63700, DE-FGB-95ER62060, R01CA55769, R01CA121197, R01CA133996, Mayo Clinic intramural research funds, and Department of Defense VITAL grant. This study was supported in part by NIH, the Intramural Research Programs of the National Cancer Institute, and the National Human Genome Research Institute. The authors had full responsibility of design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript. NR 22 TC 90 Z9 94 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD SEP 17 PY 2008 VL 100 IS 18 BP 1326 EP 1330 DI 10.1093/jnci/djn268 PG 5 WC Oncology SC Oncology GA 350BR UT WOS:000259328000012 PM 18780872 ER PT J AU Chen, XB Winters, CA Reese, TS AF Chen, Xiaobing Winters, Christine A. Reese, Thomas S. TI Life inside a thin section: Tomography SO JOURNAL OF NEUROSCIENCE LA English DT Editorial Material ID ELECTRON TOMOGRAPHY; POSTSYNAPTIC DENSITY; CRYOELECTRON MICROSCOPY; NEUROMUSCULAR-JUNCTION; TRANSMITTER RELEASE; CRYSTAL-STRUCTURES; AMPA RECEPTORS; RECONSTRUCTION; CELLS; MEMBRANE C1 [Chen, Xiaobing; Winters, Christine A.; Reese, Thomas S.] NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Reese, TS (reprint author), NINDS, Neurobiol Lab, NIH, Bldg 49 3A60, Bethesda, MD 20892 USA. EM treese@mbl.edu FU Intramural NIH HHS [Z01 NS002972-10] NR 51 TC 26 Z9 26 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 17 PY 2008 VL 28 IS 38 BP 9321 EP 9327 DI 10.1523/JNEUROSCI.2992-08.2008 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 349NZ UT WOS:000259288900001 PM 18799665 ER PT J AU Soubias, O Niu, SL Mitchell, DC Gawrisch, K AF Soubias, Olivier Niu, Shui-Lin Mitchell, Drake C. Gawrisch, Klaus TI Lipid-rhodopsin hydrophobic mismatch alters rhodopsin helical content SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID METARHODOPSIN-II; TRANSDUCIN BINDING; MEMBRANE-PROTEINS; CRYSTAL-STRUCTURE; BILAYERS; SPECTROSCOPY; RECEPTOR; MODEL; NMR; OPTIMIZATION AB The ability of photoactivated rhodopsin to achieve the enzymatically active metarhodopsin II conformation is exquisitely sensitive to bilayer hydrophobic thickness. The sensitivity of rhodopsin to the lipid matrix has been explained by the hydrophobic matching theory, which predicts that lipid bilayers adjust elastically to the hydrophobic length of transmembrane helices. Here, we examined if bilayer thickness adjusts to the length of the protein or if the protein alters its conformation to adapt to the bilayer. Purified bovine rhodopsin was reconstituted into a series of mono-unsaturated phosphatidylcholines with 14-20 carbons per hydrocarbon chain. Changes of hydrocarbon chain length were measured by H-2 NMR, and protein helical content was quantified by synchrotron radiation circular dichroism and conventional circular dichroism. Experiments were conducted on dark-adapted rhodopsin, the photo-intermediates metarhodopsin I/II/III, and opsin. Changes of bilayer thickness upon rhodopsin incorporation and photoactivation were mostly absent. In contrast, the helical content of rhodopsin increased with membrane hydrophobic thickness. Helical content did not change measurably upon photoactivation. The increases of bilayer thickness and helicity of rhodopsin are accompanied by higher metarhodopsin II/metarhodopsin I ratios, faster rates of metarhodopsin II formation, an increase of tryptophan fluorescence, and higher temperatures of rhodopsin denaturation. The data suggest a surprising adaptability of this G protein-coupled membrane receptor to properties of the lipid matrix. C1 [Soubias, Olivier; Gawrisch, Klaus] Natl Inst Alcohol Abuse & Alcoholism, Lab Membrane Biochem & Biophys, Natl Inst Hlth, Sect NMR, Bethesda, MD 20892 USA. [Niu, Shui-Lin; Mitchell, Drake C.] Natl Inst Alcohol Abuse & Alcoholism, Lab Membrane Biochem & Biophys, Natl Inst Hlth, Sect Fluorescence Studies, Bethesda, MD 20892 USA. RP Gawrisch, K (reprint author), Natl Inst Alcohol Abuse & Alcoholism, Lab Membrane Biochem & Biophys, Natl Inst Hlth, Sect NMR, Bethesda, MD 20892 USA. EM gawrisch@helix.nih.gov FU NIAAA; NIH; Office of Biological and Environmental Research; Office of Basic Energy Science, U.S. Department of Energy; NSLS FX This work was supported by the Intramural Research Program of NIAAA, . We thank Kirk Hines for extraction and purification of rhodopsin. The SRCD experiments were performed at beamline U11 at the National Synchrotron Light Source, which is supported by the Office of Biological and Environmental Research and the Office of Basic Energy Science, U.S. Department of Energy. We thank John G. Trunk, NSLS, for assistance and support. NR 32 TC 43 Z9 44 U1 0 U2 13 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD SEP 17 PY 2008 VL 130 IS 37 BP 12465 EP 12471 DI 10.1021/ja803599x PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 347KO UT WOS:000259139900061 PM 18712874 ER PT J AU Wayne, AS Reaman, GH Helman, LJ AF Wayne, Alan S. Reaman, Gregory H. Helman, Lee J. TI Progress in the curative treatment of childhood hematologic malignancies SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CHEMOTHERAPY C1 [Wayne, Alan S.] NCI, Hematol Dis Sect, Pediat Oncol Branch, Ctr Canc Res,Natl Inst Hlth, Bethesda, MD 20892 USA. George Washington Univ, Sch Med & Hlth Sci, Bethesda, MD USA. [Reaman, Gregory H.] George Washington Univ, Childrens Oncol Grp, COG Chairs Off, Bethesda, MD USA. RP Wayne, AS (reprint author), NCI, Hematol Dis Sect, Pediat Oncol Branch, Ctr Canc Res,Natl Inst Hlth, Bldg 10,Room 1W-3750,MSC 1104,9000 Rockville Pike, Bethesda, MD 20892 USA. EM waynea@mail.nih.gov NR 10 TC 15 Z9 15 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 17 PY 2008 VL 100 IS 18 BP 1271 EP 1273 DI 10.1093/jnci/djn306 PG 3 WC Oncology SC Oncology GA 350BR UT WOS:000259328000002 PM 18780861 ER PT J AU Modlin, IM Moss, SF Chung, DC Jensen, RT Snyderwine, E AF Modlin, Irvin M. Moss, Steven F. Chung, Daniel C. Jensen, Robert T. Snyderwine, Elizabeth TI Priorities for improving the management of gastroenteropancreatic neuroendocrine tumors SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID MULTIPLE ENDOCRINE NEOPLASIA; CARCINOID-TUMORS; MOLECULAR-GENETICS; GRADING SYSTEM; HEART-DISEASE; CELLS; CLASSIFICATION; SOMATOSTATIN; INTESTINE; MASTOMYS AB A National Cancer Institute summit meeting on gastroenteropancreatic neuroendocrine and carcinoid tumors was held in September 2007 to present the currently accepted standards of care for patients with these tumors and to identify areas requiring investigation and development. These tumors are clinically and pathologically heterogeneous, present commonly with obscure symptoms that lead to delays in diagnosis of years, and have an incidence in the United States of 2.5 to 5 cases per 100 000. The 5-year survival rates range between 15% and 95%, depending on the site and extent of disease. This report delineates the main conclusions of the meeting, including the best practice diagnosis and treatment strategies for gastropancreatic neuroendocrine tumors, and the identification of clinical and scientific areas that are most in need of attention. The most pressing needs were public and physician education, identification of molecular markers for early diagnosis and therapeutic monitoring, improved imaging modalities and molecular prognostication, development of a standardized pathological classification system, and creation of regional centers of expertise with tumor and laboratory data banks. In addition, adequately validated neuroendocrine tumor models and cell lines should be established to investigate the molecular mechanisms involved in the control of their growth and secretion, and to facilitate the development of specific therapies that should be examined in well-designed multicenter studies of defined patient groups. C1 [Modlin, Irvin M.] Yale Univ, Sch Med, Dept Surg Gastroenterol, New Haven, CT 06520 USA. [Moss, Steven F.] Brown Univ, Rhode Isl Hosp, Providence, RI 02912 USA. [Chung, Daniel C.] Harvard Univ, Massachusetts Gen Hosp, Dept Med, Gastrointestinal Unit, Boston, MA 02115 USA. [Jensen, Robert T.] NIDDK, Digest Dis Branch, Bethesda, MD USA. [Snyderwine, Elizabeth] NCI, NIH, Bethesda, MD 20892 USA. RP Modlin, IM (reprint author), Yale Univ, Sch Med, Dept Surg Gastroenterol, POB 208062, New Haven, CT 06520 USA. EM imodlin@optonline.net FU National Cancer Institute of the Director; National Institutes of Health (NIH) office of Rare Diseases; National Cancer Institute Division of Cancer Biology; Foundation for the National Institutes of Health (FNIH) FX Funding and other support for the conference was provided by the National Cancer Institute office of the Director, the National Institutes of Health (NIH) office of Rare Diseases, the National Cancer Institute Division of Cancer Biology, and the Foundation for the National Institutes of Health (FNIH). FNIH, an independent nonprofit organization, supports the mission of the NIH by linking the generosity of private sector donors and partners to NIH programs. The FNIH partnership with the Neuroendocrine Tumor- Carcinoid Summit Conference was substantially supported by Tercica, Ipsen, Novartis, Covidien, Molecular Insight Pharmaceuticals, and individual donations from the Capital Area Carcinoid Survivors, the Carcinoid Cancer Foundation, and the Caring for Carcinoid Foundation. NR 49 TC 112 Z9 115 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 17 PY 2008 VL 100 IS 18 BP 1282 EP 1289 DI 10.1093/jnci/djn275 PG 8 WC Oncology SC Oncology GA 350BR UT WOS:000259328000007 PM 18780869 ER PT J AU Okonkwo, QL Draisma, G Kinderen, A Brown, ML de Koning, HJ AF Okonkwo, Quirine Lamberts Draisma, Gerrit der Kinderen, Arno Brown, Martin L. de Koning, Harry J. TI Breast cancer screening policies in developing countries: A cost-effectiveness analysis for India SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID LIMITED-RESOURCE COUNTRIES; MORTALITY; PROGRAM; SURVIVAL; MODEL; NETHERLANDS; TRENDS; IMPACT; TRIALS; AGE AB Background India, the largest developing country, has a steadily rising incidence of breast cancer. Estimates and comparisons of the cost-effectiveness of feasible breast cancer screening policies in developing countries and identification of the determinants of cost and efficacy are needed. Methods A Microsimulation Screening Analysis model of breast cancer was calibrated to available data on breast cancer incidence, stage distribution, and mortality in India. The model was used to estimate the costs of screening for breast cancer in India, its effects on mortality, and its cost-effectiveness (ie, costs of screening per life-year gained or life saved). Screening using clinical breast examination (CBE) or mammography among different age groups and at various frequencies was analyzed. Costs were expressed in international dollars (Int.$), the currency used by the World Health Organization, which has the same purchasing power in India as the US dollar has in the United States. To determine which factors influenced cost-effectiveness, sensitivity analyses were performed. Results The estimated mortality reduction was the greatest for programs targeting women between age 40 and 60 years. Using a 3% discount rate, a single CBE at age 50 had an estimated cost-effectiveness ratio of Int.$793 per life year gained and a breast cancer mortality reduction of 2%. The cost-effectiveness ratio increased to Int.$1135 per life year gained for every-5-year CBE (age 40-60 years) and to Int.$1341 for biennial CBE (age 40-60 years); the corresponding reductions in breast cancer mortality were 8.2% and 16.3%, respectively. CBE performed annually from ages 40 to 60 was predicted to be nearly as efficacious as biennial mammography screening for reducing breast cancer mortality while incurring only half the net costs. The main factors affecting cost-effectiveness were breast cancer incidence, stage distribution, and cost savings on prevented palliative care. Conclusion The estimated cost-effectiveness of CBE screening for breast cancer in India compares favorably with that of mammography in developed countries. However, in view of competing priorities and economic conditions, the introduction of screening in India represents a greater challenge than it has been in more developed countries. C1 [Okonkwo, Quirine Lamberts; Draisma, Gerrit; der Kinderen, Arno; de Koning, Harry J.] Univ Med Ctr Rotterdam, Dept Publ Hlth, Erasmus MC, NL-3000 CA Rotterdam, Netherlands. [Okonkwo, Quirine Lamberts] Netherlands Inst Hlth Sci, Rotterdam, Netherlands. [Brown, Martin L.] NIH, Div Canc Control & Populat Sci, Hlth Serv, Bethesda, MD 20892 USA. [Brown, Martin L.] NIH, Div Canc Control & Populat Sci, Econ Branch, Bethesda, MD 20892 USA. RP de Koning, HJ (reprint author), Univ Med Ctr Rotterdam, Dept Publ Hlth, Erasmus MC, POB 2040, NL-3000 CA Rotterdam, Netherlands. EM h.dekoning@erasmusmc.nl NR 48 TC 60 Z9 63 U1 0 U2 10 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 SEP 17 PY 2008 VL 100 IS 18 BP 1290 EP 1300 DI 10.1093/jnci/djn292 PG 11 WC Oncology SC Oncology GA 350BR UT WOS:000259328000008 PM 18780864 ER PT J AU Baschnagel, A Wolters, PL Camphausen, K AF Baschnagel, Andrew Wolters, Pamela L. Camphausen, Kevin TI Neuropsychological testing and biomarkers in the management of brain metastases SO RADIATION ONCOLOGY LA English DT Review ID THERAPY-ONCOLOGY-GROUP; ENDOTHELIAL GROWTH-FACTOR; RANDOMIZED PHASE-III; QUALITY-OF-LIFE; PARTITIONING ANALYSIS RPA; MENTAL-STATE-EXAMINATION; NEURON-SPECIFIC ENOLASE; CENTRAL-NERVOUS-SYSTEM; CELL LUNG-CANCER; RADIATION-THERAPY AB Prognosis for patients with brain metastasis remains poor. Whole brain radiation therapy is the conventional treatment option; it can improve neurological symptoms, prevent and improve tumor associated neurocognitive decline, and prevents death from neurologic causes. In addition to whole brain radiation therapy, stereotactic radiosurgery, neurosurgery and chemotherapy also are used in the management of brain metastases. Radiosensitizers are now currently being investigated as potential treatment options. All of these treatment modalities carry a risk of central nervous system (CNS) toxicity that can lead to neurocognitive impairment in long term survivors. Neuropsychological testing and biomarkers are potential ways of measuring and better understanding CNS toxicity. These tools may help optimize current therapies and develop new treatments for these patients. This article will review the current management of brain metastases, summarize the data on the CNS effects associated with brain metastases and whole brain radiation therapy in these patients, discuss the use of neuropsychological tests as outcome measures in clinical trials evaluating treatments for brain metastases, and give an overview of the potential of biomarker development in brain metastases research. C1 [Baschnagel, Andrew; Camphausen, Kevin] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Wolters, Pamela L.] Med Illness Counseling Ctr, Bethesda, MD USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, NIH, 9000 Rockville Pike,Bldg 10-CRC,Room B2-3561, Bethesda, MD 20892 USA. EM amb26@buffalo.edu; woltersp@mail.nih.gov; camphauk@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research; Clinical Research Training Program; NIH and Pfizer Inc; NCI [HHSN261200477004C] FX This work was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. AB was supported through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc (via a grant to the Foundation for NIH from Pfizer Inc). PLW was supported by NCI contract #HHSN261200477004C with the Medical Illness Counseling Center. NR 101 TC 11 Z9 11 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND J9 RADIAT ONCOL JI Radiat. Oncol. PD SEP 17 PY 2008 VL 3 AR 26 DI 10.1186/1748-717X-3-26 PG 12 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 365OU UT WOS:000260417400001 PM 18798997 ER PT J AU Nikolovska-Coleska, Z Meagher, JL Jiang, S Yang, CY Qiu, S Roller, PP Stuckey, JA Wang, S AF Nikolovska-Coleska, Zaneta Meagher, Jennifer L. Jiang, Sheng Yang, Chao-Yie Qiu, Su Roller, Peter P. Stuckey, Jeanne A. Wang, Shaomeng TI Interaction of a cyclic, bivalent Smac mimetic with the X-linked inhibitor of apoptosis protein SO BIOCHEMISTRY LA English DT Article ID STRUCTURE-BASED DESIGN; XIAP BIR3 DOMAIN; STRUCTURAL BASIS; FLUORESCENCE POLARIZATION; CASPASE INHIBITION; IAP PROTEINS; BINDING; SMAC/DIABLO; POTENT; ANTAGONISTS AB We have designed and synthesized a cyclic, bivalent Smac mimetic (compound 3) and characterized its interaction with the X-linked inhibitor of apoptosis protein (XIAP). Compound 3 binds to XIAP containing both BIR2 and BIR3 domains with a biphasic dose-response curve representing two binding sites with IC(50) values of 0.5 and 406 nM, respectively. Compound 3 binds to XlAPs containing the BIR3-only and BIR2-only domain with K(i) values of 4 nM and 4.4 mu M, respectively. Gel filtration experiments using wild-type and mutated XIAPs showed that 3 forms a 1:2 stoichiometric complex with XIAP containing the BIR3-only domain. However, it forms a 1:1 stoichiometric complex with XIAP containing both BIR2 and BIR3 domains, and both BIR domains are involved in the binding. Compound 3 efficiently antagonizes inhibition of XIAP in a cell-free functional assay and is > 200 times more potent than its corresponding monovalent compound 2. Determination of the crystal structure of 3 in complex with the XIAP BIR3 domain confirms that 3 induces homodimerization of the XIAP BIR3 domain and provides a structural basis for the cooperative binding of one molecule of compound 3 to two XIAP BIR3 molecules. On the basis of this crystal structure, a binding model of XIAP containing both BIR2 and BIR3 domains and 3 was constructed, which sheds light on the ability of 3 to relieve the inhibition of XIAP with not only caspase-9 but also caspase-3/-7. Compound 3 is cell-permeable, effectively activates caspases in whole cells, and potently inhibits cancer cell growth. Compound 3 is a useful biochemical and pharmacological tool for further elucidating the role of XIAP in regulation of apoptosis and represents a promising lead compound for the design of potent, cell-permeable Smac mimetics for cancer treatment. C1 [Nikolovska-Coleska, Zaneta; Yang, Chao-Yie; Qiu, Su; Wang, Shaomeng] Univ Michigan, Ctr Comprehens Canc, Dept Internal Med, Ann Arbor, MI 48109 USA. [Nikolovska-Coleska, Zaneta; Yang, Chao-Yie; Qiu, Su; Wang, Shaomeng] Univ Michigan, Ctr Comprehens Canc, Dept Pharmacol, Ann Arbor, MI 48109 USA. [Nikolovska-Coleska, Zaneta; Yang, Chao-Yie; Qiu, Su; Wang, Shaomeng] Univ Michigan, Ctr Comprehens Canc, Dept Med Chem, Ann Arbor, MI 48109 USA. [Meagher, Jennifer L.; Stuckey, Jeanne A.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Jiang, Sheng; Roller, Peter P.] Natl Canc Inst, Natl Inst Hlth, Med Chem Lab, Frederick, MD 21702 USA. RP Wang, S (reprint author), Univ Michigan, Ctr Comprehens Canc, Dept Internal Med, Ann Arbor, MI 48109 USA. EM shaomeng@umich.edu FU NCI NIH HHS [R01 CA109025, R01 CA109025-01, R01 CA109025-02, R01 CA109025-03, R01 CA109025-04, R01CA109025] NR 37 TC 35 Z9 37 U1 2 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 16 PY 2008 VL 47 IS 37 BP 9811 EP 9824 DI 10.1021/bi800785y PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 347CU UT WOS:000259119000011 PM 18717598 ER PT J AU Puigbo, P Bravo, IG Garcia-Vallve, S AF Puigbo, Pere Bravo, Ignacio G. Garcia-Vallve, Santiago TI CAIcal: A combined set of tools to assess codon usage adaptation SO BIOLOGY DIRECT LA English DT Article ID HIGHLY EXPRESSED GENES; PROKARYOTIC COMPLETE GENOMES; PAPILLOMAVIRUS GENOMES; INDEX; BIAS; METABOLISM; DATABASE; SERVER; CYCLE; DB AB Background: The Codon Adaptation Index (CAI) was first developed to measure the synonymous codon usage bias for a DNA or RNA sequence. The CAI quantifies the similarity between the synonymous codon usage of a gene and the synonymous codon frequency of a reference set. Results: We describe here CAIcal, a web-server available at http://genomes.urv.es/CAIcal that includes a complete set of utilities related with the CAI. The server provides useful important features, such as the calculation and graphical representation of the CAI along either an individual sequence or a protein multiple sequence alignment translated to DNA. The automated calculation of CAI and its expected value is also included as one of the CAIcal tools. The software is also free to be downloaded as a standalone application for local use. Conclusion: The CAIcal server provides a complete set of tools to assess codon usage adaptation and to help in genome annotation. Reviewers: This article was reviewed by Purificacion Lopez-Garc a, Dan Graur, Rob Knight and Shamil Sunyaev. C1 [Puigbo, Pere; Garcia-Vallve, Santiago] Univ Rovira & Virgili, Dept Biochem & Biotechnol, Tarragona 43007, Spain. [Puigbo, Pere] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Bravo, Ignacio G.] Univ Munster, Inst Evolut & Biodivers, D-4400 Munster, Germany. RP Puigbo, P (reprint author), Univ Rovira & Virgili, Dept Biochem & Biotechnol, Campus Sescelades,C Marcelli Domingo S-N, Tarragona 43007, Spain. EM puigboap@ncbi.nlm.nih.gov; igbravo@uni-muenster.de; santi.garciavallve@urv.cat RI Puigbo, Pere/A-2214-2008; Bravo, Ignacio G./A-2483-2009; Garcia-Vallve, Santi/A-4226-2008 OI Bravo, Ignacio G./0000-0003-3389-3389; Garcia-Vallve, Santi/0000-0002-0348-7497 FU National Institutes of Health; National Library of Medicine; Volkswagen Stiftung FX This work was supported in part by the Intramural Research Program of the National Institutes of Health, National Library of Medicine. IGB is the recipient of a professorship supported by the Volkswagen Stiftung in the program Evolutionary Biology. We thank Kevin Costello of the Language Service of the Rovira i Virgili University and the NIH Fellows Editorial Board for their help with writing the manuscript. We also thank Agnes Hotz-Wagenblatt from the HUSAR Bioinformatics Laboratory at Deutsches Krebsforschungszentrum and Obdulia Rabal from the "Centro Nacional de Investigaciones Oncologicas" for testing the server. NR 27 TC 83 Z9 89 U1 2 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD SEP 16 PY 2008 VL 3 AR 38 DI 10.1186/1745-6150-3-38 PG 8 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 355JR UT WOS:000259705700001 PM 18796141 ER PT J AU Xiong, Y Mahmood, A Lu, DY Qu, CS Kazmi, H Goussev, A Zhang, ZG Noguchi, CT Schallerte, T Chopp, M AF Xiong, Ye Mahmood, Asim Lu, Dunyue Qu, Changsheng Kazmi, Humaira Goussev, Anton Zhang, Zheng Gang Noguchi, Constance T. Schallerte, Timothy Chopp, Michael TI Histological and functional outcomes after traumatic brain injury in mice null for the erythropoietin receptor in the central nervous system SO BRAIN RESEARCH LA English DT Article DE cell proliferation; erythropoietin receptor null; mouse; sensorimotor; spatial learning; traumatic brain injury ID CONTROLLED CORTICAL IMPACT; RECOMBINANT-HUMAN-ERYTHROPOIETIN; NEURAL STEM-CELLS; SUBVENTRICULAR ZONE; SPATIAL MEMORY; POSTTRAUMATIC NEURODEGENERATION; ENHANCES NEUROGENESIS; CALCIUM PRECIPITATION; ADULT NEUROGENESIS; CEREBRAL-CORTEX AB Erythropoietin (EPO) and its receptor (EPOR), essential for erythropoiesis, are expressed in the nervous system. Recombinant human EPO treatment promotes functional outcome after traumatic brain injury (TBI) and stroke, suggesting that the endogenous EPO/EPOR system plays an important role in neuroprotection and neurorestoration. This study was designed to investigate effects of the EPOR on histological and functional outcomes after TBI. Experimental TBI was induced in adult EPOR-null and wild-type mice by controlled cortical impact. Neurological function was assessed using the modified Morris Water Maze and footfault tests. Animals were sacrificed 35 days after injury and brain sections stained for immunohistochemistry. As compared to the wild-type injured mice, EPOR-null mice did not exhibit higher susceptibility to TBI as exemplified by tissue loss in the cortex, cell loss in the dentate gyrus, impaired spatial learning, angiogenesis and cell proliferation. We observed that less cortical neurogenesis occurred and that sensorimotor function (i.e., footfault) was more impaired in the EPOR-null mice after TBI. Co-accumulation of amyloid precursor protein (axonal injury marker) and calcium was observed in the ipsilateral thalamus in both EPOR-null and wild-type mice after TBI with more calcium deposits present in the wild-type mice. This study demonstrates for the first time that EPOR null in the nervous system aggravates sensorimotor deficits, impairs cortical neurogenesis and reduces thalamic calcium precipitation after TBI. (C) 2008 Elsevier B.V. All rights reserved. C1 [Zhang, Zheng Gang; Chopp, Michael] Henry Ford Hlth Syst, Dept Neurol, Detroit, MI 48202 USA. [Xiong, Ye; Mahmood, Asim; Qu, Changsheng; Kazmi, Humaira; Goussev, Anton] Henry Ford Hlth Syst, Dept Neurosurg, Detroit, MI 48202 USA. [Lu, Dunyue] Suny Downstate Med Ctr, Dept Psychiat, Brooklyn, NY 11203 USA. [Noguchi, Constance T.] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Schallerte, Timothy] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA. [Schallerte, Timothy] Univ Texas Austin, Inst Neurosci, Austin, TX 78712 USA. [Chopp, Michael] Oakland Univ, Dept Phys, Rochester, MI 48309 USA. RP Chopp, M (reprint author), Henry Ford Hlth Syst, Dept Neurol, 2799 W Grand Blvd, Detroit, MI 48202 USA. EM chopp@neuro.hfh.edu OI Xiong, Ye/0000-0001-9770-6031 FU NINDS [R01 NS52280, P01 NS4234S]; NIDDK FX This work was supported by NINDS grants R01 NS52280, P01 NS4234S and NIDDK Intramural Research. NR 53 TC 34 Z9 38 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 SEP 16 PY 2008 VL 1230 BP 247 EP 257 DI 10.1016/j.brainres.2008.06.127 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 359BW UT WOS:000259962200026 PM 18657521 ER PT J AU Azevedo, VMP Santos, MA Castier, MB Kuschnir, MCC Amino, JGDC Cunha, MOM Chaves, RBM Tura, BR Albanesi, FM Xavier, RMDA AF Azevedo, Vitor Manuel Pereira Santos, Marco Aurelio Castier, Marcia Bueno Kuschnir, Maria Cristina C. Amino, Jose Geraldo De Castro Cunha, Maria Ourinda Mesquita Chaves, Rogerio Brant Martins Tura, Bernardo Rangel Albanesi Filho, Francisco M. Xavier, Regina Maria De Aquino TI Is there any difference at presentation in infantile dilated cardiomyopathy regarding the age? SO CIRCULATION LA English DT Meeting Abstract CT World Congress of Cardiology CY MAY 18-21, 2008 CL Buenos Aires, ARGENTINA SP World Heart Federat, Argentine Soc Cardiol, Argentine Federat Cardiol C1 [Castier, Marcia Bueno; Albanesi Filho, Francisco M.] Univ Estado Rio De Janeiro, Rio De Janeiro, Brazil. [Cunha, Maria Ourinda Mesquita] Natl Canc Inst, Bethesda, MD 20892 USA. RI Azevedo, Vitor/F-7435-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 16 PY 2008 VL 118 IS 12 BP E253 EP E253 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 348QK UT WOS:000259224800467 ER PT J AU Azevedo, VMP Santos, MA Castier, MB Kuschnir, CC Amino, JGC Cunha, MOM Chaves, RBM Tura, BR Filho, FMA Xavier, RMDA AF Pereira Azevedo, Vitor Manuel Santos, Marco Aurelio Castier, Marcia Bueno Kuschnir, Cristina C. Castro Amino, Jose Geraldo M Cunha, Maria Ourinda Martins Chaves, Rogerio Brant Rangel Tura, Bernardo M Albanesi Filho, Francisco De Aquino Xavier, Regina Maria TI The role of clinical laboratory in high-risk for death groups selection using classification tree analysis for infantile dilated cardiomyopathy SO CIRCULATION LA English DT Meeting Abstract CT World Congress of Cardiology CY MAY 18-21, 2008 CL Buenos Aires, ARGENTINA SP World Heart Federat, Argentine Soc Cardiol, Argentine Federat Cardiol C1 [Castier, Marcia Bueno; M Albanesi Filho, Francisco] State Univ Rio de Janerio, Rio De Janeiro, Brazil. [M Cunha, Maria Ourinda] Natl Canc Inst, Bethesda, MD 20892 USA. RI Azevedo, Vitor/F-7435-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 16 PY 2008 VL 118 IS 12 BP E268 EP E268 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 348QK UT WOS:000259224800538 ER PT J AU Rane, NS Kang, SW Chakrabarti, O Feigenbaum, L Hegde, RS AF Rane, Neena S. Kang, Sang-Wook Chakrabarti, Oishee Feigenbaum, Lionel Hegde, Ramanujan S. TI Reduced translocation of nascent prion protein during ER stress contributes to neurodegeneration SO DEVELOPMENTAL CELL LA English DT Article ID ENDOPLASMIC-RETICULUM; SIGNAL SEQUENCE; QUALITY-CONTROL; PRIMARY NEURONS; PRP; NEUROTOXICITY; TRANSMEMBRANE; PATHWAY; DISEASE; ACCUMULATION AB During acute stress in the endoplasmic reticulum (ER), mammalian prion protein (PrP) is temporarily prevented from translocation into the ER and instead routed directly for cytosolic degradation. This "preemptive" quality control (pQC) system benefits cells by minimizing PrP aggregation in the secretory pathway during ER stress. However, the potential toxicity of cytosolic PrP raised the possibility that persistent pQC of PrP contributes to neurodegeneration in prion diseases. Here, we find evidence of ER stress and decreased translocation of nascent PrP during prion infection. Transgenic mice expressing a PrP variant with reduced translocation at levels expected during ER stress was sufficient to cause several mild age-dependent clinical and histological manifestations of PrP-mediated neurodegeneration. Thus, an ordinarily adaptive quality-control pathway can be contextually detrimental over long time periods. We propose that one mechanism of prion-mediated neurodegeneration involves an indirect ER stress-dependent effect on nascent PrP biosynthesis and metabolism. C1 [Rane, Neena S.; Kang, Sang-Wook; Chakrabarti, Oishee; Hegde, Ramanujan S.] NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. [Feigenbaum, Lionel] NCI, Lab Anim Sci, Frederick, MD 21702 USA. RP Hegde, RS (reprint author), NICHHD, Cell Biol & Metab Program, NIH, Bethesda, MD 20892 USA. EM hegder@mail.nih.gov OI Hegde, Ramanujan/0000-0001-8338-852X FU NICHD; NCI at the National Institutes of Health FX We are grateful to Christine Winters for advice on preparation of primary neuronal cultures, Yoseph Abebe for animal care, Heather Eshleman for optimizing the incorporation of His-Ubiquitin in vitro, and Heather Cameron for suggesting the use of Fluoro-Jade C. We are especially indebted to Vishu Lingappa, in whose lab the experiments with PrPSc were performed. This work was supported by the Intramural Research Programs of the NICHD and NCI at the National Institutes of Health. NR 34 TC 70 Z9 71 U1 0 U2 8 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 SEP 16 PY 2008 VL 15 IS 3 BP 359 EP 370 DI 10.1016/j.devcel.2008.06.015 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 350NA UT WOS:000259358100008 PM 18804434 ER PT J AU Li, L Baibakov, B Dean, J AF Li, Lei Baibakov, Boris Dean, Jurrien TI A subcortical maternal complex essential for preimplantation mouse embryogenesis SO DEVELOPMENTAL CELL LA English DT Article ID EARLY EMBRYONIC-DEVELOPMENT; TRANSCRIPTION FACTOR; GENOME ACTIVATION; GENE-EXPRESSION; ALPHA-AMANITIN; FIG-ALPHA; IN-VIVO; OOCYTE; PROTEIN; MICE AB We have identified a subcortical maternal complex (SCMC) that assembles during oocyte growth and is essential for zygotes to progress beyond the first embryonic cell divisions. At least four maternally encoded proteins contribute to this MDa complex: FLOPED, MATER, and TLE6 interact with each other while Filia binds independently to MATER. Although the transcripts encoding these proteins are degraded during meiotic maturation and ovulation, the SCMC proteins persist in the early embryo. The SCMC, located in the subcortex of eggs, is excluded from regions of cell-cell contact in the cleavage-stage embryo and segregates to the outer cells of the morulae and blastocyst. Floped(tm/tm) and/or Mater(tm/tm) eggs lack the SCMC but can be fertilized. However, these embryos do not progress beyond cleavage stage development and female mice are sterile. The proteins are conserved in humans, and similar maternal effect mutations may result in recurrent embryonic loss. C1 [Li, Lei; Baibakov, Boris; Dean, Jurrien] NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Li, L (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM lile@mail.nih.gov OI Li, Lei/0000-0001-5478-5681 FU Intramural Research Program of the National Institutes of Health, NIDDK FX For their help and advice, we thank Lyn Gauthier (microinjection of oocytes), Cuiling Li (establishing mutant mouse lines), Zhaohong Yi (gene expression in COS cells), David Eric Anderson (mass spectrometry analysis), Melvin DePamphilis and Matthew Kohn (Tead null embryos), and Xinhua Liao. This research was supported by the Intramural Research Program of the National Institutes of Health, NIDDK. NR 50 TC 99 Z9 107 U1 0 U2 8 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 SEP 16 PY 2008 VL 15 IS 3 BP 416 EP 425 DI 10.1016/j.devcel.2008.07.010 PG 10 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 350NA UT WOS:000259358100012 PM 18804437 ER PT J AU Doucleff, M Clore, GM AF Doucleff, Michaeleen Clore, G. Marius TI Global jumping and domain-specific intersegment transfer between DNA cognate sites of the multidomain transcription factor Oct-1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE intermolecular translocation; protein-DNA interaction; N-15(2)-exchange NMR spectroscopy; domain-specific kinetics; target searching ID POU-DOMAIN; HEREDITARY PERSISTENCE; EXCHANGE SPECTROSCOPY; PROTEIN TRANSLOCATION; CRYSTAL-STRUCTURE; FETAL-HEMOGLOBIN; BINDING; NMR; COMPLEX; RECOGNITION AB At high DNA concentration, as found in the nucleus, DNA-binding proteins search for specific binding sites by hopping between separate DNA strands. Here, we use N-15(Z)-exchange transverse relaxation optimized NMR spectroscopy to characterize the mechanistic details of intermolecular hopping for the multidomain transcription factor, human Oct-1. Oct-1 is a member of: the POU family of transcription factors and contains two helix-turn-helix DNA-binding domains, POUHD and POUS, connected by a relatively short flexible linker. The two domains were found to exchange between specific sites at significantly different rates. The cotranscription factor, Sox2, decreases the exchange rate and equilibrium dissociation constant for Oct-1 >= 5-fold and approximate to 20-fold, respectively, by slowing the exchange rate for the POUS domain. DNA-dependent exchange rates measured at physiological ionic strength indicate that the two domains use both an intersegmental transfer mechanism, which does not involve the intermediary of free protein, and a fully dissociative or jumping mechanism to translocate between cognate sites. These data represent an example of dissecting domain-specific kinetics for protein-DNA association involving a multidomain protein and provide evidence that intersegmental transfer involves a ternary intermediate, or transition state in which the DNA-binding domains bridge two different DNA fragments simultaneously. C1 [Doucleff, Michaeleen; Clore, G. Marius] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH); NIH FX We thank Jeong-Yong Sun for assistance with sample preparation. This work was supported by the Intramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health (NIDDK/NIH) and the AIDS Targeted Antiviral Program of the Office of the Director of the NIH (to G.M.C.). M.D was supported by a Nancy Nossal NIDDK/NIH Research Fellowship. NR 36 TC 51 Z9 51 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 16 PY 2008 VL 105 IS 37 BP 13871 EP 13876 DI 10.1073/pnas.0805050105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 351QG UT WOS:000259438500036 PM 18772384 ER PT J AU Gao, G McMahon, C Chen, J Rong, YS AF Gao, Guanjun McMahon, Conor Chen, Jie Rong, Yikang S. TI A powerful method combining homologous recombination and site-specific recombination for targeted mutagenesis in Drosophila SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene targeting; position effect; site-specific integration; rare-cutting endonuclease; single strand annealing ID PHI-C31 INTEGRASE; MELANOGASTER; TRANSGENESIS; PATHWAYS; REPAIR; BREAKS AB Gene targeting provides a powerful tool for dissecting gene function. However, repeated targeting of a single locus remains a practice mostly limited to unicellular organisms that afford simple targeting methodologies. We developed an efficient method to repeatedly target a single locus in Drosophila. In this method, which we term "site-specific integrase mediated repeated targeting" (SIRT), an attP attachment site for the phage phiC31 integrase is first targeted to the vicinity of the gene of interest by homologous recombination. All subsequent modifications of that gene are introduced by phiC31-mediated integration of plasmids carrying an attB attachment site and the desired mutation. This highly efficient integration results in a tandem duplication of the target locus, which is then reduced into a single copy carrying the mutation, likely by the efficient "single strand annealing" mechanism, induced with a DNA double-strand break (DSB). We used SIRT to generate a series of six mutations in the Drosophila nbs gene, ranging from single amino acid replacements and small in-frame deletions to complete deletion of the gene. Because all of the components of SIRT are functional in many different organisms, it is readily adaptable to other multicellular organisms. C1 [Gao, Guanjun; McMahon, Conor; Chen, Jie; Rong, Yikang S.] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Rong, YS (reprint author), NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM rongy@mail.nih.gov RI rong, yikang/G-6179-2011 FU NCI FX We thank Germana Collazzo and Cassie Rauser for assistance in constructing the nbs targeting clones; Natalia Wesolowska for assistance in determining the conditions for recombineering; Drs. Michael Lichten, Bruce Paterson, and Michelle Beaucher at the National Cancer Institute (NCI) for comments on the manuscript; and Drs. Michele Calos (Stanford University), Konrad Basler (University of Zurich), and Don Court (NCI) for sending reagents. Our research is supported by the intramural research program of NCI. NR 19 TC 43 Z9 47 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 SEP 16 PY 2008 VL 105 IS 37 BP 13999 EP 14004 DI 10.1073/pnas.0805843105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 351QG UT WOS:000259438500058 PM 18772376 ER PT J AU Spolski, R Kashyap, M Robinson, C Yu, ZX Leonard, WJ AF Spolski, Rosanne Kashyap, Mohit Robinson, Constance Yu, Zuxi Leonard, Warren J. TI IL-21 signaling is critical for the development of type I diabetes in the NOD mouse SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Reg genes; Th17 cells ID T-CELLS; BETA-CELLS; MICE; AUTOIMMUNITY; EXPANSION; GAMMA; REG; DIFFERENTIATION; AUTOANTIGEN; ACTIVATION AB IL-21 is a pleiotropic type I cytokine that shares the common cytokine receptor gamma chain and plays important roles for normal Ig production, terminal B cell differentiation to plasma cells, and Th17 differentiation. IL-21 is elevated in several autoimmune diseases, and blocking its action has attenuated disease in MRL/Ipr mice and in collagen-induced arthritis. The diabetes-associated Idd3 locus is at the Il2/Il21 locus, and elevated IL-21 was observed in the nonobese diabetic (NOD) mouse and suggested to contribute to diabetes by augmenting T cell homeostatic proliferation. To determine the role of IL-21 in diabetes, Il21r-knockout (KO) mice were backcrossed to NOD mice. These mice were devoid of lymphocytic infiltration into the pancreas, and only 1 of 20 animals had an elevated glucose compared with 60% of NOD mice on a wild-type (WT) background. Although TCR and Treg-related responses were normal, these mice had reduced Th17 cells and significantly higher levels of mRNAs encoding members of the Reg (regenerating) gene family whose transgenic expression protects against diabetes. Our studies establish a critical role for IL-21 in the development of type I diabetes in the NOD mouse, with obvious potential implications for type I diabetes in humans. C1 [Spolski, Rosanne; Kashyap, Mohit; Robinson, Constance; Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Yu, Zuxi] NHLBI, Pathol Core Facil, NIH, Bethesda, MD 20892 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Room 7B05, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov RI Kashyap, Mohit/F-4534-2011 FU NHLBI/NIH FX We thank Drs. David V. Serreze and Derry C. Roopenian, The Jackson Laboratory, for the NOD/LtJ mice; and Drs. Roopenian and Jian-Xin Lin, National Heart, Lung, and Blood Institute, National Institutes of Health (NHLBI/NIH) for valuable discussions and critical comments. This work was supported by the Intramural Research Program, NHLBI/NIH. NR 29 TC 115 Z9 117 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 SEP 16 PY 2008 VL 105 IS 37 BP 14028 EP 14033 DI 10.1073/pnas.0804358105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 351QG UT WOS:000259438500063 PM 18779574 ER PT J AU Chung, YJ Choi, CW Slape, C Fry, T Aplan, PD AF Chung, Yang Jo Choi, Chul Won Slape, Christopher Fry, Terry Aplan, Peter D. TI Transplantation of a myelodysplastic syndrome by a long-term repopulating hematopoietic cell SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hematopoiesis; HOX gene; leukemia; transplant; NUP98 ID ACUTE MYELOID-LEUKEMIA; NUP98 GENE; SYNDROME MDS; MICE; NUP98-HOXD13; FUSION; PROGENITORS; ENGRAFTMENT; PRECURSORS; EXPRESSION AB The myelodysplastic syndromes (MDS) comprise a group of premalignant hematologic disorders characterized by ineffective hematopoiesis, dysplasia, and transformation to acute myeloid leukemia (AML). Although it is well established that many malignancies can be transplanted, there is little evidence to demonstrate that a premalignant disease entity, such as MDS or colonic polyps, can be transplanted and subsequently undergo malignant transformation in vivo. Using mice that express a NUP98-HOXD13 (NHD13) transgene in hematopoietic tissues, we show that a MDS can be transplanted to WT recipients. Recipients of the MDS bone marrow displayed all of the critical features of MDS, including peripheral blood cytopenias, dysplasia, and transformation to AML. Even when transplanted with a 10-fold excess of WT cells, the NHD13 cells outcompeted the WT cells over a 38-week period. Limiting-dilution experiments demonstrated that the frequency of the cell that could transmit the disease was approximate to 1/6,000-1/16,000 and that the MDS was also transferable to secondary recipients as a premalignant condition. Transformation to AML in primary transplant recipients was generally delayed (46-49 weeks after transplant); however, 6 of 10 secondary transplant recipients developed AML. These findings demonstrate that MDS originates in a transplantable, premalignant, long-term repopulating, MDS-initiating cell. C1 [Chung, Yang Jo; Choi, Chul Won; Slape, Christopher; Aplan, Peter D.] NCI, Genet Branch, Natl Inst Hlth, Bethesda, MD 20889 USA. [Fry, Terry] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20889 USA. RP Aplan, PD (reprint author), NCI, Genet Branch, Natl Inst Hlth, Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM aplanp@mail.nih.gov RI Slape, Christopher/H-8586-2016; Aplan, Peter/K-9064-2016 OI Slape, Christopher/0000-0002-8407-3092; FU National Institutes of Health, National Cancer Institute FX We thank Eli Estey, R. Keith Humphries, David Caudell, and Helge Hartung for discussion; Bobby Smith and Leslie Johnston for technical assistance; and John Dennis and Danielle O'Mard for oversight of animal care. This work was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 28 TC 19 Z9 19 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 SEP 16 PY 2008 VL 105 IS 37 BP 14088 EP 14093 DI 10.1073/pnas.0804507105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 351QG UT WOS:000259438500073 PM 18768819 ER PT J AU Walum, H Westberg, L Henningsson, S Neiderhiser, JM Reiss, D Igl, W Ganiban, JM Spotts, EL Pedersen, NL Eriksson, E Lichtenstein, P AF Walum, Hasse Westberg, Lars Henningsson, Susanne Neiderhiser, Jenae M. Reiss, David Igl, Wilmar Ganiban, Jody M. Spotts, Erica L. Pedersen, Nancy L. Eriksson, Elias Lichtenstein, Paul TI Genetic variation in the vasopressin receptor 1a gene (AVPR1A) associates with pair-bonding behavior in humans SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE monogamy; neuropeptide; polymorphism; social behavior ID PRAIRIE VOLES; SOCIAL-ORGANIZATION; EXPRESSION; AUTISM; POLYMORPHISMS; BRAIN AB Pair-bonding has been suggested to be a critical factor in the evolutionary development of the social brain. The brain neuropeptide arginine vasopressin (AVP) exerts an important influence on pair-bonding behavior in voles. There is a strong association between a polymorphic repeat sequence in the 5' flanking region of the gene (avpr1a) encoding one of the AVP receptor subtypes (V1aR), and proneness for monogamous behavior in males of this species. It is not yet known whether similar mechanisms are important also for human pair-bonding. Here, we report an association between one of the human AVPR1A repeat polymorphisms (RS3) and traits reflecting pair-bonding behavior in men, including partner bonding, perceived marital problems, and marital status, and show that the RS3 genotype of the males also affects marital quality as perceived by their spouses. These results suggest an association between a single gene and pair-bonding behavior in humans, and indicate that the well characterized influence of AVP on pair-bonding in voles may be of relevance also for humans. C1 [Walum, Hasse; Igl, Wilmar; Pedersen, Nancy L.; Lichtenstein, Paul] Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. [Westberg, Lars; Henningsson, Susanne; Eriksson, Elias] Univ Gothenburg, Inst Neurosci & Physiol, Dept Pharmacol, S-40530 Gothenburg, Sweden. [Neiderhiser, Jenae M.] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Reiss, David] Yale Univ, Yale Child Study Ctr, New Haven, CT 06520 USA. [Ganiban, Jody M.] George Washington Univ, Dept Psychol, Washington, DC 20052 USA. [Spotts, Erica L.] NIA, Behav & Social Res Program, Bethesda, MD 20892 USA. RP Walum, H (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Box 281, S-17177 Stockholm, Sweden. EM hasse.walum@ki.se RI chen, xuanlan/H-4158-2011; OI lichtenstein, paul/0000-0003-3037-5287 FU National Institute of Mental Health [R01MH54610]; Bank of Sweden Tercentenary Foundation [J2004-0036:1]; Brain Foundation Sweden FX This project was supported by National Institute of Mental Health Grant R01MH54610, Bank of Sweden Tercentenary Foundation Grant J2004-0036:1, and a postdoctoral fellowship sponsored by the Brain Foundation, Sweden (to L.W.). NR 32 TC 224 Z9 226 U1 7 U2 113 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 SEP 16 PY 2008 VL 105 IS 37 BP 14153 EP 14156 DI 10.1073/pnas.0803081105 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 351QG UT WOS:000259438500084 PM 18765804 ER PT J AU Bensimhon, DR Leifer, ES Ellis, SJ Fleg, JL Keteyian, SJ Pina, IL Kitzman, DW McKelvie, RS Kraus, WE Forman, DE Kao, AJ Whellan, DJ O'Connor, CM Russell, SD AF Bensimhon, Daniel R. Leifer, Eric S. Ellis, Stephen J. Fleg, Jerome L. Keteyian, Steven J. Pina, Ileana L. Kitzman, Dalane W. McKelvie, Robert S. Kraus, William E. Forman, Daniel E. Kao, Andrew J. Whellan, David J. O'Connor, Christopher M. Russell, Stuart D. CA HF-ACTION Trial Investigators TI Reproducibility of peak oxygen uptake and other cardiopulmonary exercise testing parameters in patients with heart failure (from the Heart Failure and A Controlled Trial Investigating Outcomes of exercise traiNing) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID TREADMILL EXERCISE; GAS-EXCHANGE; TRANSPLANTATION AB Peak oxygen uptake (pVo(2)) is an important parameter in assessing the functional capacity and prognosis of patients with heart failure. In heart failure trials, change in pVo(2) was often used to assess the effectiveness of an intervention. However, the within-subject variability of pVo(2) on serial testing may limit its usefulness. This study was designed to evaluate the within-subject variability of pVo(2) over 2 baseline cardiopulmonary exercise tests. As a substudy of the HF-ACTION trial, 398 subjects (73% men, 27% women; mean age 59 years) with heart failure and left ventricular ejection fraction <= 35% underwent 2 baseline cardiopulmonary exercise tests within 14 days. Mean pVo(2) was unchanged from test 1 to test 2 (15.16 +/- 4.97 vs 15.18 +/- 4.97 ml/kg/min; p = 0.78). However, mean within-subject absolute change was 1.3 ml/kg/min (10th, 90th percentiles 0.1, 3.0), with 46% of subjects increasing and 48% decreasing on the second test. Other parameters, including the ventilation-to-carbon-dioxide production slope and Vo(2) at ventilatory threshold, also showed significant within-subject variation with minimal mean differences between tests. In conclusion, pVo(2) showed substantial within-subject variability in patients with heart failure and should be taken into account in clinical applications. However, on repeated baseline cardiopulmonary exercise tests, there appears to be no familiarization effect for Vo(2) in patients with HF. Therefore, in multicenter trials, there is no need to perform >1 baseline cardiopulmonary exercise test. (C) 2008 Elsevier Inc. All rights reserved. C1 [Russell, Stuart D.] Johns Hopkins Univ Hosp, Div Cardiol, Baltimore, MD 21287 USA. [Bensimhon, Daniel R.] Lebauer Cardiovasc Res Fdn, Greensboro, NC USA. [Leifer, Eric S.; Fleg, Jerome L.] NIH, Bethesda, MD 20892 USA. [Keteyian, Steven J.] Henry Ford Hosp, Div Cardiovasc Med, Detroit, MI 48202 USA. [Ellis, Stephen J.; O'Connor, Christopher M.] Duke Clin Res Inst, Durham, NC USA. [Pina, Ileana L.] Case Western Reserve VA Med Ctr, Div Cardiol, Cleveland, OH USA. [Kitzman, Dalane W.] Wake Forest Univ, Bowman Gray Sch Med, Cardiol Sect, Winston Salem, NC USA. [McKelvie, Robert S.] Hamilton Hlth Sci, Div Cardiol, Hamilton, ON, Canada. [Kraus, William E.] Duke Univ, Med Ctr, Div Cardiovasc Med, Durham, NC USA. [Forman, Daniel E.] Brigham & Womens Hosp, Cardiovasc Div, Boston, MA 02115 USA. [Forman, Daniel E.] Boston VA Med Ctr, Boston, MA USA. [Kao, Andrew J.] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Whellan, David J.] Thomas Jefferson Univ, Jefferson Med Coll, Div Cardiol, Philadelphia, PA 19107 USA. RP Russell, SD (reprint author), Johns Hopkins Univ Hosp, Div Cardiol, Baltimore, MD 21287 USA. EM srussel4@jhmi.edu OI Kraus, William E/0000-0003-1930-9684 FU National Institutes of Health, Bethesda, Maryland [5U01HL063747] FX This work was supported by Grant No. 5U01HL063747 from the National Institutes of Health, Bethesda, Maryland. NR 15 TC 55 Z9 56 U1 1 U2 7 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 EI 1879-1913 J9 AM J CARDIOL JI Am. J. Cardiol. PD SEP 15 PY 2008 VL 102 IS 6 BP 712 EP 717 DI 10.1016/j.amjcard.2008.04.047 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 355DS UT WOS:000259689900014 PM 18773994 ER PT J AU Lacey, JV AF Lacey, James V., Jr. TI Invited commentary: Endometrial hyperplasia - Getting back to normal SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE endometrial hyperplasia; endometrial neoplasms; endometrium; obesity; parity; smoking ID GYNECOLOGIC-ONCOLOGY-GROUP; BREAST-CANCER; MANAGEMENT; CARCINOMA; DIAGNOSIS; WOMEN; RISK; ADENOCARCINOMA; HEALTH AB Cancer precursors can help to reveal clues about how and when risk factors influence the development of carcinoma. Endometrial carcinoma is well-suited to studies of precursors: Strong risk and protective factors exist, as does a good candidate precursor lesion, called atypical endometrial hyperplasia. Atypical hyperplasia is the most severe type of endometrial hyperplasia, which ranges from mild, reversible proliferation to incipient carcinoma. In this issue of the Journal, Epplein et al. (Am J Epidemiol 2008;168:563-70) report that three established risk factors for endometrial carcinoma-obesity, parity, and smoking-are similarly associated with two types of endometrial hyperplasia: complex hyperplasia and atypical hyperplasia. How much these findings reveal about mechanistic pathways for endometrial carcinoma depends, in part, on three issues that specifically affect endometrial hyperplasia but also affect other precursors. They are: 1) potential misclassification of intermediate endpoints, 2) unsettled thresholds between low-risk and high-risk lesions, and 3) uncertain boundaries between normal tissue and early-stage precursors. In this commentary, the author explores how these issues might influence interpretation of the new data from Epplein et al. and shape future research on endometrial carcinoma precursors. C1 Natl Canc Inst, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Rockville, MD 20852 USA. RP Lacey, JV (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, 6120 Execut Blvd,MSC 7234, Rockville, MD 20852 USA. EM jimlacey@nih.gov NR 23 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2008 VL 168 IS 6 BP 571 EP 574 DI 10.1093/aje/kwn165 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 344WY UT WOS:000258959200003 ER PT J AU Chodick, G Bekiroglu, N Hauptmann, M Alexander, BH Freedman, DM Doody, MM Cheung, LC Simon, SL Weinstock, RM Bouville, A Sigurdson, AJ AF Chodick, Gabriel Bekiroglu, Nural Hauptmann, Michael Alexander, Bruce H. Freedman, D. Michal Doody, Michele Morin Cheung, Li C. Simon, Steven L. Weinstock, Robert M. Bouville, Andre Sigurdson, Alice J. TI Risk of cataract after exposure to low doses of ionizing radiation: A 20-year prospective cohort study among US radiologic technologists SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cataract; radiation; technology; radiologic; x-rays ID BLUE MOUNTAINS EYE; BEAVER DAM EYE; POSTERIOR SUBCAPSULAR CATARACTS; ATOMIC-BOMB SURVIVORS; BODY-MASS INDEX; LENS OPACITIES; EPIDEMIOLOGIC ASSOCIATIONS; LENTICULAR OPACITIES; GAMMA-RADIATION; UNITED-STATES AB The study aim was to determine the risk of cataract among radiologic technologists with respect to occupational and nonoccupational exposures to ionizing radiation and to personal characteristics. A prospective cohort of 35,705 cataract-free US radiologic technologists aged 24-44 years was followed for nearly 20 years (1983-2004) by using two follow-up questionnaires. During the study period, 2,382 cataracts and 647 cataract extractions were reported. Cigarette smoking for >= 5 pack-years; body mass index of >= 25 kg/m(2); and history of diabetes, hypertension, hypercholesterolemia, or arthritis at baseline were significantly (p <= 0.05) associated with increased risk of cataract. In multivariate models, self-report of >= 3 x-rays to the face/neck was associated with a hazard ratio of cataract of 1.25 (95% confidence interval: 1.06, 1.47). For workers in the highest category (mean, 60 mGy) versus lowest category (mean, 5 mGy) of occupational dose to the lens of the eye, the adjusted hazard ratio of cataract was 1.18 (95% confidence interval: 0.99, 1.40). Findings challenge the National Council on Radiation Protection and International Commission on Radiological Protection assumptions that the lowest cumulative ionizing radiation dose to the lens of the eye that can produce a progressive cataract is approximately 2 Gy, and they support the hypothesis that the lowest cataractogenic dose in humans is substantially less than previously thought. C1 [Chodick, Gabriel; Freedman, D. Michal; Doody, Michele Morin; Simon, Steven L.; Weinstock, Robert M.; Bouville, Andre; Sigurdson, Alice J.] Natl Canc Inst, Natl Inst Hlth, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet,Radiat Epidemiol Branc, Bethesda, MD 20892 USA. [Bekiroglu, Nural] Univ Marmara, Sch Med, Dept Biostat, Istanbul, Turkey. [Hauptmann, Michael] Natl Canc Inst, Natl Inst Hlth, Div Canc Epidemiol & Genet, Biostat Branch,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Hauptmann, Michael] Netherlands Canc Inst, Amsterdam, Netherlands. [Alexander, Bruce H.] Univ Minnesota, Div Environm Hlth Sci, Minneapolis, MN USA. [Cheung, Li C.] Informat Management Serv Inc, Silver Spring, MD USA. RP Chodick, G (reprint author), Natl Canc Inst, Natl Inst Hlth, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet,Radiat Epidemiol Branc, 6120 Execut Blvd,EPS 7049,MSC 7238, Bethesda, MD 20892 USA. EM hodik_g@mac.org.il OI Cheung, Li/0000-0003-1625-4331 FU Intramural NIH HHS; NCI NIH HHS [N01CP31018, N02CP31013] NR 49 TC 127 Z9 137 U1 2 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 15 PY 2008 VL 168 IS 6 BP 620 EP 631 DI 10.1093/aje/kwn171 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 344WY UT WOS:000258959200011 PM 18664497 ER PT J AU Deroo, LA Wilcox, AJ Drevon, CA Lie, RT AF DeRoo, Lisa A. Wilcox, Allen J. Drevon, Christian A. Lie, Rolv Terje TI First-trimester maternal alcohol consumption and the risk of infant oral clefts in Norway: A population-based case-control study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcohol drinking; cleft lip; cleft palate ID FOOD FREQUENCY QUESTIONNAIRE; BIRTH-DEFECTS; OROFACIAL CLEFTS; FATTY-ACIDS; PREGNANCY; DRINKING AB Although alcohol is a recognized teratogen, evidence is limited on alcohol intake and oral cleft risk. The authors examined the association between maternal alcohol consumption and oral clefts in a national, population-based case-control study of infants born in 1996-2001 in Norway. Participants were 377 infants with cleft lip with or without cleft palate, 196 with cleft palate only, and 763 controls. Mothers reported first-trimester alcohol consumption in self-administered questionnaires completed within a few months after delivery. Logistic regression was used to calculate odds ratios and 95% confidence intervals, adjusting for confounders. Compared with nondrinkers, women who reported binge-level drinking (>= 5 drinks per sitting) were more likely to have an infant with cleft lip with or without cleft palate (odds ratio = 2.2, 95% confidence interval: 1.1, 4.2) and cleft palate only (odds ratio = 2.6, 95% confidence interval: 1.2, 5.6). Odds ratios were higher among women who binged on three or more occasions: odds ratio = 3.2 for cleft lip with or without cleft palate (95% confidence interval: 1.0, 10.2) and odds ratio = 3.0 for cleft palate only (95% confidence interval: 0.7, 13.0). Maternal binge-level drinking may increase the risk of infant clefts. C1 [DeRoo, Lisa A.; Wilcox, Allen J.] Natl Inst Environm Hlth Sci, Epidemiol Branch, Natl Inst Hlth, Durham, NC 27709 USA. [Drevon, Christian A.] Univ Oslo, Inst Basic Med Sci, Dept Nutr, Fac Med, Oslo, Norway. [Lie, Rolv Terje] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Sect Epidemiol & Med Stat, Bergen, Norway. [Lie, Rolv Terje] Norwegian Inst Publ Hlth, Med Birth Registry Norway, Bergen, Norway. RP Deroo, LA (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, Natl Inst Hlth, POB 12233,Mail Drop A3-05, Durham, NC 27709 USA. EM DeRooL@niehs.nih.gov RI Drevon, Christian /F-6012-2010; OI Wilcox, Allen/0000-0002-3376-1311 FU National Institutes of Health; National Institute of Environmental Health Sciences FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Environmental Health Sciences. NR 30 TC 40 Z9 40 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 SEP 15 PY 2008 VL 168 IS 6 BP 638 EP 646 DI 10.1093/aje/kwn186 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 344WY UT WOS:000258959200013 PM 18667525 ER PT J AU Murphy, L Schwartz, TA Helmick, CG Renner, JB Tudor, G Koch, G Dragomir, A Kalsbeek, WD Luta, G Jordan, JM AF Murphy, Louise Schwartz, Todd A. Helmick, Charles G. Renner, Jordan B. Tudor, Gail Koch, Gary Dragomir, Anca Kalsbeek, William D. Luta, Gheorghe Jordan, Joanne M. TI Lifetime risk of symptomatic knee osteoarthritis SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID UNITED-STATES; PROGRESSION; DISEASE; WOMEN; ASSOCIATION; ALIGNMENT; HIP; PREVALENCE; ARTHRITIS; OUTCOMES AB Objective. To estimate the lifetime risk of symptomatic knee osteoarthritis (OA), overall and stratified by sex, race, education, history of knee injury, and body mass index (BMI). Methods. The lifetime risk of symptomatic OA in at least 1 knee was estimated from logistic regression models with,generalized estimating equations among 3,068 participants of the Johnston County Osteoarthritis Project, a longitudinal :1 0 0 study, of black and white women and men age >= 45 years living in rural North Carolina. Radiographic, sociodemographic, and symptomatic knee data measured at baseline (1990-1997) and first followup (1999-2003) were analyzed. Results. The lifetime risk of symptomatic knee OA was 44.7% (95% confidence interval [95% CI] 40.0-49.3%)). Cohort members with history of a knee injury had a lifetime risk of 56.8%, (95% CI 48.4-65.21%). Lifetime risk rose with increasing BMI. with a risk of 2 in 3 among those who were obese. Conclusion. Nearly half of the adults in Johnston County will develop symptomatic knee OA by age 85 years, with lifetime risk highest among obese persons. These current high risks in Johnston County may suggest similar risks in the general US Population. especially given the increase in 2 major risk factors for knee CIA, aging, kind obesity. This underscores the immediate need for greater use of clinical and public health interventions, especially those that address weight loss and self-management, to reduce the impact of having knee OA. C1 [Murphy, Louise] CDC, Arthritis Program, Div Adult & Community Hlth, Atlanta, GA 30341 USA. [Murphy, Louise] Business Comp Applicat, Atlanta, GA USA. [Schwartz, Todd A.; Renner, Jordan B.; Koch, Gary; Kalsbeek, William D.; Jordan, Joanne M.] Univ N Carolina, Chapel Hill, NC USA. [Tudor, Gail] Huston Coll, Bangor, ME USA. [Dragomir, Anca] NICHHD, NIH, Bethesda, MD 20892 USA. [Luta, Gheorghe] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. RP Murphy, L (reprint author), CDC, Arthritis Program, Div Adult & Community Hlth, 4770 Buford Highway NW,Mailstop K-51, Atlanta, GA 30341 USA. EM lmurphy1@cdc.gov RI Schwartz, Todd/D-4995-2012; OI Schwartz, Todd/0000-0002-0232-2543; Luta, George/0000-0002-4035-7632; Luta, George/0000-0001-9013-2207 FU Intramural CDC HHS [CC999999] NR 39 TC 293 Z9 301 U1 6 U2 39 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD SEP 15 PY 2008 VL 59 IS 9 BP 1207 EP 1213 DI 10.1002/art.24021 PG 7 WC Rheumatology SC Rheumatology GA 354WI UT WOS:000259669700002 PM 18759314 ER PT J AU Hicks, GE Gaines, JM Shardell, M Simonsick, EM AF Hicks, Gregory E. Gaines, Jean M. Shardell, Michelle Simonsick, Eleanor M. TI Associations of back and leg pain with health status and functional capacity of older adults: Findings from the retirement community back pain study SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID TRUNK MUSCLE COMPOSITION; PHYSICAL FUNCTION; BODY-COMPOSITION; SF-36; WOMEN; POPULATION; SYMPTOMS; RISK AB Objective. Low back pain (LBP) is the most frequently reported musculoskeletal problem in older adults, but its impact on health status is not well understood. Our objective was to determine whether LBP and concurrent leg pain are associated with health-related quality of life (HRQOL) and function in a cohort of older adults, and to examine care-seeking behaviors related to LBP. Methods. This was a population-based, cross-sectional survey study of 522 community-dwelling men and women (67.4%)) ages >= 62 living in 4 retirement communities in Maryland and northern Virginia. LBP status in the past year was categorized as no pain in the low back or leg, LBP only, and LBP with leg pain. HRQOL and function were measured with the Medical Outcomes Study Short Form 36 (SF-36). Results. A total of 26.8% of the sample reported LBP only and 21.3% reported LBP plus leg pain. Participants With LBP and LBP plus leg pain had lower scores in all SF-36 domains, reflecting worse HRQOL (P < 0.0001). LBP and LBP plus leg pain were associated with 2-fold greater odds of falling and increased difficulty lifting grocery bags, walking several blocks, and bathing. LBP plus leg pain was associated with difficulty in social interactions (odds ratio 10.63, 95% confidence interval 3.57-31.60). Less than half sought care for LBP and those who did had poorer health status and. greater pain burden. Conclusion. LBP is common among older adults and strongly associated with reduced HRQOL and function. These M findings argue strongly for both identifying cases of LBP by health care practitioners and pursuing effective treatments for LBP given the potential consequences. C1 [Hicks, Gregory E.] Univ Delaware, Dept Phys Therapy, Newark, DE 19716 USA. [Gaines, Jean M.] Erickson Fdn, Baltimore, MD USA. [Shardell, Michelle] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Simonsick, Eleanor M.] NIA, Bethesda, MD 20892 USA. RP Hicks, GE (reprint author), Univ Delaware, Dept Phys Therapy, 303 McKinly Lab, Newark, DE 19716 USA. EM ghicks@udel.edu FU NIH; National Institute on Aging FX Supported by the Intramural Research Program of the NIH, National Institute on Aging. NR 25 TC 43 Z9 44 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD SEP 15 PY 2008 VL 59 IS 9 BP 1306 EP 1313 DI 10.1002/art.24006 PG 8 WC Rheumatology SC Rheumatology GA 354WI UT WOS:000259669700013 PM 18759261 ER PT J AU Manalo, DJ Buehler, PW Baek, JH Butt, O D'Agnillo, F Alayash, AI AF Manalo, Dominador J. Buehler, Paul W. Baek, Jin Hyen Butt, Omer D'Agnillo, Felice Alayash, Abdu I. TI Acellular haemoglobin attenuates hypoxia-inducible factor-1 alpha (HIF-1 alpha) and its target genes in haemodiluted rats SO BIOCHEMICAL JOURNAL LA English DT Article DE erythropoiesis; haematocrit; haemodilution; haemoglobin (Hb); kidney; hypoxia-inducible factor-1 alpha (HIF-1 alpha) ID HYPOXIA-INDUCIBLE FACTOR; UBIQUITIN-PROTEASOME PATHWAY; HEME OXYGENASE-1 GENE; FACTOR 1-ALPHA; INTERMITTENT HYPOXIA; TRANSCRIPTION FACTORS; ENDOTHELIAL-CELLS; BOVINE HEMOGLOBIN; HIF HYDROXYLASES; FACTOR-I AB Hb (haemoglobin)-based blood substitutes represent a class of therapeutics designed to correct oxygen deficit under conditions of anaemia and traumatic blood loss. The influences of these agents on HIF-1 alpha (hypoxia-inducible factor-la) target genes involved in adaptation to hypoxia have so far not been studied. In the study presented here. rats underwent 80% ET (exchange transfusion) with either HS (hetastarch) or a polymerized Hb OG (Oxyglobin (R)). HS induced dramatic EPO (erythropoietin) gene transcription, reaching a maximum at 4 In post-ET. In contrast, OG suppressed EPO transcription until approx. 24 h post-ET. Large plasma EPO levels that were observed post-ET with HS were significantly blunted in animals transfused with OG. OG, unlike HS, induced a sharp increase in HO-1 (haem oxygenase-1) transcription at 4 In, which declined rapidly within 24 h, whereas modest increases in iNOS [inducible (nitric oxide synthase)] and constitutive NOS [eNOS (endothelial NOS)] were detected over the control. Our results demonstrate for the first time that severe haemodilution-induced erythropoietic responses in kidneys were attenuated by a low-oxygen-affinity cell-free Hb and suggest that tissue-specific oxygen-sensing pathways can be influenced by allosterically modified Hbs. C1 [Manalo, Dominador J.; Buehler, Paul W.; Baek, Jin Hyen; Butt, Omer; D'Agnillo, Felice; Alayash, Abdu I.] US FDA, LBVB, Div Hematol, CBER,NIH, Bethesda, MD 20892 USA. RP Alayash, AI (reprint author), US FDA, LBVB, Div Hematol, CBER,NIH, Bldg 29,Room 112,8800 Rockville Pike, Bethesda, MD 20892 USA. EM abdu.alayash@fda.hhs.gov FU FDA/CBER; Defense Advanced Research Projects Agency FX This work was supported in part by FDA/CBER critical path funding and by a giant from the Defense Advanced Research Projects Agency. The findings and conclusions in this paper have not been formally disseminated by the FDA and should not be construed to represent any agency determination or policy. NR 50 TC 13 Z9 13 U1 2 U2 5 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 SEP 15 PY 2008 VL 414 BP 461 EP 469 DI 10.1042/BJ2G080313 PN 3 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 352QP UT WOS:000259512500015 PM 18498252 ER PT J AU Shatkay, H Pan, FX Rzhetsky, A Wilbur, WJ AF Shatkay, Hagit Pan, Fengxia Rzhetsky, Andrey Wilbur, W. John TI Multi-dimensional classification of biomedical text: Toward automated, practical provision of high-utility text to diverse users SO BIOINFORMATICS LA English DT Article ID INFORMATION-RETRIEVAL; GENE AB Motivation: Much current research in biomedical text mining is concerned with serving biologists by extracting certain information from scientific text. We note that there is no average biologist client; different users have distinct needs. For instance, as noted in past evaluation efforts (BioCreative, TREC, KDD) database curators are often interested in sentences showing experimental evidence and methods. Conversely, lab scientists searching for known information about a protein may seek facts, typically stated with high confidence. Text-mining systems can target specific end-users and become more effective, if the system can first identify text regions rich in the type of scientific content that is of interest to the user, retrieve documents that have many such regions, and focus on fact extraction from these regions. Here, we study the ability to characterize and classify such text automatically. We have recently introduced a multi-dimensional categorization and annotation scheme, developed to be applicable to a wide variety of biomedical documents and scientific statements, while intended to support specific biomedical retrieval and extraction tasks. Results: The annotation scheme was applied to a large corpus in a controlled effort by eight independent annotators, where three individual annotators independently tagged each sentence. We then trained and tested machine learning classifiers to automatically categorize sentence fragments based on the annotation. We discuss here the issues involved in this task, and present an overview of the results. The latter strongly suggest that automatic annotation along most of the dimensions is highly feasible, and that this new framework for scientific sentence categorization is applicable in practice. C1 [Shatkay, Hagit; Pan, Fengxia] Queens Univ, Sch Comp, Computat Biol & Machine Learning Lab, Kingston, ON, Canada. [Rzhetsky, Andrey] Univ Chicago, Dept Med, Chicago, IL 60637 USA. [Rzhetsky, Andrey] Univ Chicago, Computat Inst, Dept Human Genet, Chicago, IL 60637 USA. [Rzhetsky, Andrey] Univ Chicago, Inst Genom & Syst Biol, Chicago, IL 60637 USA. [Wilbur, W. John] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20892 USA. RP Shatkay, H (reprint author), Queens Univ, Sch Comp, Computat Biol & Machine Learning Lab, Kingston, ON, Canada. EM shatkay@cs.queensu.ca RI rzhetsky, andrey/B-6118-2012; OI Rzhetsky, Andrey/0000-0001-6959-7405 FU NSERC Discovery [298292-04]; CFI New Opportunities Award [10437]; NSF [EIA-0121687] FX This work is supported by H.S.'s NSERC Discovery Grant 298292-04 and CFI New Opportunities Award 10437, and by A.R.'s NSF grant (supplement to EIA-0121687). NR 29 TC 34 Z9 36 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 EI 1460-2059 J9 BIOINFORMATICS JI Bioinformatics PD SEP 15 PY 2008 VL 24 IS 18 BP 2086 EP 2093 DI 10.1093/bioinformatics/btn381 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 344XC UT WOS:000258959600017 PM 18718948 ER PT J AU Romagnoli, R Baraldi, PG Sarkar, T Carrion, MD Cruz-Lopez, O Cara, CL Tolomeo, M Grimaudo, S Di Cristina, A Pipitone, MR Balzarini, J Gambari, R Ilaria, L Saletti, R Brancale, A Hamel, E AF Romagnoli, Romeo Baraldi, Pier Giovanni Sarkar, Taradas Carrion, Maria Dora Cruz-Lopez, Olga Cara, Carlota Lopez Tolomeo, Manlio Grimaudo, Stefania Di Cristina, Antonietta Pipitone, Maria Rosaria Balzarini, Jan Gambari, Roberto Ilaria, Lampronti Saletti, Roberto Brancale, Andrea Hamel, Ernest TI Synthesis and biological evaluation of 2-(3 ',4 ',5 '-trimethoxybenzoyl)-3-N, N-dimethylamino benzo[b] furan derivatives as inhibitors of tubulin polymerization SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE microtubules; tubulin polymerization; colchicine binding site; combretastatin A-4; bioisosteric replacement ID ONE-POT SYNTHESIS; ANTIMITOTIC AGENTS; COLCHICINE; COMBRETASTATIN-A-4; ALDEHYDES; NITRILES; GROWTH AB Molecules that target microtubules have an important role in the treatment of cancer. A new class of inhibitors of tubulin polymerization based on the 2-(3,4,5-trimethoxybenzoyl)-2-dimethylamino-benzo[b] furan molecular skeleton was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell cycle effects. The most promising compound in this series was 2(3,4,5-trimethoxybenzoyl)-3-dimethylamino-6-methoxy-benzo[b] furan, which inhibits cancer cell growth at nanomolar concentrations and interacts strongly with tubulin by binding to the colchicine site. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Carrion, Maria Dora; Cruz-Lopez, Olga; Cara, Carlota Lopez] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Sarkar, Taradas] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. [Tolomeo, Manlio] Univ Palermo, CIROC, Palermo, Italy. [Tolomeo, Manlio] Univ Palermo, AIDS Serv, Palermo, Italy. [Grimaudo, Stefania; Di Cristina, Antonietta; Pipitone, Maria Rosaria] Univ Palermo, Dipartimento Biomed Med Interna & Specialist, Palermo, Italy. [Balzarini, Jan; Hamel, Ernest] Katholieke Univ Leuven, Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. [Gambari, Roberto; Ilaria, Lampronti] Univ Ferrara, Dipartmento Biochim & Biol Mol, I-44100 Ferrara, Italy. [Saletti, Roberto; Brancale, Andrea] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3XF, S Glam, Wales. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, Via Fossato Mortara 17-19, I-44100 Ferrara, Italy. EM rmr@unife.it; baraldi@unife.it RI antonietta, di cristina/I-9251-2012; Brancale, Andrea/N-9445-2014; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Gambari, Roberto/F-9555-2015; Carrion, M. Dora/G-8638-2015; Romagnoli, Romeo/G-9887-2015; Baraldi, Pier Giovanni/B-7933-2017; Cruz-Lopez, Olga /F-3060-2017 OI PIPITONE, Rosaria Maria/0000-0002-6721-3962; Grimaudo, Stefania/0000-0003-3225-4112; Brancale, Andrea/0000-0002-9728-3419; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; Gambari, Roberto/0000-0001-9205-6033; Carrion, M. Dora/0000-0002-6794-3949; FU Intramural NIH HHS [Z99 CA999999] NR 25 TC 29 Z9 30 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD SEP 15 PY 2008 VL 16 IS 18 BP 8419 EP 8426 DI 10.1016/j.bmc.2008.08.029 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 347WY UT WOS:000259173400013 PM 18755591 ER PT J AU Melman, A Wang, B Joshi, BV Gao, ZG de Castro, S Heller, CL Kim, SK Jeong, LS Jacobson, KA AF Melman, Artem Wang, Ben Joshi, Bhalchandra V. Gao, Zhan-Guo de Castro, Sonia Heller, Cara L. Kim, Soo-Kyung Jeong, Lak Shin Jacobson, Kenneth A. TI Selective A(3) adenosine receptor antagonists derived from nucleosides containing a bicyclo[3.1.0]hexane ring system SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE G protein-coupled receptor; purines; molecular modeling; structure-activity relationship; radioligand binding; adenylate cyclase ID A(3) ADENOSINE RECEPTOR; MOUSE INTRAOCULAR-PRESSURE; HIGHLY POTENT; RAT-BRAIN; AGONISTS; DERIVATIVES; BINDING; LIGANDS; ACTIVATION; AGENTS AB We have prepared 5 '-modified derivatives of adenosine and a corresponding (N)-methanocarba nucleoside series containing a bicyclo[3.1.0] hexane ring system in place of the ribose moiety. The compounds were examined in binding assays at three subtypes of adenosine receptors (ARs) and in functional assays at the A(3)AR. The H-bonding ability of a group of 9-riboside derivatives containing a 5 '-uronamide moiety was reduced by modi. cation of the NH; however these derivatives did not display the desired activity as selective A(3)AR antagonists, as occurs with 5 '-N,N-dimethyluronamides. However, truncated (N)-methanocarba analogues lacking a 4 '-hydroxymethyl group were highly potent and selective antagonists of the human A(3) AR. The compounds were synthesized from D-ribose using a reductive free radical decarboxylation of a 5 '-carboxy intermediate. A less efficient synthetic approach began with L-ribose, which was similar to the published synthesis of (N)-methanocarba A(3)AR agonists. Compounds 33b-39b (N(6)-3-halobenzyl and related arylalkyl derivatives) were potent A(3)AR antagonists with binding K(i) values of 0.7-1.4 nM. In a functional assay of [(35)S] GTP gamma S binding, 33b (3-iodobenzyl) completely inhibited stimulation by NECA with a K(B) of 8.9 nM. Thus, a highly potent and selective series of A(3)AR antagonists has been described. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Melman, Artem; Wang, Ben; Joshi, Bhalchandra V.; Gao, Zhan-Guo; de Castro, Sonia; Heller, Cara L.; Kim, Soo-Kyung; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Jeong, Lak Shin] Ewha Womans Univ, Coll Pharm, Med Chem Lab, Seoul 120750, South Korea. [Kim, Soo-Kyung] CALTECH, Beckman Inst, Mat & Proc Simulat Ctr, Pasadena, CA 91125 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bldg 8A,Room B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI de castro, sonia/E-7303-2012; Jacobson, Kenneth/A-1530-2009 OI de castro, sonia/0000-0002-3838-6856; Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural Research Program of the NIH; National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Dr. John Lloyd and Dr. Noel Whittaker (NIDDK) for mass spectral determinations. This research was supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 26 TC 31 Z9 31 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD SEP 15 PY 2008 VL 16 IS 18 BP 8546 EP 8556 DI 10.1016/j.bmc.2008.08.007 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 347WY UT WOS:000259173400026 PM 18752961 ER PT J AU Romagnoli, R Baraldi, PG Carrion, MD Cruz-Lopez, O Cara, CL Tolomeo, M Grimaudo, S Di Cristina, A Pipitone, MR Balzarini, J Kandil, S Brancale, A Sarkar, T Hamel, E AF Romagnoli, Romeo Baraldi, Pier Giovanni Carrion, Maria Dora Cruz-Lopez, Olga Cara, Carlota Lopez Tolomeo, Manlio Grimaudo, Stefania Di Cristina, Antonietta Pipitone, Maria Rosa Balzarini, Jan Kandil, Sahar Brancale, Andrea Sarkar, Taradas Hamel, Ernest TI Synthesis and biological evaluation of 2-amino-3-(3 ',4 ',5 '-trimethoxybenzoyl)-6-substituted-4,5,6,7-tetrahydrothieno[2,3-c]pyridi ne derivatives as antimitotic agents and inhibitors of tubulin polymerization SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE microtubules; combretastatin-A4; tubulin polymerization; 4,5,6,7-tetrahydrothieno[b]pyridine; colchicine ID MICROTUBULE DYNAMICS; COLCHICINE; COMBRETASTATIN-A-4; ANALOGS; GROWTH AB Microtubules are among the most successful targets of compounds potentially useful for cancer therapy. A new series of inhibitors of tubulin polymerization based on the 2-amino-3-(3,4,5-trimethoxybenzoyl)-4,5,6,7-tetrahydrothieno[b]pyridine molecular skeleton was synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell cycle effects. The most promising compound in this series was 2-amino-3-(3,4,5-trimethoxybenzoyl)-6-methoxycarbonyl-4,5,6,7-tetrahydrothieno[b]pyridine, which inhibits cancer cell growth with IC50-values ranging from 25 to 90 nM against a panel of four cancer cell lines, and interacts strongly with tubulin by binding to the colchicine site. In this series of N-6-carbamate derivatives, any further increase in the length and in the size of the alkyl chain resulted in reduced activity. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Romagnoli, Romeo; Baraldi, Pier Giovanni; Carrion, Maria Dora; Cruz-Lopez, Olga; Cara, Carlota Lopez] Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. [Tolomeo, Manlio] Univ Palermo, Policlin P Giaccone, Dipartimento Oncol, AIDS Serv, Palermo, Italy. [Tolomeo, Manlio] Univ Palermo, Ctr Interdipartimentale Ric Oncol CIROC, Palermo, Italy. [Grimaudo, Stefania; Di Cristina, Antonietta; Pipitone, Maria Rosa] Univ Palermo, Dipartimento Biomed Med Interna & Specialist, Palermo, Italy. [Balzarini, Jan] Rega Inst, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. [Kandil, Sahar; Brancale, Andrea] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3XF, S Glam, Wales. [Sarkar, Taradas; Hamel, Ernest] NCI, Toxicol & Pharmacol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,NIH, Frederick, MD 21702 USA. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, Via Fossato Mortara 17-19, I-44100 Ferrara, Italy. EM rmr@unife.it; baraldi@unife.it RI antonietta, di cristina/I-9251-2012; Brancale, Andrea/N-9445-2014; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Carrion, M. Dora/G-8638-2015; Romagnoli, Romeo/G-9887-2015; Kandil, Sahar/L-2458-2015; Baraldi, Pier Giovanni/B-7933-2017; Cruz-Lopez, Olga /F-3060-2017; OI Brancale, Andrea/0000-0002-9728-3419; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; Carrion, M. Dora/0000-0002-6794-3949; Kandil, Sahar/0000-0003-1806-9623; PIPITONE, Rosaria Maria/0000-0002-6721-3962; Grimaudo, Stefania/0000-0003-3225-4112 FU Intramural NIH HHS [Z99 CA999999] NR 18 TC 19 Z9 20 U1 0 U2 0 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 SEP 15 PY 2008 VL 18 IS 18 BP 5041 EP 5045 DI 10.1016/j.bmcl.2008.08.006 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 347NX UT WOS:000259149400027 PM 18725179 ER PT J AU Edrington, TC Bennett, M Albert, AD AF Edrington, Thomas C. Bennett, Michael Albert, Arlene D. TI Calorimetric studies of bovine rod outer segment disk membranes support a monomeric unit for both rhodopsin and opsin SO BIOPHYSICAL JOURNAL LA English DT Article ID PROTEIN-COUPLED RECEPTOR; DIFFERENTIAL SCANNING CALORIMETRY; HALOBACTERIUM-HALOBIUM; THERMAL-DENATURATION; ACTIVATION; DIMERS; OLIGOMERIZATION; AGGREGATION; CHOLESTEROL; TRANSITIONS AB The photoreceptor rhodopsin is a G-protein coupled receptor that has recently been proposed to exist as a dimer or higher order oligomer, in contrast to the previously described monomer, in retinal rod outer segment disk membranes. Rhodopsin exhibits considerably greater thermal stability than opsin (the bleached form of the receptor), which is reflected in an similar to 15 degrees C difference in the thermal denaturation temperatures (T(m)) of rhodopsin and opsin as measured by differential scanning calorimetry. Here we use differential scanning calorimetry to investigate the effect of partial bleaching of disk membranes on the T(m) of rhodopsin and of opsin in native disk membranes, as well as in cross-linked disk membranes in which rhodopsin dimers are known to be present. The T(m)s of rhodopsin and opsin are expected to be perturbed if mixed oligomers are present. The T(m) remained constant for rhodopsin and opsin in native disks regardless of the level of bleaching. In contrast, the T(m) of cross-linked rhodopsin in disk membranes was dependent on the extent of bleaching. The energy of activation for denaturation of rhodopsin and cross-linked rhodopsin was calculated. Cross-linking rhodopsin significantly decreased the energy of activation. We conclude that in native disk membranes, rhodopsin behaves predominantly as a monomer. C1 [Edrington, Thomas C.; Albert, Arlene D.] Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT 06250 USA. [Bennett, Michael] NIAAA, Sect Fluorescence Studies, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Albert, AD (reprint author), Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT 06250 USA. EM arlene.albert@uconn.edu NR 41 TC 10 Z9 12 U1 0 U2 4 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 SEP 15 PY 2008 VL 95 IS 6 BP 2859 EP 2866 DI 10.1529/biophysj.108.128868 PG 8 WC Biophysics SC Biophysics GA 343BI UT WOS:000258826900023 PM 18586850 ER PT J AU Fang, J Sakata, T Marriott, G Iwasa, KH AF Fang, Jie Sakata, Tomoyo Marriott, Gerard Iwasa, Kuni H. TI Probing conformational changes of prestin with thiol-reactive optical switches SO BIOPHYSICAL JOURNAL LA English DT Article ID OUTER HAIR CELL; MEMBRANE MOTOR; PIEZOELECTRIC MODEL; PROTEIN; MOTILITY; ELECTROMOTILITY; CAPACITANCE; INHIBITION AB Thiol-reactive optical switch probes were used to examine conformational changes of prestin-based membrane motor. Because this motor is based on mechanoelectric coupling similar to piezoelectricity, the motile activity can be monitored by charge movements across the plasma membrane, which appears as nonlinear capacitance. When the plasma membrane is conjugated with the probes, optically induced spiro-merocyanine transition positively shifted nonlinear capacitance of outer hair cells and prestin-transfected cells by similar to 10 mV. These shifts were reversible and were eliminated by pretreatment with iodoacetamide. However, they were little affected by pretreatment with biotin maleimide, which cannot reach the cytoplasmic surface. Our results showed that merocyanine states, with a larger dipole moment, interact with the motor's extended conformation stronger than with the compact conformation by 1.6 X 10(-21) J/molecule. The interaction sites are near the cytoplasmic side of the motor protein. C1 [Fang, Jie; Iwasa, Kuni H.] Natl Inst Deafness & Other Commun Disorders, Biophys Sect, Lab Cellular Biol, NIH, Rockville, MD USA. [Sakata, Tomoyo; Marriott, Gerard] Univ Wisconsin, Dept Physiol, Madison, WI 53706 USA. RP Iwasa, KH (reprint author), Natl Inst Deafness & Other Commun Disorders, Biophys Sect, Lab Cellular Biol, NIH, Rockville, MD USA. EM iwasa@nih.gov OI Iwasa, Kuni/0000-0002-9397-7704 FU National Institute on Deafness and Other Communication Disorders, National Institutes of Health; National Institutes of Health [R01EB005217] FX This work is supported by the Intramural Research Program of the National Institute on Deafness and Other Communication Disorders, National Institutes of Health and by grant R01EB005217 to G. M. from the National Institutes of Health. NR 25 TC 4 Z9 4 U1 0 U2 3 PU BIOPHYSICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD SEP 15 PY 2008 VL 95 IS 6 BP 3036 EP 3042 DI 10.1529/biophysj.108.132878 PG 7 WC Biophysics SC Biophysics GA 343BI UT WOS:000258826900039 PM 18556757 ER PT J AU Landgren, O Goldin, LR Kristinsson, SY Helgadottir, EA Samuelsson, J Bjorkholm, M AF Landgren, Ola Goldin, Lynn R. Kristinsson, Sigurdur Y. Helgadottir, Elin A. Samuelsson, Jan Bjorkholm, Magnus TI Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24 577 first-degree relatives of 11 039 patients with myeloproliferative neoplasms in Sweden SO BLOOD LA English DT Article ID JAK2V617F MUTATION; PROGNOSTIC-FACTORS; GENETIC EVENT; DISORDERS; DIAGNOSIS; DISEASE; JAK2; CLASSIFICATION; SECONDARY; CRITERIA AB Previous small studies have reported familial clustering of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). We identified 6217 PV, 2838 ET, 1172 MF, and 812 MPN unclassifiable (NOS) patients diagnosed in Sweden, 43 550 controls, and first-degree relatives of cases (n = 24 577) and controls (n = 99 542). Using a marginal survival model, we calculated relative risks (RRs) and 95% confidence intervals as measures of familial aggregation. Relatives of MPN patients had significantly increased risks of PV (RR = 5.7; 3.5-9.1), ET (RR = 7.4; 3.7-14.8), and MPN NOS (RR = 7.5; 2.7-20.8). Analyses stratified by type of first-degree relative revealed consistently higher risks for siblings, compatible with a model of recessive genetic inheritance, which can be confirmed only by identifying the susceptibility gene(s). Mean age at MPN diagnosis was not different (P = .20) for affected relatives of cases (57.5 years) versus controls (60.6 years), and risk of MPN by age was not different for parents versus offspring of MPN cases (P=.10), providing no support for anticipation. Relatives of MPN patients had a borderline increased risk of chronic myeloid leukemia (CML; RR = 1.9; 0.9-3.8; P=.09). Our findings of 5-to 7-fold elevated risk of MPNs among first-degree relatives of MPN patients support the hypothesis that common, strong, shared susceptibility genes predispose to PV, ET, MF, and possibly CML. C1 [Landgren, Ola] Natl Canc Inst, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Landgren, Ola; Kristinsson, Sigurdur Y.; Helgadottir, Elin A.; Bjorkholm, Magnus] Karolinska Univ Hosp & Inst, Div Hematol, Dept Med, Stockholm, Sweden. [Samuelsson, Jan] Stockholm S Hosp, Dept Med, Stockholm, Sweden. [Bjorkholm, Magnus] Swedish Myeloproliferat Disorder Study Grp, Stockholm, Sweden. RP Landgren, O (reprint author), Natl Canc Inst, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Executive Blvd,Bldg EPS,Room 7110, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov RI Kristinsson, Sigurdur /M-2910-2015 OI Kristinsson, Sigurdur /0000-0002-4964-7476 FU Swedish Cancer Society; Stockholm County Council; Karolinska Institutet Foundations; Intramural Research Program of the National Institutes of Health; National Cancer Institute FX The authors thank Ms Shiva Ayobi (National Board of Health and Welfare, Stockholm, Sweden), Ms Susanne Dahllof (Statistics Sweden, Orebro, Sweden) and Ms Emily Steplowski (Information Management Services, Silver Spring, MD), for important efforts in the development of this database.; This work was supported by grants from the Swedish Cancer Society, Stockholm County Council, the Karolinska Institutet Foundations, and the Intramural Research Program of the National Institutes of Health, National Cancer Institute. NR 25 TC 110 Z9 118 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2008 VL 112 IS 6 BP 2199 EP 2204 DI 10.1182/blood-2008-03-143602 PG 6 WC Hematology SC Hematology GA 346RX UT WOS:000259088000013 PM 18451307 ER PT J AU Matsushita, K Margulies, I Onda, M Nagata, S Stetler-Stevenson, M Kreitman, RJ AF Matsushita, Kakushi Margulies, Inger Onda, Masanori Nagata, Satoshi Stetler-Stevenson, Maryalice Kreitman, Robert J. TI Soluble CD22 as a tumor marker for hairy cell leukemia SO BLOOD LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; NON-HODGKINS-LYMPHOMA; IMMUNOTOXIN RFB4(DSFV)-PE38 BL22; POLYMERASE-CHAIN-REACTION; MINIMAL RESIDUAL DISEASE; RECOMBINANT IMMUNOTOXIN; PHASE-I; PROGNOSTIC-SIGNIFICANCE; CLINICAL-SIGNIFICANCE; SIGNAL-TRANSDUCTION AB CD22 is an important immunotherapeutic target on B-cell malignancies, particularly hairy cell leukemia (HCL), but its soluble extracellular domain, sCD22, has not yet been reported in the blood. By immunoaffinity and enzyme-linked immunosorbent assay techniques using anti-CD22 monoclonal antibodies, we identified the 100-kDa extracellular domain of CD22 and an 80-kDa processed form in serum of patients with HCL. The median sCD22 level measured by enzyme-linked immunosorbent assay was 18 ng/mL for 93 patients with HCL. sCD22 levels varied from 2.1 to 163 ng/mL and were higher (P <.001) than 23 normal donors (median, 0.6 ng/mL). More than 95% of normal donors had sCD22 levels less than 1.9 ng/mL. sCD22 levels were proportional to concentrations of circulating HCL cells (P =.002), and HCL spleen size ( P <.001). sCD22 levels normalized with complete but not partial response to treatment. sCD22 levels up to 300 ng/mL had less than a 2-fold effect on the cytotoxicity of the anti-CD22 recombinant immunotoxin BL22. sCD22 levels may be useful to follow in patients with HCL and may be more specific than sCD25 in patients with CD22(+)/CD25(-) disease. Trials are listed on www.cancer.gov as NCT00002765, NCT00021983, NCT00074048, NCT00085085, NCT00337311, and NCT00462189. C1 [Matsushita, Kakushi; Margulies, Inger; Onda, Masanori; Nagata, Satoshi; Kreitman, Robert J.] NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20854 USA. [Stetler-Stevenson, Maryalice] NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20854 USA. RP Kreitman, RJ (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37,Room 5124b,9000 Rockville Pike, Bethesda, MD 20854 USA. EM kreitmar@mail.nih.gov FU NCI, National Institutes of Health (NIH) FX The authors thank Dr David Waters at SAIC, Frederick for stocking and sending samples, Dr Milton Taylor at Indiana University for providing the HCL line Eskol, Dr Mitchell Ho and Richard Beers for providing some of the sCD22-Fc used as standard, nurses Karen Bergeron, Kelly Cahill, Rita Mincemoyer, Linda Ellison, and Elizabeth Maestri and patient care coordinator Sonya Duke for arranging samples from patients, Barbara Debrah for managing the data, Drs Wyndham Wilson, John Janik, John Morris, Jeff White, and Thomas Waldmann for referring patients with T-cell malignancies, and Drs Ira Pastan and Wyndham Wilson for helpful discussions regarding the project.; This work was supported by the intramural research program of the NCI, National Institutes of Health (NIH). NR 50 TC 14 Z9 15 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 SEP 15 PY 2008 VL 112 IS 6 BP 2272 EP 2277 DI 10.1182/blood-2008-01-131987 PG 6 WC Hematology SC Hematology GA 346RX UT WOS:000259088000021 PM 18596230 ER PT J AU Enose-Akahata, Y Oh, U Grant, C Jacobson, S AF Enose-Akahata, Yoshimi Oh, Unsong Grant, Christian Jacobson, Steven TI Retrovirally induced CTL degranulation mediated by IL-15 expression and infection of mononuclear phagocytes in patients with HTLV-I-associated neurologic disease SO BLOOD LA English DT Article ID VIRUS TYPE-I; T-CELL LEUKEMIA; TROPICAL SPASTIC PARAPARESIS; KAPPA-B SITE; PERIPHERAL-BLOOD; PROVIRAL LOAD; GENE-EXPRESSION; TAX PROTEIN; CEREBROSPINAL-FLUID; HAM/TSP PATIENTS AB CD8(+) T cells contribute to central nervous system inflammation in human T-cell lymphotropic virus type I (HTLV-I) associated myelopathy/tropical spastic paraparesis (HAM/TSP). We analyzed CD8(+) T- cell dysfunction (degranulation and IFN-gamma production) and have demonstrated that CD8(+) T cells of patients with HAM/TSP (HAM/TSP patients) spontaneously degranulate and express IFN-gamma in ex vivo unstimulated culture. CD8(+) T cells of HTLV-I asymptomatic carriers and healthy donors did not. Spontaneous degranulation was detected in Tax11-19/HLA-A*201 tetramer(+) cells, but not in CMV pp65 tetramer(+) cells. Interestingly, degranulation and IFN-gamma production in CD8(+) T cells was induced by coculture with autologous CD14(+) cells, but not CD4(+) T cells, of HAM/TSP patients, which correlated with proviral DNA load in CD14(+) cells of infected patients. Moreover, the expression of IL-15, which induced degranulation and IFN-gamma production in infected patients, was enhanced on surface of CD14(+) cells in HAM/TSP patients. Blockade of MHC class I and IL-15 confirmed these results. Thus, CD8(+) T- cell dysregulation was mediated by both virus infection and enhanced IL-15 on CD14(+) cells in HAM/TSP patients. Despite lower viral expression than in CD4(+) T cells, HTLV-I-infected or -activated CD14(+) cells may be a heretofore important but under recognized reservoir particularly in HAM/TSP patients. C1 [Enose-Akahata, Yoshimi; Oh, Unsong; Grant, Christian; Jacobson, Steven] Natl Inst Neurol Disorders & Stroke, Viral Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. RP Jacobson, S (reprint author), Natl Inst Neurol Disorders & Stroke, Viral Immunol Sect, Neuroimmunol Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 5C-103, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov FU Intramural Research Program of the NINDS; NIH FX We thank Dr Y. Tanaka (University of the Ryukyus, Okinawa, Japan) for kindly providing us with anti-Tax monoclonal antibody (Lt-4).; This research was supported by the Intramural Research Program of the NINDS, NIH. NR 73 TC 17 Z9 17 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 15 PY 2008 VL 112 IS 6 BP 2400 EP 2410 DI 10.1182/blood-2008-02-138529 PG 11 WC Hematology SC Hematology GA 346RX UT WOS:000259088000035 PM 18509087 ER PT J AU Stuelten, CH Barbul, A Busch, JI Sutton, E Katz, R Sato, M Wakefield, LM Roberts, AB Niederhuber, JE AF Stuelten, Christina H. Barbul, Adrian Busch, Johanna I. Sutton, Emily Katz, Ryan Sato, Misako Wakefield, Lalage M. Roberts, Anita B. Niederhuber, John E. TI Acute wounds accelerate tumorigenesis by a T cell-dependent mechanism SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-BETA; BREAST-CANCER; TGF-BETA; TUMOR; PROGRESSION; RECURRENCE; MODEL; MICE AB We investigated the influence of acute wounding on tumor growth in a syngeneic mouse breast cancer model. Metastatic mouse breast cancer cells (4T1) were orthotopically injected into the mammary fat pads of BALB/c mice, and animals were wounded locally by full thickness dermal incisions above the mammary fat pads or remotely above the scapula 9 days later. Local, but not remote, wounding increased tumor size when compared with sham treatment. Injection of wound fluid close to the tumor site increased tumor growth, whereas in vitro wound fluid compared with serum increased the proliferation rate of 4T1 cells. Our results show that wound stroma can unfavorably influence growth of nearby tumors. This effect is T cell-dependent, as local wounding had no effect on tumor growth in nu/nu mice. The effect of wounding on tumor growth can be mimicked by acellular wound fluid, suggesting that T cells secrete or mediate secretion of cytokines or growth factors that then accelerate tumor growth. Here, we define an experimental model of wound-promoted tumor growth that will enable us to identify mechanisms and therapeutic targets to reduce the negative effect of tissue repair on residual tumors. C1 [Stuelten, Christina H.; Busch, Johanna I.; Sutton, Emily; Niederhuber, John E.] NCI, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. [Stuelten, Christina H.; Sato, Misako; Wakefield, Lalage M.; Roberts, Anita B.] NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Barbul, Adrian; Katz, Ryan] Sinai Hosp, Dept Surg, Baltimore, MD 21215 USA. [Barbul, Adrian; Katz, Ryan] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RP Stuelten, CH (reprint author), NCI, Cell & Canc Biol Branch, 37 Convent Dr, Bethesda, MD 20892 USA. EM chrisstu@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 20 TC 24 Z9 26 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 15 PY 2008 VL 68 IS 18 BP 7278 EP 7282 DI 10.1158/0008-5472.CAN-08-1842 PG 5 WC Oncology SC Oncology GA 351KE UT WOS:000259422400007 PM 18794114 ER PT J AU Kwon, M Hanna, E Lorang, D He, M Quick, JS Adem, A Stevenson, C Chung, JY Hewitt, SM Zudaire, E Esposito, D Cuttitta, F Libutti, SK AF Kwon, Mijung Hanna, Engy Lorang, Dominique He, Mei Quick, John S. Adem, Asha Stevenson, Christina Chung, Joon-Yong Hewitt, Stephen M. Zudaire, Enrique Esposito, Dominic Cuttitta, Frank Libutti, Steven K. TI Functional characterization of filamin A interacting protein 1-like, a novel candidate for antivascular cancer therapy SO CANCER RESEARCH LA English DT Article ID ACTIVATING POLYPEPTIDE-II; ENDOTHELIAL-CELL ADHESION; GENE-EXPRESSION CHANGES; TUMOR-DERIVED CYTOKINE; ACTIN; ENDOSTATIN; ANGIOGENESIS; GROWTH; MIGRATION; MECHANISMS AB Inhibiting angiogenesis has become a major therapeutic strategy for cancer treatment. To identify common intracellular mediators, we previously analyzed gene expression profiles of endothelial cells after treatment with angiogenesis inhibitors. Filamin A interacting protein 1-like (FILIPIL; previously known as down-regulated in ovarian concert) was identified as one of the genes up-regulated in endothelial cells in response to these inhibitors. However, the expression and function of FILIPIL protein is uncharacterized. Here, we provide the first description of the expression and specific subcellular localization of FILIPIL protein in human tissue. Overexpression of FILIPIL resulted in inhibition of cell proliferation and migration and increased apoptosis. In addition, overexpression of FILIPIL truncation mutants showed differential antiproliferative activity. A COOH terminal truncation mutant (FILIP1L Delta C103) was more potent than wild-type FILIPIL in mediating this activity. Targeted expression of FILIP1L Delta C103 in tumor vasculature inhibited tumor growth in vivo. Overall, these findings suggest that the novel protein FILIPIL may be an important mediator of the effects of angiogenesis inhibitors and that FILIPIL, has the potential to be an antivascular reagent for cancer therapy. C1 [Kwon, Mijung; Hanna, Engy; Lorang, Dominique; He, Mei; Quick, John S.; Adem, Asha; Stevenson, Christina; Libutti, Steven K.] NCI, Tumor Angiogenesis Sect, Surg Branch, NIH, Bethesda, MD 20892 USA. [Chung, Joon-Yong; Hewitt, Stephen M.] NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Zudaire, Enrique; Cuttitta, Frank] NCI, Angiogenesis Core Facil, NIH, Bethesda, MD 20892 USA. [Esposito, Dominic] NCI, Prot Express Lab, Adv Technol Program, Sci Applicat Int Corp,Frederick Inc, Frederick, MD 21701 USA. RP Libutti, SK (reprint author), NCI, Tumor Angiogenesis Sect, Surg Branch, NIH, Room 4W-5940,Bldg 10,10 Ctr Dr, Bethesda, MD 20892 USA. EM libuttis@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788; Chung, Joon-Yong/0000-0001-5041-5982 FU NIH; National Cancer Institute; Center for Cancer Research FX Intramural Research Program of NIH, National Cancer Institute, Center for Cancer Research. NR 50 TC 24 Z9 28 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 SEP 15 PY 2008 VL 68 IS 18 BP 7332 EP 7341 DI 10.1158/0008-5472.CAN-08-1087 PG 10 WC Oncology SC Oncology GA 351KE UT WOS:000259422400013 PM 18794120 ER PT J AU Yeung, AT Patel, BB Li, XM Seeholzer, SH Coudry, RA Cooper, HS Bellacosa, A Boman, BM Zhang, T Litwin, S Ross, EA Conrad, P Crowell, JA Kopelovich, L Knudson, A AF Yeung, Anthony T. Patel, Bhavinkumar B. Li, Xin-Ming Seeholzer, Steven H. Coudry, Renata A. Cooper, Harry S. Bellacosa, Alfonso Boman, Bruce M. Zhang, Tao Litwin, Samuel Ross, Eric A. Conrad, Peggy Crowell, James A. Kopelovich, Levy Knudson, Alfred TI One-hit effects in cancer: Altered proteome of morphologically normal colon crypts in Familial Adenomatous Polyposis SO CANCER RESEARCH LA English DT Article ID HERITABLE COLORECTAL-CANCER; CULTURED SKIN FIBROBLASTS; GENE-EXPRESSION; TUMOR-SUPPRESSOR; CLUSTER-ANALYSIS; APOPTOSIS; ACTIN; IDENTIFICATION; CYTOKERATINS; ORGANIZATION AB We studied patients with Familial Adenomatous Polyposis (FAP) because they are virtually certain to develop colon cancer, and because much is known about the causative APC gene. We hypothesized that the inherited heterozygous mutation itself leads to changes in the proteome of morphologically normal crypts and the proteins that changed may represent targets for preventive and therapeutic agents. We determined the differential protein expression of morphologically normal colon crypts of FAP patients versus those of individuals without the mutation, using two-dimensional gel electrophoresis, mass spectrometry, and validation by two-dimensional gel Western blotting. Approximately 13% of 1,695 identified proteins were abnormally expressed in the morphologically normal crypts of APC mutation carriers, indicating that a colon crypt cell under the one-hit state is already abnormal. Many of the expression changes affect pathways consistent with the function of the APC protein, including apoptosis, cell adhesion, cell motility, cytoskeletal organization and biogenesis, mitosis, transcription, and oxidative stress response. Thus, heterozygosity for a mutant APC tumor suppressor gene alters the proteome of normal-appearing crypt cells in a gene-specific manner, consistent with a detectable one-hit event. These changes may represent the earliest biomarkers of colorectal cancer development, potentially leading to the identification of molecular targets for cancer prevention. C1 [Yeung, Anthony T.; Patel, Bhavinkumar B.; Li, Xin-Ming; Seeholzer, Steven H.] Fox Chase Canc Ctr, Div Basic Sci, Philadelphia, PA 19111 USA. [Coudry, Renata A.; Cooper, Harry S.] Fox Chase Canc Ctr, Div Med Sci, Philadelphia, PA 19111 USA. [Bellacosa, Alfonso; Litwin, Samuel; Ross, Eric A.; Knudson, Alfred] Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. [Boman, Bruce M.; Zhang, Tao] Thomas Jefferson Univ, Div Genet & Prevent Med, Philadelphia, PA 19107 USA. [Conrad, Peggy] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Crowell, James A.; Kopelovich, Levy] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Yeung, AT (reprint author), Fox Chase Canc Ctr, Div Basic Sci, Room R404,333 Cottman Ave, Philadelphia, PA 19111 USA. EM AT_Yeung@fccc.edu FU National Cancer Institute [NO1-CN-15103, N01-CN-43309]; Institutional Core Grant [P30CA006927, CA119242]; Ewing Trust; Rippel Foundation; Sholler Foundation; Tobacco Settlement Funds from the Commonwealth of Pennsylvania; Pew Charitable Trust; Kresge Foundation; [DK063014] FX National Cancer Institute, Contracts No. NO1-CN-15103 (A. Knudson) and N01-CN-43309, Grant, DK063014 (B. Boman), Institutional Core Grant P30CA006927, CA119242 and the Ewing Trust (A. Yeung), the Fannie E. Rippel Foundation, The Sholler Foundation, Tobacco Settlement Funds from the Commonwealth of Pennsylvania, the Pew Charitable Trust, and the Kresge Foundation. NR 37 TC 26 Z9 26 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 SEP 15 PY 2008 VL 68 IS 18 BP 7579 EP 7586 DI 10.1158/0008-5472.CAN-08-0856 PG 8 WC Oncology SC Oncology GA 351KE UT WOS:000259422400040 PM 18794146 ER PT J AU Rao, CV Swamy, MV Patlolla, JMR Kopelovich, L AF Rao, Chinthalapally V. Swamy, Malisetty V. Patlolla, Jagan M. R. Kopelovich, Levy TI Suppression of familial adenomatous polyposis by CP-31398, a TP53 modulator, in APC(min/+) mice SO CANCER RESEARCH LA English DT Article ID HUMAN CANCER-CELLS; WILD-TYPE P53; MUTANT P53; INTESTINAL ADENOMAS; MOUSE MODEL; DNA-BINDING; IN-VIVO; CHEMOPREVENTION; RESTORATION; RESCUE AB p53 mutations occur in a large number of human malignancies. Mutant p53 is unable to affect downstream genes necessary for DNA repair, cell cycle regulation, and apoptosis. The styrylquinazoline CP-31398 can rescue destabilized mutant p53 expression and promote activity of wild-type p53. The present study examines chemopreventive effects of CP-31398 on intestinal adenoma development in an animal model of familial adenomatous polyposis. Effects were examined at both early and late stages of adenoma formation. Effects of CP-31398 on early-stage adenomas were determined by feeding 7-week-old female C57BL/6J-APC(min) (heterozygous) and wild-type C57BL/6J mice with American Institute of Nutrition-76A diets containing 0, 100, or 200 ppm of CP31398 for 75 days. To examine activity toward late-stage adenomas, CP-31398 administration was delayed until 15 weeks of age and continued for 50 days. During early-stage intervention, dietary CP-31398 suppressed development of intestinal tumors by 36% (P < 0.001) and 75% (P < 0.0001), at low and high dose, respectively. During late-stage intervention, CP-31398 also significantly suppressed intestinal polyp formation, albeit to a lesser extent than observed with early intervention. Adenomas in treated mice showed increased apoptotic cell death and decreased proliferation in conjunction with increased expression of p53, p21(WAFI/CIP), cleaved caspase-3, and cleaved poly(ADP-ribose) polymerase. These observations show for the first time that the p53-modulating agent CP-31398 possesses significant chemopreventive activity in vivo against intestinal neoplastic lesions in genetically predisposed APC(min/+) mice. Chemopreventive activity of other agents that restore tumor suppressor functions of mutant p53 in tumor cells is currently under investigation. C1 [Rao, Chinthalapally V.; Swamy, Malisetty V.; Patlolla, Jagan M. R.] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Hem Onc Sect,Canc Inst, Oklahoma City, OK 73104 USA. [Kopelovich, Levy] NCI, Canc Prevent Div, Chemoprevent Agent Dev Res Grp, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Med, Hem Onc Sect,Canc Inst, Oklahoma City, OK 73104 USA. EM cv-rao@ouhsc.edu RI Chinthalapally, Rao/B-3633-2010 FU National Cancer Institute [NCI-CA-94962, NO1-CN-25114] FX National Cancer Institute grants NCI-CA-94962 and NO1-CN-25114. NR 39 TC 28 Z9 28 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 SEP 15 PY 2008 VL 68 IS 18 BP 7670 EP 7675 DI 10.1158/0008-5472.CAN-08-1610 PG 6 WC Oncology SC Oncology GA 351KE UT WOS:000259422400050 PM 18794156 ER PT J AU Mantel, CR Wang, RH Deng, CX Broxmeyer, HE AF Mantel, Charlie R. Wang, Rui-Hong Deng, Chuxia Broxmeyer, Hal E. TI Sirt1, notch and stem cell "age asymmetry" SO CELL CYCLE LA English DT Article DE Sirt1; stem cell; aging; notch; HES1; Nanog; asymmetry ID HEMATOPOIETIC PROGENITOR CELLS; LIFE-SPAN EXTENSION; LOW OXYGEN-TENSION; HUMAN-BONE-MARROW; CALORIE RESTRICTION; TRANSCRIPTIONAL REPRESSION; NANOG EXPRESSION; COLONY FORMATION; SONIC-HEDGEHOG; CORD BLOOD AB Almost all complex multicellular organisms on earth utilize oxygen for the production of energy. This strategy carries the risk for damaging ROS to be generated and so these biochemical pathways must be highly regulated. Because of this, regulation of oxidative-phosphorylation is tightly coordinated with every aspect of cellular physiology, including stem cell regulation during embryonic development and in adult organisms. The protein-deacetylase, SIRT1, has received much attention because of its roles in oxygen metabolism, cellular stress response, aging, and has been investigated in various species and cell types including embryonic stem cells. However, there is a dearth of information on SIRT1 in adult stem cells, which have a pivotal role in adult aging processes. Here, we discuss the potential relationships between SIRT1 and the surface receptor protein, Notch, with stem cell self-renewal, asymmetric cell division, signaling and stem cell aging. C1 [Mantel, Charlie R.; Broxmeyer, Hal E.] Indiana Univ, Sch Med, Walther Oncol Ctr, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Wang, Rui-Hong; Deng, Chuxia] NIDDK, Mammalian Genet Sect, GDDB, NIH, Bethesda, MD USA. RP Mantel, CR (reprint author), Indiana Univ, Sch Med, Walther Oncol Ctr, Dept Microbiol & Immunol, 950 W Walnut St,R2-302, Indianapolis, IN 46202 USA. EM cmantel@iupui.edu RI deng, chuxia/N-6713-2016 NR 61 TC 7 Z9 8 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD SEP 15 PY 2008 VL 7 IS 18 BP 2821 EP 2825 DI 10.4161/cc.7.18.6517 PG 5 WC Cell Biology SC Cell Biology GA 348JK UT WOS:000259206600011 PM 18797187 ER PT J AU Pashtan, I Tsutsumi, S Wang, SQ Xu, WP Neckers, L AF Pashtan, Itai Tsutsumi, Shinji Wang, Suiquan Xu, Wanping Neckers, Len TI Targeting Hsp90 prevents escape of breast cancer cells from tyrosine kinase inhibition SO CELL CYCLE LA English DT Article DE ErbB tyrosine kinase; Src; Hsp90; oncogene switching; molecularly-targeted drug development ID LUNG-CANCER; GEFITINIB; THERAPY; HEAT-SHOCK-PROTEIN-90; DEGRADATION; RESISTANCE; SURFACE AB Recent studies have identified development of resistance to tyrosine kinase inhibition (TKI) as a significant roadblock to effective treatment. One mechanism of resistance recently appreciated involves `oncogene switching', or the re-activation of signaling pathways by one or more redundant upstream activators. In breast cancer models, ErbB TKIs such as gefitinib have been shown to lose the ability to modulate ErbB-driven signaling pathways over time, even though ErbB inhibition is maintained. Although incomplete ErbB inhibition has been proposed to underlie this phenomenon, our findings suggest that oncogene switching can also re-activate downstream signaling pathways in breast cancer cells, even when ErbB inhibition is complete. We find that ErbB TKI-induced Src activation mediates downstream signaling rebound in SKBR3 cells, and we show that combination of Src and ErbB inhibitors is more effective and longlasting than is either TKI alone. Finally, the Hsp90 inhibitor 17-AAG, by simultaneously and durably inhibiting multiple signaling activators including ErbB and Src kinases, does not permit oncogene switching and results in a more prolonged and robust inhibition of downstream signaling pathways in breast cancer cells than do individual TKIs. These data support the continued clinical evaluation of Hsp90 inhibitors in breast cancer. C1 [Tsutsumi, Shinji; Wang, Suiquan; Xu, Wanping; Neckers, Len] NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Pashtan, Itai] NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bldg 10-CRC,Room 1-5940,9000 Rockville Pike, Bethesda, MD 20892 USA. EM len@helix.nih.gov FU Howard Hughes Medical Institute; Intramural NIH HHS [Z01 SC010074-12] NR 19 TC 18 Z9 18 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD SEP 15 PY 2008 VL 7 IS 18 BP 2936 EP 2941 DI 10.4161/cc.7.18.6701 PG 6 WC Cell Biology SC Cell Biology GA 348JK UT WOS:000259206600026 PM 18769157 ER PT J AU Hawk, ET Matrisian, LM Nelson, WG Dorfman, GS Stevens, L Kwok, J Viner, J Hautala, J Grad, O AF Hawk, Ernest T. Matrisian, Lynn M. Nelson, William G. Dorfman, Gary S. Stevens, Lisa Kwok, Jennifer Viner, Jaye Hautala, Judith Grad, Oren CA Translational Res Working Grp TI The translational research working group developmental pathways: Introduction and overview SO CLINICAL CANCER RESEARCH LA English DT Article AB The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of the National Cancer Institute's investment in translational research and envision its future in an inclusive, representative, and transparent manner. To clarify the challenges facing translational research and facilitate its deliberations, the TRWG conceptualized translational research as a set of developmental processes or pathways focused on various clinical goals. Drawing on the collective knowledge of the TRWG members, six pathways were derived, with two addressing the development of tools designed to characterize an individual's cancer-related health status (biospecimen-based and image-based assessment modalities) and four addressing the development of interventions intended to change cancer-related health status (drugs or biological agents, immune response modifiers, interventive devices, and life-style alterations). The pathways, which share a number of common structural elements, are graphically represented by schematic flowcharts that capture relevant contingencies, decision points, and interdependencies. They are conceived not as comprehensive descriptions of the corresponding real-world processes but as tools designed to serve specific purposes including research program management and research project management, coordination of research efforts, and professional and lay education and communication. Further development of the pathways is encouraged, as is application of the pathway concept to translational research on other diseases. C1 [Hawk, Ernest T.; Viner, Jaye] NCI, Off Ctr Training & Resources, Rockville, MD USA. [Matrisian, Lynn M.] Vanderbilt Univ, Nashville, TN USA. [Nelson, William G.] Johns Hopkins Univ, Baltimore, MD USA. [Dorfman, Gary S.] Weill Cornell Med Coll, New York, NY USA. [Stevens, Lisa; Kwok, Jennifer] NCI, Off Sci Planning & Assessment, Bethesda, MD 20892 USA. [Hautala, Judith] Inst Sci & Technol Policy, Washington, DC USA. [Grad, Oren] Inst Sci & Technol Policy, Wellesley, MA USA. RP Hawk, ET (reprint author), Univ Texas MD Anderson Canc Ctr, Div Canc Prevent & Populat Sci, Unit 1370, POB 301439, Houston, TX 77230 USA. EM ehawk@mdanderson.org NR 8 TC 17 Z9 17 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 SEP 15 PY 2008 VL 14 IS 18 BP 5664 EP 5671 DI 10.1158/1078-0432.CCR-08-1268 PG 8 WC Oncology SC Oncology GA 350JC UT WOS:000259347600006 PM 18612047 ER PT J AU Srivastava, S Gray, JW Reid, BJ Grad, O Greenwood, A Hawk, ET AF Srivastava, Sudhir Gray, Joe W. Reid, Brian J. Grad, Oren Greenwood, Addison Hawk, Ernest T. CA Translational Res Working Grp TI Translational research working group developmental pathway for biospecimen-based assessment modalities SO CLINICAL CANCER RESEARCH LA English DT Article ID UROTHELIAL CARCINOMA; BREAST-CANCER; HYBRIDIZATION; OPINION; ASSAY AB The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of National Cancer Institute's investment in translational research and envision its future. The TRWG conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of biospecimen-based assays that use biomarkers for the detection, diagnosis, and prognosis of cancer and the assessment of response to cancer treatment. The biospecimen-based assessment modality pathway was conceived not as comprehensive description of the corresponding real-world processes but rather as a tool designed to facilitate movement of a candidate assay through the translational process to the point where it can be handed off for definitive clinical testing. This paper introduces the pathway in the context of prior work and discusses key challenges associated with the biomarker development process in light of the pathway. C1 [Srivastava, Sudhir] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. [Gray, Joe W.] Univ Calif Berkeley, Lawrence Berkeley Lab, Berkeley, CA 94720 USA. [Reid, Brian J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Grad, Oren] Inst Sci & Technol Policy, Wellesley, MA USA. [Greenwood, Addison] NCI, Off Commun, Bethesda, MD 20892 USA. [Hawk, Ernest T.] NCI, Off Ctr Training & Resources, Bethesda, MD 20892 USA. RP Hawk, ET (reprint author), Univ Texas MD Anderson Canc Ctr, Div Canc Prevent & Populat Sci, Unit 1370, POB 301439, Houston, TX 77230 USA. EM ehawk@mdanderson.org FU NCI NIH HHS [P50 CA 58207, P50 CA058207, U54 CA112970, U54 CA112970-04] NR 11 TC 17 Z9 18 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2008 VL 14 IS 18 BP 5672 EP 5677 DI 10.1158/1078-0432.CCR-08-1267 PG 6 WC Oncology SC Oncology GA 350JC UT WOS:000259347600007 PM 18794074 ER PT J AU Cheever, MA Schlom, J Weiner, LM Lyerly, HK Disis, ML Greenwood, A Grad, O Nelson, WG AF Cheever, Martin A. Schlom, Jeffrey Weiner, Louis M. Lyerly, H. Kim Disis, Mary L. Greenwood, Addison Grad, Oren Nelson, William G. CA Translational Res Working Grp TI Translational research working group developmental pathway for immune response modifiers SO CLINICAL CANCER RESEARCH LA English DT Article ID HER-2/NEU PROTEIN; CANCER; CHEMOTHERAPY; VACCINES; IMMUNOTHERAPY; THERAPY; GENERATION; BREAST; L1210; MICE AB The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of the investment of National Cancer Institute in translational research and envision its future. The Translational Research Working Group conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of immune response modifiers such as vaccines and cytokines. A hallmark of the Immune Response Modifier Developmental Pathway is the coordinated development of multiple components. The Immune Response Modifier Pathway was conceived not as a comprehensive description of the corresponding real-world processes but rather as a tool designed to facilitate movement of a candidate assay through the translational process to the point where it can be handed off for definitive clinical testing. This paper discusses key challenges associated with the immune response modifier agent development process in light of the pathway. C1 [Nelson, William G.] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. [Cheever, Martin A.; Disis, Mary L.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Schlom, Jeffrey] NCI, Ctr Canc Res, Bethesda, MD 20892 USA. [Greenwood, Addison] NCI, Off Commun, Bethesda, MD 20892 USA. [Weiner, Louis M.] Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC USA. [Lyerly, H. Kim] Duke Univ, Durham, NC USA. [Grad, Oren] Inst Sci & Technol Policy, Wellesley, MA USA. RP Nelson, WG (reprint author), Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, 1650 Orleans St,CRB 116, Baltimore, MD 21231 USA. EM bnelson@jhmi.edu RI Lyerly, Herbert/B-6528-2014 OI Lyerly, Herbert/0000-0002-0063-4770 NR 20 TC 16 Z9 16 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2008 VL 14 IS 18 BP 5692 EP 5699 DI 10.1158/1078-0432.CCR-08-1266 PG 8 WC Oncology SC Oncology GA 350JC UT WOS:000259347600010 PM 18794077 ER PT J AU Hawk, ET Greenwood, A Gritz, ER McTiernan, A Sellers, T Hursting, SD Leischow, S Grad, O AF Hawk, Ernest T. Greenwood, Addison Gritz, Ellen R. McTiernan, Anne Sellers, Thomas Hursting, Stephen D. Leischow, Scott Grad, Oren CA Translational Res Working Grp TI The translational research working group developmental pathway for lifestyle alterations SO CLINICAL CANCER RESEARCH LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; 12-MONTH EXERCISE INTERVENTION; POSTMENOPAUSAL WOMEN; CLINICAL-TRIAL; CIGARETTE-SMOKING; SERUM COTININE; CANCER; EPIDEMIOLOGY; PREVENTION; NUTRITION AB The Translational Research Working Group (TRWG) was created as a national initiative to evaluate the current status of National Cancer Institute's investment in translational research and envision its future. The TRWG conceptualized translational research as a set of six developmental processes or pathways focused on various clinical goals. One of those pathways describes the development of lifestyle alterations, which can, variously, be recommended to prevent cancer, modify a patient's adherence and response to cancer treatment, ameliorate side effects of cancer treatments, or improve prognosis and quality of life in cancer patients and survivors. The lifestyle alteration pathway was conceived not as a comprehensive description of the corresponding real-world processes, but rather as a tool designed to facilitate movement of a candidate lifestyle alteration through the translational process up to the point where it could be handed off for definitive testing, when appropriate. This article discusses key issues associated with the development of lifestyle alterations in light of the pathway. C1 [Hawk, Ernest T.; Greenwood, Addison] NCI, Bethesda, MD 20892 USA. [McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Sellers, Thomas] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Leischow, Scott] Univ Arizona, Arizona Canc Ctr, Tucson, AZ USA. [Grad, Oren] Inst Sci & Technol Policy, Wellesley, MA USA. [Hawk, Ernest T.] Univ Texas MD Anderson Canc Ctr, Div Canc Prevent & Populat Sci, Houston, TX 77230 USA. RP Hawk, ET (reprint author), Univ Texas MD Anderson Canc Ctr, Div Canc Prevent & Populat Sci, Unit 1370,POB 301439, Houston, TX 77230 USA. EM ehawk@mdanderson.org NR 20 TC 3 Z9 6 U1 1 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 SEP 15 PY 2008 VL 14 IS 18 BP 5707 EP 5713 DI 10.1158/1078-0432.CCR-08-1262 PG 7 WC Oncology SC Oncology GA 350JC UT WOS:000259347600012 PM 18794079 ER PT J AU van Cruijsen, H van der Veldt, AAM Vroling, L Oosterhoff, D Broxterman, HJ Scheper, RJ Giaccone, G Haanen, JBAG van den Eertwegh, AJM Boven, E Hoekman, K de Gruijl, TD AF van Cruijsen, Hester van der Veldt, Astrid A. M. Vroling, Laura Oosterhoff, Dinja Broxterman, Henk J. Scheper, Rik J. Giaccone, Giuseppe Haanen, John B. A. G. van den Eertwegh, Alfons J. M. Boven, Epie Hoekman, Klaas de Gruijl, Tanja D. TI Sunitinib-induced myeloid lineage redistribution in renal cell cancer patients: CD1c(+) dendritic cell frequency predicts progression-free survival SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TYROSINE KINASE INHIBITOR; IN-VIVO; T-CELL; HYDROGEN-PEROXIDE; PERIPHERAL-BLOOD; INTERFERON-ALPHA; FACTOR RECEPTOR; BREAST-CANCER; LUNG-CANCER AB Purpose: A disturbed myeloid lineage development with abnormally abundant neutrophils and impaired dendritic cell (DC) differentiation may contribute to tumor immune escape. We investigated the effect of sunitinib, a tyrosine kinase inhibitor of fms-like tyrosine kinase-3, KIT and vascular endothelial growth factor receptors, on myeloid differentiation in renal cell cancer (RCC) patients. Experimental Design: Twenty-six advanced RCC patients were treated with sunitinib in a 4-week on/2-week off schedule. Enumeration and extensive phenotyping of myeloid subsets in the blood was done at baseline and at weeks 4 and 6 of the first treatment cycle. Baseline patient data were compared with sex- and age-matched healthy donor data. Results: Baseline frequencies of DC subsets were lower in RCC patients than in healthy donors. After 4 weeks of sunitinib treatment, a generalized decrease in myeloid frequencies was observed. Whereas neutrophils and monocytes, which were both abnormally high at baseline, remained low during the 2-week off period, DC rates recovered, resulting in a normalized myeloid lineage distribution. Subsequent to sunitinib treatment, an increase to high levels of myeloid DC (MDC) subset frequencies relative to other myeloid subsets, was specifically observed in patients experiencing tumor regression. Moreover, high CD1c/BDCA-1(+) MDC frequencies were predictive for tumor regression and improved progression-free survival. Conclusion: The sunitinib-induced myeloid lineage redistribution observed in advanced RCC patients is consistent with an improved immune status. Immunologic recovery may contribute to clinical efficacy as suggested by the finding of highly increased MDC frequencies relative to other myeloid subsets in patients with tumor regression. C1 [van Cruijsen, Hester; van der Veldt, Astrid A. M.; Vroling, Laura; Oosterhoff, Dinja; Broxterman, Henk J.; Giaccone, Giuseppe; van den Eertwegh, Alfons J. M.; Boven, Epie; Hoekman, Klaas; de Gruijl, Tanja D.] Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, NL-1081 HV Amsterdam, Netherlands. [Scheper, Rik J.] Vrije Univ Amsterdam Med Ctr, Dept Pathol, NL-1081 HV Amsterdam, Netherlands. [Haanen, John B. A. G.] Antoni Van Leeuwenhoek Hosp, Netherlands Canc Inst, Dept Immunol, Amsterdam, Netherlands. [Giaccone, Giuseppe] NCI, Med Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. RP de Gruijl, TD (reprint author), Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, De Boelelaan 1117, NL-1081 HV Amsterdam, Netherlands. EM td.degruijl@vumc.nl RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 FU European Union (FP6) Integrated [504743]; Netherlands Organization for Scientific Research [917-56-32] FX European Union (FP6) Integrated project "Angiotargeting" (contract no.504743) and by the Netherlands Organization for Scientific Research (NWO VIDI grant 917-56-32). NR 42 TC 79 Z9 79 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2008 VL 14 IS 18 BP 5884 EP 5892 DI 10.1158/1078-0432.CCR-08-0656 PG 9 WC Oncology SC Oncology GA 350JC UT WOS:000259347600034 PM 18794101 ER PT J AU Yang, SX Steinberg, SM Nguyen, D Wu, TD Modrusan, Z Swain, SM AF Yang, Sherry X. Steinberg, Seth M. Nguyen, Dat Wu, Thomas D. Modrusan, Zora Swain, Sandra M. TI Gene expression profile and angiogenic marker correlates with response to neoadjuvant bevacizumab followed by bevacizumab plus chemotherapy in breast cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MICROVESSEL DENSITY; TUMOR ANGIOGENESIS; CARCINOMA; DOCETAXEL; ERLOTINIB AB Purpose: To identify biomarkers and gene expression profile signatures to distinguish patients. with partial response (PR) from those with stable disease (SD) and progressive disease (PD). Experimental Design: Twenty patients with inflammatory breast cancer and one patient with locally advanced breast cancer received one cycle of bevacizumab followed by six cycles of bevacizumab plus docetaxel-doxorubicin before surgery. Baseline angiogenic/tumor markers were examined by immunohistochemistry and gene expression profiles were measured by Agilent Whole Human Genome arrays. All were assessed for clinical response. Results: Fourteen patients (67%, 95% confidence interval, 43-85.4%) had PR, five had SD, and two had PD. Expression of CD31 and platelet-derived growth factor receptor-beta (PDGM-beta) in the tumor vasculature by immunohistochemistry was significantly associated with response (PR versus SD/PD; CD31 median, 33.5 versus 13.2; P = 0.0004; PDGFR-beta median, 5.9 versus 0.6; P = 0.01). Tumor VEGF-A showed a trend towards association with response (2.65 versus 0.25; P = 0.04). pVEGFR2(Y996), pVEGFR2(Y951), MVD, Ki67, apoptosis, grade, ER, HER-2/neu, and p53 were not associated with response. Twenty-six of 1,339 Gene Ontology (GO) classes at the gene transcriptional level were differentially expressed between patients with PR and SD/PD (P < 0.005). Representative significant GO classes include spindle (11 genes; P = 0.001), vascular endothelial growth factor receptor activity including PDGFR-beta (5 genes; P = 0.002), and cell motility including CD31 (80 genes; P = 0.005). Conclusions: Baseline CD31, PDGFR-beta, and GO classes for vascular endothelial growth factor receptor activity and mitosis were significantly associated with response to bevacizumab followed by bevacizumab plus chemotherapy. C1 [Swain, Sandra M.] Washington Hosp Ctr, Washington Canc Inst, Washington, DC 20001 USA. [Yang, Sherry X.; Nguyen, Dat] NCI, Natl Clin Target Validat Lab, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. [Steinberg, Seth M.] NCI, Biostat & Data Management Sect, Ctr Canc Res, Bethesda, MD 20892 USA. [Wu, Thomas D.; Modrusan, Zora] Genentech Inc, Dept Mol Biol & Bioinformat, San Francisco, CA 94080 USA. RP Swain, SM (reprint author), Washington Hosp Ctr, Washington Canc Inst, 110 Irving St NW, Washington, DC 20001 USA. EM xy32m@nih.gov OI Swain, Sandra/0000-0002-1320-3830 FU Intramural Research Program; Cancer Research, National Cancer Institute, NIH FX Intramural Research Program, Center for Cancer Research, National Cancer Institute, NIH. NR 21 TC 56 Z9 58 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD SEP 15 PY 2008 VL 14 IS 18 BP 5893 EP 5899 DI 10.1158/1078-0432.CCR-07-4762 PG 7 WC Oncology SC Oncology GA 350JC UT WOS:000259347600035 PM 18794102 ER PT J AU Sutcliffe, CG Scott, S Mugala, N Ndhlovu, Z Monze, M Quinn, TC Cousens, S Griffin, DE Moss, WJ AF Sutcliffe, Catherine G. Scott, Susana Mugala, Nanthalile Ndhlovu, Zaza Monze, Mwaka Quinn, Thomas C. Cousens, Simon Griffin, Diane E. Moss, William J. TI Survival from 9 months of age among HIV-infected and uninfected Zambian children prior to the availability of antiretroviral therapy SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID AFRICAN CHILDREN; MORTALITY; DISEASE; MOTHERS; COHORT; BORN; CARE AB Background. Few prospective studies have measured survival rates among human immunodeficiency virus (HIV)-infected children in sub-Saharan Africa prior to the availability of antiretroviral therapy. Methods. In the context of an observational study of the immunogenicity of measles vaccine in Zambia, we prospectively followed up children from approximately 9 months of age and assessed survival rates, risk factors for mortality, and circumstances at the time of death according to HIV-infection or HIV-exposure status. Results. There were 56 deaths among 492 study children during follow-up to 3 years of age. Thirty-nine percent of the 105 children with HIV infection died during the study period, compared with 5.0% of the 260 HIV-seropositive but uninfected children and 1.6% of the 127 HIV-seronegative children. Estimated survival probabilities from 9 through 36 months of age were 52% among HIV-infected children, 95% among initially HIV-seropositive but uninfected children, and 98% among HIV-seronegative children. In multivariable analyses, history of a clinic visit within the 4 weeks prior to study entry (adjusted hazard ratio, 4.6; 95% confidence interval, 1.5-13.5), hemoglobin level <8 g/dL at study entry (adjusted hazard ratio, 4.4; 95% confidence interval, 1.5-12.6), land CD4(+) T lymphocyte percentage <15% at study entry (adjusted hazard ratio, 3.2; 95% confidence interval, 1.1-9.5) were associated with mortality among HIV-infected children. Conclusions. Only approximately one-half of HIV-infected Zambian children who were alive at 9 months of age survived to 3 years of age, supporting the urgent need for the prevention of mother-to-child transmission of HIV and the early diagnosis and treatment of HIV infection in children in sub-Saharan Africa. C1 [Sutcliffe, Catherine G.; Moss, William J.] Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21218 USA. [Ndhlovu, Zaza; Griffin, Diane E.; Moss, William J.] Johns Hopkins Univ, W Harry Feinstone Dept Mol Microbiol & Immunol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Div Infect Dis, Baltimore, MD 21205 USA. [Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. [Scott, Susana; Cousens, Simon] London Sch Hyg & Trop Med, London WC1, England. [Mugala, Nanthalile; Monze, Mwaka] Univ Teaching Hosp, Virol Lab, Lusaka, Zambia. RP Moss, WJ (reprint author), Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, 615 N Wolfe St, Baltimore, MD 21218 USA. EM wmoss@jhsph.edu FU Wellcome Trust-Burroughs Fund Infectious Disease Initiative [GR059114MA]; National Institutes of Health [AI23047]; Canadian Institutes of Health Research; Division of Intramural Research; National Institute of Allergy and Infectious Diseases FX We thank the children and their parents for participation in the study and the clinical officers and nurses who assisted with the study.; Financial support. Wellcome Trust-Burroughs Fund Infectious Disease Initiative (GR059114MA) and the National Institutes of Health (AI23047). C.G.S. was supported by a Doctoral Research Award in the Area of HIV/AIDS Research from the Canadian Institutes of Health Research. T.C.Q. was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.; Potential conflicts of interest. All authors: no conflicts. NR 17 TC 23 Z9 23 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD SEP 15 PY 2008 VL 47 IS 6 BP 837 EP 844 DI 10.1086/591203 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 339IH UT WOS:000258570800018 PM 18680417 ER PT J AU Hwang, J Mehrani, T Millar, SE Morasso, MI AF Hwang, Joonsung Mehrani, Taraneh Millar, Sarah E. Morasso, Maria I. TI Dlx3 is a crucial regulator of hair follicle differentiation and cycling SO DEVELOPMENT LA English DT Article DE dlx3; hair cycle; homeobox; mouse ID MULTIPOTENT STEM-CELLS; HOMEOBOX GENE DLX3; BETA-CATENIN; ECTODERMAL DYSPLASIAS; SIGNALING PATHWAYS; SKIN; EXPRESSION; MORPHOGENESIS; GROWTH; INDUCTION AB Dlx homeobox transcription factors regulate epidermal, neural and osteogenic cellular differentiation. Here, we demonstrate the central role of Dlx3 as a crucial transcriptional regulator of hair formation and regeneration. The selective ablation of Dlx3 in the epidermis results in complete alopecia owing to failure of the hair shaft and inner root sheath to form, which is caused by the abnormal differentiation of the cortex. Significantly, we elucidate the regulatory cascade that positions Dlx3 downstream of Wnt signaling and as an upstream regulator of other transcription factors that regulate hair follicle differentiation, such as Hoxc13 and Gata3. Colocalization of phospho-Smad1/5/8 and Dlx3 is consistent with a regulatory role for BMP signaling to Dlx3 during hair morphogenesis. Importantly, mutant catagen follicles undergo delayed regression and display persistent proliferation. Moreover, ablation of Dlx3 expression in the telogen bulge stem cells is associated with a loss of BMP signaling, precluding re-initiation of the hair follicle growth cycle. Taken together with hair follicle abnormalities in humans with Tricho-Dento-Osseous (TDO) syndrome, an autosomal dominant ectodermal dysplasia linked to mutations in the DLX3 gene, our results establish that Dlx3 is essential for hair morphogenesis, differentiation and cycling programs. C1 [Hwang, Joonsung; Mehrani, Taraneh; Morasso, Maria I.] NIAMS, Dev Skin Biol Unit, NIH, Bethesda, MD 20892 USA. [Millar, Sarah E.] Univ Penn, Sch Med, Dept Dermatol & Cell & Dev Biol, Philadelphia, PA 19104 USA. RP Morasso, MI (reprint author), NIAMS, Dev Skin Biol Unit, NIH, Bethesda, MD 20892 USA. EM morassom@mail.nih.gov FU National Institute of Arthritis and Musculoskeletal and Skin Diseases; NIH FX We are grateful to Drs P. Coulombe, T. T. Sun, L. Langbein and J. Schweizer for providing antibodies; and to Dr M. Mahoney, D. Brennan and Dr C. C. Thompson for technical advice. We thank Dr S. Yuspa and members of the LCBG, NCI for helpful discussions and suggestions; Drs K. Zaal and E. Ralston of the NIAMS Light Imaging; and Dr T. Sargent for comments on the manuscript. We are very grateful to Dr A. Grinberg for assistance on early stages of the mouse work, and to C. Rivera and Y. Rivera for technical support. This work was supported by the Intramural Research Program of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. NR 64 TC 55 Z9 65 U1 0 U2 10 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 SEP 15 PY 2008 VL 135 IS 18 BP 3149 EP 3159 DI 10.1242/dev.022202 PG 11 WC Developmental Biology SC Developmental Biology GA 341OW UT WOS:000258724800017 PM 18684741 ER PT J AU Stadler, K Bonini, MG Dallas, S Jiang, JJ Radi, R Mason, RP Kadiiska, MB AF Stadler, Krisztian Bonini, Marcelo G. Dallas, Shannon Jiang, JinJie Radi, Rafael Mason, Ronald P. Kadiiska, Maria B. TI Involvement of inducible nitric oxide synthase in hydroxyl radical-mediated lipid peroxidation in streptozotocin-induced diabetes SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE diabetes; peroxynitrite; iNOS; lipid peroxidation; EPR spectroscopy ID POLY(ADP-RIBOSE) POLYMERASE ACTIVATION; PEROXYNITRITE DECOMPOSITION CATALYST; OXIDATIVE-NITROSATIVE STRESS; IN-VIVO; ENDOTHELIAL DYSFUNCTION; INSULIN-RESISTANCE; CARBON-DIOXIDE; COMPLICATIONS; INHIBITION; CELLS AB Free radical production is implicated in the pathogenesis of diabetes mellitus, where several pathways and different mechanisms were suggested in the pathophysiology of the complications. In this study, we used electron paramagnetic resonance (EPR) spectroscopy combined with in vivo spin-trapping techniques to investigate the sources and mechanisms of free radical formation in streptozotocin-induced diabetic rats. Free radical production was directly detected in the diabetic bile, which correlated with lipid peroxidation in the liver and kidney. EPR spectra showed the trapping of a lipid-derived radical. Such radicals were demonstrated to be induced by hydroxyl radical through isotope-labeling experiments. Multiple enzymes and metabolic pathways were examined as the potential Source of the hydroxyl radicals using specific inhibitors. No xanthine oxidase, cytochrome P450s, the Fenton reaction, OF macrophage activation were required for the production Of radical adducts. Interestingly, inducible nitric oxide synthase (NOS) (apparently uncoupled) was identified as the major source of radical generation. The specific NOS inhibitor 1400W as well as L-arginine pretreatment reduced the EPR signals to baseline levels, implicating peroxynitrite as the source of hydroxyl radical production. Applying immunological techniques, we localized iNOS overexpression in the liver and kidney of diabetic animals, which was closely correlated with the lipid radical generation and 4-hydroxynonenal-adducted protein formation, indicating lipid peroxidation. In addition, protein tyrosine nitration occurred in the diabetic target organs. Taken together, our studies support inducible nitric oxide synthase as a significant source of EPR-detectable reactive intermediates, which leads to lipid peroxidation and may contribute to disease progression as well. Published by Elsevier Inc. C1 [Stadler, Krisztian; Bonini, Marcelo G.; Dallas, Shannon; Jiang, JinJie; Mason, Ronald P.; Kadiiska, Maria B.] NIEHS, NIH, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. [Radi, Rafael] Univ Republica, Fac Med, Ctr Free Rad & Biomed Res, Dept Bioquim, Montevideo 11800, Uruguay. RP Stadler, K (reprint author), NIEHS, NIH, Lab Pharmacol & Chem, POB 12233,MD F0-02, Res Triangle Pk, NC 27709 USA. EM stadlerk@niehs.nih.gov FU NIH; National Institute of Environmental Health Sciences; Howar Hughes Medical Institute; International Centre of Genetic Engineering and Biotechnology FX The authors thank Dr. David S. Miller and Dr. Kevin Gerrish for valuable advice, Natasha Clayton and Yvette Rebolloso for the outstanding immunohistochemical analysis, Jean B. Corbett for excellent technical assistance, and Dr. Ann Motten and Mary J. Mason for helpful comments made during the preparation of the manuscript. This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. RR was supported by Howar Hughes Medical Institute and International Centre of Genetic Engineering and Biotechnology. NR 58 TC 52 Z9 54 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD SEP 15 PY 2008 VL 45 IS 6 BP 866 EP 874 DI 10.1016/j.freeradbiomed.2008.06.023 PG 9 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 350MT UT WOS:000259357300016 PM 18620046 ER PT J AU Andia, ME Hsing, AW Andreotti, G Ferreccio, C AF Andia, Marcelo E. Hsing, Ann W. Andreotti, Gabriella Ferreccio, Catterina TI Geographic variation of gallbladder cancer mortality and risk factors in Chile: A population-based ecologic study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE gallbladder cancer; gallstones; Mapuche; typhoid; genetics ID BILIARY-TRACT CANCER; K-RAS; MICROSATELLITE INSTABILITY; ABORIGINAL POPULATIONS; SALMONELLA-TYPHI; GALLSTONES; CHINA; EPIDEMIOLOGY; SHANGHAI; CARCINOMA AB Chile's gallbladder cancer rates are among the highest in the world, being the leading cause of cancer deaths among Chilean women. To provide insights into the etiology of gallbladder cancer, we conducted an ecologic study examining the geographical variation of gallbladder cancer and several putative risk factors. The relative risk of dying from gallbladder cancer between 1985 and 2003 was estimated for each of the 333 Chilean counties, using a hierarchical Poisson regression model, adjusting for age, sex and geographical location. The risk of gallbladder cancer mortality was analyzed in relation to region, poverty, Amerindian (Mapuche) population, typhoid fever and access to cholecystectomy, using logistic regression analysis. There were 27,183 gallbladder cancer deaths, with age and sex-adjusted county mortality rates ranging from 8.2 to 12.4 per 100,000 inhabitants. Rates were highest in inland and southern regions. Compared to the northern-coast, the northern-inland region had a 10-fold risk (95% of confidence interval (95% CI): 2.4-42.2) and the southern-inland region had a 26-fold risk (95% CI: 6.0-114.2). Independent of region, other risk factors for gallbladder cancer included a high Mapuche population (Odds ratio (011):3.9, 95% CI 1.8-8.7), high typhoid fever incidence (011:2.9, 95% Cl 1.2-6.9), high poverty (011:5.1., 95% CI 1.6-15.9), low access to cholecystectomy (011:3.9, 95% CI 1.5-10.1), low access to hospital care (011:14.2, 95% C1 4.2-48.7) and high urbanization (011:8.0, 95% CI 3.4-18.7). Our results suggest that gallbladder cancer in Chile may be related to both genetic factors and poor living conditions. Future analytic studies are needed to further clarify the role of these factors in gallbladder cancer etiology. Published 2008 Wiley-Liss, Inc. C1 [Andia, Marcelo E.; Ferreccio, Catterina] Pontificia Univ Catolica Chile, Fac Med, Dept Salud Publ, Santiago, Chile. [Andia, Marcelo E.] Pontificia Univ Catolica Chile, Fac Med, Dept Radiol, Santiago, Chile. [Hsing, Ann W.; Andreotti, Gabriella] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Hsing, Ann W.] NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Ferreccio, C (reprint author), Pontificia Univ Catolica Chile, Fac Med, Dept Salud Publ, Alameda 340, Santiago, Chile. EM cferrec@med.puc.cl OI Andia, Marcelo/0000-0002-1251-5832 FU Intramural NIH HHS [ZIA CP010158-09] NR 42 TC 43 Z9 49 U1 1 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD SEP 15 PY 2008 VL 123 IS 6 BP 1411 EP 1416 DI 10.1002/ijc.23662 PG 6 WC Oncology SC Oncology GA 338BO UT WOS:000258480100025 PM 18566990 ER PT J AU Wang, H Katagiri, Y McCann, TE Unsworth, E Goldsmith, P Yu, ZX Tan, F Santiago, L Mills, EM Wang, Y Symes, AJ Geller, HM AF Wang, Hang Katagiri, Yasuhiro McCann, Thomas E. Unsworth, Edward Goldsmith, Paul Yu, Zu-Xi Tan, Fei Santiago, Lizzie Mills, Edward M. Wang, Yu Symes, Aviva J. Geller, Herbert M. TI Chondroitin-4-sulfation negatively regulates axonal guidance and growth SO JOURNAL OF CELL SCIENCE LA English DT Article DE chondroitin sulfate proteoglycan; sulfation; axonal guidance; axonal growth ID CHONDROITIN SULFATE PROTEOGLYCANS; SPINAL-CORD-INJURY; NEURITE OUTGROWTH; HEPARAN-SULFATE; NERVOUS-SYSTEM; REGENERATION; GLYCOSAMINOGLYCANS; ASTROCYTES; EXPRESSION; BRAIN AB Glycosaminoglycan (GAG) side chains endow extracellular matrix proteoglycans with diversity and complexity based upon the length, composition and charge distribution of the polysaccharide chain. Using cultured primary neurons, we show that specific sulfation in the GAG chains of chondroitin sulfate mediates neuronal guidance cues and axonal growth inhibition. Chondroitin-4-sulfate (CS-A), but not chondroitin-6-sulfate (CS-C), exhibits a strong negative guidance cue to mouse cerebellar granule neurons. Enzymatic and gene-based manipulations of 4-sulfation in the GAG side chains alter their ability to direct growing axons. Furthermore, 4-sulfated chondroitin sulfate GAG chains are rapidly and significantly increased in regions that do not support axonal regeneration proximal to spinal cord lesions in mice. Thus, our findings show that specific sulfation along the carbohydrate backbone carries instructions to regulate neuronal function. C1 [Wang, Hang; Katagiri, Yasuhiro; McCann, Thomas E.; Tan, Fei; Santiago, Lizzie; Geller, Herbert M.] NCI, Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. [Yu, Zu-Xi] NCI, NHLBI, NIH, Bethesda, MD 20892 USA. [Unsworth, Edward; Goldsmith, Paul] NCI, Basic Res Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Mills, Edward M.] Univ Texas Austin, Coll Pharm, Div Pharmacol Toxicol, Austin, TX 78712 USA. [Wang, Yu; Symes, Aviva J.] Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. RP Katagiri, Y (reprint author), NCI, Dev Neurobiol Sect, NIH, Bethesda, MD 20892 USA. EM katagir@helix.nih.gov RI Symes, Aviva/S-7471-2016; OI Symes, Aviva/0000-0003-2557-9939; Geller, Herbert/0000-0002-7048-6144 FU Intramural NIH HHS [Z99 HL999999] NR 50 TC 94 Z9 96 U1 1 U2 5 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 SEP 15 PY 2008 VL 121 IS 18 BP 3083 EP 3091 DI 10.1242/jcs.032649 PG 9 WC Cell Biology SC Cell Biology GA 343XL UT WOS:000258889400012 PM 18768934 ER PT J AU Wang, QJ Hanada, KI Yang, JC AF Wang, Qiong J. Hanada, Ken-ichi Yang, James C. TI Characterization of a novel nonclassical T cell clone with broad reactivity against human renal cell carcinomas SO JOURNAL OF IMMUNOLOGY LA English DT Article ID APOPTOSIS-INDUCING LIGAND; ANTITUMOR IMMUNITY; DENDRITIC CELLS; TUMOR; LYMPHOCYTES; CANCER; ANTIGEN; RECOGNITION; INNATE; IDENTIFICATION AB A CD4(+) T cell clone (HC/2G-1) was established by stimulating peripheral blood T cells from a patient with renal cell carcinoma (RCC) with dendritic cells preincubated with the autologous apoptotic renal tumor line in the presence of IFN-alpha. It recognizes the autologous RCC and most allogeneic RCC lines by IFN-gamma release (10 of 11 lines) and lysis (9 of 10 lines), but does not recognize multiple EBV B cells or fibroblasts. It shows little or no recognition of a panel of melanomas, breast cancers and non-small-cell lung cancers. Phenotypically, HC/2G-1 is CD3(+)CD4(+) TCR alpha beta(+), but CD161(-)CD16(-)NKG2D(-). Tumor recognition by clone HC/2G-1 was not blocked by Abs to HLA class I or class 11, but was significantly reduced by anti-TCR alpha beta Ab. Furthermore, tumor recognition was beta(2)-microglobulin-independent. HC/2G-1 does not use a V alpha or V beta described for classical NKT cells, but rather V alpha 14 and V beta 2.1. Allogeneic T cells cotransfected with mRNAs encoding the alpha and beta chains of the HC/2G-1 TCR recognized renal tumor lines, demonstrating that tumor recognition is TCR-mediated. Interestingly, TRAIL appears to play a role in tumor recognition by HC/2G-1 in that reactivity was blocked by anti-TRAIL Ab, and soluble TRAIL could enhance IFN-gamma secretion by HC/2G-1 in response to renal tumors. Our findings suggest that clone HC/2G-1 represents a novel type of CD4(+) cell that has broad TCR-mediated recognition of a determinant widely expressed by RCC. C1 [Wang, Qiong J.; Hanada, Ken-ichi; Yang, James C.] NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Yang, JC (reprint author), NCI, Surg Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Room 3W-3840, Bethesda, MD 20892 USA. EM James-Yang@nih.gov RI Hanada, Ken-ichi/L-2481-2013 OI Hanada, Ken-ichi/0000-0003-2959-1257 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 28 TC 9 Z9 11 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 SEP 15 PY 2008 VL 181 IS 6 BP 3769 EP 3776 PG 8 WC Immunology SC Immunology GA 349AE UT WOS:000259250400009 PM 18768829 ER PT J AU Yu, Q Quinn, WJ Salay, T Crowley, JE Cancro, MP Sen, JM AF Yu, Qing Quinn, William J., III Salay, Theresa Crowley, Jenni E. Cancro, Michael P. Sen, Jyoti Misra TI Role of beta-catenin in B cell development and function SO JOURNAL OF IMMUNOLOGY LA English DT Article ID BLIMP-1 EXPRESSION; PLASMA-CELLS; MICE; DIFFERENTIATION; LYMPHOPOIESIS; MATURATION; HEMATOPOIESIS; PROGENITORS; ACTIVATION; SELECTION AB beta-Catenin is a central mediator of Wnt signaling pathway, components of which have been implicated in B cell development and function. B cell progenitors and bone marrow stromal cells express Wnt ligands, Frizzled receptors and Wnt antagonists, suggesting fine tuned regulation of this pathway in B cell development. In particular, deletion of Frizzled 9 gene results in developmental defects at the pre-B stage of development and an accumulation of plasma cells. Furthermore, Writ signals regulate B cell proliferation through lymphocyte enhancer-binding factor-1. However, it is not known whether Wnt signaling in B cell development is mediated by beta-catenin and whether beta-catenin plays a role in mature B cell function. In this report, we show that mice bearing B cell-specific deletion of beta-catenin have normal B cell development in bone marrow and periphery. A modest defect in plasma cell generation in vitro was documented, which correlated with a defective expression of IRF-4 and Blimp-1. However, B cell response to T-dependent and T-independent Ags in vivo was found to be normal. Thus, beta-catenin expression was found to be dispensable for normal B cell development and function. C1 [Yu, Qing; Salay, Theresa; Sen, Jyoti Misra] NIA, NIH, Lymphocyte Dev Unit, Immunol Lab, Baltimore, MD 21224 USA. [Quinn, William J., III; Crowley, Jenni E.; Cancro, Michael P.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. RP Sen, JM (reprint author), NIA, NIH, Lymphocyte Dev Unit, Immunol Lab, 4B08 GRC Bldg,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Jyoti-Sen@nih.gov FU National Institute on Aging; Oak Ridge Institute for Science and Education's Research Associates FX We thank Dr. Robert Wersto, Francis J. Chrest, and Curing Nguyen for expert cell sorting of B cell subpopulations; Donna Tignor, Dawn Phillips, Dawn Nines. Anna Butler, Crystal Gifford, and Ernest Dabney for maintaining- animals: Dr. Shengyuan Luo and his team for genotyping animals; P. J. O'Neill and M. Z. Hossain for technical help; and members of our laboratories for support throughout the project. This research was supported by the Intramural Research Program of the National Institute on Aging at the National Institutes of Health and in part by an appointment to the Oak Ridge Institute for Science and Education's Research Associates Program at the National Institutes of Health. NR 25 TC 13 Z9 13 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 SEP 15 PY 2008 VL 181 IS 6 BP 3777 EP 3783 PG 7 WC Immunology SC Immunology GA 349AE UT WOS:000259250400010 PM 18768830 ER PT J AU Sly, LM Kalesnikoff, J Lam, V Wong, D Song, C Omeis, S Chan, K Lee, CWK Siraganian, RP Rivera, J Krystal, G AF Sly, Laura M. Kalesnikoff, Janet Lam, Vivian Wong, Dana Song, Christine Omeis, Stephanie Chan, Karen Lee, Corinna W. K. Siraganian, Reuben P. Rivera, Juan Krystal, Gerald TI IgE-induced mast cell survival requires the prolonged generation of reactive oxygen species SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FC-EPSILON-RI; IMMUNOGLOBULIN-E; MONOMERIC IGE; INDUCED DEGRANULATION; CYTOKINE PRODUCTION; MULTIPLE CYTOKINES; NADPH OXIDASES; NITRIC-OXIDE; STEEL FACTOR; ACTIVATION AB We show in this study that the ability of five different monomeric IgEs to enhance murine bone marrow-derived mast cell (BMMC) survival correlates with their ability to stimulate extracellular calcium (Ca2+) entry. However, whereas IgE+Ag more potently stimulates Ca2+ entry, it does not enhance survival under our conditions. Exploring this further, we found that whereas all five monomeric IgEs stimulate a less robust Ca2+ entry than IgE+Ag initially, they all trigger a more prolonged Ca2+ influx, generation of reactive oxygen species (ROS), and ERK phosphorylation. These prolonged signaling events correlate with their survival-enhancing ability and positively feedback on each other to generate the prosurvival cytokine, IL-3. Interestingly, the prolonged ERK phosphorylation induced by IgE appears to be regulated by a MAPK phosphatase rather than MEK. IgE-induced ROS generation, unlike that triggered by IgE+Ag, is not mediated by 5-lipoxygenase. Moreover, ROS inhibitors, which block both IgE-induced ROS production and C2+ influx, convert the prolonged ERK phosphorylation induced by IgE into the abbreviated phosphorylation pattern observed with IgE+Ag and prevent IL-3 generation. In support of the essential role that IgE-induced ROS plays in IgE-enhanced BMMC survival, we found the addition of H2O2 to IgE+Ag-stimulated BMMCs leads to IL-3 secretion. C1 [Sly, Laura M.; Lam, Vivian; Wong, Dana; Song, Christine; Omeis, Stephanie; Chan, Karen; Lee, Corinna W. K.; Krystal, Gerald] British Columbia Canc Agcy, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. [Kalesnikoff, Janet] Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. [Siraganian, Reuben P.] Natl Inst Dent & Craniofacial Res, Receptors & Signal Transduct Sect, Oral Infect & Immun Branch, Bethesda, MD 20892 USA. [Rivera, Juan] NIAMSD, Lab Immune Cell Signaling, NIH, Bethesda, MD 20892 USA. RP Krystal, G (reprint author), British Columbia Canc Res Ctr, 675 W 10th Ave, Vancouver, BC V5Z 1L3, Canada. EM gkrystal@bccrc.ca RI Chan, Karen/E-4041-2015 OI Chan, Karen/0000-0001-9947-4713 FU National Cancer Institute of Canada; British Columbia Cancer Foundation; British Columbia Cancer Agency; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Child Health and Human Development; National Institutes of Health FX This work was supported by the National Cancer Institute of Canada, with core support from the British Columbia Cancer Foundation and the British Columbia Cancer Agency. The work of J.R, and R.P.S. was supported by the intramural research programs of National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Institute of Child Health and Human Development, National Institutes of Health. NR 60 TC 25 Z9 25 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 SEP 15 PY 2008 VL 181 IS 6 BP 3850 EP 3860 PG 11 WC Immunology SC Immunology GA 349AE UT WOS:000259250400019 PM 18768839 ER PT J AU Bajenoff, M Glaichenhaus, N Germain, RN AF Bajenoff, Marc Glaichenhaus, Nicolas Germain, Ronald N. TI Fibroblastic reticular cells guide T lymphocyte entry into and migration within the splenic T cell zone SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HIGH ENDOTHELIAL VENULES; MARGINAL-ZONE; DENDRITIC CELLS; WHITE PULP; IN-VIVO; INTRAVITAL MICROSCOPY; MONOCLONAL-ANTIBODY; BRIDGING CHANNELS; NODE; MOTILITY AB Although a great deal is known about T cell entry into lymph nodes, much less is understood about how T lymphocytes access the splenic white pulp (WP). We show in this study that, as recently described for lymph nodes, fibroblastic reticular cells (FRCs) form a network in the T cell zone (periarteriolar lymphoid sheath, PALS) of the WP on which T lymphocytes migrate. This network connects the PALS to the marginal zone (MZ), which is the initial site of lymphocyte entry from the blood. T cells do not enter the WP at random locations but instead traffic to that site using the FRC-rich MZ bridging channels (MZBCs). These data reveal that FRCs form a substrate for T cells in the spleen, guiding these lymphocytes from their site of entry in the MZ into the PALS, within which they continue to move on the same network. C1 [Bajenoff, Marc; Germain, Ronald N.] NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Bajenoff, Marc; Glaichenhaus, Nicolas] Univ Nice Sophia Antipolis, INSERM, Valbonne, France. [Bajenoff, Marc] Univ Nice Sophia Antipolis, CNRS, Valbonne, France. RP Germain, RN (reprint author), NIAID, Lymphocyte Biol Sect, Immunol Lab, NIH, Bldg 10,Room 11N-311,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM rgermain@niaid.nih.gov FU Intramural Research Program of National Institute of Allergy and Infectious Diseases; National Institutes of Health; Department of Health and Human Services; Institut de la Sante et de la Recherche Medicale (INSERM); Centre National de la Recherche Scientifique (CNRS) FX This research was supported in part by the Intramural Research Program of National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, by the Institut de la Sante et de la Recherche Medicale (INSERM). and by the Centre National de la Recherche Scientifique (CNRS). NR 41 TC 95 Z9 98 U1 0 U2 8 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2008 VL 181 IS 6 BP 3947 EP 3954 PG 8 WC Immunology SC Immunology GA 349AE UT WOS:000259250400029 PM 18768849 ER PT J AU Guo, LY Urban, JF Zhu, JF Paul, WE AF Guo, Liying Urban, Joseph F. Zhu, Jinfang Paul, William E. TI Elevating calcium in Th2 cells activates multiple pathways to induce IL-4 transcription and mRNA stabilization SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROTEIN-KINASE; T-CELLS; C-REL; SIGNAL-TRANSDUCTION; GENE-EXPRESSION; MAP KINASES; P38; INVOLVEMENT; LYMPHOCYTES; APOPTOSIS AB PMA and ionomycin cause T cell cytokine production. We report that ionomycin alone induces IL-4 and IFN-gamma, but not IL-2, from in vivo- and in vitro-generated murine Th2 and Th1 cells. Ionomycin-induced cytokine production requires NFAT, p38, and calmodulin-dependent kinase IV (CaMKIV). Ionomycin induces p38 phosphorylation through a calcium-dependent, cyclosporine A-inhibitable pathway. Knocking down ASK1 inhibits ionomycin-induced p38 phosphorylation and IL-4 production. lonomycin also activates CaMKIV, which, together with p38, induces AP-1. Cooperation between AP-1 and NFAT leads to 114 gene transcription. p38 also regulates IL-4 production by mRNA stabilization. TCR stimulation also phosphorylates p38, partially through the calcium-dependent pathway; activated p38 is required for optimal IL-4 and IFN-gamma. C1 [Guo, Liying; Zhu, Jinfang; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Urban, Joseph F.] USDA ARS, Nutrient Requirements & Funct Lab, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. RP Guo, LY (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N322,10 Ctr Dr,MSC 1892, Bethesda, MD 20892 USA. EM lguo@niaid.nih.gov RI Zhu, Jinfang/B-7574-2012; OI Urban, Joseph/0000-0002-1590-8869 FU Intramural Research Program of the National Institutes of Health; National Institute of Allergy and Infections Diseases FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Allergy and Infections Diseases. NR 50 TC 23 Z9 23 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2008 VL 181 IS 6 BP 3984 EP 3993 PG 10 WC Immunology SC Immunology GA 349AE UT WOS:000259250400033 PM 18768853 ER PT J AU Kamperschroer, C Roberts, DM Zhang, YQ Weng, NP Swain, SL AF Kamperschroer, Cris Roberts, Deborah M. Zhang, Yongqing Weng, Nan-ping Swain, Susan L. TI SAP enables T cells to help B cells by a mechanism distinct from Th cell programming or CD40 ligand regulation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LINKED LYMPHOPROLIFERATIVE DISEASE; CXC CHEMOKINE RECEPTOR-5; HUMORAL IMMUNE-RESPONSES; MICE DEFICIENT; TERMINAL DIFFERENTIATION; CYTOKINE REGULATION; CUTTING EDGE; HYPER-IGM; SLAM; ICOS AB Genetic mutations disrupting the function of signaling lymphocytic activation molecule-associated protein (SAP) lead to T cell intrinsic defects in T cell-dependent Ab responses. To better understand how SAP enables Th cells to help B cells, we first assessed whether molecules important for B cell help are dystregulated in SAP-deficient (SAP knockout (KO)) mice. CD40 ligand (CD40L) expression was enhanced on unpolarized SAP KO T cells; however, Th2 polarization returned their CD40L expression to wildtype levels without rescuing their ability to help B cells. CD40L also localized normally to the site of contact between SAP KO T cells and Ag-bearing B cells. Finally, CD40L-deficient Th cells and SAP KO Th cells differed in their abilities to help B cells in vitro. These data argue that Ab defects caused by SAP deficiency do not result from a loss of CD40L regulation or CD40L, function on CD4 T cells. SAP KO Th cells additionally displayed normal patterns of migration and expression of ICOS and CXCR5. Global gene expression was remarkably similar in activated SAP KO vs wild-type T cells, prompting us to investigate whether SAP is necessary for "programming" T cells to become B cell helpers. By restricting SAP expression during differentiation, we determined that SAP is not required during the first 5 days of T cell activation/differentiation to generate Th cells capable of helping B cells. Instead, SAP is necessary for very late stages of differentiation or, most likely, for allowing Th cells to communicate during cognate T:B interactions. C1 [Kamperschroer, Cris; Roberts, Deborah M.; Swain, Susan L.] Trudeau Inst Inc, Saranac Lake, NY 12983 USA. [Zhang, Yongqing] NIA, DNA Array Unit, NIH, Baltimore, MD 21224 USA. [Weng, Nan-ping] NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. RP Kamperschroer, C (reprint author), Pfizer Inc, MS 8274-1406,Eastern Point Rd, Groton, CT 06340 USA. EM Cris.Kamperschroer@pfizer.com FU National Institutes of Health [AI22125-17, AI46530, AI066684-01]; Trudeau Institute.; Intramural Research Progrant of the National Institute on Aging; National Institutes of Health FX This work was Supported by National Institutes of Health Grants AI22125-17 (to S.L.S.), AI46530 (to S.L.S.). and AI066684-01 (to C.K.) and by the Trudeau Institute. K.G.B. and N.P.W. were supported by the Intramural Research Progrant of the National Institute on Aging, National Institutes of Health. NR 50 TC 25 Z9 25 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2008 VL 181 IS 6 BP 3994 EP 4003 PG 10 WC Immunology SC Immunology GA 349AE UT WOS:000259250400034 PM 18768854 ER PT J AU Dyer, KD Moser, JM Czapiga, M Siegel, SJ Percopo, CM Rosenberg, HF AF Dyer, Kimberly D. Moser, Jennifer M. Czapiga, Meggan Siegel, Steven J. Percopo, Caroline M. Rosenberg, Helene F. TI Functionally competent eosinophils differentiated ex vivo in high purity from normal mouse bone marrow SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; TUMOR-NECROSIS-FACTOR; GATA-3-TRANSGENIC MICE; PULMONARY EOSINOPHILIA; IMMUNE-RESPONSES; PROGENITOR CELLS; PNEUMONIA VIRUS; TNF-ALPHA; I RELEASE; INFECTION AB We have devised an ex vivo culture system which generates large numbers of eosinophils at high purity (>90%) from unselected mouse bone marrow progenitors. In response to 4 days of culture with recombinant mouse FLT3-L and recombinant mouse stern cell factor followed by recombinant mouse IL-5 alone thereafter, the resulting bone marrow-derived eosinophils (bmEos) express immunoreactive major basic protein, Siglec F, IL-511 alpha-chain, and transcripts encoding mouse eosinophil peroxidase, CCR3, the IL-3/IL-5/GM-CSF receptor common beta-chain, and the transcription factor GATA-1. BmEos are functionally competent: they undergo chemotaxis toward mouse eotaxin-1 and produce characteristic cytokines, including IFN-gamma, IL-4, MIP-1 alpha, and IL-6. The rodent pathogen pneumonia virus of mice replicates in bmEos and elevated levels of IL-6 are detected in supernatants of bmEos cultures in response to active infection. Finally, differentiating bmEos are readily transfected with lentiviral vectors, suggesting a means for rapid production of genetically manipulated cells. C1 [Dyer, Kimberly D.; Moser, Jennifer M.; Siegel, Steven J.; Percopo, Caroline M.; Rosenberg, Helene F.] NIAID, Eosinophil Biol Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Czapiga, Meggan] NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Dyer, KD (reprint author), NIAID, Eosinophil Biol Sect, Lab Allerg Dis, NIH, 10 Ctr Dr,MSC 1883,Bldg 10,Room 11C216, Bethesda, MD 20892 USA. EM kdyer@niaid.nih.gov FU NIAID Division of Intramural Research FX This work was funded by the NIAID Division of Intramural Research. NR 41 TC 111 Z9 112 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 15 PY 2008 VL 181 IS 6 BP 4004 EP 4009 PG 6 WC Immunology SC Immunology GA 349AE UT WOS:000259250400035 PM 18768855 ER PT J AU Read, SW Lempicki, RA Di Mascio, M Srinivasula, S Burke, R Sachau, W Bosche, M Adelsberger, JW Sereti, I Davey, RT Tavel, JA Huang, CY Issaq, HJ Fox, SD Lane, HC Kovacs, JA AF Read, Sarah W. Lempicki, Richard A. Di Mascio, Michele Srinivasula, Sharat Burke, Rosanne Sachau, William Bosche, Marjorie Adelsberger, Joseph W. Sereti, Irini Davey, Richard T., Jr. Tavel, Jorge A. Huang, Chiung-Yu Issaq, Haleem J. Fox, Stephen D. Lane, H. Clifford Kovacs, Joseph A. TI CD4 T cell survival after intermittent interleukin-2 therapy is predictive of an increase in the CD4 T cell count of HIV-infected patients SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 15th Conference on Retroviruses and Opportunistic Infections CY FEB 03-06, 2008 CL Boston, MA ID RANDOMIZED CONTROLLED-TRIAL; HUMAN-IMMUNODEFICIENCY-VIRUS; SUBCUTANEOUS INTERLEUKIN-2; ANTIRETROVIRAL THERAPY; LYMPHOCYTES; EXPANSION AB Administration of interleukin (IL)-2 to human immunodeficiency virus (HIV) -infected patients leads to significant increases in CD4 T cell counts. We previously have shown that IL-2 induces increased proliferation and survival of CD4 T cells. Deuterium labeling studies were undertaken to study the relationship between IL-2 induced increases in the CD4 Tcell count and the effects of IL-2 on cell proliferation and survival. A strong inverse correlation was noted between the rate of decay of the label in CD4 cells and increases in CD4 cell counts (R= -0.67; P<. 001). This correlation was not seen with the level of proliferating cells. Although the CD4 cell count at baseline and the number of CD4 cells expressing CD25 were also predictive of increases in the CD4 cell count, the rate of decay remained the most statistically significant predictor in multivariate regression models. Thus, an increase in the survival ofCD4T cells appears to be the critical mechanism leading to sustained increases in the CD4 cell counts of HIV-infected patients receiving intermittent IL-2 therapy. C1 [Read, Sarah W.] NIAID, Div Aids, Bethesda, MD 20892 USA. [Di Mascio, Michele; Huang, Chiung-Yu] NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. [Tavel, Jorge A.] NIAID, Div Clin Res, Bethesda, MD 20892 USA. [Burke, Rosanne; Sachau, William; Sereti, Irini; Davey, Richard T., Jr.; Lane, H. Clifford] NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. [Kovacs, Joseph A.] NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Srinivasula, Sharat] NCI, Biostat Res Branch, Frederick, MD 21701 USA. [Issaq, Haleem J.; Fox, Stephen D.] NCI, Adv Technol Program, Lab Prote & Analyt Technol, Frederick, MD 21701 USA. [Lempicki, Richard A.; Bosche, Marjorie; Adelsberger, Joseph W.] NCI, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Read, SW (reprint author), 6700 B Rockledge Dr,Rm 5111, Bethesda, MD 20892 USA. EM readsa@niaid.nih.gov RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU Intramural NIH HHS [Z01 CL000191-10, Z01 CL000036-20, Z01 AI000865-08]; NCI NIH HHS [N01 CO012400, N01-CO-12400, N01CO12400] NR 15 TC 16 Z9 16 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD SEP 15 PY 2008 VL 198 IS 6 BP 843 EP 850 DI 10.1086/591250 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 340RA UT WOS:000258661500008 PM 18684102 ER PT J AU Aban, IB Wolfe, GI Cutter, GR Kaminski, HJ Jaretzki, A Minisman, G Conwit, R Newsom-Davis, J AF Aban, Inmaculada B. Wolfe, Gil I. Cutter, Gary R. Kaminski, Henry J. Jaretzki, Alfred, III Minisman, Greg Conwit, Robin Newsom-Davis, John CA MGTX Advisory Comm TI The MGTX experience: Challenges in planning and executing an international, multicenter clinical trial SO JOURNAL OF NEUROIMMUNOLOGY LA English DT Article DE Myasthenia gravis; Thymectomy; Regulatory approval ID MYASTHENIA-GRAVIS; DISEASE; EPIDEMIOLOGY; CHINESE AB We present Our experience planning and launching a multinational, NIH/NINDS funded Study of thymectomy in myasthenia gravis. We highlight the additional steps required for international sites and analyze and contrast the time investment required to bring U.S. and non-U.S. sites into full regulatory compliance. Results show the mean time for non-U.S. centers to achieve regulatory approval was significantly longer(mean 13.4 +/- 0.96 months) than for U.S. sites (9.67 +/- 0.74 months; p= 0.0 175, t-test). The delay for non-U.S. sites was mainly attributable to Federalwide Assurance certification and State Department clearance. (C) 2008 Elsevier B.V. All rights reserved. C1 [Aban, Inmaculada B.; Cutter, Gary R.; Minisman, Greg] Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. [Wolfe, Gil I.] Univ Texas SW Med Ctr Dallas, Dept Neurol, Dallas, TX 75390 USA. [Kaminski, Henry J.] St Louis Univ, Med Ctr, Dept Neurol & Psychiat, St Louis, MO 63104 USA. [Jaretzki, Alfred, III] Columbia Univ, Med Ctr, Dept Surg, New York, NY 10032 USA. [Conwit, Robin] NINDS, Div Extramural Res, NIH, Ctr Neurosci, Bethesda, MD 20892 USA. [Newsom-Davis, John] Univ Oxford, John Radcliffe Hosp, Dept Clin Neurol, Oxford OX3 9DU, England. RP Aban, IB (reprint author), Univ Alabama, Dept Biostat, 1665 Univ Blvd, Birmingham, AL 35294 USA. EM caban@uab.edu FU National Institute of Neurological Disorders and Stroke [5U0INS4268503]; MGTX Advisory Committee; Myasthenia Gravis Foundation of America FX This research is Supported by a grant from the National Institute of Neurological Disorders and Stroke (5U0INS4268503 - Thymectomy in Non-Thymomatous MG Patients on Prednisone) and funding from the Myasthenia Gravis Foundation of America. The authors Would also like to acknowledge the MGTX Advisory Committee members who have recruited at least 2 patients to date in this study: Dr. Claudio Mazia (Centro de Asistencia Docencia e Investigacion en Miastenia, Buenos Aires, Argentina), Dr. Gabriel Cea (Universidad de Chile, Santiago, Chile), Dr. Amelia Evoli (Catholic University, Rome, Italy), Dr. John King (Royal Melbourne Hospital, Victoria, Australia), Dr. Giovanni Antonini (University of Rome, Rome, Italy), Dr. Jeanine Heckmann (University of Cape Town, Cape Town, South Africa), Dr. Joel Oger (Univeristy of British Columbia, Vancouver, Canada), Dr. Bashar Katirji (Case Western Reserve University, Cleveland, Ohio), Dr. Bryan Lecky (Walton Hospital for Neurology, Liverpool, United Kingdorn), Dr. Wilfred Nix (Johannes Guternberg-Universitat, Mainz, Gerniany), Dr. Mike Pulley (University of Florida, Jacksonville, Florida), Dr. Elza Tosta (Hospital de Base do Distrito Federal, Brasilia, Brazil), and Dr. Hiroaki Yoshikawa (Kanazawa University, Ishikawa, Japan). NR 12 TC 16 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-5728 J9 J NEUROIMMUNOL JI J. Neuroimmunol. PD SEP 15 PY 2008 VL 201 SI SI BP 80 EP 84 DI 10.1016/j.jneuroim.2008.05.031 PG 5 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 363VK UT WOS:000260294800013 PM 18675464 ER PT J AU Plested, AJR AF Plested, Andrew J. R. TI How 2C a channel that's (almost) not there SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material ID NMDA RECEPTORS C1 NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. RP Plested, AJR (reprint author), NICHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. EM plesteda@mail.nih.gov OI Plested, Andrew/0000-0001-6062-0832 FU Intramural NIH HHS NR 6 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD SEP 15 PY 2008 VL 586 IS 18 BP 4339 EP 4340 DI 10.1113/jphysiol.2008.160366 PG 2 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 348RY UT WOS:000259228800001 PM 18794300 ER PT J AU Sharabi, Y Imrich, R Holmes, C Pechnik, S Goldstein, DS AF Sharabi, Yehonatan Imrich, Richard Holmes, Courtney Pechnik, Sandra Goldstein, David S. TI Generalized and neurotransmitter-selective noradrenergic denervation in Parkinson's disease with orthostatic hypotension SO MOVEMENT DISORDERS LA English DT Article DE dysautonomia; Parkinson's disease; multiple system atrophy; noradrenergic ID PURE AUTONOMIC FAILURE; CARDIAC SYMPATHETIC DENERVATION; MULTIPLE SYSTEM ATROPHY; PLASMA-LEVELS; MIBG UPTAKE; TYRAMINE; CATECHOLS; VASODILATION; SENSITIVITY; RELEASE AB Patients with Parkinson's disease (PD) often have manifestations of autonomic failure. About 40% have neurogenic orthostatic hypotension (NOH), and among PD+NOH patients virtually all have evidence of cardiac sympathetic denervation; however, whether PD+NOH entails extra-cardiac noradrenergic denervation has been less clear. Microdialysate concentrations of the main neuronal metabolite of norepinephrine (NE) and dihydroxyphenyl glycol (DHPG) were measured in skeletal muscle, and plasma concentrations of NE and DHPG were measured in response to i.v. tyramine, yohimbine, and isoproterenol, in patients with PD+NOH, patients with pure autonomic failure (PAF), which is characterized by generalized catecholaminergic denervation, and control subjects. Microdialysate DHPG concentrations were similarly low in PD+NOH and PAF compared to control subjects (163 +/- 25, 153 +/- 27, and 304 +/- 27 pg/mL, P < 0.01 each vs. control). The two groups also had similarly small plasma DHPG responses to tyramine (71 +/- 58 and 82 +/- 105 vs. 313 +/- 94 pg/mL; P < 0.01 each vs. control) and NE responses to yohimbine (223 +/- 37 and 61 +/- 15 vs. 672 +/- 130 pg/mL, P < 0.01 each vs. control), and Virtually absent NE responses to isoproterenol (20 +/- 34 and 14 +/- 15 vs. 336 +/- 78 pg/mL, P < 0.01 each vs. control). Patients with PD+NOH had normal bradycardia responses to edrophonium and normal epinephrine responses to glucagon. The results support the concept of generalized noradrenergic denervation in PD+NOH, with similar severity to that seen in PAF. In contrast, the parasympathetic cholinergic and adrenomedullary hormonal components of the autonomic nervous system seem intact in PD+NOH. (C) 2008 Movement Disorder Society. C1 [Sharabi, Yehonatan; Imrich, Richard; Holmes, Courtney; Pechnik, Sandra; Goldstein, David S.] Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, Bethesda, MD USA. RP Goldstein, DS (reprint author), Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov FU NIH; NINDS FX This research was supported by the Intramural Research Program of the NIH, NINDS. We thank Dr. Basil Eldadah for assistance in carrying out many clinical procedures that were Crucial for this report. NR 43 TC 26 Z9 28 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD SEP 15 PY 2008 VL 23 IS 12 BP 1725 EP 1732 DI 10.1002/mds.22226 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 356GU UT WOS:000259767500012 PM 18661549 ER PT J AU Allard, JS Heilbronn, LK Smith, C Hunt, ND Ingram, DK Ravussin, E de Cabo, R AF Allard, Joanne S. Heilbronn, Leonie K. Smith, Carolina Hunt, Nicole D. Ingram, Donald K. Ravussin, Eric de Cabo, Rafael CA Pennington CALERIE Team TI In Vitro Cellular Adaptations of Indicators of Longevity in Response to Treatment with Serum Collected from Humans on Calorie Restricted Diets SO PLOS ONE LA English DT Article AB Calorie restriction (CR) produces several health benefits and increases lifespan in many species. Studies suggest that alternate-day fasting (ADF) and exercise can also provide these benefits. Whether CR results in lifespan extension in humans is not known and a direct investigation is not feasible. However, phenotypes observed in CR animals when compared to ad libitum fed (AL) animals, including increased stress resistance and changes in protein expression, can be simulated in cells cultured with media supplemented with blood serum from CR and AL animals. Two pilot studies were undertaken to examine the effects of ADF and CR on indicators of health and longevity in humans. In this study, we used sera collected from those studies to culture human hepatoma cells and assessed the effects on growth, stress resistance and gene expression. Cells cultured in serum collected at the end of the dieting period were compared to cells cultured in serum collected at baseline (before the dieting period). Cells cultured in serum from ADF participants, showed a 20% increase in Sirt1 protein which correlated with reduced triglyceride levels. ADF serum also induced a 9% decrease in proliferation and a 25% increase in heat resistance. Cells cultured in serum from CR participants induced an increase in Sirt1 protein levels by 17% and a 30% increase in PGC-1a mRNA levels. This first in vitro study utilizing human serum to examine effects on markers of health and longevity in cultured cells resulted in increased stress resistance and an up-regulation of genes proposed to be indicators of increased longevity. The use of this in vitro technique may be helpful for predicting the potential of CR, ADF and other dietary manipulations to affect markers of longevity in humans. C1 [Allard, Joanne S.; Smith, Carolina; Hunt, Nicole D.; Ingram, Donald K.; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Heilbronn, Leonie K.; Ingram, Donald K.; Ravussin, Eric] Pennington Biomed Res Ctr, Baton Rouge, LA USA. RP Allard, JS (reprint author), NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov RI de Cabo, Rafael/E-7996-2010; Heilbronn, Leonie/H-1874-2013; de Cabo, Rafael/J-5230-2016; OI Heilbronn, Leonie/0000-0003-2106-7303; de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Research Program of the NIH, National Institute on Aging [U01 AG20478] FX This research was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, and also in part by research grant U01 AG20478 from the National Institutes of Health. NR 57 TC 42 Z9 43 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 SEP 15 PY 2008 VL 3 IS 9 AR e3211 DI 10.1371/journal.pone.0003211 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422KX UT WOS:000264427700006 PM 18791640 ER PT J AU Ramdhan, DH Kamijima, M Yamada, N Ito, Y Yanagiba, Y Nakamura, D Okamura, A Ichihara, G Aoyama, T Gonzalez, FJ Nakajima, T AF Ramdhan, Doni Hikmat Kamijima, Michihiro Yamada, Naoyasu Ito, Yuki Yanagiba, Yukie Nakamura, Daichi Okamura, Ai Ichihara, Gaku Aoyama, Toshifumi Gonzalez, Frank J. Nakajima, Tamie TI Molecular mechanism of trichloroethylene-induced hepatotoxicity mediated by CYP2E1 SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE trichloroethylene; CYP2E1; metabolism; hepatotoxicity; PPAR alpha; NF kappa B ID NF-KAPPA-B; GENERALIZED SKIN DISORDERS; ALPHA PPAR-ALPHA; RAT-LIVER; METABOLIZING ENZYMES; RISK-ASSESSMENT; MICE; TOXICITY; ACTIVATION; EXPRESSION AB Cytochrome P450 (CYP) 2E1 was suggested to be the major enzyme involved in trichloroethylene (TRI) metabolism and TRI-induced hepatotoxicity, although the latter Molecular mechanism is not fully understood. The involvement of CYP2E1 in TRI-induced hepatotoxicity and its underlying molecular mechanism were studied by comparing hepatotoxicity in cyp2e1(+/+) and cyp2e1(-/-) mice. The mice were exposed by inhalation to 0 (control), 1000, or 2000 ppm of TRI for 8 h a day, for 7 days, and TRI-hepatotoxicity was assessed by measuring plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and histopathology. Urinary metabolites of trichloroethanol and trichloroacetic acid (TCA) were considerably greater in cyp2e1(+/+) compared to cyp2e1(-/-) mice, suggesting that CYP2E1 is the major P450 involved in the formation of these metabolites. Consistent with elevated plasma ALT and AST activities, cyp2e1(+/+) mice in the 2000 ppm group showed histopathological inflammation. TRI significantly upregulated PPAR alpha, which might function to inhibit NF kappa B p50 and p65 signalling. In addition, TRI-induced NF kappa B p52 mRNA, and significantly positive correlation between NF kappa B p52 mRNA expression and plasma ALT activity levels were observed, Suggesting the involvement of p52 in liver inflammation. Taken together, the current Study directly demonstrates that CYP2E1 was the major P450 involved in the first step of the TRI metabolism, and the metabolites produced may have two opposing roles: one inducing hepatotoxicity and the other protecting against the toxicity. Intermediate metabolite(s) from TRI to chloral hydrate produced by CYP2E1-mediated oxidation may be involved in the former, and TCA in the latter. (C) 2008 Elsevier Inc. All Fights reserved. C1 [Ramdhan, Doni Hikmat; Kamijima, Michihiro; Yamada, Naoyasu; Ito, Yuki; Yanagiba, Yukie; Nakamura, Daichi; Okamura, Ai; Ichihara, Gaku; Nakajima, Tamie] Nagoya Univ, Grad Sch Med, Dept Environm & Occupat Hlth, Nagoya, Aichi 4668550, Japan. [Aoyama, Toshifumi] Shinshu Univ, Grad Sch Med, Inst Aging & Adaptat, Dept Metab Regulat, Matsumoto, Nagano, Japan. [Gonzalez, Frank J.] Natl Canc Inst, Lab Metab, NIH, Bethesda, MD USA. RP Nakajima, T (reprint author), Nagoya Univ, Grad Sch Med, Dept Environm & Occupat Hlth, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan. EM tnasu23@med.nagoya-u.ac.jp RI Ito, Yuki/C-3698-2008 FU Japan Society for the Promotion of Science (JSPS) [18659169, B 15406026, 17659175] FX The authors would like to express their gratitude to the Japan Association for Hygiene of Chlorinated Solvents for their kind gift of trichloroethylene. This study was supported in part by Grants-in-Aid for Scientific Research (18659169, B 15406026, 17659175) from the Japan Society for the Promotion of Science (JSPS). NR 39 TC 24 Z9 31 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 15 PY 2008 VL 231 IS 3 BP 300 EP 307 DI 10.1016/j.taap.2008.04.020 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 353AG UT WOS:000259537900004 PM 18565563 ER PT J AU Jun, DY Park, HS Kim, JS Kim, JS Park, W Song, BH Kim, HS Taub, D Kim, YH AF Jun, Do Youn Park, Hae Sun Kim, Jun Seok Kim, Jong Sik Park, Wan Song, Bang Ho Kim, Hee-Sook Taub, Dennis Kim, Young Ho TI 17 alpha-estradiol arrests cell cycle progression at G(2)/M and induces apoptotic cell death in human acute leukemia Jurkat T cells SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE 17 alpha-estradiol, G2/M arrest; apoptosis; mitochondrial cytochrome c; caspase cascade; Bcl-2; leukemia cells ID CYTOCHROME-C RELEASE; N-TERMINAL KINASE; CASPASE-8 ACTIVATION; BREAST-CANCER; ESTROGEN-RECEPTORS; OXIDATIVE STRESS; IN-VITRO; ESTRADIOL; MECHANISM; PROTEIN AB A pharmacological dose (2.5-10 mu M) of 17 alpha-estradiol (17 alpha-E-2) exerted a cytotoxic effect on human leukemias Jurkat T and U937 cells, which was not suppressed by the estrogen receptor (ER) antagonist ICI 182,780. Along with cytotoxicity in Jurkat T cells, several apoptotic events including mitochondrial cytochrome c release, activation of caspase-9, -3, and -8, PARP degradation, and DNA fragmentation were induced. The cytotoxicity of 17 alpha-E-2 was not blocked by the anti-Fas neutralizing antibody ZB-4. While undergoing apoptosis, there was a remarkable accumulation of G(2)/M cells with the upregulatoin of cdc2 kinase activity, which was reflected in the Thr56 phosphorylation of Bcl-2. Dephosphorylation at Tyr15 and phosphorylation at Thr161 of cdc2, and significant increase in the cyclin B1 level were underlying factors for the cdc2 kinase activation. Whereas the 17 alpha-E-2-induced apoptosis was completely abrogated by overexpression of Bcl-2 or by pretreatment with the pan-caspase inhibitor z-VAD-fmk, the accumulation of G(2)/M cells significantly increased. The caspase-8 inhibitor z-IETD-fmk failed to influence 17 alpha-E-2-mediated caspase-9 activation, but it markedly reduced caspase-3 activation and PARP degradation with the suppression of apoptosis, indicating the contribution of caspase-8; not as an upstream event of the mitochondrial cytochrome c release, but to caspase-3 activation. In the presence of hydroxyurea, which blocked the cell cycle progression at the G(1)/S boundary, 17 alpha-E-2 failed to induce the G(2)/M arrest as well as apoptosis. These results demonstrate that the cytotoxicity of 17 alpha-E-2 toward Jurkat T cells is attributable to apoptosis mainly induced in G(2)/M-arrested cells, in an ER-independent manner, via a mitochondria-dependent caspase pathway regulated by Bcl-2. (C) 2008 Elsevier Inc. All rights reserved. C1 [Jun, Do Youn; Park, Hae Sun; Kim, Jun Seok; Park, Wan; Kim, Young Ho] Kyungpook Natl Univ, Coll Nat Sci, Sch Life Sci & Biotechnol, Dept Microbiol,Lab Immunobiol, Taegu 702701, South Korea. [Kim, Jong Sik] Andong Natl Univ, Dept Biol Sci, Andong 760749, Kyungbuk, South Korea. [Song, Bang Ho] Kyungpook Natl Univ, Teachers Coll, Dept Biol Educ, Taegu 702701, South Korea. [Kim, Hee-Sook] Kyungpook Natl Univ, Coll Nursing, Taegu 702701, South Korea. [Taub, Dennis] NIA, Immunol Lab, Gerontol Res Ctr, NIH, Bethesda, MD 20892 USA. RP Kim, YH (reprint author), Kyungpook Natl Univ, Coll Nat Sci, Sch Life Sci & Biotechnol, Dept Microbiol,Lab Immunobiol, Taegu 702701, South Korea. EM ykim@knu.ac.kr FU Korean Research Foundation [KRF-2003-J00103]; Korean Ministry of Agriculture and Forestry [HTDP 202060-03]; National Institute on Aging; National Institutes of Health, USA FX This work was supported by a grant from the Korean Research Foundation (KRF-2003-J00103) and a grant from the Korean Ministry of Agriculture and Forestry (HTDP 202060-03), and in part by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, USA. NR 46 TC 19 Z9 19 U1 0 U2 8 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X EI 1096-0333 J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD SEP 15 PY 2008 VL 231 IS 3 BP 401 EP 412 DI 10.1016/j.taap.2008.05.023 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 353AG UT WOS:000259537900015 PM 18603276 ER PT J AU Barozzi, P Bonini, C Potenza, L Masetti, M Cappelli, G Gruarin, P Whitby, D Gerunda, GE Mondino, A Riva, G Vallerini, D Quadrelli, C Bosco, R Ciceri, F Bordignon, C Schulz, TF Torelli, G Luppi, M AF Barozzi, Patrizia Bonini, Chiara Potenza, Leonardo Masetti, Michele Cappelli, Gianni Gruarin, Paola Whitby, Denise Gerunda, Giorgio E. Mondino, Anna Riva, Giovanni Vallerini, Daniela Quadrelli, Chiara Bosco, Raffaella Ciceri, Fabio Bordignon, Claudio Schulz, Thomas F. Torelli, Giuseppe Luppi, Mario TI Changes in the immune responses against human herpesvirus-8 in the disease course of posttransplant Kaposi sarcoma SO TRANSPLANTATION LA English DT Article DE posttransplant Kaposi sarcoma; HHV-8; immunity; sirolimus ID ACTIVE ANTIRETROVIRAL THERAPY; STEM-CELL TRANSPLANTATION; T-LYMPHOCYTE EPITOPES; HIV-INFECTED PATIENTS; VIRAL LOAD; CYTOMEGALOVIRUS; IDENTIFICATION; SIROLIMUS; FAILURE AB In nine patients with posttransplant Kaposi sarcoma (KS) T-cell responses to human herpesvirus (HHV)-8 latent and lytic antigens, as detected by enzyme-linked-immunospot (Elispot) assay, were absent at disease onset. Virus-specific T-cell responses were detected in six renal recipients at remission after a reduction of calcineurin inhibitors (CIs), and in two HHV-8 seropositive renal recipients without KS. In two liver recipients undergoing switch from CIs to sirolimus (SRL), normalization of the T-cell repertoire and recovery of both HHV-8-specific effector and memory T lymphocytes were associated with complete KS remission. In a renal recipient undergoing SRL conversion, the early recovery of HHV-8-specific effector but not of memory T lymphocytes, was associated only with partial remission. Neither rejection nor changes in graft function were observed after SRL conversion. HHV-8-specific T-cell responses are required to achieve posttransplant KS remission, and may be restored under SRL, while maintaining effective immunosuppression. C1 [Barozzi, Patrizia; Potenza, Leonardo; Riva, Giovanni; Vallerini, Daniela; Quadrelli, Chiara; Bosco, Raffaella; Torelli, Giuseppe; Luppi, Mario] Univ Modena & Reggio Emilia, Dept Oncol & Hematol, Azienda Osped Policlin, I-41100 Modena, Italy. [Bonini, Chiara; Gruarin, Paola; Mondino, Anna; Ciceri, Fabio; Bordignon, Claudio] Ist Sci San Raffaele, Hematol & Bone Marrow Transplantat Unit, Canc Immunotherapy & Gene Therapy Program, Expt Hematol Lab, I-20132 Milan, Italy. [Masetti, Michele; Gerunda, Giorgio E.] Univ Modena & Reggio Emilia, Div Liver & Multivisceral Transplant Ctr, Azienda Osped Policlin, I-41100 Modena, Italy. [Cappelli, Gianni] Univ Modena & Reggio Emilia, Div Nephrol, Azienda Osped Policlin, I-41100 Modena, Italy. [Whitby, Denise] Sci Applicat Int Corp, Natl Canc Inst, Viral Epidemiol Sect, AIDS Vaccine Program, Frederick, MD USA. [Schulz, Thomas F.] Hannover Med Sch, Inst Virol, D-30623 Hannover, Germany. RP Luppi, M (reprint author), Univ Modena & Reggio Emilia, Dept Oncol & Hematol, Azienda Osped Policlin, Via Pozzo 71, I-41100 Modena, Italy. EM mario.luppi@unimore.it RI Cappelli, Gianni/F-8277-2012; bonini, chiara/I-9202-2012; Luppi, Mario/J-3668-2016; Gerunda, Giorgio Enrico/J-8658-2016; Potenza, Leonardo/P-9579-2016; Barozzi, Patrizia/Q-2638-2016; OI Cappelli, Gianni/0000-0003-2304-5001; Luppi, Mario/0000-0002-0373-1154; Gerunda, Giorgio Enrico/0000-0003-2898-1886; Potenza, Leonardo/0000-0002-2738-6105; Barozzi, Patrizia/0000-0002-8936-1114; BONINI, Maria Chiara/0000-0002-0772-1674 FU Italian Ministry for Education, Universities and Research (MIUR), Rome, Italy; Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy; European Commission's FP6 Life-Science-Health Programme [LSHC-CT-2005-018704]; Programma Regione ER-Universita 2007-09 FX This study was supported by the Italian Ministry for Education, Universities and Research (MIUR), Rome, Italy; the Associazione Italiana per la Ricerca sul Cancro (AIRC), Milan, Italy; and the European Commission's FP6 Life-Science-Health Programme (INCA project; LSHC-CT-2005-018704) and Programma Regione ER-Universita 2007-09. NR 24 TC 33 Z9 33 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD SEP 15 PY 2008 VL 86 IS 5 BP 738 EP 744 DI 10.1097/TP.0b013e318184112c PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 350OI UT WOS:000259361700019 PM 18791457 ER PT J AU Moore, MD Fu, W Soheilian, F Nagashima, K Ptak, RG Pathak, VK Hu, WS AF Moore, Michael D. Fu, William Soheilian, Ferri Nagashima, Kunio Ptak, Roger G. Pathak, Vinay K. Hu, Wei-Shau TI Suboptimal inhibition of protease activity in human immunodeficiency virus type 1: Effects on virion morphogenesis and RNA maturation SO VIROLOGY LA English DT Article DE HIV-1; protease inhibitor; virus maturation; RNA dimer; virion morphology ID MURINE LEUKEMIA-VIRUS; VIRAL INFECTIVITY; GAGPOL PRECURSOR; CAPSID PROTEIN; DIMERIC RNA; WILD-TYPE; HIV-1; TERMINUS; CLEAVAGE; RELEASE AB Protease activity within nascently released human immunodeficiency virus type 1 (HIV-1) particles is responsible for the cleavage of the viral polyproteins Gag and Gag-Pol into their constituent parts, which results in the subsequent condensation of the mature conical core surrounding the viral genomic RNA. Concomitant with Viral maturation is a conformational change in the packaged viral RNA from a loosely associated dimer into a more thermodynamically stable form. In this study we used suboptimal concentrations of two protease inhibitors, lopinavir and atazanavir, to study their effects on Gag polyprotein processing and on the properties of the RNA in treated virions. Analysis of the treated virions demonstrated that even with high levels of inhibition of viral infectivity (IC90), most of the Gag and Gag-Pol polyproteins were processed, although slight but significant increases in processing intermediates of Gag were detected. Drug treatments also caused a significant increase in the proportion of viruses displaying either immature or aberrant Mature morphologies, The aberrant mature particles were characterized by an electron-dense region at the viral periphery and an electron-lucent core structure in the viral center, possibly indicating exclusion of the genomic RNA from these viral cores. intriguingly, drug treatments caused only a slight decrease in overall thermodynamic stability of the viral RNA dimer, suggesting that the dimeric viral RNA was able to mature in the absence of correct core condensation. Published by Elsevier Inc. C1 [Moore, Michael D.; Pathak, Vinay K.; Hu, Wei-Shau] Natl Canc Inst, HIV Drug Resistance Program, Frederick, MD 21702 USA. [Fu, William; Ptak, Roger G.] So Res Inst, Frederick, MD 21701 USA. [Soheilian, Ferri; Nagashima, Kunio] SAIC Frederick Inc, Image Anal Lab, Natl Canc Inst, Frederick, MD 21702 USA. RP Hu, WS (reprint author), Natl Canc Inst, HIV Drug Resistance Program, POB B,Bldg 535,Room 336, Frederick, MD 21702 USA. EM whu@ncifcrf.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; NCI [N01-CO-12400]; Southern Research Institute FX We thank Anne Arthur for expert editorial help, and Drs. Alan Rein and Rebecca Russell for discussions and critical reading of this manuscript. Human anti-HIV immunoglobulin, anti-HIV-RT antibody, and TZM-b1 cells were obtained through the NIH AIDS Research and Reference Reagent Program, Division of AIDS, MAID, NIH. This research Was Supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, in part by NCI contract no. N01-CO-12400, and in part by internal funding from Southern Research Institute. NR 35 TC 16 Z9 16 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 15 PY 2008 VL 379 IS 1 BP 152 EP 160 DI 10.1016/j.virol.2008.06.030 PG 9 WC Virology SC Virology GA 346WS UT WOS:000259100900017 PM 18657842 ER PT J AU Yin, JM Dai, A Kutzler, MA Shen, A LeCureux, J Lewis, MG Waldmann, T Weiner, DB Boyer, JD AF Yin, Jiangmei Dai, Anlan Kutzler, Michele A. Shen, Anding LeCureux, Jonathan Lewis, Mark G. Waldmann, Thomas Weiner, David B. Boyer, Jean D. TI Sustained suppression of SHIV89.6P replication in macaques by vaccine-induced CD8(+) memory T cells SO AIDS LA English DT Article DE CD8(+) memory T cell; DNA vaccine; IL-15; SHIV replication; suppression ID SIMIAN IMMUNODEFICIENCY VIRUS; TYPE-1 INFECTION; RHESUS-MONKEYS; DISEASE PROGRESSION; IMMUNE-RESPONSES; IL-15 PLASMID; LYMPHOCYTES; DEPLETION; VIREMIA; INTERLEUKIN-15 AB Objective: We previously demonstrated that a strategy of co-immunizing cynomologous macaques with a simian/human immunodeficiency virus DNA-based vaccine and a plasmid encoding macaque interleukin (IL)-15 induces a strong CD8(+) and CD4(+) effector T-cell response that, upon subsequent challenge with SHIV89.6P, controls viral replication and protects immunized animals against ongoing infection. In this follow-up study, we measured viral replication 2 years after vaccination challenge and determined the mechanism by which antigen-specific CD8(+) T cells suppress viral replication. Method: From the original group of 18, we assessed the immune response in the 13 Surviving animals. In addition, using cM-T807, we depleted CD8 lymphocytes to assess the role CD8 cells play in suppression of viral replication. Result: We found that peripheral blood mononuclear cells from vaccinated animals had a robust simian immunodeficiency virus Gag-specific IFN-gamma response. In addition, in the DNA and IL-15 group, we observed higher levels of simian immunodeficiency virus Gag-specific, proliferating CD8(+) T cells. The profile of these cells revealed more central memory than effector cells. When we transiently depleted animals of CD8(+) T cells, plasma viral load increased, and peak viral load was lower in the DNA and IL-15 group compared with the DNA alone and control groups, As CD8(+) T cells recovered, viral replication was controlled and we observed an increase in the number of antigen-specific effector CD8(+) T cells. Conclusion: We conclude that co-immunization with a simian/human immunodeficiency virus DNA-based vaccine and IL-15 achieves sustained viral suppression and that vaccine-induced CD8(+) memory T cells, which differentiate into effector cells, are central to that suppression. (C) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Yin, Jiangmei; Dai, Anlan; Weiner, David B.; Boyer, Jean D.] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. [Kutzler, Michele A.] Drexel Univ, Coll Med, Philadelphia, PA 19104 USA. [Shen, Anding; LeCureux, Jonathan] Calvin Coll, Dept Biol, Grand Rapids, MI 49506 USA. [Lewis, Mark G.] Bioqual, Res Sect, Rockville, MD USA. [Waldmann, Thomas] NCI, Metab Branch, Frederick, MD 21701 USA. RP Boyer, JD (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, 505 SCL,422 Curie Blvd, Philadelphia, PA 19104 USA. EM boyerj@mail.med.upenn.edu RI Yin, Jiangmei/C-5597-2011; Yin, Jiangmei/G-1952-2011; Weiner, David/H-8579-2014; OI LeCureux, Jonathan/0000-0003-4444-8790 FU National Institutes of Health (NIH) [N01-AI-50010, P01-A1-071739, R-01-A1-071186]; National Institutes of Health Intramural Research Program FX This research was supported in part by National Institutes of Health (NIH) Grants N01-AI-50010, P01-A1-071739, R-01-A1-071186, and the National Institutes of Health Intramural Research Program. J.M., A.D., A.S., J.L., and M.G.L. all performed research and generated the data presented. M.A.K., TW, and D.B.W provided reagents and guidance. J.D.B. designed experiments and oversaw the project and writing of the paper. NR 40 TC 8 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 12 PY 2008 VL 22 IS 14 BP 1739 EP 1748 DI 10.1097/QAD.0b013e32830efdae PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 353DQ UT WOS:000259546700008 PM 18753858 ER PT J AU Salazar, JC Cahn, P Yogev, R Della Negra, M Castell-Gattinara, G Fortuny, C Flynn, PM Giaquinto, C Ruan, PK Smith, ME Mikl, J Jelaska, A AF Salazar, Juan C. Cahn, Pedro Yogev, Ram Della Negra, Marinella Castell-Gattinara, Guido Fortuny, Claudia Flynn, Patrica M. Giaquinto, Carlo Ruan, Ping K. Smith, M. Elizabeth Mikl, Jaromir Jelaska, Ante CA PACTG 1051 BI Study Team TI Efficacy, safety and tolerability of tipranavir coadministered with ritonavir in HIV-1-infected children and adolescents SO AIDS LA English DT Article DE antiretroviral therapy; efficacy; pediatric; protease inhibitor; ritonavir; safety; tipranavir ID ACTIVE ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-INFECTED CHILDREN; REVERSE-TRANSCRIPTASE INHIBITORS; TREATMENT-EXPERIENCED PATIENTS; RANDOMIZED CONTROLLED-TRIAL; VIROLOGICAL RESPONSE; PROTEASE INHIBITORS; DRUG-RESISTANCE; PLUS RITONAVIR AB Objective: To evaluate the efficacy, safety and tolerability of ritonavir-boosted tipranavir (TPV/r) in HIV-1-infected pediatric patients. Design: Open-label randomized pediatric trial (1182.14/PACTG1051) comparing TPV/r at two doses including an optimized background regimen. Methods: HIV-1-infected patients (2-18 years) with plasma viral load 1500 copies/ml or more were randomized to TPV/r 290/115 or 375/150 mg/m(2) twice-daily oral solution and optimized background regimen. Week 48 efficacy, safety and tolerability results were evaluated. Results: Children (n = 115; 97% treatment experienced) were randomized to low or high dose therapy. Eighty-eight remained on-treatment through 48 weeks. Baseline characteristics were similar between dose groups. At study entry, half of the HIV-1 isolates were resistant to all protease inhibitors. At 48 weeks, 39.7% low-dose and 45.6% high-dose TPV/r recipients had viral load less than 400 copies/ml and 34.5 and 35.1%, respectively, achieved viral load less than 50 copies/ml. Vomiting, cough and diarrhea were the most frequent adverse events. Grade 3 alanine aminotransferase elevations were observed in 6.3% of patients. No grade 4 alanine aminotransferase or grade 3/4 aspartate aminotransferase elevations were reported. Conclusions: TPV/r achieved a sustained virologic response, showed a good safety profile and was well tolerated at either dose. In pediatric patients with high baseline resistance profiles, high-dose TPV/r tended to demonstrate a better sustained response. (C) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins. C1 [Salazar, Juan C.] Univ Connecticut, Sch Med, Connecticut Childrens Med Ctr, Hartford, CT 06106 USA. [Cahn, Pedro] Fdn Huesped, Buenos Aires, DF, Argentina. [Yogev, Ram] Northwestern Univ, Childrens Mem Hosp, Sch Med, Chicago, IL 60611 USA. [Della Negra, Marinella] Inst Infectol Emilio Ribas, Sao Paulo, Brazil. [Castell-Gattinara, Guido] Bambino Gesu Pediat Hosp, Rome, Italy. [Fortuny, Claudia] Hosp St Joan Deu, Barcelona, Spain. [Flynn, Patrica M.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Giaquinto, Carlo] Azienda Osped Padova, Padua, Italy. [Ruan, Ping K.] Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. [Smith, M. Elizabeth] NIAID, Pediat Med Branch, DAIDS, NIH,DHHS, Bethesda, MD 20892 USA. [Mikl, Jaromir; Jelaska, Ante] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA. RP Salazar, JC (reprint author), Univ Connecticut, Sch Med, Connecticut Childrens Med Ctr, 282 Washington St, Hartford, CT 06106 USA. EM jsalaza@ccmckids.org FU National Institute of Allergy and Infectious Diseases [U01AI068632, 1U01AI068616]; University of Connecticut Health Center's Clinical Research Center [M01RR06192]; PACTG 2# [5U01AI069512] FX The PACTG/IMPAACT was supported by Grant Number U01AI068632 and 1U01AI068616 from the National Institute of Allergy and Infectious Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. Juan C. Salazar also had Support from the University of Connecticut Health Center's Clinical Research Center Grant M01RR06192 and R. Yogev from PACTG 2# 5U01AI069512. NR 32 TC 26 Z9 28 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP 12 PY 2008 VL 22 IS 14 BP 1789 EP 1798 DI 10.1097/QAD.0b013e32830c481b PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 353DQ UT WOS:000259546700013 PM 18753862 ER PT J AU Bourdi, M Korrapati, MC Chakraborty, M Yee, SB Pohl, LR AF Bourdi, Mohammed Korrapati, Midhun C. Chakraborty, Mala Yee, Steven B. Pohl, Lance R. TI Protective role of c-Jun N-terminal kinase 2 in acetaminophen-induced liver injury SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE acetaminophen; cyclin D1; hepatoprotection; c-Jun N-terminal kinase 2; JNK2; liver injury; proliferating cell nuclear antigen; repair ID N-TERMINAL-KINASE; OXIDATIVE STRESS; INDUCED HEPATOTOXICITY; POLYETHYLENE-GLYCOL; DIMETHYL-SULFOXIDE; REPERFUSION INJURY; HEME OXYGENASE-1; PROTEIN-KINASE; JNK INHIBITOR; RAT-LIVER AB Recent studies in mice suggest that stress-activated c-Jun N-terminal protein kinase 2 (JNK2) plays a pathologic role in acetaminophen (APAP)-induced liver injury (AILI), a major cause of acute liver failure (ALF). In contrast, we present evidence that JNK2 can have a protective role against AILI When male C57BL/6J wild type (WT) and JNK2(-/-) mice were treated with 300 mg APAP/kg, 90% of JNK2(-/-) mice died of ALF compared to 20% of WT mice within 48 h. The high susceptibility of JNK2(-/-) mice to AILI appears to be due in part to deficiencies in hepatocyte proliferation and repair. Therefore, our findings are consistent with JNK2 signaling playing a protective role in AILI and further suggest that the use of JNK inhibitors as a potential treatment for AILI as has been recommended by other investigators, should be reconsidered. Published by Elsevier Inc. C1 [Bourdi, Mohammed; Korrapati, Midhun C.; Chakraborty, Mala; Yee, Steven B.; Pohl, Lance R.] NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Bourdi, M (reprint author), NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, NIH,Dept Hlth & Human Serv, Bldg 10,Room 8N 110,9000 Rockville Pike, Bethesda, MD 20892 USA. EM bourdim@nih.gov FU Intramural Research Program of the NIH; NHLBI FX The authors thank John W. George (NHLBI, NIH, Bethesda, MD) for expert animal care and technical assistance. This work was supported by the Intramural Research Program of the NIH and the NHLBI. NR 43 TC 21 Z9 21 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 12 PY 2008 VL 374 IS 1 BP 6 EP 10 DI 10.1016/j.bbrc.2008.06.065 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 342QN UT WOS:000258798700002 PM 18586006 ER PT J AU Pohludka, M Simeckova, K Vohanka, J Yilma, P Novak, P Krause, MW Kostrouchova, M Kostrouch, Z AF Pohludka, Michal Simeckova, Katerina Vohanka, Jaroslav Yilma, Petr Novak, Petr Krause, Michael W. Kostrouchova, Marta Kostrouch, Zdenek TI Proteomic analysis uncovers a metabolic phenotype in C. elegans after nhr-40 reduction of function SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE nuclear hormone receptors; Caenorhabditis elegans; NHR-40; transcription; development; muscle; chromatography ID NUCLEAR RECEPTOR SUPERFAMILY; MYOSIN HEAVY-CHAIN; CAENORHABDITIS-ELEGANS; LOCALIZATION; EXPRESSION; GENES AB Coenorhabditis elegans has an unexpectedly large number (284) of genes encoding nuclear hormone receptors, most of which are nematode-specific and are of unknown function. WE! have exploited comparative two-dimensional chromatography of synchronized cultures of wild type C. elegans larvae and a mutant in nhr-40 to determine if proteomic approaches will provide additional insight into gene function. Chromatofocusing, followed by reversed-phase chromatography and mass spectrometry, identified altered chromatographic patterns for a set of proteins, many of which function in muscle and metabolism. Prompted by the proteomic analysis, we find that the penetrance of the developmental phenotypes in the mutant is enhanced at low temperatures and by food restriction. The combination of our phenotypic and proteomic analysis strongly suggests that NHR-40 Provides a link between metabolism and Muscle development. Our results highlight the utility of comparative two-dimensional chromatography to provide a relatively rapid method to gain insight into gene function. (C) 2008 Elsevier Inc. All rights reserved. C1 [Pohludka, Michal; Yilma, Petr; Kostrouch, Zdenek] Charles Univ Prague, Fac Med 1, Inst Inherited Metab Disorders, Lab Mol Pathol, CZ-12801 Prague, Czech Republic. [Simeckova, Katerina; Vohanka, Jaroslav; Kostrouchova, Marta] Charles Univ Prague, Fac Med 1, Inst Inherited Metab Disorders, Lab Mol Biol & Genet, CZ-12801 Prague, Czech Republic. [Novak, Petr] Acad Sci Czech Republic, Lab Mol Struct Characterizat, Inst Microbiol, CZ-14220 Prague, Czech Republic. [Krause, Michael W.] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kostrouch, Z (reprint author), Charles Univ Prague, Fac Med 1, Inst Inherited Metab Disorders, Lab Mol Pathol, Ke Karlovu 2, CZ-12801 Prague, Czech Republic. EM zdenek.kostrouch@lf1.cuni.cz RI Novak, Petr/F-9655-2014; OI Novak, Petr/0000-0001-8688-529X; Krause, Michael/0000-0001-6127-3940 FU Ministry of Education, Youth and Sports of the Czech Republic [301/05/0859, 304/08/0970, 304/07/0529, 0021620806, LC 7017]; NIH; NIDDK IMIC [AVOZ50200510] FX Some strains used in this work were provided by the Caenorhabditis Genetics Center, which is funded by the NIH National Center for Research Resources (NCRR). Authors thank Marketa Kostrouchova for valuable help and advice and Dr. Mukesh Malic (Beckman Coulter, Inc.) for advice and critical reading of the manuscript. This work was supported by Grants 301/05/0859, 304/08/0970, and 304/07/0529 awarded by the Czech Science Foundation, 0021620806 from the Ministry of Education, Youth and Sports of the Czech Republic, and (in part) by the Intramural Research Program of the NIH, NIDDK IMIC institutional research concept (AVOZ50200510), and the Ministry of Education, Youth and Sports of the Czech Republic (LC 7017) are gratefully acknowledged for financial support as well. NR 28 TC 5 Z9 11 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD SEP 12 PY 2008 VL 374 IS 1 BP 49 EP 54 DI 10.1016/j.bbrc.2008.06.115 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 342QN UT WOS:000258798700010 PM 18616929 ER PT J AU Chakrabarti, A Sadler, AJ Kar, N Young, HA Silverman, RH Williams, BRG AF Chakrabarti, Arindam Sadler, Anthony J. Kar, Niladri Young, Howard A. Silverman, Robert H. Williams, Bryan R. G. TI Protein kinase R-dependent regulation of interleukin-10 in response to double-stranded RNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; PLASMACYTOID DENDRITIC CELLS; IL-10 GENE-EXPRESSION; NECROSIS-FACTOR-ALPHA; TOLL-LIKE RECEPTOR-3; HUMAN T-CELLS; HUMAN MONOCYTES; RIG-I; ANTIINFLAMMATORY CYTOKINES; TRANSCRIPTION FACTOR AB The double-stranded RNA-activated protein kinase R (PKR) is an important component of antiviral defense. PKR participates in different signaling pathways in response to various stimuli to regulate translation via phosphorylation of the eukaryotic initiation factor 2 alpha, and transcription via activating NF-kappa B and IRF-1, to induce pro-inflammatory cytokines. Here we show PKR regulates interleukin-10 induction in response to double-stranded RNA, bacterial lipopolysaccaride, and Sendai virus infection. Using chemical inhibitors, dominant negative constructs, and genetic knockouts, we demonstrate that the PKR-mediated interleukin-10 induction engages JNK and NF-kappa B. Together, our data demonstrate the role of PKR in regulating an anti-inflammatory cytokine. The findings have significance in antiviral as well as broader innate immune responses. C1 [Sadler, Anthony J.; Williams, Bryan R. G.] Monash Univ, Monash Med Ctr, Monash Inst Med Res, Clayton, Vic 3168, Australia. [Chakrabarti, Arindam; Kar, Niladri; Silverman, Robert H.] Cleveland Clin, Lerner Res Inst, Dept Canc Biol, Cleveland, OH 44195 USA. [Kar, Niladri] Cleveland Clin, Lerner Res Inst, Dept Mol Cardiol, Cleveland, OH 44195 USA. [Young, Howard A.] NCI, Expt Immunol Lab, NIH, Frederick, MD 21702 USA. RP Williams, BRG (reprint author), Monash Univ, Monash Med Ctr, Monash Inst Med Res, 246 Clayton Rd, Clayton, Vic 3168, Australia. EM bryan.williams@med.monash.edu.au RI Williams, Bryan/A-5021-2009 OI Williams, Bryan/0000-0002-4969-1151 FU National Institutes of Health [R01 AI034039, P01 CA062220] FX This work was supported, in whole or in part, by National Institutes of Health Grants R01 AI034039 and P01 CA062220. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 53 TC 25 Z9 25 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 SEP 12 PY 2008 VL 283 IS 37 BP 25132 EP 25139 DI 10.1074/jbc.M804770200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 345QZ UT WOS:000259012700005 PM 18625702 ER PT J AU Islam, A Jones, H Hiroi, T Lam, J Zhang, J Moss, J Vaughan, M Levine, SJ AF Islam, Aminul Jones, Heather Hiroi, Toyoko Lam, Jonathan Zhang, Jing Moss, Joel Vaughan, Martha Levine, Stewart J. TI cAMP-dependent protein kinase a (PKA) signaling induces TNFR1 exosome-like vesicle release via anchoring of PKA regulatory subunit RII beta to BIG2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-NECROSIS-FACTOR; FACTOR-BINDING-PROTEIN; CELL-DERIVED-EXOSOMES; BREFELDIN-A; MULTIVESICULAR BODY; FACTOR RECEPTOR; AKAP BINDING; PATHWAY; SPECIFICITY; MECHANISM AB The 55-kDa TNFR1 (type I tumor necrosis factor receptor) can be released to the extracellular space by two mechanisms, the proteolytic cleavage and shedding of soluble receptor ectodomains and the release of full-length receptors within exosome-like vesicles. We have shown that the brefeldin A-inhibited guanine nucleotide exchange protein BIG2 associates with TNFR1 and selectively modulates the release of TNFR1 exosome-like vesicles via an ARF1- and ARF3-dependent mechanism. Here, we assessed the role of BIG2 A kinase-anchoring protein (AKAP) domains in the regulation of TNFR1 exosome-like vesicle release from human vascular endothelial cells. We show that 8-bromo-cyclic AMP induced the release of full-length, 55-kDa TNFR1 within exosome-like vesicles via a protein kinase A (PKA)-dependent mechanism. Using RNA interference to decrease specifically the levels of individual PKA regulatory subunits, we demonstrate that RII beta modulates both the constitutive and cAMP-induced release of TNFR1 exosome-like vesicles. Consistent with its AKAP function, BIG2 was required for the cAMP-induced PKA-dependent release of TNFR1 exosome-like vesicles via a mechanism that involved the binding of RII beta to BIG2 AKAP domains B and C. We conclude that both the constitutive and cAMP-induced release of TNFR1 exosome-like vesicles occur via PKA-dependent pathways that are regulated by the anchoring of RII beta to BIG2 via AKAP domains B and C. Thus, BIG2 regulates TNFR1 exosome-like vesicle release by two distinct mechanisms, as a guanine nucleotide exchange protein that activates class I ADP-ribosylation factors and as an AKAP for RII beta that localizes PKA signaling within cellular TNFR1 trafficking pathways. C1 [Islam, Aminul; Lam, Jonathan; Zhang, Jing; Levine, Stewart J.] NHLBI, Pulm & Vasc Med Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Jones, Heather; Hiroi, Toyoko; Moss, Joel; Vaughan, Martha] NHLBI, Translat Med Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Pulm & Vasc Med Branch, Natl Inst Hlth, Bldg 10,Rm 6D03,MSC 1590, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU Division of Intramural Research; NHLBI; National Institutes of Health FX This work was supported, in whole or in part, by the Division of Intramural Research, NHLBI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 46 TC 9 Z9 10 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 SEP 12 PY 2008 VL 283 IS 37 BP 25364 EP 25371 DI 10.1074/jbc.M804966200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 345QZ UT WOS:000259012700031 PM 18625701 ER PT J AU Kyriazis, GA Wei, Z Vandermey, M Jo, DG Xin, O Mattson, MP Chan, SL AF Kyriazis, George A. Wei, Zelan Vandermey, Miriam Jo, Dong-Gyu Xin, Ouyang Mattson, Mark P. Chan, Sic L. TI Numb Endocytic adapter proteins regulate the transport and processing of the amyloid precursor protein in an isoform-dependent manner - Implications for Alzheimer disease pathogenesis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOSPHOTYROSINE-BINDING DOMAIN; FATE DETERMINANT NUMB; CELL FATE; MAMMALIAN NUMB; MEDIATED ENDOCYTOSIS; BETA-PROTEIN; PTB DOMAIN; INTRACELLULAR DOMAIN; CALCIUM HOMEOSTASIS; GAMMA-SECRETASE AB Central to the pathogenesis of Alzheimer disease is the aberrant processing of the amyloid precursor protein (APP) to generate amyloid beta-peptide (A beta), the principle component of amyloid plaques. The cell fate determinant Numb is a phosphotyrosine binding domain (PTB)-containing endocytic adapter protein that interacts with the carboxyl-terminal domain of APP. The physio-logical relevance of this interaction is unknown. Mammals produce four alternatively spliced variants of Numb that differ in the length of their PTB and proline-rich region. In the current study, we determined the influence of the four human Numb isoforms on the intracellular trafficking and processing of APP. Stable expression of Numb isoforms that differ in the PTB but not in the proline-rich region results in marked differences in the sorting of APP to the recycling and degradative pathways. Neural cells expressing Numb isoforms that lack the insert in the PTB (short PTB (SPTB)) exhibited marked accumulation of APP in Rab5A-labeled early endosomal and recycling compartments, whereas those expressing isoforms with the insertion in the PTB (long PTB (LPTB)) exhibited reduced amounts of cellular APP and its proteolytic derivatives relative to parental control cells. Neither the activities of the beta- and gamma-secretases nor the expression of APP mRNA were significantly different in the stably transfected cells, suggesting that the differential effects of the Numb proteins on APP metabolism is likely to be secondary to altered APP trafficking. In addition, the expression of SPTB-Numb increases at the expense of LPTB-Numb in neuronal cultures subjected to stress, suggesting a role for Numb in stress-induced A beta production. Taken together, these results suggest distinct roles for the human Numb isoforms in APP metabolism and may provide a novel potential link between altered Numb isoform expression and increased A beta generation. C1 [Kyriazis, George A.; Wei, Zelan; Vandermey, Miriam; Chan, Sic L.] Univ Cent Florida, Burnett Sch Biomed Sci, Biomol Sci Ctr, Orlando, FL 32816 USA. [Jo, Dong-Gyu] Sungkyunkwan Univ, Coll Pharm, Suwon 440746, South Korea. [Xin, Ouyang; Mattson, Mark P.] NIA, Neurosci Lab, Natl Inst Hlth, Intramural Res Program, Baltimore, MD 21224 USA. RP Chan, SL (reprint author), Univ Cent Florida, Burnett Sch Biomed Sci, Biomol Sci Ctr, 4000 Cent Florida Blvd, Orlando, FL 32816 USA. EM schan@mail.ucf.edu RI Mattson, Mark/F-6038-2012 NR 60 TC 46 Z9 47 U1 1 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 SEP 12 PY 2008 VL 283 IS 37 BP 25492 EP 25502 DI 10.1074/jbc.M802072200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 345QZ UT WOS:000259012700045 PM 18599481 ER PT J AU Jeong, W Lee, DY Park, S Rhee, SG AF Jeong, Woojin Lee, Duck-Yeon Park, Sunjoo Rhee, Sue Goo TI ERp16, an endoplasmic reticulum-resident thiol-disulfide oxidoreductase - Biochemical properties and role in apoptosis induced by endoplasmic reticulum stress SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MEMBRANE-PROTEINS; HUMAN CASPASE-12; QUALITY-CONTROL; ACTIVE-SITE; THIOREDOXIN; ISOMERASE; ER; ACTIVATION; FAMILY; CELLS AB We have characterized the properties and putative role of a mammalian thioredoxin-like protein, ERp16 (previously designated ERp18, ERp19, or hTLP19). The predicted amino acid sequence of the 172-residue human protein contains an NH2-terminal signal peptide, a thioredoxin-like domain with an active site motif (CGAC), and a COOH-terminal endoplasmic reticulum (ER) retention sequence (EDEL). Analyses indicated that the mature protein (comprising 146 residues) is generated by cleavage of the 26-residue signal peptide and is localized in the lumen of the ER. Biochemical experiments with the recombinant mature protein revealed it to be a thioldisulfide oxidoreductase. Its redox potential was about -165 mV; its active site cysteine residue Cys(66) was nucleophilic with a pK(a) value of similar to 6.6; it catalyzed the formation, reduction, and isomerization of disulfide bonds, with the unusual CGAC active site motif being responsible for these activities; and it existed as a dimer and underwent a redox-dependent conformational change. The observations that the redox potential of ERp16 (-165 mV) was within the range of that of the ER (-135 to -185 mV) and that ERp16 catalyzed disulfide isomerization of scrambled ribonuclease A suggest a role for ERp16 in protein disulfide isomerization in the ER. Expression of ERp16 in HeLa cells inhibited the induction of apoptosis by agents that elicit ER stress, including brefeldin A, tunicamycin, and dithiothreitol. In contrast, expression of a catalytically inactive mutant of ERp16 potentiated such apoptosis, as did depletion of ERp16 by RNA interference. Our results suggest that ERp16 mediates disulfide bond formation in the ER and plays an important role in cellular defense against prolonged ER stress. C1 [Jeong, Woojin; Park, Sunjoo; Rhee, Sue Goo] Ewha Womans Univ, Div Life & Pharmaceut Sci, Seoul 120750, South Korea. [Lee, Duck-Yeon] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Rhee, SG (reprint author), Ewha Womans Univ, Div Life & Pharmaceut Sci, 11-1 Daehyun Dong, Seoul 120750, South Korea. EM rheesg@ewha.ac.kr FU Bio RD Program [M10642040002-07N4204-00210, M10642040001-07N4204-00110]; National Honor Scientist Program [R09-2006-000-10002-0]; National Core Research Center Program [R15-2006-020]; Ministry of Education, Science, and Technology; Brain Korea 21 Scholars Program FX This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported by Bio R&D Program Grants M10642040002-07N4204-00210 ( to W.J.) and M10642040001-07N4204-00110 ( to S. G. R.), National Honor Scientist Program Grant R09-2006-000-10002- 0 ( to S. G. R.), and National Core Research Center Program Grant R15-2006-020 ( to W.J.) through the Korea Science and Engineering Foundation funded by the Ministry of Education, Science, and Technology, and by the Brain Korea 21 Scholars Program ( to S. P). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 45 TC 18 Z9 18 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 SEP 12 PY 2008 VL 283 IS 37 BP 25557 EP 25566 DI 10.1074/jbc.M803804200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 345QZ UT WOS:000259012700051 PM 18628206 ER PT J AU Tomita, T Kido, T Kurotani, R Iemura, SI Sterneck, E Natsume, T Vinson, C Kimura, S AF Tomita, Takeshi Kido, Taketomo Kurotani, Reiko Iemura, Shun-ichiro Sterneck, Esta Natsume, Tohru Vinson, Charles Kimura, Shioko TI CAATT/enhancer-binding proteins alpha and delta interact with NKX2-1 to synergistically activate mouse secretoglobin 3A2 gene expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR-I; HEPATOCYTE NUCLEAR FACTOR-3; SP-A GENE; C/EBP-ALPHA; REGULATES EXPRESSION; EPITHELIAL-CELLS; LUNG DEVELOPMENT; B PROMOTER; RAT LUNG; SURFACTANT AB Secretoglobin (SCGB) 3A2 is a small molecular weight secreted protein predominantly expressed in lung airways. We previously demonstrated that the expression of SCGB3A2 is regulated by homeodomain transcription factor NKX2-1. Here we show that CCAAT/enhancer-binding proteins, C/EBP alpha and C/EBP delta, regulate mouse Scgb3a2 gene transcription in vivo and in vitro by binding to specific sites located in the Scgb3a2 promoter and the activity is synergistically enhanced through cooperative interaction with NKX2-1. Six C/EBP binding sites lie within 500 bp of the Scgb3a2 gene promoter, of which two sites, located at -44 to -54 bp and -192 to -201 bp, appear to be critical for the synergistic activation of Scgb3a2 gene transcription with NKX2-1. All three transcription factors, C/EBP alpha, C/EBP delta, and NKX2-1, are expressed in the epithelial cells of airways, particularly the bronchus, where high expression of SCGB3A2 is found. The expression of these transcription factors markedly increases toward the end of gestation, which coincides with the marked increase of SCGB3A2, suggesting the importance of C/EBP alpha and C/EBP delta, and their synergistic interaction with NKX2-1 in mouse Scgb3a2 gene transcription and lung development. C1 [Tomita, Takeshi; Kido, Taketomo; Kurotani, Reiko; Vinson, Charles; Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. [Kurotani, Reiko] Yokohama City Univ, Cardiovasc Res Inst, Yokohama, Kanagawa 2360006, Japan. [Iemura, Shun-ichiro; Natsume, Tohru] Natl Inst Adv Ind Sci & Technol, Biol Informat Res Ctr, Tokyo 1350064, Japan. [Sterneck, Esta] NCI, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. RP Kimura, S (reprint author), NCI, Lab Metab, NIH, Bldg 37,Rm 3112B, Bethesda, MD 20892 USA. EM kimuras@mail.nih.gov FU National Cancer Institute, Center for Cancer Research; New Energy and Industrial Technology Development Organization FX This work was authored, in whole or in part, by National Institutes of Health staff. This work was supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research, and in part by the New Energy and Industrial Technology Development Organization ( to T. N.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. NR 46 TC 13 Z9 14 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 SEP 12 PY 2008 VL 283 IS 37 BP 25617 EP 25627 DI 10.1074/jbc.M805140200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 345QZ UT WOS:000259012700057 PM 18632661 ER PT J AU Kubota, T Matsuoka, M Chang, TH Tailor, P Sasaki, T Tashiro, M Kato, A Ozato, K AF Kubota, Toru Matsuoka, Mayumi Chang, Tsung-Hsien Tailor, Prafullakumar Sasaki, Tsuguo Tashiro, Masato Kato, Atsushi Ozato, Keiko TI Virus infection triggers SUMOylation of IRF3 and IRF7, leading to the negative regulation of type I interferon gene expression SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IFN-BETA PROMOTER; NF-KAPPA-B; DOUBLE-STRANDED-RNA; TOLL-LIKE RECEPTORS; RIG-I; SUMO-1 MODIFICATION; TRANSCRIPTIONAL REPRESSION; ISG15 CONJUGATION; SIGNALING PATHWAY; UBIQUITIN LIGASE AB Viral infection activates Toll-like receptor and RIG-I (retinoic acid-inducible gene I) signaling pathways, leading to phosphorylation of IRF3 (interferon regulatory factor 3) and IRF7 and stimulation of type I interferon (IFN) transcription, a process important for innate immunity. We show that upon vesicular stomatitis virus infection, IRF3 and IRF7 are modified not only by phosphorylation but by the small ubiquitin-related modifiers SUMO1, SUMO2, and SUMO3. SUMOylation of IRF3 and IRF7 was dependent on the activation of Toll-like receptor and RIG-I pathways but not on the IFN-stimulated pathway. However, SUMOylation of IRF3 and IRF7 was not dependent on their phosphorylation, and vice versa. We identified Lys(152) of IRF3 and Lys(406) of IRF7 to be their sole small ubiquitin-related modifier (SUMO) conjugation site. IRF3 and IRF7 mutants defective in SUMOylation led to higher levels of IFN mRNA induction after viral infection, relative to the wild type IRFs, indicating a negative role for SUMOylation in IFN transcription. Together, SUMO modification is an integral part of IRF3 and IRF7 activity that contributes to postactivation attenuation of IFN production. C1 [Kubota, Toru; Tashiro, Masato; Kato, Atsushi] Natl Inst Infect Dis, Dept Virol 3, Tokyo 2080011, Japan. [Matsuoka, Mayumi; Sasaki, Tsuguo] Natl Inst Infect Dis, Dept Bacterial Pathogenesis & Infect Control, Tokyo 2080011, Japan. [Chang, Tsung-Hsien; Tailor, Prafullakumar; Ozato, Keiko] NICHD, Lab Mol Growth Regulat, Genom Differentiat Program, NIH, Bethesda, MD 20892 USA. RP Kubota, T (reprint author), Natl Inst Infect Dis, Dept Virol 3, Gakuen 4-7-1, Tokyo 2080011, Japan. EM kubota@nih.go.jp FU National Institutes of Health Intramural Research Program; NICHD; Trans-National Institutes of Health Biodefense Program FX This work was supported, in whole or in part, by the National Institutes of Health Intramural Research Program, NICHD, and the Trans-National Institutes of Health Biodefense Program. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 65 TC 81 Z9 81 U1 2 U2 14 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 SEP 12 PY 2008 VL 283 IS 37 BP 25660 EP 25670 DI 10.1074/jbc.M804479200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 345QZ UT WOS:000259012700061 PM 18635538 ER PT J AU Maeda, K Das, D Yin, PD Tsuchiya, K Ogata-Aoki, H Nakata, H Norman, RB Hackney, LA Takaoka, Y Mitsuya, H AF Maeda, Kenji Das, Debananda Yin, Philip D. Tsuchiya, Kiyoto Ogata-Aoki, Hiromi Nakata, Hirotomo Norman, Rachael B. Hackney, Lauren A. Takaoka, Yoshikazu Mitsuya, Hiroaki TI Involvement of the second extracellular loop and transmembrane residues of CCR5 in inhibitor binding and HIV-1 fusion: Insights into the mechanism of allosteric inhibition SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV-1; CCR5 inhibitor; GPCR structure; allosteric inhibition; extracellular loop ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHEMOKINE RECEPTOR CCR5; SMALL-MOLECULE CCR5; PROTEIN-COUPLED RECEPTOR; HIGHLY POTENT; MONONUCLEAR PHAGOCYTES; ANTI-HIV-1 ACTIVITY; ANTAGONIST TAK-220; CRYSTAL-STRUCTURE; TYPE-1 ENVELOPE AB C-C chemokine receptor 5 (CCR5), a member of G-protein-coupled receptors, serves as a coreceptor for human immunodeficiency virus type I (HIV-1). In the present study, we examined the interactions between CCR5 and novel CCR5 inhibitors containing the spirodiketopiperazine scaffolds AK530 and AK317, both of which were lodged in the hydrophobic cavity located between the upper transmembrane domain and the second extracellular loop (ECL2) of CCR5. Although substantial differences existed between the two inhibitors-AK530 had 10-fold-greater CCR5-binding affinity (K-d = 1.4 nM) l than AK317 (16.7 nM)-their antiviral potencies were virtually identical (IC50=2.1 nM and 1.5 nM, respectively). Molecular dynamics simulations for unbound CCR5 showed hydrogen bond interactions among transmembrane residues Y108, E283, and Y251, which were crucial for HIV-1-gp120/sCD4 complex binding and HIV-1 fusion. indeed, AK530 and AK317, when bound to CCR5, disrupted these interhelix hydrogen bond interactions, a salient molecular mechanism enabling allosteric inhibition. Mutagenesis and structural analysis showed that ECL2 consists of a part of the hydrophobic cavity for both inhibitors, although AK317 is more tightly engaged with ECL2. than AK530, explaining their similar anti-HIV-1 potencies despite the difference in K-d values. We also found that amino acid residues in the 1-hairpin structural motif of ECL2 are critical for HIV-1-elicited fusion and binding of the spirodiketopiperazine-based inhibitors to CCR5. The direct ECL2-engaging property of the inhibitors likely produces an ECL2 conformation, which HIV-1 gp120 cannot bind to, but also prohibits. HFV-1 from utilizing the "irthibitor-bound" CCR5 for cellular entry-a mechanism of HIV-1's resistance to CCR5 inhibitors. The data should not only help delineate the dynamics of CCR5 following inhibitor binding but also aid in designing CCR5 inhibitors that are more potent against HIV-1 and prevent or delay the emergence of resistant HIV-1 variants. Published by Elsevier Ltd. C1 [Maeda, Kenji; Das, Debananda; Yin, Philip D.; Tsuchiya, Kiyoto; Nakata, Hirotomo; Norman, Rachael B.; Hackney, Lauren A.; Mitsuya, Hiroaki] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. [Ogata-Aoki, Hiromi; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, Dept Hematol, Kumamoto, Japan. [Ogata-Aoki, Hiromi; Mitsuya, Hiroaki] Kumamoto Univ, Grad Sch Med & Pharmaceut Sci, Dept Infect Dis, Kumamoto, Japan. [Takaoka, Yoshikazu] Ono Pharmaceut Co Ltd, Minase Res Inst, Osaka, Japan. RP Mitsuya, H (reprint author), NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. EM hmitsuya@helix.nih.gov RI Tsuchiya, Kiyoto/L-8650-2013; OI Tsuchiya, Kiyoto/0000-0002-8233-6653; Goldman, Lauren/0000-0002-8469-2416 FU Center for Cancer Research; National Cancer Institute; NIH; Ministry of Health, Welfare, and Labor of Japan; Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases FX The authors thank David A. Davis and Yasuhiro Koh for critical reading of the manuscript. This work was supported, in part, by the Intramural Research Program of the Center for Cancer Research, National Cancer Institute, NIH, and in part by a Grant for the Promotion of AIDS Research from the Ministry of Health, Welfare, and Labor of Japan, and the Grant to the Cooperative Research Project on Clinical and Epidemiological Studies of Emerging and Reemerging Infectious Diseases (Renkei Jigyo: No. 78, Kumamoto University) of Monbu-Kagakusho (H. M.). We also thank the Center for Information Technology, NTH., for providing Computational resources on the NTH Beowulf Linux cluster, and Susan Chacko and David Hoover for help with batch job configuration on the cluster. NR 55 TC 43 Z9 47 U1 1 U2 11 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 SEP 12 PY 2008 VL 381 IS 4 BP 956 EP 974 DI 10.1016/j.jmb.2008.06.041 PG 19 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 345BP UT WOS:000258971300013 PM 18590744 ER PT J AU Diep, BA Palazzolo-Ballance, AM Tattevin, P Basuino, L Braughton, KR Whitney, AR Chen, L Kreiswirth, BN Otto, M Deleo, FR Chambers, HF AF Diep, Binh An Palazzolo-Ballance, Amy M. Tattevin, Pierre Basuino, Li Braughton, Kevin R. Whitney, Adeline R. Chen, Liang Kreiswirth, Barry N. Otto, Michael DeLeo, Frank R. Chambers, Henry F. TI Contribution of Panton-Valentine Leukocidin in Community-Associated Methicillin-Resistant Staphylococcus aureus Pathogenesis SO PLOS ONE LA English DT Article AB Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains typically carry genes encoding Panton-Valentine leukocidin (PVL). We used wild-type parental and isogenic PVL-deletion (Delta pvl) strains of USA300 (LAC and SF8300) and USA400 (MW2) to test whether PVL alters global gene regulatory networks and contributes to pathogenesis of bacteremia, a hallmark feature of invasive staphylococcal disease. Microarray and proteomic analyses revealed that PVL does not alter gene or protein expression, thereby demonstrating that any contribution of PVL to CA-MRSA pathogenesis is not mediated through interference of global gene regulatory networks. Inasmuch as a direct role for PVL in CA-MRSA pathogenesis remains to be determined, we developed a rabbit bacteremia model of CA-MRSA infection to evaluate the effects of PVL. Following experimental infection of rabbits, an animal species whose granulocytes are more sensitive to the effects of PVL compared with the mouse, we found a contribution of PVL to pathogenesis over the time course of bacteremia. At 24 and 48 hours post infection, PVL appears to play a modest, but measurable role in pathogenesis during the early stages of bacteremic seeding of the kidney, the target organ from which bacteria were not cleared. However, the early survival advantage of this USA300 strain conferred by PVL was lost by 72 hours post infection. These data are consistent with the clinical presentation of rapid-onset, fulminant infection that has been associated with PVL-positive CA-MRSA strains. Taken together, our data indicate a modest and transient positive effect of PVL in the acute phase of bacteremia, thereby providing evidence that PVL contributes to CA-MRSA pathogenesis. C1 [Diep, Binh An; Tattevin, Pierre; Basuino, Li; Chambers, Henry F.] Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Div Infect Dis, San Francisco, CA 94143 USA. [Palazzolo-Ballance, Amy M.; Braughton, Kevin R.; Whitney, Adeline R.; Otto, Michael; DeLeo, Frank R.] National Inst Allergy & Infect Dis, NIH, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, Hamilton, MT USA. [Chen, Liang; Kreiswirth, Barry N.] Univ Med & Dent New Jersey, Publ Hlth Res Inst, Newark, NJ USA. RP Diep, BA (reprint author), Univ Calif San Francisco, San Francisco Gen Hosp, Dept Med, Div Infect Dis, San Francisco, CA 94143 USA. EM hchambers@medsfgh.ucsf.edu RI Chen, Liang/D-3583-2009; OI DeLeo, Frank/0000-0003-3150-2516; Otto, Michael/0000-0002-2222-4115 FU US Public Health Service [AI070289]; Intramural Research Program of the National Institutes of Health, National Institutes of Allergy and Infectious Diseases; Societe de Pathologie Infectieuse de Langue Francaise (SPILF); Pontchaillou University Hospital, Rennes, France; Microbial Pathogenesis and Host Defense Postdoctoral Fellowship [5T32AI060537-02] FX This work was supported by US Public Health Service Grant AI070289 (H.F. Chambers) and the Intramural Research Program of the National Institutes of Health, National Institutes of Allergy and Infectious Diseases (F.R. DeLeo and M. Otto). P. Tattevin was supported by a grant from the Societe de Pathologie Infectieuse de Langue Francaise (SPILF) and by the Pontchaillou University Hospital, Rennes, France. B.A. Diep was supported by a Microbial Pathogenesis and Host Defense Postdoctoral Fellowship (5T32AI060537-02). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 32 TC 124 Z9 125 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 12 PY 2008 VL 3 IS 9 AR e3198 DI 10.1371/journal.pone.0003198 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422KI UT WOS:000264426200004 PM 18787708 ER PT J AU Kuiken, T Taubenberger, JK AF Kuiken, Thijs Taubenberger, Jeffery K. TI Pathology of human influenza revisited SO VACCINE LA English DT Article DE Influenza; Human; Pathology; Pathogenesis ID A VIRUS-INFECTION; LOWER RESPIRATORY-TRACT; SYSTEMIC CYTOKINE RESPONSES; POLYMERASE-CHAIN-REACTION; AIRWAY EPITHELIAL-CELLS; FOWL PLAGUE VIRUS; ASIAN INFLUENZA; ACUTE ENCEPHALOPATHY; RECEPTOR SPECIFICITY; DISTRESS-SYNDROME AB The pathology of human influenza has been studied most intensively during the three pandemics of the last century, the last of which occurred in 1968. It is important to revisit this subject because of the recent emergence of avian H5N1 influenza in humans as well as the threat of a new pandemic. Uncomplicated human influenza virus infection causes transient tracheo-bronchitis, corresponding with predominant virus attachment to tracheal and bronchial epithelial cells. The main complication is extension of viral infection to the alveoli, often with secondary bacterial infection, resulting in severe pneumonia. Complications in extra-respiratory tissues such as encephalopathy, myrocarditis, and myopathy occur occasionally. Sensitive molecular and immunological techniques allow us to investigate whether these complications are a direct result of virus infection or an indirect result of severe pneumonia. Human disease from avian influenza virus infections is most severe for subtype H5N1, but also has been reported for H7 and H9 subtypes. In contrast to human influenza viruses, avian H5N1 virus attaches predominantly to alveolar and bronchiolar epithelium, Corresponding with diffuse alveolar damage as the primary lesion. Viremia and extra-respiratory complications appear to be more common for infections with avian H5N1 virus than with human influenza viruses. Further understanding and comparison of the pathology of human and avian influenza virus infections only can be achieved by directed and careful pathological analysis of additional influenza cases. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Kuiken, Thijs] Erasmus MC, Dept Virol, NL-3015 GE Rotterdam, Netherlands. [Taubenberger, Jeffery K.] NIAID, Infect Dis Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Kuiken, T (reprint author), Erasmus MC, Dept Virol, Dr Molewaterpl 50, NL-3015 GE Rotterdam, Netherlands. EM t.kuiken@erasmusmc.nl FU Intramural NIH HHS [Z01 AI000995-01] NR 97 TC 158 Z9 163 U1 2 U2 28 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 SEP 12 PY 2008 VL 26 SU 4 BP D59 EP D66 DI 10.1016/j.vaccine.2008.07.025 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 362NO UT WOS:000260204600014 PM 19230162 ER PT J AU Pierson, TC Fremont, DH Kuhn, RJ Diamond, MS AF Pierson, Theodore C. Fremont, Daved H. Kuhn, Richard J. Diamond, Michael S. TI Structural insights into the mechanisms of antibody-mediated neutralization of flavivirus infection: Implications for vaccine development SO CELL HOST & MICROBE LA English DT Review ID WEST-NILE-VIRUS; TICK-BORNE ENCEPHALITIS; DENGUE HEMORRHAGIC-FEVER; PROTEIN DOMAIN-III; ENVELOPE PROTEIN; MONOCLONAL-ANTIBODIES; DEPENDENT ENHANCEMENT; EPITOPE DETERMINANTS; IMMUNE-RESPONSES; ANIMAL VIRUSES AB Flaviviruses are a group of small RNA viruses that cause severe disease in humans worldwide and are the target of several vaccine development programs. A primary goal of these efforts is to elicit a protective humoral response directed against the envelope proteins arrayed on the surface of the flavivirus virion. Advances in the structural biology of these viruses has catalyzed rapid progress toward understanding the complexity of the flavivirus immunogen and the molecular basis of antibody-mediated neutralization. These insights have identified factors that govern the potency of neutralizing antibodies and will inform the design and evaluation of novel vaccines. C1 [Pierson, Theodore C.] NIH, Viral Pathogenesis Sect, Viral Dis Lab, Bethesda, MD 20892 USA. [Fremont, Daved H.; Diamond, Michael S.] Washington Univ, Sch Med, Dept Pathol, St Louis, MO 63110 USA. [Fremont, Daved H.; Diamond, Michael S.] Washington Univ, Sch Med, Dept Immunol, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Med, St Louis, MO 63110 USA. [Diamond, Michael S.] Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. [Kuhn, Richard J.] Purdue Univ, Dept Biol Sci, W Lafayette, IN 47907 USA. RP Pierson, TC (reprint author), NIH, Viral Pathogenesis Sect, Viral Dis Lab, 33 N Dr,Bldg 33,Room IE19A2, Bethesda, MD 20892 USA. EM piersontc@mail.nih.gov FU National Institute of Allergy and Infectious Diseases (NIAID); Pediatric Dengue Vaccine Initiative (PDVI); NIH [AI55672, AI061373, AI073755, AI77955]; Burroughs Wellcome Fund FX We would like to thank members of our laboratories for helpful discussion and Dr. Shee Mei Lok (Purdue University) for contributing unpublished images used in the preparation on our figures. This work was supported by the intramural program of the National Institute of Allergy and Infectious Diseases (NIAID) (T.C.P.), the Pediatric Dengue Vaccine Initiative (PDVI) (individual awards to T.C.P., D.H.F., R.J.K.. and M.S.D.), NIH grants AI55672 (R.J.K.). AI061373, AI073755, and AI77955 (M.S.D.). and a Burroughs Wellcome Fund Clinical Scientist Award (M.S.D.). NR 79 TC 121 Z9 123 U1 2 U2 12 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 SEP 11 PY 2008 VL 4 IS 3 BP 229 EP 238 DI 10.1016/j.chom.2008.03.004 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 354GT UT WOS:000259627600009 PM 18779049 ER PT J AU Lisco, A Vanpouille, C Tchesnokov, EP Grivel, JC Biancotto, A Brichacek, B Elliott, J Fromentin, E Shattock, R Anton, P Gorelick, R Balzarini, J McGuigan, C Derudas, M Gotte, M Schinazi, RF Margolis, L AF Lisco, Andrea Vanpouille, Christophe Tchesnokov, Egor P. Grivel, Jean-Charles Biancotto, Angelique Brichacek, Beda Elliott, Julie Fromentin, Emilie Shattock, Robin Anton, Peter Gorelick, Robert Balzarini, Jan McGuigan, Christopher Derudas, Marco Goette, Matthias Schinazi, Raymond F. Margolis, Leonid TI Acyclovir is activated into a HIV-1 reverse transcriptase inhibitor in herpesvirus-infected human tissues SO CELL HOST & MICROBE LA English DT Article ID IMMUNODEFICIENCY-VIRUS-INFECTION; SUICIDE GENE-THERAPY; SIMPLEX-VIRUS; POLYMERASE TRANSLOCATION; THYMIDINE KINASE; DNA-POLYMERASE; DOUBLE-BLIND; EX-VIVO; SUPPRESSION; RNA AB For most viruses, there is a need for antimicrobials that target unique viral molecular properties. Acyclovir (ACV) is one such drug. It is activated into a human herpesvirus (HHV) DNA polymerase inhibitor exclusively by HHV kinases and, thus, does not suppress other viruses. Here, we show that ACV suppresses HIV-1 in HHV-coinfected human tissues, but not in HHV-free tissue or cell cultures. However, addition of HHV-6-infected cells renders these cultures sensitive to anti-HIV ACV activity. We hypothesized that such HIV suppression requires ACV phosphorylation by HHV kinases. Indeed, an ACV monophosphorylated prodrug bypasses the HHV requirement for HIV suppression. Furthermore, phosphorylated ACV directly inhibits HIV-1 reverse transcriptase (RT), terminating DNA chain elongation, and can trap RT at the termination site. These data suggest that ACV anti-HIV-1 activity may contribute to the response of HIV/HHV-coinfected patients to ACV treatment and could guide strategies for the development of new HIV-1 FIT inhibitors. C1 [Lisco, Andrea; Vanpouille, Christophe; Grivel, Jean-Charles; Biancotto, Angelique; Brichacek, Beda; Margolis, Leonid] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. [Tchesnokov, Egor P.; Goette, Matthias] McGill Univ, Dept Microbiol & Immunol, Montreal, PQ H3A 2B4, Canada. [Elliott, Julie; Anton, Peter] Univ Calif Los Angeles, David Geffen Sch Med, UCLA AIDS Inst, Ctr Prevent Res, Los Angeles, CA 90095 USA. [Fromentin, Emilie; Schinazi, Raymond F.] Emory Univ, Sch Med, Vet Affairs Med Ctr, Decatur, GA 30033 USA. [Shattock, Robin] St Georges Univ London, London SW17 0RE, England. [Gorelick, Robert] SAIC Frederick Inc, AIDS Vaccine Program, NCI, Frederick, MD 21702 USA. [Balzarini, Jan] Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. [McGuigan, Christopher; Derudas, Marco] Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3NB, S Glam, Wales. RP Margolis, L (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, NIH, Bethesda, MD 20892 USA. EM margolis@helix.nih.gov RI McGuigan, Chris/P-1580-2014 OI McGuigan, Chris/0000-0001-8409-710X FU Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH; National Cancer Institute, NIH [NO1-CO-12400]; NIH [5P30-AI-50409 (CFAR), 5R37-AI-041980]; Geconcerteerde Onderzoeksacties [05/19]; Canadian Institutes of Health Research FX We thank Dr. M. Santi and the entire staff of the Department of Pathology of Children's National Medical Center for their generous assistance in obtaining human tonsillar tissues. This research was supported in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH. and by federal funds from the National Cancer Institute, NIH, under contract NO1-CO-12400. R.F.S. is supported, in part, by NIH grants 5P30-AI-50409 (CFAR), 5R37-AI-041980, and the Department of Veterans Affairs. J.B. is supported by the Geconcerteerde Onderzoeksacties (GOA No. 05/19). M.G. is the recipient of a national career award and a research grant from the Canadian Institutes of Health Research. L.M. dedicates this paper to the 80th birthday of his mentor, Professor Ju. M. Vasiliev. NR 44 TC 76 Z9 76 U1 0 U2 2 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 SEP 11 PY 2008 VL 4 IS 3 BP 260 EP 270 DI 10.1016/j.chom.2008.07.008 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 354GT UT WOS:000259627600012 PM 18779052 ER PT J AU Duan, D Sigano, DM Kelley, JA Lai, CC Lewin, NE Kedei, N Peach, ML Lee, J Abeyweera, TP Rotenberg, SA Kim, H Kim, YH El Kazzouli, S Chung, JU Young, HA Young, MR Baker, A Colburn, NH Haimovitz-Friedman, A Truman, JP Parrish, DA Deschamps, JR Perry, NA Surawski, RJ Blumberg, PM Marquez, VE AF Duan, Dehui Sigano, Dina M. Kelley, James A. Lai, Christopher C. Lewin, Nancy E. Kedei, Noemi Peach, Megan L. Lee, Jeewoo Abeyweera, Thushara P. Rotenberg, Susan A. Kim, Hee Kim, Young Ho El Kazzouli, Said Chung, Jae-Uk Young, Howard A. Young, Matthew R. Baker, Alyson Colburn, Nancy H. Haimovitz-Friedman, Adriana Truman, Jean-Philip Parrish, Damon A. Deschamps, Jeffrey R. Perry, Nicholas A. Surawski, Robert J. Blumberg, Peter M. Marquez, Victor E. TI Conformationally constrained analogues of diacylglycerol. 29. Cells sort diacylglycerol-lactone chemical zip codes to produce diverse and selective biological activities SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; AMYLOID PRECURSOR PROTEIN; PHORBOL ESTERS; DAG-LACTONES; PKC-ALPHA; COMBINATORIAL CHEMISTRY; CERAMIDE SYNTHASE; INDUCED APOPTOSIS; BINDING-AFFINITY; GAMMA PRODUCTION AB Diacylglycerol-lactone (DAG-lactone) libraries generated by a solid-phase approach using IRORI technology produced a variety of unique biological activities. Subtle differences in chemical diversity in two areas of the molecule, the combination of which generates what we have termed "chemical zip codes", are able to transform a relatively small chemical space into a larger universe of biological activities, as membrane-containing organelles within the cell appear to be able to decode these "chemical zip codes". It is postulated that after binding to protein kinase C (PKC) isozymes or other nonkinase target proteins that contain diacylglycerol responsive, membrane interacting domains (C1 domains), the resulting complexes are directed to diverse intracellular sites where different sets of substrates are accessed. Multiple cellular bioassays show that DAG-lactones, which bind in vitro to PKC alpha to varying degrees, expand their biological repertoire into a larger domain, eliciting distinct cellular responses. C1 [Duan, Dehui; Sigano, Dina M.; Kelley, James A.; Lai, Christopher C.; El Kazzouli, Said; Marquez, Victor E.] NCI, NIH, Med Chem Lab, Frederick, MD 21702 USA. [Lewin, Nancy E.; Kedei, Noemi; Perry, Nicholas A.; Surawski, Robert J.; Blumberg, Peter M.] NCI, NIH, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. [Peach, Megan L.] Basic Res Program SAIC Frederick Inc, NCI Frederick, Frederick, MD 21702 USA. [Lee, Jeewoo; Chung, Jae-Uk] Seoul Natl Univ, Coll Pharm, Res Inst Pharmaceut Sci, Med Chem Lab, Seoul 151742, South Korea. [Duan, Dehui; Abeyweera, Thushara P.; Rotenberg, Susan A.] CUNY Queens Coll, Dept Chem & Biochem, Flushing, NY 11367 USA. [Kim, Young Ho] Digital Biotech, Ansa Si 425839, Kyonggi Do, South Korea. [Young, Howard A.] NCI, NIH, Expt Immunol Lab, Frederick, MD 21702 USA. [Young, Matthew R.; Baker, Alyson; Colburn, Nancy H.] NCI, NIH, Lab Canc Prevent, Frederick, MD 21702 USA. [Haimovitz-Friedman, Adriana; Truman, Jean-Philip] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10021 USA. [Parrish, Damon A.; Deschamps, Jeffrey R.] USN, Res Lab, Washington, DC 20375 USA. RP Marquez, VE (reprint author), NCI, NIH, Med Chem Lab, 376 Boyles St, Frederick, MD 21702 USA. EM marquezv@mail.nih.gov RI Kim, Young Ho/J-5414-2012; Sigano, Dina/M-6144-2014; OI Sigano, Dina/0000-0001-7489-9555; Deschamps, Jeffrey/0000-0001-5845-0010 FU NIH; National Cancer Institute; Center for Career Research; National Institutes of Health [N01-CO-12400]; Ministry of Health and Welfare [A020601]; NIH [CA105125-02, CA125632]; National Institute on Drug Abuse (NIDA) [Y1-DA6002] FX This paper is dedicated to Dr. John S. Driscoll, former Chief of the Laboratory of Medicinal Chemistry at NCI. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Career Research, and in part with federal funds from the National Cancer Institute, National Institutes of Health. under contract N01-CO-12400. The coment 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 work was also supported in part by the Korea Health 21 R&D Grant (A020601) from the Ministry of Health and Welfare, by NIH Grant RO1 no. CA105125-02 to A.H.-F. and by NIH CA125632 to S.A.R. X-ray crystallographic Studies were Supported in part under contract Y1-DA6002 from the National Institute on Drug Abuse (NIDA). NR 69 TC 25 Z9 25 U1 0 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 11 PY 2008 VL 51 IS 17 BP 5198 EP 5220 DI 10.1021/jm8001907 PG 23 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 345ET UT WOS:000258979600004 PM 18698758 ER PT J AU Richardson, RD Ma, G Oyola, Y Zancanella, M Knowles, LM Cieplak, P Romo, D Smith, JW AF Richardson, Robyn D. Ma, Gil Oyola, Yatsandra Zancanella, Manuel Knowles, Lynn M. Cieplak, Piotr Romo, Daniel Smith, Jeffrey W. TI Synthesis of novel beta-lactone inhibitors of fatty acid synthase SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PANCREATIC LIPASE INHIBITOR; BREAST-CARCINOMA PATIENTS; THIOESTERASE DOMAIN; PROSTATE-CANCER; EXPRESSION; ORLISTAT; MODEL; SELECTIVITY; INDUCTION; CONCISE AB Fatty acid synthase (FAS) is necessary for growth and survival of tumor cells and is a promising drug target for oncology. Here, we report oil the syntheses and activity of novel inhibitors of the thioesterase domain of FAS. Using the structure of orlistat as a starting point, which contains a beta-lactone as the central pharmacophore, 28 novel congeners were synthesized and examined. Structural features such as the length of the alpha- and beta-alkyl chains, their chemical composition, and arnino ester substitutions were altered and tile resulting compounds explored for inhibitory activity toward the thioesterase domain of FAS. Nineteen congeners show improved potency for FAS in biochemical assays relative to orlistat. Three of that subset, including the natural product valilactone, also display all increased potency in inducing tumor cell death and improved solubility compared to orlistat. These findings Support the idea that all orlistat congener can be optimized for use in a preclinical drug design and for clinical drug development. C1 [Richardson, Robyn D.; Knowles, Lynn M.; Cieplak, Piotr; Smith, Jeffrey W.] Burnham Inst Med Res, NCI, Ctr Canc, La Jolla, CA 92037 USA. [Ma, Gil; Oyola, Yatsandra; Zancanella, Manuel; Romo, Daniel] Texas A&M Univ, Dept Chem, College Stn, TX 77842 USA. RP Smith, JW (reprint author), Burnham Inst Med Res, NCI, Ctr Canc, 10901 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM romo@mail.chem.tamu.edu; jsmith@burnham.org FU NIH [CA10658, CA81713]; Welch Foundation FX We thank the NIH (NCI CA10658 D.I. and J.W.S.; CA81713. J.W.S.) and the Welch Foundation (D.R.) for Support of these investigations. We thank Dr. Wei Zhang for assistance with manuscript preparation and Ms. Li Yang for technical assistance with purity chromatograms. Helpful conversations with Dr. Adam Richardson and Dr. Russell Dahl are gratefully acknowledged. NR 24 TC 31 Z9 32 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 11 PY 2008 VL 51 IS 17 BP 5285 EP 5296 DI 10.1021/jm800321h PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 345ET UT WOS:000258979600010 PM 18710210 ER PT J AU Neres, J Labello, NP Somu, RV Boshoff, HI Wilson, DJ Vannada, J Chen, L Barry, CE Bennett, EM Aldrich, CC AF Neres, Joao Labello, Nicholas P. Somu, Ravindranadh V. Boshoff, Helena I. Wilson, Daniel J. Vannada, Jagadeshwar Chen, Liqiang Barry, Clifton E., III Bennett, Eric M. Aldrich, Courtney C. TI Inhibition of siderophore biosynthesis in Mycobacterium tuberculosis with nucleoside bisubstrate analogues: Structure-activity relationships of the nucleobase domain of 5 '-O-[N-(salicyl)sulfamoyl]adenosine SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Review ID PURINE NUCLEOSIDES; IRON ACQUISITION; YERSINIA-PESTIS; PSEUDOMONAS-AERUGINOSA; ANTITUBERCULAR AGENTS; PEPTIDE SYNTHETASES; MOLECULAR-DYNAMICS; BACILLUS-ANTHRACIS; RECEPTOR AGONISTS; ACID ADENYLATION AB 5'-O-[N-(salicyl)sulfamoyl]adenosine (Sal-AMS) is a prototype for a new class of antitubercular agents that inhibit the aryl acid adenylating enzyme (AAAE) known as MbtA involved in biosynthesis of the mycobactins. Herein, we report the structure-based design, synthesis, biochemical, and biological evaluation of a comprehensive and systematic series of analogues, exploring the structure-activity relationship of the purine nucleobase domain of Sal-AMS. Significantly, 2-phenyl-Sal-AMS derivative 26 exhibited exceptionally potent antitubercular activity with an MIC(99) under iron-deficient conditions of 0.049 mu M while the N-6-cyclopropyl-Sal-AMS 16 led to improved potency and to a 64-enhancement in activity under iron-deficient conditions relative to iron-replete conditions, a phenotype concordant with the designed mechanism of action. The most potent MbtA inhibitors disclosed here display in vitro antitubercular activity superior to most current first line TB drugs, and these compounds are also expected to be useful against a wide range of pathogens that require aryl-capped siderphores for virulence. C1 [Neres, Joao; Labello, Nicholas P.; Somu, Ravindranadh V.; Wilson, Daniel J.; Vannada, Jagadeshwar; Chen, Liqiang; Bennett, Eric M.; Aldrich, Courtney C.] Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA. [Boshoff, Helena I.; Barry, Clifton E., III] NIAID, TB Res Sect, Bethesda, MD 20892 USA. RP Aldrich, CC (reprint author), Univ Minnesota, Acad Hlth Ctr, Ctr Drug Design, Minneapolis, MN 55455 USA. EM aldri015@umn.edu RI Barry, III, Clifton/H-3839-2012; Neres, Joao/A-1241-2011 OI Neres, Joao/0000-0003-4488-2423 FU NIH [R01A1070219]; Academic Health Center, University of Minnesota; National Institute of Allergy and Infectious Disease FX This research was supported by a grant from the NIH (Grant R01A1070219) and funding from the Center for Drug Design, Academic Health Center, University of Minnesota to C.C.A. We thank the Minnesota Supercomputing Institute for computing time. This research supported in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Disease. NR 101 TC 81 Z9 82 U1 1 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 11 PY 2008 VL 51 IS 17 BP 5349 EP 5370 DI 10.1021/jm800567v PG 22 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 345ET UT WOS:000258979600017 PM 18690677 ER PT J AU El Kazzouli, S Lewin, NE Blumberg, PM Marquez, VE AF El Kazzouli, Said Lewin, Nancy E. Blumberg, Peter M. Marquez, Victor E. TI Conformationally constrained analogues of diacylglycerol. 30. An investigation of diacylglycerol-lactones containing heteroaryl groups reveals compounds with high selectivity for Ras guanyl nucleotide-releasing proteins SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID KINASE-C; PHORBOL ESTERS; DAG-LACTONES; BINDING-AFFINITY; DOMAIN; ACTIVATION; TARGETS; DELTA AB Using a diacylglycerol-lactone (DAG-lactone) template previously developed in our laboratory as a scaffold with high binding affinity for C I domains, we describe herein a series of novel DAG-lactones containing heterocyclic moieties (pyridines, quinolines, and indoles) as alpha-arylidene fragments. Some of the DAG-lactones obtained show selective binding to RasGRP3 as compared to PKC alpha by more than 2 orders of magnitude and possess subnanomolar affinities. Because activated C1 domains bound to their ligands (DAG or DAG-lactones) insert into membranes, the lipid composition of membranes (cellular, nuclear, and those of internal organelles) is an important determinant for specificity. Therefore, reaching a proper hydrophilic/lipophilic balance for these molecules is critical. This was achieved by carefully selecting partnering acyl fragments for the DAG-lactones with the appropriate lipophilicity. The results clearly show that the combination of chemical and physical properties in these molecules needs to be perfectly balanced to achieve the desired specificity. C1 [El Kazzouli, Said; Marquez, Victor E.] NCI, NIH, Ctr Canc Res, Med Chem Lab, Frederick, MD 21702 USA. [Lewin, Nancy E.; Blumberg, Peter M.] NCI, NIH, Ctr Canc Res, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Marquez, VE (reprint author), NCI, NIH, Ctr Canc Res, Med Chem Lab, 376 Boyles St, Frederick, MD 21702 USA. EM marqueza@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research FX This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. The authors thank Dr. Dina M. Sigano for her help during the prearation of this manuscript. NR 27 TC 11 Z9 11 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD SEP 11 PY 2008 VL 51 IS 17 BP 5371 EP 5386 DI 10.1021/jm800380b PG 16 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 345ET UT WOS:000258979600018 PM 18707088 ER PT J AU Larkin, JD Bhat, KL Markham, GD James, TD Brooks, BR Bock, CW AF Larkin, Joseph D. Bhat, Krishna L. Markham, George D. James, Tony D. Brooks, Bernard R. Bock, Charles W. TI A computational characterization of boron-oxygen multiple bonding in HN=CH-CH=CH-NH-BO SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Review ID GAUSSIAN-BASIS SETS; CORRELATED MOLECULAR CALCULATIONS; INFRARED DIODE-LASER; METHYL TRANSFER-REACTIONS; MANY-ELECTRON SYSTEMS; BORIC-ACID CLUSTERS; AB-INITIO; CORRELATION-ENERGY; WAVE-FUNCTIONS; MICROWAVE SPECTROSCOPY AB Structures, relative energies, and bonding characteristics for various conformers of 3-imino-N-(oxoboryl)prop-1-en-1-amine, HN=CH-CH=CH-NH-BO,and the corresponding borocycle (-HN=CH-CH=CH-NH-B-)O are discussed using results from second-order Moller-Plesset (MP2) perturbation theory with the Dunning-Woon correlation-consistent cc-pVDZ, aug-cc-pVDZ, and cc-pVTZ basis sets. These MP2 results are compared to those from computationally efficient density functional theory (DFT) calculations using the LDA, PBE, TPSS, BLYP, B3LYP. BVP86, OLYP, O3LYP, and PBE1PBE functionals in conjunction with the economical Pople-type 6-311 ++G(d,p) basis set to evaluate the suitability of these DFT/6-311 ++G(d,p) levels for use With larger boron-containing systems. The effects of an aqueous environment were incorporated into the calculations using COSMO methodology. The calculated boron-oxygen bond lengths, orbital compositions, and bond orders in all the (acyclic) HN=CH-CH=CH-NH-BO conformers were consistent with the presence of a boron-oxygen triple bond, similar to that found in H-B O and H2N-B O. The (-HN=CH-CH=CH-NH-B-)O borocycle is predicted to be planar (C,, symmetry), and it is similar to 30 kcal/mol lower in energy than any of the (acyclic) HN=CH-CH=CH-NH-BO conformers; the boron-oxygen bond in this borocycle has significant double bond character, a bonding scheme for which there has been only one experimental structure reported in the literature (Vidovic, D.; et al. J. Am. Chem. Soc. 2005, 127, 4566-4569). C1 [Larkin, Joseph D.] Bloomsburg Univ Penn, Dept Chem, Bloomsburg, PA 17815 USA. [Bock, Charles W.] Philadelphia Univ, Sch Sci & Hlth, Dept Chem & Biochem, Philadelphia, PA 19144 USA. [Markham, George D.; Bock, Charles W.] Fox Chase Canc Ctr, Inst Canc Res, Philadelphia, PA 19111 USA. [Larkin, Joseph D.; Brooks, Bernard R.] NHLBI, NIH, Bethesda, MD 20851 USA. [James, Tony D.] Univ Bath, Dept Chem, Bath BA2 7AY, Avon, England. [Bhat, Krishna L.] Widener Univ, Dept Chem, Chester, PA 19013 USA. RP Larkin, JD (reprint author), Bloomsburg Univ Penn, Dept Chem, Bloomsburg, PA 17815 USA. EM jlarkin@bloomu.edu RI James, Tony/B-5125-2009 OI James, Tony/0000-0002-4095-2191 FU NIH; NHLBI; National Textile Center [C03-PH01]; NIH [GM31186, CA06927]; NCI; Commonwealth of Pennsylvania FX This research was supported, in part, by the Intramural Research Program of the NIH, NHLBI. K.L.B. would like to thank the National Textile Center (C03-PH01); G.D.M. would like to thank NIH (GM31186, CA06927) and NCI for financial support of this work, which was also supported by an appropriation from the Commonwealth of Pennsylvania. The High Performance Computing Facility at the Fox Chase Cancer Center was used for some of the calculations described in this manuscript. NR 105 TC 8 Z9 8 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD SEP 11 PY 2008 VL 112 IS 36 BP 8446 EP 8454 DI 10.1021/jp800125p PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 345FE UT WOS:000258980700029 PM 18707068 ER PT J AU Pesu, M Watford, WT Wei, L Xu, LL Fuss, I Strober, W Andersson, J Shevach, EM Quezado, M Bouladoux, N Roebroek, A Belkaid, Y Creemers, J O'Shea, JJ AF Pesu, Marko Watford, Wendy T. Wei, Lai Xu, Lili Fuss, Ivan Strober, Warren Andersson, John Shevach, Ethan M. Quezado, Martha Bouladoux, Nicolas Roebroek, Anton Belkaid, Yasmine Creemers, John O'Shea, John J. TI T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance SO NATURE LA English DT Article ID ACTIVATION; BETA; GROWTH; MICE; CONVERSION; INDUCTION; COLITIS; MASTER; FOXP3 AB Furin is one of seven proprotein convertase family members that promote proteolytic maturation of proproteins(1). It is induced in activated T cells and is reported to process a variety of substrates including the anti- inflammatory cytokine transforming growth factor (TGF)-beta 1 ( refs 2 - 4), but the non- redundant functions of furin versus other proprotein convertases in T cells are unclear. Here we show that conditional deletion of furin in T cells allowed for normal T- cell development but impaired the function of regulatory and effector T cells, which produced less TGF-beta 1. Furin-deficient T regulatory (T-reg) cells were less protective in a T- cell transfer colitis model and failed to induce Foxp3 in normal T cells. Additionally, furin- deficient effector cells were inherently over-active and were resistant to suppressive activity of wild- type T-reg cells. Thus, our results indicate that furin is indispensable in maintaining peripheral tolerance, which is due, at least in part, to its non- redundant, essential function in regulating TGF-beta 1 production. Targeting furin has emerged as a strategy in malignant and infectious disease(5,6). Our results suggest that inhibiting furin might activate immune responses, but may result in a breakdown in peripheral tolerance. C1 [Pesu, Marko; Watford, Wendy T.; Wei, Lai; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. [Xu, Lili; Fuss, Ivan; Strober, Warren] NIAID, Mucosal Immun Sect, Host Def Lab, NIH, Bethesda, MD 20892 USA. [Andersson, John; Shevach, Ethan M.] NIAID, Cellular Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. [Bouladoux, Nicolas; Belkaid, Yasmine] NIAID, Mucosal Immunol Unit, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Quezado, Martha] NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. [Roebroek, Anton; Creemers, John] Katholieke Univ Leuven, Biochem Neuroendocrinol Lab, B-3000 Louvain, Belgium. [Roebroek, Anton; Creemers, John] VIB, B-3000 Louvain, Belgium. RP Pesu, M (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. EM pesum@mail.nih.gov RI Andersson, John/A-4436-2009; Pesu, marko/L-6344-2013; Wei, Lai/D-1088-2014; OI Andersson, John/0000-0003-2799-6349 FU Intramural Research Program of NIAMS; Academy of Finland; Finnish Medical Foundation; Maud Kuistila Memorial Foundation; Fonds voor Wetenschappelijk Onderzoek Vlaanderen; Geconcerteerde Onderzoeksactie van de Vlaamse Gemeenschap FX We thank J. Bonifacino (National Institute of Child Health and Human Development) and S. Wahl (National Institute of Dental and Craniofacial Research) for providing comments and reading the manuscript, A. Singer (National Cancer Institute) and L. Pobenzinsky (NCI) for providing suggestions, and M. Oukka (HarvardMedical School) for providing Foxp3- GFP mice. This work was supported by the Intramural Research Program of NIAMS, Academy of Finland, the Finnish Medical Foundation, the Maud Kuistila Memorial Foundation, the 'Fonds voor Wetenschappelijk Onderzoek Vlaanderen' and 'Geconcerteerde Onderzoeksactie van de Vlaamse Gemeenschap'. NR 25 TC 89 Z9 94 U1 2 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 11 PY 2008 VL 455 IS 7210 BP 246 EP U73 DI 10.1038/nature07210 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 346SZ UT WOS:000259090800052 PM 18701887 ER PT J AU Butt, SJB Sousa, VH Fuccillo, MV Hjerling-Leffler, J Miyoshi, G Kimura, S Fishell, G AF Butt, Simon J. B. Sousa, Vitor H. Fuccillo, Marc V. Hjerling-Leffler, Jens Miyoshi, Goichi Kimura, Shioko Fishell, Gord TI The requirement of Nkx2-1 in the temporal specification of cortical interneurion subtypes SO NEURON LA English DT Article ID CENTRAL-NERVOUS-SYSTEM; GANGLIONIC EMINENCE; CHOLINERGIC NEURONS; SONIC HEDGEHOG; TRANSCRIPTIONAL ACTIVITY; VENTRAL FOREBRAIN; PROGENITOR CELLS; COLUMN IDENTITY; MOUSE FOREBRAIN; HOMEOBOX GENES AB Previous work has demonstrated that the character of mouse cortical interneuron subtypes can be directly related to their embryonic temporal and spatial origins. The relationship between embryonic origin and the character of mature interneurons is likely reflected by the developmental expression of genes that direct cell fate. However, a thorough understanding of the early genetic events that specify subtype identity has been hampered by the perinatal lethality resulting from the loss of genes implicated in the determination of cortical interneurons. Here, we employ a conditional loss-of-function approach to demonstrate that the transcription factor Nkx2-1 is required for the proper specification of specific interneuron subtypes. Removal of this gene at distinct neurogenic time points results in a switch in the subtypes of neurons observed at more mature ages. Our strategy reveals a causal link between the embryonic genetic specification by Nkx2-1 in progenitors and the functional attributes of their neuronal progeny in the mature nervous system. C1 [Butt, Simon J. B.; Sousa, Vitor H.; Fuccillo, Marc V.; Hjerling-Leffler, Jens; Miyoshi, Goichi; Kimura, Shioko; Fishell, Gord] NYU, Smilow Neurosci Program, New York, NY 10016 USA. [Butt, Simon J. B.; Sousa, Vitor H.; Fuccillo, Marc V.; Hjerling-Leffler, Jens; Miyoshi, Goichi; Kimura, Shioko; Fishell, Gord] NYU, Dept Cell Biol, New York, NY 10016 USA. [Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Fishell, G (reprint author), NYU, Smilow Neurosci Program, 550 1St Ave, New York, NY 10016 USA. EM fishell@saturn.med.nyu.edu RI Hjerling-Leffler, Jens/B-3307-2008; Hjerling-Leffler, Jens/E-3775-2012; Miyoshi, Goichi/H-4759-2012; Sousa, Vitor/E-3679-2016 OI Butt, Simon/0000-0002-2399-0102; Hjerling-Leffler, Jens/0000-0002-4539-1776; Sousa, Vitor/0000-0001-8768-2742 FU Human Frontier Science Program Organization Long-Term Fellowship; Swedish Brain Foundation (Hjarnfonden); Japan Society for the Promotion of Science; National Institutes of Health; National Institute of Mental Health and National Institute of Neurological Disorders and Stroke [R01MH068469, R01NS039007]; National Cancer Institute; Center for Cancer Research FX We wish to thank Dr. Hirohide Takebayashi for providing the Olig2 CreER (TM) mouse. cDNA in situ probe templates were kindly provided by J. Ericson (Nkx6-2), A. Joyner (Cre, Gli1, Nkx2-1, Shh), V. Pachnis (Lhx6), J. Rubenstein (Dlx2), and M. Studer (CoupTF-II). The polyclonal rabbit anti-Lhx6 antibody was a kind gift from V. Pachnis. We would also like to thank Lihong Yin and Jiali Deng for excellent technical help. S.J.B.B. is a recipient of a Human Frontier Science Program Organization Long-Term Fellowship; J.H.-L. is a recipient of a postdoctoral fellowship from the Swedish Brain Foundation (Hjarnfonden); G.M. is supported by a grant from the Japan Society for the Promotion of Science. Research in the Fishell laboratory is supported by National Institutes of Health (National Institute of Mental Health and National Institute of Neurological Disorders and Stroke Grants R01MH068469 and R01NS039007). S.K. is supported by the Intramural Research Program of the National Cancer Institute, Center for Cancer Research. NR 56 TC 148 Z9 151 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 11 PY 2008 VL 59 IS 5 BP 722 EP 732 DI 10.1016/j.neuron.2008.07.031 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 349DG UT WOS:000259258400007 PM 18786356 ER PT J AU Nobrega-Pereira, S Kessaris, N Du, TG Kimura, S Anderson, SA Marin, O AF Nobrega-Pereira, Sandrina Kessaris, Nicoletta Du, Tonggong Kimura, Shioko Anderson, Stewart A. Marin, Oscar TI Postmitotic Nkx2-1 controls the migration of telencephalic interneurons by direct repression of guidance receptors SO NEURON LA English DT Article ID FOREBRAIN CHOLINERGIC NEURONS; MEDIAL GANGLIONIC EMINENCE; TRANSCRIPTION FACTOR-I; LIM HOMEOBOX GENE; AXON GUIDANCE; BASAL FOREBRAIN; HOMEODOMAIN PROTEINS; SONIC HEDGEHOG; CELL-MIGRATION; NEURAL-TUBE AB The homeodomain transcription factor Nkx2-1 plays key roles in the developing telencephalon, where it regulates the identity of progenitor cells in the medial ganglionic eminence (MGE) and mediates the specification of several classes of GABAergic and cholinergic neurons. Here, we have investigated the post-mitotic function of Nkx2-1 in the migration of interneurons originating in the MGE. Experimental manipulations and mouse genetics show that down-regulation of Nkx2-1 expression in postmitotic cells is necessary for the migration of interneurons to the cortex, whereas maintenance of Nkx2-1 expression is required for interneuron migration to the striatum. Nkx2-1 exerts this role in the migration of MGE-derived interneurons by directly regulating the expression of a guidance receptor, Neuropilin-2, which enables interneurons to invade the developing striatum. Our results demonstrate a role for the cell-fate determinant Nkx2-1 in regulating neuronal migration by direct transcriptional regulation of guidance receptors in postmitotic cells. C1 [Nobrega-Pereira, Sandrina; Marin, Oscar] CSIC, Inst Neurociencias Alicante, Sant Joan dAlacant 03550, Spain. [Nobrega-Pereira, Sandrina; Marin, Oscar] Univ Miguel Hernandez, Sant Joan dAlacant 03550, Spain. [Nobrega-Pereira, Sandrina] Univ Coimbra, Programme Expt Biol & Biomed, Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal. [Kessaris, Nicoletta] UCL, Wolfson Inst Biomed Res, London WC1E 6AE, England. [Kessaris, Nicoletta] UCL, Dept Cell & Dev Biol, London WC1E 6AE, England. [Du, Tonggong; Anderson, Stewart A.] Cornell Univ, Dept Psychiat, Weill Med Coll, New York, NY 10021 USA. [Kimura, Shioko] NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Marin, O (reprint author), CSIC, Inst Neurociencias Alicante, Sant Joan dAlacant 03550, Spain. EM o.marin@umh.es RI Kessaris, Nicoletta/C-7249-2008; Marin, Oscar/F-3856-2012; OI Kessaris, Nicoletta/0000-0003-1191-6009; Marin, Oscar/0000-0001-6264-7027; Nobrega-Pereira, Sandrina/0000-0002-9652-1382 FU Spanish Ministry of Education and Science [BFU2005-04773/BMC]; CONSOLIDER [CSD2007-00023]; Fundacio "la Caixa"; European Commission [005139 (INTERDEVO)]; EURYI; NINDS; NIMH; UK Medical Research Council; European Research Council; Foundation for Science and Technology [POCI 2010/FSE] FX We thank M. Bonete, T. Gil, M. Perez, M. Grist, and A. Rubin for excellent technical assistance, V. Pachnis, M. Tessier-Lavigne, and J.M. Ortiz for plasmids, A. Barco for the q-PCR equipment, C. Garcia-Frigola and J. Galceran for advice on ChIP and luminescence experiments, respectively, and A. Nagy and S. Srinivas for Gfp and Rosa-EYFP mice, respectively. We are grateful to J. Galceran and members of the Mann and Rico labs for stimulating discussions and critical reading of this manuscript. We are also very grateful to F.J. Martini and M. Valdeolmillos for their help on pilot single-cell RT-PCR experiments. This work was supported by grants from Spanish Ministry of Education and Science BFU2005-04773/BMC and CONSOLIDER CSD2007-00023, Fundacio "la Caixa," the European Commission through STREP contract number 005139 (INTERDEVO), and the EURYI program (to O.M.), NINDS and NIMH (to S.A.A.), and UK Medical Research Council and European Research Council (to N.K.). S.N.-P. was supported by a predoctoral fellowship from the Foundation for Science and Technology (POCI 2010/FSE), Portugal. NR 61 TC 113 Z9 113 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD SEP 11 PY 2008 VL 59 IS 5 BP 733 EP 745 DI 10.1016/j.neuron.2008.07.024 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 349DG UT WOS:000259258400008 PM 18786357 ER PT J AU Sun, C Dobi, A Mohamed, A Li, H Thangapazham, RL Furusato, B Shaheduzzaman, S Tan, SH Vaidyanathan, G Whitman, E Hawksworth, DJ Chen, Y Nau, M Patel, V Vahey, M Gutkind, JS Sreenath, T Petrovics, G Sesterhenn, IA McLeod, DG Srivastava, S AF Sun, C. Dobi, A. Mohamed, A. Li, H. Thangapazham, R. L. Furusato, B. Shaheduzzaman, S. Tan, S-H Vaidyanathan, G. Whitman, E. Hawksworth, D. J. Chen, Y. Nau, M. Patel, V. Vahey, M. Gutkind, J. S. Sreenath, T. Petrovics, G. Sesterhenn, I. A. McLeod, D. G. Srivastava, S. TI TMPRSS2-ERG fusion, a common genomic alteration in prostate cancer activates C-MYC and abrogates prostate epithelial differentiation SO ONCOGENE LA English DT Article DE ERG; prostate cancer; oncogene; C-MYC; PSA; TMPRSS2-ERG ID ETS TRANSCRIPTION FACTOR; ANDROGEN RECEPTOR; EXPRESSION; REARRANGEMENTS; LEUKEMIA; TARGETS; ADULTS; GENES; ERG AB The high prevalence of TMPRSS2-ERG rearrangements (similar to 60%) in prostate cancer (CaP) leads to androgenic induction of the ETS-related gene (ERG) expression. However, the biological functions of ERG overexpression in CaP remain to be understood. ERG knockdown in TMPRSS2-ERG expressing CaP cells induced striking morphological changes and inhibited cell growth both in cell culture and SCID mice. Evaluation of the transcriptome and specific gene promoters in ERG siRNA-treated cells and investigation of gene expression signatures of human prostate tumors revealed ERG-mediated activation of C-MYC oncogene and the repression of prostate epithelial differentiation genes (PSA and SLC45A3/Prostein). Taken together, these data combining cell culture and animal models and human prostate tumors reveal that ERG overexpression in prostate tumor cells may contribute to the neoplastic process by activating C-MYC and by abrogating prostate epithelial differentiation as indicated by prostate epithelial specific markers. C1 [Sun, C.; Dobi, A.; Mohamed, A.; Li, H.; Thangapazham, R. L.; Furusato, B.; Shaheduzzaman, S.; Tan, S-H; Vaidyanathan, G.; Whitman, E.; Hawksworth, D. J.; Chen, Y.; Sreenath, T.; Petrovics, G.; McLeod, D. G.; Srivastava, S.] Uniformed Serv Univ Hlth Sci, Ctr Prostate Dis Res, Dept Surg, Rockville, MD 20852 USA. [Furusato, B.; Sesterhenn, I. A.] Armed Forces Inst Pathol, Dept Genitourinary Pathol, Washington, DC 20306 USA. [Whitman, E.; Hawksworth, D. J.; McLeod, D. G.] Walter Reed Army Med Ctr, Urol Serv, Dept Surg, Washington, DC 20307 USA. [Nau, M.; Vahey, M.] Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD USA. [Patel, V.; Gutkind, J. S.] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Natl Inst Hlth, Bethesda, MD USA. [Dobi, A.; Sesterhenn, I. A.; McLeod, D. G.; Srivastava, S.] US Mil Canc Inst, Washington, DC USA. RP Srivastava, S (reprint author), Uniformed Serv Univ Hlth Sci, Ctr Prostate Dis Res, Dept Surg, 1530 E Jefferson St, Rockville, MD 20852 USA. EM ssrivastava@cpdr.org RI Gutkind, J. Silvio/A-1053-2009; OI Furusato, Bungo/0000-0003-4614-9882 FU US Army Medical Research and Materiel Command; NIH Grants [RO1 DK065977, RO1 CA106653] FX Authors express sincere thanks to Ms Lakshmi Ravindranath, Ms Atekelt Y Tadese, Ms Suma Ravulapalli and Mr Christopher Cook for their superb technical support of this study. The prostate tissue specimens used in this study were obtained under an IRB-approved protocol at Walter Reed Army Medical Center. This work was funded by the CPDR through an ongoing grant from the US Army Medical Research and Materiel Command, NIH Grants RO1 DK065977 to S. S and G. P. and RO1 CA106653 to S. S. and A. D. The views expressed in this manuscript are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense or the US Government. NR 22 TC 121 Z9 122 U1 0 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 11 PY 2008 VL 27 IS 40 BP 5348 EP 5353 DI 10.1038/onc.2008.183 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 346UW UT WOS:000259096100007 PM 18542058 ER PT J AU Calvo, A Catena, R Noble, MS Carbott, D Gil-Bazo, I Gonzalez-Moreno, O Huh, JI Sharp, R Qiu, TH Anver, MR Merlino, G Dickson, RB Johnson, MD Green, JE AF Calvo, A. Catena, R. Noble, M. S. Carbott, D. Gil-Bazo, I. Gonzalez-Moreno, O. Huh, J-I Sharp, R. Qiu, T-H Anver, M. R. Merlino, G. Dickson, R. B. Johnson, M. D. Green, J. E. TI Identification of VEGF-regulated genes associated with increased lung metastatic potential: functional involvement of tenascin-C in tumor growth and lung metastasis SO ONCOGENE LA English DT Article DE metastasis; vascular endothelial growth factor; transgenic mice; mammary cancer; tenascin-C ID BREAST-CANCER METASTASIS; TRANSGENIC MICE; EXTRACELLULAR-MATRIX; MAMMARY-CANCER; MOUSE MAMMARY; ANGIOGENESIS; INVASION; MYC; EXPRESSION; PROGRESSION AB Metastasis is the primary cause of death in patients with breast cancer. Overexpression of c-myc in humans correlates with metastases, but transgenic mice only show low rates of micrometastases. We have generated transgenic mice that overexpress both c-myc and vascular endothelial growth factor (VEGF) (Myc/VEGF) in the mammary gland, which develop high rates of pulmonary macrometastases. Gene expression pro. ling revealed a set of deregulated genes in Myc/VEGF tumors compared to Myc tumors associated with the increased metastatic phenotype. Cross-comparisons between this set of genes with a human breast cancer lung metastasis gene signature identified five common targets: tenascin-C (TNC), matrix metalloprotease-2, collagen-6-A1, mannosidase-alpha-1A and HLA-DPA1. Signaling blockade or knockdown of TNC in MDA-MB-435 cells resulted in a significant impairment of cell migration and anchorage-independent cell proliferation. Mice injected with clonal MDA-MB-435 cells with reduced expression of TNC demonstrated a signifiant decrease (P < 0.05) in (1) primary tumor growth; (2) tumor relapse after surgical removal of the primary tumor and (3) incidence of lung metastasis. Our results demonstrate that VEGF induces complex alterations in tissue architecture and gene expression. The TNC signaling pathway plays an important role in mammary tumor growth and metastases, suggesting that TNC may be a relevant target for therapy against metastatic breast cancer. C1 [Calvo, A.; Huh, J-I; Sharp, R.; Qiu, T-H; Merlino, G.; Green, J. E.] NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. [Calvo, A.; Catena, R.; Gil-Bazo, I.; Gonzalez-Moreno, O.] Univ Navarra, Ctr Appl Med Res CIMA, Div Oncol, E-31080 Pamplona, Spain. [Calvo, A.; Catena, R.; Gil-Bazo, I.; Gonzalez-Moreno, O.] Univ Navarra, Dept Histol & Pathol, E-31080 Pamplona, Spain. [Noble, M. S.; Carbott, D.; Dickson, R. B.; Johnson, M. D.] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Dept Oncol, Washington, DC 20007 USA. [Gil-Bazo, I.] Univ Navarra Clin, Dept Oncol, Pamplona, Spain. [Anver, M. R.] Frederick Canc Res & Dev Ctr, Pathol & Histol Lab, SAIC, Frederick, MD USA. RP Johnson, MD (reprint author), NCI, Dr Lab Canc Biol & Genet, NIH, Bldg 37 Room 4054 37 Convent Dr, Bethesda, MD 20892 USA. EM Johnsom@georgetown.edu; jegreen@nih.gov FU Intramural Research Program of the NIH; National Cancer Institute; Center for Cancer Research; NIH [NO1-CO-12400, R01 CA72460, 2R01 CA104963, 2 R01 AG14963-06]; Susan G Komen Foundation; DOD Breast Cancer Program [DAMD17-01-1-0255]; ISCIII-RETIC [RD06/0020]; Fulbright-MEC fellowship; Spanish MEC fellowship FX We would like to thank Ms Mercedes Calvo for manuscript preparation, Victor Segura and Elizabeth Guruceaga (CEIT and Tecnun, Pamplona, Spain) for their help in bioinformatic analysis, GlaxoSmithKline for the GW654652 compound, Dr Rene Bernards (The Netherlands Cancer Institute) for the pMSCV-Delta 31LTR vector, Dr Linda Metheny-Barlow (at the LCCC) for helpful discussions, Edward C Rosfjord and Sandra L Deming and Gloria Chepko for contributions to the initial Myc/VEGF crossbreeding study. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, with funds from NIH(to GM) under Contract No. NO1-CO-12400, a grant from the Susan G Komen Foundation (to RBD), a grant from the DOD Breast Cancer Program DAMD17-01-1-0255 (to MDJ), NIH R01 CA72460 (to RBD), NIH 2R01 CA104963 (to RBD) ISCIII-RETIC (RD06/0020, to AC) and a Fulbright-MEC fellowship (AC); O G-M was supported by a Spanish MEC fellowship, and RBD by an NIH grant 2 R01 AG14963-06. NR 35 TC 47 Z9 48 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP 11 PY 2008 VL 27 IS 40 BP 5373 EP 5384 DI 10.1038/onc.2008.155 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 346UW UT WOS:000259096100010 PM 18504437 ER PT J AU Schmidt, MR Appel, MC Giassi, LJ Greiner, DL Shultz, LD Woodland, RT AF Schmidt, Madelyn R. Appel, Michael C. Giassi, Lisa J. Greiner, Dale L. Shultz, Leonard D. Woodland, Robert T. TI Human BLyS Facilitates Engraftment of Human PBL Derived B Cells in Immunodeficient Mice SO PLOS ONE LA English DT Article AB The production of fully immunologically competent humanized mice engrafted with peripheral lymphocyte populations provides a model for in vivo testing of new vaccines, the durability of immunological memory and cancer therapies. This approach is limited, however, by the failure to efficiently engraft human B lymphocytes in immunodeficient mice. We hypothesized that this deficiency was due to the failure of the murine microenvironment to support human B cell survival. We report that while the human B lymphocyte survival factor, B lymphocyte stimulator (BLyS/BAFF) enhances the survival of human B cells ex vivo, murine BLyS has no such protective effect. Although human B cells bound both human and murine BLyS, nuclear accumulation of NF-kappa B p52, an indication of the induction of a protective anti-apoptotic response, following stimulation with human BLyS was more robust than that induced with murine BLyS suggesting a fundamental disparity in BLyS receptor signaling. Efficient engraftment of both human B and T lymphocytes in NOD rag1(-/-) Prf1(-/-) immunodeficient mice treated with recombinant human BLyS is observed after adoptive transfer of human PBL relative to PBS treated controls. Human BLyS treated recipients had on average 40-fold higher levels of serum Ig than controls and mounted a de novo antibody response to the thymus-independent antigens in pneumovax vaccine. The data indicate that production of fully immunologically competent humanized mice from PBL can be markedly facilitated by providing human BLyS. C1 [Schmidt, Madelyn R.; Woodland, Robert T.] Univ Massachusetts, Sch Med, Dept Mol Genet & Microbiol, Worcester, MA 01655 USA. [Appel, Michael C.] Natl Inst Diabetes & Digest & Kidney Dis NIDDK, NIH, Bethesda, MD USA. [Giassi, Lisa J.; Greiner, Dale L.] Univ Massachusetts, Med Sch, Div Diabetes, Dept Med, Amherst, MA 01003 USA. [Shultz, Leonard D.] Jackson Lab, Bar Harbor, ME USA. RP Schmidt, MR (reprint author), Univ Massachusetts, Sch Med, Dept Mol Genet & Microbiol, Worcester, MA 01655 USA. EM Madelyn.Schmidt@umassmed.edu FU National Institutes of Health [AI 041054, AI57463, HL77642, AI46629]; Diabetes Endocrinology Research Center (DERC) [DK32520]; Cancer Center Core [CA34196]; Beta Cell Biology Consortium; Juvenile Diabetes Foundation, International FX This work was supported by National Institutes of Health Grants AI 041054, AI57463, HL77642, AI46629, an institutional Diabetes Endocrinology Research Center (DERC) grant DK32520, a Cancer Center Core grant CA34196, the Beta Cell Biology Consortium, and the Juvenile Diabetes Foundation, International. Human Genome Sciences supplied human recombinant BLyS for some experiments. The contents, study design and interpretation of the data in this publication are solely the responsibility of the authors and do not represent the views of the funding agencies. NR 73 TC 32 Z9 32 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 SEP 11 PY 2008 VL 3 IS 9 AR e3192 DI 10.1371/journal.pone.0003192 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422KF UT WOS:000264425900011 PM 18784835 ER PT J AU Jeang, KT AF Jeang, Kuan-Teh TI Recognizing mid-career productivity: the 2008 Retrovirology Prize, call for nomination SO RETROVIROLOGY LA English DT Editorial Material ID SCIENCE; WINS AB A recent analysis suggested a narrow age range for productivity of innovative work by researchers. The Retrovirology Prize seeks to recognize the research of a mid-career retrovirologist between the ages of 45 and 60. The 2007 Retrovirology Prize was awarded to Dr. Karen Beemon. Nominations are being solicited for the 2008 prize. C1 NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM kjeang@niaid.nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 4 TC 1 Z9 1 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD SEP 11 PY 2008 VL 5 AR 80 DI 10.1186/1742-4690-5-80 PG 2 WC Virology SC Virology GA 352HA UT WOS:000259485500002 ER PT J AU Rodriguez-Collazo, P Snyder, SK Chiffer, RC Bressler, EA Voss, TC Anderson, EP Genieser, HG Smith, CL AF Rodriguez-Collazo, Pedro Snyder, Sara K. Chiffer, Rebecca C. Bressler, Erin A. Voss, Ty C. Anderson, Eric P. Genieser, Hans-Gottfried Smith, Catharine L. TI cAMP signaling regulates histone H3 phosphorylation and mitotic entry through a disruption of G2 progression SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE cAMP signaling; histone phosphorylation; cell cycle; protein kinase A; cyclin-dependent kinase; cyclin B ID PROTEIN-KINASE-A; MITOSIS-SPECIFIC PHOSPHORYLATION; METAPHASE CHROMOSOME ALIGNMENT; MEDIATED GROWTH-INHIBITION; CELL-CYCLE PROGRESSION; MAP KINASE; CDC25 PHOSPHATASES; GENE-EXPRESSION; VPR ARRESTS; AURORA-B AB CAMP signaling is known to have significant effects oil cell growth, either inhibitory or stimulatory depending oil the cell type. Study of cAMP-induced growth inhibition in mammalian somatic cells has focused mainly on the combined role of protein kinase A (PI(A) and nitogen-activated protein (MAP) kinases in regulation of progression through the G1 phase of the cell cycle. Here we show that cAMP signaling regulates histone H3 phosphorylation in a cell cycle-dependent fashion, increasing it in quiescent cells but dramatically reducing it in cycling cells. The latter is due to a rapid and dramatic loss of mitotic histone H3 phosphorylation caused by a disruption in G2 progression, as evidenced by the inhibition of mitotic entry and decreased activity of the CyclinB/ Cdk1 kinase. The inhibition of G2 progression induced through CAMP signaling is dependent on expression of the Catalytic Subunit of PKA and is highly sensitive to intracellular CAMP concentration. The mechanism by which G2 progression is inhibited is independent of both DNA damage and MAP kinase signaling. Our results suggest that CAMP signaling activates a G2 checkpoint by a unique mechanism and provide new insight into normal cellular regulation of G2 progression. (c) 2008 Elsevier Inc. All rights reserved. C1 [Smith, Catharine L.] Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, Tucson, AZ 85721 USA. [Rodriguez-Collazo, Pedro; Snyder, Sara K.; Chiffer, Rebecca C.; Bressler, Erin A.; Voss, Ty C.; Anderson, Eric P.; Smith, Catharine L.] NCI, NIH, Lab Receptor Biol & Gene Express, Bethesda, MD 20892 USA. [Genieser, Hans-Gottfried] BIOLOG Life Sci Inst, D-28071 Bremen, Germany. RP Smith, CL (reprint author), Univ Arizona, Coll Pharm, Dept Pharmacol & Toxicol, 1703 E Mabel St, Tucson, AZ 85721 USA. EM csmith@pharmacy.arizona.edu OI Genieser, Hans-Gottfried/0000-0002-4904-5790 FU Intramural Research Award (NCI); NCI [1K01CA122177-01A1] FX We are garateful to members of the Laboratory of Receptor Biology and Gene Expression (NCI) for helpful discussion, to Barbara Taylor (NCI) at the Center for Cancer Research (CCR) FACS Core Facility for assistance with FACS analysis, and to Tatiana Karpova (NCI) and the CCR Core Fluorescence Imaging Facility for training and assistance with the confocal microscope. We also thank Drs. Carole Parent (NCI), Michael Bustin (NCI) and Ted Weinert (University of Arizona) for a critical reading of the manuscript. This project was supported in part through an Intramural Research Award (NCI) to CLS and NCI 1K01CA122177-01A1 to PRC. NR 82 TC 4 Z9 4 U1 2 U2 5 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD SEP 10 PY 2008 VL 314 IS 15 BP 2855 EP 2869 DI 10.1016/j.yexcr.2008.06.022 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 346XS UT WOS:000259103500012 PM 18644368 ER PT J AU Oza, AM Eisenhauer, EA Elit, L Cutz, JC Sakurada, A Tsao, MS Hoskins, PJ Biagi, J Ghatage, P Mazurka, J Provencher, D Dore, N Dancey, J Fyles, A AF Oza, Amit M. Eisenhauer, Elizabeth A. Elit, Laurie Cutz, Jean-Claude Sakurada, Akira Tsao, Ming S. Hoskins, Paul J. Biagi, Jim Ghatage, Prafull Mazurka, John Provencher, Diane Dore, Naomi Dancey, Janet Fyles, Anthony TI Phase II study of erlotinib in recurrent or metastatic endometrial cancer: NCICIND-148 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; CELL LUNG-CANCER; EXPRESSION; CARCINOMA; PREDICTORS; INHIBITOR; GEFITINIB; EGFR; P53; MUTATIONS AB Purpose Epidermal growth factor receptor (EGFR) overexpression is common in endometrial cancers and may have a major role in tumor growth and progression. Erlotinib is an orally active, selective inhibitor of EGFR tyrosine kinase activity. Patients and Methods A multinomial design two-stage phase II study was performed to evaluate single-agent activity of erlotinib in women with advanced endometrial cancer with recurrent or metastatic disease who were chemotherapy naive and had received up to one line of prior hormonal therapy. Erlotinib was administered at daily dose of 150 mg. Archival tumor tissue was analyzed for EGFR expression by immunohistochemistry (IHC) and gene amplification by fluorescent in situ hybridization (FISH). Mutational status of EGFR was determined in responders. Results Thirty-two of 34 entered patients are assessable for response. Treatment was well tolerated and severe toxicity infrequent, with the only grade 4 toxicity being an elevation of transaminases (AST). There were four confirmed partial responses (PRs; 12.5%; 95% CI, 3.5% to 29%) lasting 2 to 36 months. Fifteen patients had stable disease (SD), with median duration of 3.7 months (range, 2 to 12 months). EGFR expression was analyzed in thirty patients; 19 were positive, nine were negative, and two were not assessable. Of the 19 patients who were EGFR positive, three had PR (16%), seven SD, and eight progressive disease, and one was not assessable. No mutations were identified in responders. FISH showed no correlation of response with gene amplification. Conclusion Erlotinib is well tolerated with an overall objective response rate of 12.5%. Molecular analysis did not identify EGFR mutations in responders or correlation of response with gene amplification. C1 [Oza, Amit M.] Univ Toronto, Princess Margaret Hosp, Univ Hlth Network, Bras Family Drug Dev Program, Toronto, ON M5G 2M9, Canada. Queens Univ, Natl Canc Inst Canada, Clin Trials Grp, Kingston, ON, Canada. Canc Ctr SE Ontario, Kingston, ON, Canada. Juravinski Canc Ctr, Hamilton, ON, Canada. British Columbia Canc Agcy, Vancouver Clin, Vancouver, BC V5Z 4E6, Canada. Tom Baker Canc Clin, Calgary, AB, Canada. CHU Montreal, Montreal, PQ, Canada. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Oza, AM (reprint author), Univ Toronto, Princess Margaret Hosp, Univ Hlth Network, Bras Family Drug Dev Program, 610 Univ Ave,Suite 5-700, Toronto, ON M5G 2M9, Canada. EM amit.oza@uhn.on.ca OI Fyles, Anthony/0000-0002-3633-2483 FU National Cancer Institute of Canada; Canadian Cancer Society; Bras Drug Development Program FX Supported by grants from the National Cancer Institute of Canada with funds received from the Canadian Cancer Society; correlative translational studies were supported by research grants (A.M.O.) and the Bras Drug Development Program. NR 28 TC 58 Z9 60 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 10 PY 2008 VL 26 IS 26 BP 4319 EP 4325 DI 10.1200/JCO.2007.15.8808 PG 7 WC Oncology SC Oncology GA 350KD UT WOS:000259350400015 PM 18591547 ER PT J AU Jabr-Milane, L van Vlerken, L Devalapally, H Shenoy, D Komareddy, S Bhavsar, M Amiji, M AF Jabr-Milane, Lara van Vlerken, Lilian Devalapally, Harikrishna Shenoy, Dinesh Komareddy, Sushma Bhavsar, Mayank Amiji, Mansoor TI Multi-functional nanocarriers for targeted delivery of drugs and genes SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE multi-functional nanocarriers; stimuli-responsive; drug delivery; gene delivery; biological barriers; multi-drug resistance ID POLY(BETA-AMINO ESTER) NANOPARTICLES; PH-SENSITIVE SYSTEM; MULTIDRUG-RESISTANCE; PROGNOSTIC-SIGNIFICANCE; HYDROPHOBIC DRUGS; PLASMID DNA; POLYMERIC NANOPARTICLES; OVARIAN-CANCER; BREAST-CANCER; SOLID TUMOR AB In this review article, we describe the different nano-platforms developed in our laboratory at Northeastern University in Boston, MA for the targeted delivery of drugs and genes. Special emphasis is placed on nano-platforms that offer opportunities for multi-functionalization to allow for targeted stimuli-responsive and/or simultaneous strategic delivery of multiple drugs, genes, as well as the combination of therapeutic systems with image contrast enhancers. Polymeric and lipid-based nanocarriers can provide versatile platforms for the delivery of multiple pharmacological agents, specifically to enhance therapeutic effect and overcome drug resistance in cancer. In addition, polymeric nanoparticles and nanoparticles-in-microsphere oral system (NiMOS) are useful for systemic and oral gene therapy, respectively. (C) 2008 Elsevier B.V. All rights reserved. C1 [Jabr-Milane, Lara; Amiji, Mansoor] Northeastern Univ, Sch Pharm, Dept Pharmaceut Sci, Boston, MA 02115 USA. [van Vlerken, Lilian] Cytlmmune Inc, Rockville, MD 20850 USA. [Devalapally, Harikrishna] NCI, Nanotechnol Charaterizat Labs, Frederick, MD 21702 USA. [Shenoy, Dinesh] Novavax Inc, Rockville, MD 20850 USA. [Komareddy, Sushma] Novartis Inst Biomed Res, Cambridge, MA 02139 USA. [Bhavsar, Mayank] ArQule Inc, Woburn, MA 01801 USA. RP Amiji, M (reprint author), Northeastern Univ, Sch Pharm, Dept Pharmaceut Sci, Boston, MA 02115 USA. EM m.amiji@neu.edu RI Amiji, Mansoor/A-4365-2014 OI Amiji, Mansoor/0000-0001-6170-881X FU National Institutes of Health FX Our work on nanotechnology-based drug and gene delivery systems has received sustained funding from the National Institutes of Health, pharmaceutical and medical device companies, and foundation. The authors are deeply grateful for the excellent collaborative opportunities with many academic and industrial scientists in the Boston area, especially Professor Robert Langer at MIT, Professor Vladimir Torchilin at Northeastern University, Dr. Michael Seiden at Massachusetts General Hospital, and Dr. Takeshi Sano at Beth Israel Deaconess Medical Center. NR 42 TC 108 Z9 110 U1 7 U2 69 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 SEP 10 PY 2008 VL 130 IS 2 BP 121 EP 128 DI 10.1016/j.jconrel.2008.04.016 PG 8 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 351IW UT WOS:000259419000005 PM 18538887 ER PT J AU Argilli, E Sibley, DR Malenka, RC England, PM Bonci, A AF Argilli, Emanuela Sibley, David R. Malenka, Robert C. England, Pamela M. Bonci, Antonello TI Mechanism and time course of cocaine-induced long-term potentiation in the ventral tegmental area SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cocaine; dopamine; glutamate receptor; long-term potentiation (LTP); patch clamp; ventral tegmental area ID AMPA RECEPTOR TRAFFICKING; CALCIUM-PERMEABLE AMPA; PROTEIN-SYNTHESIS; SYNAPTIC PLASTICITY; DOPAMINE NEURONS; IN-VIVO; MESSENGER-RNA; EXCITATORY SYNAPSES; CA1 REGION; RAT AB Synaptic plasticity in the ventral tegmental area (VTA) has been implicated in the acquisition of a drug-dependent state. Even a single exposure to cocaine in naive animals is sufficient to trigger sustained changes on VTA glutamatergic synapses that resemble activity-dependent long-term potentiation (LTP) in other brain regions. However, an insight into its time course and mechanisms of action is limited. Here, we show that cocaine acts locally within the VTA to induce an LTP-like enhancement of AMPA receptor-mediated transmission that is not detectable minutes after drug exposure but is fully expressed within 3 h. This cocaine-induced LTP appears to be mediated via dopamine D-5 receptor activation of NMDA receptors and to require protein synthesis. Increased levels of high-conductance GluR1-containing AMPA receptors at synapses are evident at 3 h after cocaine exposure. Furthermore, our data suggest that cocaine-induced LTP might share the same molecular substrates for expression with activity-dependent LTP induced in the VTA by a spike-timing-dependent (STD) protocol, because we observed that STD LTP is significantly reduced or not inducible in VTA neurons previously exposed to cocaine in vivo or in vitro. C1 [Argilli, Emanuela; Bonci, Antonello] Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, Emeryville, CA 94608 USA. [Argilli, Emanuela; Bonci, Antonello] Univ Calif San Francisco, Dept Neurol, Emeryville, CA 94608 USA. [Sibley, David R.] Natl Inst Neurol Disorders & Stroke, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. [Malenka, Robert C.] Stanford Univ, Sch Med, Dept Psychiat & Behav Sci, Nancy Pritzker Lab, Palo Alto, CA 94304 USA. [England, Pamela M.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. [England, Pamela M.] Univ Calif San Francisco, Dept Mol & Cellular Pharmacol, San Francisco, CA 94158 USA. RP Bonci, A (reprint author), Univ Calif San Francisco, Ernest Gallo Clin & Res Ctr, 5858 Horton St,Suite 200, Emeryville, CA 94608 USA. EM antonello.bonci@ucsf.edu FU National Institute on Drug Abuse [1R01DA15096]; state of California for medical research on alcohol and substance abuse FX This work was supported by National Institute on Drug Abuse Grant 1R01DA15096 (A. B.) and by funding from the state of California for medical research on alcohol and substance abuse through the University of California, San Francisco (A. B.). We thank the members of the Bonci and Malenka laboratories for helpful discussions and Lisa G. Daitch for proofreading. NR 54 TC 144 Z9 145 U1 2 U2 12 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 SEP 10 PY 2008 VL 28 IS 37 BP 9092 EP 9100 DI 10.1523/JNEUROSCI.1001-08.2008 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 346UJ UT WOS:000259094800004 PM 18784289 ER PT J AU Bassett, DS Bullmore, ET Verchinski, BA Mattay, VS Weinberger, DR Meyer-Lindenberg, A AF Bassett, Danielle S. Bullmore, Edward T. Verchinski, Beth A. Mattay, Venkata S. Weinberger, Daniel R. Meyer-Lindenberg, Andreas TI Hierarchical organization of human cortical networks in health and schizophrenia SO JOURNAL OF NEUROSCIENCE LA English DT Article DE anatomy; network; hierarchy; systems; MRI; schizophrenia; neurodevelopment ID HUMAN BRAIN; SMALL-WORLD; FUNCTIONAL CONNECTIVITY; CEREBRAL-CORTEX; THEORETICAL NEUROANATOMY; WIRING OPTIMIZATION; ARCHITECTURE; POLYMORPHISM; METAANALYSIS; MORPHOMETRY AB The complex organization of connectivity in the human brain is incompletely understood. Recently, topological measures based on graph theory have provided a new approach to quantify large-scale cortical networks. These methods have been applied to anatomical connectivity data on nonhuman species, and cortical networks have been shown to have small-world topology, associated with high local and global efficiency of information transfer. Anatomical networks derived from cortical thickness measurements have shown the same organizational properties of the healthy human brain, consistent with similar results reported in functional networks derived from resting state functional magnetic resonance imaging (MRI) and magnetoencephalographic data. Here we show, using anatomical networks derived from analysis of inter-regional covariation of gray matter volume in MRI data on 259 healthy volunteers, that classical divisions of cortex (multimodal, unimodal, and transmodal) have some distinct topological attributes. Although all cortical divisions shared nonrandom properties of small-worldness and efficient wiring (short mean Euclidean distance between connected regions), the multimodal network had a hierarchical organization, dominated by frontal hubs with low clustering, whereas the transmodal network was assortative. Moreover, in a sample of 203 people with schizophrenia, multimodal network organization was abnormal, as indicated by reduced hierarchy, the loss of frontal and the emergence of nonfrontal hubs, and increased connection distance. We propose that the topological differences between divisions of normal cortex may represent the outcome of different growth processes for multimodal and transmodal networks and that neurodevelopmental abnormalities in schizophrenia specifically impact multimodal cortical organization. C1 [Bassett, Danielle S.; Bullmore, Edward T.] Addenbrookes Hosp, Dept Psychiat, Brain Mapping Unit, Cambridge CB2 2QQ, England. [Bassett, Danielle S.; Weinberger, Daniel R.; Meyer-Lindenberg, Andreas] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. [Verchinski, Beth A.; Mattay, Venkata S.] NIMH, Neuroimaging Core Facil, NIH, Bethesda, MD 20892 USA. [Bassett, Danielle S.] Univ Cambridge, Dept Phys, Biol Soft Syst Sector, Cambridge CB2 1TN, England. [Bullmore, Edward T.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 1TN, England. [Meyer-Lindenberg, Andreas] Cent Inst Mental Hlth, D-68072 Mannheim, Germany. RP Bullmore, ET (reprint author), Addenbrookes Hosp, Dept Psychiat, Brain Mapping Unit, Hills Rd, Cambridge CB2 2QQ, England. EM etb23@cam.ac.uk RI Bullmore, Edward/C-1706-2012; Meyer-Lindenberg, Andreas/H-1076-2011 OI Bullmore, Edward/0000-0002-8955-8283; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU National Institute of Biomedical Imaging and Bioengineering; National Institute of Mental Health; National Institutes of Health FX This work was supported by a Human Brain Project Grant from the National Institute of Biomedical Imaging and Bioengineering and the National Institute of Mental Health and by the Intramural Research Program of the National Institutes of Health, National Institute of Mental Health. D. S. B. was supported by the National Institutes of Health Graduate Partnerships Program. We thank Sophie Achard for useful discussions regarding network statistics. NR 54 TC 481 Z9 489 U1 9 U2 48 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 SEP 10 PY 2008 VL 28 IS 37 BP 9239 EP 9248 DI 10.1523/JNEUROSCI.1929-08.2008 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 346UJ UT WOS:000259094800019 PM 18784304 ER PT J AU Donroe, J Tincopa, M Gilman, RH Brugge, D Moore, DAJ AF Donroe, Joseph Tincopa, Monica Gilman, Robert H. Brugge, Doug Moore, David A. J. TI Pedestrian Road Traffic Injuries in Urban Peruvian Children and Adolescents: Case Control Analyses of Personal and Environmental Risk Factors SO PLOS ONE LA English DT Article AB Background: Child pedestrian road traffic injuries (RTIs) are an important cause of death and disability in poorer nations, however RTI prevention strategies in those countries largely draw upon studies conducted in wealthier countries. This research investigated personal and environmental risk factors for child pedestrian RTIs relevant to an urban, developing world setting. Methods: This is a case control study of personal and environmental risk factors for child pedestrian RTIs in San Juan de Miraflores, Lima, Peru. The analysis of personal risk factors included 100 cases of serious pedestrian RTIs and 200 age and gender matched controls. Demographic, socioeconomic, and injury data were collected. The environmental risk factor study evaluated vehicle and pedestrian movement and infrastructure at the sites in which 40 of the above case RTIs occurred and 80 control sites. Findings: After adjustment, factors associated with increased risk of child pedestrian RTIs included high vehicle volume (OR 7.88, 95%CI 1.97-31.52), absent lane demarcations (OR 6.59, 95%CI 1.65-26.26), high vehicle speed (OR 5.35, 95%CI 1.55-18.54, ), high street vendor density (OR 1.25, 95%CI 1.01-1.55), and more children living in the home (OR 1.25, 95%CI 1.00-1.56). Protective factors included more hours/day spent in school (OR 0.52, 95%CI 0.33-0.82) and years of family residence in the same home (OR 0.97, 95%CI 0.95-0.99). Conclusion: Reducing traffic volumes and speeds, limiting the number of street vendors on a given stretch of road, and improving lane demarcation should be evaluated as components of child pedestrian RTI interventions in poorer countries. C1 [Donroe, Joseph] Asociac Benefica PRISMA, Fogarty Int Ctr, Ellison Med Fdn, Lima, Peru. [Tincopa, Monica] Johns Hopkins Sch Med, Baltimore, MD USA. [Gilman, Robert H.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD USA. [Gilman, Robert H.; Moore, David A. J.] Asociac Benefica PRISMA, Lima, Peru. [Gilman, Robert H.; Moore, David A. J.] Univ Peruana Cayetano Heredia, Lab Investigac Enfermedades Infecciosas, Lima, Peru. [Brugge, Doug] Tufts Univ, Sch Med, Medford, MA 02155 USA. [Moore, David A. J.] Imperial Coll London, Wellcome Ctr Clin Trop Med, Fac Med, Dept Infect Dis & Immun, London, England. RP Donroe, J (reprint author), Asociac Benefica PRISMA, Fogarty Int Ctr, Ellison Med Fdn, Lima, Peru. EM jdonroe@gmail.com FU Tutorial in Tropical Health at JHU [5T35AI007646]; Fogarty International Center/ Ellison Medical Foundation-Overseas Fellowships in Global Health and Clinical Research; Wellcome Trust FX The study was funded in part by the Tutorial in Tropical Health at JHU/Peru Overseas Sites Grant (5T35AI007646) and the Fogarty International Center/ Ellison Medical Foundation-Overseas Fellowships in Global Health and Clinical Research. DAJM is supported by the Wellcome Trust. The authors' work was independent of the funders. NR 29 TC 16 Z9 17 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 10 PY 2008 VL 3 IS 9 AR e3166 DI 10.1371/journal.pone.0003166 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422KD UT WOS:000264425700007 PM 18781206 ER PT J AU Nechaev, S Severinov, K AF Nechaev, Sergei Severinov, Konstantin TI RapA: Completing the transcription cycle? SO STRUCTURE LA English DT Editorial Material ID POLYMERASE-ASSOCIATED PROTEIN; REPAIR COUPLING FACTOR; RNA-POLYMERASE; BACTERIAL HOMOLOG; ESCHERICHIA-COLI; TRANSLOCATION; SWI2/SNF2; FAMILY; MFD AB In this issue of Structure, Shaw et al. (2008) report a crystal structure of the Escherichia coli RapA protein, the only bacterial member of the SWI/SNF2 family (Lewis et al., 1992; Bork and Koonin, 1993). The structure reported is also the first structure of any full-sized SWI/SNF2 family protein. C1 [Severinov, Konstantin] Rutgers State Univ, Waksman Inst, Piscataway, NJ 08854 USA. [Nechaev, Sergei] NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. [Severinov, Konstantin] Russian Acad Sci, Inst Mol Genet, Moscow, Russia. [Severinov, Konstantin] Russian Acad Sci, Inst Gene Biol, Moscow, Russia. RP Severinov, K (reprint author), Rutgers State Univ, Waksman Inst, Piscataway, NJ 08854 USA. EM severik@waksman.rutgers.edu RI Severinov, Konstantin/C-8545-2016 NR 10 TC 5 Z9 5 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD SEP 10 PY 2008 VL 16 IS 9 BP 1294 EP 1295 DI 10.1016/j.str.2008.08.001 PG 2 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 347TR UT WOS:000259164500004 PM 18786392 ER PT J AU Shaw, G Gan, JH Zhou, YN Zhi, HJ Subburaman, P Zhang, RG Joachimiak, A Jin, DJ Ji, XH AF Shaw, Gary Gan, Jianhua Zhou, Yan Ning Zhi, Huijun Subburaman, Priadarsini Zhang, Rongguang Joachimiak, Andrzej Jin, Ding Jun Ji, Xinhua TI Structure of RapA, a Swi2/Snf2 protein that recycles RNA polymerase during transcription SO STRUCTURE LA English DT Article ID CHROMATIN-REMODELING COMPLEXES; ESCHERICHIA-COLI; CRYSTAL-STRUCTURES; BACTERIAL HOMOLOG; SNF2 FAMILY; DNA-REPAIR; RESOLUTION; HELICASES; BINDING; CRYSTALLOGRAPHY AB RapA, as abundant as sigma(70) in the cell, is an RNA polymerase (RNAP)-associated Swi2/Snf2 protein with ATPase activity. It stimulates RNAP recycling during transcription. We report a structure of RapA that is also a full-length structure for the entire Swi2/Snf2 family. RapA contains seven domains, two of which exhibit novel protein folds. Our model of RapA in complex with ATP and double-stranded DNA (dsDNA) suggests that RapA may bind to and translocate on dsDNA. Our kinetic template-switching assay shows that RapA facilitates the release of sequestered RNAP from a posttranscrption/posttermination complex for transcription reinitiation. Our in vitro competition experiment indicates that RapA binds to core RNAP only but is readily displaceable by sigma(70). RapA is likely another general transcription factor, the structure of which provides a framework for future studies of this bacterial Swi2/Snf2 protein and its important roles in RNAP recycling during transcription. C1 [Shaw, Gary; Gan, Jianhua; Zhou, Yan Ning; Zhi, Huijun; Subburaman, Priadarsini; Jin, Ding Jun; Ji, Xinhua] NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. [Zhang, Rongguang; Joachimiak, Andrzej] Argonne Natl Lab, Struct Biol Ctr, Argonne, IL 60439 USA. RP Jin, DJ (reprint author), NCI, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM djjin@helix.nih.gov; jix@ncifcrf.gov RI Ji, Xinhua/C-9664-2012 OI Ji, Xinhua/0000-0001-6942-1514 FU NIH; National Cancer Institute FX We thank Jack Simpson and Robert Fisher for help with mass spectrometry; Di Xia and Lothar Esser for help with cryoprotection; Michelle Andrykovitch for help with crystallization; Brian Austin and David Waugh for help with cloning; and Donald Court, Mikhail Kashlev, and Lucyna Lubkowski for discussion and review of the manuscript. X-ray diffraction and initial phasing were performed at the 19-ID beamline of SBC-CAT and the 22-ID beamline of SERCAT, Advanced Photon Source, Argonne National Laboratory. This research was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 47 TC 30 Z9 30 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD SEP 10 PY 2008 VL 16 IS 9 BP 1417 EP 1427 DI 10.1016/j.str.2008.06.012 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 347TR UT WOS:000259164500017 PM 18786404 ER PT J AU Marinello, J Marchand, C Mott, BT Bain, A Thomas, CJ Pommier, Y AF Marinello, Jessica Marchand, Christophe Mott, Bryan T. Bain, Anjali Thomas, Craig J. Pommier, Yves TI Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants SO BIOCHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INHIBITOR BINDING; DNA INTEGRATION; ACTIVE-SITE; IN-VITRO; TYPE-1; REPLICATION; MUTATIONS; PROTEASE; FITNESS AB HIV-1 integrase (IN) is the molecular target of the newly approved anti-AIDS drug raltegravir (MK-0518, Isentress) while elvitegravir (GS-9137, JTK-303) is in clinical trials. The aims of the present study were (1) to investigate and compare the effects of raltegravir and elvitegravir on the three IN-mediated reactions, 3'-processing (3'-P), strand transfer (ST), and disintegration, (2) to determine the biochemical activities of seven IN mutants (T66I, L74M, E92Q, F121Y, Q148K, S153Y, and N155H) previously selected from drug-resistant patients and isolates, and (3) to determine the resistance profile for raltegravir and elvitegravir in those IN mutants. Our findings demonstrate that both raltegravir and elvitegravir are potent IN inhibitors and are highly selective for the ST reaction of IN. Elvitegravir was more potent than raltegravir, but neither drug could block disintegration. All resistance mutations were at least partially impaired for ST. Q148K was also markedly impaired for 3'-P. Both drugs exhibited a parallel resistance profile, although resistance was generally greater for elvitegravir. Q148K and T661 conferred the highest resistance to both drugs while S153Y conferred relatively greater resistance to elvitegravir than raltegravir. Drug resistance could not be overcome by preincubating the drugs with IN, consistent with the binding of raltegravir and elvitegravir at the IN-DNA interface. Finally, we found an inverse correlation between resistance and catalytic activity of the IN Mutants. C1 [Marinello, Jessica; Marchand, Christophe; Pommier, Yves] NCI, NIH, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Mott, Bryan T.; Bain, Anjali; Thomas, Craig J.] NHGRI, NIH, NIH Chem Genom Ctr, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, NIH, Ctr Canc Res, Mol Pharmacol Lab, 37 Convent Dr, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Marchand, Christophe/D-8559-2016 FU Center for Cancer Research (CCR); National Cancer Institute (NCI); National Human Genome Research Institute (NHGRI); University of Padova FX These studies were supported by the Center for Cancer Research (CCR), National Cancer Institute (NCI), and the NIH Chemical Genomics Center (NCGC) of the National Human Genome Research Institute (NHGRI). J.M. was supported by a grant from the University of Padova. NR 29 TC 94 Z9 96 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD SEP 9 PY 2008 VL 47 IS 36 BP 9345 EP 9354 DI 10.1021/bi800791q PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343PT UT WOS:000258866700001 PM 18702518 ER PT J AU Blinova, K Levine, RL Boja, ES Griffiths, GL Shi, ZD Ruddy, B Balaban, RS AF Blinova, Ksenia Levine, Rodney L. Boja, Emily S. Griffiths, Gary L. Shi, Zhen-Dan Ruddy, Brian Balaban, Robert S. TI Mitochondrial NADH fluorescence is enhanced by Complex I binding SO BIOCHEMISTRY LA English DT Article ID REDUCED PYRIDINE NUCLEOTIDE; NICOTINAMIDE ADENINE-DINUCLEOTIDE; MEMBRANE-PROTEIN COMPLEXES; BOVINE HEART-MITOCHONDRIA; OXIDATIVE-PHOSPHORYLATION; NATIVE ELECTROPHORESIS; LACTATE-DEHYDROGENASE; MALATE-DEHYDROGENASE; 2-PHOTON EXCITATION; HYDROPHILIC DOMAIN AB Mitochondrial NADH fluorescence has been a useful tool in evaluating mitochondrial energetics both in vitro and in vivo. Mitochondrial NADH fluorescence is enhanced several-fold in the matrix through extended fluorescence lifetimes (EFL). However, the actual binding sites responsible for NADH EFL are unknown. We tested the hypothesis that NADH binding to Complex I is a significant source of mitochondrial NADH fluorescence enhancement. To test this hypothesis, the effect of Complex I binding on NADH fluorescence efficiency was evaluated in purified protein, and in native gels of the entire porcine heart mitochondria proteome. To avoid the oxidation of NADH in these preparations, we conducted the binding experiments under anoxic conditions in a specially designed apparatus. Purified intact Complex I enhanced NADH fluorescence in native gels approximately 10-fold. However, no enhancement was detected in denatured individual Complex I subunit proteins. In the Clear and Ghost native gels of the entire rnitochondrial proteome. NADH fluorescence enhancement was localized to regions where NADH oxidation Occurred in the presence of oxygen. Inhibitor and mass spectroscopy Studies revealed that the fluorescence enhancement was specific to Complex I proteins. No fluorescence enhancement was detected for MDH or other dehydrogenases in this assay system, at physiological mole fractions of the matrix proteins. These data suggest that NADH associated with Complex I significantly contributes to the overall mitochondrial NADH fluorescence signal and provides an explanation for the well established close correlation of mitochondrial NADH fluorescence and the metabolic state. C1 [Blinova, Ksenia; Balaban, Robert S.] NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. [Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. [Boja, Emily S.] NHLBI, Lab Appl Mass Spectrometry, NIH, Bethesda, MD 20892 USA. [Griffiths, Gary L.; Shi, Zhen-Dan; Ruddy, Brian] NHLBI, Image Probe Dev Ctr, NIH, Bethesda, MD 20892 USA. RP Balaban, RS (reprint author), NHLBI, Cardiac Energet Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM balabanr@nhlbi.nih.gov RI Levine, Rodney/D-9885-2011 FU Intramural NIH HHS [ZIA HL004601-25] NR 57 TC 46 Z9 46 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 SEP 9 PY 2008 VL 47 IS 36 BP 9636 EP 9645 DI 10.1021/bi800307y PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 343PT UT WOS:000258866700030 PM 18702505 ER PT J AU Osorio, A Pollan, M Pita, G Schmutzler, RK Versmold, B Engel, C Meindl, A Arnold, N Preisler-Adams, S Niederacher, D Hofmann, W Gadzicki, D Jakubowska, A Hamann, U Lubinski, J Toloczko-Grabarek, A Cybulski, C Debniak, T Llort, G Yannoukakos, D Diez, O Peissel, B Peterlongo, P Radice, P Heikkinen, T Nevanlinna, H Mai, PL Loud, JT McGuffog, L Antoniou, AC Benitez, J AF Osorio, A. Pollan, M. Pita, G. Schmutzler, R. K. Versmold, B. Engel, C. Meindl, A. Arnold, N. Preisler-Adams, S. Niederacher, D. Hofmann, W. Gadzicki, D. Jakubowska, A. Hamann, U. Lubinski, J. Toloczko-Grabarek, A. Cybulski, C. Debniak, T. Llort, G. Yannoukakos, D. Diez, O. Peissel, B. Peterlongo, P. Radice, P. Heikkinen, T. Nevanlinna, H. Mai, P. L. Loud, J. T. McGuffog, L. Antoniou, A. C. Benitez, J. CA CIMBA TI An evaluation of the polymorphisms Ins16bp and Arg72Pro in p53 as breast cancer risk modifiers in BRCA1 and BRCA2 mutation carriers SO BRITISH JOURNAL OF CANCER LA English DT Article DE BRCA1; BRCA2; p53; breast cancer ID SUSCEPTIBILITY GENES; TP53 CODON-72; HAPLOTYPES; VARIANTS AB The close functional relationship between p53 and the breast cancer susceptibility genes BRCA1 and BRCA2 has promoted the investigation of various polymorphisms in the p53 gene as possible risk modifiers in BRCA1/2 mutation carriers. Specifically, two polymorphisms in p53, c.97-147ins16bp and p.Arg72Pro have been analysed as putative breast cancer susceptibility variants, and it has been recently reported that a p53 haplotype combining the absence of the 16-bp insertion and the presence of proline at codon 72 (No Ins-72Pro) was associated with an earlier age at the onset of the first primary tumour in BRCA2 mutation carriers in the Spanish population. In this study, we have evaluated this association in a series of 2932 BRCA1/2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. C1 Spanish Natl Canc Ctr CNIO, Human Genet Grp, Human Canc Genet Programme, Madrid 28029, Spain. [Osorio, A.; Benitez, J.] Inst Salud Carlos III, Natl Epidemiol Ctr, Madrid, Spain. [Pollan, M.] CIBERESP, Madrid, Spain. [Pita, G.; Benitez, J.] Spanish Natl Canc Ctr CNIO, Genotyping Unit, Human Canc Genet Programme, Madrid 28029, Spain. [Schmutzler, R. K.; Versmold, B.] Univ Cologne, Dept Obstet & Gynaecol, Div Mol Gynaecooncol, Cologne, Germany. [Engel, C.] Univ Leipzig, Inst Med Informat Stat & Epidemiol, Leipzig, Germany. [Meindl, A.] Tech Univ Munich, Dept Obstet & Gynaecol, Munich, Germany. [Arnold, N.] Univ Schleswig Holstein, Dept Obstet & Gynaecol, Kiel, Germany. [Preisler-Adams, S.] Univ Munster, Inst Human Genet, D-4400 Munster, Germany. [Niederacher, D.] Univ Dusseldorf, Mol Genet Lab, Dept Obstet & Gynaecol, Dusseldorf, Germany. [Hofmann, W.] Charite Univ Med Ctr, Inst Human Genet, Berlin, Germany. [Gadzicki, D.] Med Univ, Inst Cellular & Mol Pathol, Hannover, Germany. [Jakubowska, A.; Lubinski, J.; Toloczko-Grabarek, A.; Cybulski, C.; Debniak, T.] Pomeranian Med Univ, Dept Genet & Pathol, Szczecin, Poland. [Hamann, U.] German Canc Res Ctr, D-6900 Heidelberg, Germany. [Llort, G.] ICO, Canc Genet Counselling Program, Barcelona, Spain. [Yannoukakos, D.] NCSR Demokritos, IRRP, Mol Diagnost Lab, Athens, Greece. [Diez, O.] Hosp Santa Creu & Sant Pau, Genet Serv, Barcelona, Spain. [Diez, O.] Hosp Gen Valle Hebron, Oncogenet Lab, Barcelona, Spain. [Peissel, B.] Fdn IRCCS Ist Nazl Tumori, Med Genet Serv, Milan, Italy. [Peterlongo, P.; Radice, P.] Fdn IRCCS Ist Nazl Tumori, Dept Expt Oncol, Unit Genet Susceptibil Canc, Milan, Italy. [Peterlongo, P.; Radice, P.] Fdn Ist FIRC Oncol Mol, IFOM, Milan, Italy. [Heikkinen, T.; Nevanlinna, H.] Univ Helsinki, Cent Hosp, Dept Obstet & Gynecol, FIN-00290 Helsinki, Finland. [Mai, P. L.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Bethesda, MD 20892 USA. [McGuffog, L.; Antoniou, A. C.] Univ Cambridge, Dept Publ Hlth & Primary Care, Canc Res UK Genet Epidemiol Unit, Cambridge, England. RP Osorio, A (reprint author), Spanish Natl Canc Ctr CNIO, Human Genet Grp, Human Canc Genet Programme, C Melchor Femandez Almagro 3, Madrid 28029, Spain. EM aosorio@cnio.es RI Arnold, Norbert/E-3012-2010; Radice, Paolo/O-3119-2013; Pollan, Marina/M-3259-2014; Jakubowska, Anna/O-8050-2014; Peissel, Bernard/E-8187-2017; Osorio, Ana/I-4324-2014; OI Pollan, Marina/0000-0002-4328-1565; Arnold, Norbert/0000-0003-4523-8808; Peissel, Bernard/0000-0001-9233-3571; Osorio, Ana/0000-0001-8124-3984; Nevanlinna, Heli/0000-0002-0916-2976; Yannoukakos, Drakoulis/0000-0001-7509-3510 FU Mutua Madrilena, Genome Spain; Marato TV Foundations; Fondazione Italiana per la Ricerca sul Cancro; Cancer Research UK; Associazione Italiana per la Ricerca sul Cancro FX CNIO study: we thank RM Alonso and RL Milne for their assistance. This study was partially supported by Mutua Madrilena, Genome Spain and Marato TV Foundations. The Milan study is supported by the Fondazione Italiana per la Ricerca sul Cancro. DKFZ study: we thank D Torres and MU Rashid for providing DNA samples and supplying data. AC Antoniou, L McGuffog and the CIMBA data management are funded by Cancer Research UK. NR 18 TC 10 Z9 10 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD SEP 9 PY 2008 VL 99 IS 6 BP 974 EP 977 DI 10.1038/sj.bjc.6604624 PG 4 WC Oncology SC Oncology GA 346IK UT WOS:000259061800018 PM 18781154 ER PT J AU Liu, BG Xia, XJ Zhu, F Park, E Carbajal, S Kiguchi, K DiGiovanni, J Fischer, SM Hu, YL AF Liu, Bigang Xia, Xiaojun Zhu, Feng Park, Eunmi Carbajal, Steve Kiguchi, Kaoru DiGiovanni, John Fischer, Susan M. Hu, Yinling TI IKK alpha is required to maintain skin homeostasis and prevent skin cancer SO CANCER CELL LA English DT Article ID KAPPA-B-KINASE; GROWTH-FACTOR RECEPTOR; V-HA-RAS; STEM-CELLS; EGF RECEPTOR; MICE LACKING; TARGETED DISRUPTION; TRANSGENIC MICE; MAMMARY-GLAND; MORPHOGENESIS AB It has long been known that excessive mitotic activity due to H-Ras can block keratinocyte differentiation and cause skin cancer. It is not clear whether there are any innate surveillants that are able to ensure that keratinocytes undergo terminal differentiation, preventing the disease. IKK alpha induces keratinocyte terminal differentiation, and its downregulation promotes skin tumor development. However, its intrinsic function in skin cancer is unknown. Here, we found that mice with IKK alpha deletion in keratinocytes develop a thickened epidermis and spontaneous squamous cell-like carcinomas. Inactivation of epidermal growth factor receptor (EGFR) or reintroduction of IKK alpha inhibits excessive mitosis, induces terminal differentiation, and prevents skin cancer through repressing an EGFR-driven autocrine loop. Thus, IKK alpha serves as an innate surveillant. C1 [Liu, Bigang; Xia, Xiaojun; Zhu, Feng; Park, Eunmi; Carbajal, Steve; Kiguchi, Kaoru; DiGiovanni, John; Fischer, Susan M.; Hu, Yinling] Univ Texas MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX 78957 USA. RP Hu, YL (reprint author), NCI, Canc & Inflammat Program, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM huy2@mail.nih.gov FU National Cancer Institute [CA102510, CA117314, CA105345, CA16672] FX We thank J. Parker-Thornburg for assisting in the generation of Ikk alphaF/F mice, W. Zhang and L. Hu for microarray analyses, and P. Chambon for providing tamoxifen-inducible K5.Cre mice. This work was supported by National Cancer Institute grants CA102510 and CA117314 (to Y.H.), CA105345 (to S.M.F.). and CA16672. NR 43 TC 62 Z9 64 U1 1 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD SEP 9 PY 2008 VL 14 IS 3 BP 212 EP 225 DI 10.1016/j.ccr.2008.07.017 PG 14 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 349WI UT WOS:000259313600005 PM 18772111 ER PT J AU Rudy, Y Ackerman, MJ Bers, DM Clancy, CE Houser, SR London, B McCulloch, AD Przywara, DA Rasmusson, RL Solaro, RJ Trayanova, NA Van Wagoner, DR Varro, A Weiss, JN Lathrop, DA AF Rudy, Yoram Ackerman, Michael J. Bers, Donald M. Clancy, Colleen E. Houser, Steven R. London, Barry McCulloch, Andrew D. Przywara, Dennis A. Rasmusson, Randall L. Solaro, R. John Trayanova, Natalia A. Van Wagoner, David R. Varro, Andras Weiss, James N. Lathrop, David A. TI Systems approach to understanding electromechanical activity in the human heart - A national heart, lung, and blood institute workshop summary SO CIRCULATION LA English DT Article DE arrhythmia; cardiovascular diseases; contractility; electrophysiology; mechanics ID LONG-QT SYNDROME; CARDIAC ION CHANNELS; K+ CHANNEL; CALCIUM; ARRHYTHMIAS; CHANNELOPATHIES; MYOCYTES; BIOLOGY; SODIUM; MODELS AB The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of cardiologists, cardiac electrophysiologists, cell biophysicists, and computational modelers on August 20 and 21, 2007, in Washington, DC, to advise the NHLBI on new research directions needed to develop integrative approaches to elucidate human cardiac function. The workshop strove to identify limitations in the use of data from nonhuman animal species for elucidation of human electromechanical function/activity and to identify what specific information on ion channel kinetics, calcium handling, and dynamic changes in the intracellular/extracellular milieu is needed from human cardiac tissues to develop more robust computational models of human cardiac electromechanical activity. This article summarizes the workshop discussions and recommendations on the following topics: (1) limitations of animal models and differences from human electrophysiology, (2) modeling ion channel structure/function in the context of whole-cell electrophysiology, ( 3) excitation-contraction coupling and regulatory pathways, (4) whole-heart simulations of human electromechanical activity, and (5) what human data are currently needed and how to obtain them. The recommendations can be found on the NHLBI Web site at http://www.nhlbi.nih.gov/meetings/workshops/electro.htm. C1 [Rudy, Yoram] Washington Univ, Cardiac Bioelect & Arrhythmia Ctr, St Louis, MO 63130 USA. [Rudy, Yoram] Washington Univ, Dept Biomed Engn, St Louis, MO 63130 USA. [Rudy, Yoram] Washington Univ, Dept Cell Biol & Physiol, St Louis, MO 63130 USA. [Rudy, Yoram] Washington Univ, Dept Med, St Louis, MO 63130 USA. [Rudy, Yoram] Washington Univ, Dept Radiol, St Louis, MO 63130 USA. [Rudy, Yoram] Washington Univ, Dept Pediat, St Louis, MO 63130 USA. [Ackerman, Michael J.] Mayo Clin, Dept Med, Rochester, MN USA. [Ackerman, Michael J.] Mayo Clin, Dept Pediat, Rochester, MN USA. [Ackerman, Michael J.] Mayo Clin, Dept Mol Pharmacol, Rochester, MN USA. [Ackerman, Michael J.] Mayo Clin, Dept Expt Therapeut, Rochester, MN USA. [Bers, Donald M.] Univ Calif Davis, Dept Pharmacol, Davis, CA 95616 USA. [Clancy, Colleen E.] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA. [Houser, Steven R.] Temple Univ, Sch Med, Dept Physiol, Philadelphia, PA 19122 USA. [London, Barry] Univ Pittsburgh, Cardiovasc Inst, Pittsburgh, PA USA. [McCulloch, Andrew D.] Univ Calif San Diego, Dept Bioengn, La Jolla, CA 92093 USA. [Przywara, Dennis A.; Lathrop, David A.] NHLBI, Div Cardiovasc Dis, Natl Inst Hlth, Bethesda, MD 20892 USA. [Rasmusson, Randall L.] SUNY Buffalo, Dept Physiol & Biophys, Buffalo, NY 14260 USA. [Solaro, R. John] Univ Illinois, Cardiovasc Res Ctr, Chicago, IL USA. [Solaro, R. John] Univ Illinois, Dept Physiol & Biophys, Chicago, IL USA. [Trayanova, Natalia A.] Johns Hopkins Univ, Baltimore, MD USA. [Van Wagoner, David R.] Cleveland Clin, Lerner Coll Med CWRU, Dept Mol Cardiol, Cleveland, OH 44106 USA. [Van Wagoner, David R.] Cleveland Clin, Lerner Coll Med CWRU, Dept Mol Med, Cleveland, OH 44106 USA. [Varro, Andras] Hungarian Acad Sci, Div Cardiovasc Pharmacol, Szeged, Hungary. [Weiss, James N.] Univ Calif Los Angeles, Sch Med, Div Cardiol, Los Angeles, CA 90024 USA. RP Rudy, Y (reprint author), Washington Univ, Cardiac Bioelect & Arrhythmia Ctr, Campus Box 1097,Whitaker Hall Room 290B,1 Brookin, St Louis, MO 63130 USA. EM rudy@wustl.edu RI Van Wagoner, David/C-6783-2008; Clancy, Colleen/B-2528-2010; Trayanova, Natalia/A-3386-2010; Bers, Donald/C-4507-2012; Varro, Andras/M-2647-2016; OI Van Wagoner, David/0000-0001-8250-9828; Varro, Andras/0000-0003-0745-3603; Bers, Donald/0000-0002-2237-9483 FU Medical Research Council [G9900432]; NHLBI NIH HHS [R01 HL063195, R01 HL063195-09, R01 HL064035, R01 HL064724, R01 HL082729, R01 HL082729-03, R01 HL085592] NR 59 TC 45 Z9 47 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 9 PY 2008 VL 118 IS 11 BP 1202 EP 1211 DI 10.1161/CIRCULATIONAHA.108.772715 PG 10 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 345ZX UT WOS:000259039300013 PM 18779456 ER PT J AU Rutter, MK Wilson, PWF Sullivan, LM Fox, CS D'Agostino, RB Meigs, JB AF Rutter, Martin K. Wilson, Peter W. F. Sullivan, Lisa M. Fox, Caroline S. D'Agostino, Ralph B. Meigs, James B. TI Response to letter regarding article, "use of alternative thresholds defining insulin resistance to predict incident type 2 diabetes mellitus and cardiovascular disease" SO CIRCULATION LA English DT Letter C1 [Rutter, Martin K.] Univ Manchester, Cardiovasc Res Grp, Manchester, England. [Wilson, Peter W. F.] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Sullivan, Lisa M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [D'Agostino, Ralph B.] Boston Univ, Dept Math & Stat, Consulting Unit, Boston, MA 02215 USA. [Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. RP Rutter, MK (reprint author), Univ Manchester, Cardiovasc Res Grp, Manchester, England. OI Rutter, Martin/0000-0001-6380-539X NR 3 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD SEP 9 PY 2008 VL 118 IS 11 BP E157 EP E157 DI 10.1161/CIRCULATIONAHA.108.789495 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 345ZX UT WOS:000259039300019 ER PT J AU Weller, ML Stone, IM Goss, A Rau, T Rova, C Poulsen, DJ AF Weller, M. L. Stone, I. M. Goss, A. Rau, T. Rova, C. Poulsen, D. J. TI Selective overexpression of excitatory amino acid transporter 2 (EAAT2) in astrocytes enhances neuroprotection from moderate but not severe hypoxia-ischemia SO NEUROSCIENCE LA English DT Article DE hypoxia; ischemia; glutamate transport; ceftriaxone; EAAT2 ID RAT CEREBRAL-CORTEX; BETA-LACTAM ANTIBIOTICS; CENTRAL-NERVOUS-SYSTEM; GLUTAMATE TRANSPORTER; SLICE CULTURES; UP-REGULATION; CELL-DEATH; EXPRESSION; NEURONS; BRAIN AB Attempts have been made to elevate excitatory amino acid transporter 2 (EAAT2) expression in an effort to compensate for loss of function and expression associated with disease or pathology. Increased EAAT2 expression has been noted following treatment with beta-lactam antibiotics, and during ischemic preconditioning (IPC). However, both of these conditions induce multiple changes in addition to alterations in EAAT2 expression that could potentially contribute to neuroprotection. Therefore, the aim of this study was to selectively overexpress EAAT2 in astrocytes and characterize the cell type specific contribution of this transporter to neuroprotection. To accomplish this we used a recombinant adeno-associated virus vector, AAV1-glial fibrillary acidic protein (GFAP)-EAAT2, designed to selectively drive the overexpression of EAAT2 within astrocytes. Both viral-mediated gene delivery and beta-lactam antibiotic (penicillin-G) treatment of rat hippocampal slice cultures resulted in a significant increase in both the expression of EAAT2, and dihydrokainate (DHK) sensitive glutamate uptake. Penicillin-G provided significant neuroprotection in rat hippocampal slice cultures under conditions of both moderate and severe oxygen glucose deprivation (OGD). In contrast, viral-mediated overexpression of EAAT2 in astrocytes provided enhanced neuroprotection only following a moderate OGD insult. These results indicate that functional EAAT2 can be selectively overexpressed in astrocytes, leading to enhanced neuroprotection. However, this cell type specific increase in EAAT2 expression offers only limited protection compared to treatment with penicillin-G. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved. C1 [Weller, M. L.; Stone, I. M.; Goss, A.; Rau, T.; Rova, C.; Poulsen, D. J.] Univ Montana, NIH COBRE Ctr Struct & Funct Neurosci, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA. RP Poulsen, DJ (reprint author), Univ Montana, NIH COBRE Ctr Struct & Funct Neurosci, Dept Biomed & Pharmaceut Sci, 32 Campus Dr,1552, Missoula, MT 59812 USA. EM david.poulsen@umontana.edu FU NCRR; NINDS [P20 RR15583, P20 RR017670, R21 NS058541-01] FX This publication was supported by grants from NCRR and NINDS (P20 RR15583, P20 RRO17670, R21 NS058541-01). NR 47 TC 40 Z9 41 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD SEP 9 PY 2008 VL 155 IS 4 BP 1204 EP 1211 DI 10.1016/j.neuroscience.2008.05.059 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 348LY UT WOS:000259213200018 PM 18620031 ER PT J AU Kofinger, J Hummer, G Dellago, C AF Koefinger, Juergen Hummer, Gerhard Dellago, Christoph TI Macroscopically ordered water in nanopores SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE 1D confinement; antiferro-electric; carbon nanotubes; proton transfer; phase transition ID CARBON NANOTUBES; MASS-TRANSPORT; PROTON; TRANSITION; CONDUCTION; MEMBRANES; PROTEINS; CHANNEL; MODELS; PORES AB Water confined into the interior channels of narrow carbon nanotubes or transmembrane proteins forms collectively oriented molecular wires held together by tight hydrogen bonds. Here, we explore the thermodynamic stability and dipolar orientation of such 1D water chains from nanoscopic to macroscopic dimensions. We show that a dipole lattice model accurately recovers key properties of 1D confined water when compared to atomically detailed simulations. In a major reduction in computational complexity, we represent the dipole model in terms of effective Coulombic charges, which allows us to study pores of macroscopic lengths in equilibrium with a water bath (or vapor). We find that at ambient conditions, the water chains filling the tube are essentially continuous up to macroscopic dimensions. At reduced water vapor pressure, we observe a 1D Ising-like filling/emptying transition without a true phase transition in the thermodynamic limit. In the filled state, the chains of water molecules in the tube remain dipole-ordered up to macroscopic lengths of approximate to 0.1 mm, and the dipolar order is estimated to persist for times up to approximate to 0.1 s. The observed dipolar order in continuous water chains is a precondition for the use of nanoconfined 1D water as mediator of fast long-range proton transport, e.g., in fuel cells. For water-filled nanotube bundles and membranes, we expect anti-ferroelectric behavior, resulting in a rich phase diagram similar to that of a 2D Coulomb gas. C1 [Koefinger, Juergen; Dellago, Christoph] Univ Vienna, Fac Phys, A-1090 Vienna, Austria. [Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Dellago, C (reprint author), Univ Vienna, Fac Phys, Boltzmanngasse 5, A-1090 Vienna, Austria. EM christoph.dellago@univie.ac.at RI Dellago, Christoph/E-1625-2011; Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Austrian Science Fund (FWF) [P17178-N02]; Science College "Computational Materials Science" [W004]; SimBioMa; European Science Foundation; National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases FX We thank Andreas Troster for useful discussions. This work was supported by the Austrian Science Fund (FWF) Grant P17178-N02 and Science College "Computational Materials Science" Grant W004 (to J.K. and C.D.), by a short-visit grant within the activity SimBioMa: 'Molecular Simulations in Biosystems and Material Science' from European Science Foundation (J.K.), and by the National Institutes of Health. G.H. was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 33 TC 83 Z9 84 U1 9 U2 47 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 SEP 9 PY 2008 VL 105 IS 36 BP 13218 EP 13222 DI 10.1073/pnas.0801448105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349AR UT WOS:000259251700010 PM 18765798 ER PT J AU Sprouse, RO Karpova, TS Mueller, F Dasgupta, A McNally, JG Auble, DT AF Sprouse, Rebekka O. Karpova, Tatiana S. Mueller, Florian Dasgupta, Arindam McNally, James G. Auble, David T. TI Regulation of TATA-binding protein dynamics in living yeast cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE fluorescence recovery after photobleaching; Mot1; TFIID ID RNA-POLYMERASE-II; TRANSCRIPTION IN-VIVO; GENE-EXPRESSION; SACCHAROMYCES-CEREVISIAE; FLUORESCENCE RECOVERY; PROMOTER; CHROMATIN; COMPLEX; TBP; ACTIVATOR AB Although pathways for assembly of RNA polymerase (Pol) II transcription preinitiation complexes (PICs) have been well established in vitro, relatively little is known about the dynamic behavior of Pol II general transcription factors in vivo. In vitro, a subset of Pol II factors facilitates reinitiation by remaining very stably bound to the promoter. This behavior contrasts markedly with the highly dynamic behavior of RNA Pol I transcription complexes in vivo, which undergo cycles of disassembly/reassembly at the promoter for each round of transcription. To determine whether the dynamic behavior of the Pol II machinery in vivo is fundamentally different from that of Pol I and whether the static behavior of Pol II factors in vitro fully recapitulates their behavior in vivo, we used fluorescence recovery after photobleaching (FRAP). Surprisingly, we found that all or nearly all of the TATA-bincling protein (TBP) population is highly mobile in vivo, displaying FRAP recovery rates of < 15 s. These high rates require the activity of the TBP-associated factor Mot1, suggesting that TBIP/chromatin interactions are destabilized by active cellular processes. Furthermore, the distinguishable FRAP behavior of TBP and TBP-associated factor 1 indicates that there are populations of these molecules that are independent of one another. The distinct FRAP behavior of most Pol II factors that we tested suggests that transcription complexes assemble via stochastic multistep pathways. Our data indicate that active Pol II PICs can be much more dynamic than previously considered. C1 [Sprouse, Rebekka O.; Dasgupta, Arindam; Auble, David T.] Univ Virginia Hlth Syst, Dept Biochem & Mol Genet, Charlottesville, VA 22908 USA. [Karpova, Tatiana S.; Mueller, Florian; McNally, James G.] NCI, Ctr Canc Res, Core Fluorescence Imaging Facil, Lab Receptor Biol & Gene Express,NIH, Bethesda, MD 20892 USA. RP Auble, DT (reprint author), Univ Virginia Hlth Syst, Dept Biochem & Mol Genet, 1340 Jefferson Pk Ave, Charlottesville, VA 22908 USA. EM dta4n@virginia.edu RI Mueller, Florian/C-9075-2012 OI Mueller, Florian/0000-0002-9622-4396 FU National Institutes of Health [GM55763]; National Cancer Institute; Center for Cancer Research FX We thank Tom Misteli and Sui Huang for discussions and Staton Wade and Woo-sin Park for comments on this manuscript. This work was supported by National Institutes of Health Grant GM55763 (to D.T.A.) and the intramural program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research. NR 49 TC 46 Z9 46 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 9 PY 2008 VL 105 IS 36 BP 13304 EP 13308 DI 10.1073/pnas.0801901105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349AR UT WOS:000259251700025 PM 18765812 ER PT J AU O'Brien, EP Ziv, G Haran, G Brooks, BR Thirumalai, D AF O'Brien, Edward P. Ziv, Guy Haran, Gilad Brooks, Bernard R. Thirumalai, D. TI Effects of denaturants and osmolytes on proteins are accurately predicted by the molecular transfer model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE denatured state ensemble; FRET and SAXS experiments; protein L; cold shock protein; protein collapse ID AQUEOUS UREA SOLUTIONS; GLOBULAR-PROTEINS; TRANSITION-STATE; LATTICE MODELS; PEPTIDE; SPECTROSCOPY; STABILITY; COLLAPSE; FLUORESCENCE; MECHANISMS AB Interactions between denaturants and proteins are commonly used to probe the structures of the denatured state ensemble and their stabilities. Osmolytes, a class of small intracellular organic molecules found in all taxa, also profoundly affect the equilibrium properties of proteins. We introduce the molecular transfer model, which combines simulations in the absence of denaturants or osmolytes, and Tanford's transfer model to predict the dependence of equilibrium properties of proteins at finite concentration of osmolytes. The calculated changes in the thermodynamic quantities (probability of being in the native basin of attraction, m values, FRET efficiency, and structures of the denatured state ensemble) with GdmCl concentration [C] for the protein L and cold shock protein CspTm compare well with experiments. The radii of gyration of the subpopulation of unfolded molecules for both proteins decrease (i.e., they undergo a collapse transition) as [C] decreases. Although global folding is cooperative, residual secondary structures persist at high denaturant concentrations. The temperature dependence of the specific heat shows that the folding temperature (T-F) changes linearly as urea and trimethylamine N-oxide (TMAO) concentrations increase. The increase in TF in TIVIAO can be as large as 20 degrees C, whereas urea decreases TF by as much as 35 degrees C. The stabilities of protein L and CspTm also increase linearly with the concentration of osmolytes (proline, sorbitol, sucrose, TMAO, and sarcosine). C1 [O'Brien, Edward P.; Thirumalai, D.] Univ Maryland, Biophys Program, Inst Phys Sci & Technol, College Pk, MD 20742 USA. [O'Brien, Edward P.; Thirumalai, D.] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [O'Brien, Edward P.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Ziv, Guy; Haran, Gilad] Weizmann Inst Sci, Dept Chem Phys, IL-76100 Rehovot, Israel. RP Thirumalai, D (reprint author), Univ Maryland, Biophys Program, Inst Phys Sci & Technol, College Pk, MD 20742 USA. EM thirum@umd.edu RI O'Brien, Edward/C-3587-2015; HARAN, GILAD/K-1489-2012 FU National Science Foundation [05-14056]; US-Israeli Binational Science Foundation [2002371]; National Institutes of Health [1 R01GM080515]; National Institutes of Health GPP Biophysics Fellowship; Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health FX We thank Ben Schuler and Ngo Toan for useful discussions. This work was supported in part by National Science Foundation Grants 05-14056 (to D.T.), the US-Israeli Binational Science Foundation Grant2002371 (to D.T. and G.H.), National Institutes of Health Grant 1 R01GM080515 (to G.H.), and a National Institutes of Health GPP Biophysics Fellowship (to E.O.), and the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health (B.B.). NR 51 TC 97 Z9 97 U1 2 U2 26 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 SEP 9 PY 2008 VL 105 IS 36 BP 13403 EP 13408 DI 10.1073/pnas.0802113105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349AR UT WOS:000259251700042 PM 18757747 ER PT J AU Ding, W Li, CX Hu, TH Graves-Deal, R Fotia, AB Weissman, AM Coffey, RJ AF Ding, Wei Li, Cunxi Hu, Tianhui Graves-Deal, Ramona Fotia, Andrew B. Weissman, Allan M. Coffey, Robert J. TI EGF receptor-independent action of TGF-alpha protects Naked2 from AO7-mediated ubiquitylation and proteasomal degradation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE AO7/RNF25; E3 ligase; Wnt antagonist ID GROWTH-FACTOR-ALPHA; POLARIZED EPITHELIAL-CELLS; UBIQUITIN; EXPRESSION; PRECURSOR; MEMBRANE; PATHWAY; COMPLEX; DOMAIN AB Naked family members (Drosophila Naked Cuticle and mammalian Naked1 and Naked2) have been identified as inducible antagonists of canonical Wnt signaling. We recently reported that Naked2, but not Naked1, interacts with the cytoplasmic tail of TGF-alpha, thereby coating TGF-alpha-containing exocytic vesicles and directing these vesicles to the basolateral corner of polarized epithelial cells. Here, we show that Naked2 is a short-lived protein with a half-life of 60 min caused by its rapid ubiquitin-mediated proteasomal degradation. Overexpression of TGF-alpha stabilizes Naked2 protein in an EGF receptor (EGFR)-independent manner; a physical interaction between the cytoplasmic tail of TGF-alpha and Naked2 is necessary and sufficient for this protection. We have identified a RING finger protein, AO7/RNF25, as a ubiquitin ligase for Naked2, and we have shown that overexpression of TGF-alpha reduces binding of AO7 to Naked2. These results identify an EGFR-independent action of TGF-alpha, in which it protects Naked2 from proteasomal degradation, thus ensuring its delivery to the basolateral surface of polarized epithelial cells. C1 [Ding, Wei; Coffey, Robert J.] Vanderbilt Univ, Dept Cell & Dev Biol, Nashville, TN 37232 USA. [Ding, Wei; Li, Cunxi; Hu, Tianhui] Vanderbilt Univ, Dept Med, Nashville, TN 37232 USA. [Coffey, Robert J.] Dept Vet Affairs Med Ctr, Nashville, TN 37232 USA. [Fotia, Andrew B.; Weissman, Allan M.] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA. RP Coffey, RJ (reprint author), Vanderbilt Univ, Dept Cell & Dev Biol, Suite 4140 MRB 3,465 21st Ave S, Nashville, TN 37232 USA. EM robert.coffey@vanderbilt.edu RI Hu, T/G-3381-2010 FU National Cancer Institute/ National Institutes of Health [CA 46413]; Special Program of Research Excellence [CA 95103]; Mouse Models of Human Cancers Consortium [U01 084239]; Vascular Biology Training [HL007751]; Center for Cancer Research; National Cancer Institute/National Institutes of Health FX We thank Kevin L. Lorick for assistance in initiating yeast two-hybrid studies. This work was supported by National Cancer Institute/ National Institutes of Health Grant CA 46413, Special Program of Research Excellence Grant CA 95103, and Mouse Models of Human Cancers Consortium Grant U01 084239 (to R.J.C.), Vascular Biology Training Grant HL007751 (to T.H.), and by the Center for Cancer Research, National Cancer Institute/National Institutes of Health. NR 23 TC 12 Z9 17 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 SEP 9 PY 2008 VL 105 IS 36 BP 13433 EP 13438 DI 10.1073/pnas.0806298105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349AR UT WOS:000259251700047 PM 18757723 ER PT J AU Chin, JY Kuan, JY Lonkar, PS Krause, DS Seidman, MM Peterson, KR Nielsen, PE Kole, R Glazer, PM AF Chin, Joanna Y. Kuan, Jean Y. Lonkar, Pallavi S. Krause, Diane S. Seidman, Michael M. Peterson, Kenneth R. Nielsen, Peter E. Kole, Ryszard Glazer, Peter M. TI Correction of a splice-site mutation in the beta-globin gene stimulated by triplex-forming peptide nucleic acids SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE beta-thalassemia; gene correction; triplex-forming oligonucleotides; gene targeting ID NUCLEOTIDE EXCISION-REPAIR; CELL SYNCHRONIZATION; MAMMALIAN-CELLS; DUPLEX DNA; BIS-PNA; RECOMBINATION; RECOGNITION; OLIGONUCLEOTIDE; EXPRESSION; EFFICIENCY AB Splice-site mutations in the beta-globin gene can lead to aberrant transcripts and decreased functional beta-globin, causing betathalassemia. Triplex-forming DNA oligonucleoticles (TFOs) and peptide nucleic acids (PNAs) have been shown to stimulate recombination in reporter gene loci in mammalian cells via site-specific binding and creation of altered helical structures that provoke DNA repair. We have designed a series of triplex-forming PNAs that can specifically bind to sequences in the human beta-globin gene. We demonstrate here that these PNAs, when cotransfected with recombinatory donor DNA fragments, can promote single base-pair modification at the start of the second intron of the beta-globin gene, the site of a common thalassernia-associated mutation. This single base pair change was detected by the restoration of proper splicing of transcripts produced from a green fluorescent proteinbeta-globin fusion gene. The ability of these PNAs to induce recombination was dependent on dose, sequence, cell-cycle stage, and the presence of a homologous donor DNA molecule. Enhanced recombination, with frequencies up to 0.4%, was observed with use of the lysomotropic agent chloroquine. Finally, we demonstrate that these PNAs were effective in stimulating the modification of the endogenous beta-globin locus in human cells, including primary hematopoietic progenitor cells. This work suggests that PNAs can be effective tools to induce heritable, site-specific modification of disease-related genes in human cells. C1 [Chin, Joanna Y.; Kuan, Jean Y.; Lonkar, Pallavi S.; Glazer, Peter M.] Yale Univ, Sch Med, Dept Therapeut Radiol, New Haven, CT 06520 USA. [Chin, Joanna Y.; Kuan, Jean Y.; Lonkar, Pallavi S.; Glazer, Peter M.] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06520 USA. [Krause, Diane S.] Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06520 USA. [Krause, Diane S.] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06520 USA. [Seidman, Michael M.] NIA, NIH, Lab Mol Gerontol, Baltimore, MD 21224 USA. [Peterson, Kenneth R.] Univ Kansas, Med Ctr, Dept Biochem & Mol Biol, Kansas City, KS 66160 USA. [Nielsen, Peter E.] Univ Copenhagen, Panum Inst, DK-2200 Copenhagen, Denmark. [Kole, Ryszard] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. [Kole, Ryszard] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. RP Glazer, PM (reprint author), Dept Therapeut Radiol, 15 York St,Hunter 313, New Haven, CT 06510 USA. EM peter.glazer@yale.edu FU Yale Center of Excellence in Molecular Hematology; National Institutes of Health [DK072442, R01CA64186, R01HL082655, 5T32GM07205] FX We thank Bernard Forget (Yale University School of Medicine, New Haven, CT) for helpful discussions and members of the Glazer Lab for their assistance. The hCD-14+ cells were obtained from the Yale Center of Excellence in Molecular Hematology (National Institutes of Health grant DK072442). This work is supported National Institutes of Health grants R01CA64186 and R01HL082655 (to P.M.G.) and MSTP training grant 5T32GM07205 (to J.Y.C.). NR 26 TC 44 Z9 47 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 9 PY 2008 VL 105 IS 36 BP 13514 EP 13519 DI 10.1073/pnas.0711793105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349AR UT WOS:000259251700061 PM 18757759 ER PT J AU Lenz, G Wright, GW Emre, NCT Kohlhammer, H Dave, SS Davis, RE Carty, S Lam, LT Shaffer, AL Xiao, WM Powell, J Rosenwald, A Ott, G Muller-Hermelink, HK Gascoyne, RD Connors, JM Campo, E Jaffe, ES Delabie, J Smeland, EB Rimsza, LM Fisher, RI Weisenburger, DD Chan, WC Staudt, LM AF Lenz, Georg Wright, George W. Emre, N. C. Tolga Kohlhammer, Holger Dave, Sandeep S. Davis, R. Eric Carty, Shannon Lam, Lloyd T. Shaffer, A. L. Xiao, Wenming Powell, John Rosenwald, Andreas Ott, German Muller-Hermelink, Hans Konrad Gascoyne, Randy D. Connors, Joseph M. Campo, Elias Jaffe, Elaine S. Delabie, Jan Smeland, Erlend B. Rimsza, Lisa M. Fisher, Richard I. Weisenburger, Dennis D. Chan, Wing C. Staudt, Louis M. TI Molecular subtypes of diffuse large B-cell lymphoma arise by distinct genetic pathways SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE gene-expression profiling; oncogenes; tumor suppressor genes; comparative genomic hybridization ID HODGKIN LYMPHOMA; COPY NUMBER; EXPRESSION; SUBGROUPS; PROFILES; SURVIVAL; GENOME; CANCER; FOXP1; IDENTIFICATION AB Gene-expression profiling has been used to define 3 molecular subtypes of diffuse large B-cell lymphoma (DLBCL), termed germinal center B-cell-like (GCB) DLBCL, activated B-cell-like (ABC) DLBCL, and primary mediastinal B-cell lymphoma (PMBL). To investigate whether these DLBCL subtypes arise by distinct pathogenetic mechanisms, we analyzed 203 DLBCL biopsy samples by high-resolution, genome-wide copy number analysis coupled with gene-expression profiling. Of 272 recurrent chromosomal aberrations that were associated with gene-expression alterations, 30 were used differentially by the DLBCL subtypes (P < 0.006). An amplicon on chromosome 19 was detected in 26% of ABC DLBCLs but in only 3% of GCB DLBCLs and PMBLs. A highly up-regulated gene in this amplicon was SPIB, which encodes an ETS family transcription factor. Knockdown of SPIB by RNA interference was toxic to ABC DLBCL cell lines but not to GCB DLBCL, PMBL, or myeloma cell lines, strongly implicating SPIB as an oncogene involved in the pathogenesis of ABC DLBCL. Deletion of the INK4a/ARF tumor suppressor locus and trisomy 3 also occurred almost exclusively in ABC DLBCLs and was associated with inferior outcome within this subtype. FOXP1 emerged as a potential oncogene in ABC DLBCL that was up-regulated by trisomy 3 and by more focal high-level amplifications. In GCB DLBCL, amplification of the oncogenic mir-17-92 microRNA cluster and deletion of the tumor suppressor PTEN were recurrent, but these events did not occur in ABC DLBCL. Together, these data provide genetic evidence that the DLBCL subtypes are distinct diseases that use different oncogenic pathways. C1 [Lenz, Georg; Emre, N. C. Tolga; Kohlhammer, Holger; Dave, Sandeep S.; Davis, R. Eric; Carty, Shannon; Lam, Lloyd T.; Shaffer, A. L.; Staudt, Louis M.] NCI, Metab Branch, Bethesda, MD 20892 USA. [Wright, George W.] NCI, Biometr Res Branch, Bethesda, MD 20892 USA. [Xiao, Wenming] NCI, Ctr Informat Technol, Bethesda, MD 20892 USA. [Jaffe, Elaine S.] NCI, Ctr Canc Res, Pathol Lab, Bethesda, MD 20892 USA. [Rosenwald, Andreas; Ott, German; Muller-Hermelink, Hans Konrad] Univ Wurzburg, Dept Pathol, D-97080 Wurzburg, Germany. [Ott, German] Robert Bosch Krankenhaus, Dept Clin Pathol, D-70376 Stuttgart, Germany. [Gascoyne, Randy D.; Connors, Joseph M.] British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. [Campo, Elias] Univ Barcelona, Hosp Clin, E-08036 Barcelona, Spain. [Delabie, Jan] Rikshosp Hosp, Pathol Clin, Oslo, Norway. [Smeland, Erlend B.] Rikshosp Hosp, Inst Canc Res, Oslo, Norway. [Smeland, Erlend B.] Norwegian Radium Hosp, Fac Div, Ctr Canc Biomed, N-0310 Oslo, Norway. [Rimsza, Lisa M.] Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA. [Fisher, Richard I.] SW Oncol Grp, Ann Arbor, MI 48106 USA. [Fisher, Richard I.] Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY 14642 USA. [Weisenburger, Dennis D.; Chan, Wing C.] Univ Nebraska, Dept Pathol & Microbiol, Omaha, NE 68198 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov RI Lenz, Georg/I-6844-2012; OI Delabie, Jan/0000-0001-5023-0689; Campo, elias/0000-0001-9850-9793 FU National Institutes of Health (NIH); National Cancer Institute (NCI); Center for Cancer Research; National Cancer Institute Strategic Partnering to Evaluate Cancer Signatures [UO1-CA 114778]; German Research Foundation; National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institutes of Health (NIH), the National Cancer Institute (NCI), the Center for Cancer Research, and National Cancer Institute Strategic Partnering to Evaluate Cancer Signatures Grant UO1-CA 114778. G.L also was supported by a research grant from the German Research Foundation. This study used the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health (http:Hbiowulf. nih.gov). NR 33 TC 420 Z9 429 U1 2 U2 18 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 9 PY 2008 VL 105 IS 36 BP 13520 EP 13525 DI 10.1073/pnas.0804295105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349AR UT WOS:000259251700062 PM 18765795 ER PT J AU Sun, MK Hongpaisan, J Nelson, TJ Alkon, DL AF Sun, Miao-Kun Hongpaisan, Jarin Nelson, Thomas J. Alkon, Daniel L. TI Poststroke neuronal rescue and synaptogenesis mediated in vivo by protein kinase C in adult brains SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bryostatin; ischemia; neuroprotection; protein kinase C; rat ID ORGANOTYPIC HIPPOCAMPAL SLICE; TISSUE-PLASMINOGEN ACTIVATOR; ACUTE ISCHEMIC-STROKE; ALZHEIMERS-DISEASE; CEREBRAL-ISCHEMIA; CELL-DEATH; PKC; MEMORY; THERAPY; EPSILON AB Global cerebral ischemia/hypoxia, as can occur during human Stroke, damages brain neural networks and synaptic functions. The recently demonstrated protein kinase C (PKC) activation-induced synaptogenesis in rat hippocampus suggested the potential of PKC-mediated antiapoptosis and synaptogenesis during conditions of neurodegeneration. Consequently, we examined the effects of chronic bryostatin-1, a PKC activator, on the cerebral ischemia/hypoxia-incluced impairment of synapses and neurotrophic activity in the hippocampal CA1 area and on hippocampus-dependent spatial learning and memory. Postischernic/hypoxic bryostatin-1 treatment effectively rescued ischemia-induced deficits in synaptogenesis, neurotrophic activity, and spatial learning and memory. These results highlight a neuroprotective signaling pathway, as well as a therapeutic strategy with an extended time window for reducing brain damage due to stroke by activating particular PKC isozymes. C1 [Sun, Miao-Kun; Hongpaisan, Jarin; Nelson, Thomas J.; Alkon, Daniel L.] W Virginia Univ, Blanchette Rockefeller Neurosci Inst, Morgantown, WV 26505 USA. [Hongpaisan, Jarin] Natl Inst Neurol Disorders & Stroke, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Sun, MK (reprint author), W Virginia Univ, Blanchette Rockefeller Neurosci Inst, Morgantown, WV 26505 USA. EM mksun@brni-jhu.org NR 37 TC 64 Z9 64 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 9 PY 2008 VL 105 IS 36 BP 13620 EP 13625 DI 10.1073/pnas.0805952105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349AR UT WOS:000259251700079 PM 18768786 ER PT J AU Steele, AD Hutter, G Jackson, WS Heppner, FL Borkowski, AW King, OD Raymond, GJ Aguzzi, A Lindquist, S AF Steele, Andrew D. Hutter, Gregor Jackson, Walker S. Heppner, Frank L. Borkowski, Andrew W. King, Oliver D. Raymond, Gregory J. Aguzzi, Adriano Lindquist, Susan TI Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neurodegeneration; HSF1; transmissible spongiform encephalopathy; PrP; protein misfolding ID UNFOLDED PROTEIN RESPONSE; TRANSCRIPTION FACTOR; MOLECULAR CHAPERONES; TARGETED DISRUPTION; STRESS-RESPONSE; MOUSE-BRAIN; IN-VIVO; MICE; HSF1; NEURODEGENERATION AB Prion diseases are fatal, transmissible, neurodegenerative diseases caused by the misfolding of the prion protein (PrP). At present, the molecular pathways underlying prion-mediated neurotoxicity are largely unknown. We hypothesized that the transcriptional regulator of the stress response, heat shock factor 1 (HSF1), would play an important role in prion disease. Uninoculated HSF1 knockout (KO) mice used in our study do not show signs of neurodegeneration as assessed by survival, motor performance, or histopathology. When inoculated with Rocky Mountain Laboratory (RML) prions HSF1 KC) mice had a dramatically shortened lifespan, succumbing to disease approximate to 20% faster than controls. Surprisingly, both the onset of home-cage behavioral symptoms and pathological alterations occurred at a similar time in HSF1 KC) and control mice. The accumulation of proteinase K (PK)-resistant PrP also occurred with similar kinetics and prion infectivity accrued at an equal or slower rate. Thus, HSF1 provides an important protective function that is specifically manifest after the onset of behavioral symptoms of prion disease. C1 [Steele, Andrew D.; Jackson, Walker S.; Borkowski, Andrew W.; King, Oliver D.; Lindquist, Susan] MIT, Howard Hughes Med Inst, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. [Hutter, Gregor; Heppner, Frank L.; Aguzzi, Adriano] Univ Hosp, Inst Neuropathol, CH-8091 Zurich, Switzerland. [Raymond, Gregory J.] NIAID, Natl Inst Hlth, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Lindquist, S (reprint author), MIT, Howard Hughes Med Inst, Whitehead Inst Biomed Res, Cambridge, MA 02142 USA. EM lindquist_admin@wi.mit.edu RI Hutter, Gregor/A-1254-2011; Aguzzi, Adriano/A-3351-2008; OI Hutter, Gregor/0000-0002-7570-3902; Aguzzi, Adriano/0000-0002-0344-6708 FU U.S. Dept of Defense [DAMD17-00-1-0296]; Howard Hughes Medical Institute; Ellison Medical Research Foundation; National Institutes of Health-National In stitute of Allergy and Infectious Diseases; Journal of Cell Science Travel Fellowship FX We thank Artur Topolszki, Melissa Topolszki, Petra Schwarz, and Marianne Konig for expert technical assistance; Karen Allen-doerfer for critical comments on the manuscript; and Elisabeth Christians and Ivor Benjamin (University of Utah) for providing the HSF1 knockout mice. This work was supported by U.S. Dept of Defense Grant DAMD17-00-1-0296, the Howard Hughes Medical Institute, the Ellison Medical Research Foundation, the Intramural Research Program at the National Institutes of Health-National In stitute of Allergy and Infectious Diseases, and the Journal of Cell Science Travel Fellowship. NR 55 TC 43 Z9 43 U1 1 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 SEP 9 PY 2008 VL 105 IS 36 BP 13626 EP 13631 DI 10.1073/pnas.0806319105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 349AR UT WOS:000259251700080 PM 18757733 ER PT J AU Chen, J Gu, D Jaquish, CE Chen, CS Rao, DC Liu, D Hixson, JE Hamm, LL Gu, CC Whelton, PK He, J AF Chen, Jing Gu, Dongfeng Jaquish, Cashell E. Chen, Chung-Shiuan Rao, D. C. Liu, Depei Hixson, James E. Hamm, L. Lee Gu, C. Charles Whelton, Paul K. He, Jiang CA GenSalt Collaborative Res Grp TI Association between blood pressure responses to the cold pressor test and dietary sodium intervention in a Chinese population SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID SYMPATHETIC-NERVE ACTIVITY; SALT-SENSITIVITY; CARDIOVASCULAR-DISEASE; HYPERTENSION; HUMANS; NOREPINEPHRINE; MECHANISMS; PREVENTION; POTASSIUM; PREDICTOR AB Background: Blood pressure (BP) responses to the cold pressor test (CPT) and to dietary sodium intake might be related to the risk of hypertension. We examined the association between BP responses to the CPT and to dietary sodium and potassium interventions. Methods: The CPT and dietary intervention were conducted among 1906 study participants in rural China. The dietary intervention included three 7-day periods of low sodium intake (3 g/d of salt [sodium chloride] [51.3 mmol/d of sodium]), high sodium intake (18 g/d of salt [307.8 mmol/d of sodium]), and high sodium intake plus potassium chloride supplementation (60 mmol/d). A total of 9 BP measurements were obtained during the 3-day baseline observation and the last 3 days of each intervention using a random-zero sphygmomanometer. Results: Blood pressure response to the CPT was significantly associated with BP changes during the sodium and potassium interventions (all P < .001). Compared with the lowest quartile of BP response to the CPT (quartile 1), systolic BP changes (95% confidence intervals) for the quartiles 2, 3, and 4 were -2.02 (-2.87 to-1.16) mmHg, -3.17 (-4.05 to-2.28) mm Hg, and -5.98 (-6.89 to-5.08) mm Hg, respectively, during the low-sodium intervention. Corresponding systolic BP changes during the high-sodium intervention were 0.40 (-0.36 to 1.16) mm Hg, 0.44 (-0.35 to 1.22) mm Hg, and 2.30 (1.50 to 3.10) mmHg, respectively, and during the high-sodium plus potassium supplementation intervention were -0.26 (-0.99 to 0.46) mmHg, -0.95 (-1.70 to-0.20) mmHg, and -1.59 (-2.36 to-0.83) mm Hg, respectively. Conclusions: These results indicate that BP response to the CPT was associated with salt sensitivity and potassium sensitivity. Furthermore, a low-sodium or high-potassium diet might be more effective to lower BP among individuals with high responses to the CPT. C1 [Chen, Jing; Hamm, L. Lee; He, Jiang] Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. [Chen, Jing; Chen, Chung-Shiuan; He, Jiang] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA. [Gu, Dongfeng] Chinese Acad Med Sci, Fuwai Hosp, Beijing 100037, Peoples R China. [Gu, Dongfeng] Chinese Acad Med Sci, Cardiovasc Inst, Beijing 100037, Peoples R China. [Liu, Depei] Chinese Acad Med Sci, Inst Basic Med Sci, Lab Med Mol Biol, Beijing 100730, Peoples R China. Peking Union Med Coll, Beijing 100021, Peoples R China. [Gu, Dongfeng] Chinese Natl Ctr Cardiovasc Dis Control & Res, Beijing, Peoples R China. [Jaquish, Cashell E.] NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. [Rao, D. C.; Gu, C. Charles] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Hixson, James E.] Univ Texas Houston, Sch Publ Hlth, Dept Epidemiol, Houston, TX USA. [Whelton, Paul K.] Loyola Univ, Med Ctr, Off President, Maywood, IL 60153 USA. RP Chen, J (reprint author), Tulane Univ, Sch Med, Dept Med, 1443 Tulane Ave SL45, New Orleans, LA 70112 USA. EM jchen@tulane.edu RI Gu, Charles/A-7934-2010 OI Gu, Charles/0000-0002-8527-8145 FU National Heart, Lung, and Blood Institute [U01HL072507]; National Institutes of Health, Bethesda, Maryland FX The Genetic Epidemiology Network of Salt Sensitivity (GenSalt) is supported by a cooperative agreement project grant (U01HL072507) from the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland. NR 36 TC 14 Z9 16 U1 0 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD SEP 8 PY 2008 VL 168 IS 16 BP 1740 EP 1746 DI 10.1001/archinte.168.16.1740 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 345XI UT WOS:000259030600003 PM 18779460 ER PT J AU Kuprash, DV Qin, ZH Ito, D Grivennikov, SI Abe, K Drutskaya, LN Blankenstein, T Nedospasov, SA AF Kuprash, Dmitry V. Qin, Zhihai Ito, Daisuke Grivennikov, Sergei I. Abe, Koichiro Drutskaya, Ludmila N. Blankenstein, Thomas Nedospasov, Sergel A. TI Ablation of TNF or lymphotoxin signaling and the frequency of spontaneous tumors in p53-deficient mice SO CANCER LETTERS LA English DT Article DE cytokine and chemokine biology; p53/mdm2; tumor immunology; knockout mice ID NECROSIS-FACTOR-ALPHA; DEFICIENT MICE; KNOCKOUT MICE; CELL-DEVELOPMENT; BETA RECEPTOR; CANCER; METASTASIS; INFLAMMATION; ANTITUMOR; THERAPY AB TNF plays diverse and contrasting roles in cancer, promoting skin carcinogenesis and metastasis, but also possessing potent antitumor effects in mice. TNF via TNFR1 axis induces NF kappa B, and may contribute to inflammation-facilitated neoplasia. On the other hand, lymphomas are cited as rare complications of anti-TNF therapy in humans. In order to address possible modulating role of TNF and of a related cytokine, LT alpha, in spontaneous tumorigenesis, we compared mice with p53-TNF, p53-LT alpha, p53-TNFR1 and p53-TNF-LT combined deficiencies. Unexpectedly, neither of these mice showed significant modulation of their survival or shift in the spectrum of emerging tumors, as compared to p53-deficient mice, arguing against direct link between TNF blockade and lymphoma development. (C) 2008 Elsevier Ireland Ltd. All rights reserved. C1 [Kuprash, Dmitry V.; Qin, Zhihai; Grivennikov, Sergei I.; Nedospasov, Sergel A.] Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. [Blankenstein, Thomas] Charite, Inst Immunol, D-12200 Berlin, Germany. [Ito, Daisuke; Grivennikov, Sergei I.; Abe, Koichiro; Drutskaya, Ludmila N.] NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Ito, Daisuke; Grivennikov, Sergei I.; Abe, Koichiro; Drutskaya, Ludmila N.] NCI, Basic Res Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Blankenstein, Thomas] Max Delbruck Ctr Mol Med, D-13092 Berlin, Germany. [Nedospasov, Sergel A.] German Rheumatism Res Ctr DRFZ, D-10117 Berlin, Germany. [Qin, Zhihai] Chinese Acad Sci, Inst Biophys, Beijing 100101, Peoples R China. RP Kuprash, DV (reprint author), Russian Acad Sci, VA Engelhardt Mol Biol Inst, Moscow 119991, Russia. EM kuprash@online.ru RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Kuprash, Dmitry/O-4899-2015; Nedospasov, Sergei/Q-7319-2016 OI Kuprash, Dmitry/0000-0002-1488-4148; FU Deutsche Forschungsgemeinschaft [B1 288, SFB633]; Russian Academy of Sciences; National Cancer Institute, National Institutes of Health [N01-CO-12400]; Helmholtz-Humboldt award FX We are indebted to M. Anver and J.M. Ward for pathology analysis and the discussion. We thank H. Bluethmann for TNFR1 KO mice, S. Durum for sharing breeders of p53 KO mice and F. Ruseetti for generous help with mouse housing. We are grateful to D. Devor-Henneman, T. Stuhl, S. Stuhl and C. Westen for their expert technical assistance.; This study was supported by Deutsche Forschungsgemeinschaft (B1 288 and SFB633), MCB grants from the Russian Academy of Sciences and by the National Cancer Institute, National Institutes of Health (the Intramural Research Program, Center for Cancer Research and Contract # N01-CO-12400). S.A.N. is International Research Scholar of Howard Hughes Medical Institute and the recipient of the Helmholtz-Humboldt award.; The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products or organizations imply endorsement by US Government. NR 44 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 EI 1872-7980 J9 CANCER LETT JI Cancer Lett. PD SEP 8 PY 2008 VL 268 IS 1 BP 70 EP 75 DI 10.1016/j.canlet.2008.03.023 PG 6 WC Oncology SC Oncology GA 360EB UT WOS:000260038900008 PM 18442881 ER PT J AU Turville, SG Aravantinou, M Miller, T Kenney, J Teitelbaum, A Hu, LY Chudolij, A Zydowsky, TM Piatak, M Bess, JW Lifson, JD Blanchard, J Gettie, A Robbiani, M AF Turville, Stuart G. Aravantinou, Meropi Miller, Todd Kenney, Jessica Teitelbaum, Aaron Hu, Lieyu Chudolij, Anne Zydowsky, Tom M. Piatak, Michael, Jr. Bess, Julian W., Jr. Lifson, Jeffrey D. Blanchard, James Gettie, Agegnehu Robbiani, Melissa TI Efficacy of Carraguard (R)-Based Microbicides In Vivo Despite Variable In Vitro Activity SO PLOS ONE LA English DT Article AB Anti-HIV microbicides are being investigated in clinical trials and understanding how promising strategies work, coincident with demonstrating efficacy in vivo, is central to advancing new generation microbicides. We evaluated Carraguard (R) and a new generation Carraguard-based formulation containing the non-nucleoside reverse transcriptase inhibitor (NNRTI) MIV-150 (PC-817). Since dendritic cells (DCs) are believed to be important in HIV transmission, the formulations were tested for the ability to limit DC-driven infection in vitro versus vaginal infection of macaques with RT-SHIV (SIVmac239 bearing HIV reverse transcriptase). Carraguard showed limited activity against cell-free and mature DC-driven RT-SHIV infections and, surprisingly, low doses of Carraguard enhanced infection. However, nanomolar amounts of MIV-150 overcame enhancement and blocked DC-transmitted infection. In contrast, Carraguard impeded infection of immature DCs coincident with DC maturation. Despite this variable activity in vitro, Carraguard and PC-817 prevented vaginal transmission of RT-SHIV when applied 30 min prior to challenge. PC-817 appeared no more effective than Carraguard in vivo, due to the limited activity of a single dose of MIV-150 and the dominant barrier effect of Carraguard. However, 3 doses of MIV-150 in placebo gel at and around challenge limited vaginal infection, demonstrating the potential activity of a topically applied NNRTI. These data demonstrate discordant observations when comparing in vitro and in vivo efficacy of Carraguard-based microbicides, highlighting the difficulties in testing putative anti-viral strategies in vitro to predict in vivo activity. This work also underscores the potential of Carraguard-based formulations for the delivery of anti-viral drugs to prevent vaginal HIV infection. C1 [Turville, Stuart G.; Aravantinou, Meropi; Miller, Todd; Kenney, Jessica; Teitelbaum, Aaron; Hu, Lieyu; Chudolij, Anne; Zydowsky, Tom M.; Robbiani, Melissa] Ctr Biomed Res, Populat Council, HIV & AIDS Program, New York, NY USA. [Piatak, Michael, Jr.; Bess, Julian W., Jr.; Lifson, Jeffrey D.] NCI, SAIC Frederick, AIDS & Canc Virus Program, Frederick, MD USA. [Blanchard, James] Tulane Univ Hlth Sci Ctr, Tulane Natl Primate Res Ctr, Covington, LA USA. [Gettie, Agegnehu] Rockefeller Univ, Aaron Diamond AIDS Res Ctr, New York, NY USA. RP Turville, SG (reprint author), Univ Sydney, Westmead Hosp, Westmead Millennium Inst, Ctr Virus Res, Sydney, NSW, Australia. EM mrobbiani@popcouncil.org FU USAID [GPO-A-00-04-00019-00]; NIH [R37 AI040877, AI065412, RR00164]; 2002 Elizabeth Glaser Scientist; NH&MRC of Australia [CJ Martin Fellowship] FX Supported by the USAID Cooperative Agreement GPO-A-00-04-00019-00, NIH grants R37 AI040877 and AI065412, and the NIH base grant RR00164. MR is a 2002 Elizabeth Glaser Scientist. SGT is supported by a CJ Martin Fellowship of the NH&MRC of Australia. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript NR 81 TC 60 Z9 62 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 SEP 8 PY 2008 VL 3 IS 9 AR e3162 DI 10.1371/journal.pone.0003162 PG 14 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422JQ UT WOS:000264424300007 PM 18776937 ER PT J AU Liu, SN Govind, N Pedersen, LG AF Liu, Shubin Govind, Niranjan Pedersen, Lee G. TI Exploring the origin of the internal rotational barrier for molecules with one rotatable dihedral angle SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID DENSITY-FUNCTIONAL THEORY; HUNDS MULTIPLICITY RULE; SIGNAL-TRANSDUCTION PATHWAYS; TRIPLET ENERGY DIFFERENCES; FERMI HOLE; ELECTRON-DENSITY; PAULI ENERGY; HOMOGENEOUS FUNCTIONALS; STAGGERED CONFORMATION; LOCALIZED ORBITALS AB Continuing our recent endeavor, we systematically investigate in this work the origin of internal rotational barriers for small molecules using the new energy partition scheme proposed recently by one of the authors [S. B. Liu, J. Chem. Phys. 126, 244103 (2007)], where the total electronic energy is decomposed into three independent components, steric, electrostatic, and fermionic quantum. Specifically, we focus in this work on six carbon, nitrogen, and oxygen containing hydrides, CH(3)CH(3), CH(3)NH(2), CH(3)OH, NH(2)NH(2), NH(2)OH, and H(2)O(2), with only one rotatable dihedral angle angle H-X-Y-H (X,Y=C,N,O). The relative contributions of the different energy components to the total energy difference as a function of the internal dihedral rotation will be considered. Both optimized-geometry (adiabatic) and fixed-geometry (vertical) differences are examined, as are the results from the conventional energy partition and natural bond orbital analysis. A wealth of strong linear relationships among the total energy difference and energy component differences for different systems have been observed but no universal relationship applicable to all systems for both cases has been discovered, indicating that even for simple systems such as these, there exists no omnipresent, unique interpretation on the nature and origin of the internal rotation barrier. Different energy components can be employed for different systems in the rationalization of the barrier height. Confirming that the two differences, adiabatic and vertical, are disparate in nature, we find that for the vertical case there is a unique linear relationship applicable to all the six molecules between the total energy difference and the sum of the kinetic and electrostatic energy differences. For the adiabatic case, it is the total potential energy difference that has been found to correlate well with the total energy difference except for ethane whose rotation barrier is dominated by the quantum effect. (C) 2008 American Institute of Physics. C1 [Liu, Shubin] Univ N Carolina, Renaissance Comp Inst, Chapel Hill, NC 27599 USA. [Liu, Shubin] Univ N Carolina, Ctr Res Comp, Chapel Hill, NC 27599 USA. [Govind, Niranjan] Pacific NW Natl Lab, Wiliam R Wiley Environm Mol Sci Lab, Richland, WA 99352 USA. [Pedersen, Lee G.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Pedersen, Lee G.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. RP Liu, SN (reprint author), Univ N Carolina, Renaissance Comp Inst, Chapel Hill, NC 27599 USA. EM shubin@email.unc.edu; lee_pedersen@unc.edu RI Liu, Shubin/B-1502-2009; pedersen, lee/A-8567-2009; Govind, Niranjan/D-1368-2011; Pedersen, Lee/E-3405-2013 OI Liu, Shubin/0000-0001-9331-0427; Pedersen, Lee/0000-0003-1262-9861 FU U. S. Department of Energy [DE-AC06-76RLO 1830]; DOE's Office of Biological and Environmental Research; National Institutes of Health [HL-06350]; NSF [ITP/APS-0121361] FX The authors are grateful to Robert G. Parr of the University of North Carolina and Paul W. Ayers of McMaster University, Canada, for their valuable comments and suggestions. The work at Pacific Northwest National Laboratory (PNNL) was supported by the U. S. Department of Energy under Contract No. DE-AC06-76RLO 1830 (Office of Biological and Environmental Research, Environmental Molecular Sciences Laboratory operations). The Pacific Northwest National Laboratory is operated by the Battelle Memorial Institute. The Environmental Molecular Sciences Laboratory operations are supported by the DOE's Office of Biological and Environmental Research. This work was partly supported by the National Institutes of Health (Grant No. HL-06350) and NSF (Grant No. ITP/APS-0121361). We acknowledge the use of the computational resources provided by ITS/RENCI at UNC-CH and the Biomedical Unit of the PSC. NR 67 TC 30 Z9 30 U1 1 U2 18 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD SEP 7 PY 2008 VL 129 IS 9 AR 094104 DI 10.1063/1.2976767 PG 10 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 345DJ UT WOS:000258976000006 PM 19044862 ER PT J AU Zitserman, VY Berezhkovskii, AM Pustovoit, MA Bezrukov, SM AF Zitserman, Vladimir Yu. Berezhkovskii, Alexander M. Pustovoit, Mark A. Bezrukov, Sergey M. TI Relaxation and fluctuations of the number of particles in a membrane channel at arbitrary particle-channel interaction SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID ESCHERICHIA-COLI; OUTER-MEMBRANE; NOISE-ANALYSIS; SUGAR BINDING; CONDUCTANCE; POLYMERS; MALTOPORIN; DYNAMICS; KINETICS; STATE AB We analyze the relaxation of the particle number fluctuations in a membrane channel at arbitrary particle-channel interaction and derive general expressions for the relaxation time and low-frequency limit of the power spectral density. These expressions simplify significantly when the channel is symmetric. For a square-well potential of mean force that occupies the entire channel, we verify the accuracy of the analytical predictions by Brownian dynamics simulations. For such a channel we show that as the depth of the well increases, the familiar scaling of the relaxation time with the channel length squared is transformed into a linear dependence on the length. (C) 2008 American Institute of Physics. C1 [Zitserman, Vladimir Yu.] Russian Acad Sci, Joint Inst High Temp, Moscow 125412, Russia. [Berezhkovskii, Alexander M.] NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. [Pustovoit, Mark A.] St Petersburg Nucl Phys Inst, Gatchina 188300, Russia. [Bezrukov, Sergey M.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Lab Phys & Struct Biol, Program Phys Biol, NIH, Bethesda, MD 20892 USA. RP Zitserman, VY (reprint author), Russian Acad Sci, Joint Inst High Temp, Izhorskaya 13-19, Moscow 125412, Russia. EM bezrukos@mail.nih.gov FU NIH, Center for Information Technology; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Russian Foundation [08-02-00314a] FX This study was supported by the Intramural Research Program of the NIH, Center for Information Technology and Eunice Kennedy Shriver National Institute of Child Health and Human Development. M. A. P. also thanks Russian Foundation for Basic Research (Project No. 08-02-00314a) and the State Programs "Quantum Macrophysics," "Strongly Correlated Electrons in Metals, Superconductors, Semiconductors and Magnetic Materials," and " Neutron Studies of Matter" for partial support. NR 25 TC 2 Z9 2 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD SEP 7 PY 2008 VL 129 IS 9 AR 095101 DI 10.1063/1.2972981 PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 345DJ UT WOS:000258976000033 PM 19044889 ER PT J AU Shackelton, LA Holmes, EC AF Shackelton, Laura A. Holmes, Edward C. TI The role of alternative genetic codes in viral evolution and emergence SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE genetic codes; evolution; viral origins; emerging viruses; antiviral defense ID OPHIOSTOMA-NOVO-ULMI; ELM DISEASE FUNGUS; HYPOVIRULENT STRAIN; CODON REASSIGNMENT; RNA ELEMENT; VIRUS; GENOME; SEQUENCE; CANDIDA AB Although the 'universal' genetic code is widespread among life-forms, a number of diverse lineages have evolved unique codon reassignments. The proteomes of these organisms and organelles must, by necessity, use the same codon assignments. Likewise, for an exogenous genetic element, such as an infecting viral genome, to be accurately and completely expressed with the host's translation system it, must employ the same genetic code. This raises a number of intriguing questions regarding the origin and evolution of viruses. In particular, it is extremely unlikely that viruses of hosts utilizing the universal genetic code would emerge, via cross-species transmission, in hosts utilizing alternative codes, and vice versa. Consequently, more parsimonious scenarios for the origins of such viruses include the prolonged co-evolution of viruses with cellular life, or the escape of genetic material from host genomes. Further, we raise the possibility that emerging viruses provide the selection pressure favoring the use of alternative codes in potential hosts, such that the evolution of a variant genetic code acts as a unique and powerful antiviral strategy. As such, in the face of new emerging viruses, hosts with codon reassignments would have a significant selective advantage compared to hosts utilizing the universal code. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Shackelton, Laura A.; Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, Mueller Lab, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, Mueller Lab, University Pk, PA 16802 USA. EM ech15@psu.edu OI Holmes, Edward/0000-0001-9596-3552 NR 32 TC 17 Z9 18 U1 1 U2 6 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 J9 J THEOR BIOL JI J. Theor. Biol. PD SEP 7 PY 2008 VL 254 IS 1 BP 128 EP 134 DI 10.1016/j.jtbi.2008.05.024 PG 7 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 344OW UT WOS:000258938200014 PM 18589455 ER PT J AU Blom, ES Holmans, P Arepalli, S Adighibe, O Hamshere, ML Gatz, M Pedersen, NL Bergem, ALM Owen, MJ Hollingworth, P Goate, A Williams, J Lannfelt, L Hardy, J Vrieze, FWD Glaser, A AF Blom, Elin S. Holmans, Peter Arepalli, Sampath Adighibe, Omanma Hamshere, Marian L. Gatz, Margaret Pedersen, Nancy L. Bergem, A. L. Mina Owen, Michael J. Hollingworth, Paul Goate, Alison Williams, Julie Lannfelt, Lars Hardy, John Vrieze, Fabienne Wavrant-De Glaser, Anna TI Does APOE explain the linkage of Alzheimer's disease to chromosome 19q13? SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE Alzheimer's disease; APOE; linkage; age at onset; apolipoprotein E ID APOLIPOPROTEIN-E; GENOME SCREEN; VASCULAR DEMENTIA; ONSET; FAMILIES; GENE; AGE; IDENTIFICATION; HERITABILITY; PROGRAM AB We have studied the impact of the apolipoprotein E gene (APOE) on the chromosome 19 linkage peak from an analysis of sib-pairs affected by Alzheimer's disease. We genotyped 417 affected sib-pairs (ASPs) collected in Sweden and Norway (SWE), the UK and the USA for 10 microsatellite markers on chromosome 19. The highest Zlr (3.28, chromosome-wide P-value 0.036) from the multi-point linkage analysis was located approximately 1 Mb from APOE, at marker D19S178. The linkage to chromosome 19 was well explained by APOE in the whole sample as well as in the UK and USA subsamples, as identity by descent (IBD) increased with the number of epsilon 4 alleles in ASPs. There was a suggestion from the SWE subsample that linkage was higher than would be expected from APOE alone, although the test for this did not reach formal statistical significance. There was also a significant age at onset (aao) effect on linkage to chromosome 19q13 in the whole sample, which manifested itself as increased IBD sharing in relative pairs with lower mean aao. This effect was partially, although not completely, explained by APOE. The aao effect varied considerably between the different subsamples, with most of the effect coming from the UK sample. The other samples showed smaller effects in the same direction, but these were not significant. (c) 2007 Wiley-Liss, Inc. C1 [Blom, Elin S.; Lannfelt, Lars; Glaser, Anna] Uppsala Univ, Dept Publ Hlth & Caring Sci, Sect Mol Geriatr, Uppsala, Sweden. [Holmans, Peter; Hamshere, Marian L.; Owen, Michael J.; Hollingworth, Paul; Williams, Julie] Cardiff Univ, Wales Sch Med, Dept Psychol Med, Cardiff, S Glam, Wales. [Holmans, Peter; Hamshere, Marian L.; Owen, Michael J.; Hollingworth, Paul; Williams, Julie] Cardiff Univ, Wales Sch Med, Biostat & Bioinformat Unit, Cardiff, S Glam, Wales. [Arepalli, Sampath; Adighibe, Omanma; Hardy, John; Vrieze, Fabienne Wavrant-De] NIA, NIH, Neurogenet Lab, Bethesda, MD 20892 USA. [Gatz, Margaret; Pedersen, Nancy L.] Univ So Calif, Dept Psychol, Los Angeles, CA 90089 USA. [Gatz, Margaret; Pedersen, Nancy L.] Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. [Bergem, A. L. Mina] Aker Univ Hosp, Dept Mental Hlth, Oslo, Norway. [Goate, Alison] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. RP Blom, ES (reprint author), Rudbeck Lab, Dag Hammarskjolds Vag 20, S-75185 Uppsala, Sweden. EM elin.blom@pubcare.uu.se RI turton, miranda/F-4682-2011; Hardy, John/C-2451-2009; Holmans, Peter/F-4518-2015 OI Holmans, Peter/0000-0003-0870-9412 FU The Swedish Research Council; The Swedish Alzheimer Foundation, APOPIS [LSHM-CT-2003-503330]; NIH [R01 AG08724]; Alzheimer's Research Trust; Medical Research Council FX Grant sponsor: The Swedish Research Council; Grant sponsor: The Swedish Alzheimer Foundation, APOPIS; Grant number: LSHM-CT-2003-503330; Grant sponsor: NIH; Grant number R01 AG08724; Grant sponsor: Alzheimer's Research Trust; Grant sponsor: Medical Research Council. NR 21 TC 6 Z9 6 U1 1 U2 1 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 SEP 5 PY 2008 VL 147B IS 6 BP 778 EP 783 DI 10.1002/ajmg.b.30681 PG 6 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 346EB UT WOS:000259050100016 PM 18161859 ER PT J AU Seidita, G Mirisola, M D'Anna, RP Gallo, A Jensen, RT Mantey, SA Gonzalez, N Falco, M Zingale, M Elia, M Cucina, L Chiavetta, V Romano, V Cali, F AF Seidita, G. Mirisola, M. D'Anna, R. P. Gallo, A. Jensen, R. T. Mantey, S. A. Gonzalez, N. Falco, M. Zingale, M. Elia, M. Cucina, L. Chiavetta, V. Romano, V. Cali, F. TI Analysis of the gastrin-releasing peptide receptor gene in Italian patients with autism spectrum disorders SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE autism; gastrin-releasing peptide receptor; signal transduction; G-protein-coupled receptor; association study ID HUMAN ORPHAN RECEPTOR; BOMBESIN RECEPTORS; MECP2 MUTATIONS; MOLECULAR-BASIS; DOWN-REGULATION; RETT-SYNDROME; GRPR LOCUS; PROTEINS; PHOSPHORYLATION; INTERNALIZATION AB The gastrin-releasing peptide receptor (GRPR) was implicated for the first time in the pathogenesis of Autism spectrum disorders (ASD) by Ishikawa-Brush et al. [Ishikawa-Birush et al. (1997): Hum Mol Genet 6: 1241-1250]. Since this original observation, only one association study [Marui et al. (2004): Brain Dev 26: 5-7] has further investigated, though unsuccessfully, the involvement of the GRPR gene in ASD. With the aim of contributing further information to this topic we have sequenced the entire coding region and the intron/exon junctions of the GRPR gene in 149 Italian autistic patients. The results of this study led to the identification of four novel point mutations, two of which, that is, C6S and L181F, involve amino acid changes identified in two patients with ASD and Rett syndrome, respectively. Both the leucine at position 181 and the cysteine at position 6 are strongly conserved in vertebrates. C6S and L181F mutant proteins were expressed in COS-7 and BALB/3T3 cells, but they did not affect either GRP's binding affinity or its potency for stimulating phospholipase C-mediated production of inositol 1,4,5-trisphosphate. In summary, our results do not provide support for a major role of the GRPR gene in ASD in the population of patients we have studied. However, there is a potential role of C6S and L181F mutations on GRPR function, and possibly in the pathogenesis of the autistic disorders in the two patients. (c) 2008 Wiley-Liss, Inc. C1 [Romano, V.] Univ Palermo, Dipartimento Oncol Sperimentale & Applicaz Clin, I-90146 Palermo, Italy. [Seidita, G.; Mirisola, M.; D'Anna, R. P.; Gallo, A.] Univ Palermo, Dipartimento Biopatol & Metodol Biomed, I-90146 Palermo, Italy. [Jensen, R. T.; Mantey, S. A.; Gonzalez, N.] NIH, Digest Dis Branch, Bethesda, MD 20892 USA. [Falco, M.; Zingale, M.; Elia, M.; Cucina, L.; Chiavetta, V.; Cali, F.] Assoc OASI Maria SS IRCCS, Troina, EN, Italy. RP Romano, V (reprint author), Univ Palermo, Dipartimento Oncol Sperimentale & Applicaz Clin, Via San Lorenzo Colli 312, I-90146 Palermo, Italy. EM vromano@unipa.it RI Elia, Maurizio/K-3285-2016; Chiavetta, Valeria/D-8798-2017; Cali, Francesco/D-9178-2017; Zingale, Marinella/D-5692-2017; OI Elia, Maurizio/0000-0002-0414-1359; Chiavetta, Valeria/0000-0002-9101-6440; Cali, Francesco/0000-0001-8667-8223; Zingale, Marinella/0000-0002-0675-4343; Romano, Valentino/0000-0003-3238-5702; Scavuzzo, Cataldo/0000-0002-3905-4191 NR 36 TC 7 Z9 7 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD SEP 5 PY 2008 VL 147B IS 6 BP 807 EP 813 DI 10.1002/ajmg.b.30752 PG 7 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 346EB UT WOS:000259050100020 PM 18393381 ER PT J AU Liang, KY Wang, Y Shugart, YY Grados, M Fyer, AJ Rauch, S Murphy, D McCracken, J Rasmussen, S Cullen, B Hoehn-Saric, R Greenberg, B Pinto, A Knowles, J Piacentini, J Pauls, D Bienvenu, O Riddle, M Samuels, J Nestadt, G AF Liang, Kung-Yee Wang, Ying Shugart, Yin Yao Grados, Marco Fyer, Abby J. Rauch, Scott Murphy, Dennis McCracken, James Rasmussen, Steven Cullen, Bernadette Hoehn-Saric, Rudolf Greenberg, Benjamin Pinto, Anthony Knowles, James Piacentini, John Pauls, David Bienvenu, O. Riddle, Mark Samuels, Jack Nestadt, Gerald TI Evidence for potential relationship between SLC1A1 and a putative genetic linkage region on chromosome 14q to obsessive-compulsive disorder with compulsive hoarding SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE OCD; linkage; compulsive hoarding; epistasis; SLC1A1 ID OCD COLLABORATIVE GENETICS; FAMILIES AB Obsessive-compulsive disorder (OCD) is likely a disorder involving complex genetic transmission. This suggests that multiple genetic and environmental factors are involved in its etiology. This is complicated further by the probability of genetic heterogeneity for this phenotype. In this report, we describe a preliminary approach to deal with both complexities. SLC1A1, a glutamate transporter gene on chromosome 9p, was originally proposed to be related to OCD based on two linkage studies, and subsequently association of OCD to the gene has been replicated. Additionally, genetic linkage to a subtype of OCD, compulsive hoarding, has been reported on chromosome 14q. We hypothesized that both genomic regions contribute to OCD in some instances. Using the analytic program GENEFINDER we found that conditioning linkage on chromosome 14q to a marker adjacent to SLC1A1, reduced the size of the linkage region on chromosome 14q and provided evidence for interaction between the regions on chromosomes 9p and 14q. (c) 2008 Wiley-Liss, Inc. C1 [Liang, Kung-Yee] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Wang, Ying; Grados, Marco; Cullen, Bernadette; Hoehn-Saric, Rudolf; Bienvenu, O.; Riddle, Mark; Samuels, Jack; Nestadt, Gerald] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Shugart, Yin Yao] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Fyer, Abby J.] New York State Psychiat Inst & Hosp, New York, NY 10032 USA. [Rauch, Scott] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Murphy, Dennis] NIMH, Bethesda, MD 20892 USA. [McCracken, James] Univ Calif Los Angeles, Los Angeles, CA USA. [Rasmussen, Steven] Brown Univ, Dept Psychiat, Providence, RI USA. [Knowles, James] Univ So Calif, Dept Child Psychiat, Los Angeles, CA USA. RP Nestadt, G (reprint author), Meyer 109,600 N Wolfe St, Baltimore, MD 21287 USA. EM gnestadt@jhmi.edu RI Piacentini, John/C-4645-2011; Liang, Kung-Yee/F-8299-2011; Pinto, Anthony/D-2718-2017; OI Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 FU National Institute of Health [R01-MH-50214, NIH/NCRR/OPD] FX Grant sponsor National Institute of Health; Grant numbers: R01-MH-50214, NIH/NCRR/OPD. NR 17 TC 19 Z9 21 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 SEP 5 PY 2008 VL 147B IS 6 BP 1000 EP 1002 DI 10.1002/ajmg.b.30713 PG 3 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 346EB UT WOS:000259050100047 PM 18286588 ER PT J AU Xu, H Wang, XY Partilla, JS Bishop-Mathis, K Benaderet, TS Dersch, CM Simpson, DS Prisinzano, TE Rothman, RB AF Xu, Heng Wang, Xiaoying Partilla, John S. Bishop-Mathis, Kristen Benaderet, Tova S. Dersch, Christina M. Simpson, Denise S. Prisinzano, Thomas E. Rothman, Richard B. TI Differential effects of opioid agonists on G protein expression in CHO cells expressing cloned human opioid receptors SO BRAIN RESEARCH BULLETIN LA English DT Article DE opioid; biased agonism; G protein; opioid receptor ID PEPTIDE RECEPTOR; BETA-ARRESTIN; MORPHINE; ACTIVATION; TOLERANCE; EFFICACY AB Recent evidence indicates that agonist ligands of G protein coupled receptors (GPCR) can activate different signaling systems. Such "agonist-directed" signaling also occurs with opioid receptors. Previous work from our laboratory showed that chronic morphine, but not DAMGO, up-regulates the expression of G alpha 12 and that both morphine and DAMGO decreased G alpha i3 expression in CHO cells expressing the cloned human mu opioid receptor. In this study, we tested the hypothesis that chronic opioid regulation of G protein expression is agonist-directed. Following a 20h treatment of CHO cells expressing the cloned human mu (hMOR-CHO), delta (hDOR-CHO) or kappa (hKOR-CHO) opioid receptors with various opioid agonists, we determined the expression level of G alpha 12 and G alpha i3 by Western blots. Among five mu agonists (morphine, etorphine, DADLE, DAMCO, herkinorin) tested with hMOR-CHO cells, only chronic morphine and etorphine up-regulated G alpha 12 expression. All five mu agonists decreased G alpha i3 expression. Among six delta agonists (SNC80, DPDPE, deltorphin-1, morphine, DADLE, etorphine) tested with hDOR-CHO cells, all six agonists down-regulated G alpha i3 expression or moderately up-regulated G alpha 12 expression. Among five kappa agonists, ((-)-ethylketocyclazocine, salvinorin A, U69,593, etorphine, (-)-U50,488) tested with hKOR-CHO cells, only chronic (-)-U50,488 and (-)-EKC up-regulated Got 12 expression. All kappa agonists decreased Gai3 expression. These data demonstrate that chronic opioid agonist regulation of G protein expression depends not only on the agonist tested, but also on the type of opioid receptor expressed in a common cellular host, providing additional evidence for agonist-directed signaling. Published by Elsevier Inc. C1 [Xu, Heng; Wang, Xiaoying; Partilla, John S.; Bishop-Mathis, Kristen; Benaderet, Tova S.; Dersch, Christina M.; Rothman, Richard B.] NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. [Simpson, Denise S.; Prisinzano, Thomas E.] Univ Kansas, Dept Med Chem, Lawrence, KS 66049 USA. RP Rothman, RB (reprint author), NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. EM rrothman@mail.nih.gov RI Prisinzano, Thomas/B-7877-2010 FU NIH; National Institute on Drug Abuse [DA018151] FX This research was supported by the Intramural Research Program of the NIH, National Institute on Drug Abuse and funding NIDA grant DA018151 to Dr. Prisinzano. NR 24 TC 12 Z9 12 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0361-9230 J9 BRAIN RES BULL JI Brain Res. Bull. PD SEP 5 PY 2008 VL 77 IS 1 BP 49 EP 54 DI 10.1016/j.brainresbull.2008.05.003 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 338EK UT WOS:000258488300008 PM 18639745 ER PT J AU Yoder, A Yu, DY Dong, L Iyer, SR Xu, XH Kelly, J Liu, J Wang, WF Vorster, PJ Agulto, L Stephany, DA Cooper, JN Marsh, JW Wu, YT AF Yoder, Alyson Yu, Dongyang Dong, Li Iyer, Subashini R. Xu, Xuehua Kelly, Jeremy Liu, Juan Wang, Weifeng Vorster, Paul J. Agulto, Liane Stephany, David A. Cooper, James N. Marsh, Jon W. Wu, Yuntao TI HIV envelope-CXCR4 signaling activates cofilin to overcome cortical actin restriction in resting CD4 T cells SO CELL LA English DT Article ID IMMUNOLOGICAL SYNAPSE; CULTURED-CELLS; TARGET-CELLS; G-PROTEIN; LYMPHOCYTES; INFECTION; CHEMOKINE; ENTRY; NEF; TRANSCRIPTION AB Binding of the HIV envelope to the chemokine coreceptors triggers membrane fusion and signal transduction. The fusion process has been well characterized, yet the role of coreceptor signaling remains elusive. Here, we describe a critical function of the chemokine coreceptor signaling in facilitating HIV infection of resting CD4 T cells. We find that static cortical actin in resting T cells represents a restriction and that HIV utilizes the G alpha i-dependent signaling from the chemokine coreceptor CXCR4 to activate a cellular actin-depolymerizing factor, cofilin, to overcome this restriction. HIV envelope-mediated cofilin activation and actin dynamics are important for a postentry process that leads to viral nuclear localization. Inhibition of HIV-mediated actin rearrangement markedly diminishes viral latent infection of resting T cells. Conversely, induction of active cofilin greatly facilitates it. These findings shed light on viral exploitation of cellular machinery in resting T cells, where chemokine receptor signaling becomes obligatory. C1 [Marsh, Jon W.; Wu, Yuntao] NIMH, Sect Mol Virol, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. [Yoder, Alyson; Yu, Dongyang; Dong, Li; Iyer, Subashini R.; Kelly, Jeremy; Liu, Juan; Wang, Weifeng; Vorster, Paul J.; Agulto, Liane; Cooper, James N.] George Mason Univ, Dept Mol & Microbiol, Manassas, VA 20110 USA. [Xu, Xuehua] NIAID, Immunogenet Lab, NIH, Rockville, MD 20851 USA. [Stephany, David A.] NIAID, Flow Cytometry Sect, NIH, Bethesda, MD 20892 USA. [Marsh, Jon W.; Wu, Yuntao] NIMH, Sect Mol Virol, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Marsh, JW (reprint author), NIMH, Sect Mol Virol, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. EM marshj@mail.nih.gov; ywu8@gmu.edu RI wang, weifeng/N-4140-2013; OI xu, xuehua/0000-0002-3863-9593 FU National Defense Science and Engineering Fellowship; GMU; NIMH/NIH; NIAID [AI069981] FX We thank the George Mason University (GMU) Student Health Center; the Department of Transfusion Medicine, the National Institutes of Health (NIH); V. Chandhoke and C. Bailey for blood donation; the NIH AIDS Research and Reference Reagent Program for reagents; H. A. Nash of the National Institute of Mental Health (NIMH)/NIH; K. Jeang of the National Institute of Allergy and Infectious Diseases (NIAID)/NIH; D. Rekosh of the University of Virginia; L. Liotta, E. Petricoin and D. Cox for comments; T. Meckel and T. Jin of NIAID/NIH for confocal microscopy and imaging analyses; K. L. Holmes of NIAID/NIH for fusion assay; A. Biancotto and L. Margolis of the National Institute of Child Health and Human Development/NIH for tonsillar T cells; Y. Samstag for protocols; and A. Wu for digital graphic design. A. Y. was supported by the National Defense Science and Engineering Fellowship. This work was supported by GMU, the Intramural Program of the NIMH/NIH, and in part by the Public Health Service grant AI069981 from NIAID to Y. W. NR 48 TC 148 Z9 152 U1 0 U2 14 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD SEP 5 PY 2008 VL 134 IS 5 BP 782 EP 792 DI 10.1016/j.cell.2008.06.036 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 344SL UT WOS:000258947500018 PM 18775311 ER PT J AU Hoffert, JD Fenton, RA Moeller, HB Simons, B Tchapyjnikov, D McDill, BW Yu, MJ Pisitkun, T Chen, F Knepper, MA AF Hoffert, Jason D. Fenton, Robert A. Moeller, Hanne B. Simons, Brigitte Tchapyjnikov, Dmitry McDill, Bradley W. Yu, Ming-Jiun Pisitkun, Trairak Chen, Feng Knepper, Mark A. TI Vasopressin-stimulated increase in phosphorylation at Ser(269) potentiates plasma membrane retention of aquaporin-2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID KIDNEY COLLECTING DUCT; WATER CHANNEL; RAT; PERMEABILITY; ENDOCYTOSIS; PROTEIN; CELLS; TRAFFICKING; KINASE; LOCALIZATION AB Vasopressin controls water excretion through regulation of aquaporin-2 (AQP2) trafficking in renal collecting duct cells. Using mass spectrometry, we previously demonstrated four phosphorylated serines (Ser(256), Ser(261), Ser(264), and Ser(269)) in the carboxyl-terminal tail of rat AQP2. Here, we used phospho-specific antibodies and protein mass spectrometry to investigate the roles of vasopressin and cyclic AMP in the regulation of phosphorylation at Ser(269) and addressed the role of this site in AQP2 trafficking. The V2 receptor-specific vasopressin analog dDAVP increased Ser(P)(269)-AQP2 abundance more than 10-fold, but at a rate much slower than the corresponding increase in Ser(256) phosphorylation. Vasopressin-mediated changes in phosphorylation at both sites were mimicked by cAMP addition and inhibited by protein kinase A (PKA) antagonists. In vitro kinase assays, however, demonstrated that PKA phosphorylates Ser(256), but not Ser(269). Phosphorylation of AQP2 at Ser(269) did not occur when Ser(256) was replaced by an unphosphorylatable amino acid, as seen in both S256L-AQP2 mutant mice and in Madin-Darby canine kidney cells expressing an S256A mutant, suggesting that Ser(269) phosphorylation depends upon prior phosphorylation at Ser256. Immunogold electron microscopy localized Ser(P)(269)-AQP2 solely in the apical plasma membrane of rat collecting duct cells, in contrast to the other three phospho-forms (found in both apical plasma membrane and intracellular vesicles). Madin-Darby canine kidney cells expressing an S269D "phosphomimic" AQP2 mutant showed constitutive localization at the plasma membrane. The data support a model in which vasopressin-mediated phosphorylation of AQP2 at Ser(269): (a) depends on prior PKA-mediated phosphorylation of Ser(256) and (b) enhances apical plasma membrane retention of AQP2. C1 [Hoffert, Jason D.; Simons, Brigitte; Tchapyjnikov, Dmitry; Yu, Ming-Jiun; Pisitkun, Trairak; Knepper, Mark A.] NHLBI, NIH, Bethesda, MD 20892 USA. [Fenton, Robert A.; Moeller, Hanne B.] Univ Aarhus, Water & Salt Res Ctr, DK-8000 Aarhus, Denmark. [Simons, Brigitte] Appl Biosyst MDS Sciex, Concord, ON L4K 4V8, Canada. [McDill, Bradley W.; Chen, Feng] Washington Univ, Sch Med, Dept Internal Med, St Louis, MO 63110 USA. RP Knepper, MA (reprint author), NHLBI, NIH, 10 Ctr Dr,Bldg 10,Rm 6N260, Bethesda, MD 20892 USA. EM KnepperM@nhlbi.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271; YU, MING-JIUN/0000-0003-0393-4696 FU National Institutes of Health [RO1DK067386, P30DK079333]; NHLBI [Z01-HL001285]; Danish National Research Foundation (Danmarks Grundforskningsfond); Department of Internal Medicine/Renal Division at Washington University School of Medicine; March of Dimes Award [FY06-343] FX This work was supported, in whole or in part, by National Institutes of Health Grants RO1DK067386 and P30DK079333 (to F. C.) and by NHLBI, National Institutes of Health Intramural Budget Project Z01-HL001285 (to J. D. H., M. Y., T. P., and M. A. K.). This work was also supported by a Marie Curie Intra-European Fellowship and funds from the Danish National Research Foundation (Danmarks Grundforskningsfond) (to R. A. F.) and by funds from the Department of Internal Medicine/Renal Division at Washington University School of Medicine and March of Dimes Award FY06-343 (to F. C.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. Section 1734 solely to indicate this fact. NR 43 TC 102 Z9 105 U1 3 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD SEP 5 PY 2008 VL 283 IS 36 BP 24617 EP 24627 DI 10.1074/jbc.M803074200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 342YR UT WOS:000258820000034 PM 18606813 ER PT J AU Luo, YQ Lathia, J Mughal, M Mattson, MP AF Luo, Yongquan Lathia, Justin Mughal, Mohammed Mattson, Mark P. TI SDF1 alpha/CXCR4 Signaling, via ERKs and the Transcription Factor Egr1, Induces Expression of a 67-kDa Form of Glutamic Acid Decarboxylase in Embryonic Hippocampal Neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHEMOKINE RECEPTOR CXCR4; CELL-DERIVED FACTOR-1; CENTRAL-NERVOUS-SYSTEM; DENTATE GRANULE CELLS; GENE-EXPRESSION; STEM-CELLS; PROGENITOR CELLS; RAT HIPPOCAMPUS; MESSENGER-RNAS; NEURAL STEM AB Stromal cell-derived factor alpha(SDF1 alpha) and its cognate receptor CXCR4 play an important role in neuronal development in the hippocampus, but the genes directly regulated by SDF1 alpha/CXCR4 signaling are unknown. To study the role of CXCR4 targeted genes in neuronal development, we used neuronal cultures established from embryonic day 18 rats. Hippocampal neurons express CXCR4 receptor proteins and are stimulated by SDF1 alpha resulting in activation of extracellular signal-regulated kinase (ERK) 1/2 and the transcription factor cAMP-response element-binding protein. SDF1 alpha rapidly induces the expression of the early growth response gene Egr1, a transcription factor involved in activity-dependent neuronal responses, in a concentration-dependent manner. Gel-shift analysis showed that SDF1 alpha enhances DNA binding activity to the Egr1-containing promoter for GAD67. Chromatin immunoprecipitation analysis using an Egr1 antibody indicated that SDF1 alpha stimulation increases binding of Egr1 to a GAD67 promoter DNA sequence. SDF1 alpha stimulation increases the expression of GAD67 at both them RNA and protein levels, and increases the amount and neurite localization of gamma-aminobutyric acid (GABA) in neurons already expressing GABA. SDF1 alpha-induced Egr1/GAD67 expression is mediated by the G protein-coupled CXCR4 receptor and activation of the ERK pathway. Reduction of Egr1 gene expression using small interfering RNA technology lowers the level of GAD67 transcripts and inhibits SDF1 alpha-induced GABA production. Inhibition of CXCR4 activation in the developing mouse brain in utero greatly reduced Egr1 and GAD67 mRNA levels and GAD67 protein levels, suggesting a pivotal role for CXCR4 signaling in the development of GABAergic neurons in vivo. Our data suggest that SDF1 alpha/CXCR4/G protein/ERK signaling induces the expression of the GAD67 system via Egr1 activation, a mechanism that may promote the maturation of GABAergic neurons during development. C1 [Luo, Yongquan; Lathia, Justin; Mughal, Mohammed; Mattson, Mark P.] NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Mattson, MP (reprint author), Rm 4F01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mattsonm@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU NIA, Intramural Research Program FX This work was supported, in whole or in part, by a National Institutes of Health grant from the NIA, Intramural Research Program. NR 65 TC 32 Z9 33 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 SEP 5 PY 2008 VL 283 IS 36 BP 24789 EP 24800 DI 10.1074/jbc.M800649200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 517MA UT WOS:000271617300005 PM 18606818 ER PT J AU Aravind, P Wistow, G Sharma, Y Sankaranarayanan, R AF Aravind, Penmatsa Wistow, Graeme Sharma, Yogendra Sankaranarayanan, Rajan TI Exploring the limits of sequence and structure in a variant beta gamma-crystallin domain of the protein absent in melanoma-1 (AIM1) SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE beta gamma-crystallin; Greek key motif; AIM1g1; Tyr corner; Trp corner ID CALCIUM-BINDING PROPERTIES; X-RAY-ANALYSIS; LENS CRYSTALLINS; EYE LENS; PRECURSOR STRUCTURE; NMR STRUCTURE; KILLER TOXIN; STABILITY; EVOLUTION; SINGLE AB bg-Crystallins belong to a superfamily of proteins in prokaryotes and eukaryotes that are based on duplications of a characteristic, highly conserved Greek key motif. Most members of the superfamily in vertebrates are structural proteins of the eye lens that contain four motifs arranged as two structural domains. Absent in melanoma 1 (AIM1), an unusual member of the superfamily whose expression is associated with suppression of malignancy in melanoma, contains 12 beta gamma-crystallin motifs in six domains. Some of these motifs diverge considerably from the canonical motif sequence. AIM1g1, the first beta gamma-crystallin domain of AIM1, is the most variant of beta gamma-crystallin domains currently known. In order to understand the limits of sequence variation on the structure, we report the crystal structure of AIM1g1 at 1.9 angstrom resolution. Despite having changes in key residues, the domain retains the overall beta gamma-crystallin fold. The domain also contains an unusual extended surface loop that significantly alters the shape of the domain and its charge profile. This structure illustrates the resilience of the beta gamma fold to considerable sequence changes and its remarkable ability to adapt for novel functions. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Aravind, Penmatsa; Sharma, Yogendra; Sankaranarayanan, Rajan] Ctr Cellular & Mol Biol, Hyderabad 500007, Andhra Pradesh, India. [Wistow, Graeme] NEI, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Sharma, Y (reprint author), Ctr Cellular & Mol Biol, Uppal Rd, Hyderabad 500007, Andhra Pradesh, India. EM yogendra@ccmb.res.in; sankar@ccmb.res.in OI Rajan, Sankaranarayanan/0000-0003-4524-9953 FU Department of Science and Technology, Government of India; Wellcome Trust International fellowship; National Eye Institute FX This work was supported by a Department of Science and Technology, Government of India grant (Y.S.) and a Wellcome Trust International fellowship (R.S.). G.W. was supported by the intramural program of the National Eye Institute. Thanks to Drs. Orval Bateman of Birkbeck College, Jeff Trent and Paul Meltzer of National Human Genome Research Institute and Caroline Graham of National Eye Institute, NIH for the clone of AIM1g1. NR 34 TC 19 Z9 21 U1 0 U2 2 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 SEP 5 PY 2008 VL 381 IS 3 BP 509 EP 518 DI 10.1016/j.jmb.2008.06.019 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 341TB UT WOS:000258736700001 PM 18582473 ER PT J AU Sordet, O Larochelle, S Nicolas, E Stevens, EV Zhang, C Shokat, KM Fisher, RP Pommier, Y AF Sordet, Olivier Larochelle, Stephane Nicolas, Estelle Stevens, Ellen V. Zhang, Chao Shokat, Kevan M. Fisher, Robert P. Pommier, Yves TI Hyperphosphorylation of RNA polymerase II in response to topoisomerase I cleavage complexes and its association with transcription- and BRCA1-dependent degradation of topoisomerase I SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE RNA polymerase II; topoisomerase I; transcription; Cdk7; Brca1 ID MEDIATED DNA-DAMAGE; CARBOXYL-TERMINAL DOMAIN; HUMAN-CELLS; MAMMALIAN-CELLS; LARGEST SUBUNIT; NUCLEAR-MATRIX; STRAND BREAKS; CAMPTOTHECIN; REPAIR; PHOSPHORYLATION AB The progression of RNA polymerase II can be blocked by lesions on the DNA template. In this study, we focused on the modifications of the largest subunit of RNA polymerase II, Rpb1, in response to stabilized topoisomerase I (Top1)-DNA cleavage complexes. In addition to DNA modifications (base damages and strand breaks), Top1 cleavage complexes can be trapped by camptothecin (CPT) and its derivatives used in cancer treatment. We found that, within a few minutes, CPT produces the complete hyperphosphorylation of Rpb1 in both primary and transformed cancer cells. Hyperphoshorylation is rapidly reversible following CPT removal. Hyperphosphorylation occurs selectively on the serine 5 residue of the conserved heptapeptide repeats in the Rpb1 carboxy-terminal domain and is mediated principally by the transcription factor IIH-associated cyclin-dependent kinase Cdk7. Hyperphosphorylated Rpb1 is not primarily targeted for proteosomal degradation and instead is subjected to cycles of phosphorylation and dephosphorylation as long as Top1 cleavage complexes are trapped by CPT. Finally, we show that transcription-induced degradation of Top1. is Brca1 dependent, suggesting a role for Brca1 in the repair or removal of transcription-blocking Top1-DNA cleavage complexes. Published by Elsevier Ltd. C1 [Sordet, Olivier; Stevens, Ellen V.; Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Larochelle, Stephane; Fisher, Robert P.] Mem Sloan Kettering Canc Ctr, Program Mol Biol, New York, NY 10021 USA. [Nicolas, Estelle] Univ Toulouse 3, UMR5088, CNRS, LBCMCP, F-31062 Toulouse, France. [Zhang, Chao; Shokat, Kevan M.] Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, Natl Inst Hlth, 37 Convent Dr, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Larochelle, Stephane/D-3662-2012; Sordet, Olivier/M-3271-2014; Nicolas, Estelle/C-4425-2008 OI Larochelle, Stephane/0000-0002-4594-4342; Nicolas, Estelle/0000-0003-0412-8477 FU NIH NCI Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH NCI Center for Cancer Research. We thank W.H. Lee for Brca1-deficient and Brca1-complemented MEF cells. We also thank K.W. Kohn, A. Jobson, and G. Aune for helpful discussions and protocols. NR 58 TC 31 Z9 31 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 SEP 5 PY 2008 VL 381 IS 3 BP 540 EP 549 DI 10.1016/j.jmb.2008.06.028 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 341TB UT WOS:000258736700004 PM 18588899 ER PT J AU Tuncbag, N Gursoy, A Guney, E Nussinov, R Keskin, O AF Tuncbag, Nurcan Gursoy, Attila Guney, Emre Nussinov, Ruth Keskin, Ozlem TI Architectures and functional coverage of protein-protein interfaces SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein interfaces; protein interaction; structure and function; binding; interface database ID STRUCTURAL GENOMICS; INTERACTION NETWORKS; MOLECULAR BIOLOGIST; REFERENCE DATABASE; SYSTEMS BIOLOGY; HOT-SPOTS; SEQUENCE; DOMAIN; RECOGNITION; PREDICTION AB The diverse range of cellular functions is performed by a limited number of protein folds existing in nature. One may similarly expect that cellular functional diversity would be covered by a limited number of protein-protein interface architectures. Here, we present 8205 interface clusters, each representing a unique interface architecture. This data set of protein-protein interfaces is analyzed and compared with older data sets. We observe that the number of both biological and crystal interfaces increases significantly compared to the number of Protein Data Bank entries. Furthermore, we find that the number of distinct interface architectures grows at a much faster rate than the number of folds and is yet to level off. We further analyze the growth trend of the functional coverage by constructing functional interaction networks from interfaces. The functional coverage is also found to steadily increase. Interestingly, we also observe that despite the diversity of interface architectures, some are more favorable and frequently used, and of particular interest, are the ones that are also preferred in single chains. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Tuncbag, Nurcan; Gursoy, Attila; Guney, Emre; Keskin, Ozlem] Koc Univ, Coll Engn, Ctr Computat Biol & Bioinformat, TR-34450 Istanbul, Turkey. [Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Nussinov, Ruth] Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), Koc Univ, Coll Engn, Ctr Computat Biol & Bioinformat, TR-34450 Istanbul, Turkey. EM ruthn@ncifcrf.gov; okeskin@ku.edu.tr RI Tuncbag, Nurcan/D-3383-2011; Gursoy, Attila/E-9565-2015; Guney, Emre/B-2568-2017 OI Gursoy, Attila/0000-0002-2297-2113; Guney, Emre/0000-0002-3466-6535 FU National Cancer Institute; National Institutes of Health (NIH), [N01-CO-12400]; TUBITAK [104T504]; Turkish Academy of Sciences Young Investigator Programme (TUBA-GEBIP); Center for Cancer Research FX This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health (NIH), under contract number N01-CO-12400 and TUBITAK (Research Grant No 104T504). O.K. received a grant from the Turkish Academy of Sciences Young Investigator Programme (TUBA-GEBIP). N.T. was supported by a TUBITAK fellowship. 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 57 TC 72 Z9 72 U1 1 U2 7 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 SEP 5 PY 2008 VL 381 IS 3 BP 785 EP 802 DI 10.1016/j.jmb.2008.04.071 PG 18 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 341TB UT WOS:000258736700024 PM 18620705 ER PT J AU Gearhart, PJ Sen, R AF Gearhart, Patricia J. Sen, Ranjan TI Regulating antibody diversity: Taming a mutagen SO MOLECULAR CELL LA English DT Editorial Material ID SOMATIC HYPERMUTATION; DIVERSIFICATION; AID; RECOMBINATION; GENE AB In a recent issue of Molecular Cell, Conticello et al. (2008) identified a protein that interacts with the activation induced deaminase protein and affects somatic hypermutation, class switching, and gene conversion in immunoglobulin genes, possibly via the spliceosome transcription complex. C1 [Gearhart, Patricia J.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Sen, Ranjan] NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP Gearhart, PJ (reprint author), NIA, Lab Mol Gerontol, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM gearhartp@grc.nia.nih.gov NR 10 TC 0 Z9 0 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP 5 PY 2008 VL 31 IS 5 BP 615 EP 616 DI 10.1016/j.molcel.2008.08.016 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 347BL UT WOS:000259113800001 PM 18775319 ER PT J AU Du, HS Ishii, H Pazin, MJ Sen, R AF Du, Hansen Ishii, Haruhiko Pazin, Michael J. Sen, Ranjan TI Activation of 12/23-RSS-dependent RAG cleavage by hSWI/SNF complex in the absence of transcription SO MOLECULAR CELL LA English DT Article ID RECOMBINATION SIGNAL SEQUENCE; CHROMATIN-REMODELING COMPLEX; REGION GENE SEGMENTS; T-CELL DEVELOPMENT; V(D)J RECOMBINATION; C-TERMINUS; B-CELL; HISTONE ACETYLATION; NUCLEOSOMAL DNA; ALPHA-ENHANCER AB Maintenance of genomic integrity during antigen receptor gene rearrangements requires (1) regulated access of the V(D)J recombinase to specific loci and (2) generation of double-strand DNA breaks only after recognition of a pair of matched recombination signal sequences (RSSs). Here we recapitulate both key aspects of regulated recombinase accessibility in a cell-free system using plasmid substrates assembled into chromatin. We show that recruitment of the SWI/SNF chromatin-remodeling complex to both RSSs increases coupled cleavage by RAG1 and RAG2 proteins. SWI/SNF functions by altering local chromatin structure in the absence of RNA polymerase II-dependent transcription or histone modifications. These observations demonstrate a direct role for cis-sequence-regulated local chromatin remodeling in RAG1/2-dependent initiation of V(D)J recombination. C1 [Du, Hansen; Pazin, Michael J.; Sen, Ranjan] NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. RP Sen, R (reprint author), NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. EM rs465z@nih.gov OI Pazin, Michael/0000-0002-7561-3640 FU Intramural NIH HHS [Z01 AG000524-03, ZIA AG000374-03]; NIGMS NIH HHS [GM38925, R01 GM038925] NR 65 TC 21 Z9 21 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD SEP 5 PY 2008 VL 31 IS 5 BP 641 EP 649 DI 10.1016/j.molcel.2008.08.012 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 347BL UT WOS:000259113800006 PM 18775324 ER PT J AU Xie, ZH Geiger, TR Johnson, EN Nyborg, JK Druey, KM AF Xie, Zhihui Geiger, Timothy R. Johnson, Eric N. Nyborg, Jennifer K. Druey, Kirk M. TI RGS13 acts as a nuclear repressor of CREB SO MOLECULAR CELL LA English DT Article ID ELEMENT-BINDING PROTEIN; CAMP-RESPONSE ELEMENT; GENOME-WIDE ANALYSIS; TRANSCRIPTION FACTOR; B-CELLS; KIX DOMAIN; PHOSPHORYLATION; ACTIVATION; RECEPTOR; EXPRESSION AB Cyclic AMP-induced phosphorylation of the transcription factor CREB elicits expression of genes mediating diverse biological functions. In lymphoid organs, the neurotransmitter norepinephrine stimulates beta(2)-adrenergic receptors on B lymphocytes to promote CREB-dependent expression of genes like the B cell Oct 2 coactivator (OCA-B). Although CREB phosphorylation recruits cofactors. such as CBP/p300 to stimulate transcription, bona fide endogenous inhibitors of CREB-coactivator or CREB-DNA interactions have not emerged. Here, we identified RGS13, a member of the Regulator of G protein Signaling (RGS) protein family, as a nuclear factor that suppresses CREB-mediated gene expression. cAMP or Ca2+ signaling promoted RGS13 accumulation in the nucleus, where it formed a complex with phosphorylated CREB and CBP/p300. RGS13 reduced the apparent affinity of pCIREB for both the CRE and CBP. B lymphocytes from Rgs13(-/-) mice had more beta(2)-agonist-induced OCA-B expression. Thus, RGS13 inhibits CREB-dependent transcription of target genes through disruption of complexes formed at the promoter. C1 [Xie, Zhihui; Johnson, Eric N.; Druey, Kirk M.] NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. [Geiger, Timothy R.; Nyborg, Jennifer K.] Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. RP Druey, KM (reprint author), NIAID, Mol Signal Transduct Sect, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM kdruey@niaid.nih.gov FU NIH [CA55035] FX We thank K. Ravnskjaer and M. Montminy (Salk Institute, La Jolla, CA) and H. Rosenberg (NIAID/NIH) for reagents and helpful advice, J. Kehrl (NIAID, NIH) for the RGS13 antibody, and D. Metcalfe for his support. This research was supported by the Intramural Research Program of the NIH, MAID and by NIH grant no. CA55035 (to J.K.N.). Z.X., T.R.G., E.N.J., and K.M.D. planned and did experiments, analyzed data, and wrote the paper, and J.K.N. planned research, analyzed data, and reviewed the paper. NR 46 TC 27 Z9 27 U1 0 U2 1 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 SEP 5 PY 2008 VL 31 IS 5 BP 660 EP 670 DI 10.1016/j.molcel.2008.06.024 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 347BL UT WOS:000259113800008 PM 18775326 ER PT J AU Komissarova, N Velikodvorskaya, T Sen, R King, RA Banik-Maiti, S Weisberg, RA AF Komissarova, Natalia Velikodvorskaya, Tatiana Sen, Ranjan King, Rodney A. Banik-Maiti, Sarbani Weisberg, Robert A. TI Inhibition of a transcriptional pause by RNA anchoring to RNA polymerase SO MOLECULAR CELL LA English DT Article ID NASCENT ANTITERMINATOR RNA; ELONGATION RATE; TERMINATION EFFICIENCY; ACTIVE-SITE; PHAGE HK022; DNA; MECHANISM; CLEAVAGE; COMPLEX; MOLECULES AB We describe a mechanism by which nascent RNA inhibits transcriptional pausing. PutL RNA of bacteriophage HK022 suppresses transcription termination at downstream terminators and pausing within a nearby U-rich sequence. In vitro transcription and footprinting assays reveal that this pausing results from backtracking of RNA polymerase and that binding of nascent putL RNA to polymerase limits backtracking by restricting re-entry of the transcript into the RNA exit channel. The restriction is local and relaxes as the transcript elongates. Our results suggest that putL RNA binds to the surface of polymerase close to the RNA exit channel, a region that includes amino acid residues important for antitermination. Although binding is essential for antipausing and antitermination, these two activities of put differ: antipausing is limited to the immediate vicinity of the putL site, but antitermination is not. We propose that RNA anchoring to the elongation complex is a widespread mechanism of pause regulation. C1 [Komissarova, Natalia; Velikodvorskaya, Tatiana; Sen, Ranjan; King, Rodney A.; Banik-Maiti, Sarbani; Weisberg, Robert A.] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Sect Microbial Genet, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Weisberg, RA (reprint author), 6B-3B308,6 Ctr Dr, Bethesda, MD 20892 USA. EM rweisberg@nih.gov FU Intramural NIH HHS [Z01 HD000066-37, Z99 HD999999] NR 51 TC 12 Z9 12 U1 1 U2 1 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 SEP 5 PY 2008 VL 31 IS 5 BP 683 EP 694 DI 10.1016/j.molcel.2008.06.019 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 347BL UT WOS:000259113800010 PM 18775328 ER PT J AU Firasat, S Riaziddin, SA Hejtmancik, JF Riazuddin, S AF Firasat, Sabika Riaziddin, S. Amer Hejtmancik, J. Fielding Riazuddin, Sheikh TI Primary congenital glaucoma localizes to chromosome 14q24.2-24.3 in two consanguineous Pakistani families SO MOLECULAR VISION LA English DT Article ID NON-SYNDROMIC MICROPHTHALMIA/ANOPHTHALMIA; ANTERIOR-CHAMBER ANGLE; CYTOCHROME P4501B1; COENZYME-Q; MUTATIONS; GENE; IDENTIFICATION; BUPHTHALMOS; CYP1B1; LOCUS AB Purpose: Two consanguineous Pakistani families with autosomal recessive primary congenital glaucoma were recruited to identify the disease locus. Methods: Ophthalmic examinations including slit lamp biomicroscopy and applanation tonometry were employed to classify the phenotype. Blood samples were collected and genomic DNA was extracted. A genome wide scan was performed on both families with 382 polymorphic microsatellite markers. Two point LOD scores were calculated, and haplotypes were constructed to define the disease interval. Results: Clinical records and ophthalmic examinations suggest that affected individuals in families PKGL005 and PKGL025 have primary congenital glaucoma. Maximum two-point LOD scores of 5.88 with D14S61 at theta=0 and 6.19 with D14S43 at theta=0 were obtained for families PKGL005 and PKGL025, respectively. Haplotype analysis defined the disease locus as spanning a 6.56 cM (similar to 4.2 Mb) genetic interval flanked by D14S289 proximally and D14S85 distally. Conclusions: Linkage analysis localizes autosomal recessive primary congenital glaucoma to chromosome 14q24.2-24.3 in consanguineous Pakistani families. C1 [Firasat, Sabika; Riaziddin, S. Amer; Riazuddin, Sheikh] Univ Punjab, Natl Ctr Excellence Mol Biol, Lahore 53700, Pakistan. [Hejtmancik, J. Fielding] NEI, NIH, Ophthalm Genet & Visual Funct Branch, Bethesda, MD 20892 USA. RP Riazuddin, S (reprint author), Univ Punjab, Natl Ctr Excellence Mol Biol, 87 W Canal Bank Rd, Lahore 53700, Pakistan. EM riaz@lhr.comsats.net.pk RI SHEIKH, RIAZUDDIN/L-2406-2015 NR 30 TC 16 Z9 17 U1 0 U2 0 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD SEP 5 PY 2008 VL 14 IS 196-97 BP 1659 EP 1665 PG 7 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 347LR UT WOS:000259143600001 PM 18776954 ER PT J AU Shen, H Luo, Y Kuo, CC Wang, Y AF Shen, Hui Luo, Yu Kuo, Chi-Chung Wang, Yun TI BMP7 reduces synergistic injury induced by methamphetamine and ischemia in mouse brain SO NEUROSCIENCE LETTERS LA English DT Article DE bone morphogenetic protein 7; methamphetamine; ischemia; stroke; protection ID BONE MORPHOGENETIC PROTEIN-7; MIDDLE CEREBRAL-ARTERY; OSTEOGENIC PROTEIN-1; STROKE RATS; INHALATION; APOPTOSIS; LIGATION; PROTECTS; RECEPTOR; MODEL AB Previous studies have indicated that methamphetamine (MA) potentiates neurodegeneration induced by ischemia in brain. We, and others, have reported that bone morphogenetic protein 7 (BMP7) is protective against MA and ischemic brain injury. The purpose of this study is to examine whether BMP7 reduces synergistic injury induced by both MA and cerebral ischemia. Adult CD-1 mice were treated with MA (4 x 10 mg/kg, each dose 2 h apart) or saline. Using the quantitative real time polymerase chain reaction, we found that MA suppressed the expression of BMP7 mRNA in the cerebral cortex 1 day after injection. Ischemic and reperfusional injuries were introduced by ligation of the right middle cerebral artery for 90 min after MA injection. Animals were sacrificed for caspase-3/7 activity assay and tri-phenyl-tetrazolium chloride staining at I h and 2 days after reperfusion, respectively. Cerebral infarction and caspase-3/7 activity were enhanced in the stroke animals pretreated with MA; both responses were attenuated by pretreatment with BMP7. In conclusion, our data suggest that MA facilitates cerebral infarction after ischemia possibly mediated, in part, through the suppression of BMP7. Published by Elsevier Ireland Ltd. C1 [Shen, Hui; Luo, Yu; Kuo, Chi-Chung; Wang, Yun] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. RP Wang, Y (reprint author), Natl Inst Drug Abuse, Intramural Res Program, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM ywang@intra.nida.nih.gov RI luo, Yu (Agnes)/E-4446-2010 FU National Institute on Drug Abuse, NIH FX This work was supported by the National Institute on Drug Abuse, NIH. NR 19 TC 18 Z9 18 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD SEP 5 PY 2008 VL 442 IS 1 BP 15 EP 18 DI 10.1016/j.neulet.2008.06.052 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 344RI UT WOS:000258944600004 PM 18598737 ER PT J AU Santiago, ML Montano, M Benitez, R Messer, RJ Yonemoto, W Chesebro, B Hasenkrug, KJ Greene, WC AF Santiago, Mario L. Montano, Mauricio Benitez, Robert Messer, Ronald J. Yonemoto, Wes Chesebro, Bruce Hasenkrug, Kim J. Greene, Warner C. TI Apobec3 encodes Rfv3, a gene influencing neutralizing antibody control of retrovirus infection SO SCIENCE LA English DT Article ID FRIEND-VIRUS LEUKEMIA; HIV-1 VIF; RESISTANCE GENE; ENZYME APOBEC3G; EDITING ENZYME; RECOVERY; MOUSE; MICE; IDENTIFICATION; REPLICATION AB Recovery from Friend virus 3 ( Rfv3) is a single autosomal gene encoding a resistance trait that influences retroviral neutralizing antibody responses and viremia. Despite extensive research for 30 years, the molecular identity of Rfv3 has remained elusive. Here, we demonstrate that Rfv3 is encoded by Apobec3. Apobec3 maps to the same chromosome region as Rfv3 and has broad inhibitory activity against retroviruses, including HIV. Not only did genetic inactivation of Apobec3 convert Rfv3- resistant mice to a susceptible phenotype, but Apobec3 was also found to be naturally disabled by aberrant messenger RNA splicing in Rfv3- susceptible strains. The link between Apobec3 and neutralizing antibody responses highlights an Apobec3- dependent mechanism of host protection that might extend to HIV and other human retroviral infections. C1 [Messer, Ronald J.; Chesebro, Bruce; Hasenkrug, Kim J.] NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. [Santiago, Mario L.; Montano, Mauricio; Benitez, Robert; Yonemoto, Wes; Greene, Warner C.] Gladstone Inst Virol & Immunol, San Francisco, CA 94158 USA. [Greene, Warner C.] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Greene, Warner C.] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. RP Hasenkrug, KJ (reprint author), NIAID, Persistent Viral Dis Lab, Rocky Mt Labs, Hamilton, MT 59840 USA. EM khasenkrug@nih.gov; wgreene@gladstone.ucsf.edu OI Santiago, Mario L./0000-0001-7792-2706 FU NIAID Division of Intramural Research at NIH; NIH [R01 AI065329] FX We thank the Transgenic Core Laboratory, the Animal Facility, and S. Espineda at the J. David Gladstone Institutes for technical assistance; L. Evans, J. Portis, R. Gallo, R. Locksley, and members of the Greene and Hasenkrug Laboratory for helpful discussions; and R. Givens, S. Cammack, and G. Howard for manuscript preparation. This work was supported by the NIAID Division of Intramural Research at NIH to K. J. H. and B. C., an NIH R01 AI065329 to W. C. G., and an NIH facility grant to the J. David Gladstone Institutes. Sequences are deposited in GenBank, with accession numbers EU707568 to EU707571. NR 26 TC 520 Z9 532 U1 11 U2 89 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 EI 1095-9203 J9 SCIENCE JI Science PD SEP 5 PY 2008 VL 321 IS 5894 BP 1343 EP 1346 DI 10.1126/science.1161121 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 344GG UT WOS:000258914300047 PM 18772435 ER PT J AU Smirnov, MS Kiyatkin, EA AF Smirnov, Michael S. Kiyatkin, Eugene A. TI Behavioral and temperature effects of delta 9-tetrahydrocannabinol in human-relevant doses in rats SO BRAIN RESEARCH LA English DT Article DE brain metabolism; brain and body temperature; cannabinoid; natural arousing stimuli; intravenous cocaine; vasoconstriction ID CONDITIONED PLACE PREFERENCE; BODY-TEMPERATURE; BRAIN TEMPERATURE; COCAINE; DELTA(9)-TETRAHYDROCANNABINOL; VASOCONSTRICTION; CANNABINOIDS; RECEPTORS; MICE; THC AB Marijuana smoking dramatically alters responses to various environmental stimuli. To study this phenomenon, we assessed how delta-9-tetrahydrocannabinol (THC), a primary psychoactive ingredient of marijuana, affects locomotor and brain (nucleus accumbens or NAcc), muscle and skin temperature responses to natural arousing stimuli (one-minute tail-pinch and one-minute social interaction with another male rat) and iv cocaine (1 mg/kg) in male rats. THC was administered at three widely varying doses (0.5, 2.0 and 8.0 mg/kg, ip), and the drug-induced changes in basal values and responses to stimuli were compared to those occurring following ip vehicle injections (control). Each stimulus in control conditions caused acute locomotor activation, a prolonged increase in brain and muscle temperature (0.6-1.0 degrees C for 20-50 min) and transient decrease in skin temperature (-0.6 degrees C for 1-3 min). While THC at any dose had a tendency to decrease spontaneous locomotion as well as brain and muscle temperatures, true hypothermia and hypoactivity as well as clearly diminished locomotor and temperature responses to all stimuli were only seen following the largest dose. In this case, temperature decreases in the NAcc were stronger than in the muscle, suggesting metabolic brain inhibition as the primary cause of hypoactivity, hypothermia and hyporesponsiveness. While weaker in strength and without associated vasodilatation, this response pattern is mimicked by general anesthetics, questioning to what extent the hypothermic action of THC is specific (i.e., mediated via endogenous cannabinoid receptors) or non-specific, reflecting drug interaction with membrane lipids or other receptors. In contrast, weaker behavioral and temperature effects of THC at lower doses resemble those of diazepam, whose locomotion- and temperature-decreasing effects are evident only in activated conditions, when rats are moving and basal temperatures are elevated. Published by Elsevier B.V. C1 [Smirnov, Michael S.; Kiyatkin, Eugene A.] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov OI Smirnov, Michael/0000-0003-2248-8863 FU NIH; NIDA FX This research was supported by the Intramural Research Program of the NIH, NIDA. We wish to thank Dr. Murat Oz for the valuable comments regarding the issues discussed in this manuscript. NR 40 TC 14 Z9 14 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 SEP 4 PY 2008 VL 1228 BP 145 EP 160 DI 10.1016/j.brainres.2008.06.069 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 352QL UT WOS:000259512000017 PM 18619424 ER PT J AU La Scola, B Desnues, C Pagnier, I Robert, C Barrassi, L Fournous, G Merchat, M Suzan-Monti, M Forterre, P Koonin, E Raoult, D AF La Scola, Bernard Desnues, Christelle Pagnier, Isabelle Robert, Catherine Barrassi, Lina Fournous, Ghislain Merchat, Michele Suzan-Monti, Marie Forterre, Patrick Koonin, Eugene Raoult, Didier TI The virophage as a unique parasite of the giant mimivirus SO NATURE LA English DT Article ID MULTIPLE SEQUENCE ALIGNMENT; BACTERIAL; VIRUSES AB Viruses are obligate parasites of Eukarya, Archaea and Bacteria. Acanthamoeba polyphaga mimivirus ( APMV) is the largest known virus; it grows only in amoeba and is visible under the optical microscope. Mimivirus possesses a 1,185- kilobase double- stranded linear chromosome whose coding capacity is greater than that of numerous bacteria and archaea(1-3). Here we describe an icosahedral small virus, Sputnik, 50 nm in size, found associated with a new strain of APMV. Sputnik cannot multiply in Acanthamoeba castellanii but grows rapidly, after an eclipse phase, in the giant virus factory found in amoebae co- infected with APMV(4). Sputnik growth is deleterious to APMV and results in the production of abortive forms and abnormal capsid assembly of the host virus. The Sputnik genome is an 18.343- kilobase circular double- stranded DNA and contains genes that are linked to viruses infecting each of the three domains of life Eukarya, Archaea and Bacteria. Of the 21 predicted protein- coding genes, eight encode proteins with detectable homologues, including three proteins apparently derived from APMV, a homologue of an archaeal virus integrase, a predicted primase helicase, a packaging ATPase with homologues in bacteriophages and eukaryotic viruses, a distant homologue of bacterial insertion sequence transposase DNA- binding subunit, and a Zn- ribbon protein. The closest homologues of the last four of these proteins were detected in the Global Ocean Survey environmental data set(5), suggesting that Sputnik represents a currently unknown family of viruses. Considering its functional analogy with bacteriophages, we classify this virus as a virophage. The virophage could be a vehicle mediating lateral gene transfer between giant viruses. C1 [La Scola, Bernard; Desnues, Christelle; Pagnier, Isabelle; Robert, Catherine; Barrassi, Lina; Fournous, Ghislain; Suzan-Monti, Marie; Raoult, Didier] Univ Aix Marseille 2, URMITE, Ctr Natl Rech Sci, Fac Med,UMR IRD 6236, F-13385 Marseille 5, France. [Merchat, Michele] Climespace, F-75012 Paris, France. [Forterre, Patrick] Univ Paris 11, Ctr Orsay, Inst Microbiol & Genet, F-91405 Orsay, France. [Forterre, Patrick] Inst Pasteur, Dept Microbiol, F-75724 Paris 15, France. [Koonin, Eugene] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Raoult, D (reprint author), Univ Aix Marseille 2, URMITE, Ctr Natl Rech Sci, Fac Med,UMR IRD 6236, 27 Blvd Jean Moulin, F-13385 Marseille 5, France. EM didier.raoult@gmail.com RI Desnues, Christelle/B-1383-2010; LA SCOLA, Bernard/P-6477-2016; OI Desnues, Christelle/0000-0002-2178-0355; LA SCOLA, Bernard/0000-0001-8006-7704; Pagnier, Isabelle/0000-0002-1724-3450 FU Centre National de la Recherche Scientifique; CIFFRE fellowship; Intramural Research Program of the National Institutes of Health; National Library of Medicine; Institut Universitaire de France FX We thank X. de Lamballerie, S. Azza, P. de Clocquement, L. Espinosa, B. Campagna, N. Aldrovandi, V. Brice, A. Bernard, C. Ivars, B. Giumelli and Y. Wolf for expert assistance. This work was funded by the Centre National de la Recherche Scientifique (CNRS, credits recurrents). I. P. is funded by a CIFFRE fellowship, E. K. is supported by the Intramural Research Program of the National Institutes of Health, National Library of Medicine, and P. F. is funded by the Institut Universitaire de France. NR 27 TC 233 Z9 262 U1 10 U2 94 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 4 PY 2008 VL 455 IS 7209 BP 100 EP U65 DI 10.1038/nature07218 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 343XS UT WOS:000258890200045 PM 18690211 ER PT J AU Liu, J Bartesaghi, A Borgnia, MJ Sapiro, G Subramaniam, S AF Liu, Jun Bartesaghi, Alberto Borgnia, Mario J. Sapiro, Guillermo Subramaniam, Sriram TI Molecular architecture of native HIV-1 gp120 trimers SO NATURE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ENVELOPE GLYCOPROTEIN; ELECTRON TOMOGRAPHY; VACCINE DESIGN; NEUTRALIZATION; BINDING; REPLICATION; RECEPTOR; LACKING; EPITOPE AB The envelope glycoproteins (Env) of human and simian immunodeficiency viruses ( HIV and SIV, respectively) mediate virus binding to the cell surface receptor CD4 on target cells to initiate infection(1). Env is a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein ( gp120), and forms trimers on the surface of the viral membrane. Using cryo- electron tomography combined with three- dimensional image classification and averaging, we report the three- dimensional structures of trimeric Env displayed on native HIV- 1 in the unliganded state, in complex with the broadly neutralizing antibody b12 and in a ternary complex with CD4 and the 17b antibody. By fitting the known crystal structures(2,3) of the monomeric gp120 core in the b12- and CD4/17b-bound conformations into the density maps derived by electron tomography, we derive molecular models for the native HIV- 1 gp120 trimer in unliganded and CD4- bound states. We demonstrate that CD4 binding results in a major reorganization of the Env trimer, causing an outward rotation and displacement of each gp120 monomer. This appears to be coupled with a rearrangement of the gp41 region along the central axis of the trimer, leading to closer contact between the viral and target cell membranes. Our findings elucidate the structure and conformational changes of trimeric HIV- 1 gp120 relevant to antibody neutralization and attachment to target cells. C1 [Liu, Jun; Bartesaghi, Alberto; Borgnia, Mario J.; Subramaniam, Sriram] NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Sapiro, Guillermo] Univ Minnesota, Dept Elect & Comp Engn, Minneapolis, MN 55455 USA. RP Subramaniam, S (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM ss1@nih.gov FU National Cancer Institute; National Science Foundation and the Department of Defense FX We thank J. Bess and J. Lifson for providing purified, AT-2 treated HIV-1 BaL virus; P. Kwong for providing purified preparations of Fab fragments of the neutralizing antibodies b12 and 17b; S. Fellini and colleagues for assistance with use of the high- performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland (http://biowulf.nih.gov); E. Tyler for assistance with figures; T. M. Chou for assistance with microscope maintenance; and A. Bennett, J. Milne and T. White for comments on the manuscript. This work was supported by funds from the intramural programme of the National Cancer Institute (to S.S.), and from the National Science Foundation and the Department of Defense (to G.S.). NR 30 TC 432 Z9 442 U1 5 U2 63 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 4 PY 2008 VL 455 IS 7209 BP 109 EP U76 DI 10.1038/nature07159 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 343XS UT WOS:000258890200047 PM 18668044 ER PT J AU Sakamoto, T Webb, MR Forgacs, E White, HD Sellers, JR AF Sakamoto, Takeshi Webb, Martin R. Forgacs, Eva White, Howard D. Sellers, James R. TI Direct observation of the mechanochemical coupling in myosin Va during processive movement SO NATURE LA English DT Article ID SINGLE-MOLECULE; KINETIC MECHANISM; NECK LENGTH; MOTOR; ADP; ATP; LOCALIZATION; ACTOMYOSIN AB Myosin Va transports intracellular cargoes along actin filaments in cells(1). This processive, two- headed motor takes multiple 36- nm steps in which the two heads swing forward alternately towards the barbed end of actin driven by ATP hydrolysis(2). The ability of myosin Va to move processively is a function of its long lever arm, the high duty ratio of its kinetic cycle and the gating of the kinetics between the two heads such that ADP release from the lead head is greatly retarded(3-10). Mechanical studies at the multiple- and the single- molecule level suggest that there is tight coupling ( that is, one ATP is hydrolysed per power stroke), but this has not been directly demonstrated(4,5,11). We therefore investigated the coordination between the ATPase mechanism of the two heads of myosin Va and directly visualized the binding and dissociation of single fluorescently labelled nucleotide molecules, while simultaneously observing the stepping motion of the fluorescently labelled myosin Va as it moved along an actin filament. Here we show that preferential ADP dissociation from the trail head of mouse myosin Va is followed by ATP binding and a synchronous 36- nm step. Even at low ATP concentrations, the myosin Va molecule retained at least one nucleotide ( ADP in the lead head position) when moving. Thus, we directly demonstrate tight coupling between myosin Va movement and the binding and dissociation of nucleotidebysimultaneouslyimagingwithnearnanometreprecision. C1 [Sakamoto, Takeshi; Sellers, James R.] NHLBI, Lab Mol Physiol, Bethesda, MD 20892 USA. [Webb, Martin R.] Natl Inst Med Res, MRC, London NW7 1AA, England. [Forgacs, Eva; White, Howard D.] Eastern Virginia Med Sch, Dept Physiol Sci, Norfolk, VA 23507 USA. RP Sellers, JR (reprint author), NHLBI, Lab Mol Physiol, Bldg 10, Bethesda, MD 20892 USA. EM Sellersj@mail.nih.gov FU Medical Research Council, UK; National Heart, Lung and Blood Intramural Program; NIH [EB00209]; American Heart Association FX We thank F. Zhang, A. Smith and G. Reid for technical assistance; E. Yokoi for the TIRF illuminator to combine two optical cables; C. Fanghella for technical help in the calculation of the number of photons; and C. Weaver for help with Metamorph. We are appreciative of the critical comments on the manuscript made by P.J. Knight and E. Homsher. M.R.W. was supported by the Medical Research Council, UK. J.R.S. and T.S. were supported by the National Heart, Lung and Blood Intramural Program. H. D. W. and E. F. were supported by NIH EB00209 and a postdoctoral fellowship from the American Heart Association. NR 27 TC 71 Z9 72 U1 4 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD SEP 4 PY 2008 VL 455 IS 7209 BP 128 EP U99 DI 10.1038/nature07188 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 343XS UT WOS:000258890200051 PM 18668042 ER PT J AU Rosenberg, SA Dudley, ME Restifo, NP AF Rosenberg, Steven A. Dudley, Mark E. Restifo, Nicholas P. TI Cancer immunotherapy SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID LYMPHOCYTES; REGRESSION C1 [Rosenberg, Steven A.; Dudley, Mark E.; Restifo, Nicholas P.] NCI, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Bethesda, MD 20892 USA. EM sar@nih.gov RI Restifo, Nicholas/A-5713-2008 NR 5 TC 26 Z9 27 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 SEP 4 PY 2008 VL 359 IS 10 BP 1072 EP 1072 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 343KN UT WOS:000258852500024 PM 18768956 ER PT J AU Chen, J Ruczinski, I Jorgensen, TJ Yenokyan, G Yao, Y Alani, R Liegeois, NJ Hoffman, SC Hoffman-Bolton, J Strickland, PT Helzlsouer, KJ Alberg, AJ AF Chen, Jiping Ruczinski, Ingo Jorgensen, Timothy J. Yenokyan, Gayane Yao, Yin Alani, Rhoda Liegeois, Nanette J. Hoffman, Sandra C. Hoffman-Bolton, Judith Strickland, Paul T. Helzlsouer, Kathy J. Alberg, Anthony J. TI Nonmelanoma skin cancer and risk for subsequent malignancy SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID BASAL-CELL CARCINOMA; ULTRAVIOLET-RADIATION; UNITED-STATES; ASSOCIATION; POPULATION; IMPUTATION; DIAGNOSIS; HISTORY; TUMORS AB Background Individuals with a personal history of nonmelanoma skin cancer (NMSC) may have an increased risk of subsequent noncutaneous malignancies. To test this hypothesis, we carried out a community-based, prospective cohort study. Methods In the CLUE (Give Us a Clue to Cancer and Heart Disease) II cohort, which was established in Washington County, MD, in 1989, the risk of new malignancies was compared among individuals with (n = 769) and without (n = 18 405) a personal history of NMSC (total n = 19 174) during a 16-year follow-up period. Pathologically confirmed NMSC (and other malignancies) were ascertained from the Washington County Cancer Registry. Cox regression analysis with time-dependent covariates was used to determine the hazard ratios (presented as multivariable-adjusted relative risks [RRs]) and 95% confidence intervals (CIs) of second primary malignancies associated with a previously confirmed NMSC diagnosis. All statistical tests were two-sided. Results The crude incidence rate (per 10 000 person-years) of subsequent cancers other than NMSC among participants with a positive personal history of NMSC was 293.5 and with a negative history was 77.8. Compared with persons with no personal history of NMSC, those with such a history had a statistically significantly increased risk of being diagnosed with a subsequent cancer other than NMSC (RR = 1.99, 95% CI = 1.70 to 2.33) after adjusting for age, sex, body mass index, smoking status, and educational level. The association was observed for both basal cell carcinoma (multivariable-adjusted RR = 2.03, 95% CI = 1.70 to 2.42) and squamous cell carcinoma (multivariable-adjusted RR = 1.97, 95% CI = 1.50 to 2.59) of the skin. NMSC was a statistically significantly stronger cancer risk factor in younger age groups than in older age groups (P for interaction = .022). Conclusions This community-based, prospective cohort study provides evidence for an association between an NMSC diagnosis and an increased risk of subsequent cancer, even after adjusting for individual-level risk factors. C1 [Chen, Jiping] Natl Canc Inst, Canc Prevent Div, Rockville, MD USA. [Ruczinski, Ingo] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD USA. [Jorgensen, Timothy J.; Yenokyan, Gayane; Yao, Yin; Hoffman, Sandra C.; Hoffman-Bolton, Judith; Helzlsouer, Kathy J.; Alberg, Anthony J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Strickland, Paul T.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD USA. [Jorgensen, Timothy J.] Georgetown Univ, Sch Med, Dept Radiat Med, Washington, DC USA. [Alani, Rhoda; Liegeois, Nanette J.] Johns Hopkins Univ, Sch Med, Dept Dermatol, Baltimore, MD 21205 USA. [Alani, Rhoda] Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. [Hoffman, Sandra C.; Hoffman-Bolton, Judith; Helzlsouer, Kathy J.; Alberg, Anthony J.] George W Comstock Ctr Publ Hlth Res & Prevent, Washington Cty, MD USA. [Helzlsouer, Kathy J.] Mercy Med Ctr, Baltimore, MD USA. [Alberg, Anthony J.] Med Univ S Carolina, Hollings Canc Ctr, Dept Biostat Bioinformat & Epidemiol, Charleston, SC 29425 USA. RP Alberg, AJ (reprint author), Med Univ S Carolina, Hollings Canc Ctr, Dept Biostat Bioinformat & Epidemiol, 86 Jonathan Lucas St,POB 250955, Charleston, SC 29425 USA. EM alberg@musc.edu OI Alani, Rhoda/0000-0003-2741-2665; Yenokyan, Gayane/0000-0003-1482-5612 FU National Cancer Institute (NCI) [CA105069] FX This research was made possible by funding from the National Cancer Institute (NCI) (CA105069). J. C. received support from NCI's Cancer Prevention Fellowship Program. The authors had full responsibility for the design of the study, the collection of the data, the analysis and interpretation of the data, the decision to submit the manuscript for publication, and the writing of the manuscript. NR 35 TC 59 Z9 62 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-. Natl. Cancer Inst. PD SEP 3 PY 2008 VL 100 IS 17 BP 1215 EP 1222 DI 10.1093/jnci/djn260 PG 8 WC Oncology SC Oncology GA 348IV UT WOS:000259205100006 PM 18728282 ER PT J AU You, ZB Wang, B Zitzman, D Wise, RA AF You, Zhi-Bing Wang, Bin Zitzman, Dawnya Wise, Roy A. TI Acetylcholine release in the mesocorticolimbic dopamine system during cocaine seeking: Conditioned and unconditioned contributions to reward and motivation SO JOURNAL OF NEUROSCIENCE LA English DT Article DE acetylcholine receptor; acetylcholine; ACh; cocaine; dopamine; rat; ventral tegmental area ID VENTRAL TEGMENTAL AREA; NUCLEUS-ACCUMBENS DOPAMINE; CENTRAL-NERVOUS-SYSTEM; SUBSTANTIA-NIGRA; SELF-STIMULATION; RAT-BRAIN; INTRAVENOUS COCAINE; PONTOMESENCEPHALIC TEGMENTUM; PEDUNCULOPONTINE NUCLEUS; GLUTAMATE RECEPTORS AB Microdialysis was used to assess the contribution to cocaine seeking of cholinergic input to the mesocorticolimbic dopamine system in ventral tegmental area (VTA). VTA acetylcholine (ACh) was elevated in animals lever pressing for intravenous cocaine and in cocaine-experienced and cocaine-naive animals passively receiving similar "yoked" injections. In cocaine-trained animals, the elevations comprised an initial ( first hour) peak to similar to 160% of baseline and a subsequent plateau of 140% of baseline for the rest of the cocaine intake period. In cocaine-naive animals, yoked cocaine injections raised ACh levels to the 140% plateau but did not cause the initial 160% peak. In cocaine-trained animals that received unexpected saline ( extinction conditions) rather than the expected cocaine, the initial peak was seen but the subsequent plateau was absent. VTA ACh levels played a causal role and were not just a correlate of cocaine seeking. Blocking muscarinic input to the VTA increased cocaine intake; the increase in intake offset the decrease in cholinergic input, resulting in the same VTA dopamine levels as were seen in the absence of the ACh antagonists. Increased VTA ACh levels ( resulting from 10 mu M VTA neostigmine infusion) increased VTA dopamine levels and reinstated cocaine seeking in cocaine-trained animals that had undergone extinction; these effects were strongly attenuated by local infusion of a muscarinic antagonist and weakly attenuated by a nicotinic antagonist. These findings identify two cholinergic responses to cocaine self-administration, an unconditioned response to cocaine itself and a conditioned response triggered by cocaine-predictive cues, and confirm that these cholinergic responses contribute to the control of cocaine seeking. C1 [You, Zhi-Bing; Wang, Bin; Zitzman, Dawnya; Wise, Roy A.] NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP You, ZB (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM zyou@intra.nida.nih.gov RI Wise, Roy/A-6465-2012 FU National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services FX This work was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. NR 65 TC 40 Z9 42 U1 2 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD SEP 3 PY 2008 VL 28 IS 36 BP 9021 EP 9029 DI 10.1523/JNEUROSCI.0694-08.2008 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 343XY UT WOS:000258890900019 PM 18768696 ER PT J AU Trisciuoglio, D Uranchimeg, B Cardellina, JH Meragelman, TL Matsunaga, S Fusetani, N Del Bufalo, D Shoemaker, RH Melillo, G AF Trisciuoglio, Daniela Uranchimeg, Badarch Cardellina, John H. Meragelman, Tamara L. Matsunaga, Shigeki Fusetani, Nobuhiru Del Bufalo, Donatella Shoemaker, Robert H. Melillo, Giovanni TI Induction of apoptosis in human cancer cells by candidaspongiolide, a novel sponge polyketide SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID PROTEIN-KINASE PKR; EUKARYOTIC TRANSLATION INITIATION; ENDOPLASMIC-RETICULUM STRESS; CAP-DEPENDENT TRANSLATION; ER-STRESS; RIBOSOMAL-SUBUNIT; ACTIVATION; HYPOXIA; DEATH; PHOSPHORYLATION AB Background Candidaspongiolide (CAN), a novel polyketide from a marine sponge, is the active component of a mixture that was found to be potently cytotoxic in the National Cancer Institute's 60-cell-line screen. Methods Effects of CAN on U251 glioma and HCT116 colorectal cancer cells and on normal fibroblasts were assessed using radiolabeling studies to measure protein synthesis, clonogenic assays to measure cell survival, flow cytometry of annexin V- and propidium iodide-stained cells to measure apoptosis, and western blots in the presence or absence of specific inhibitors to assess accumulation and phosphorylation of potential downstream target proteins. Results CAN inhibited protein synthesis and potently induced apoptosis in both U251 and HCT116 cells, the latter in part by a caspase 12-dependent pathway. For example, 25%-30% of U251 or HCT116 cells became apoptotic after 24 hours of treatment with 100 nM CAN. CAN also rapidly induced sustained phosphorylation of eukaryotic translation initiation factor-2 (eIF2)-alpha at Ser51 and of the translation elongation factor eEF2 at Thr56, which could contribute to its dose-dependent inhibition of protein synthesis. Stable expression of dominant-negative eIF2 alpha was sufficient to prevent CAN-induced eIF2 alpha phosphorylation and induction of apoptosis but insufficient to prevent inhibition of protein synthesis. CAN induction of eIF2 alpha phosphorylation did not occur by a classic endoplasmic reticulum stress pathway. However, an inhibitor of and small-interfering RNAs to the double-stranded RNA-dependent protein kinase PKR prevented CAN-mediated eIF2 alpha phosphorylation and apoptosis, respectively. Although CAN inhibited protein synthesis in both cancer cells and normal human fibroblasts, it induced eIF2 alpha phosphorylation and apoptosis only in cancer cells. Conclusions CAN triggers PKR/eIF2 alpha/caspase 12-dependent apoptosis and inhibits protein synthesis in cancer cells but only inhibits protein synthesis in normal cells. C1 [Trisciuoglio, Daniela; Uranchimeg, Badarch; Melillo, Giovanni] SAIC Frederick Inc, Tumor Hypoxia Lab, Frederick, MD USA. [Cardellina, John H.; Meragelman, Tamara L.; Shoemaker, Robert H.] NCI, Screening Technol Branch, Dev Therapeut Program, Frederick, MD 21702 USA. [Matsunaga, Shigeki; Fusetani, Nobuhiru] Univ Tokyo, Marine Biochem Lab, Tokyo, Japan. [Trisciuoglio, Daniela; Del Bufalo, Donatella] Regina Elena Inst Canc Res, Expt Chemotherapy Lab, Rome, Italy. RP Melillo, G (reprint author), NCI, DTP Tumor Hypoxia Lab, Bldg 432,Rm 218, Frederick, MD 21702 USA. EM melillog@ncifcrf.gov RI trisciuoglio, Daniela/H-2131-2016 OI trisciuoglio, Daniela/0000-0002-7007-7914 FU Italian Foundation for Cancer Research (FIRC); National Cancer Institute; National Institutes of Health [N01-CO-12400]; Division of Cancer Treatment and Diagnosis of the National Cancer Institute; Associazione Italiana per la Ricerca sul Cancro FX Dr Daniela Trisciuoglio is a recipient of a fellowship from the Italian Foundation for Cancer Research (FIRC). This project has been funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400. This research was supported (in part) by the Developmental Therapeutics Program in the Division of Cancer Treatment and Diagnosis of the National Cancer Institute. NR 46 TC 20 Z9 21 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 3 PY 2008 VL 100 IS 17 BP 1233 EP 1246 DI 10.1093/jnci/djn239 PG 14 WC Oncology SC Oncology GA 348IV UT WOS:000259205100008 PM 18728285 ER PT J AU Deye, J Purdy, J Vikram, B AF Deye, James Purdy, James Vikram, Bhadrasain TI Re: Intensity-modulated radiation therapy dose prescription, recording, and delivery: Patterns of variability among institutions and treatment planning systems SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 [Deye, James; Vikram, Bhadrasain] Natl Canc Inst, Radiat Res Program, Bethesda, MD USA. [Purdy, James] Univ Calif Davis, Med Ctr, Sacramento, CA 95817 USA. RP Deye, J (reprint author), 6130 Execut Blvd,MSC 7440,EPN 6018, Bethesda, MD 20892 USA. EM deyej@mail.nih.gov NR 3 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD SEP 3 PY 2008 VL 100 IS 17 BP 1263 EP 1264 DI 10.1093/jnci/djn236 PG 2 WC Oncology SC Oncology GA 348IV UT WOS:000259205100012 PM 18728288 ER PT J AU Shen, L Pearson, KJ Xiong, Y Lo, CM Tso, P Woods, SC Davidson, WS Liu, M AF Shen, Ling Pearson, Kevin J. Xiong, Ye Lo, Chun-Min Tso, Patrick Woods, Stephen C. Davidson, W. Sean Liu, Min TI Characterization of apolipoprotein A-IV in brain areas involved in energy homeostasis SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE apolipoproteins; immunohistochemistry; blood brain barrier; neuropeptides ID HYPOTHALAMIC PARAVENTRICULAR NUCLEUS; HIGH-FAT DIET; FOOD-INTAKE; RAT HYPOTHALAMUS; GENE-EXPRESSION; NEUROPEPTIDE-Y; BODY-WEIGHT; LEPTIN; AIV; NEURONS AB Apolipoprotein A-IV (apo A-IV) is a satiation protein synthesized in the small intestine and hypothalamus. To further understand its anorectic mechanisms. we used immunohistochemical techniques to characterize the distribution of apo A-IV in brain areas involved in energy homeostasis. Dense apo A-IV staining was detected in the arcuate (ARC) and ventromedial hypothalamic nuclei with less staining in cells in the paraventricular and dorsomedial nuclei. In the brainstem, apo A-IV staining was found in the nucleus of the solitary tract. Double-staining immunohistochemistry revealed co-existence of apo A-IV with neuronal nuclei (a neuronal marker), but less with glial fibrillary acidic protein (a glial marker), in ARC, suggesting that apo A-IV is largely present in neurons. In the ARC, apo A-IV was co-localized with pro-opiomelanocortin (POMC), and apo A-IV administration stimulated hypothalamic POMC gene expression, suggesting that the brain apo A-IV system suppresses food intake by stimulating the ARC POMC system. To ascertain whether the apo A-IV detected in the brain is derived from the circulation, I-125-labeled recombinant rat apo A-IV was intravenously injected into mice. No increase of radioactive apo A-IV was found in the brain, consistent with a lack of uptake of co-injected Tc-99m-labeled albumin, indicating that circulating apo A-IV is unable to cross the blood brain barrier. These data collectively support the hypothesis that apo A-IV, produced by neuronal cells, may exert its anorectic action by interacting with catabolic regulatory neuropeptides. (c) 2008 Elsevier Inc. All rights reserved. C1 [Shen, Ling; Xiong, Ye; Lo, Chun-Min; Tso, Patrick; Davidson, W. Sean; Liu, Min] Univ Cincinnati, Coll Med, Dept Pathol & Lab Med, Cincinnati, OH 45237 USA. [Shen, Ling; Lo, Chun-Min; Tso, Patrick; Woods, Stephen C.; Davidson, W. Sean; Liu, Min] Univ Cincinnati, Coll Med, Obes Res Ctr, Cincinnati, OH 45237 USA. [Woods, Stephen C.] Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH 45237 USA. [Pearson, Kevin J.] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RP Liu, M (reprint author), Univ Cincinnati, Coll Med, Dept Pathol & Lab Med, Cincinnati, OH 45237 USA. EM lium@uc.edu FU National Institutes of Health [DK63907, DK70992, DK54890, DK17844, DK56863, HL082734] FX The authors acknowledge the technical assistance of Drs. Mingdian Zhang and Li-yun Ma. This work was supported by research grants from the National Institutes of Health DK63907, DK70992, DK54890, DK17844, DK56863 and HL082734. NR 37 TC 23 Z9 25 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD SEP 3 PY 2008 VL 95 IS 1-2 BP 161 EP 167 DI 10.1016/j.physbeh.2008.05.022 PG 7 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 352ZO UT WOS:000259536100026 PM 18577393 ER PT J AU Gupta, PK Moayeri, M Crown, D Fattah, RJ Leppla, SH AF Gupta, Pradeep K. Moayeri, Mahtab Crown, Devorah Fattah, Rasem J. Leppla, Stephen H. TI Role of N-Terminal Amino Acids in the Potency of Anthrax Lethal Factor SO PLOS ONE LA English DT Article AB Anthrax lethal factor (LF) is a Zn+2-dependent metalloprotease that cleaves several MAPK kinases and is responsible for the lethality of anthrax lethal toxin (LT). We observed that a recombinant LF (LF-HMA) which differs from wild type LF (LF-A) by the addition of two residues (His-Met) to the native Ala (A) terminus as a result of cloning manipulations has 3-fold lower potency toward cultured cells and experimental animals. We hypothesized that the "N-end rule'', which relates the half-life of proteins in cells to the identity of their N-terminal residue, might be operative in the case of LF, so that the N-terminal residue of LF would determine the cytosolic stability and thereby the potency of LF. Mutational studies that replaced the native N-terminal residue of LF with known N-end rule stabilizing or destabilizing residues confirmed that the N-terminal residue plays a significant role in determining the potency of LT for cultured cells and experimental animals. The fact that a commercially-available LF preparation (LF-HMA) that is widely used in basic research studies and for evaluation of vaccines and therapeutics is 3-fold less potent than native LF (LF-A) should be considered when comparing published studies and in the design of future experiments. C1 [Gupta, Pradeep K.; Moayeri, Mahtab; Crown, Devorah; Fattah, Rasem J.; Leppla, Stephen H.] NIAID, Lab Bacterial Dis, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Gupta, PK (reprint author), NIAID, Lab Bacterial Dis, Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov FU Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases FX This research was supported by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 41 TC 39 Z9 39 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD SEP 3 PY 2008 VL 3 IS 9 AR e3130 DI 10.1371/journal.pone.0003130 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 422HM UT WOS:000264418300011 PM 18769623 ER PT J AU Heidemann, C Sun, Q van Dam, RM Meigs, JB Zhang, CL Tworoger, SS Mantzoros, CS Hu, FB AF Heidemann, Christin Sun, Qi van Dam, Rob M. Meigs, James B. Zhang, Cuilin Tworoger, Shelley S. Mantzoros, Christos S. Hu, Frank B. TI Total and high-molecular-weight adiponectin and resistin in relation to the risk for type 2 diabetes in women SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID CORONARY-ARTERY-DISEASE; INSULIN-RESISTANCE; METABOLIC SYNDROME; SERUM RESISTIN; PLASMA RESISTIN; ADIPOSE-TISSUE; OLDER MEN; MELLITUS; OBESITY; HUMANS AB Background: Adiponectin and resistin are recently discovered adipokines that may provide a molecular link between adiposity and type 2 diabetes. Objective: To evaluate whether total and high-molecular-weight adiponectin and resistin are associated with future risk for type 2 diabetes, independent of obesity and other known diabetes risk factors. Design: Prospective, nested, case - control study. Setting: United States. Participants: 1038 initially healthy women of the Nurses' Health Study who developed type 2 diabetes after blood sampling (1989 to 1990) through 2002 and 1136 matched control participants. Measurements: Plasma concentrations of total and high-molecular-weight adiponectin and resistin. Results: In multivariate models including body mass index, higher total and high-molecular-weight adiponectin levels were associated with a substantially lower risk for type 2 diabetes (odds ratio [OR] comparing the highest with the lowest quintiles, 0.17 [95% CI, 0.12 to 0.25] for total adiponectin and 0.10 [CI, 0.06 to 0.15] for high-molecular-weight adiponectin). A higher ratio of high-molecular-weight to total adiponectin was associated with a statistically significantly lower risk even after adjustment for total adiponectin (OR, 0.45 [CI, 0.31 to 0.65]). In the multivariate model without body mass index, higher resistin levels were associated with a higher risk for diabetes (OR, 1.68 [CI, 1.25 to 2.25]), but the association was no longer statistically significant after adjustment for body mass index (OR, 1.28 [CI, 0.93 to 1.76]). Limitation: The findings apply mainly to white women and could be partly explained by residual confounding from imperfectly measured or unmeasured variables. Conclusion: Adiponectin is strongly and inversely associated with risk for diabetes, independent of body mass index, whereas resistin is not. The ratio of high-molecular-weight to total adiponectin is related to risk for diabetes independent of total adiponectin, suggesting an important role of the relative proportion of high-molecular-weight adiponectin in diabetes pathogenesis. C1 Harvard Univ, Sch Publ Hlth, Massachusetts Gen Hosp, Brigham & Womens Hosp, Boston, MA 02215 USA. Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. NIH, Bethesda, MD 20892 USA. RP Hu, FB (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave, Boston, MA 02215 USA. EM frank.hu@channing.harvard.edu RI van Dam, Rob/F-9674-2010; OI van Dam, Rob/0000-0002-7354-8734; Tworoger, Shelley/0000-0002-6986-7046 FU National Institute of Child Health & Human Development [CA87969, DK58845, DK58785]; German Academic Exchange Service; Hans & Eugenia Juetting Foundation; American Diabetes; Tanita Corporation; Beth Israel Deaconess Medical Center FX By the National Institutes of Health and the Intramural Research Program of the National Institute of Child Health & Human Development (grants CA87969, DK58845 and DK58785). Dr. Heidemann was supported by fellowships of the German Academic Exchange Service and the Hans & Eugenia Juetting Foundation. Dr. Meigs received a Career Development Award from the American Diabetes. Dr. Mantzoros was supported by discretionary grants from the Tanita Corporation and Beth Israel Deaconess Medical Center. NR 48 TC 121 Z9 126 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 2 PY 2008 VL 149 IS 5 BP 307 EP W66 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 348SD UT WOS:000259229300003 PM 18765700 ER PT J AU Laiyemo, AO Lanza, E Schatzkin, A AF Laiyemo, Adeyinka O. Lanza, Elaine Schatzkin, Arthur TI Should we shorten or lengthen postpolypectomy surveillance intervals? In response SO ANNALS OF INTERNAL MEDICINE LA English DT Letter C1 [Laiyemo, Adeyinka O.; Lanza, Elaine; Schatzkin, Arthur] NCI, Bethesda, MD 20892 USA. RP Laiyemo, AO (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD SEP 2 PY 2008 VL 149 IS 5 BP 360 EP 361 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 348SD UT WOS:000259229300014 ER PT J AU Zamboni, G Huey, ED Krueger, F Nichelli, PF Grafman, J AF Zamboni, G. Huey, E. D. Krueger, F. Nichelli, P. F. Grafman, J. TI Apathy and disinhibition in frontotemporal dementia - Insights into their neural correlates SO NEUROLOGY LA English DT Article ID FRONTAL-SUBCORTICAL CIRCUITS; LOBAR DEGENERATION; SOCIAL-BEHAVIOR; BASAL GANGLIA; CORTEX; DYSFUNCTION; NETWORKS; DISEASE; SYSTEMS AB Background: Aberrant social behavior is a defining symptom of frontotemporal dementia (FTD) and may eventually occur in all syndromes composing the FTD spectrum. Two main behavioral abnormalities have been described: apathy and disinhibition, but their neuroanatomical correlates remain underspecified. Methods: Sixty-two patients with a clinical diagnosis of FTD participated in the study. Voxel-based morphometry of MRI data was performed to explore the association between gray matter loss and severity of the two behavioral profiles as measured by the Apathy and Disinhibition subscales of the Frontal Systems Behavior Scale. Results: Compared with a group of controls, the FTD group showed extensive bilateral atrophy predominantly involving frontal and temporal lobes. Within the FTD group, the severity of apathy correlated with atrophy in the right dorsolateral prefrontal cortex. The severity of disinhibition correlated with atrophy in the right nucleus accumbens, right superior temporal sulcus, and right mediotemporal limbic structures. Conclusions: Prefrontal and temporal regions are differentially associated with apathy and disinhibition. Our results support the view that successful execution of complex social behaviors relies on the integration of social knowledge and executive functions, represented in the prefrontal cortex, and reward attribution and emotional processing, represented in mesolimbic structures. C1 [Zamboni, G.; Huey, E. D.; Krueger, F.; Grafman, J.] Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Zamboni, G.; Nichelli, P. F.] Univ Modena & Reggio Emilia, Dipartimento Neurosci, Modena, Italy. RP Grafman, J (reprint author), Natl Inst Neurol Disorders & Stroke, Cognit Neurosci Sect, NIH, Bldg 10,Room 7D43,MSC 1440, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov RI Nichelli, Paolo/F-7336-2015; Zamboni, Giovanna/F-3583-2017; OI Nichelli, Paolo/0000-0001-9756-6796; Zamboni, Giovanna/0000-0002-6133-3373; Grafman, Jordan H./0000-0001-8645-4457 FU National Institute of Neurological Disorders and Stroke Intramural Research Program; Italian Ministry of University and Research FX Supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program (G.Z., E.D.H., F.K., and J.G.) and the Italian Ministry of University and Research (G.Z. and P.F.N.). NR 38 TC 104 Z9 109 U1 3 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD SEP 2 PY 2008 VL 71 IS 10 BP 736 EP 742 DI 10.1212/01.wnl.0000324920.96835.95 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 343WC UT WOS:000258885100007 PM 18765649 ER PT J AU Fischer, D Kley, RA Strach, K Meyer, C Sommer, T Eger, K Rolfs, A Meyer, W Pou, A Pradas, J Heyer, CM Grossmann, A Huebner, A Kress, W Reimann, J Schroder, R Eymard, B Fardeau, M Udd, B Goldfarb, L Vorgerd, M Olive, M AF Fischer, D. Kley, R. A. Strach, K. Meyer, C. Sommer, T. Eger, K. Rolfs, A. Meyer, W. Pou, A. Pradas, J. Heyer, C. M. Grossmann, A. Huebner, A. Kress, W. Reimann, J. Schroeder, R. Eymard, B. Fardeau, M. Udd, B. Goldfarb, L. Vorgerd, M. Olive, M. TI Distinct muscle imaging patterns in myofibrillar myopathies SO NEUROLOGY LA English DT Article ID DESMIN-RELATED MYOPATHIES; SKELETAL MYOPATHY; DISTAL MYOPATHY; MUTATION; GENE; PHENOTYPE; MYOTILINOPATHY; DESMINOPATHIES; POSITIVITY; SPECTRUM AB Objective: To compare muscle imaging findings in different subtypes of myofibrillar myopathies (MFM) in order to identify characteristic patterns of muscle alterations that may be helpful to separate these genetic heterogeneous muscular disorders. Methods: Muscle imaging and clinical findings of 46 patients with MFM were evaluated (19 desminopathy, 12 myotilinopathy, 11 filaminopathy, 1 alpha B-crystallinopathy, and 3 ZASPopathy). The data were collected retrospectively in 43 patients and prospectively in 3 patients. Results: In patients with desminopathy, the semitendinosus was at least equally affected as the biceps femoris, and the peroneal muscles were never less involved than the tibialis anterior (sensitivity of these imaging criteria to detect desminopathy in our cohort 100%, specificity 95%). In most of the patients with myotilinopathy, the adductor magnus showed more alterations than the gracilis muscle, and the sartorius was at least equally affected as the semitendinosus (sensitivity 90%, specificity 93%). In filaminopathy, the biceps femoris and semitendinosus were at least equally affected as the sartorius muscle, and the medial gastrocnemius was more affected than the lateral gastrocnemius. The semimembranosus mostly showed more alterations than the adductor magnus (sensitivity 88%, specificity 96%). Early adult onset and cardiac involvement was most often associated with desminopathy. In patients with filaminopathy, muscle weakness typically beginning in the 5th decade of life was mostly pronounced proximally, while late adult onset (> 50 years) with distal weakness was more often present in myotilinopathy. Conclusions: Muscle imaging in combination with clinical data may be helpful for separation of distinct myofibrillar myopathy subtypes and in scheduling of genetic analysis. C1 [Fischer, D.] Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland. [Fischer, D.] Univ Childrens Hosp Basel, Dept Neuropediat, Basel, Switzerland. [Kley, R. A.; Vorgerd, M.] Ruhr Univ Bochum, Neuromuscular Ctr Ruhrgebiet, Dept Neurol, Bochum, Germany. [Strach, K.; Meyer, C.; Sommer, T.] Univ Hosp Bonn, Dept Radiol, Bonn, Germany. [Fischer, D.; Reimann, J.] Univ Hosp Bonn, Dept Neurol, Bonn, Germany. [Eger, K.] Univ Hosp Halle, Dept Neurol, Halle, Germany. [Rolfs, A.; Meyer, W.] Univ Hosp Rostock, Dept Neurol, Rostock, Germany. [Grossmann, A.] Univ Hosp Rostock, Dept Radiol, Rostock, Germany. [Pou, A.] Hosp del Mar, Servei Neurol, Barcelona, Spain. [Pradas, J.] Hosp Santa Creu & Sant Pau, Sevei Neurol, Barcelona, Spain. [Heyer, C. M.] Univ Hosp Bergmannsheil, Dept Radiol, Bochum, Germany. [Huebner, A.] Tech Univ Dresden, Childrens Hosp, Dresden, Germany. [Kress, W.] Univ Wurzburg, Biozentrum, Inst Human Genet, D-97070 Wurzburg, Germany. [Udd, B.] Univ Helsinki, Tampere Med Sch, Dept Neurol, FIN-00014 Helsinki, Finland. [Udd, B.] Univ Helsinki, Univ Hosp, FIN-00014 Helsinki, Finland. [Udd, B.] Univ Helsinki, Vaasa Cent Hosp, FIN-00014 Helsinki, Finland. [Udd, B.] Univ Helsinki, Folkhalsan Inst Genet, FIN-00014 Helsinki, Finland. [Udd, B.] Univ Helsinki, Dept Med Genet, FIN-00014 Helsinki, Finland. [Schroeder, R.] Univ Hosp Erlangen, Inst Neuropathol, Erlangen, Germany. [Schroeder, R.] Univ Hosp Erlangen, Dept Neurol, Erlangen, Germany. [Eymard, B.; Fardeau, M.] Grp Hosp Pitie Salpetriere, Inst Myol, F-75634 Paris, France. [Goldfarb, L.] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. [Olive, M.] Hosp Llobregat, Bellvitge Hosp, IDIBELL, Inst Neuropatol, Barcelona, Spain. [Meyer, W.] Queen Mary Univ London, St Bartholomews & Royal London Sch Med, London, England. RP Fischer, D (reprint author), Univ Basel Hosp, Dept Neurol, CH-4031 Basel, Switzerland. EM fischerdi@uhbs.ch RI Schroder, Rolf/B-2774-2011; OI Olive, Montse/0000-0001-5727-0165 FU DFG [Fi 913/2-1]; BONFOR; German network on muscular dystrophies MD-NET [01GM0601]; German ministry of education and research (BMBF, Bonn, Germany); Finnish Academy; Juselius Foundation; Genetic Research Funds of Folkhalsan Foundation; Spanish Ministry of Health; Instituto de Salud Carlos III [PI05/1213] FX D.F. was supported by the DFG (Fi 913/2-1) and BONFOR. D.F., R.K., R.S., W.K., and M.V. are members of the German network on muscular dystrophies (MD-NET, 01GM0601) funded by the German ministry of education and research (BMBF, Bonn, Germany). B. U. was supported by the Finnish Academy, the Juselius Foundation, and the Genetic Research Funds of Folkhalsan Foundation. M.O. was supported by the Spanish Ministry of Health, Instituto de Salud Carlos III (PI05/1213). NR 34 TC 66 Z9 68 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 SEP 2 PY 2008 VL 71 IS 10 BP 758 EP 765 DI 10.1212/01.wnl.0000324927.28817.9b PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 343WC UT WOS:000258885100010 PM 18765652 ER PT J AU Rosenberg, SA AF Rosenberg, Steven A. TI Overcoming obstacles to the effective immunotherapy of human cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID ADOPTIVE CELL TRANSFER; CD8(+) T-CELLS; METASTATIC MELANOMA; LYMPHOCYTES; REGRESSION; ANTIGENS; AUTOIMMUNITY; THERAPY; GENES; TCR C1 NCI, Surg Branch, Bethesda, MD 20892 USA. RP Rosenberg, SA (reprint author), NCI, Surg Branch, Bldg 10, Bethesda, MD 20892 USA. EM sar@nih.gov NR 20 TC 27 Z9 28 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD SEP 2 PY 2008 VL 105 IS 35 BP 12643 EP 12644 DI 10.1073/pnas.0806877105 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 350HJ UT WOS:000259343000005 PM 18753635 ER PT J AU Kim, YC Tang, C Clore, GM Hummer, G AF Kim, Young C. Tang, Chun Clore, G. Marius Hummer, Gerhard TI Replica exchange simulations of transient encounter complexes in protein-protein association SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE protein binding; transient nonspecific encounter complexes; paramagnetic relaxation enhancement; bacterial phosphotransferase system ID PARAMAGNETIC RELAXATION ENHANCEMENT; PHOSPHORYL TRANSFER COMPLEX; N-TERMINAL DOMAIN; PHOSPHOTRANSFERASE SYSTEM; TRANSITION-STATE; NMR STRUCTURE; CYTOCHROME-C; ENZYME I; A-DOMAIN; BINDING AB Recent paramagnetic relaxation enhancement (PRE) studies on several weakly interacting protein complexes have unequivocally demonstrated the existence of transient encounter complexes. Here, we present a computational method to study protein-protein binding by creating equilibrium ensembles that include both specific and nonspecific protein complexes. In a joint analysis of simulation and experiment we explore the physical nature and underlying physicochemical characteristics of encounter complexes involving three protein-protein interactions of the bacterial phosphotransferase system. Replica exchange Monte Carlo simulations using a coarse-grained energy function recover the structures of the specific complexes and produce binding affinities in good agreement with experiment. Together with the specific complex, a relatively small number of distinct nonspecific complexes largely accounts for the measured PRE data. The combined relative population of the latter is less than similar to 10%. The binding interfaces of the specific and nonspecific complexes differ primarily in size but exhibit similar amino acid compositions. We find that the overall funnel-shaped energy landscape of complex formation is dominated by the specific complex, a small number of structured nonspecific complexes, and a diffuse cloud of loosely bound complexes connecting the specific and nonspecific binding sites with each other and the unbound state. Nonspecific complexes may not only accelerate the binding kinetics by enhancing the rate of success of random diffusional encounters but also play a role in protein function as alternative binding modes. C1 [Kim, Young C.; Tang, Chun; Clore, G. Marius; Hummer, Gerhard] NIDDK, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. EM mariusc@mail.nih.gov; gerhard.hummer@nih.gov RI Clore, G. Marius/A-3511-2008; Hummer, Gerhard/A-2546-2013 OI Clore, G. Marius/0000-0003-3809-1027; Hummer, Gerhard/0000-0001-7768-746X FU Intramural Research Program; National Institutes of Health; National Institute of Diabetes and Digestive and Kidney Diseases FX This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. NR 34 TC 63 Z9 64 U1 2 U2 25 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 SEP 2 PY 2008 VL 105 IS 35 BP 12855 EP 12860 DI 10.1073/pnas.0802460105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 350HJ UT WOS:000259343000044 PM 18728193 ER PT J AU Pichiorri, F Suh, SS Ladetto, M Kuehl, M Palumbo, T Drandi, D Taccioli, C Zanesi, N Alder, H Hagan, JP Munker, R Volinia, S Boccadoro, M Garzon, R Palumbo, A Aqeilan, RI Croce, CM AF Pichiorri, Flavia Suh, Sung-Suk Ladetto, Marco Kuehl, Michael Palumbo, Tiziana Drandi, Daniela Taccioli, Cristian Zanesi, Nicola Alder, Hansjuerg Hagan, John P. Munker, Reinhold Volinia, Stefano Boccadoro, Mario Garzon, Ramiro Palumbo, Antonio Aqeilan, Rami I. Croce, Carlo M. TI MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE PCAF; SOCS-1; tumor suppressor gene; MGUS; plasma cells ID TUMOR-SUPPRESSOR; BONE-MARROW; IN-SITU; EXPRESSION; LEUKEMIA; CANCER; SIGNATURE; TARGETS; CELLS; DIFFERENTIATION AB Progress in understanding the biology of multiple myeloma (MM), a plasma cell malignancy, has been slow. The discovery of microRNAs (miRNAs), a class of small noncoding RNAs targeting multiple mRNAs, has revealed a new level of gene expression regulation. To determine whether miRNAs play a role in the malignant transformation of plasma cells (PCs), we have used both miRNA microarrays and quantitative real time PCR to profile miRNA expression in MM-derived cell lines (n = 49) and CD138+ bone marrow PCs from subjects with MM (n = 16), monoclonal gammopathy of undetermined significance (MGUS) (n = 6), and normal donors (n = 6). We identified overexpression of miR-21, miR-106b similar to 25 cluster, miR-181a and b in MM and MGUS samples with respect to healthy PCs. Selective up-regulation of miR-32 and miR-17 similar to 92 cluster was identified in MM subjects and cell lines but not in MGUS subjects or healthy PCs. Furthermore, two miRNAs, miR-19a and 19b, that are part of the miR-17 similar to 92 cluster, were shown to down regulate expression of SOCS-1, a gene frequently silenced in MM that plays a critical role as inhibitor of IL-6 growth signaling. We also identified p300-CBP-associated factor, a gene involved in p53 regulation, as a bona fide target of the miR106b similar to 25 cluster, miR-181a and b, and miR-32. Xenograft studies using human MM cell lines treated with miR-19a and b, and miR-181a and b antagonists resulted in significant suppression of tumor growth in nude mice. In summary, we have described a MM miRNA signature, which includes miRNAs that modulate the expression of proteins critical to myeloma pathogenesis. C1 [Pichiorri, Flavia; Suh, Sung-Suk; Palumbo, Tiziana; Taccioli, Cristian; Zanesi, Nicola; Alder, Hansjuerg; Hagan, John P.; Volinia, Stefano; Aqeilan, Rami I.; Croce, Carlo M.] Ohio State Univ, Dept Mol Virol, Columbus, OH 43210 USA. [Pichiorri, Flavia; Suh, Sung-Suk; Palumbo, Tiziana; Taccioli, Cristian; Zanesi, Nicola; Alder, Hansjuerg; Hagan, John P.; Volinia, Stefano; Aqeilan, Rami I.; Croce, Carlo M.] Ohio State Univ, Dept Immunol, Columbus, OH 43210 USA. [Pichiorri, Flavia; Suh, Sung-Suk; Palumbo, Tiziana; Taccioli, Cristian; Zanesi, Nicola; Alder, Hansjuerg; Hagan, John P.; Volinia, Stefano; Aqeilan, Rami I.; Croce, Carlo M.] Ohio State Univ, Dept Human Genet, Columbus, OH 43210 USA. [Garzon, Ramiro] Ohio State Univ, Ctr Comprehens Canc, Dept Med, Div Hematol & Oncol, Columbus, OH 43210 USA. [Ladetto, Marco; Drandi, Daniela; Boccadoro, Mario; Palumbo, Antonio] Univ Turin, Div Hematol, I-10126 Turin, Italy. [Kuehl, Michael] NCI, Genet Branch, Ctr Canc Res, Bethesda, MD 20889 USA. [Munker, Reinhold] Louisiana State Univ, Hlth Sci Ctr, Div Hematol Oncol, Shreveport, LA 71130 USA. RP Aqeilan, RI (reprint author), Hebrew Univ Jerusalem, Lautenberg Ctr Gen & Tumor Immunol, IL-91120 Jerusalem, Israel. EM aqeilan@cc.huji.ac.il; carlo.croce@osumc.edu RI Taccioli, Cristian/F-8801-2010; Garzon, Ramiro/E-3104-2011; Volinia, Stefano/A-3029-2010; drandi, daniela/Q-6504-2016; Aqeilan, Rami/R-4443-2016; OI Taccioli, Cristian/0000-0003-2995-5612; Volinia, Stefano/0000-0003-0910-3893; Aqeilan, Rami/0000-0002-6034-023X; LADETTO, Marco/0000-0002-8283-2681; Hagan, John/0000-0003-0295-4898 FU National Cancer Institute; Kimmel Foundation awards; Ohio Cancer Research Associates FX We thank Dr. Kay Huebner and Dr. Hiroshi Okumura for their support and scientific advice, Dorothee Wernicke-Jameson for research supervision, and Sharon Palko for administrative support. This work was supported by National Cancer Institute grants (to C.M.C.), Kimmel Foundation awards (to R.I.A., N.Z., and R.G.), and an Ohio Cancer Research Associates grant (to R.I.A.). NR 37 TC 305 Z9 329 U1 2 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 SEP 2 PY 2008 VL 105 IS 35 BP 12885 EP 12890 DI 10.1073/pnas.0806202105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 350HJ UT WOS:000259343000049 PM 18728182 ER PT J AU Herrero, R Hildesheim, A Rodriguez, AC Wacholder, S Bratti, C Solomon, D Gonzalez, P Porras, C Jimenez, S Guillen, D Morales, J Alfaro, M Cyr, J Morrisey, K Estrada, Y Cortes, B Morera, LA Freer, E Schussler, J Schiller, J Lowy, D Schiffman, M AF Herrero, Rolando Hildesheim, Allan Rodriguez, Ana C. Wacholder, Sholom Bratti, Concepcion Solomon, Diane Gonzalez, Paula Porras, Carolina Jimenez, Silvia Guillen, Diego Morales, Jorge Alfaro, Mario Cyr, Jean Morrisey, Kerrygrace Estrada, Yenory Cortes, Bernal Morera, Lidia Ana Freer, Enrique Schussler, John Schiller, John Lowy, Douglas Schiffman, Mark CA Costa Rica Vaccine Trial CVT Grp TI Rationale and design of a community-based double-blind randomized clinical trial of an HPV 16 and 18 vaccine in Guanacaste, Costa Rica SO VACCINE LA English DT Article DE HPV vaccine; Costa Rica; clinical trial ID HUMAN-PAPILLOMAVIRUS INFECTION; HYBRID CAPTURE 2; CERVICAL-CANCER; YOUNG-WOMEN; PARTICLE VACCINE; BROAD-SPECTRUM; PCR ASSAY; HIGH-RISK; DNA; NEOPLASIA AB We report the rationale, design, methods and details of participation of a community-based, double-blind, randomized clinical trial of an HPV 16 and 18 vaccine conducted in two provinces of Costa Rica to investigate the efficacy and population impact of the vaccine in the prevention of cervical cancer precursors. More than 24,000 women between 18 and 25 years of age were invited to participate and pre-screened for eligibility, with recruitment of 7466 women (30% of those pre-screened, 59% of those eligible) who were randomized to receive 3 doses of the HPV vaccine or hepatitis A vaccine as control. A complex protocol of data and specimen collection was applied, including an interview, pelvic exam for sexually active women, blood for serology and cell-mediated immunity, cervical secretions for local immunity and cells for HPV, Chlamydia trachomatis and gonorrhea testing. Eighty percent of the women received three doses, 12.4% two doses and 7.4% one dose. At visits, compliance with data and specimen collection was close to 100%. Baseline characteristics and age-specific prevalence of HPV and cervical neoplasia are reported. Overall prevalence of HPV was high (50%), with 8.3% of women having HPV 16 and 3.2% HPV 18. LSIL was detected in 12.7% of women at baseline and HSIL in 1.9%. Prevalence of Chlamydia was 14.2%. There was very good agreement in HPV detection between clinician-collected and self-collected specimens (89.4% agreement for all types, kappa 0.59). Follow up will continue with yearly or more frequent examinations for at least 4 years for each participant. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Herrero, Rolando; Rodriguez, Ana C.; Bratti, Concepcion; Gonzalez, Paula; Porras, Carolina; Jimenez, Silvia; Guillen, Diego; Morales, Jorge; Alfaro, Mario; Estrada, Yenory; Cortes, Bernal; Morera, Lidia Ana] Proyecto Epidemiol Guanocaste Fdn INCIENSA, San Jose, Costa Rica. [Hildesheim, Allan; Rodriguez, Ana C.; Wacholder, Sholom; Schiffman, Mark] NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Solomon, Diane] NCI, Div Canc Prevent & Control, Rockville, MD 20852 USA. [Cyr, Jean; Schussler, John] IMS, Rockville, MD USA. [Morrisey, Kerrygrace] Westat Corp, Rockville, MD USA. [Freer, Enrique] Univ Costa Rica, Ctr Invest Estructuras Microscop CIEMIC, San Jose, Costa Rica. [Schiller, John; Lowy, Douglas] NCI, Ctr Canc Res, Rockville, MD USA. RP Herrero, R (reprint author), Proyecto Epidemiol Guanocaste Fdn INCIENSA, 300 Oeste ICE,Piso 7, San Jose, Costa Rica. EM rherrero@amnet.co.cr; hildesha@exchange.nih.gov RI Hildesheim, Allan/B-9760-2015 OI Hildesheim, Allan/0000-0003-0257-2363 FU NCI [N01-CP-11005]; NIH Office; GSK [FDA BB-IND 7920] FX The trial is sponsored and funded by NCI (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. GSK also provided support for aspects of the trial associated with regulatory submission needs of the company under FDA BB-IND 7920. NR 33 TC 67 Z9 67 U1 1 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 SEP 2 PY 2008 VL 26 IS 37 BP 4795 EP 4808 DI 10.1016/j.vaccine.2008.07.002 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 353AT UT WOS:000259539200004 PM 18640170 ER PT J AU Xu, R Megati, S Roopchand, V Luckay, A Masood, A Garcia-Hand, D Rosati, M Weiner, DB Felber, BK Pavlakis, GN Sidhu, MK Eldridge, JH Egan, MA AF Xu, Rong Megati, Shakuntala Roopchand, Vidia Luckay, Amara Masood, Amjed Garcia-Hand, Dorys Rosati, Margherita Weiner, David B. Felber, Barbara K. Pavlakis, George N. Sidhu, Maninder K. Eldridge, John H. Egan, Michael A. TI Comparative ability of various plasmid-based cytokines and chemokines to adjuvant the activity of HIV plasmid DNA vaccines SO VACCINE LA English DT Article DE plasmid DNA; cytokine; chemokine; molecular adjuvant; HIV ID CELLULAR IMMUNE-RESPONSES; COLONY-STIMULATING FACTOR; T-LYMPHOCYTE RESPONSES; VIRUS TYPE-1 INFECTION; GM-CSF; RHESUS MACAQUES; IN-VIVO; DENDRITIC CELLS; ORAL IMMUNIZATION; GENE-GUN AB The effectiveness of plasmid DNA (pDNA) vaccines can be improved by the co-delivery of plasmid-encoded molecular adjuvants. We evaluated pDNAs encoding GM-CSF, Flt-3L, IL-12 alone, or in combination, for their relative ability to serve as adjuvants to augment humoral and cell-mediated immune responses elicited by prototype pDNA vaccines. In Balb/c mice we found that co-administration of plasmid-based murine GM-CSF (pmGM-CSF), murine Flt-3L (pmFlt-3L) or murine IL-12 (pmIL-12) could markedly enhance the cell-mediated immune response elicited by an HIV-1 env pDNA vaccine. Plasmid mGM-CSF also augmented the immune response elicited by DNA vaccines expressing HIV-1 Gag and Nef-Tat-Vif. in addition, the use of pmGM-CSF as a vaccine adjuvant appeared to markedly increase antigen-specific proliferative responses and improved the quality of the resulting T-cell response by increasing the percentage of polyfunctional memory CD8(+) T cells. Co-delivery of pmFlt-3L with pmGM-CSF did not result in a further increase in adjuvant activity. However, the co-administration of pmGM-CSF with pmIL-12 did significantly enhance env-specific proliferative responses and vaccine efficacy in the murine vaccinia virus challenge model relative to mice immunized with the env pDNA vaccine adjuvanted with either pmGM-CSF or pmIL-12 alone. These data support the testing of pmGM-CSF and pmIL-12, used alone or in combination, as plasmid DNA vaccine adjuvants in future macaque challenge studies. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Xu, Rong; Megati, Shakuntala; Roopchand, Vidia; Luckay, Amara; Masood, Amjed; Garcia-Hand, Dorys; Sidhu, Maninder K.; Eldridge, John H.; Egan, Michael A.] Wyeth Vaccines Res, Pearl River, NY 10992 USA. [Rosati, Margherita; Felber, Barbara K.; Pavlakis, George N.] NCI Frederick, Frederick, MD 21702 USA. [Weiner, David B.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. RP Egan, MA (reprint author), Wyeth Vaccines Res, Vaccine Discovery, 401 N Middletown Rd,Bldg 180-216-10, Pearl River, NY 10965 USA. EM eganm@profectusbiosciences.com RI Weiner, David/H-8579-2014 NR 55 TC 42 Z9 43 U1 0 U2 5 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 SEP 2 PY 2008 VL 26 IS 37 BP 4819 EP 4829 DI 10.1016/j.vaccine.2008.06.103 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 353AT UT WOS:000259539200007 PM 18657584 ER PT J AU Brown, PH Balbo, A Schuck, P AF Brown, Patrick H. Balbo, Andrea Schuck, Peter TI A Bayesian Approach for Quantifying Trace Amounts of Antibody Aggregates by Sedimentation Velocity Analytical Ultracentrifugation SO AAPS JOURNAL LA English DT Article DE analytical ultracentrifugation; Bayesian analysis; hydrodynamic separation; sedimentation velocity; size-distribution; trace aggregates ID FIELD-FLOW FRACTIONATION; SIZE-DISTRIBUTION ANALYSIS; MAXIMUM-ENTROPY ANALYSIS; PROTEIN AGGREGATION; QUANTITATION; CHROMATOGRAPHY; DISTRIBUTIONS; MODEL AB Sedimentation velocity analytical ultracentrifugation (SV-AUC) has become an important tool for the characterization of the purity of protein therapeutics. The work presented here addresses a need for methods orthogonal to size-exclusion chromatography for ensuring the reliable quantitation of immunogenic oligomers, for example, in antibody preparations. Currently the most commonly used approach for SV-AUC analysis is the diffusion-deconvoluted sedimentation coefficient distribution c(s) method, previously developed by us as a general purpose technique and implemented in the software SEDFIT. In both practical and theoretical studies, different groups have reported a sensitivity of c(s) for trace oligomeric fractions well below the 1% level. In the present work we present a variant of c(s) designed for the purpose of trace detection, with customized Bayesian regularization. The original c(s) method relies on maximum entropy regularization providing the most parsimonious distribution consistent with the data. In the present paper, we use computer simulations of an antibody system as example to demonstrate that the standard maximum entropy regularization, due to its design, leads to a theoretical lower limit for the detection of oligomeric traces and a consistent underestimate of the trace populations by -0.1% (dependent on the level of regularization). This can be overcome with a recently developed Bayesian extension of c(s) (Brown et al., Biomacromolecules, 8:2011-2024, 2007), utilizing the known regions of sedimentation coefficients for the monomer and oligomers of interest as prior expectation for the peak positions in the distribution. We show that this leads to more clearly identifiable and consistent peaks and lower theoretical limits of quantization by approximately an order of magnitude for some experimental conditions. Implications for the experimental design of SV-AUC and practical detection limits are discussed. C1 [Brown, Patrick H.; Balbo, Andrea; Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Bioengn & Phys Sci, NIH, Bethesda, MD 20892 USA. RP Brown, PH (reprint author), Natl Inst Biomed Imaging & Bioengn, Dynam Macromol Assembly Sect, Lab Bioengn & Phys Sci, NIH, Bldg 13,Rm 3N17,13 South Dr, Bethesda, MD 20892 USA. EM brownpatr@mail.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU Intramural Research Program of the National Institutes of Health; NIBIB FX This work was supported by the Intramural Research Program of the National Institutes of Health, NIBIB. The authors wish to thank A. Pekar and his colleagues for providing access to preprints of their recent publication concerning trace detection during the preparation of this manuscript. NR 36 TC 21 Z9 21 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1550-7416 J9 AAPS J PD SEP PY 2008 VL 10 IS 3 BP 481 EP 493 DI 10.1208/s12248-008-9058-z PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 370OC UT WOS:000260770500008 PM 18814037 ER PT J AU Sexson, SB Thomas, CR Pope, K AF Sexson, Sandra B. Thomas, Christopher R. Pope, Kayla TI Models of Integrated Training in Psychiatry and Child and Adolescent Psychiatry SO ACADEMIC PSYCHIATRY LA English DT Article AB Objective: Previous studies indicate declining interest in child. and adolescent psychiatry (CAP) as a career choice during psychiatry residency training. Programs have developed integrated training in psychiatry and CAP as a means to address the workforce shortage in CAP, but little is known about the number or nature of these training tracks. Methods: A survey was conducted among all program directors of Accreditation Council for Graduate Medical Education (ACGME) accredited CAP residency training programs in the United States. Those reporting integrated training with their affiliated psychiatry training programs were contacted for in-depth interview Integrated research programs were not included in this survey. Results: Of the 115 ACGME accredited CAP programs at the time of the survey, 93 responded and 33 of those indicated having some form of integrated training in psychiatry and CAP. Only seven programs identified residents in integrated training in the first year of residency. Conclusion: There is no consensus regarding a definition of integrated psychiatry and CAP training. Even though integrated training may provide opportunities for recruitment and retention of child and adolescent psychiatrists, few programs currently offer fully integrated training. This article describes several potential models for integrated training tracks, identifying factors to consider when developing such pathways. Academic Psychiatry 2008; 32:377-385 C1 [Sexson, Sandra B.; Thomas, Christopher R.] Univ Texas Med Branch, Med Coll Georgia, Dept Psychiat, Galveston, TX USA. [Sexson, Sandra B.; Thomas, Christopher R.] Univ Maryland, College Pk, MD 20742 USA. [Pope, Kayla] NIMH, Childrens Natl Med Ctr, Bethesda, MD 20892 USA. RP Sexson, SB (reprint author), Med Coll Georgia, Dept Psychiat, 997 St Sebastian Way, Augusta, GA 30912 USA. EM ssexson@mcg.edu NR 6 TC 1 Z9 1 U1 0 U2 0 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 SEP-OCT PY 2008 VL 32 IS 5 BP 377 EP 385 DI 10.1176/appi.ap.32.5.377 PG 9 WC Education & Educational Research; Psychiatry SC Education & Educational Research; Psychiatry GA 362MQ UT WOS:000260202200007 PM 18945976 ER PT J AU Ducci, F Goldman, D AF Ducci, Francesca Goldman, David TI Genetic approaches to addiction: genes and alcohol SO ADDICTION LA English DT Review DE alcoholism; GABA; HTT; intermediate phenotypes; MAOA; review; WGA ID CATECHOL-O-METHYLTRANSFERASE; OPIOID RECEPTOR GENE; SEROTONIN TRANSPORTER GENE; WHOLE-GENOME ASSOCIATION; SUBSTANCE USE DISORDERS; ANTISOCIAL PERSONALITY-DISORDER; NATIONAL EPIDEMIOLOGIC SURVEY; QUANTITATIVE TRAIT LOCUS; POPULATION-BASED SAMPLE; CHILDHOOD SEXUAL-ABUSE AB Aims Alcoholism is a chronic relapsing disorder with an enormous societal impact. Understanding the genetic basis of alcoholism is crucial to characterize individuals' risk and to develop efficacious prevention and treatment strategies. Methods We examined the available scientific literature to provide an overview of different approaches that are being integrated increasingly to advance our knowledge of the genetic bases of alcoholism. Examples of genes that have been shown to influence vulnerability to alcoholism and related phenotypes are also discussed. Results Genetic factors account for more than 50% of the variance in alcoholism liability. Susceptibility loci for alcoholism include both alcohol-specific genes acting either at the pharmacokinetic or pharmacodynamic levels, as well as loci moderating neuronal pathways such as reward, behavioral control and stress resiliency, that are involved in several psychiatric diseases. In recent years, major progress in gene identification has occurred using intermediate phenotypes such as task-related brain activation that confer the advantage of increased power and the opportunity of exploring the neuronal mechanisms through which genetic variation is translated into behavior. Fundamental to the detection of gene effects is also the understanding of the interplay between genes as well as genes/environment interactions. Whole Genome Association studies represent a unique opportunity to identify alcohol-related loci in hypothesis-free fashion. Finally, genome-wide analyses of transcripts and chromatin remodeling promise an increase in our understanding of the genome function and of the mechanisms through which gene and environment cause diseases. Conclusions Although the genetic bases of alcoholism remain largely unknown, there are reasons to think that more genes will be discovered in the future. Multiple and complementary approaches will be required to piece together the mosaic of causation. C1 [Ducci, Francesca; Goldman, David] NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. RP Ducci, F (reprint author), NIAAA, Neurogenet Lab, Rockville, MD 20852 USA. EM francesca.ducci@iop.kcl.ac.uk RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z01 AA000301-09] NR 130 TC 112 Z9 116 U1 11 U2 38 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD SEP PY 2008 VL 103 IS 9 BP 1414 EP 1428 DI 10.1111/j.1360-0443.2008.02203.x PG 15 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 335FK UT WOS:000258276000004 PM 18422824 ER PT J AU Gilman, JM Hommer, DW AF Gilman, Jodi M. Hommer, Daniel W. TI Modulation of brain response to emotional images by alcohol cues in alcohol-dependent patients SO ADDICTION BIOLOGY LA English DT Article DE addiction; affect; alcoholism; drug cues; emotion; fMRI ID SELECTIVE ATTENTIONAL BIAS; NEGATIVE MOOD REGULATION; SECONDARY DEPRESSION; THREATENING STIMULI; COCAINE CRAVINGS; DRUG CUES; ACTIVATION; ANXIETY; STROOP; CORTEX AB Alcohol is often used to modulate mood states. Alcohol drinkers report that they use alcohol both to enhance positive affect and to reduce dysphoria, and alcohol-dependent patients specifically state reduction of negative affect as a primary reason for drinking. The current study proposes that alcohol cues may reduce negative affect in alcoholics. We used functional magnetic resonance imaging to examine brain activation in response to combination images that juxtaposed negative or positive International Affective Picture System (IAPS) images with an alcohol or non-alcohol-containing beverage. We found that in the absence of the alcohol cue, alcoholics showed more activation to negative than to positive images and greater activation than controls to negative images. When the IAPS images were presented with the alcohol cue, there was a decreased difference in activation between the positive and negative images among the alcoholics, and a decreased difference in response to the negative images between controls and alcoholics. Additionally, in the neutral-beverage conditions, anxiety ratings significantly predicted activation in the right parahippocampal gyrus but did not predict activation when the alcohol cues were presented. In conclusion, the alcohol cues may have modulated cortical networks involved in the processing of emotional stimuli by eliciting a conditioned response in the alcoholics, but not in the controls, which may have decreased responsiveness to the negative images. C1 [Gilman, Jodi M.; Hommer, Daniel W.] NIAAA, Sect Brain Elect & Imaging, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. RP Gilman, JM (reprint author), NIAAA, Sect Brain Elect & Imaging, Lab Clin & Translat Studies, NIH, 10 Ctr Dr,10CRC-15330, Bethesda, MD 20892 USA. EM gilmanj@mail.nih.gov FU Intramural NIH HHS NR 57 TC 53 Z9 54 U1 7 U2 11 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD SEP PY 2008 VL 13 IS 3-4 BP 423 EP 434 DI 10.1111/j.1369-1600.2008.00111.x PG 12 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 335FG UT WOS:000258275600018 PM 18507736 ER PT J AU Harakeh, Z Neiderhiser, JM Spotts, EL Engels, RCME Scholte, RHJ Reiss, D AF Harakeh, Zeena Neiderhiser, Jenae M. Spotts, Erica L. Engels, Rutger C. M. E. Scholte, Ron H. J. Reiss, David TI Genetic factors contribute to the association between peers and young adults smoking: Univariate and multivariate behavioral genetic analyses SO ADDICTIVE BEHAVIORS LA English DT Article DE peers; smoking; adolescents; young adults ID NICOTINE DEPENDENCE; ENVIRONMENTAL-INFLUENCES; ADOLESCENT SMOKING; INITIATION; TWIN; SIBLINGS; FRIENDS AB This present study investigated the genetic and environmental influences on the associations between adolescents' peer characteristics (i.e., peer college orientation, and peer delinquency) and smoking in young adulthood. We used longitudinal data from the Nonshared Environment and Adolescent Development (NEAD) project. Parents' reports on adolescents' peer characteristics and adolescents' self-reports on smoking in young adulthood were examined. Genetic and environmental influences on each construct as well as on the association between the two were analyzed. Findings showed that genetic and nonshared environmental influences contributed to peer college orientation and smoking status. Genetic, shared and nonshared environmental influences contributed to peer delinquency. Further, genetic and nonshared environmental influences contributed to the association between adolescents' peer college orientation and smoking in young adulthood. Genetic and shared environmental influences contributed to the association between adolescents' peer delinquency and smoking in young adulthood. In conclusion, the present study showed that genetic influences contributed to adolescents' peer characteristics and, in addition, genetic factors mediated the association between peer characteristics and smoking. (C) 2008 Published by Elsevier Ltd. C1 [Harakeh, Zeena] Univ Utrecht, NL-3508 TC Utrecht, Netherlands. [Engels, Rutger C. M. E.; Scholte, Ron H. J.] Radboud Univ Nijmegen, Inst Behav Sci, NL-6500 HE Nijmegen, Netherlands. [Neiderhiser, Jenae M.] Penn State Univ, Dept Psychol, University Pk, PA 16802 USA. [Spotts, Erica L.] NIA, NIH, Bethesda, MD 20892 USA. [Reiss, David] Austen Riggs Ctr Inc, Stockbridge, MA USA. RP Harakeh, Z (reprint author), Univ Utrecht, POB 80-140, NL-3508 TC Utrecht, Netherlands. EM z.harakeh@uu.nl RI Engels, Rutger/A-5984-2010; scholte, ron/G-2030-2012 FU NIMH NIH HHS [R01 MH43373, R01 MH059014, R01 MH065563, R01 MH48825, R01 MH59014] NR 24 TC 5 Z9 5 U1 2 U2 4 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 SEP PY 2008 VL 33 IS 9 BP 1113 EP 1122 DI 10.1016/j.addbeh.2008.02.017 PG 10 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 331XT UT WOS:000258046600003 PM 18584970 ER PT J AU Ungvari, Z Krasnikov, BF Csiszar, A Labinskyy, N Mukhopadhyay, P Pacher, P Cooper, AJL Podlutskaya, N Austad, SN Podlutsky, A AF Ungvari, Zoltan Krasnikov, Boris F. Csiszar, Anna Labinskyy, Nazar Mukhopadhyay, Partha Pacher, Pal Cooper, Arthur J. L. Podlutskaya, Natalia Austad, Steven N. Podlutsky, Andrej TI Testing hypotheses of aging in long-lived mice of the genus Peromyscus: association between longevity and mitochondrial stress resistance, ROS detoxification pathways, and DNA repair efficiency SO AGE LA English DT Article DE aging; oxidative stress; mitochondrial stress; DNA repair; Peromyscus; longevity ID PERMEABILITY TRANSITION PORE; KAPPA-B ACTIVATION; NAKED MOLE-RAT; OXIDATIVE STRESS; TRANSCRIPTION FACTOR; CALORIC RESTRICTION; UP-REGULATION; SUPEROXIDE-PRODUCTION; ANTIOXIDANT DEFENSES; CORONARY-ARTERIES AB In the present review we discuss the potential use of two long-lived mice of the genus Peromyscus-the white-footed mouse (P. leucopus) and the deer mouse (P. maniculatus) maximum lifespan potential similar to 8 years for both-to test predictions of theories about aging from the oxidative stress theory, mitochondrial theory and inflammatory theory. Previous studies have shown that P. leucopus cells exhibit superior antioxidant defense mechanisms and lower cellular production of reactive oxygen species (ROS) than do cells of the house mouse, Mus musculus (maximum lifespan similar to 3.5 years). We present new data showing that mitochondria in P. leucopus cells produce substantially less ROS than mitochondria in M. musculus cells, and that P. leucopus mitochondria exhibit superior stress resistance to those of M. musculus. We also provide evidence that components of the DNA repair system (e.g., pathways involved in repair of DNA damage induced by gamma-irradiation) are likely to be more efficient in P. leucopus than in M. musculus. We propose that mitochondrial stress resistance, ROS detoxification pathways and more efficient DNA repair contribute to the previously documented resistance of P. leucopus cells toward oxidative stress-induced apoptosis. The link between these three pathways and species longevity is discussed. C1 [Ungvari, Zoltan; Csiszar, Anna; Labinskyy, Nazar] New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. [Krasnikov, Boris F.; Cooper, Arthur J. L.] New York Med Coll, Dept Biochem & Mol Biol, Valhalla, NY 10595 USA. [Mukhopadhyay, Partha; Pacher, Pal] NIAAA, Sect Oxidat Stress Tissue Injury, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. [Podlutskaya, Natalia; Austad, Steven N.; Podlutsky, Andrej] Univ Texas Hlth Sci Ctr San Antonio, Sam & Ann Barshop Inst Longev & Aging Studies, San Antonio, TX 78245 USA. RP Ungvari, Z (reprint author), New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. EM zoltan_ungvari@nymc.edu; podlutsky@uthscsa.edu RI MUKHOPADHYAY, PARTHA/G-3890-2010; Pacher, Pal/B-6378-2008; Podlutsky, Andrej/F-5421-2015; Cooper, Arthur/H-5171-2016; OI MUKHOPADHYAY, PARTHA/0000-0002-1178-1274; Pacher, Pal/0000-0001-7036-8108; Krasnikov, Boris/0000-0001-9525-4385 FU American Heart Association [0435140N]; NIH [HL077256, HL43023, AG022873, AG025063]; Philip Morris International and Philip Morris USA and the San Antonio Area Foundation; Intramural Research Program of the NIH FX This work was supported by grants from the American Heart Association (0435140N) San Antonio Area, the NIH (HL077256, HL43023, AG022873 and AG025063), Philip Morris International and Philip Morris USA and the San Antonio Area Foundation and by the Intramural Research Program of the NIH. Apologies are extended to all those whose findings or opinions pertinent to this topic were not referenced or discussed due to limitations of space or inadvertent omissions. NR 79 TC 26 Z9 26 U1 0 U2 10 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 J9 AGE JI Age PD SEP PY 2008 VL 30 IS 2-3 BP 121 EP 133 DI 10.1007/s11357-008-9059-y PG 13 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 343UR UT WOS:000258881300006 PM 19424862 ER PT J AU Quinn, TC AF Quinn, Thomas C. TI HIV epidemiology and the effects of antiviral therapy on long-term consequences SO AIDS LA English DT Article; Proceedings Paper CT Meeting on Pulmonary Arterial Hypertension and Other Cardiovascular Complications Related to HIV CY APR 21-22, 2007 CL Zurich, SWITZERLAND DE AIDS; epidemiology; HIV; mortality ID SUB-SAHARAN AFRICA; ANTIRETROVIRAL THERAPY; MALE CIRCUMCISION; MORTALITY; TRIAL; PREVENTION; RESISTANCE; ADHERENCE; UGANDA; RATES AB Twenty-seven years have now elapsed since the first description of AIDS in homosexual men in San Francisco, USA. Since those early reports in 1981, millions of people have died from this disease and millions are living with HIV infection worldwide. The rate of new cases of HIV infection has stabilized in some parts of the developed world, but in other areas of the world, especially in Africa, south-east Asia and eastern Europe, the number of newly infected individuals continues to rise alarmingly. Despite international commitment, there is still much to be done to improve access to antiretroviral drugs in areas of greatest need, especially sub-Saharan Africa. The availability of antiretroviral drugs is a key factor in limiting the pandemic and prolonging the lives of those infected, but a more universal, targeted approach, incorporating prevention, early diagnosis, counselling and treatment, will only succeed in stemming the spread of the virus. In the face of the apparent inability to control the increasing rate of new infections there are some positive signs in the battle against HIV/AIDS. In developed countries, the introduction of antiretroviral drugs has resulted in a significant reduction in AIDS-related mortality and improved survival. As access to antiretroviral drugs in the developing world improves, it is hoped that these trends will begin to be reflected worldwide. As HIV/AIDS shifts from a fatal to a chronic disease, however, a new range of health complications and threats to mortality are beginning to arise. (c) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Quinn, Thomas C.] Johns Hopkins Univ, Johns Hopkins Ctr Global Hlth, Baltimore, MD USA. [Quinn, Thomas C.] NIAID, Div Intramural Res, NIH, Bethesda, MD 20892 USA. RP Quinn, TC (reprint author), Johns Hopkins Med Inst, Ross 1159,720 Rutland Ave, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu FU Intramural NIH HHS [Z01 AI000361-25] NR 23 TC 50 Z9 51 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD SEP PY 2008 VL 22 SU 3 BP S7 EP S12 DI 10.1097/01.aids.0000327510.68503.e8 PG 6 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 365VI UT WOS:000260436700002 PM 18845925 ER PT J AU Parker, CC Ponicsan, H Spencer, RL Holmes, A Johnson, TE AF Parker, Clarissa Carlin Ponicsan, Heather Spencer, Robert Leon Holmes, Andrew Johnson, Thomas Eugene TI Restraint stress and exogenous corticosterone differentially alter sensitivity to the sedative-hypnotic effects of ethanol in inbred long-sleep and inbred short-sleep mice SO ALCOHOL LA English DT Article DE corticosterone; ethanol; ethanol sensitivity; inbred long-sleep mice; inbred short-sleep mice; loss of righting reflex; stress; restraint stress; BEC ID RECEPTOR ANTAGONISTS; ALCOHOL SENSITIVITY; LOCOMOTOR-ACTIVITY; RESPONSES; STRAINS; SONS; TRANSPORTER; DOPAMINE; BEHAVIOR; SYSTEMS AB Decreased sensitivity to ethanol is a genetically mediated trait implicated in susceptibility to developing alcoholism. Here, we explore genotype by environment differences in ethanol sensitivity. The relationship between acute- and repeated -restraint stress, corticosterone (CORT) levels, and sensitivity to sedative-hypnotic properties of ethanol was explored using inbred long-sleep (ILS) and inbred short-sleep (ISS) mice. In ILS mice, acute restraint decreased ethanol sensitivity at a 4.1 g/kg dose, as measured by a decrease in the duration of loss of the righting reflex (LORE) and an increase in blood ethanol concentration at regain of the righting response (BECRR). Repeated restraint also decreased LORE duration, but had no effect on BECRR. In the ISS mice, there was no effect of acute restraint on either LORE duration or BECRR. However, repeated restraint increased ethanol sensitivity at a 4.1 g/kg dose; with an increase in LORE duration, but a decrease in BECRR. Differences in hypothalamic-pituitary-adrenal (HPA) axis responsiveness to restraint stress (as measured by plasma CORT) were also examined between genotypes. ILS mice displayed habituation to repeated restraint, whereas ISS mice did not. Lastly, the effect of enhanced CORT levels independent of psychological stress was examined for its effects on the sedative-hypnotic effects of ethanol. There were no effects of CORT pretreatment on LORE duration or BECRR in ILS mice compared to saline- or noninjected littermates. In contrast, ISS mice injected with CORT showed a decreased duration of LORE, but no effects on BECRR. These findings suggest that in addition to genetic susceptibility, environmental factors (e.g., restraint stress, exogenous CORT administration) also influence sensitivity to the sedative effects of ethanol through alteration of central nervous system sensitivity and pharmacokinetic parameters, and do so in a genotype-dependent manner. (C) 2008 Elsevier Inc. All rights reserved. C1 [Parker, Clarissa Carlin; Ponicsan, Heather; Johnson, Thomas Eugene] Univ Colorado, Inst Behav Genet, Boulder, CO 80303 USA. [Parker, Clarissa Carlin; Spencer, Robert Leon; Johnson, Thomas Eugene] Univ Colorado, Ctr Neurosci, Boulder, CO 80309 USA. [Spencer, Robert Leon] Univ Colorado, Dept Psychol, Boulder, CO 80309 USA. [Johnson, Thomas Eugene] Dept Integrat Physiol, Boulder, CO USA. [Holmes, Andrew] NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. RP Parker, CC (reprint author), Univ Colorado, Inst Behav Genet, 1480 30th St, Boulder, CO 80303 USA. EM clarissa.parker@colorado.edu; robert.spencer@colorado.edu; holmesan@mail.nih.gov; johnsont@colorado.edu OI JOHNSON, THOMAS/0000-0001-7147-8237 FU NIH [1 F31 AA016261-01, T32 DA017637-01, T32 HDO07289, RO1 AA08940] FX This work was supported by NIH grants (1 F31 AA016261-01, T32 DA017637-01, T32 HDO07289, and RO1 AA08940). The authors thank Cathy Ruf, Jonathan Hayes, and Sarah Howes for their technical assistance in completing this study. The authors also appreciate the insightful and valuable comments provided by Drs. Chris Downing, Beth Bennett, and Richard Radcliffe on earlier versions of the manuscript, and Dr. Al Collins for his insight and guidance on the research design and on the manuscript. Lastly, the authors gratefully acknowledge the reviewers of this manuscript for their patience, helpful advice, and suggestions in its preparation. NR 42 TC 8 Z9 8 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 J9 ALCOHOL JI Alcohol PD SEP PY 2008 VL 42 IS 6 BP 477 EP 485 DI 10.1016/j.alcohol.2008.05.004 PG 9 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 352NE UT WOS:000259503100005 PM 18760716 ER PT J AU Hodgkinson, CA Yuan, QP Xu, K Shen, PH Heinz, E Lobos, EA Binder, EB Cubells, J Ehlers, CL Gelernter, J Mann, J Riley, B Roy, A Tabakoff, B Todd, RD Zhou, ZF Goldman, D AF Hodgkinson, Colin A. Yuan, Qiaoping Xu, Ke Shen, Pei-Hong Heinz, Elizabeth Lobos, Elizabeth A. Binder, Elizabeth B. Cubells, Joe Ehlers, Cindy L. Gelernter, Joel Mann, John Riley, Brien Roy, Alec Tabakoff, Boris Todd, Richard D. Zhou, Zhifeng Goldman, David TI Addictions biology: Haplotype-based analysis for 130 candidate genes on a single array SO ALCOHOL AND ALCOHOLISM LA English DT Article ID GENOME-WIDE ASSOCIATION; ALCOHOL DEPENDENCE; LINKAGE DISEQUILIBRIUM; POPULATION-STRUCTURE; INTERMEDIATE PHENOTYPES; ENDOPHENOTYPE CONCEPT; SUSCEPTIBILITY LOCI; BIPOLAR DISORDER; WORLDWIDE SURVEY; BREAST-CANCER AB Aims: To develop a panel of markers able to extract full haplotype information for candidate genes in alcoholism, other addictions and disorders of mood and anxiety. Methods: A total of 130 genes were haplotype tagged and genotyped in 7 case/control populations and 51 reference populations using Illumina GoldenGate SNP genotyping technology, determining haplotype coverage. We also constructed and determined the efficacy of a panel of 186 ancestry informative markers. Results: An average of 1465 loci were genotyped at an average completion rate of 91.3%, with an average call rate of 98.3% and replication rate of 99.7%. Completion and call rates were lowered by the performance of two datasets, highlighting the importance of the DNA quality in high throughput assays. A comparison of haplotypes captured by the Addictions Array tagging SNPs and commercially available whole-genome arrays from Illumina and Affymetrix shows comparable performance of the tag SNPs to the best whole-genome array in all populations for which data are available. Conclusions: Arrays of haplotype-tagged candidate genes, such as this addictions-focused array, represent a cost-effective approach to generate high-quality SNP genotyping data useful for the haplotype-based analysis of panels of genes such as these 130 genes of interest to alcohol and addictions researchers. The inclusion of the 186 ancestry informative markers allows for the detection and correction for admixture and further enhances the utility of the array. C1 [Hodgkinson, Colin A.; Yuan, Qiaoping; Xu, Ke; Shen, Pei-Hong; Heinz, Elizabeth; Zhou, Zhifeng; Goldman, David] NIAAA, DICBR, Neurogenet Lab, Rockville, MD 20852 USA. [Lobos, Elizabeth A.; Todd, Richard D.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO USA. [Binder, Elizabeth B.; Cubells, Joe] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA USA. [Binder, Elizabeth B.; Cubells, Joe] Emory Univ, Sch Med, Dept Psychiat, Atlanta, GA USA. [Binder, Elizabeth B.; Cubells, Joe] Emory Univ, Sch Med, Dept Behav Sci, Atlanta, GA USA. [Ehlers, Cindy L.] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA. [Ehlers, Cindy L.] Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA. [Gelernter, Joel] Yale Univ, Sch Med, Div Human Genet Psychiat, Dept Psychiat, New Haven, CT USA. [Mann, John] Columbia Univ, Dept Psychiat, New York, NY 10027 USA. [Riley, Brien] Virginia Commonwealth Univ, Virginia Inst Psychiat & Behav Genet, Richmond, VA USA. [Roy, Alec] New Jersey Hlth Syst, Psychiat Serv, Dept Vet Affairs, E Orange, NJ USA. [Tabakoff, Boris] Univ Colorado, Dept Pharmacol, Aurora, CO USA. [Tabakoff, Boris] Hlth Sci Ctr, Aurora, CO USA. RP Hodgkinson, CA (reprint author), NIAAA, DICBR, Neurogenet Lab, 5625 Fishers Lane,Room 3S32 MSC9412, Rockville, MD 20852 USA. EM chodg@mail.nih.gov RI Binder, Elisabeth/K-8905-2014; Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU The Blanche F. Ittleson Endowment Fund; NIH [R01 DA 12422, K02 DA 15766, MH062185, MH048514, MH056390]; Glaxo-Smith-Kline; National Institute on Alcohol Abuse and Alcoholism Intramural Research Program; [1RO1 AA13640]; [5P50AA11998]; [1RO1 NS43762]; [AA06420]; [AA10201] FX We would like to thank Amy Doebber and Rema Paudel for technical assistance. This work was supported by 1RO1 AA13640, 5P50AA11998, 1RO1 NS43762, The Blanche F. Ittleson Endowment Fund (RDT), NIH Grants R01 DA 12422, K02 DA 15766 (JFC) and an unrestricted research grant from Glaxo-Smith-Kline (EBB), grants AA06420 and AA10201 to CLE and NIH grants MH062185, MH048514 and MH056390 to J.J.M. This project was also supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program. NR 51 TC 162 Z9 163 U1 0 U2 7 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD SEP-OCT PY 2008 VL 43 IS 5 BP 505 EP 515 DI 10.1093/alcalc/agn032 PG 11 WC Substance Abuse SC Substance Abuse GA 343NC UT WOS:000258859800001 PM 18477577 ER PT J AU Shukla, SD Velazquez, J French, SW Lu, SC Ticku, MK Zakhari, S AF Shukla, Shivendra D. Velazquez, Jose French, Samuel W. Lu, Shelly C. Ticku, Maharaj K. Zakhari, Samir TI Emerging role of epigenetics in the actions of alcohol SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Review DE acetylation; DNA; epigenetics; ethanol; histone; methylation ID CHRONIC ETHANOL TREATMENT; MALLORY BODY FORMATION; S-ADENOSYLMETHIONINE SYNTHETASE; NMDA RECEPTOR SUBUNIT; HISTONE LYSINE METHYLATION; MESSENGER-RNA EXPRESSION; MOUSE CORTICAL-NEURONS; DRUG-PRIMED MICE; METHIONINE ADENOSYLTRANSFERASE; GENE-EXPRESSION AB This review deals with the recent developments on the epigenetic effects of ethanol. A large body of data have come from studies in liver and in neuronal systems and involve post-translational modifications in histones and methylations in DNA. Ethanol causes site selective acetylation, methylation, and phosphorylation in histone. With respect to methylations the methyl group donating system involving S-adenosyl methionine appears to play a central role. There is contrasting effect of acetylation versus methylation on the same site of histone, as it relates to the transcriptional activation. Epigenetic memory also appears to correlate with liver pathology and Mallory body formation. Experimental evidence supports transcriptional regulation of genes in the CNS by DNA methylations. These studies are contributing towards a better understanding of a novel epigenetic regulation of gene expression in the context of alcohol. The critical steps and the enzymes (e.g., histone acetyltransferase, histone deacetylase, DNA methyltransferase) responsible for the epigenetic modifications are prime targets for intense investigation. The emerging data are also beginning to offer novel insight towards defining the molecular actions of ethanol and may contribute to potential therapeutic targets at the nucleosomal level. These epigenetic studies have opened up a new avenue of investigation in the alcohol field. C1 [Shukla, Shivendra D.] Univ Missouri, Sch Med, Dept Med Pharmacol & Physiol, Columbia, MO 65212 USA. [Velazquez, Jose; Zakhari, Samir] NIAAA, Div Metab & Hlth Effects, Bethesda, MD USA. [French, Samuel W.] Harbor UCLA Med Ctr, Dept Pathol, Torrance, CA 90509 USA. [Lu, Shelly C.] Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. [Ticku, Maharaj K.] UTHSC, Dept Pharmacol, San Antonio, TX USA. RP Shukla, SD (reprint author), Univ Missouri, Sch Med, Dept Med Pharmacol & Physiol, Columbia, MO 65212 USA. EM shuklasd@missouri.edu NR 92 TC 101 Z9 105 U1 1 U2 13 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD SEP PY 2008 VL 32 IS 9 BP 1525 EP 1534 DI 10.1111/j.1530-0277.2008.00729.x PG 10 WC Substance Abuse SC Substance Abuse GA 341PN UT WOS:000258726700001 PM 18616668 ER PT J AU Braithwaite, RS Conigliaro, J McGinnis, KA Maisto, SA Bryant, K Justice, AC AF Braithwaite, R. Scott Conigliaro, Joseph McGinnis, Kathleen A. Maisto, Stephen A. Bryant, Kendall Justice, Amy C. TI Adjusting alcohol quantity for mean consumption and intoxication threshold improves prediction of nonadherence in HIV patients and HIV-negative controls SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE human immunodeficiency virus; alcohol; nonadherence ID OLDER-ADULTS; PRIMARY-CARE; ADHERENCE; DRINKING; DRINKERS; VETERANS; RELIABILITY; TOXICITY; OUTCOMES; FRAILTY AB Background: Screening for hazardous drinking may fail to detect a substantial proportion of individuals harmed by alcohol. We investigated whether considering an individual's usual drinking quantity or threshold for alcohol-induced cognitive impairment improves the prediction of nonadherence with prescribed medications. Method: Cross-sectional analysis of participants in a large, multi-site cohort study. We used the timeline followback to reconstruct 30-day retrospective drinking histories and the timeline followback modified for adherence to reconstruct 30-day medication adherence histories among 3,152 individuals in the Veterans Aging Cohort Study, 1,529 HIV infected and 1,623 uninfected controls. We categorized daily alcohol consumption by using quantity alone, quantity after adjustment for the individual's mean daily alcohol consumption, and self-reported level of impairment corresponding to each quantity. A standard drink was defined as 14 g of ethanol. Nonadherence was defined as the proportion of days with >= 1 medication doses missed or taken >= 2 hours late, and clinically significant nonadherence was defined as >= 5% absolute increase in the proportion of days with nonadherence. Results: The mean adjusted- and impairment-based methods showed greater discrimination of nonadherence risk compared to the measure based on quantity alone (quantity-based categorization, 3.2-fold increase; quantity adjusted for mean daily consumption, 4.6-fold increase, impairment-based categorization, 3.6-fold increase). The individualized methods also detected greater numbers of days with clinically significant nonadherence associated with alcohol. Alcohol was associated with clinically significant nonadherence at a lower threshold for HIV infected versus uninfected patients (2 standard drinks vs. 4 standard drinks) using quantity-based categorization, but this difference was no longer apparent when individualized methods were used. Conclusions: Tailoring screening questions to an individual's usual level of alcohol consumption or threshold for impairment improves the ability to predict alcohol-associated medication nonadherence. C1 [Braithwaite, R. Scott; Justice, Amy C.] Yale Univ, Sch Med, Dept Med, Gen Internal Med Sect, West Haven, CT 06516 USA. [Braithwaite, R. Scott; Justice, Amy C.] Connecticut Vet Adm Med Ctr, West Haven, CT USA. [Conigliaro, Joseph] Univ Kentucky, Dept Med, Gen Internal Med Sect, Lexington, KY 40506 USA. [McGinnis, Kathleen A.] VA Pittsburgh Healthcare Syst, Ctr Hlth Equ Res & Promot, Pittsburgh, PA USA. [Maisto, Stephen A.] Syracuse Univ, Dept Psychol, Syracuse, NY USA. [Bryant, Kendall] NIAAA, NIH, Bethesda, MD USA. RP Braithwaite, RS (reprint author), Yale Univ, Sch Med, Dept Gen Internal Med, VA Connecticut Healthcare Syst, 11ACSLG,950 Campbell Ave, West Haven, CT 06516 USA. EM ronald.braithwaite@med.va.gov FU National Institute of Alcohol Abuse and Alcoholism [K23 AA14483-01, R21 AA015894-01] FX This work was funded by Grants K23 AA14483-01 and R21 AA015894-01 from the National Institute of Alcohol Abuse and Alcoholism. This study was approved by the Yale University and West Haven VA Institutional Review Boards. NR 25 TC 25 Z9 26 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD SEP PY 2008 VL 32 IS 9 BP 1645 EP 1651 DI 10.1111/j.1530-0277.2008.00732.x PG 7 WC Substance Abuse SC Substance Abuse GA 341PN UT WOS:000258726700015 PM 18616666 ER PT J AU Zweben, A Pettinati, HM Weiss, RD Youngblood, M Cox, CE Mattson, ME Gorroochurn, P Ciraulo, D AF Zweben, Allen Pettinati, Helen M. Weiss, Roger D. Youngblood, Marston Cox, Christine E. Mattson, Margaret E. Gorroochurn, Prakash Ciraulo, Domenic TI Relationship between medication adherence and treatment outcomes: The COMBINE study SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE naltrexone; acamprosate; medication adherence; combined behavioral intervention; medical management ID RANDOMIZED CONTROLLED-TRIAL; SUBSTANCE USE DISORDERS; ALCOHOL DEPENDENCE; NALTREXONE; PHARMACOTHERAPY; PREDICTORS; ABUSE; INTERVENTIONS; DURATION; EFFICACY AB Background: Within the alcoholism field, there is mounting evidence supporting an important relationship between medication adherence and drinking outcomes. Little is known however, about the complex relationships between medication and treatment variables and drinking outcomes. The present paper reports on the differential impact of medication adherence and treatment factors on drinking outcomes. Data derived from the COMBINE Study was used to investigate the interrelationships between medication adherence, combination treatments and drinking outcomes. Methods: Twelve hundred and twenty-six patients were randomized to 1 of 8 different combination treatments involving 2 medications-naltrexone and acamprosate and placebo, and 2 behavioral treatments-medical management (MM) and combined behavioral intervention (CBI). Two primary drinking outcomes were percent days abstinent (PDA) and time to first heavy drinking day. Medication adherence was defined as a proportion that reflects the number of pills taken by the maximum number of pills expected to be taken over the course of the trial. A generalized linear mixed model was used to estimate the effects of adherence on PDA while proportional hazards model was used to examine similar co-variate effects on time to first heavy drinking day. Results: Concerning time to first heavy drinking day, a significant three-way interaction was found between medication adherence, CBI and naltrexone (p = 0.0160). Within the MM only plus placebo group (no CBI), significant differences were found in "recovery" (i.e., no heavy drinking days) rates between adherers and nonadherers (40% vs. 10%, p < 0.0001). Such differences became nonsignificant (p = 0.12) when CBI was introduced into the relationship. CBI did not add any such advantage to naltrexone-treated patients. Conclusions: CBI might serve a protective function for nonadherers in the placebo group; the median relapse time was reduced when these nonadherers were exposed to the alcohol specialty intervention. CBI offered little additional benefit to nonadherers in the naltrexone group. Among nonadherers in the naltrexone group, relapse rates appear to be more a function of inadequate exposure to the active medication and less influenced by CBI. C1 [Zweben, Allen] Columbia Univ, Sch Social Work, New York, NY 10027 USA. [Pettinati, Helen M.] Univ Penn, Philadelphia, PA 19104 USA. [Weiss, Roger D.] Harvard Univ, McLean Hosp, Belmont, MA 02178 USA. [Youngblood, Marston; Cox, Christine E.] Univ N Carolina, Dept Biostat, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Mattson, Margaret E.] NIAAA, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. [Gorroochurn, Prakash] Columbia Univ, Dept Biostat, Mailman Sch Publ Hlth, New York, NY USA. [Ciraulo, Domenic] Boston Univ, Sch Med, Boston, MA 02118 USA. [Ciraulo, Domenic] Vet Affairs Boston Healthcare Syst, Boston, MA USA. RP Zweben, A (reprint author), Columbia Univ, Sch Social Work, 1255 Amsterdam Ave, New York, NY 10027 USA. EM az173@columbia.edu OI Ciraulo, Domenic/0000-0001-7706-8765 FU National Institute on Alcohol Abuse and Alcoholism (NIAAA) Cooperative Agreements [U10AA11715, 11716, 11721, 11727, 11756, 11768, 11773, 11776, 11777, 11783, 11787, 11799]; [K05AA014715]; [K05AA00133]; [K24DA022288]; [K23AA00329] FX Data presented in this report were collected as part of the multisite COMBINE trial sponsored by the National Institute on Alcohol Abuse and Alcoholism, in collaboration with the COMBINE Study Research Group. The Combine study was supported by National Institute on Alcohol Abuse and Alcoholism (NIAAA) Cooperative Agreements U10AA11715, 11716, 11721, 11727, 11756, 11768, 11773, 11776, 11777, 11783, 11787, 11799, and 11773 and by career scientist awards K05AA014715, K05AA00133, K24DA022288 and K23AA00329. A full listing of the staff of the COMBINE Study can be found a thttp://www.cscc.unc.edu/combine/. NR 32 TC 14 Z9 14 U1 2 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD SEP PY 2008 VL 32 IS 9 BP 1661 EP 1669 DI 10.1111/j.1530-0277.2008.00743.x PG 9 WC Substance Abuse SC Substance Abuse GA 341PN UT WOS:000258726700017 PM 18616687 ER PT J AU Merenstein, D Yang, Y Schneider, MF Goparaju, L Weber, K Sharma, A Levine, AM Sharp, GB Gandhi, M Liu, CL AF Merenstein, Daniel Yang, Yang Schneider, Michael F. Goparaju, Lakshmi Weber, Kathleen Sharma, Anjali Levine, Alexandra M. Sharp, Gerald B. Gandhi, Monica Liu, Chenglong TI ASSOCIATION OF COMPLEMENTARY AND ALTERNATIVE MEDICINE USE WITH HIGHLY ACTIVE ANTIRETROVIRAL THERAPY INITIATION SO ALTERNATIVE THERAPIES IN HEALTH AND MEDICINE LA English DT Article AB Objective To assess whether complementary and alternative medicine (CAM) use is associated with the timing of highly active antiretroviral therapy (HAART) initiation among human immunodeficiency virus (HIV)-infected participants of the Women's Interagency HIV Study. Study Methods Prospective cohort study between January 1996 and March 2002. Differences in the cumulative incidence of HAART initiation were compared between CAM users and non-CAM users using a logrank test. Cox regression model was used to assess associations of CAM exposures with time to HAART initiation. Main Outcome and Exposures Study outcome was time from January 1996 to initiation of HAART. Primary exposure was use of any CAM modality before January 1996, and secondary exposures included the number and type of CAM modalities used (ingestible CAM medication, body practice, or spiritual healing) during the same period. Results One thousand thirty-four HIV-infected women contributed a total of 4987 person-visits during follow-up. At any time point, the cumulative incidence of HAART initiation among CAM users was higher than that among non CAM users. After adjustment for potential con-founders, those reporting CAM use were 1.34 times (95% confidence interval: 1.09, 1.64) more likely to initiate HAART than non CAM users. Conclusion Female CAM users initiated HAART regimens earlier than non CAM users. Initiation of HAART is an important clinical marker, but more research is needed to elucidate the role specific CAM modalities play in HIV disease progression. (Altern Ther Health Med. 2008;14(5):18-22.) C1 [Merenstein, Daniel] Georgetown Univ, Med Ctr, Res Programs Family Med, Washington, DC 20007 USA. [Yang, Yang] Georgetown Univ, Dept Biostat Bioinformat & Biomath, Washington, DC 20007 USA. [Schneider, Michael F.] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Goparaju, Lakshmi; Liu, Chenglong] Georgetown Univ, Dept Med, Washington, DC 20007 USA. [Weber, Kathleen] John H Stroger Hosp Cook Cty, Chicago, IL USA. [Sharma, Anjali] Suny Downstate Med Ctr, Div Infect Dis, Brooklyn, NY 11203 USA. [Levine, Alexandra M.] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Sharp, Gerald B.] NIAID, Epidemiol Branch, Basic Sci Program, NIH, Bethesda, MD 20892 USA. [Gandhi, Monica] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. RP Merenstein, D (reprint author), Georgetown Univ, Med Ctr, Res Programs Family Med, Washington, DC 20007 USA. FU National Cancer Institute, the National Institute on Drug Abuse [UO1-AI-35004, UO1-AI-31834, UO1-A1-34994, UOI-A1-34989, UOI-AI-34993, UO1-A1-42590]; National Institute of Child Health and Human Development [UO1-HD-32632]; National Center for Research Resources [MO1-RR-00071, MO1-RR-00079, MO1-RR-00083] FX Data in this manuscript were collected by the Women's Interagency HIV Study (WIHS) Collaborative Study Group with centers (principal investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, New York (Howard Minkoff): Washington. DC. Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gauge). The WIHS is funded by the National Institute of Allergy and Infectious Diseases with supplemental funding from the National Cancer Institute, the National Institute on Drug Abuse (UO1-AI-35004, UO1-AI-31834, UO1-A1-34994, UOI-A1-34989, UOI-AI-34993, and UO1-A1-42590). Funding is also provided by the National Institute of Child Health and Human Development (UO1-HD-32632) and the National Center for Research Resources (MO1-RR-00071, MO1-RR-00079, and MO1-RR-00083). NR 34 TC 8 Z9 8 U1 0 U2 0 PU INNOVISION COMMUNICATIONS PI ALISO VIEJO PA 101 COLUMBIA, ALISO VIEJO, CA 92656 USA SN 1078-6791 J9 ALTERN THER HEALTH M JI Altern. Ther. Health Med. PD SEP-OCT PY 2008 VL 14 IS 5 BP 18 EP 22 PG 5 WC Integrative & Complementary Medicine SC Integrative & Complementary Medicine GA V12YT UT WOS:000207635200002 PM 18780580 ER PT J AU Chomba, E McClure, EM Wright, LL Carlo, WA Chakraborty, H Harris, H AF Chomba, Elwyn McClure, Elizabeth M. Wright, Linda L. Carlo, Waldemar A. Chakraborty, Hrishikesh Harris, Hillary TI Effect of WHO newborn care training on neonatal mortality by education SO AMBULATORY PEDIATRICS LA English DT Article DE education; maternal; neonatal mortality; newborn care ID MATERNAL EDUCATION; PERINATAL-MORTALITY; CHILD-MORTALITY; BIRTH-WEIGHT; DETERMINANTS; INFANT; POPULATION; SOUTHERN; NEPAL AB Background.-Ninety-nine percent of the 4 million neonatal deaths per year occur in developing countries. The World Health Organization (WHO) Essential Newborn Care (ENC) course sets the minimum accepted standard for training midwives on aspects of infant care (neonatal resuscitation, breastfeeding, kangaroo care. small baby care, and thermoregulation), many of which are provided by the mother. Objective.-The aim of this study was to determine the association of ENC with all-cause 7-day (early) neonatal mortality among infants of less educated mothers compared with those of mothers with more education. Methods.-Protocol- and ENC-certified research nurses trained all 123 college-educated midwives from 18 low-risk, first-level urban community health centers (Zambia) in data collection (I week) and ENC (1 week) as part of a controlled study to test the clinical impact of ENC implementation. The mothers were categorized into 2 groups, those who had completed 7 years of school education (primary education) and those with 8 or more years of education. Results.-ENC training is associated with decreases in early neonatal mortality; rates decreased from 11.2 per 1000 live births pre-ENC to 6.2 per 1000 following ENC implementation (P <.001). Prenatal care, birth weight, race, and gender did not differ between the groups. Mortality for infants of mothers with 7 years of education decreased from 12.4 to 6.0 per 1000 (P <.0001) but did not change significantly for those with 8 or more years of education (8.7 to 6.3 per 1000, P =. 14). Conclusions.-ENC training decreases early neonatal mortality, and the impact is larger in infants of mothers without secondary education. The impact of ENC may be optimized by training health care workers who treat women with less formal education. C1 [Chomba, Elwyn] Univ Zambia, Lusaka, Zambia. [McClure, Elizabeth M.; Chakraborty, Hrishikesh; Harris, Hillary] Res Triangle Inst, Durham, NC USA. [Wright, Linda L.] NICHHD, Bethesda, MD 20892 USA. [Carlo, Waldemar A.] Univ Alabama, Birmingham, AL USA. RP Chomba, E (reprint author), Univ Teaching Hosp, Dept Paediat & Child Hlth, Nationalist Rd, Lusaka 10101, Zambia. EM echomba@zamnet.zm RI Sandall, Jane/D-4146-2009 OI Sandall, Jane/0000-0003-2000-743X FU National Institute of Child Health; Human Development Global Network for Women's and Children's Health Research [HD43475, HD404636]; Bill and Melinda Gates Foundation; NIH [U01 HD40636, U01 HD43464] FX This study was funded by the National Institute of Child Health and Human Development Global Network for Women's and Children's Health Research (HD43475, HD404636) and the Bill and Melinda Gates Foundation (NIH Grants U01 HD40636 [Carlo] and U01 HD43464 [McClure]). NR 27 TC 36 Z9 40 U1 2 U2 12 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1530-1567 J9 AMBUL PEDIATR JI Ambul. Pediatr. PD SEP-OCT PY 2008 VL 8 IS 5 BP 300 EP 304 DI 10.1016/j.ambp.2008.04.006 PG 5 WC Pediatrics SC Pediatrics GA 356NL UT WOS:000259784800007 PM 18922503 ER PT J AU Ding, JZ Kritchevsky, SB Hsu, FC Harris, TB Burke, GL Detrano, RC Szklo, M Criqui, MH Allison, M Ouyang, P Brown, ER Carr, JJ AF Ding, Jingzhong Kritchevsky, Stephen B. Hsu, Fang-Chi Harris, Tamara B. Burke, Gregory L. Detrano, Robert C. Szklo, Moyses Criqui, Michael H. Allison, Matthew Ouyang, Pamela Brown, Elizabeth R. Carr, J. Jeffrey TI Association between non-subcutaneous adiposity and calcified coronary plaque: a substudy of the Multi-Ethnic Study of Atherosclerosis SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article ID AMERICAN-HEART-ASSOCIATION; BEAM COMPUTED-TOMOGRAPHY; ECTOPIC FAT STORAGE; ARTERY-DISEASE; RISK-FACTOR; TISSUE; INFLAMMATION; MEN; MESA; COMMITTEE AB Background: Excessive non-subcutaneous fat deposition may impair the functions of surrounding tissues and organs through the release of inflammatory cytokines and free fatty acids. Objective: We examined the cross-sectional association between non-subcutaneous adiposity and calcified coronary plaque, a non-invasive measure of coronary artery disease burden. Design: Participants in the Multi-Ethnic Study of Atherosclerosis underwent computed tomography (CT) assessment of calcified coronary plaque. We measured multiple fat depots in 398 white and black participants (47% men, 43% black), aged 47-86 y, from Forsyth County, NC, during 2002-2005, with the use of cardiac and abdominal CT scans. In addition to examining each depot separately, we also created a non-subcutaneous fat index with the standard scores of non-subcutaneous fat depots. Results: A total of 219 participants (55%) were found to have calcified coronary plaque. After adjusting for demographics, lifestyle factors, and height, calcified coronary plaque was associated with a 1 SD increment in the non-subcutaneous fat index [odds ratio (OR): 1.41; 95% CI: 1.08, 1.84], pericardial fat (OR: 1.38; 95% CI: 1.04, 1.84), abdominal visceral fat (OR: 1.35; 95% CI: 1.03, 1.76) but not with fat content in the liver, intermuscular fat, or abdominal subcutaneous fat. The relation between non-subcutaneous fat index and calcified coronary plaque remained after further adjustment for abdominal subcutaneous fat (OR: 1.40; 95% CI: 1.00, 1.94). The relation did not differ by sex and ethnicity. Conclusions: The overall burden of non-subcutaneous fat deposition, but not abdominal subcutaneous fat, may be a correlate of coronary atherosclerosis. C1 [Ding, Jingzhong; Kritchevsky, Stephen B.] Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Winston Salem, NC 27157 USA. [Hsu, Fang-Chi; Burke, Gregory L.] Wake Forest Univ, Bowman Gray Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27157 USA. [Harris, Tamara B.] NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. [Detrano, Robert C.] Los Angeles Biomed Res Inst, Div Cardiol, Torrance, CA USA. [Szklo, Moyses] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Criqui, Michael H.; Allison, Matthew] Univ Calif San Diego, Dept Family & Prevent Med, San Diego, CA 92103 USA. [Ouyang, Pamela] Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD USA. [Brown, Elizabeth R.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Carr, J. Jeffrey] Wake Forest Univ, Bowman Gray Sch Med, Dept Radiol, Winston Salem, NC 27157 USA. RP Ding, JZ (reprint author), Wake Forest Univ, Bowman Gray Sch Med, Sticht Ctr Aging, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jding@wfubmc.edu RI Brown, Elizabeth/A-8984-2008; Carr, John/A-1938-2012; OI Carr, John/0000-0002-4398-8237; Allison, Matthew/0000-0003-0777-8272 FU NHLBI NIH HHS [N01-HC-95159, N01-HC-95165, N01-HC-95169, N01HC95159, N01HC95165, N01HC95169, R01 HL085323, R01-HL-085323]; NIA NIH HHS [P30 AG021332, P30 AG021332-03, P30-AG21332] NR 33 TC 35 Z9 36 U1 0 U2 0 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 SEP 1 PY 2008 VL 88 IS 3 BP 645 EP 650 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 346GV UT WOS:000259057700009 PM 18779279 ER PT J AU Desai, V Kaler, SG AF Desai, Vishal Kaler, Stephen G. TI Role of copper in human neurological disorders SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT Symposium on Molecular Biomarkers of Cooper Homeostasis CY SEP 26-29, 2007 CL Vina del Mar, CHILE ID OCCIPITAL-HORN-SYNDROME; P-TYPE ATPASES; MENKES-DISEASE; NEURODEGENERATIVE DISORDERS; ALZHEIMERS; BINDING; SUPPLEMENTATION; HOMEOSTASIS; DYSFUNCTION; DEFICIENCY AB Copper is a trace element present in all tissues and is required for cellular respiration, peptide amidation, neurotransmitter biosynthesis, pigment formation, and connective tissue strength. Copper is a cofactor for numerous enzymes and plays an important role in central nervous system development; low concentrations of copper may result in incomplete development, whereas excess copper maybe injurious. Copper may be involved in free radical production, via the Haber-Weiss reaction, that results in mitochondrial damage, DNA breakage, and neuronal injury. Evidence of abnormal copper transport and aberrant copper-protein interactions in numerous human neurological disorders supports the critical importance of this trace metal for proper neurodevelopment and neurological function. The biochemical phenotypes of human disorders that involve copper homeostasis suggest possible biomarkers of copper status that may be applicable to general populations. C1 [Desai, Vishal; Kaler, Stephen G.] NICHHD, Unit Pediat Genet, Program Mol Med, NIH, Bethesda, MD 20892 USA. RP Kaler, SG (reprint author), Bldg 10,Room 5-2571,10 Ctr Dr MSC 1832, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov NR 41 TC 100 Z9 103 U1 1 U2 17 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 SEP 1 PY 2008 VL 88 IS 3 SU S BP 855S EP 858S PG 4 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 346GX UT WOS:000259057900009 PM 18779308 ER PT J AU Shi, M Umbach, DM Vermeulen, SH Weinberg, CR AF Shi, M. Umbach, D. M. Vermeulen, S. H. Weinberg, C. R. TI Making the most of case-mother/control-mother studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; genetics; linear models; polymorphism, single nucleotide; risk ID CASE-PARENT TRIADS; GENES; JOINT AB The prenatal environment plays an important role in many conditions, particularly those with onset early in life, such as childhood cancers and birth defects. Because both maternal and fetal genotypes can influence risk, investigators sometimes use a case-mother/control-mother design, with mother-offspring pairs as the unit of analysis, to study genetic factors. Risk models should account for both the maternal genotype and the correlated fetal genotype to avoid confounding. The usual logistic regression analysis, however, fails to fully exploit the fact that these are mothers and offspring. Consider an autosomal, diallelic locus, which could be related to disease susceptibility either directly or through linkage with a polymorphic causal locus. Three nested levels of assumptions are often natural and plausible. The first level simply assumes Mendelian inheritance. The second further assumes parental mating symmetry for the studied locus in the source population. The third additionally assumes parental allelic exchangeability. Those assumptions imply certain nonlinear constraints; the authors enforce those constraints by using Poisson regression together with the expectation-maximization algorithm. Calculations reveal that improvements in efficiency over the usual logistic analysis can be substantial, even if only the Mendelian assumption is honored. Benefits are even more marked if, as is typical, information on genotype is missing for some individuals. C1 [Shi, M.; Umbach, D. M.; Weinberg, C. R.] Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Vermeulen, S. H.] Radboud Univ Nijmegen, Med Ctr, Dept Endocrinol, NL-6525 ED Nijmegen, Netherlands. [Vermeulen, S. H.] Radboud Univ Nijmegen, Med Ctr, Dept Epidemiol, NL-6525 ED Nijmegen, Netherlands. [Vermeulen, S. H.] Radboud Univ Nijmegen, Med Ctr, Dept Biostat & HTA, NL-6525 ED Nijmegen, Netherlands. [Vermeulen, S. H.] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, NL-6525 ED Nijmegen, Netherlands. RP Weinberg, CR (reprint author), Natl Inst Environm Hlth Sci, Biostat Branch, Mail Drop A3-03 101-A315, Res Triangle Pk, NC 27709 USA. EM weinber2@niehs.nih.gov RI Vermeulen, H.H.M./L-4716-2015 FU Intramural Research Program; NIH; National Institute of Environmental Health Sciences; Ter Meulen Fund FX This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences. It was also supported by the Ter Meulen Fund. NR 10 TC 24 Z9 25 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD SEP 1 PY 2008 VL 168 IS 5 BP 541 EP 547 DI 10.1093/aje/kwn149 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 343MZ UT WOS:000258859500010 PM 18650222 ER PT J AU Chalasani, N Fontana, R Davern, T Bonkovsky, H Rochon, J Serrano, J Watkins, P AF Chalasani, Naga Fontana, Robert Davern, Timothy Bonkovsky, Herbert Rochon, James Serrano, Jose Watkins, Paul TI Characteristics of patients with idiosyncratic drug induced liver injury (DILI) who receive systemic corticosteroids: Initial results from the u. s. DILI network prospective study SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 73rd Annual Meeting of the American-College-of-Gastroenterology CY OCT 03-08, 2008 CL Orlando, FL SP Amer Coll Gastroenterol C1 Indiana Univ, Sch Med, Indianapolis, IN USA. Carolina Med Ctr, Charlotte, NC USA. Univ N Carolina, Chapel Hill, NC USA. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIDDK, Bethesda, MD USA. Duke Clin Res Inst, Raleigh, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD SEP PY 2008 VL 103 SU S MA 375 BP S144 EP S145 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 347MH UT WOS:000259145200375 ER PT J AU Laiyemo, A Kamangar, F Marcus, P Taylor, P Virtamo, J Albanes, D Stolzenberg-Solomon, R AF Laiyemo, Adeyinka Kamangar, Farin Marcus, Pamela Taylor, Philip Virtamo, Jarmo Albanes, Demetrius Stolzenberg-Solomon, Rachael TI Serum pepsinogen level, atrophic gastritis and the risk of incident colorectal cancer - a long-term prospective study SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 73rd Annual Meeting of the American-College-of-Gastroenterology CY OCT 03-08, 2008 CL Orlando, FL SP Amer Coll Gastroenterol C1 Natl Canc Inst, Canc Prevent Fellowship Program, Div Canc Epidemiol & Genet, Canc Prevent Div, Bethesda, MD USA. Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. RI Albanes, Demetrius/B-9749-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD SEP PY 2008 VL 103 SU S MA 1390 BP S544 EP S545 PG 2 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 347MH UT WOS:000259145201378 ER PT J AU Laiyemo, A Kamangar, F Marcus, P Taylor, P Virtamo, J Albanes, D Stolzenberg-Solomon, R AF Laiyemo, Adeyinka Kamangar, Farin Marcus, Pamela Taylor, Philip Virtamo, Jarmo Albanes, Demetrius Stolzenberg-Solomon, Rachael TI Serum pepsinogen level, atrophic gastritis and the risk of incident pancreatic cancer - a long-term prospective study SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 73rd Annual Meeting of the American-College-of-Gastroenterology CY OCT 03-08, 2008 CL Orlando, FL SP Amer Coll Gastroenterol C1 NCI, Canc Prevent Div, Div Canc Epidemiol & Genet, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. RI Albanes, Demetrius/B-9749-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD SEP PY 2008 VL 103 SU S MA 199 BP S77 EP S77 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 347MH UT WOS:000259145200200 ER PT J AU Marotta, F Yadav, H Gumaste, U Signorelli, P Minelli, E Marandola, P AF Marotta, Francesco Yadav, Hariom Gumaste, Upendra Signorelli, Paola Minelli, Emilio Marandola, Paolo TI Protective nutragenomic effect of a phytocompound on oxidative stress and DNA fragmentation against paracetamol-induced liver damage SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Meeting Abstract CT 73rd Annual Meeting of the American-College-of-Gastroenterology CY OCT 03-08, 2008 CL Orlando, FL SP Amer Coll Gastroenterol C1 Univ Milan, WHO cnt Biotech & Nat Med, Milan, Italy. NIDDK, GAIA Fdn, Agharkar Res Inst, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD SEP PY 2008 VL 103 SU S MA 313 BP S121 EP S121 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 347MH UT WOS:000259145200313 ER PT J AU Alexander, RL Miller, NA Cotch, MF Janiszewski, R AF Alexander, Robert L., Jr. Miller, Nancy A. Cotch, Mary Frances Janiszewski, Rosemary TI Factors that influence the receipt of eye care SO AMERICAN JOURNAL OF HEALTH BEHAVIOR LA English DT Article DE health education; health professionals; vision; receipt of care; qualitative research ID DIABETIC-RETINOPATHY; UNITED-STATES; VISUAL IMPAIRMENT; PREVALENCE; BLINDNESS; AMERICANS; SERVICES; LATINOS; DISEASE; ADULTS AB Objectives: To better understand what factors influence the receipt of eye care so that screening and education programs can be designed to promote early detection and treatment. Methods: Twenty focus groups were conducted. Analyses entailed debriefing sessions, coding, and interpreting transcribed data. Results: Attitudes about eyesight and eye exams influence the receipt of preventive eye care. Limited knowledge about certain eye diseases and conditions was reported. Participants stated that their primary care providers did not communicate information with them about eyesight nor did they conduct basic eye screenings. Conclusions: Improving provider-patient interactions and developing public health messages about eye diseases and preventive eye care can facilitate increased use of appropriate eye care services. C1 [Alexander, Robert L., Jr.] Macro Int Inc, Atlanta, GA 30329 USA. [Miller, Nancy A.] Univ Maryland, Dept Publ Policy, Baltimore, MD 21201 USA. [Cotch, Mary Frances] NEI, Epidemiol Branch, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. RP Alexander, RL (reprint author), Macro Int Inc, 3 Corp Sq NE,Suite 370, Atlanta, GA 30329 USA. EM robert.l.alexander.jr@macrointernational.com OI Cotch, Mary Frances/0000-0002-2046-4350 FU Intramural NIH HHS [ZIA EY000402-10, Z01 EY000402-07, ZIA EY000402-09, ZIA EY000402-08, Z01 EY000402-06, Z99 EY999999]; PHS HHS [263-01-D-0174] NR 29 TC 14 Z9 15 U1 0 U2 4 PU PNG PUBLICATIONS PI STAR CITY PA PO BOX 4593, STAR CITY, WV 26504-4593 USA SN 1087-3244 J9 AM J HEALTH BEHAV JI Am. J. Health Behav. PD SEP-OCT PY 2008 VL 32 IS 5 BP 547 EP 556 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 343FT UT WOS:000258839100010 PM 18241139 ER PT J AU Oron-Herman, M Kamari, Y Grossman, E Yeger, G Peleg, E Shabtay, Z Shamiss, A Sharabi, Y AF Oron-Herman, Mor Kamari, Yehuda Grossman, Ehud Yeger, Gill Peleg, Edna Shabtay, Zehava Shamiss, Arie Sharabi, Yehonatan TI Metabolic syndrome: Comparison of the two commonly used animal models SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article ID SPONTANEOUSLY HYPERTENSIVE-RATS; INSULIN-RESISTANCE SYNDROME; PLASMA-LIPIDS; SYNDROME-X; FISH-OIL; FRUCTOSE; SUCROSE; EPIDEMIC; DISEASE; GLUCOSE AB BACKGROUND The etiology of the metabolic syndrome (MS) includes both genetic and environmental factors. The two most commonly studied animal models of the MS are the high-sucrose diet given to spontaneously hypertensive rats (SHRs) and high-fructose diet given to Sprague Dawley rats (SDRs). This study compares between these two models. METHODS The two rat strains were examined; within each group, the rats were assigned to either the high-sugar diet (SDRs with fructose-enriched diet and SHRs with sucrose-enriched diet) or standard rat chow (control group). The rats were followed for 7 weeks. The main MS components (obesity, hypertension, impaired glucose tolerance, hyperinsulinemia, hypertriglyceridemia, and hypercholesterolemia) were measured. RESULTS At baseline systolic blood pressure (SBP), fasting blood levels of triglycerides and insulin, as well as glucose intolerance, were significantly higher among the SHRs compared to SDRs. Following fructose enrichment, SDRs became hyperinsulinemic, hypertriglyceridemic, hypercholesterolemic, hypertensive, and insulin resistant, whereas SHRs responded to sucrose supplementation by a significant elevation in blood pressure and mild worsening of insulin resistance. Endpoint results revealed superiority of sucrose-SHR model in terms of hypertension and superiority of fructose-SDR model in terms of hyperinsulinemia, hypertriglyceridemia, and hypercholesterolemia. Both models showed similar postintervention degree of glucose tolerance. CONCLUSIONS The fructose-fed SDR model represents a predominantly environmentally acquired MS, whereas the SHR model is less affected by dietary intervention and better displays the predominantly genetic spontaneous appearance of the syndrome. This fundamental difference should be taken into consideration when choosing an animal model to study the MS. C1 [Oron-Herman, Mor; Kamari, Yehuda; Grossman, Ehud; Yeger, Gill; Peleg, Edna; Shabtay, Zehava; Shamiss, Arie; Sharabi, Yehonatan] Chaim Sheba Med Ctr, Hypertens Unit, Tel Aviv, Israel. [Sharabi, Yehonatan] Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Sharabi, Y (reprint author), Chaim Sheba Med Ctr, Hypertens Unit, Tel Aviv, Israel. EM sharabiy@sheba.health.gov.il OI Grossman, Ehud/0000-0001-8353-0661 NR 32 TC 48 Z9 48 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD SEP PY 2008 VL 21 IS 9 BP 1018 EP 1022 DI 10.1038/ajh.2008.218 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 341GM UT WOS:000258702200012 PM 18566592 ER PT J AU Nelson, RG AF Nelson, Robert G. TI Kidney disease in childhood-onset diabetes SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Editorial Material ID PIMA-INDIANS; BLOOD-PRESSURE; MICROVASCULAR COMPLICATIONS; METABOLIC-CONTROL; YOUNG-ADULTS; RISK-FACTORS; MICROALBUMINURIA; MELLITUS; NEPHROPATHY; RETINOPATHY C1 NIDDK, NIH, Phoenix, AZ 85014 USA. RP Nelson, RG (reprint author), NIDDK, 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 [Z01 DK069036-19] NR 32 TC 1 Z9 1 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 SEP PY 2008 VL 52 IS 3 BP 407 EP 411 DI 10.1053/j.ajkd.2008.00.001 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 343ML UT WOS:000258857900007 PM 18676074 ER PT J AU Jain, M Wallis, D Robin, NH De Vrieze, FW Hardy, JA Ghadami, M Bosse, K Betz, RC Nothen, MM Arcos-Burgos, M Muenke, M AF Jain, Mahim Wallis, Deeann Robin, Nathaniel H. De Vrieze, Fabienne Wavrant Hardy, John A. Ghadami, Mohsen Bosse, Kristin Betz, Regina C. Noethen, Markus M. Arcos-Burgos, Mauricio Muenke, Maximilian TI Locus homogeneity between syndactyly type 1A craniosynostosis Philadelphia type? SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Letter ID MICRORNA TARGETS; LINKAGE ANALYSIS; GENE C1 [Jain, Mahim; Wallis, Deeann; Arcos-Burgos, Mauricio; Muenke, Maximilian] NHGRI, NIH, Med Genet Branch, Bethesda, MD 20892 USA. [Robin, Nathaniel H.] Univ Alabama, Dept Genet, Birmingham, AL USA. [De Vrieze, Fabienne Wavrant; Hardy, John A.] Natl Inst Aging, Natl Inst Hlth, Neurogenet Lab, Bethesda, MD USA. [Ghadami, Mohsen] Meharry Med Coll, Dept Obstet & Gynecol, Nashville, TN 37208 USA. [Bosse, Kristin; Betz, Regina C.; Noethen, Markus M.] Univ Bonn, Inst Human Genet, D-5300 Bonn, Germany. RP Muenke, M (reprint author), NHGRI, NIH, Med Genet Branch, 35 Convent Dr,MSC 3717,Bldg 35,Room 1B-203, Bethesda, MD 20892 USA. EM mmuenke@nhgri.nih.gov RI Betz, Regina/E-8591-2011 OI Betz, Regina/0000-0001-5024-3623 FU Intramural NIH HHS [Z99 HG999999]; Medical Research Council [G0701075] 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 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD SEP 1 PY 2008 VL 146A IS 17 BP 2308 EP 2311 DI 10.1002/ajmg.a.32445 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 347GP UT WOS:000259128900020 PM 18680190 ER PT J AU Krawczyk, E Suprynowicz, FA Liu, XF Dai, YH Hartmann, DP Hanover, J Schlegel, R AF Krawczyk, Ewa Suprynowicz, Frank A. Liu, Xuefeng Dai, Yuhai Hartmann, Dan P. Hanover, John Schlegel, Richard TI Koilocytosis - A cooperative interaction between the human papillomavirus E5 and E6 oncoproteins SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID EPITHELIAL-CELLS; RECEPTOR ACTIVATION; PROTEIN; TYPE-16; EXPRESSION; GENE; TRANSFORMATION; KERATINOCYTES; APOPTOSIS; MEMBRANE AB A long-recognized, pathognomonic feature of human papillomavirus (HPV) infection is the appearance of halo or koilocytotic cells in the differentiated layers of the squamous epithelium. These koilocytes are squamous epithelial cells that contain an acentric, hyperchromatic nucleus that is displaced by a large perinuclear vacuole. However, the genesis of the cytoplasmic vacuole has remained unclear, particularly because both HPV DNA replication and virion assembly occur exclusively in the nucleus. in clinical biopsies, koilocytosis is observed in both low- and high-risk HPV infections; therefore, in this study, we demonstrated that the E5 and E6 proteins from both low- and high-risk HPVs cooperate to induce koilocyte formation in human cervical cells in vitro, using both stable and transient assays. Both E5 and E6 also induce koilocytosis in human foreskin keratinocytes but not in primate COS cells. Deletion of the 20 C-terminal amino acids of E5 completely abrogates koilocytosis, whereas a 10-amino acid-deletion mutant retains similar to 50% of its activity. Because the E6 protein from both the low- and high-risk HPVs is capable of potentiating koilocytosis with E5, it is apparent that the targeting of both p53 and PDZ proteins by E6 is not involved. Our data suggest new, cooperative functions for both the E5 and E6 proteins, hinting at additional targets and roles for these oncoproteins in the viral life cycle. C1 [Krawczyk, Ewa; Suprynowicz, Frank A.; Liu, Xuefeng; Dai, Yuhai; Hartmann, Dan P.; Schlegel, Richard] Georgetown Univ, Sch Med, Dept Pathol, Washington, DC 20057 USA. [Hanover, John] NIDDK, NIH, Lab Cell Biochem & Biol, Bethesda, MD USA. RP Schlegel, R (reprint author), Georgetown Univ, Sch Med, Dept Pathol, 3900 Reservoir Rd NW, Washington, DC 20057 USA. EM schleger@georgetown.edu FU NCI NIH HHS [R01 CA106400, R01 CA053371, R01-CA053371] NR 41 TC 46 Z9 49 U1 0 U2 5 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 SEP PY 2008 VL 173 IS 3 BP 682 EP 688 DI 10.2353/ajpath.2008.080280 PG 7 WC Pathology SC Pathology GA 344JD UT WOS:000258921900008 PM 18688031 ER PT J AU Jorgacevski, J Stenovec, M Kreft, M Bajic, A Rituper, B Vardjan, N Stojilkovic, S Zorec, R AF Jorgacevski, Jernej Stenovec, Matjaz Kreft, Marko Bajic, Aleksandar Rituper, Bostjan Vardjan, Nina Stojilkovic, Stanko Zorec, Robert TI Hypotonicity and peptide discharge from a single vesicle SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE prolactin; hormone secretion; rat lactotrophs; fusion pore; postfusion release regulation ID ADRENAL CHROMAFFIN CELLS; FROG NEUROMUSCULAR-JUNCTION; ANTERIOR-PITUITARY-CELLS; DENSE-CORE VESICLES; KISS-AND-RUN; MEMBRANE CAPACITANCE; NEUROENDOCRINE CELLS; TRANSMITTER RELEASE; GROWTH-HORMONE; FUSION PORES AB Neuroendocrine secretory vesicles discharge their cargo in response to a stimulus, but the nature of this event is poorly understood. We studied the release of the pituitary hormone prolactin by hypotonicity, because this hormone also contributes to osmoregulation. In perfused rat lactotrophs, hypotonicity resulted in a transient increase followed by a sustained depression of prolactin release, as monitored by radioimmunoassay. In single cells imaged by confocal microscopy, hypotonicity elicited discharge of the fluorescently labeled atrial natriuretic peptide cargo from similar to 2% of vesicles/cell. In contrast, KCl-induced depolarization resulted in a response of similar to 10% of vesicles/cell, with different unloading/loading time course of the two fluorescent probes. In cell-attached studies, discrete changes in membrane capacitance were recorded in both unstimulated and stimulated conditions, reflecting single vesicle fusion/fissions with the plasma membrane. In stimulated cells, the probability of occurrence of full fusion events was low and unchanged, whereas over 95% of fusion events were transient, with the open fusion pore probability, the average pore dwell-time, the frequency of occurrence, and the fusion pore conductance increased. Hypotonicity only rarely elicited new fusion events in silent membrane patches. The results indicate that, in hypotonicity-stimulated lactotrophs, transient vesicle fusion mediates hormone release. C1 [Jorgacevski, Jernej; Stenovec, Matjaz; Kreft, Marko; Rituper, Bostjan; Vardjan, Nina; Zorec, Robert] Univ Ljubljana, Fac Med, Lab Neuroendocrinol Mol Cell Physiol, Ljubljana, Slovenia. [Stenovec, Matjaz; Kreft, Marko; Vardjan, Nina; Zorec, Robert] Celica Biomed Ctr, Ljubljana, Slovenia. [Bajic, Aleksandar] NICHHD, Sect Cellular Signaling, Dev Neurosci Program, Bethesda, MD 20892 USA. RP Zorec, R (reprint author), Univ Ljubljana, Fac Med, Inst Pathophysiol, LN MCP,Zaloska 4, Ljubljana 1000, Slovenia. EM robert.zorec@mf.uni-lj.si OI Rituper, Bostjan/0000-0002-1618-3636; Jorgacevski, Jernej/0000-0003-3550-2011; Bajic, Aleksandar/0000-0002-1255-9835 FU Ministry of Education, Sciences and Sports of the Republic of Slovenia [P3 521 0381, P3 0310 0381, Z3-3510-1683]; National Institutes of Health [R01-NS36665-05] FX This work was supported by Grants P3 521 0381, P3 0310 0381, and Z3-3510-1683 from the Ministry of Education, Sciences and Sports of the Republic of Slovenia and by R01-NS36665-05 from the National Institutes of Health. NR 53 TC 15 Z9 15 U1 0 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD SEP PY 2008 VL 295 IS 3 BP C624 EP C631 DI 10.1152/ajpcell.00303.2008 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 345KJ UT WOS:000258995000007 PM 18632733 ER PT J AU Yu, MJ Pisitkun, T Wang, GH Aranda, JF Gonzales, PA Tchapyjnikov, D Shen, RF Alonso, MA Knepper, MA AF Yu, Ming-Jiun Pisitkun, Trairak Wang, Guanghui Aranda, Juan F. Gonzales, Patricia A. Tchapyjnikov, Dmitry Shen, Rong-Fong Alonso, Miguel A. Knepper, Mark A. TI Large-scale quantitative LC-MS/MS analysis of detergent-resistant membrane proteins from rat renal collecting duct SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE aquaporin-2; vasopressin; membrane rafts; mass spectrometry; proteomics ID GPI-ANCHORED PROTEINS; AQUAPORIN-2 TRAFFICKING; WATER CHANNEL; LIPID RAFTS; ARGININE-VASOPRESSIN; PLASMA-MEMBRANES; APICAL SURFACE; MDCK CELLS; MYOSIN-II; KIDNEY AB In the renal collecting duct, vasopressin controls transport of water and solutes via regulation of membrane transporters such as aquaporin-2 (AQP2) and the epithelial urea transporter UT-A. To discover proteins potentially involved in vasopressin action in rat kidney collecting ducts, we enriched membrane "raft" proteins by harvesting detergent-resistant membranes (DRMs) of the inner medullary collecting duct (IMCD) cells. Proteins were identified and quantified with LC-MS/MS. A total of 814 proteins were identified in the DRM fractions. Of these, 186, including several characteristic raft proteins, were enriched in the DRMs. Immunoblotting confirmed DRM enrichment of representative proteins. Immunofluorescence confocal microscopy of rat IMCDs with antibodies to DRM proteins demonstrated heterogeneity of raft sub-domains: MAL2 (apical region), RalA (predominant basolateral labeling), caveolin-2 (punctate labeling distributed throughout the cells), and flotillin-1 (discrete labeling of large intracellular structures). The DRM proteome included GPI-anchored, doubly acylated, singly acylated, cholesterol-binding, and integral membrane proteins (IMPs). The IMPs were, on average, much smaller and more hydrophobic than IMPs identified in non-DRM-enriched IMCD. The content of serine 256-phosphorylated AQP2 was greater in DRM than in non-DRM fractions. Vasopressin did not change the DRM-to-non-DRM ratio of most proteins, whether quantified by tandem mass spectrometry (LC-MS/MS, n = 22) or immunoblotting (n = 6). However, Rab7 and annexin-2 showed small increases in the DRM fraction in response to vasopressin. In accord with the long-term goal of creating a systems-level analysis of transport regulation, this study has identified a large number of membrane-associated proteins expressed in the IMCD that have potential roles in vasopressin action. C1 [Yu, Ming-Jiun; Pisitkun, Trairak; Gonzales, Patricia A.; Tchapyjnikov, Dmitry; Knepper, Mark A.] Natl Heart Lung & Blood Inst, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. [Wang, Guanghui; Shen, Rong-Fong] Natl Heart Lung & Blood Inst, Proteom Core Facil, NIH, Bethesda, MD 20892 USA. [Aranda, Juan F.] Univ Autonoma Madrid, Madrid, Spain. [Alonso, Miguel A.] Consejo Super Invest Cient, Madrid, Spain. RP Knepper, MA (reprint author), Natl Heart Lung & Blood Inst, Kidney & Electrolyte Metab Lab, NIH, Bldg 10,Rm 6N260,10 Ctr Dr,MSC-1603, Bethesda, MD 20892 USA. EM knepperm@nhlbi.nih.gov RI Alonso, Miguel/J-3945-2016; OI Alonso, Miguel/0000-0002-7001-8826; Pisitkun, Trairak/0000-0001-6677-2271; YU, MING-JIUN/0000-0003-0393-4696 FU NHLBI Intramural Research [ZO1-HL-001285] FX This research was supported by NHLBI Intramural Research Program Project ZO1-HL-001285. NR 60 TC 25 Z9 25 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD SEP PY 2008 VL 295 IS 3 BP C661 EP C678 DI 10.1152/ajpcell.90650.2007 PG 18 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 345KJ UT WOS:000258995000011 PM 18596208 ER PT J AU Murphy, E Wong, R Steenbergen, C AF Murphy, Elizabeth Wong, Renee Steenbergen, Charles TI Signalosomes: delivering cardioprotective signals from GPCRs to mitochondria SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Editorial Material ID ISCHEMIA; INJURY C1 [Murphy, Elizabeth; Wong, Renee] NHLBI, Pulm Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Steenbergen, Charles] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Murphy, E (reprint author), NHLBI, Pulm Vasc Med Branch, NIH, Bldg 10,Rm 7N112,10 Ctr Dr, Bethesda, MD 20892 USA. EM murphy1@mail.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [R01-HL-39752, R01 HL039752] NR 11 TC 9 Z9 10 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD SEP PY 2008 VL 295 IS 3 BP H920 EP H922 DI 10.1152/ajpheart.00738.2008 PG 3 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 344TC UT WOS:000258949200003 PM 18660439 ER PT J AU Sonin, D Zhou, SY Cronin, C Sonina, T Wu, J Jacobson, KA Pappano, A Liang, BT AF Sonin, Dmitry Zhou, Si-Yuan Cronin, Chunxia Sonina, Tatiana Wu, Jeffrey Jacobson, Kenneth A. Pappano, Achilles Liang, Bruce T. TI Role of P2X purinergic receptors in the rescue of ischemic heart failure SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE purines; contractility; infarction ID MYOCARDIAL-INFARCTION; IMPROVES SURVIVAL; MICE; CALSEQUESTRIN; HYPERTROPHY; OVEREXPRESSION; CARDIOMYOPATHY; EXPRESSION; MYOCYTES; THERAPY AB Evidence is accumulating to support the presence of P2X purinergic receptors in the heart. However, the biological role of this receptor remains to be defined. The objectives here were to determine the role of cardiac P2X receptors in modulating the progression of post-myocardial infarction ischemic heart failure and to investigate the underlying mechanism. The P2X(4) receptor (P2X(4)R) is an important subunit of native cardiac P2X receptors, and the cardiac-specific transgenic overexpression of P2X(4)R (Tg) was developed as a model. Left anterior descending artery ligation resulted in similar infarct size between Tg and wildtype (WT) mice (P > 0.1). However, Tg mice showed an enhanced cardiac contractile performance at 7 days, 1 mo, and 2 mo after infarction and an increased survival at 1 and 2 mo after infarction (P < 0.01). The enhanced intact heart function was manifested by a greater global left ventricular developed pressure and rate of contraction of left ventricular pressure in vitro and by a significantly increased fractional shortening and systolic thickening in the noninfarcted region in vivo (P < 0.05). The salutary effects on the ischemic heart failure phenotype were seen in both sexes and were not the result of any difference in infarct size in Tg versus WT hearts. An enhanced contractile function of the noninfarcted area in the Tg heart was likely an important rescuing mechanism. The cardiac P2X receptor is a novel target to treat post-myocardial infarction ischemic heart failure. C1 [Sonin, Dmitry; Zhou, Si-Yuan; Cronin, Chunxia; Sonina, Tatiana; Wu, Jeffrey; Pappano, Achilles; Liang, Bruce T.] Univ Connecticut, Ctr Hlth, Pat & Jim Calhoun Cardiol Ctr, Farmington, CT 06030 USA. [Jacobson, Kenneth A.] NIDDK, NIH, Bethesda, MD USA. RP Liang, BT (reprint author), Univ Connecticut, Ctr Hlth, Pat & Jim Calhoun Cardiol Ctr, MC 3946,263 Farmington Ave, Farmington, CT 06030 USA. EM bliang@uchc.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU National Heart, Lung, and Blood Institute [RO1-HL-48225]; Ray Neag Distinguished Professorship; National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program FX This work was supported in part by National Heart, Lung, and Blood Institute Grant RO1-HL-48225 and Ray Neag Distinguished Professorship (to B. T. Liang). K. A. Jacobson acknowledges support from the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program. NR 24 TC 23 Z9 24 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD SEP PY 2008 VL 295 IS 3 BP H1191 EP H1197 DI 10.1152/ajpheart.00577.2008 PG 7 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 344TC UT WOS:000258949200037 PM 18641271 ER PT J AU Card, JW Zeldin, DC Bonner, JC Nestmann, ER AF Card, Jeffrey W. Zeldin, Darryl C. Bonner, James C. Nestmann, Earle R. TI Pulmonary applications and toxicity of engineered nanoparticles SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Review DE nanotechnology; nanomaterials; respiratory system; lung ID TITANIUM-DIOXIDE PARTICLES; WALLED-CARBON-NANOTUBES; SYNCYTIAL VIRUS-INFECTION; LUNG-CANCER CELLS; AEROSOLIZED NANOSTRUCTURED ITRACONAZOLE; INSOLUBLE IRIDIUM PARTICLES; SOLID LIPID NANOPARTICLES; ALLERGIC AIRWAY DISEASE; IN-VITRO TOXICITY; ULTRAFINE PARTICLES AB Because of their unique physicochemical properties, engineered nanoparticles have the potential to significantly impact respiratory research and medicine by means of improving imaging capability and drug delivery, among other applications. These same properties, however, present potential safety concerns, and there is accumulating evidence to suggest that nanoparticles may exert adverse effects on pulmonary structure and function. The respiratory system is susceptible to injury resulting from inhalation of gases, aerosols, and particles, and also from systemic delivery of drugs, chemicals, and other compounds to the lungs via direct cardiac output to the pulmonary arteries. As such, it is a prime target for the possible toxic effects of engineered nanoparticles. The purpose of this article is to provide an overview of the potential usefulness of nanoparticles and nanotechnology in respiratory research and medicine and to highlight important issues and recent data pertaining to nanoparticle-related pulmonary toxicity. C1 [Card, Jeffrey W.; Nestmann, Earle R.] Cantox Hlth Sci Int, Mississauga, ON L5N 2X7, Canada. [Zeldin, Darryl C.] NIEHS, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. [Bonner, James C.] N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27695 USA. RP Card, JW (reprint author), Cantox Hlth Sci Int, 2233 Argentia Rd,Suite 308, Mississauga, ON L5N 2X7, Canada. EM jcard@cantox.com FU National Institutes of Health (NIH); National Institute of Environmental Health Sciences; College of Agricultural and Life Sciences at North Carolina State University; NIH [R21 ES015801-01] FX D. C. Zeldin is supported by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences. J. C. Bonner is supported by the College of Agricultural and Life Sciences at North Carolina State University and by NIH Grant R21 ES015801-01. NR 164 TC 139 Z9 141 U1 6 U2 37 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD SEP PY 2008 VL 295 IS 3 BP L400 EP L411 DI 10.1152/ajplung.00041.2008 PG 12 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 343SH UT WOS:000258874700002 PM 18641236 ER PT J AU Pratt, CA Stevens, J Daniels, S AF Pratt, Charlotte A. Stevens, June Daniels, Stephen TI Childhood obesity prevention and treatment - Recommendations for future research SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID ADOLESCENTS; CHILDREN AB This report summarizes the National Heart, Lung, and Blood Institute Working Group's recommendations on future research directions in childhood obesity prevention and treatment. The Working Group consisted of leader and representatives from public and private academic and medical institutions with expertise in a variety of health specialties. They reviewed the literature and discussed the findings as well as their own experiences in the prevention and treatment of childhood obesity. The Working Group made recommendations that were based on scientific importance, the potential likelihood of public health impact, and the feasibility and timeliness for childhood obesity prevention and treatment research. These recommendations are intended to assist investigators in the development of research agendas to advance the knowledge of effective childhood obesity prevention and treatment. C1 [Pratt, Charlotte A.] NHLBI, Div Prevent & Populat Sci, NIH, Bethesda, MD 20892 USA. [Stevens, June] Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. [Daniels, Stephen] Univ Colorado, Sch Med, Denver, CO 80202 USA. RP Pratt, CA (reprint author), NHLBI, Div Prevent & Populat Sci, NIH, 6701 Rockledge Dr,MSC 7936,Room 10118, Bethesda, MD 20892 USA. EM pratte@nhlbi.nih.gov FU Intramural NIH HHS [Z99 HL999999] NR 6 TC 42 Z9 42 U1 2 U2 8 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 SEP PY 2008 VL 35 IS 3 BP 249 EP 252 DI 10.1016/j.amepre.2008.05.025 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 341UC UT WOS:000258739600010 PM 18617353 ER PT J AU Wethington, HR Hahn, RA Fuqua-Whitley, DS Sipe, TA Crosby, AE Johnson, RL Liberman, AM Moscicki, E Price, LN Tuma, FK Kalra, G Chattopadhyay, SK AF Wethington, Holly R. Hahn, Robert A. Fuqua-Whitley, Dawna S. Sipe, Theresa Ann Crosby, Alex E. Johnson, Robert L. Liberman, Akiva M. Moscicki, Eve Price, LeShawndra N. Tuma, Farris K. Kalra, Geetika Chattopadhyay, Sajal K. CA Task Force Community Preventive Se TI The effectiveness of interventions to reduce psychological harm from traumatic events among children and adolescents - A systematic review SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID POSTTRAUMATIC-STRESS-DISORDER; RANDOMIZED CONTROLLED-TRIAL; SEXUALLY-ABUSED-CHILDREN; COMMUNITY-PREVENTIVE-SERVICES; EYE-MOVEMENT DESENSITIZATION; COGNITIVE-BEHAVIORAL THERAPY; CLINICAL-TRIAL; FOLLOW-UP; PRESCHOOL-CHILDREN; COST-EFFECTIVENESS AB Children and adolescents in the U.S. and worldwide are commonly exposed to traumatic events, yet practitioners treating these young people to reduce subsequent psychological harm may not be aware of-or use-interventions based oil (lie best available evidence. This systematic review evaluated interventions commonly used to reduce psychological harm among children and adolescents exposed to traumatic events. Guide to Community Preventive Services (Community Guide) criteria were used to assess study design and execution. Meta-analyses were conducted, stratifying by traumatic exposures. Evaluated interventions were conducted in high-income economies, published up to March 2007. Subjects in studies were <= 21 years of age, exposed to individual/mass, intentional/unintentional, or manmade/natural traumatic events. The seven evaluated interventions were individual cognitive-behavioral therapy, group cognitive behavioral therapy, play therapy, art therapy, psychodynamic therapy, and pharmacologic therapy for symptomatic children and adolescents, and psychological debriefing, regardless of symptoms. The main outcome measures were indices of depressive disorders, anxiety and posttraumatic stress disorder, internalizing and externalizing disorders, and suicidal behavior. Strong evidence (according to Community Guide rules) showed that. individual and group cognitive-behavioral therapy can decrease psychological harm among symptomatic children and adolescents exposed to trauma. Evidence was insufficient. to determine the effectiveness of play therapy, art therapy, pharmacologic therapy, psychodynamic therapy, or psychological debriefing in reducing psychological harm. Personnel treating children and adolescents exposed to traumatic events should use interventions for which evidence of effectiveness is available, such as individual and group cognitive-behavior therapy. Interventions should be adapted for use in diverse populations and settings. Research should be pursued oil the effectiveness of interventions For which evidence is currently insufficient. C1 [Wethington, Holly R.; Hahn, Robert A.; Fuqua-Whitley, Dawna S.; Sipe, Theresa Ann; Kalra, Geetika; Chattopadhyay, Sajal K.] CDC, Natl Ctr Hlth Mkt, Atlanta, GA 30333 USA. [Crosby, Alex E.] CDC, Natl Ctr Injury Prevent & Control, Atlanta, GA 30333 USA. [Johnson, Robert L.] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [Liberman, Akiva M.] Natl Inst Justice, Washington, DC USA. [Moscicki, Eve; Price, LeShawndra N.; Tuma, Farris K.] NIH, Bethesda, MD 20892 USA. RP Hahn, RA (reprint author), CDC, Natl Ctr Hlth Mkt, 1600 Clifton Rd NE,MS E-69, Atlanta, GA 30333 USA. EM rhahn@cdc.gov RI Sipe, Theresa/C-2262-2012 FU Oak Ridge Institute for Scientific Education (ORISE) FX The work of Kalra, Fuqua-Whitley, and Wethington was supported b) funding from the Oak Ridge Institute for Scientific Education (ORISE). NR 89 TC 72 Z9 73 U1 3 U2 45 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 SEP PY 2008 VL 35 IS 3 BP 287 EP 313 DI 10.1016/j.amepre.2008.06.024 PG 27 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 341UC UT WOS:000258739600018 PM 18692745 ER PT J AU Blachman, DR Abrams, D AF Blachman, Dara R. Abrams, David TI Behavioral and social science contributions to preventing teen motor crashes - Systems integrative and interdisciplinary approaches SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material C1 [Blachman, Dara R.] Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Abrams, David] NIH, Bethesda, MD 20892 USA. RP Blachman, DR (reprint author), Off Behav & Social Sci Res, 31 Ctr Dr,Bldg 31,Room B1C19, Bethesda, MD 20892 USA. EM blachmand@od.nih.gov NR 23 TC 5 Z9 5 U1 1 U2 5 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 SEP PY 2008 VL 35 IS 3 SU S BP S285 EP S288 DI 10.1016/j.amepre.2008.06.003 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 341UG UT WOS:000258740000006 PM 18702983 ER PT J AU Simons-Morton, BG Ouimet, MC Catalano, RF AF Simons-Morton, Bruce G. Ouimet, Marie Claude Catalano, Richard F. TI Parenting and the young driver problem SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID TEEN DRIVING PRIVILEGES; CHECKPOINTS PROGRAM; BRIEF INTERVENTION; LICENSING SYSTEM; LEARNER DRIVERS; UNITED-STATES; SUBSTANCE USE; NOVICE; TEENAGERS; BEHAVIOR AB Crash rates increase sharply at the age at which teenagers begin to drive and remain elevated relative to adult levels until drivers are well into their twenties. Parents have important roles to play in managing the risk for teenage drivers before and after licensure. Parents can be involved in their teenagers' driving, allowing them to test for permit and licensure, supervising practice driving, providing access to a vehicle, and setting and enforcing limits on driving privileges after licensure. However, the management practices of many parents may not be sufficient to provide safety effects. The literature indicates that the two most important decisions parents can make to reduce teenagers' driving risk are to delay licensure and impose limits on high-risk driving conditions (such as driving at night and with teenage passengers) during the first year of licensure. Two intervention programs have been shown to increase parental limit setting as a means of reducing risky driving behaviors and improving driving performance among novice teenage drivers. This article describes the contexts of and opportunities for parental involvement in teenage driving and the effectiveness of interventions to increase and improve parental management of young drivers. C1 [Simons-Morton, Bruce G.; Ouimet, Marie Claude] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. [Catalano, Richard F.] Univ Washington, Sch Social Work, Social Dev Res Grp, Seattle, WA 98195 USA. RP Simons-Morton, BG (reprint author), Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Prevent Res Branch, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,7B05, Bethesda, MD 20892 USA. EM mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [Z01 HD001707-09]; NICHD NIH HHS [R24 HD042828, R24 HD042828-10] NR 93 TC 41 Z9 41 U1 1 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD SEP PY 2008 VL 35 IS 3 SU S BP S294 EP S303 DI 10.1016/j.amepre.2008.06.018 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 341UG UT WOS:000258740000008 PM 18702985 ER PT J AU Miranda, J McGuire, TG Williams, DR Wang, P AF Miranda, Jeanne McGuire, Thomas G. Williams, David R. Wang, Philip TI Mental health in the context of health disparities SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID ACUTE MYOCARDIAL-INFARCTION; NATIONAL COMORBIDITY SURVEY; BLACK CARIBBEAN IMMIGRANTS; DSM-IV DISORDERS; QUALITY-OF-CARE; RACIAL-DIFFERENCES; UNITED-STATES; ASIAN-AMERICANS; STATISTICAL DISCRIMINATION; PSYCHIATRIC-DISORDERS C1 [Miranda, Jeanne] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. RP Miranda, J (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, 10920 Wilshire Blvd,Ste 300, Los Angeles, CA 90095 USA. EM mirandaj@ucla.edu NR 50 TC 76 Z9 76 U1 0 U2 9 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2008 VL 165 IS 9 BP 1102 EP 1108 DI 10.1176/appi.ajp.2008.08030333 PG 7 WC Psychiatry SC Psychiatry GA 344BF UT WOS:000258899500007 PM 18765491 ER PT J AU Blair, K Shaywitz, J Smith, BW Rhodes, R Geraci, M Jones, M McCaffrey, D Vythilingam, M Finger, E Mondillo, K Jacobs, M Charney, DS Blair, RJR Drevets, WC Pine, DS AF Blair, Karina Shaywitz, Jonathan Smith, Bruce W. Rhodes, Rebecca Geraci, Marilla Jones, Matthew McCaffrey, Daniel Vythilingam, Meena Finger, Elizabeth Mondillo, Krystal Jacobs, Madeline Charney, Dennis S. Blair, R. J. R. Drevets, Wayne C. Pine, Daniel S. TI Response to emotional expressions in generalized social phobia and generalized anxiety disorder: Evidence for separate disorders SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 62nd Annual Meeting of the Society-of-Biological-Psychiatry CY MAY 17-20, 2007 CL San Diego, CA SP Soc Biol Psychiat ID AMYGDALA ACTIVATION; BRAIN ACTIVATION; FACES; ADOLESCENTS; CORTEX; COMMON; ANGRY AB Objective: Generalized social phobia involves fear/avoidance, specifically of social situations, whereas generalized anxiety disorder involves intrusive worry about diverse circumstances. It remains unclear the degree to which these two, often comorbid, conditions represent distinct disorders or alternative presentations of a single, core underlying pathology. Functional magnetic resonance imaging assessed the neural response to facial expressions in generalized social phobia and generalized anxiety disorder. Method: Individuals matched on age, IQ, and gender with generalized social phobia without generalized anxiety disorder (N=17), generalized anxiety disorder (N= 17), or no psychopathology (N=17) viewed neutral, fearful, and angry expressions while ostensibly making a simple gender judgment. Results: The patients with generalized social phobia without generalized anxiety disorder showed increased activation to fearful relative to neutral expressions in several regions, including the amygdala, compared to healthy individuals. This increased amygdala response related to self-reported anxiety in patients with generalized social phobia without generalized anxiety disorder. In contrast, patients with generalized anxiety disorder showed significantly less activation to fearful relative to neutral faces compared to the healthy individuals. They did show significantly increased response to angry expressions relative to healthy individuals in a lateral region of the middle frontal gyrus. This increased lateral frontal response related to self-reported anxiety in patients with generalized anxiety disorder. Conclusions: These results suggest that neural circuitry dysfunctions differ in generalized social phobia and generalized anxiety disorder. C1 [Blair, Karina] NIMH, Mood & Anxiety Program, NIH, Bethesda, MD 20892 USA. Univ New Mexico, Dept Psychol, Albuquerque, NM 87131 USA. Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, MRC, Ctr Clin Sci, London SW7 2AZ, England. Mt Sinai Sch Med, New York, NY USA. RP Blair, K (reprint author), NIMH, Mood & Anxiety Program, NIH, 15K N Dr,MSC 2670, Bethesda, MD 20892 USA. EM peschark@mail.nih.gov FU Intramural NIH HHS [ZIA MH002780-08, ZIA MH002781-08, ZIA MH002782-08] NR 32 TC 118 Z9 120 U1 2 U2 24 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD SEP PY 2008 VL 165 IS 9 BP 1193 EP 1202 DI 10.1176/appi.ajp.2008.07071060 PG 10 WC Psychiatry SC Psychiatry GA 344BF UT WOS:000258899500021 PM 18483136 ER PT J AU Blum, N Fee, E AF Blum, Nava Fee, Elizabeth TI The first mental hospital in China SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Blum, Nava] Univ Haifa, Sch Publ Hlth, Fac Social Welf & Hlth Sci, IL-31905 Haifa, Israel. [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Blum, N (reprint author), Univ Haifa, Sch Publ Hlth, Fac Social Welf & Hlth Sci, IL-31905 Haifa, Israel. EM navablum@hotmail.com NR 6 TC 1 Z9 1 U1 1 U2 1 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 SEP PY 2008 VL 98 IS 9 BP 1593 EP 1593 DI 10.2105/AJPH.2008.134577 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 338AF UT WOS:000258476400019 PM 18633073 ER PT J AU Abel, EYK Fee, E Brown, TM AF Abel, Emi Y. K. Fee, Elizabeth Brown, Theodore M. TI The World Health Organization and its work SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 [Fee, Elizabeth] Natl Lib Med, NIH, Bethesda, MD 20894 USA. [Abel, Emi Y. K.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Brown, Theodore M.] Univ Rochester, Dept Hist & Community & Prevent Med, Rochester, NY USA. RP Fee, E (reprint author), Natl Lib Med, NIH, Bldg 38,Room 1E-21,8600 Rockville Pike, Bethesda, MD 20894 USA. EM elizabeth_Jee@nlm.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD SEP PY 2008 VL 98 IS 9 BP 1594 EP + PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 338AF UT WOS:000258476400020 ER PT J AU Abel, EK Fee, E Brown, TM AF Abel, Emily K. Fee, Elizabeth Brown, Theodore M. TI Milton I. Roemer - Advocate of social medicine, international health, and national health insurance SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 [Fee, Elizabeth] NIH, Natl Lib Med, Bethesda, MD 20894 USA. [Abel, Emily K.] Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. [Brown, Theodore M.] Univ Rochester, Dept Hist & Community & Prevent Med, Rochester, NY USA. RP Fee, E (reprint author), NIH, Natl Lib Med, Bldg 38,Room 1E-21,8600 Rockville Pike, Bethesda, MD 20894 USA. EM elizabeth_fee@nlm.nih.gov NR 1 TC 1 Z9 1 U1 0 U2 2 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 SEP PY 2008 VL 98 IS 9 BP 1596 EP 1597 DI 10.2105/AJPH.2008.134189 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 338AF UT WOS:000258476400021 PM 18633074 ER PT J AU Warnecke, RB Oh, A Breen, N Gehlert, S Paskett, E Tucker, KL Lurie, N Rebbeck, T Goodwin, J Flack, J Srinivasan, S Kerner, J Heurtin-Roberts, S Abeles, R Tyson, FL Patmios, G Hiatt, RA AF Warnecke, Richard B. Oh, April Breen, Nancy Gehlert, Sarah Paskett, Electra Tucker, Katherine L. Lurie, Nicole Rebbeck, Timothy Goodwin, James Flack, John Srinivasan, Shobha Kerner, Jon Heurtin-Roberts, Suzanne Abeles, Ronald Tyson, Frederick L. Patmios, Georgeanne Hiatt, Robert A. TI Approaching health disparities from a population perspective: The National Institutes of Health Centers for Population Health and Health Disparities SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID SOCIOECONOMIC-STATUS; SOCIAL INTEGRATION; HISPANIC ELDERS; PUBLIC-HEALTH; MORTALITY; STRESS; CANCER; MASSACHUSETTS; DISADVANTAGE; ENVIRONMENTS AB Addressing health disparities has been a national challenge for decades. The National Institutes of Health-sponsored Centers for Population Health and Health Disparities are the first federal initiative to support transdisciplinary multilevel research on the determinants of health disparities. Their novel research approach combines population, clinical, and basic science to elucidate the complex determinants of health disparities. The centers are partnering with community-based, public, and quasi-public organizations to disseminate scientific findings and guide clinical practice in communities. In turn, communities and public health agents are shaping the research. The relationships forged through these complex collaborations increase the likelihood that the centers' scientific findings will be relevant to communities and contribute to reductions in health disparities. C1 [Warnecke, Richard B.; Oh, April] Univ Illinois, CPHHD, Chicago, IL 60608 USA. [Breen, Nancy; Srinivasan, Shobha; Kerner, Jon] NCI, NIH, Bethesda, MD 20892 USA. [Abeles, Ronald] NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. [Tyson, Frederick L.] NIEHS, NIH, Bethesda, MD USA. [Patmios, Georgeanne] NIA, NIH, Bethesda, MD 20892 USA. [Gehlert, Sarah] Univ Chicago, Ctr Interdisciplinary Hlth Disparities, Chicago, IL 60637 USA. [Paskett, Electra] Ohio State Univ, CPHHD, Columbus, OH 43210 USA. [Paskett, Electra] Univ Michigan, Ann Arbor, MI 48109 USA. [Tucker, Katherine L.] Tufts Univ, CPHHD, Boston, MA 02111 USA. [Tucker, Katherine L.] Northeastern Univ, Boston, MA 02115 USA. [Lurie, Nicole] RAND Corp, CPHHD, Santa Monica, CA USA. [Rebbeck, Timothy] Univ Penn, CPHHD, Philadelphia, PA 19104 USA. [Goodwin, James] Univ Texas Med Branch, CPHHD, Galveston, TX USA. [Flack, John] Wayne State Univ, Ctr Urban & African Amer Hlth, Detroit, MI USA. [Heurtin-Roberts, Suzanne] NCI, Behav Res Program, NIH, Bethesda, MD 20892 USA. [Hiatt, Robert A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Lurie, Nicole] RAND Corp, CPHHD, Washington, DC USA. [Lurie, Nicole] RAND Corp, CPHHD, Pittsburgh, PA USA. RP Warnecke, RB (reprint author), Univ Illinois, Ctr Canc, Program Canc Control & Populat Sci, 1747 W Roosevelt Rd,Ste 558,MC 275, Chicago, IL 60608 USA. EM warneche@uic.edu RI Tucker, Katherine/A-4545-2010; Heurtin-Roberts, Suzanne/D-7274-2013; OI Kerner, Jon/0000-0002-8792-3830; Tucker, Katherine/0000-0001-7640-662X FU National Institute of Environmental Health Sciences [P50 ES012395, P50 ES012382, P50 ES012383]; National Institute of Aging [AG02323394]; National Cancer Institute [P50 CA1065631, P50 CA015632, P50 CA 106743, P50 CA105641] FX This research was funded by the National Institute of Environmental Health Sciences (grants P50 ES012395, P50 ES012382, and P50 ES012383), the National Institute of Aging (grant Put AG02323394), and the National Cancer Institute (grants P50 CA1065631, P50 CA015632, P50 CA 106743, and P50 CA105641).; This article was originated by the leadership of the CPHHD program.; The authors acknowledge the editorial assistance of Lisa Kelly-Wilson at the Survey Research Laboratory, University of Illinois at Chicago. NR 67 TC 132 Z9 134 U1 0 U2 13 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 SEP PY 2008 VL 98 IS 9 BP 1608 EP 1615 DI 10.2105/AJPH.2006.102525 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 338AF UT WOS:000258476400023 PM 18633099 ER PT J AU Mittal, P Romero, R Kusanovic, JP Edwin, SS Gotsch, F Mazaki-Tovi, S Espinoza, J Erez, O Nhan-Chang, CL Than, NG Vaisbuch, E Hassan, SS AF Mittal, Pooja Romero, Roberto Kusanovic, Juan Pedro Edwin, Samuel S. Gotsch, Francesca Mazaki-Tovi, Shali Espinoza, Jimmy Erez, Offer Nhan-Chang, Chia-Ling Than, Nandor G. Vaisbuch, Edi Hassan, Sonia S. TI CXCL6 (granulocyte chemotactic protein-2): A novel chemokine involved in the innate immune response of the amniotic cavity SO AMERICAN JOURNAL OF REPRODUCTIVE IMMUNOLOGY LA English DT Review DE amniotic fluid; chemokine; CXCL6; intra-amniotic inflammation/infection; pregnancy; pre-term labor ID CERVICAL-MUCUS PLUG; MACROPHAGE INFLAMMATORY PROTEIN-1-ALPHA; ACTIVATING PEPTIDE-1 INTERLEUKIN-8; LARGE GRANULAR LYMPHOCYTES; TUMOR-NECROSIS-FACTOR; PRETERM LABOR; INTRAAMNIOTIC INFECTION; FLUID INTERLEUKIN-6; MICROBIAL INVASION; ANTIBACTERIAL PROPERTIES AB Problem CXCL6 is a potent pro-inflammatory neutrophil chemoattractant and activator whose activity during pregnancy is not well-established. The purpose of this study was to determine if CXCL6 is present in amniotic fluid (AF) and if CXCL6 concentrations in AF change with labor (pre-term and term) or intra-amniotic infection/inflammation (IAI). Method of study A cross-sectional study was designed including the following groups: (1) mid-trimester (n = 65); (2) term no labor (n = 20); (3) term labor (n = 44); (4) patients with pre-term labor (PTL) with subsequent term delivery (n = 57); (5) PTL without IAI who delivered pre-term (n = 47); and (6) PTL with IAI (n = 62). AF CXCL6 concentrations were determined by ELISA. Results CXCL6 was present in all term samples, but undetectable in 64/65 mid-trimester specimens. Patients with PTL and IAI had a significantly higher median AF CXCL6 concentration than those with PTL without IAI [228.9 pg/mL (0.0-8344.8) versus 55.7 pg/mL (0-454.4); P < 0.05] and those with PTL and term delivery [41.5 pg/mL (0-279.0); P < 0.05]. The median AF CXCL6 concentration did not change with spontaneous term labor [term no labor: 81.1 pg/mL (8.5-201.7) versus term labor: 75.2 pg/mL (6.7-378.7): P = 0.7]. Conclusion (1) CXCL6 is detectable in AF and its concentration increases with gestational age; (2) IAI results in increased AF CXCL6 concentrations, suggesting that CXCL6 plays a role in the deployment of an inflammatory response; (3) In contrast to related chemokines, specifically IL-8, AF CXCL6 does not appear to be involved in spontaneous term parturition. These observations are novel, and suggest a role for CXCL6 in the innate immune response to microbial invasion of the amniotic cavity. C1 [Mittal, Pooja] Wayne State Univ, Hutzel Womens Hosp, NICHD NIH DHHS, Perinatol Res Branch, Detroit, MI 48201 USA. [Mittal, Pooja; Kusanovic, Juan Pedro; Mazaki-Tovi, Shali; Espinoza, Jimmy; Erez, Offer; Nhan-Chang, Chia-Ling; Hassan, Sonia S.] Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. [Mittal, Pooja; Romero, Roberto; Kusanovic, Juan Pedro; Edwin, Samuel S.; Gotsch, Francesca; Mazaki-Tovi, Shali; Espinoza, Jimmy; Erez, Offer; Nhan-Chang, Chia-Ling; Than, Nandor G.; Vaisbuch, Edi; Hassan, Sonia S.] NICHD NIH DHHS, Perinatol Res Branch, Bethesda, MD USA. [Romero, Roberto] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. RP Mittal, P (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD NIH DHHS, Perinatol Res Branch, 3990 John R,Box 4, Detroit, MI 48201 USA. EM prbchiefstaff@med.wayne.edu OI Vaisbuch, Edi/0000-0002-8400-9031 FU Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIH; DHHS FX This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS. NR 102 TC 28 Z9 28 U1 0 U2 0 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 SEP PY 2008 VL 60 IS 3 BP 246 EP 257 DI 10.1111/j.1600-0897.2008.00620.x PG 12 WC Immunology; Reproductive Biology SC Immunology; Reproductive Biology GA 337MO UT WOS:000258440400009 PM 18782286 ER PT J AU Punturieri, A Croxton, TL Weinmann, GG Kiley, JP AF Punturieri, Antonello Croxton, Thomas L. Weinmann, Gail G. Kiley, James P. TI Chronic obstructive pulmonary disease - A view from the NHLBI SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Editorial Material ID LUNG-CANCER; MANAGEMENT; EMPHYSEMA; COPD; REHABILITATION; EXACERBATIONS; INFLAMMATION; MORTALITY; PROGRESS; THERAPY C1 [Punturieri, Antonello; Croxton, Thomas L.; Weinmann, Gail G.; Kiley, James P.] NHLBI, Div Lung Dis, NIH, Bethesda, MD 20892 USA. RP Kiley, JP (reprint author), NHLBI, Div Lung Dis, NIH, 6701 Rockledge Dr, Bethesda, MD 20892 USA. EM kileyj@nhlbi.nih.gov NR 33 TC 22 Z9 22 U1 1 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 1 PY 2008 VL 178 IS 5 BP 441 EP 443 DI 10.1164/rccm.200807-1128OE PG 3 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 343GM UT WOS:000258841200004 PM 18713849 ER PT J AU Martinez, FJ Han, MK Andrei, AC Wise, R Murray, S Curtis, JL Sternberg, A Criner, G Gay, SE Reilly, J Make, B Ries, AL Sciurba, F Weinmann, G Mosenifar, Z DeCamp, M Fishman, AP Celli, BR AF Martinez, Fernando J. Han, MeiLan K. Andrei, Adin-Cristian Wise, Robert Murray, Susan Curtis, Jeffrey L. Sternberg, Alice Criner, Gerard Gay, Steven E. Reilly, John Make, Barry Ries, Andrew L. Sciurba, Frank Weinmann, Gail Mosenifar, Zab DeCamp, Malcolm Fishman, Alfred P. Celli, Bartolome R. CA National Emphysema Treatment Trial TI Longitudinal change in the BODE index predicts mortality in severe emphysema SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE chronic obstructive pulmonary disease; survival; multidimensional index ID VOLUME-REDUCTION SURGERY; AIR-FLOW OBSTRUCTION; EXERCISE CAPACITY INDEX; PULMONARY-DISEASE; MASS INDEX; RANDOMIZED-TRIAL; WALK DISTANCE; DYSPNEA; SURVIVAL; IMPROVEMENT AB Rationale:. The predictive value of longitudinal change in BODE (Body mass index, airflow Obstruction, Dyspnea, and Exercise capacity) index has received limited attention. We hypothesized that decrease in a modified BODE (mBODE) would predict survival in National Emphysema Treatment Trial (NETT) patients. Objectives: To determine how the mBODE score changes in patients with lung volume reduction surgery versus medical therapy and correlations with survival. Methods: Clinical data were recorded using standardized instruments. The mBODE was calculated and patient-specific mBODE trajectories during 6, 12, and 24 months of follow-up were estimated using separate regressions for each patient. Patients were classified as having decreasing, stable, increasing, or missing mBODE based on their absolute change from baseline. The predictive ability of mBODE change on survival was assessed using multivariate Cox regression models. The index of concordance was used to directly compare the predictive ability of mBODE and its separate components. Measurements and Main Results: The entire cohort (610 treated medically and 608 treated surgically) was characterized by severe airflow obstruction, moderate breathlessness, and increased mBODE at baseline. A wide distribution of change in mBODE was seen at follow-up. An increase in mBODE of more than 1 point was associated with increased mortality in surgically and medically treated patients. Surgically treated patients were less likely to experience death or an increase greater than 1 in mBODE. Indices of concordance showed that mBODE change predicted survival better than its separate components. Conclusions: The mBODE demonstrates short- and intermediate-term responsiveness to intervention in severe chronic obstructive pulmonary disease. Increase in mBODE of more than 1 point from baseline to 6, 12, and 24 months of follow-up was predictive of subsequent mortality. Change in mBODE may prove a good surrogate measure of survival in therapeutic trials in severe chronic obstructive pulmonary disease. C1 [Martinez, Fernando J.; Han, MeiLan K.; Curtis, Jeffrey L.; Gay, Steven E.] Univ Michigan, Med Ctr, Div Pulm & Crit Care Med, Ann Arbor, MI USA. [Andrei, Adin-Cristian] Univ Wisconsin, Dept Biostat & Med Informat, Sch Med & Publ Hlth, Madison, WI USA. [Wise, Robert; Sternberg, Alice] Johns Hopkins Univ, Div Pulm & Crit Care Med, Baltimore, MD USA. [Murray, Susan] Univ Michigan, Sch Publ Hlth, Dept Biostat, Ann Arbor, MI 48109 USA. [Curtis, Jeffrey L.] Ann Arbor Vet Affairs Med Ctr, Pulm Sect, Ann Arbor, MI USA. [Criner, Gerard] Temple Univ, Philadelphia, PA 19122 USA. [Reilly, John] Brigham & Womens Hosp, Div Pulm Med, Boston, MA 02115 USA. [Make, Barry] Natl Jewish Med & Res Ctr, Div Pulm & Crit Care Med, Denver, CO USA. [Ries, Andrew L.] Univ Calif San Diego, Dept Med, San Diego, CA 92103 USA. [Sciurba, Frank] Univ Pittsburgh, Div Pulm & Crit Care Med, Pittsburgh, PA USA. [Weinmann, Gail] NHLBI, Div Lung Dis, Bethesda, MD 20892 USA. [Mosenifar, Zab] Cedars Sinai Med Ctr, Div Pulm Med, Los Angeles, CA 90048 USA. [DeCamp, Malcolm] Beth Israel Deaconess Med Ctr, Thorac Surg Sect, Boston, MA 02215 USA. [Fishman, Alfred P.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Celli, Bartolome R.] St Elizabeths Med Ctr, Pulm Crit Care & Sleep Med Div, Boston, MA USA. RP Martinez, FJ (reprint author), Univ Michigan Hlth Syst, 1500 E Med Ctr Dr,3916 Taubman Ctr, Ann Arbor, MI 48109 USA. EM fmartine@umich.edu OI Murray, Susan/0000-0003-4387-7673; Wise, Robert/0000-0002-8353-2349; Curtis, Jeffrey/0000-0001-5191-4847 FU National Heart, Lung, and Blood Institute [N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110,, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, N01HR76119]; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; Research Enhancement Award Program (REAP) from the Biomedical Laboratory Research and Development Service, Department of Veterans Affairs FX The National Emphysema Treatment Trial (NEM was supported by contracts with the National Heart, Lung, and Blood Institute (N01HR76101, N01HR76102, N01HR76103, N01HR76104, N01HR76105, N01HR76106, N01HR76107, N01HR76108, N01HR76109, N01HR76110, N01HR76111, N01HR76112, N01HR76113, N01HR76114, N01HR76115, N01HR76116, N01HR76118, and N01HR76119), the Centers for Medicare and Medicaid Services (formerly the Health Care Financing Administration), and the Agency for Healthcare Research and Quality. J.L.C. is supported by funding from a Research Enhancement Award Program (REAP) from the Biomedical Laboratory Research and Development Service, Department of Veterans Affairs. NR 13 TC 57 Z9 59 U1 0 U2 5 PU AMER THORACIC SOC PI NEW YORK PA 61 BROADWAY, FL 4, NEW YORK, NY 10006 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD SEP 1 PY 2008 VL 178 IS 5 BP 491 EP 499 DI 10.1164/rccm.200709-1383OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 343GM UT WOS:000258841200011 PM 18535255 ER PT J AU Carney, JA Stratakis, CA AF Carney, J. Aidan Stratakis, Constantine A. TI Stromal, fibrous, and fatty gastrointestinal tumors in a patient with a PDGFRA gene mutation SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE GIST; gastrointestinal fibromas; gastrointestinal fibroid tumors; intestinal lipomas; PDGFRA Mutation; GIST syndrome ID OF-FUNCTION MUTATIONS; RECEPTOR-ALPHA GENE; GERMLINE MUTATION; CARNEY TRIAD; KIT; NEUROFIBROMATOSIS; PARAGANGLIOMA; LIPOMATOSIS; DIAGNOSIS; IMATINIB AB We report the case of a woman with 3 different types of gastrointestinal tumors-stromal, fibrous, and fatty-and a germline defect of the platelet-derived growth factor receptor U. (PDGFRA) gene (V561D). The patient, now 52 years old, presented in 1977 at age 22 years with a gastric tumor and a duodenal lipoma. Subsequently, she developed obstructing small intestinal fibrous tumors that required 3 laparotomies and intestinal resections. Most recently (in 2002), more than 100 fibrous tumors were resected and also Multiple Small intestinal lipomas and Multiple gastric KIT, PDGFR alpha, and CD34-positive stromal tumors. The nosology of the fibrous tumors was not clear. The lesions, were hypocellular and featured poorly Outlined spindle, stellate, and polygonal CD34 positive, and KIT- and PDGFR alpha-negative cells. They extended through the muscularis propria, expanded the Subserosa, and occasionally extended into the mesentery but did not metasize. The patient is currently asymptomatic; radiologic Study in June 2007 revealed postoperative changes only. None of the patient's primary relatives have had similar tumours. C1 [Carney, J. Aidan] Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. [Stratakis, Constantine A.] NICHD, Sect Endocrinol & Genet, DEB, NIH, Bethesda, MD USA. RP Carney, JA (reprint author), Mayo Clin, Dept Lab Med & Pathol, 200 SW 1st St, Rochester, MN 55905 USA. EM carney.aidan@mayo.edu FU Intramural NIH HHS [Z01 HD000642-10] NR 27 TC 11 Z9 11 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 SEP PY 2008 VL 32 IS 9 BP 1412 EP 1420 DI 10.1097/PAS.0b013e31816250ce PG 9 WC Pathology; Surgery SC Pathology; Surgery GA 347WL UT WOS:000259172000018 PM 18670346 ER PT J AU Kadin, ME Pinkus, JL Pinkus, GS Duran, IH Fuller, CE Onciu, M Kawaguchi, H Morris, SW AF Kadin, Marshall E. Pinkus, Jack L. Pinkus, Geraldine S. Duran, Ivan H. Fuller, Christine E. Onciu, Mihaela Kawaguchi, Hiroyuki Morris, Stephan W. TI Primary cutaneous ALCL with phosphorylated/activated cytoplasmic ALK and novel phenotype: EMA/MUCI cutaneous lymphocyte antigen negative SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE anapiastic large cell lymphoma; ALK; cutaneous ID LARGE-CELL LYMPHOMA; CD30(+) LYMPHOPROLIFERATIVE DISORDERS; VARIANT ANAPLASTIC LYMPHOMA; IN-SITU HYBRIDIZATION; T-CELL; TRANSLOCATION; PAPULOSIS; PARTNER; PROTEIN AB Primary Cutaneous anaplastic large-cell lymphoma (ALCL) ordinarily is distinguished from systemic ALCL by clinical presentation, absence of anaplastic lymphoma kinase (ALK) expression. and immunophenotype (CLA+, EMA/ MUCI -). We present an exceptional case of all elderly man with primary cutaneous ALCL and no systemic disease for a 13-year period. Recurrent skin tumors in this patient were characterized by anaplastic, often multinucleated, cells infiltrating the lymphatics and associated with psudoepitheliomatous hyperplasia. Cutaneous lymphocyte antigen was absent and EMA/MUCI, typical of systemic ALCL was strongly expressed by the tumor cells. Remarkably, the tumor cells expressed a cytoplasmic-only variant of ALK protein, as reported in 3 previous cases of primary cutaneous ALCL. Fluorescence in situ hybridization revealed lack of rearrangements of the chromosome 2 ALK gene locus usually involved by translocation 1(2:5) or other chromosomal rearrangements that generate nucleophosinin-ALK or the variant ALK fusions that occur ill systemic ALCL. Nonetheless, the cytoplasmic ALK protein in the patient's tumour cells was shown to be phosphorylated/activated. suggesting a novel mechanism of ALK activation. Primary cutaneous ALCL of this novel Subtype Should be distinguished from systemic ALCL to ensure proper clinical management. C1 [Kadin, Marshall E.] Roger Williams Med Ctr, Dept Dermatol, Providence, RI 02908 USA. [Kadin, Marshall E.] Roger Williams Med Ctr, Ctr Biomed Res Excellence, Providence, RI USA. [Kadin, Marshall E.; Pinkus, Geraldine S.] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. [Kadin, Marshall E.] Brigham & Womens Hosp, Dept Dermatol, Boston, MA 02115 USA. [Pinkus, Jack L.; Pinkus, Geraldine S.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Duran, Ivan H.] St Annes Hosp, Dept Pathol, Fall River, MA USA. [Fuller, Christine E.] SUNY Syracuse, Upstate Med Univ, Dept Pathol, Syracuse, NY USA. [Onciu, Mihaela; Kawaguchi, Hiroyuki; Morris, Stephan W.] St Jude Childrens Hosp, Dept Pathol, Memphis, TN 38105 USA. [Morris, Stephan W.] St Jude Childrens Hosp, Dept Oncol, Memphis, TN 38105 USA. [Kawaguchi, Hiroyuki] Ichikawa Gen Hosp, Tokyo Dent Coll, Dept Pediat, Chiba, Japan. RP Kadin, ME (reprint author), Roger Williams Med Ctr, Dept Dermatol, 50 Maude St,Elmhurst Bldg, Providence, RI 02908 USA. EM mkadin@rwmc.org FU NIH [P20RRO18757, CA-69129]; Cancer Center Support (CORE) [CA-21765]; National Cancer Institute; American Lebanese Syrian Associated Charities (ALSAC); St Jude Children's Research Hospital FX Supported in part by NIH grant P20RRO18757 (M.E.K.), grants CA-69129 (S.WAM.). and Cancer Center Support (CORE) CA-21765 both from the National Cancer Institute, and by the American Lebanese Syrian Associated Charities (ALSAC). St Jude Children's Research Hospital. NR 23 TC 18 Z9 20 U1 0 U2 1 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 SEP PY 2008 VL 32 IS 9 BP 1421 EP 1426 DI 10.1097/PAS.0b013e3181648d6d PG 6 WC Pathology; Surgery SC Pathology; Surgery GA 347WL UT WOS:000259172000019 PM 18670345 ER PT J AU Brunet, BR Barnes, AJ Scheidweiler, KB Mura, P Huestis, MA AF Brunet, Bertrand R. Barnes, Allan J. Scheidweiler, Karl B. Mura, Patrick Huestis, Marilyn A. TI Development and validation of a solid-phase extraction gas chromatography-mass spectrometry method for the simultaneous quantification of methadone, heroin, cocaine and metabolites in sweat SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE sweat; GC; MS; methadone; cocaine; opiates; heroin ID ORAL FLUID; EXCRETION; ADDICTS; SALIVA; DELTA(9)-TETRAHYDROCANNABINOL; METHAMPHETAMINE; ACETYLCODEINE; AMPHETAMINE; DISPOSITION; DRIVERS AB A sensitive and specific method is presented to simultaneously quantify methadone, heroin, cocaine and metabolites in sweat. Drugs were eluted from sweat patches with sodium acetate buffer, followed by SPE and quantification by GC/MS with electron impact ionization and selected ion monitoring. Daily calibration for anhydroecgonine methyl ester, ecgonine methyl ester, cocaine, benzoylecgonine (BE), codeine, morphine, 6-acetylcodeine, 6-acetylmorphine (6AM), heroin (5-1000 ng/patch) and methadone (10-1000 ng/patch) achieved determination coefficients of > 0.995, and calibrators quantified to within +/- 20% of the target concentrations. Extended calibration curves (1000-10,000 ng/patch) were constructed for methadone, cocaine, BE and 6AM by modifying injection techniques. Within (N=5) and between-run (N=20) imprecisions were calculated at six control levels across the dynamic ranges with coefficients of variation of < 6.5%. Accuracies at these concentrations were +/- 11.9% of target. Heroin hydrolysis during specimen processing was < 11%. This novel assay offers effective monitoring of drug exposure during drug treatment, workplace and criminal justice monitoring programs. C1 [Barnes, Allan J.; Scheidweiler, Karl B.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. [Brunet, Bertrand R.] Univ Poitiers, CHU Poitiers, Fac Med & Pharm, INSERM E 0324, F-86021 Poitiers, France. [Mura, Patrick] Ctr Hosp Reg & Univ Poitiers, Lab Toxicol & Pharmacocinet, F-86021 Poitiers, France. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, 251 Bayview Blvd, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000412-10] NR 32 TC 28 Z9 30 U1 2 U2 14 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD SEP PY 2008 VL 392 IS 1-2 BP 115 EP 127 DI 10.1007/s00216-008-2228-0 PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 339BY UT WOS:000258554300016 PM 18607576 ER PT J AU Vitorino, R Guedes, S Tomer, K Domingues, P Duarte, J Amado, F AF Vitorino, Rui Guedes, Sofia Tomer, Kenneth Domingues, Pedro Duarte, Jose Amado, Francisco TI On-plate digestion using a commercial microfraction collector for nano-HPLC matrix-assisted laser desorption/ionization tandem time-of-flight protein analysis SO ANALYTICAL BIOCHEMISTRY LA English DT Editorial Material ID ACQUIRED ENAMEL PELLICLE; IN-VIVO; IDENTIFICATION; MS AB A new method for on-plate protein digestion and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry analysis is proposed involving an automated one-step sample separation using nano-flow HPLC followed by nanoliter fraction collection and on-plate digestion with trypsin. This procedure uses a commercial automatic nanoliter fraction collection system for on-line spotting of the eluent onto a MALDI target. After protein digestion, the reaction is stopped by the addition of acidified matrix using the same automated system. Collected spots are subsequently analyzed using a MALDI tandem time-of-flight (TOF/TOF) mass spectrometer for protein sequencing and identification. (c) 2008 Elsevier Inc. All rights reserved. C1 [Vitorino, Rui; Guedes, Sofia; Domingues, Pedro; Amado, Francisco] Univ Aveiro, Dept Chem, P-3810193 Aveiro, Portugal. [Tomer, Kenneth] Natl Inst Environm Hlth Sci, Natl Inst Hlth, Struct Biol Lab, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Duarte, Jose] Univ Porto, Fac Sport, CIAFEL, P-4200450 Oporto, Portugal. RP Vitorino, R (reprint author), Univ Aveiro, Dept Chem, P-3810193 Aveiro, Portugal. EM rvitorino@ua.pt RI Domingues, Pedro/E-5202-2010; Duarte, Jose/F-1443-2013; PTMS, RNEM/C-1589-2014; Vitorino, Rui/G-7356-2014; Amado, Francisco/M-5337-2015 OI Domingues, Pedro/0000-0002-8060-7675; Duarte, Jose/0000-0003-4756-5917; Vitorino, Rui/0000-0003-3636-5805; Guedes, Sofia de Morais/0000-0001-9556-3639; Amado, Francisco/0000-0001-8256-1749 FU Intramural NIH HHS [Z01 ES050171-08] NR 8 TC 9 Z9 9 U1 0 U2 11 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD SEP 1 PY 2008 VL 380 IS 1 BP 128 EP 130 DI 10.1016/j.ab.2008.05.006 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 329VI UT WOS:000257898300018 PM 18519023 ER PT J AU Smith, V AF Smith, Vonda TI Grant opportunities at NIH: Analytical chemistry applications are not square pegs in round holes! SO ANALYTICAL CHEMISTRY LA English DT Article AB A short guide through the complicated landscape of NIH grants. C1 [Smith, Vonda] NIH, EBT Study Sect, Bethesda, MD 20892 USA. RP Smith, V (reprint author), 6701 Rockledge Dr,MSC 7806,Rm 4148, Bethesda, MD 20892 USA. EM smithvo@csr.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD SEP 1 PY 2008 VL 80 IS 17 BP 6467 EP 6471 DI 10.1021/ac801490y PG 5 WC Chemistry, Analytical SC Chemistry GA 343PF UT WOS:000258865300005 PM 18754651 ER PT J AU Ishwaran, H Kogalur, UB Blackstone, EH Lauer, MS AF Ishwaran, Hemant Kogalur, Udaya B. Blackstone, Eugene H. Lauer, Michael S. TI RANDOM SURVIVAL FORESTS SO ANNALS OF APPLIED STATISTICS LA English DT Article DE Conservation of events; cumulative hazard function; ensemble; out-of-bag; prediction error; survival tree ID CENSORED-DATA; OBESITY; REGRESSION; OVERWEIGHT; TREES; UNDERWEIGHT; MORTALITY AB We introduce random survival forests, a random forests method for the analysis of right-censored survival data. New survival splitting rules for growing survival trees are introduced, as is a new missing data algorithm for imputing missing data. A conservation-of-events principle for survival forests is introduced and used to define ensemble mortality, a simple interpretable measure of mortality that can be used as a predicted outcome. Several illustrative examples are given, including a case study of the prognostic implications of body mass for individuals with coronary artery disease. Computations for all examples were implemented using the freely available R-software package. randomSurvivalForest. C1 [Ishwaran, Hemant] Cleveland Clin, Dept Quantitat Hlth Sci, Cleveland, OH 44195 USA. [Kogalur, Udaya B.] Columbia Univ, Dept Stat, New York, NY 10027 USA. [Blackstone, Eugene H.] Cleveland Clin, Dept Thorac & Cardiovasc Surg, Cleveland, OH 44195 USA. [Lauer, Michael S.] NHLBI, Div Prevent & Populat Sci, Rockledge Ctr 2, Bethesda, MD 20892 USA. RP Ishwaran, H (reprint author), Cleveland Clin, Dept Quantitat Hlth Sci, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM hemant.ishwaran@gmail.com; ubk2101@columbia.edu; blackse@ccf.org; lauerm@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 FU National Institutes of Health [HL-072771] FX Supported in part by National Institutes of Health RO1 Grant HL-072771. NR 37 TC 201 Z9 204 U1 4 U2 27 PU INST MATHEMATICAL STATISTICS PI CLEVELAND PA 3163 SOMERSET DR, CLEVELAND, OH 44122 USA SN 1932-6157 J9 ANN APPL STAT JI Ann. Appl. Stat. PD SEP PY 2008 VL 2 IS 3 BP 841 EP 860 DI 10.1214/08-AOAS169 PG 20 WC Statistics & Probability SC Mathematics GA 374QD UT WOS:000261057900003 ER PT J AU Hu, Y Li, L Seidelmann, SB Timur, AA Shen, PH Driscoll, DJ Wang, QK AF Hu, Y. Li, L. Seidelmann, S. B. Timur, A. A. Shen, P. H. Driscoll, D. J. Wang, Q. K. TI Identification of association of common AGGF1 variants with susceptibility for Klippel-Trenaunay syndrome using the structure association program SO ANNALS OF HUMAN GENETICS LA English DT Article DE AGGF1 (VG5Q); single nucleotide polymorphism (SNP); Klippel-Trenaunay Syndrome (KTS); case-control association study; linkage disequilibrium (LD) block; ancestry-informative markers (AIMs); structured association ID MULTILOCUS GENOTYPE DATA; CORONARY-ARTERY-DISEASE; MOLECULAR CHARACTERIZATION; MYOCARDIAL-INFARCTION; TISSUE OVERGROWTH; CHROMOSOME 9P21; LETHAL GENES; 4 SNPS; POPULATION; POLYMORPHISMS AB Klippel-Trenaunay syndrome (KTS) is a severe congenital disorder characterized by capillary malformations, venous malformations or varicose veins, and hypertrophy of the affected tissues. The angiogenic factor gene AGGF1 was previously identified as a candidate susceptibility gene for KTS, but further genetic studies are needed to firmly establish the genetic relationship between AGGF1 and KTS. We analyzed HapMap data and identified two tagSNPs, rs13155212 and rs7704267 that capture information for all common variants in AGGF1. The two SNPs were genotyped in 173 Caucasian KTS patients and 477 Caucasian non-KTS controls, and both significantly associated with susceptibility for KTS (P = 0.004 and 0.013, respectively). Permutation testing also showed a significant empirical P value for the association (empirical P = 0.006 and 0.015, respectively). To control for potential confounding due to population stratification, the population structure for both cases and controls was characterized by genotyping of 38 ancestry-informative markers (AIMs) and the STRUCTURE program. The association between the AGGF1 SNPs and KTS remained significant after multivariate analysis by incorporating the inferred cluster scores as a covariate or after removal of outlier individuals identified by STRUCTURE. These results suggest that common AGGF1 variants confer risk of KTS. C1 [Hu, Y.; Li, L.; Seidelmann, S. B.; Timur, A. A.; Wang, Q. K.] Case Western Reserve Univ, Center Cardiovasc Genet,Dept Mol Med, Dept Mol Cardiol,Lerner Coll Med,Tausig Canc Ctr, Lerner Res Inst,Dept Cardiovasc Med,Clivland Clin, Cleveland, OH 44195 USA. [Shen, P. H.] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Driscoll, D. J.] Mayo Clin, Dept Pediat, Rochester, MN USA. [Wang, Q. K.] Huazhong Univ Sci & Technol, Key Lab Mol Biophys, Minist Educ, Coll Life Sci & Technol, Wuhan, Peoples R China. [Wang, Q. K.] Huazhong Univ Sci & Technol, Ctr Human Genome Res, Wuhan, Peoples R China. RP Wang, QK (reprint author), Cleveland Clin, Ctr Cardiovasc Genet NE4-202, Cleveland, OH 44195 USA. EM wangq2@ccf.org FU NHLBI NIH HHS [P50 HL077107-029002, P50 HL077107, P50 HL077107-019002, P50 HL077107-039002, P50 HL077107-049002, P50 HL081011, P50 HL77107, P50 HL81011, R01 HL066251, R01 HL066251-01A2, R01 HL066251-02, R01 HL066251-03, R01 HL066251-04, R01 HL66251] NR 26 TC 26 Z9 29 U1 0 U2 4 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0003-4800 J9 ANN HUM GENET JI Ann. Hum. Genet. PD SEP PY 2008 VL 72 BP 636 EP 643 DI 10.1111/j.1469-1809.2008.00458.x PN 5 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 336PB UT WOS:000258376000007 PM 18564129 ER PT J AU Peuralinna, T Oinas, M Polvikoski, T Paetau, A Sulkava, R Niinisto, L Kalimo, H Hernandez, D Hardy, J Singleton, A Tienari, PJ Myllykangas, L AF Peuralinna, Terhi Oinas, Minna Polvikoski, Tuomo Paetau, Anders Sulkava, Raimo Niinisto, Leena Kalimo, Hannu Hernandez, Dena Hardy, John Singleton, Andrew Tienari, Pentti J. Myllykangas, Liisa TI Neurofibrillary tau pathology modulated by genetic variation of alpha-synuclein SO ANNALS OF NEUROLOGY LA English DT Article ID SPORADIC PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; DEMENTIA; ASSOCIATION; SUSCEPTIBILITY; POPULATION; CONSORTIUM; MUTATION AB We analyzed whether genetic variation of alpha-synuclein modulates the extent of neuropathological changes in a population-based autopsied sample of 272 elderly Finns. None of the 11 markers was associated with the extent of neocortical P-amyloid pathology. The intron 4 marker rs2572324 was associated with the extent of neurofibrillary pathology (p = 0.0006, permuted p = 0.004; Braak stages IV-VI vs 0-II). The same variant also showed a trend for association with neocortical Lewy-related pathology. These results suggest for the first time that variation of alpha-synuclein modulates neurofibrillary tau pathology and support the recent observations of an interaction of alpha-synuclein and tau in neurodegeneration. C1 [Tienari, Pentti J.] Helsinki Univ Cent Hosp, Dept Neurol, Helsinki 00290, Finland. [Tienari, Pentti J.] Univ Helsinki, Dept Neurol, FIN-00014 Helsinki, Finland. [Peuralinna, Terhi; Tienari, Pentti J.] Univ Helsinki, Mol Neurol Programme, Biomedicum, FIN-00014 Helsinki, Finland. [Oinas, Minna; Polvikoski, Tuomo; Paetau, Anders; Kalimo, Hannu; Myllykangas, Liisa] Univ Helsinki, Helsinki Univ Cent Hosp, HUSLAB, Helsinki, Finland. [Oinas, Minna; Polvikoski, Tuomo; Paetau, Anders; Kalimo, Hannu; Myllykangas, Liisa] Univ Helsinki, Dept Pathol, Helsinki, Finland. [Polvikoski, Tuomo] Univ Newcastle, Inst Hlth & Aging, Newcastle Upon Tyne, Tyne & Wear, England. [Sulkava, Raimo] Univ Kuopio, Dept Publ Hlth & Gen Practice, Div Geriatr, FIN-70211 Kuopio, Finland. [Sulkava, Raimo] Kuopio Univ Cent Hosp, Kuopio, Finland. [Niinisto, Leena] Katriina Geriatr Hosp, Helsinki, Finland. [Hernandez, Dena; Hardy, John; Singleton, Andrew] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Hardy, John] UCL, London, England. [Myllykangas, Liisa] Folkhalsan Inst Genet, FIN-00014 Helsinki, Finland. RP Tienari, PJ (reprint author), Helsinki Univ Cent Hosp, Dept Neurol, POB 340, Helsinki 00290, Finland. EM pentti.tienari@hus.fi RI Hardy, John/C-2451-2009; Singleton, Andrew/C-3010-2009; Tienari, Pentti/A-4893-2012 FU Medical Research Council [G0701075]; Parkinson's UK [G-0907] NR 21 TC 12 Z9 14 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD SEP PY 2008 VL 64 IS 3 BP 348 EP 352 DI 10.1002/ana.21446 PG 5 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 355AT UT WOS:000259681700018 PM 18661559 ER PT J AU Besse, B Smit, E Felip, E Siena, S Blackhall, F Barlesi, F Giaccone, G AF Besse, B. Smit, E. Felip, E. Siena, S. Blackhall, F. Barlesi, F. Giaccone, G. TI FIRST-LINE ERLOTINIB IN STAGE IIIB/IV NON-SMALL-CELL LUNG CANCER (NSCLC) WITH DOSE ESCALATION TO TOXICITY IN CURRENT AND FORMER SMOKERS (C/FS): A PHASE II STUDY SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 33rd European-Society-for-Medical-Oncology Congress CY SEP 12-16, 2008 CL Stockholm, SWEDEN SP European Soc Med Oncol C1 [Besse, B.] Inst Gustave Roussy, Villejuif, France. [Smit, E.] Vrije Univ Amsterdam, Med Ctr, Dept Pulm Dis, Amsterdam, Netherlands. [Felip, E.] Vall Hebron Univ Hosp, Barcelona, Spain. [Siena, S.] Osped Niguarda Ca Granda, Milan, Italy. [Blackhall, F.] Christie Hosp NHS Trust, Dept Med Oncol, Manchester M20 4BX, Lancs, England. [Barlesi, F.] Univ Mediterranee Assistance, Marseille, France. [Giaccone, G.] NCI, Med Oncol Branch, CCR, NIH, Bethesda, MD USA. RI Blackhall, Fiona/N-2186-2015 OI Blackhall, Fiona/0000-0001-8716-3395 NR 0 TC 2 Z9 2 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2008 VL 19 BP 101 EP 101 PG 1 WC Oncology SC Oncology GA 359GB UT WOS:000259973300267 ER PT J AU Rixe, O Dutcher, JP Motzer, RJ Wilding, G Stadler, WM Kim, S Tarazi, J Rosbrook, B Rini, B AF Rixe, O. Dutcher, J. P. Motzer, R. J. Wilding, G. Stadler, W. M. Kim, S. Tarazi, J. Rosbrook, B. Rini, B. TI ASSOCIATION BETWEEN DIASTOLIC BLOOD PRESSURE (DBP) >= 90 MMHG AND EFFICACY IN PATIENTS (PTS) WITH METASTATIC RENAL CELL CARCINOMA (MRCC) RECEIVING AXITINIB (AG-013736; AG) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 33rd European-Society-for-Medical-Oncology Congress CY SEP 12-16, 2008 CL Stockholm, SWEDEN SP European Soc Med Oncol C1 [Rixe, O.] Natl Canc Inst, Ctr Canc Res, Med Oncol Branch, Bethesda, MD USA. [Dutcher, J. P.] Our Lady Mercy Med Ctr, Bronx, NY 10466 USA. [Motzer, R. J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Wilding, G.] Univ Wisconsin, Carbone Comprehens Canc Ctr, Madison, WI 53706 USA. [Stadler, W. M.] Univ Chicago, Med Ctr, Chicago, IL 60637 USA. [Kim, S.; Tarazi, J.; Rosbrook, B.] Pfizer Global Res & Dev, San Diego, CA USA. [Rini, B.] Cleveland Clin, Taussig Canc Inst, Dept Solid Tumor Oncol, Cleveland, OH 44106 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2008 VL 19 BP 189 EP 189 PG 1 WC Oncology SC Oncology GA 359GB UT WOS:000259973300586 ER PT J AU Dutcher, JP Rixe, O Motzer, RJ Wilding, G Stadler, WM Kim, S Tarazi, J Rosbrook, B Rini, B AF Dutcher, J. P. Rixe, O. Motzer, R. J. Wilding, G. Stadler, W. M. Kim, S. Tarazi, J. Rosbrook, B. Rini, B. TI LEVOTHYROXIN TREATMENT OF HYPOTHYROIDISM AND AXITINIB (AG-013736) EFFICACY IN PATIENTS (PTS) WITH METASTATIC RENAL CELL CARCINOMA (MRCC) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 33rd European-Society-for-Medical-Oncology Congress CY SEP 12-16, 2008 CL Stockholm, SWEDEN SP European Soc Med Oncol C1 [Dutcher, J. P.] Our Lady Mercy Med Ctr, Bronx, NY 10466 USA. [Rixe, O.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Motzer, R. J.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Wilding, G.] Univ Wisconsin, Carbone Comprehens Canc Ctr, Madison, WI 53706 USA. [Stadler, W. M.] Univ Chicago, Chicago, IL 60637 USA. [Kim, S.; Tarazi, J.; Rosbrook, B.] Pfizer Global Res & Dev, San Diego, CA USA. [Rini, B.] Cleveland Clin, Taussig Canc Inst, Dept Solid Tumor Oncol, Cleveland, OH 44106 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2008 VL 19 BP 194 EP 194 PG 1 WC Oncology SC Oncology GA 359GB UT WOS:000259973300599 ER PT J AU Brown, J Roberts, A Seymour, JF Wierda, W O'Connor, O Czuczman, M Xiong, H Enschede, S Krivoshik, A Wilson, W AF Brown, J. Roberts, A. Seymour, J. F. Wierda, W. O'Connor, O. Czuczman, M. Xiong, H. Enschede, S. Krivoshik, A. Wilson, W. TI ONGOING PHASE 1 STUDIES OF ABT-263; PHARMACOKINETICS, SAFETY AND ANTI-TUMOR ACTIVITY IN PATIENTS WITH RELAPSED CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)/SMALL LYMPHOCYTIC LYMPHOMA (SLL) SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 33rd European-Society-for-Medical-Oncology Congress CY SEP 12-16, 2008 CL Stockholm, SWEDEN SP European Soc Med Oncol C1 [Brown, J.] Harvard Univ, Dept Med, Boston, MA USA. [Brown, J.] Dana Farber Canc Inst, Lymphoma Program Dfci, Boston, MA 02115 USA. [Roberts, A.] Royal Melbourne Hosp, Dept Clin Haematol & Med Oncol, Parkville, Vic 3050, Australia. [Seymour, J. F.] Peter MacCallum Canc Inst, Dept Clin Haematol & Med Oncol, Melbourne, Australia. [Wierda, W.] MD Anderson Canc Ctr, Dept Leukemia, Houston, TX USA. [O'Connor, O.] Columbia Univ, Ctr Med, Irving Canc Res Ctr, New York, NY USA. [Czuczman, M.] Roswell Pk Canc Inst, Lymphoma Myeloma Serv, Buffalo, NY 14263 USA. [Xiong, H.; Enschede, S.; Krivoshik, A.] Abbott Labs, Abbott Pk, IL 60064 USA. [Wilson, W.] NCI, Lymphoma Therapeut Sect, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2008 VL 19 BP 229 EP 229 PG 1 WC Oncology SC Oncology GA 359GB UT WOS:000259973300727 ER PT J AU Zucali, PA Ruiz, MG Giovannetti, E Destro, A Varella-Garcia, M Floor, K Ceresoli, GL Rodriguez, JA Garassino, I Comoglio, P Roncalli, M Santoro, A Giaccone, G AF Zucali, P. A. Ruiz, M. G. Giovannetti, E. Destro, A. Varella-Garcia, M. Floor, K. Ceresoli, G. L. Rodriguez, J. A. Garassino, I. Comoglio, P. Roncalli, M. Santoro, A. Giaccone, G. TI Role of cMET expression in non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitors SO ANNALS OF ONCOLOGY LA English DT Article DE activated cMET; gefitinib resistance; multitarget therapy; NSCLC ID GROWTH-FACTOR RECEPTOR; GEFITINIB RESISTANCE; MET; ERLOTINIB; ACTIVATION; PATHWAYS; ADENOCARCINOMAS; PHOSPHORYLATION; OVEREXPRESSION; AMPLIFICATION AB Background: Approximately 10% of unselected non-small-cell lung cancer (NSCLC) patients responded to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. However, resistance mechanisms are not well understood. We evaluated several potential biological markers of intrinsic EGFR-TKIs-resistance in NSCLC. Materials and methods: pAKT, pERK, cSRC, E-cadherin, cMET[pY1003], cMET[pY1230/1234/1235], and cMET[pY1349] immunohistochemistry, cMET FISH analysis, and EGFR-, KRAS-, and cMET mutation analysis were carried out on tumor samples from 51 gefitinib-treated NSCLC patients. Biological parameters and survival end points were compared by univariate and multivariate analyses. cMET expression was also investigated in two additional series of patients. The in vitro antiproliferative activity of gefitinib alone or in combination with hepatocyte growth factor and the cMET antibody DN-30 was assessed in NSCLC cells. Results: EGFR19 deletion and pAKT expression were significantly associated with response (P < 0.0001) and longer time to progression (TTP) (P = 0.007), respectively. Strong cMET[pY1003] membrane immunoreactivity was expressed in 6% of 149 tumors analyzed and was significantly associated with progressive disease (P = 0.019) and shorter TTP (P = 0.041). In vitro, the DN-30 combination synergistically (CI < 1) enhanced gefitinib-induced growth inhibition in all cMET[pY1003]-expressing cell lines studied. Conclusions: Activated cMET[pY1003] appears to be a marker of primary gefitinib resistance in NSCLC patients. cMET may be a target in treatment of NSCLC. C1 [Zucali, P. A.; Ceresoli, G. L.; Garassino, I.; Santoro, A.] Ist Clin Humanitas, Dept Med Oncol & Hematol, Milan, Italy. [Ruiz, M. G.; Giovannetti, E.; Floor, K.; Rodriguez, J. A.; Giaccone, G.] Vrije Univ Amsterdam Med Ctr, Dept Med Oncol, Amsterdam, Netherlands. [Destro, A.; Roncalli, M.] Ist Clin Humanitas, Dept Human Pathol, Milan, Italy. [Destro, A.; Roncalli, M.] Univ Milan, Sch Med, Milan, Italy. [Varella-Garcia, M.] Univ Colorado, Ctr Canc, Dept Med Med Oncol, Aurora, CO USA. [Comoglio, P.] Univ Turin, Sch Med, Inst Canc Res & Treatment, Div Mol Oncol, Turin, Italy. RP Giaccone, G (reprint author), Natl Canc Inst, Clin Canc Res, Natl Inst Hlth, 10 Ctr Dr Bldg 10,Room 12 N226, Bethesda, MD 20892 USA. EM giacconeg@mail.nih.gov RI Giovannetti, Elisa/F-4261-2011; Giaccone, Giuseppe/E-8297-2017; OI Giaccone, Giuseppe/0000-0002-5023-7562; Roncalli, Massimo/0000-0002-7901-8910; Giovannetti, Elisa/0000-0002-7565-7504; Comoglio, Paolo/0000-0002-7056-5328 NR 26 TC 54 Z9 62 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD SEP PY 2008 VL 19 IS 9 BP 1605 EP 1612 DI 10.1093/annonc/mdn240 PG 8 WC Oncology SC Oncology GA 352OA UT WOS:000259505400014 PM 18467317 ER PT J AU Stojanov, S Dejaco, C Lohse, P Huss, K Duftner, C Belohradsky, BH Herold, M Schirmer, M AF Stojanov, S. Dejaco, C. Lohse, P. Huss, K. Duftner, C. Belohradsky, B. H. Herold, M. Schirmer, M. TI Clinical and functional characterisation of a novel TNFRSF1A c.605T > A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID TNF-RECEPTOR; RHEUMATOID-ARTHRITIS; DISEASE; MUTANT; HETEROGENEITY; PATHOGENESIS; PHENOTYPE; FAMILY; R92Q AB Objectives: To study the clinical outcome, treatment response, T-cell subsets and functional consequences of a novel tumour necrosis factor (TNF) receptor type 1 (TNFRSF1A) mutation affecting the receptor cleavage site. Methods: Patients with symptoms suggestive of tumour necrosis factor receptor-associated periodic syndrome (TRAPS) and 22 healthy controls (HC) were screened for mutations in the TNFRSF1A gene. Soluble TNFRSF1A and inflammatory cytokines were measured by ELISAs. TNFRSF1A shedding was examined by stimulation of peripheral blood mononuclear cells (PBMCs) with phorbol 12-myristate 13-acetate followed by flow cytometric analysis (FACS). Apoptosis of PBMCs was studied by stimulation with TNF alpha in the presence of cycloheximide and annexin V staining. T cell phenotypes were monitored by FACS. Results: TNFRSF1A sequencing disclosed a novel V173D/p.Val202Asp substitution encoded by exon 6 in one family, the c.194-14G>A splice variant in another and the R92Q/p.Arg121Gln substitution in two families. Cardiovascular complications (lethal heart attack and peripheral arterial thrombosis) developed in two V173D patients. Subsequent etanercept treatment of the V173D carriers was highly effective over an 18-month follow-up period. Serum TNFRSF1A levels did not differ between TRAPS patients and HC, while TNFRSF1A cleavage from monocytes was significantly reduced in V173D and R92Q patients. TNF alpha-induced apoptosis of PBMCs and T-cell senescence were comparable between V173D patients and HC. Conclusions: The TNFRSF1A V173D cleavage site mutation may be associated with an increased risk for cardiovascular complications and shows a strong response to etanercept. T-cell senescence does not seem to have a pathogenetic role in affected patients. C1 [Stojanov, S.; Huss, K.; Belohradsky, B. H.] Univ Munich, Childrens Hosp, Dept Infect Dis & Immunol, D-8000 Munich, Germany. [Dejaco, C.; Duftner, C.; Herold, M.; Schirmer, M.] Innsbruck Med Univ, Dept Internal Med, Innsbruck, Austria. [Dejaco, C.; Duftner, C.; Schirmer, M.] Gen Hosp Elisabethinen, Klagenfurt, Austria. [Lohse, P.] Univ Munich, Dept Clin Chem Grosshadern, Munich, Germany. RP Stojanov, S (reprint author), NIAMSD, Genet & Genom Branch, NIH, Bldg 10,Room 9N210,10 Ctr Dr, Bethesda, MD 20892 USA. EM stojanos@mail.nih.gov RI Schirmer, Michael/B-1893-2012 OI Schirmer, Michael/0000-0001-9208-7809 NR 31 TC 30 Z9 30 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD SEP PY 2008 VL 67 IS 9 BP 1292 EP 1298 DI 10.1136/ard.2007.079376 PG 7 WC Rheumatology SC Rheumatology GA 336WN UT WOS:000258395700017 PM 18180277 ER PT J AU Ashktorab, H Tsang, S Luke, B Sun, ZH Adam-Campbell, L Kwagyan, J Poirier, R Akter, S Akhgar, A Smoot, D Munroe, DJ Ali, IU AF Ashktorab, Hassan Tsang, Shirley Luke, Brian Sun, Zhonghe Adam-Campbell, Lucile Kwagyan, John Poirier, Richard Akter, Shahina Akhgar, Ahmad Smoot, Duane Munroe, David J. Ali, Iqbal Unnisa TI Protective Effect of Cox-2 Allelic Variants on Risk of Colorectal Adenoma Development in African Americans SO ANTICANCER RESEARCH LA English DT Article DE Cox-2 polymorphisms; colorectal adenoma; African Americans ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CYTOKINE GENE POLYMORPHISMS; PROSTATE-CANCER RISK; COLON-CANCER; CYCLOOXYGENASE-2; PREVENTION; CELECOXIB; ASSOCIATION AB Background: Recent evidence indicates that single nucleotide polymorphisms (SNPs) in the Cox-2 gene may modulate the risk of colorectal adenoma development. Patients and Methods: We explored possible associations between Cox-2 polymorphisms and risk of adenoma development in an African American case-control study comprising 72 cases of advanced adenomas and 146 polyp-free controls. An exhaustive approach of genotyping 13 haplotype-tagging SNPs (ht SNPs) distributed over the entire COX-2 gene was used. Results: Statistically significant inverse associations were observed between the heterozygous genotypes at the 5229 G>T polymorphism in intron 5 [odds ratio (OR)=0.42; confidence interval (CI)=0.19-0.92; p=0.03] and at the 10935 A>G polymorphism in the 3' flanking region downstream from the poly A signals (OR=0.39; CI=0.18-0.83; p=0.01) and the risk for colorectal adenoma development. Conclusion: The data from our pilot study suggest that allelic variants of the COX-2 gene significantly influence the risk of adenoma development in the African American population. C1 [Ashktorab, Hassan; Adam-Campbell, Lucile; Kwagyan, John; Akter, Shahina; Akhgar, Ahmad; Smoot, Duane] Howard Univ, Coll Med, Dept Med, Washington, DC USA. [Ashktorab, Hassan; Adam-Campbell, Lucile; Kwagyan, John; Akter, Shahina; Akhgar, Ahmad; Smoot, Duane] Howard Univ, Coll Med, Ctr Canc, Washington, DC USA. [Tsang, Shirley; Sun, Zhonghe; Munroe, David J.] SAIC Frederick, Lab Mol Technol, Frederick, MD USA. [Luke, Brian] SAIC Frederick, Adv Biomed Comp Ctr, Frederick, MD USA. [Poirier, Richard; Ali, Iqbal Unnisa] NCI, Canc Prevent Div, Bethesda, MD 20892 USA. RP Ali, IU (reprint author), Univ Karachi, Int Ctr Chem & Biol Sci, Panjwani Ctr Mol Med & Drug Res, Mol Oncol Program, Karachi, Pakistan. EM iuali@cyber.net.pk OI Ali, Imran/0000-0001-6511-8374 FU National Cancer Institute and GCRC [CA102681] FX This work was supported by Grant #CA102681, funded by the National Cancer Institute and GCRC. NR 22 TC 3 Z9 4 U1 0 U2 1 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 SEP-OCT PY 2008 VL 28 IS 5B BP 3119 EP 3123 PG 5 WC Oncology SC Oncology GA 367MC UT WOS:000260555100045 PM 19031967 ER PT J AU Huang, WY Hayes, RB AF Huang, Wen-Yi Hayes, Richard B. CA PLCO Res Team TI OUR CURRENT UNDERSTANDING OF THE ETIOLOGY OF COLORECTAL TUMORS: ONGOING RESEARCH FINDINGS FROM THE PLCO TRIAL SO ANTICANCER RESEARCH LA English DT Meeting Abstract C1 [Huang, Wen-Yi; Hayes, Richard B.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 SEP-OCT PY 2008 VL 28 IS 5C MA 285 BP 3323 EP 3323 PG 1 WC Oncology SC Oncology GA 367ME UT WOS:000260555300286 ER PT J AU Hurt, EM AF Hurt, Elaine M. TI PROSTATE CANCER STEM CELLS SO ANTICANCER RESEARCH LA English DT Meeting Abstract C1 [Hurt, Elaine M.] NCI, Ctr Canc Res, Lab Canc Prevent, Canc Stem Cells Sect, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 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 SEP-OCT PY 2008 VL 28 IS 5C MA 286 BP 3323 EP 3323 PG 1 WC Oncology SC Oncology GA 367ME UT WOS:000260555300287 ER PT J AU Cerliani, JP Giulianelli, S Fabris, VT Novaro, V Gongora, A Baldi, A Molinolo, A Lanari, C Lamb, CA AF Pablo Cerliani, Juan Giulianelli, Sebastian Fabris, Victoria T. Novaro, Virginia Gongora, Adrian Baldi, Alberto Molinolo, Alfredo Lanari, Claudia Lamb, Caroline A. TI STROMAL FGF-2 PARTICIPATES IN HORMONE INDEPENDENT TUMOR GROWTH SO ANTICANCER RESEARCH LA English DT Meeting Abstract C1 [Pablo Cerliani, Juan; Giulianelli, Sebastian; Fabris, Victoria T.; Novaro, Virginia; Gongora, Adrian; Baldi, Alberto; Lanari, Claudia; Lamb, Caroline A.] Inst Biol & Med Expt, RA-2490 Buenos Aires, DF, Argentina. [Molinolo, Alfredo] NIDCR, NIH, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 SEP-OCT PY 2008 VL 28 IS 5C MA 380 BP 3367 EP 3367 PG 1 WC Oncology SC Oncology GA 367ME UT WOS:000260555300381 ER PT J AU Salerno, E Scaglione, B Coffman, F Fernandes, H Marti, G Raveche, E AF Salerno, Erica Scaglione, Brian Coffman, Frederick Fernandes, Helen Marti, Gerald Raveche, Elizabeth TI MICRORNA MIR-16 LINKED TO THE DEVELOPMENT AND PROGRESSION OF B-CELL MALIGNANCIES IN THE NZB MURINE MODEL OF CHRONIC LYMPHOCYTIC LEUKEMIA SO ANTICANCER RESEARCH LA English DT Meeting Abstract C1 [Salerno, Erica; Scaglione, Brian; Coffman, Frederick; Fernandes, Helen; Raveche, Elizabeth] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [Marti, Gerald] NIH, Bethesda, MD 20812 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 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 SEP-OCT PY 2008 VL 28 IS 5C MA 560 BP 3459 EP 3460 PG 2 WC Oncology SC Oncology GA 367ME UT WOS:000260555300561 ER PT J AU Raveche, E Baskar, S Salerno, E Scaglione, B Rader, C Bauer, S Hundle, R Marti, G AF Raveche, Elizabeth Baskar, Sivasubramanian Salerno, Erica Scaglione, Brian Rader, Christoph Bauer, Steven Hundle, Rameet Marti, Gerald TI AGE-ASSOCIATED INCREASE IN CANCER STEM CELLS DETECTED AS THE SIDE POPULATION IN THE NZB MODEL OF CLL SO ANTICANCER RESEARCH LA English DT Meeting Abstract C1 [Raveche, Elizabeth; Salerno, Erica; Scaglione, Brian; Hundle, Rameet] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [Baskar, Sivasubramanian; Rader, Christoph; Marti, Gerald] NIH, Bethesda, MD 20812 USA. NR 0 TC 0 Z9 0 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 SEP-OCT PY 2008 VL 28 IS 5C MA 561 BP 3460 EP 3460 PG 1 WC Oncology SC Oncology GA 367ME UT WOS:000260555300562 ER PT J AU Holodniy, M Penzak, SR Straight, TM Davey, RT Lee, KK Goetz, MB Raisch, DW Cunningham, F Lin, ET Olivo, N Deyton, LR AF Holodniy, Mark Penzak, Scott R. Straight, Timothy M. Davey, Richard T. Lee, Kelvin K. Goetz, Matthew Bidwell Raisch, Dennis W. Cunningham, Francesca Lin, Emil T. Olivo, Noemi Deyton, Lawrence R. TI Pharmacokinetics and tolerability of oseltamivir combined with probenecid SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID INFLUENZA-A H5N1; NEURAMINIDASE; VIRUS; TRANSMISSION; INHIBITOR; ELIMINATION; VOLUNTEERS; PHOSPHATE; BINDING; H9N2 AB Oseltamivir is an inhibitor of influenza virus neuraminidase, which is approved for use for the treatment and prophylaxis of influenza A and B virus infections. In the event of an influenza pandemic, oseltamivir supplies may be limited; thus, alternative dosing strategies for oseltamivir prophylaxis should be explored. Healthy volunteers were randomized to a three-arm, open-label study and given 75 mg oral oseltamivir every 24 h (group 1), 75 mg oseltamivir every 48 h (q48h) combined with 500 mg probenecid four times a day (group 2), or 75 mg oseltamivir q48h combined with 500 mg probenecid twice a day (group 3) for 15 days. Pharmacokinetic data, obtained by noncompartmental methods, and safety data are reported. Forty-eight subjects completed the pharmacokinetic analysis. The study drugs were generally well tolerated, except for one case of reversible grade 4 thrombocytopenia in a subject in group 2. The calculated 90% confidence intervals (CIs) for the geometric mean ratios between groups 2 and 3 and group 1 were outside the bioequivalence criteria boundary (0.80 to 1.25) at 0.63 to 0.89 for group 2 versus group 1 and 0.57 to 0.90 for group 3 versus group 1. The steady-state apparent oral clearance of oseltamivir carboxylate was significantly less in groups 2 (7.4 liters/h; 90% CI, 6.08 to 8.71) and 3 (7.19 liters/h; 90% CI, 6.41 to 7.98) than in group 1 (9.75 liters/h; 90% CI, 6.91 to 12.60) (P < 0.05 for both comparisons by analysis of variance). The (arithmetic) mean concentration at 48 h for group 2 was not significantly different from the mean concentration at 24 h for group 1 (42 +/- 76 and 81 +/- 54 ng/ml, respectively; P = 0.194), but the mean concentration at 48 h for group 3 was significantly less than the mean concentration at 24 h for group 1 (23 +/- 26 and 81 +/- 54 ng/ml, respectively; P = 0.012). Alternate-day dosing of oseltamivir plus dosing with probenecid four times daily achieved trough oseltamivir carboxylate concentrations adequate for neuraminidase inhibition in vitro, and this combination should be studied further. C1 [Holodniy, Mark] VA Palo Alto Hlth Care Syst, Publ Hlth Res Ctr, Palo Alto, CA 94304 USA. [Holodniy, Mark; Deyton, Lawrence R.] US Dept Vet Affairs, Off Publ Hlth & Environm Hazards, Washington, DC USA. [Holodniy, Mark] Stanford Univ, Div Infect Dis & Geog Med, Stanford, CA 94305 USA. [Penzak, Scott R.] NIH, Clin Pharmacokinet Res Lab, Bethesda, MD 20892 USA. [Straight, Timothy M.] Brooke Army Med Ctr, Dept Clin Invest, Ft Sam Houston, TX 78234 USA. [Davey, Richard T.] CRS LIR NIAID, NIH, Bethesda, MD USA. [Lee, Kelvin K.] VA Cooperat Studies Program, Palo Alto, CA USA. [Goetz, Matthew Bidwell] Greater Angeles Hlth Care Syst, Los Angeles, CA USA. [Goetz, Matthew Bidwell] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Infect Dis Sect, Los Angeles, CA 90095 USA. [Raisch, Dennis W.] Clin Res Pharm Coordinating Ctr, VA Cooperat Studies Program, Albuquerque, NM USA. [Cunningham, Francesca] US Dept Vet Affairs, Pharm Benefits Management Grp, Hines, IL USA. [Lin, Emil T.] UCSF, Dept Biopharmaceut Sci, San Francisco, CA USA. [Deyton, Lawrence R.] George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20052 USA. RP Holodniy, M (reprint author), VA Palo Alto Hlth Care Syst, Publ Hlth Res Ctr, 3801 Miranda Ave 132, Palo Alto, CA 94304 USA. EM Holodniy@stanford.edu OI Goetz, Matthew/0000-0003-4542-992X FU U.S. Department of Veterans Affairs Merit; U.S. Departments of Defense; Health and Human Services FX This work was supported by a U.S. Department of Veterans Affairs Merit review grant to Mark Holodniy and additional financial support from the U.S. Departments of Defense (T. M. Straight) and Health and Human Services (R. T. Davey and S. R. Penzak).; None of the authors have any significant conflict of interest related to this study.; We thank the study participants, Cooperative Studies Program staff (Nigel Gladhart, Lauren Uyeda, Sachiko Kutsuna) for data management, and the data safety monitoring committee members (Thomas C. Merigan, Rex Jamison, and Larry Mole). NR 37 TC 33 Z9 35 U1 2 U2 2 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 SEP PY 2008 VL 52 IS 9 BP 3013 EP 3021 DI 10.1128/AAC.00047-08 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 340TG UT WOS:000258667300003 PM 18559644 ER PT J AU Robbins, BL Capparelli, EV Chadwick, EG Yogev, R Serchuck, L Worrell, C Smith, ME Alvero, C Fenton, T Heckman, B Pelton, SI Aldrovandi, G Borkowsky, W Rodman, J Havens, PL AF Robbins, Brian L. Capparelli, Edmund V. Chadwick, Ellen G. Yogev, Ram Serchuck, Leslie Worrell, Carol Smith, Mary Elizabeth Alvero, Carmelita Fenton, Terence Heckman, Barbara Pelton, Stephen I. Aldrovandi, Grace Borkowsky, William Rodman, John Havens, Peter L. CA PACTG 1038 Team TI Pharmacokinetics of high-dose lopinavir-ritonavir with and without saquinavir or nonnucleoside reverse transcriptase inhibitors in human immunodeficiency virus-infected pediatric and adolescent patients previously treated with protease inhibitors SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PATIENTS RECEIVING LOPINAVIR/RITONAVIR; HIV-1-INFECTED CHILDREN; ANTIRETROVIRAL THERAPY; VIROLOGICAL RESPONSE; PLUS SAQUINAVIR; COMBINATION; SAFETY; EFFICACY; REGIMEN; PLASMA AB Human immunodeficiency virus (HIV)-infected children and adolescents who are failing antiretrovirals may have a better virologic response when drug exposures are increased, using higher protease inhibitor doses or ritonavir boosting. We studied the pharmacokinetics and safety of high-dose lopinavir-ritonavir (LPV/r) in treatment-experienced patients, using an LPV/r dose of 400/100 mg/m2 orally every 12 h ( p.o. q12h) ( without nonnucleoside reverse transcriptase inhibitor [NNRTI]), or 480/120 mg/m(2) p. o. q12h ( with NNRTI). We calculated the LPV inhibitory quotient (IQ), and when the IQ was < 15, saquinavir (SQV) 750 mg/m(2) p. o. q12h was added to the regimen. We studied 26 HIV-infected patients. The median age was 15 years ( range, 7 to 17), with 11.5 prior antiretroviral medications, 197 CD4 cells/ml, viral load of 75,577 copies/ml, and a 133-fold change in LPV resistance. By treatment week 2, 14 patients had a viral-load decrease of > 0.75 log(10), with a median maximal decrease in viral load of -1.57 log10 copies/ml at week 8. At week 2, 19 subjects showed a median LPV area under the concentration-time curve (AUC) of 157.2 ( range, 62.8 to 305.5) mu g (.) h/ml and median LPV trough concentration (C(trough)) of 10.8 ( range, 4.1 to 25.3) mu g/ml. In 16 subjects with SQV added, the SQV median AUC was 33.7 (range, 4.4 to 76.5) mu g (.) h/ml and the median SQV C(trough) was 2.1 (range, 0.2 to 4.1) mu g/ml. At week 24, 18 of 26 (69%) subjects remained in the study. Between weeks 24 and 48, one subject withdrew for nonadherence and nine withdrew for persistently high virus load. In antiretroviral-experienced children and adolescents with HIV, high doses of LPV/r with or without SQV offer safe options for salvage therapy, but the modest virologic response and the challenge of adherence to a regimen with a high pill burden may limit the usefulness of this approach. C1 [Robbins, Brian L.; Rodman, John] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Capparelli, Edmund V.] Univ Calif San Diego, San Diego, CA 92103 USA. [Chadwick, Ellen G.; Yogev, Ram] Northwestern Univ, Childrens Mem Hosp, Feinberg Sch Med, Chicago, IL 60614 USA. [Serchuck, Leslie; Worrell, Carol] NICHHD, NIH, Rockville, MD USA. [Smith, Mary Elizabeth] NIH, Div Aids, Bethesda, MD USA. [Alvero, Carmelita; Fenton, Terence] Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. [Heckman, Barbara] Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. [Pelton, Stephen I.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Pelton, Stephen I.] Boston Univ, Sch Publ Hlth, Boston, MA 02118 USA. [Aldrovandi, Grace] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Borkowsky, William] New York Sch Med, New York, NY USA. [Havens, Peter L.] Childrens Hosp Wisconsin, Childrens Res Inst, Med Coll Wisconsin, Milwaukee, WI 53201 USA. RP Havens, PL (reprint author), Childrens Hosp Wisconsin, Childrens Res Inst, Med Coll Wisconsin, Suite C450,POB 1997, Milwaukee, WI 53201 USA. EM phavens@mcw.edu OI Pelton, Stephen/0000-0003-4862-5344 FU Pediatric AIDS Clinical Trials Group (PACTG) [U01 AI 41089]; International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) [U01 AI 068632, 1 U01 AI 068616]; National Institute of Allergy and Infectious Diseases; National Institute of Child Health and Development [NO1-HD-3-3345]; National Institutes of Health; Abbott Laboratories and Roche Pharmaceuticals; ALSAC, the American Lebanese-Syrian Associated Charities FX This work was supported by Pediatric AIDS Clinical Trials Group (PACTG) grant U01 AI 41089 and International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Group grants U01 AI 068632 and grant 1 U01 AI 068616, all of the National Institute of Allergy and Infectious Diseases; grant NO1-HD-3-3345 from the National Institute of Child Health and Development, National Institutes of Health; and by Abbott Laboratories and Roche Pharmaceuticals. The work was supported in part by ALSAC, the American Lebanese-Syrian Associated Charities. NR 40 TC 12 Z9 12 U1 1 U2 3 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 SEP PY 2008 VL 52 IS 9 BP 3276 EP 3283 DI 10.1128/AAC.00224-08 PG 8 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 340TG UT WOS:000258667300038 PM 18625762 ER PT J AU Simitsopoulou, M Roilides, E Paliogianni, F Likartsis, C Ioannidis, J Kanellou, K Walsh, TJ AF Simitsopoulou, Maria Roilides, Emmanuel Paliogianni, Fotini Likartsis, Christodoulos Ioannidis, John Kanellou, Kalliopi Walsh, Thomas J. TI Immunomodulatory effects of voriconazole on monocytes challenged with Aspergillus fumigatus: Differential role of toll-like receptors SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID COLONY-STIMULATING FACTOR; INVASIVE PULMONARY ASPERGILLOSIS; AMPHOTERICIN-B; ANTIFUNGAL ACTIVITY; MONONUCLEAR PHAGOCYTES; GENE-EXPRESSION; POLYMORPHONUCLEAR; MACROPHAGES; ACTIVATION; DEFENSE AB Voriconazole (VRC) has activity against Aspergillus fumigatus, the most frequent cause of invasive aspergillosis in immunocompromised patients. The combination of VRC and A. fumigatus hyphae induced a more pronounced profile of expression of genes encoding inflammatory molecules in human monocytes than Aspergillus alone did. Herein, we provide further evidence of the potential mechanism underlying this immunomodulatory effect of VRC on human monocytes in response to A. fumigatus hyphae. A significant additive antifungal effect was shown when VRC was combined with monocytes against A. fumigatus hyphae. Both A. fumigatus hyphae and VRC induced pronounced profiles of mRNA and protein expression of Toll-like receptor 2 (TLR2) as well as tumor necrosis factor alpha (TNF-alpha) in THP-1 monocytic cells compared to untreated cells. The VRC-induced increase was greater than that induced by hyphae. The combination of VRC and hyphae increased mRNA and protein expression of TLR2 and TNF-alpha to even higher levels than did either VRC or hyphae alone. In contrast, TLR4 expression, both at the mRNA and protein levels, was not increased by either VRC or hyphae or their combination. In addition, significantly more NF-kappa B was translocated to the nuclei of THP-1 cells treated with VRC than untreated cells. While VRC induced more NF-kappa B than hyphae did, treatment with the combination of the two factors induced the greatest NF-kappa B expression. The pronounced profile of TLR2 signaling, TNF-alpha expression, and NF-kappa B activation in the presence of VRC suggests an immunomodulatory effect leading to a more efficient response to A. fumigatus. C1 [Roilides, Emmanuel; Walsh, Thomas J.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Simitsopoulou, Maria; Roilides, Emmanuel] Aristotle Univ Thessaloniki, Hippokrat Hosp, Sch Med, Lab Infect Dis,Dept Pediat 3, Thessaloniki 54642, Greece. [Paliogianni, Fotini] Univ Patras, Sch Med, Dept Microbiol, Patras 26500, Greece. [Simitsopoulou, Maria; Likartsis, Christodoulos; Ioannidis, John; Kanellou, Kalliopi] Technol Educ Inst Thessaloniki, Lab Med Biotechnol, Dept Lab Med, Thessaloniki 57400, Greece. RP Walsh, TJ (reprint author), NCI, Pediat Oncol Branch, Bldg 10,CRC 1-5750, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov RI Ioannidis, John/G-9836-2011 FU European Social Fund & National Resources-EPEAEK II-ARCHIMIDIS; National Cancer Institute, Bethesda, MD FX This study was supported by the European Social Fund & National Resources-EPEAEK II-ARCHIMIDIS and the intramural research program of the National Cancer Institute, Bethesda, MD. We thank P. Siourda for assistance with THP-1 cell line preparations. NR 37 TC 29 Z9 32 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD SEP PY 2008 VL 52 IS 9 BP 3301 EP 3306 DI 10.1128/AAC.01018-07 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 340TG UT WOS:000258667300041 PM 18625774 ER PT J AU Vicente, E Villar, R Burguete, A Solano, B Perez-Silanes, S Aldana, I Maddry, JA Lenaerts, AJ Franzblau, SG Cho, SH Monge, A Goldman, RC AF Vicente, Esther Villar, Raquel Burguete, Asuncion Solano, Beatriz Perez-Silanes, Silvia Aldana, Ignacio Maddry, Joseph A. Lenaerts, Anne J. Franzblau, Scott G. Cho, Sang-hyun Monge, Antonio Goldman, Robert C. TI Efficacy of quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives in experimental tuberculosis SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID DRUG-RESISTANT TUBERCULOSIS; MYCOBACTERIUM-BOVIS BCG; GENE-DISRUPTED MICE; ANTIMYCOBACTERIAL ACTIVITY; ANTITUBERCULOSIS ACTIVITY; COENZYME F-420; AGENTS; BIOSYNTHESIS; PA-824; ASSAY AB This study extends earlier reports regarding the in vitro efficacies of the 1,4-di-N-oxide quinoxaline derivatives against Mycobacterium tuberculosis and has led to the discovery of a derivative with in vivo efficacy in the mouse model of tuberculosis. Quinoxaline-2-carboxylate 1,4-di-N-oxide derivatives were tested in vitro against a broad panel of single-drug-resistant M. tuberculosis strains. The susceptibilities of these strains to some compounds were comparable to those of strain H(37)Rv, as indicated by the ratios of MICs for resistant and nonresistant strains, supporting the premise that 1,4-di-N-oxide quinoxaline derivatives have a novel mode of action unrelated to those of the currently used antitubercular drugs. Specific derivatives were further evaluated in a series of in vivo assays, including evaluations of the maximum tolerated doses, the levels of oral bioavailability, and the efficacies in a low-dose aerosol model of tuberculosis in mice. One compound, ethyl 7-chloro-3-methylquinoxaline-2-carboxylate 1,4-dioxide, was found to be (i) active in reducing CFU counts in both the lungs and spleens of infected mice following oral administration, (ii) active against PA-824-resistant Mycobacterium bovis, indicating that the pathway of bioreduction/activation is different from that of PA-824 ( a bioreduced nitroimidazole that is in clinical trials), and (iii) very active against nonreplicating bacteria adapted to low-oxygen conditions. These data indicate that 1,4-di-N-oxide quinoxalines hold promise for the treatment of tuberculosis. C1 [Vicente, Esther; Villar, Raquel; Burguete, Asuncion; Solano, Beatriz; Perez-Silanes, Silvia; Aldana, Ignacio; Monge, Antonio] Univ Navarra, CIFA, Unidad Invest Desarrollo Medicamentos, E-31080 Pamplona, Spain. [Goldman, Robert C.] NIAID, Therapeut Res Program, Div Aids, Bethesda, MD 20892 USA. [Maddry, Joseph A.] So Res Inst, Birmingham, AL 35225 USA. [Lenaerts, Anne J.] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. [Franzblau, Scott G.; Cho, Sang-hyun] Univ Illinois, Inst TB Res, Chicago, IL 60612 USA. RP Perez-Silanes, S (reprint author), Univ Navarra, CIFA, Unidad Invest Desarrollo Medicamentos, C Irunlarrea S-N, E-31080 Pamplona, Spain. EM sperez@unav.es RI Perez-Silanes, Silvia/B-5284-2008; Vicente, Esther/P-2308-2016; Lenaerts, Anne/F-1353-2017; OI Perez-Silanes, Silvia/0000-0002-6284-4546; Vicente, Esther/0000-0002-1061-2292; Franzblau, Scott/0000-0002-8698-0243 FU National Institute of Allergy and Infectious Diseases (NIAID) [N01-AI-95364, N01-AI-95385] FX Antimycobacterial data were provided by the TAACF through research and development contracts.; This research was funded in part by contracts N01-AI-95364 (Southern Research Institute/University of Illinois at Chicago) and N01-AI-95385 (Colorado State University) from the National Institute of Allergy and Infectious Diseases (NIAID). NR 32 TC 36 Z9 38 U1 0 U2 8 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 SEP PY 2008 VL 52 IS 9 BP 3321 EP 3326 DI 10.1128/AAC.00379-08 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 340TG UT WOS:000258667300044 PM 18625764 ER PT J AU Mueller, NH Pattabiraman, N Ansarah-Sobrinho, C Viswanathan, P Pierson, TC Padmanabhan, R AF Mueller, Niklaus H. Pattabiraman, Nagarajan Ansarah-Sobrinho, Camilo Viswanathan, Prasanth Pierson, Theodore C. Padmanabhan, R. TI Identification and biochemical characterization of small-molecule inhibitors of West Nile virus serine protease by a high-throughput screen SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID YELLOW-FEVER VIRUS; DENGUE VIRUS; AMINO-ACIDS; SUBSTRATE-SPECIFICITY; SUBGENOMIC REPLICONS; VIRAL REPLICATION; DRUG DISCOVERY; RNA-SYNTHESIS; IN-VITRO; NS2B AB West Nile virus and dengue virus are mosquito-borne flaviviruses that cause a large number of human infections each year. No vaccines or chemotherapeutics are currently available. These viruses encode a serine protease that is essential for polyprotein processing, a required step in the viral replication cycle. In this study, a high-throughput screening assay for the West Nile virus protease was employed to screen similar to 32,000 small-molecule compounds for identification of inhibitors. Lead inhibitor compounds with three distinct core chemical structures (1 to 3) were identified. In a secondary screening of selected compounds, two compounds, belonging to the 8-hydroxyquinoline family (compounds A and B) and containing core structure 1, were identified as potent inhibitors of the West Nile virus protease, with K(i) values of 3.2 +/- 0.3 mu M and 3.4 +/- 0.6 mu M, respectively. These compounds inhibited the dengue virus type 2 protease with Ki values of 28.6 +/- 5.1 mu M and 30.2 +/- 8.6 mu M, respectively, showing some selectivity in the inhibition of these viral proteases. However, the compounds show no inhibition of cellular serine proteases, trypsin, or factor Xa. Kinetic analysis and molecular docking of compound B onto the known crystal structure of the West Nile virus protease indicate that the inhibitor binds in the substrate-binding cleft. Furthermore, compound B was capable of inhibiting West Nile virus RNA replication in cultured Vero cells (50% effective concentration, 1.4 +/- 0.4 mu M; selectivity index, 100), presumably by inhibition of polyprotein processing. C1 [Padmanabhan, R.] Georgetown Univ, Sch Med, Dept Microbiol & Immunol, Med Ctr, Washington, DC 20057 USA. [Pattabiraman, Nagarajan] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20057 USA. [Ansarah-Sobrinho, Camilo; Pierson, Theodore C.] NIAID, Viral Pathogenesis Sect, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Padmanabhan, R (reprint author), Georgetown Univ, Sch Med, Dept Microbiol & Immunol, Med Ctr, 3900 Reservoir Rd NW,Med Dent SW309, Washington, DC 20057 USA. EM rp55@georgetown.edu RI Pattabiraman, Nagarjan /A-9347-2011 FU NIH [AI57705, AI070791]; MARCE [AI-02-031]; NIH; National Institute of Allergy and Infectious Diseases (NIAID) FX The work was supported by grants AI57705 and AI070791 from NIH and by a Development grant from MARCE (AI-02-031) awarded to Myron Levine (U54 AI57168) and in part by the Intramural Research Program of the NIH, National Institute of Allergy and Infectious Diseases (NIAID). We thank the faculty and staff of the New England Regional Center of Excellence (NSRB), including Su Chiang, Stewart Rudnicki, Dara Greenhouse, Sean Johnston, and Katrina Schulberg, for help in the use of the HTS facility. NR 35 TC 62 Z9 66 U1 0 U2 4 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 SEP PY 2008 VL 52 IS 9 BP 3385 EP 3393 DI 10.1128/AAC.01508-07 PG 9 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 340TG UT WOS:000258667300051 PM 18606844 ER PT J AU Scheidemann, F Therrien, JP Pfutzner, W AF Scheidemann, Frank Therrien, Jean-Philippe Pfuetzner, Wolfgang TI Selectable bicistronic vectors in skin gene therapy SO ARCHIVES OF DERMATOLOGICAL RESEARCH LA English DT Article DE gene therapy; bicistronic retroviral vector; keratinocyte; fibroblast ID RIBOSOME ENTRY SITE; TRICISTRONIC RETROVIRAL VECTORS; MULTIDRUG-RESISTANCE GENE; GREEN FLUORESCENT PROTEIN; EXPRESSION IN-VIVO; KERATINOCYTES; CELLS; IRES; FIBROBLASTS; PROMOTERS AB Bicistronic vectors (BCV) are important tools for gene therapy applications allowing selection for increased expression of a desired gene by linking it to a selectable gene, such as the multi-drug resistance (MDR) gene. However, both the design of the BCV and the cell type to be transduced can have a strong impact on the vector performance in the target cells. To analyze which factors might influence the efficiency of BCV in achieving high gene expression levels in skin and to determine the best suited BCV for cutaneous transduction, both keratinocytes (KC) and fibroblasts (FB) were transduced with different BCV constructs, BGIM, BMIG and QGIM. In BGIM, expression of the BCV cassette encompassing the green fluorescent protein (GFP) gene connected to the MDR gene was driven by a retroviral LTR-promoter. In BMIG, the order of the two genes was reversed, while in QGIM the GFP- and MDR-gene were arranged similar as in BGIM, but expressed by a CMV- instead of an LTR-promoter. FACS-analysis revealed that the percentage of genetically modified cells varied substantially with 47.9% QGIM-, 35.5% BMIG- and 17.9% BGIM-transduced KC expressing both genes. For FB the numbers were 56.7% (QGIM), 38.4% (BMIG) and 8.3% (BGIM). Furthermore, the choice of BCV determined the intensity of GFP-expression with the highest levels measured in BGIM-, followed by QGIM- and then BMIG-transduced cells. Interestingly, highly efficient enrichment through colchicine selection was possible for QGIM- (up to 97.1% KC, 97.8% FB) and BMIG- (85.0% KC and 98.0% FB) but not BGIM- (29.9% KC and 18.6% FB) transduced cells. Finally, immunohistochemistry and FACS-analysis demonstrated, that colchicine selection of QGIM-transduced skin equivalents led to increased numbers of GFP-expressing KC (from 51.2% up to 72.3%) and enhanced GFP-intensity in the skin. These results show that BCV present a promising vector system to enhance the expression of a desired gene in skin but important parameters taken into account when employing a selectable BCV for skin gene therapy applications are the retroviral vector backbone, the order in which the genes are arranged, and the target cells to be transduced and selected. C1 [Pfuetzner, Wolfgang] Univ Giessen & Marburg, Dept Dermatol & Allergol, D-35037 Marburg, Germany. [Scheidemann, Frank; Pfuetzner, Wolfgang] Univ Munich, Dept Dermatol & Allergol, Munich, Germany. [Therrien, Jean-Philippe] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Pfutzner, W (reprint author), Univ Giessen & Marburg, Dept Dermatol & Allergol, Deutschhausstr 9, D-35037 Marburg, Germany. EM wpfuetzn@med.uni-marburg.de FU Canadian Institutes of Health Research; [Pf 344/2-2] FX This work was supported by Grant No. Pf 344/2-2. Jean-Philippe Therrien is a recipient of a postdoctoral fellowship from the Canadian Institutes of Health Research. The authors thank Ines Nachtigall for expert technical assistance. NR 24 TC 4 Z9 4 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0340-3696 J9 ARCH DERMATOL RES JI Arch. Dermatol. Res. PD SEP PY 2008 VL 300 IS 8 BP 415 EP 423 DI 10.1007/s00403-008-0878-6 PG 9 WC Dermatology SC Dermatology GA 341HF UT WOS:000258704100002 PM 18663457 ER PT J AU Patel, AR Pavletic, SZ Turner, ML Cowen, EW AF Patel, Asha R. Pavletic, Steven Z. Turner, Maria L. Cowen, Edward W. TI The isomorphic response in morphealike chronic graft-vs-host disease SO ARCHIVES OF DERMATOLOGY LA English DT Letter ID KOEBNER C1 [Cowen, Edward W.] NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Cowen, EW (reprint author), NCI, Dermatol Branch, NIH, 10 Ctr Dr,MSC 1908,Bldg 10,Room 12N238, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 5 TC 7 Z9 7 U1 0 U2 0 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 SEP PY 2008 VL 144 IS 9 BP 1229 EP 1231 DI 10.1001/archderm.144.9.1229 PG 3 WC Dermatology SC Dermatology GA 348RQ UT WOS:000259228000025 PM 18794477 ER PT J AU SanGiovanni, JP Chew, EY Agron, E Clemons, TE Ferris, FL Gensler, G Lindblad, AS Milton, RC Seddon, JM Klein, R Sperduto, RD AF SanGiovanni, John Paul Chew, Emily Y. Agron, Elvira Clemons, Traci E. Ferris, Frederick L., III Gensler, Gary Lindblad, Anne S. Milton, Roy C. Seddon, Johanna M. Klein, Ronald Sperduto, Robert D. CA Age-Related Eye Dis Study Res Grp TI The relationship of dietary omega-3 long-chain polyunsaturated fatty acid intake with incident age-related macular degeneration - AREDS report no. 23 SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID DOCOSAHEXAENOIC ACID; OXIDATIVE STRESS; RISK-FACTORS; EYE DISEASE; MACULOPATHY; PHOTORECEPTORS; APOPTOSIS; RETINA; DESIGN; HEALTH AB Objective: To examine the association of dietary omega-3 long-chain polyunsaturated fatty acid and fish intake with incident neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA). Methods: Multicenter clinic-based prospective cohort study from a clinical trial including Age-Related Eye Disease Study (AREDS) participants with bilateral drusen at enrollment. Main outcome measures were incident neovascular AMD and CGA, ascertained from annual stereoscopic color fundus photographs (median follow-up, 6.3 years). We estimated nutrient and food intake from a validated food frequency questionnaire (FFQ) at baseline, with intake of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), combined EPA and DHA, and fish as primary exposures. Results: After controlling for known covariates, we observed a reduced likelihood of progression from bilateral drusen to CGA among people who reported the highest levels of EPA (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.87) and EPA + DHA ( OR, 0.45; 95% CI, 0.23-0.90) consumption. Levels of DHA were associated with CGA in age- ,sex-, and calorie-adjusted models (OR, 0.51; 95% CI, 0.26-1.00); however, this statistical relationship did not persist in multivariable models. Conclusions: Dietary lipid intake is a modifiable factor that may influence the likelihood of developing sight-threatening forms of AMD. Our findings suggest that dietary omega-3 long-chain polyunsaturated fatty acid intake is associated with a decreased risk of progression from bilateral drusen to CGA. C1 [SanGiovanni, John Paul; Clemons, Traci E.; Gensler, Gary; Lindblad, Anne S.; Milton, Roy C.] EMMES Corp, AREDS Coordinating Ctr, Rockville, MD 20850 USA. [SanGiovanni, John Paul; Chew, Emily Y.; Agron, Elvira; Ferris, Frederick L., III; Sperduto, Robert D.] NEI, Bethesda, MD 20892 USA. [Seddon, Johanna M.] Tufts Univ New England Med Ctr, New England Eye Ctr, Boston, MA USA. [Klein, Ronald] Univ Wisconsin, Sch Med & Publ Hlth, Dept Ophthalmol & Visual Sci, Madison, WI 53706 USA. RP SanGiovanni, JP (reprint author), EMMES Corp, AREDS Coordinating Ctr, 401 N Washington St,Ste 700, Rockville, MD 20850 USA. EM aredspub@emmes.com RI SanGiovanni, John Paul/A-7605-2008 FU National Eye Institute; National Institutes of Health, Department of Health and Human Services FX This study was supported by contracts from the National Eye Institute, National Institutes of Health, Department of Health and Human Services. NR 29 TC 109 Z9 111 U1 3 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD SEP PY 2008 VL 126 IS 9 BP 1274 EP 1279 DI 10.1001/archopht.126.9.1274 PG 6 WC Ophthalmology SC Ophthalmology GA 345XQ UT WOS:000259031500015 PM 18779490 ER PT J AU Yeh, S Nussenblatt, RB AF Yeh, Steven Nussenblatt, Robert B. TI Fluocinolone acetonide for the treatment of uveitis - Weighing the balance between local and systemic immunosuppression SO ARCHIVES OF OPHTHALMOLOGY LA English DT Editorial Material ID INTRAVITREAL TRIAMCINOLONE ACETONIDE; CYSTOID MACULAR EDEMA; POSTERIOR UVEITIS; EFFICACY; SAFETY C1 [Nussenblatt, Robert B.] NEI, Natl Inst Hlth, Immunol Lab, Bethesda, MD 20892 USA. RP Nussenblatt, RB (reprint author), NEI, Natl Inst Hlth, Immunol Lab, Bldg 10,10N112, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov FU Intramural NIH HHS NR 20 TC 3 Z9 3 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD SEP PY 2008 VL 126 IS 9 BP 1287 EP 1289 DI 10.1001/archopht.126.9.1287 PG 3 WC Ophthalmology SC Ophthalmology GA 345XQ UT WOS:000259031500017 PM 18779492 ER PT J AU SanGiovanni, JP AF SanGiovanni, John Paul TI Lutein/Zeaxanthin - Reply SO ARCHIVES OF OPHTHALMOLOGY LA English DT Letter ID ZEAXANTHIN; LUTEIN C1 NEI, NIH, Clin Trials Branch, Bethesda, MD 20892 USA. RP SanGiovanni, JP (reprint author), NEI, NIH, Clin Trials Branch, 10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. EM jpsangio@post.harvard.edu NR 4 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 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD SEP PY 2008 VL 126 IS 9 BP 1313 EP 1314 DI 10.1001/archopht.126.9.1313-b PG 3 WC Ophthalmology SC Ophthalmology GA 345XQ UT WOS:000259031500025 ER PT J AU Hsia, J Otvos, JD Rossouw, JE Wu, L Wassertheil-Smoller, S Hendrix, SL Robinson, JG Lund, B Kuller, LH AF Hsia, Judith Otvos, James D. Rossouw, Jacques E. Wu, LieLing Wassertheil-Smoller, Sylvia Hendrix, Susan L. Robinson, Jennifer G. Lund, Bernedine Kuller, Lewis H. CA Women's Hlth Initiative Res Grp TI Lipoprotein particle concentrations may explain the absence of coronary protection in the women's health initiative hormone trials SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE lipoproteins; estrogen; women; coronary heart disease ID RANDOMIZED CONTROLLED-TRIAL; ESTROGEN PLUS PROGESTIN; MAGNETIC-RESONANCE SPECTROSCOPY; LOW-DENSITY-LIPOPROTEIN; HEART-DISEASE; POSTMENOPAUSAL WOMEN; CARDIOVASCULAR-DISEASE; SUBCLASSES; THERAPY; EVENTS AB Objective-The Women's Health Initiative randomized hormone trials unexpectedly demonstrated an increase in early coronary events. In an effort to explain this finding, we examined lipoprotein particle concentrations and their interactions with hormone therapy in a case-control substudy. Methods and Results-We randomized 16 608 postmenopausal women with intact uterus to conjugated estrogens 0.625 mg with medroxyprogesterone acetate 2.5 mg daily or to placebo, and 10 739 women with prior hysterectomy to conjugated estrogens 0.625 mg daily or placebo, and measured lipoprotein subclasses by nuclear magnetic resonance spectroscopy at baseline and year 1 in 354 women with early coronary events and matched controls. Postmenopausal hormone therapy raised high-density lipoprotein cholesterol and particle concentration and reduced low-density lipoprotein cholesterol (LDL-C; all P<0.001 versus placebo). In contrast, neither unopposed estrogen nor estrogen with progestin lowered low-density lipoprotein particle concentration (LDL-P). Conclusions-Postmenopausal hormone therapy-induced reductions in LDL-C were not paralleled by favorable effects on LDL-P. This finding may account for the absence of coronary protection conferred by estrogen in the randomized hormone trials. C1 [Hsia, Judith] George Washington Univ, Dept Med, Washington, DC USA. [Otvos, James D.] Liposcience Inc, Raleigh, NC USA. [Rossouw, Jacques E.] NHLBI, NIH, Bethesda, MD 20892 USA. [Wu, LieLing; Lund, Bernedine] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Wassertheil-Smoller, Sylvia] Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10467 USA. [Hendrix, Susan L.] Detroit Med Ctr, Dept Obstet & Gynecol, Detroit, MI USA. [Robinson, Jennifer G.] Univ Iowa, Dept Med, Iowa City, IA 52242 USA. [Kuller, Lewis H.] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15260 USA. RP Hsia, J (reprint author), AstraZeneca LP, 1800 Concord Pike,Room C3C-123,POB 15437, Wilmington, DE 19850 USA. EM judith.hsia@astrazeneca.com FU National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221] FX The Women's Health Initiative program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221. NR 21 TC 37 Z9 38 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD SEP 1 PY 2008 VL 28 IS 9 BP 1666 EP 1671 DI 10.1161/ATVBAHA.108.170431 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 339WP UT WOS:000258608300016 PM 18599797 ER PT J AU Bartlett, SJ Ling, SM Bingham, CO AF Bartlett, Susan J. Ling, Shari M. Bingham, Clifton O., III TI Patterns of joint space narrowing over two years in knee OA SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Ling, Shari M.] NIA, Intramural Res Program, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S675 EP S676 PG 2 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244201619 ER PT J AU Christodoulou, MI Kapsogeorgou, EK Moutsopouios, NM Moutsopoulos, HM AF Christodoulou, M. I. Kapsogeorgou, E. K. Moutsopouios, N. M. Moutsopoulos, H. M. TI Inflammatory cells at the autoimmune minor salivary gland (MSG) lesions of Sjogren's syndrome (SS): Differential distribution depending on lesion severity and correlation with adverse prognostic factors SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Christodoulou, M. I.; Kapsogeorgou, E. K.; Moutsopoulos, H. M.] Athens Med Sch, Dept Pathophysiol, Athens, Greece. [Moutsopouios, N. M.] Nat Inst Dent & Craniofacial Res NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S792 EP S793 PG 2 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202185 ER PT J AU Cobb, BL Wang, Y Kaufman, KM Guthridge, J Jonsson, R Bolstad, AI Brun, JG Rischmueller, M Lester, SE Illei, GG Witte, T Mariette, X Kimberly, RP Edberg, JC Bae, SC Jacob, CO Alarcon-Riquelme, ME Vyse, TJ Gilkeson, G Kamen, DL Moser, K Gaffney, P Merrill, J James, JA Harley, JB AF Cobb, Beth L. Wang, Yukun Kaufman, Kenneth M. Guthridge, Joel Jonsson, Roland Bolstad, Anne Isine Brun, Johan G. Rischmueller, Maureen Lester, Susan E. Illei, Gabor G. Witte, Torsten Mariette, Xavier Kimberly, Robert P. Edberg, Jeff C. Bae, Sang-Cheol Jacob, Chaim O. Alarcon-Riquelme, Marta E. Vyse, Tim J. Gilkeson, Gary Kamen, Diane L. Moser, Kathy Gaffney, Patrick Merrill, Joan James, Judith A. Harley, John B. TI Association of BLK with Sjogren's syndrome (SS) and systemic lupus erythematosus (SLE) initially identified by whole genome DNA pooling SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Cobb, Beth L.; Wang, Yukun; Kaufman, Kenneth M.; Guthridge, Joel; Moser, Kathy; Gaffney, Patrick; Merrill, Joan; James, Judith A.; Harley, John B.] Oklahoma Med Res Fdn, Oklahoma City, OK 73104 USA. [Jonsson, Roland; Bolstad, Anne Isine; Brun, Johan G.] Univ Bergen, Bergen, Norway. [Lester, Susan E.] Hanson Inst, Adelaide, SA, Australia. [Illei, Gabor G.] NIDCR, Natl Inst Hlth, Bethesda, MD USA. [Witte, Torsten] Hannover Med Sch, D-3000 Hannover, Germany. [Mariette, Xavier] Univ Paris 11, Le Kremlin Bicetre, France. [Kimberly, Robert P.; Edberg, Jeff C.] Univ Alabama, Birmingham, AL USA. [Bae, Sang-Cheol] Hanyang Univ, Seoul 133791, South Korea. [Jacob, Chaim O.] Univ So Calif, Los Angeles, CA USA. [Alarcon-Riquelme, Marta E.] Uppsala Univ, Uppsala, Sweden. [Vyse, Tim J.] Univ London Imperial Coll Sci Technol & Med, London, England. [Gilkeson, Gary; Kamen, Diane L.] Med Univ S Carolina, Charleston, SC 29425 USA. RI Witte, Torsten/B-5783-2016 NR 0 TC 0 Z9 0 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S791 EP S791 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202181 ER PT J AU Coyle, K Pokrovnichka, A French, K Joe, G Shrader, J Swan, L Cabalar, I Harris-Love, M Plotz, P Miller, F Gourley, M AF Coyle, K. Pokrovnichka, A. French, K. Joe, G. Shrader, J. Swan, L. Cabalar, I. Harris-Love, M. Plotz, P. Miller, F. Gourley, M. TI Randomized, double-blind, placebo-controlled trial of infliximab in patients with polymyositis and dermatomyositis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Coyle, K.; Pokrovnichka, A.; French, K.; Joe, G.; Shrader, J.; Swan, L.; Cabalar, I.; Harris-Love, M.; Plotz, P.; Miller, F.; Gourley, M.] NIH, Bethesda, MD 20892 USA. NR 0 TC 6 Z9 6 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S923 EP S924 PG 2 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202541 ER PT J AU Evans, D Reveille, JD Weisman, MH Stone, MA Ward, MM Savage, L Zhou, XD Wordsworth, BP Brown, MA AF Evans, David Reveille, John D. Weisman, Michael H. Stone, Millicent A. Ward, Michael M. Savage, Laurie Zhou, Xiaodong Wordsworth, B. Paul Brown, Matthew A. TI Diagnostic capacity of genetic tests in Ankylosing spondylitis can exceed MRI scanning SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Evans, David] Univ Bristol, Bristol, Avon, England. [Reveille, John D.; Zhou, Xiaodong] Univ Texas Houston, HSC, Houston, TX USA. [Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Stone, Millicent A.] RNHRD, Bath, Avon, England. [Ward, Michael M.] NIAMS, Bethesda, MD USA. [Savage, Laurie] Spondylitis Assn Amer, Sherman Oaks, TX USA. [Wordsworth, B. Paul] Univ Oxford, Oxford, England. [Brown, Matthew A.] Univ Queensland, Brisbane, Qld, Australia. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S904 EP S904 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202492 ER PT J AU Flower, CH Hennis, AJM Nicholson, GD Hambleton, IR Liang, MH Kimberly, R Parks, CG AF Flower, Cindy H. Hennis, Anselm J. M. Nicholson, George D. Hambleton, Ian R. Liang, Matthew H. Kimberly, Robert Parks, Christine G. TI A population study of SLE incidence, prevalence and clinical features: The Barbados Lupus Study SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Flower, Cindy H.; Nicholson, George D.] Univ W Indies, Sch Clin Med & Res, St Michael, Barbados. [Hennis, Anselm J. M.; Hambleton, Ian R.] Chron Dis Res Ctr, St Michael, Barbados. [Liang, Matthew H.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Kimberly, Robert] Univ Alabama, Birmingham, AL USA. [Parks, Christine G.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S883 EP S883 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202440 ER PT J AU Goldbach-Mansky, RT Plass, N Chapelle, D Stone, D Sara, P Kastner, DL AF Goldbach-Mansky, Raphaela T. Plass, Nicole Chapelle, Daewn Stone, Deborah Sara, Plehn Kastner, Daniel L. CA NOMID Study Grp TI Treatment of neonatal-onset multisystem inflammatory disease (NOMID/CINCA) with the IL-1 blocker, anakinra: after 3 years on treatment SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Goldbach-Mansky, Raphaela T.; Plass, Nicole; Chapelle, Daewn; Stone, Deborah; Sara, Plehn; Kastner, Daniel L.; NOMID Study Grp] NIAMS, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S633 EP S633 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244201503 ER PT J AU Huter, EN Sturturivoll, GH Shevach, EM AF Huter, Eva N. Sturturivoll, Georg H. Shevach, Ethan M. TI Antigen-specific TGF beta-induced Treg suppress Th17-mediated autoimmune disease SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Huter, Eva N.; Shevach, Ethan M.] NIH, Bethesda, MD 20892 USA. [Sturturivoll, Georg H.] Med Univ Vienna, Vienna, Austria. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S840 EP S840 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202321 ER PT J AU Kiel, DP Hannan, MT Barton, BA Lang, TF Bouxsein, ML Brown, K Shane, E Magaziner, J Zimmerman, S Harris, T Rubin, CT AF Kiel, D. P. Hannan, M. T. Barton, B. A. Lang, T. F. Bouxsein, M. L. Brown, K. Shane, E. Magaziner, J. Zimmerman, S. Harris, T. Rubin, C. T. TI Non-pharmacologic low magnitude mechanical stimulation (LMMS) to improve bone mineral densitv (BMD): the "VIBES" trial. SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Kiel, D. P.; Hannan, M. T.] Inst Aging Res, Boston, MA USA. [Barton, B. A.; Brown, K.] Maryland Med Res Inst, Baltimore, MD USA. [Lang, T. F.] UCSF, San Francisco, CA USA. [Bouxsein, M. L.] BIDMC, Ortho Biomech Lab, Boston, MA USA. [Shane, E.] Columbia Univ, Dept Med, New York, NY USA. [Magaziner, J.] Univ MD, Baltimore, MD USA. [Zimmerman, S.] UNC, Cecil G Sheps Ctr Hlth Serv Rsch, Chapel Hill, NC USA. [Harris, T.] NIA, Bethesda, MD 20892 USA. [Rubin, C. T.] SUNY Stony Brook, Stony Brook, NY 11794 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S162 EP S162 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244200005 ER PT J AU Lapidus, SK Chitkara, P Feder, H Salazar, JC Ward, M Aksentijevich, I Barham, B Athreya, B Barron, K Kastner, D Stojanov, S AF Lapidus, Sivia K. Chitkara, Puja Feder, Henry Salazar, Juan C. Ward, Michael Aksentijevich, Ivona Barham, Beverly Athreya, Balu Barron, Karyl Kastner, Daniel Stojanov, Silvia TI Immune Dysregulation in periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis (PFAPA) syndrome involving the gamma interferon-inducible protein 10 (IP-10), a cytokine chemotactic for T lymphocytes SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Lapidus, Sivia K.; Chitkara, Puja; Ward, Michael; Aksentijevich, Ivona; Barham, Beverly; Barron, Karyl; Kastner, Daniel; Stojanov, Silvia] NIH, Bethesda, MD 20892 USA. [Feder, Henry; Salazar, Juan C.] Univ Connecticut Hlth Sci Ctr, Connecticut Childrens Med Ctr, Hartford, CT USA. [Athreya, Balu] Thomas Jefferson Univ, AI DuPont Hosp Children, Wilmington, DE USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S499 EP S499 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244201160 ER PT J AU Lee, HS Kim, YJ Lee, AT Remmers, EF Kastner, DL Bae, SC Gregersen, PK AF Lee, Hye-Soon Kim, Yun Jung Lee, Annette T. Remmers, Elaine F. Kastner, Daniel L. Bae, Sang-Cheol Gregersen, Peter K. TI No common variants in the large LD block of PTPN22 are associated with RA in Koreans SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Lee, Hye-Soon; Kim, Yun Jung; Bae, Sang-Cheol] Hanyang Univ, Coll Med, Seoul 133791, South Korea. [Lee, Annette T.; Gregersen, Peter K.] Feinstein Inst Med Res, Manhasset, NY USA. [Remmers, Elaine F.; Kastner, Daniel L.] NIAMSD, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S214 EP S214 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244200147 ER PT J AU Louie, GH Ward, MM AF Louie, Grant H. Ward, Michael M. TI Gender differences in self-reported physical function among the elderly: NHANES III SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Louie, Grant H.; Ward, Michael M.] NIAMSD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S206 EP S207 PG 2 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244200127 ER PT J AU Lozano, E Corbera-Bellalta, M Espigol-Frigole, G Segarra, M Garcia-Martinez, A Hemandez-Rodriguez, J Cid, MC AF Lozano, Ester Corbera-Bellalta, Marc Espigol-Frigole, Georgina Segarra, Marta Garcia-Martinez, Ana Hemandez-Rodriguez, Jose Cid, Maria C. TI Proinflammatory functions of vascular smooth muscle cells (VSMC) In giant cell arteritis (GCA) SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Lozano, Ester; Corbera-Bellalta, Marc; Espigol-Frigole, Georgina; Garcia-Martinez, Ana; Hemandez-Rodriguez, Jose; Cid, Maria C.] Univ Barcelona, Hosp Clin, IDIBAPS, Barcelona, Spain. [Segarra, Marta] NIH, Bethesda, MD 20892 USA. RI Lozano, Ester/H-2215-2014 OI Lozano, Ester/0000-0002-6307-9807 NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S928 EP S929 PG 2 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202553 ER PT J AU Masters, SL Brydges, S Cleland, SY Siegel, RM Kastner, DL AF Masters, Seth L. Brydges, Susannah Cleland, Sophia Y. Siegel, Richard M. Kastner, Daniel L. TI Characterization of mice deficient for Pstpip1, the gene mutated in PAPA syndrome SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Masters, Seth L.; Brydges, Susannah; Cleland, Sophia Y.; Siegel, Richard M.; Kastner, Daniel L.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S722 EP S722 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202005 ER PT J AU Mayes, MD Keyes-Elstein, L Crofford, LJ Csuka, ME Furst, DE Goldmuntz, E McSweeney, P Nash, R Wallace, D Sullivan, K AF Mayes, Maureen D. Keyes-Elstein, Lynette Crofford, Leslie J. Csuka, Mary Ellen Furst, Daniel E. Goldmuntz, Ellen McSweeney, Peter Nash, Richard Wallace, Dennis Sullivan, Keith CA SCOT Trail Invest TI Gastric antral vascular ectasia (GAVE) in early diffuse SSc: Report from the SCOT trial SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Mayes, Maureen D.] Univ Texas Houston, Houston, TX USA. [Keyes-Elstein, Lynette] Rho Fed Syst Inc, Chapel Hill, NC USA. [Crofford, Leslie J.] Univ Kentucky, Lexington, KY USA. [Csuka, Mary Ellen] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Furst, Daniel E.] Univ Calif Los Angeles, Los Angeles, CA USA. [Goldmuntz, Ellen] NIAID, NIH, Bethesda, MD 20892 USA. [McSweeney, Peter] Rocky Mt Canc Ctr, Denver, CO USA. [Nash, Richard] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Wallace, Dennis] RTI Int, Res Triangle Pk, NC USA. [Sullivan, Keith] Duke Univ, Med Ctr, Durham, NC USA. RI Crofford, Leslie/J-8010-2013 NR 0 TC 1 Z9 1 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S378 EP S379 PG 2 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244200593 ER PT J AU Nikolov, NP Patel, A Alba, MI Leakan, RA Bebris, L Ghosh-Dastidar, S Colombo, J Illei, GG AF Nikolov, Nikolay P. Patel, Ankur Alba, Maria I. Leakan, Rose Anne Bebris, Lolita Ghosh-Dastidar, Samanwoy Colombo, Joe Illei, Gabor G. TI Dysautonomia in primary Sjogren's syndrome (pSS) patients as assessed in the outpatient setting using real-time digital autonomic nervous system monitoring SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Nikolov, Nikolay P.; Patel, Ankur; Alba, Maria I.; Leakan, Rose Anne; Bebris, Lolita; Illei, Gabor G.] NIDCR, NIH, Bethesda, MD USA. [Ghosh-Dastidar, Samanwoy; Colombo, Joe] ANSAR Med Technol Inc, Philadelphia, PA USA. RI Ghosh-Dastidar, Samanwoy/A-5232-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S788 EP S788 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202173 ER PT J AU Nikolov, NP Burbelo, PD Leahy, HP Groot, S Alba, MI Baraniuk, JN Iadarola, ML Illei, GG AF Nikolov, Nikolay P. Burbelo, Peter D. Leahy, Hannah P. Groot, Sandra Alba, Maria I. Baraniuk, James N. Iadarola, Michael L. Illei, Gabor G. TI Autoantibodies against aquaporins in primary Sjogren's syndrome(pSS) SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Nikolov, Nikolay P.; Burbelo, Peter D.; Leahy, Hannah P.; Groot, Sandra; Alba, Maria I.; Baraniuk, James N.; Iadarola, Michael L.; Illei, Gabor G.] NIDCR, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S788 EP S788 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202172 ER PT J AU Pandey, GS Sabina, RL Wortmann, RL Pistilli, E VanderMeulen, J Rawat, R Raben, N Plotz, PH Nagaraju, K AF Pandey, Gouri S. Sabina, Richard L. Wortmann, Robert L. Pistilli, Emidio VanderMeulen, Jack Rawat, Rashmi Raben, Nina Plotz, Paul H. Nagaraju, Kanneboyina TI Role of adenine nucleotide catabolic enzymes in mediating muscle weakness in myositis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Pandey, Gouri S.; Pistilli, Emidio; VanderMeulen, Jack; Rawat, Rashmi; Nagaraju, Kanneboyina] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Sabina, Richard L.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Wortmann, Robert L.] Dartmouth Hitchcock Med Ctr, Lebanon, NH 03766 USA. [Raben, Nina; Plotz, Paul H.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S922 EP S922 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202537 ER PT J AU Park, MM Parks, CG Cooper, GS Gilkeson, GS Dooley, MA AF Park, Melissa M. Parks, Christine G. Cooper, Glinda S. Gilkeson, Gary S. Dooley, Mary Anne TI The association of early family characteristics with adult-onset systemic lupus erythematosus (SLE) SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 Univ N Carolina, Chapel Hill, NC USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. US EPA, Washington, DC 20460 USA. Med Univ S Carolina, Charleston, SC 29425 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S808 EP S808 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202231 ER PT J AU Penzak, S Pham, TH Pucino, F Goldbach-Mansky, R AF Penzak, Scott Pham, Tuyet-Hang Pucino, Frank Goldbach-Mansky, Raphaela TI The pharmacokinetics (PK) of single- and multiple-dose anakinra in patients with neonatal-onset multisystem inflammatory disease (NOMID/CINCA) SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Penzak, Scott; Pham, Tuyet-Hang; Pucino, Frank; Goldbach-Mansky, Raphaela] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S481 EP S481 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244201111 ER PT J AU Pharn, TH Plass, N Chapelle, D Plehn, S Goldbach-Mansky, R AF Pharn, Tuvet-Hang Plass, Nicole Chapelle, Dawn Plehn, Sara Goldbach-Mansky, Raphaela TI Microbial factors differentially induce IL-1 production in "CIAS1 Mutation Positive and Negative" patients with neonatal-onset multisystem inflammatory disease (NOMID) SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Pharn, Tuvet-Hang; Plass, Nicole; Chapelle, Dawn; Plehn, Sara; Goldbach-Mansky, Raphaela] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S668 EP S668 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244201599 ER PT J AU Prots, I Skapenko, A Lipsky, PE Schulze-Koops, H AF Prots, Iryna Skapenko, Aila Lipsky, Peter E. Schulze-Koops, Hendrik TI The neuropeptide npT1 is specifically expressed in human CD25+ regulatory T cells SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Prots, Iryna; Skapenko, Aila; Schulze-Koops, Hendrik] Univ Munich, Munich, Germany. [Lipsky, Peter E.] NIAMS, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S838 EP S838 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202314 ER PT J AU Rawat, R Pistilli, EE Francia, DL Raben, N Plotz, PH Hoffman, EP Nagaraju, K AF Rawat, Rashmi Pistilli, Emidio E. Francia, Dwight L. Raben, Nina Plotz, Paul H. Hoffman, Eric P. Nagaraju, Kanneboyina TI Role of tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) in mediating muscle fiber damage in myositis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Rawat, Rashmi; Pistilli, Emidio E.; Francia, Dwight L.; Hoffman, Eric P.; Nagaraju, Kanneboyina] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Plotz, Paul H.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S226 EP S226 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244200183 ER PT J AU Raychaudhuri, S Remmers, EF Lee, AT Korman, BD Padyukov, L Kurreeman, FAS Mil, AHMVDHV Coblyn, J Criswell, LA Amos, CI Seldins, MF Kastner, DL Alfredsson, L Huzinga, TWJ Shadick, NA Weinblatt, ME Worthington, J Seielstad, M Toes, REM Karlson, EW Begovich, AB Klareskog, L Gregersen, PK Daly, MJ Plenge, RM AF Raychaudhuri, Sournya Remmers, Elaine F. Lee, Annette T. Korman, Benjamin D. Padyukov, Leonid Kurreeman, Fina A. S. Mil, Annette H. M. van der Helm-van Coblyn, Jonathon Criswell, Lindsey A. Amos, Christopher I. Seldins, Michael F. Kastner, Daniel L. Alfredsson, Lars Huzinga, Tom W. J. Shadick, Nancy A. Weinblatt, Michael E. Worthington, Jane Seielstad, Mark Toes, Rene E. M. Karlson, Elizabeth W. Begovich, Ann B. Klareskog, Lars Gregersen, Peter K. Daly, Mark J. Plenge, Robert M. TI A common variant at the CD40 locus confers risk of rheumatoid SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Raychaudhuri, Sournya; Coblyn, Jonathon; Weinblatt, Michael E.; Karlson, Elizabeth W.; Plenge, Robert M.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Raychaudhuri, Sournya; Coblyn, Jonathon; Weinblatt, Michael E.; Karlson, Elizabeth W.; Plenge, Robert M.] BRASS Registry, Boston, MA USA. [Korman, Benjamin D.; Kastner, Daniel L.] NIAMS, Bethesda, MD USA. [Lee, Annette T.; Gregersen, Peter K.] Feinstein Inst Med Res, Manhasset, NY USA. [Padyukov, Leonid; Alfredsson, Lars; Klareskog, Lars] Karolinska Inst, Stockholm, Sweden. [Kurreeman, Fina A. S.; Mil, Annette H. M. van der Helm-van] Leiden Univ, Med Ctr, Leiden, Netherlands. [Criswell, Lindsey A.] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Amos, Christopher I.] MD Anderson Canc Ctr, Houston, TX USA. [Seldins, Michael F.] Univ Calif Davis, Davis, CA USA. [Worthington, Jane] Univ Manchester, Manchester, Lancs, England. [Seielstad, Mark] Genome Inst Singapore, Singapore, Singapore. [Begovich, Ann B.] Celera Diagnost, Alameda, CA USA. [Daly, Mark J.] Broad Inst, Boston, MA USA. RI Padyukov, Leonid/A-4890-2009 OI Padyukov, Leonid/0000-0003-2950-5670 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S620 EP S620 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244201469 ER PT J AU Reveille, JD Sims, AM Maksymowych, WP Ward, MM Stone, MA Rahman, P Weisman, MH Inman, RD Gladman, DD Davis, JC Learch, TJ Savage, L Diekman, L Danoy, P Pointon, JJ Zhou, XD Evans, D Wordsworth, BP Brown, MA AF Reveille, John D. Sims, Anne-Marie Maksymowych, Walter P. Ward, Michael M. Stone, Millicent A. Rahman, Proton Weisman, Michael H. Inman, Robert D. Gladman, Dafna D. Davis, John C. Learch, Thomas J. Savage, Laurie Diekman, Laura Danoy, Patrick Pointon, Jennifer J. Zhou, Xiaodong Evans, David Wordsworth, B. Paul Brown, Matthew A. TI Genomewide association study in Ankylosing spondylitis identifies major Non-MHC genetic determinants of disease susceptibility SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Reveille, John D.; Diekman, Laura; Zhou, Xiaodong] Univ Texas Houston, Hlth Sci Ctr, Houston, TX USA. [Sims, Anne-Marie; Danoy, Patrick; Brown, Matthew A.] Univ Queensland, Brisbane, Qld, Australia. [Maksymowych, Walter P.] Univ Alberta, Edmonton, AB, Canada. [Ward, Michael M.] NIAMS, Intramural Res Program, Bethesda, MD USA. [Stone, Millicent A.] RNHRD, Bath, Avon, England. [Rahman, Proton] Mem Univ Newfoundland, St John, NF, Canada. [Weisman, Michael H.; Learch, Thomas J.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Inman, Robert D.; Gladman, Dafna D.] Toronto Western Hosp, Toronto, ON M5T 2S8, Canada. [Davis, John C.] UCSF, San Francisco, CA USA. [Pointon, Jennifer J.; Wordsworth, B. Paul] Univ Oxford, Oxford, England. [Evans, David] Univ Bristol, Bristol, Avon, England. NR 0 TC 2 Z9 2 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S609 EP S609 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244201442 ER PT J AU Rider, L Lachenbruch, P James-Newton, L Cabalar, I Feldman, BM Ravelli, A Myones, B Rennebohm, R Pachman, L Villalba, M Adams, E Lindsley, C Wallace, C Ballinger, S Zemel, L Reed, A Miller, F AF Rider, L. Lachenbruch, P. James-Newton, L. Cabalar, I. Feldman, B. M. Ravelli, A. Myones, B. Rennebohm, R. Pachman, L. Villalba, M. Adams, E. Lindsley, C. Wallace, C. Ballinger, S. Zemel, L. Reed, A. Miller, F. TI Predictors of calcinosis in juvenile and adult dermatomyositis (DM) SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Rider, L.; Lachenbruch, P.; James-Newton, L.; Cabalar, I.; Feldman, B. M.; Ravelli, A.; Myones, B.; Rennebohm, R.; Pachman, L.; Villalba, M.; Adams, E.; Lindsley, C.; Wallace, C.; Ballinger, S.; Zemel, L.; Reed, A.; Miller, F.] NIEHS, IMACS Grp, NIH, DHHS, Bethesda, MD USA. RI Feldman, Brian/A-8586-2011 NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S230 EP S230 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244200192 ER PT J AU Rider, L Lachenbruch, P James-Newton, L Cabalar, I Feldman, BM Ravelli, A Myones, B Rennebohm, R Pachman, L Villalba, M Adams, E Lindsley, C Wallace, C Ballinger, S Zemel, L Reed, A Miller, F AF Rider, L. Lachenbruch, P. James-Newton, L. Cabalar, I. Feldman, B. M. Ravelli, A. Myones, B. Rennebohm, R. Pachman, L. Villalba, M. Adams, E. Lindsley, C. Wallace, C. Ballinger, S. Zemel, L. Reed, A. Miller, F. TI Effects of treatment on disease damage in juvenile and adult myositis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Rider, L.; Lachenbruch, P.; James-Newton, L.; Cabalar, I.; Feldman, B. M.; Ravelli, A.; Myones, B.; Rennebohm, R.; Pachman, L.; Villalba, M.; Adams, E.; Lindsley, C.; Wallace, C.; Ballinger, S.; Zemel, L.; Reed, A.; Miller, F.] NIEHS, IMACS Grp, NIH, DHHS, Bethesda, MD USA. RI Feldman, Brian/A-8586-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S229 EP S229 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244200191 ER PT J AU Ryan, JG Booty, MG Barham, B Remmers, EF Barron, K Kastner, DL Aksentijevich, I Masters, SL AF Ryan, John G. Booty, Matthew G. Barham, Beverly Remmers, Elaine F. Barron, Karyl Kastner, Daniel L. Aksentijevich, Ivona Masters, Seth L. TI Clinical and functional significance of P369S and R408Q variants in the familial Mediterranean fever-associated gene MEFV SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Ryan, John G.; Booty, Matthew G.; Barham, Beverly; Remmers, Elaine F.; Kastner, Daniel L.; Aksentijevich, Ivona; Masters, Seth L.] NIAMSD, Bethesda, MD 20892 USA. [Barron, Karyl] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S614 EP S614 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244201454 ER PT J AU Ryan, JG Balow, JE Barham, BK Sun, HW Barron, KS Kasmer, DL Aksentijevich, I AF Ryan, John G. Balow, James E., Jr. Barham, Beverly K. Sun, Hong-Wei Barron, Karyl S. Kasmer, Daniel L. Aksentijevich, Ivona TI Identification and analysis of gene-expression signatures in peripheral blood leukocytes of patients with the tumor necrosis factor receptor-associated periodic syndrome (TRAPS) SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Ryan, John G.; Balow, James E., Jr.; Barham, Beverly K.; Sun, Hong-Wei; Kasmer, Daniel L.; Aksentijevich, Ivona] NIAMSD, Bethesda, MD 20892 USA. [Barron, Karyl S.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S613 EP S614 PG 2 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244201453 ER PT J AU Ryan, JG Booty, MG Balow, JE Barham, BK Sun, HW Barron, KS Kastner, DL Aksentijevich, I AF Ryan, John G. Booty, Matthew G. Balow, James E., Jr. Barham, Beverly K. Sun, Hong-Wei Barron, Karyl S. Kastner, Daniel L. Aksentijevich, Ivona TI Identification and analysis of gene-expression signatures in peripheral blood leukocytes of patients with hyperimmunoglobulinemia D with periodic fever syndrome (HIDS) SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Ryan, John G.; Booty, Matthew G.; Balow, James E., Jr.; Barham, Beverly K.; Sun, Hong-Wei; Kastner, Daniel L.; Aksentijevich, Ivona] Natl Inst Arthrit & Musculoskeletal & Skin Dis, Bethesda, MD USA. [Barron, Karyl S.] NIAID, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0004-3591 J9 ARTHRITIS RHEUM-US JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S496 EP S496 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244201151 ER PT J AU Stummvoll, GH DiPaolo, RJ Huter, EN Davidson, TS Glass, D Ward, JM Shevach, EM AF Stummvoll, Georg H. DiPaolo, Richard J. Huter, Eva N. Davidson, Todd S. Glass, Deborah Ward, Jerrold M. Shevach, Ethan M. TI Naturally occurring regulatory T cells (nTreg) can effectively suppress autoimmune disease mediated by in vitro pre-differentiated Th1 and Th2, but not Th17 effector T cells SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Stummvoll, Georg H.] Med Univ Vienna, Vienna, Austria. [DiPaolo, Richard J.] Dept Mol Microbiol & Immunol, St Louis, MO USA. [Huter, Eva N.; Davidson, Todd S.; Glass, Deborah; Shevach, Ethan M.] NIAID, Immunol Lab, Cellular Immunol Sect, NIH, Bethesda, MD 20892 USA. [Ward, Jerrold M.] NIAID, Comparat Med Branch, Infect Dis Pathogenesis Sect, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S840 EP S840 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202320 ER PT J AU Takatori, H Kanno, Y Tat, CM Weiss, G O'Shea, JJ AF Takatori, Hiroaki Kanno, Yuka Tat, Cristina M. Weiss, Greta O'Shea, John J. TI Lymphoid tissue inducer-like cells are an innate source of tL-17 and IL-22 SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Takatori, Hiroaki; Kanno, Yuka; O'Shea, John J.] NIAMSD, LCBS, MIIB, Bethesda, MD 20892 USA. [Tat, Cristina M.] DNAX Res Inst Mol & Cellular Biol Inc, Dept Discovery Res, Palo Alto, CA 94304 USA. [Weiss, Greta] UPENN NIH Grad Program, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S189 EP S189 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244200079 ER PT J AU Tzioufas, AG Hirai, H Wu, T Kingman, A Notkins, AL AF Tzioufas, Athanasios G. Hirai, H. Wu, T. Kingman, A. Notkins, A. L. TI Development of liquid phase radioimmunoprecipitation assays for the detection of major and minor autoantigens in primary Sjogren's syndrome (pss). Sensitivity, specificity and comparison with Elisa and counterimmunoelectrophoresis (cie) SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Tzioufas, Athanasios G.] Univ Athens Greece, Sch Med, Athens, Greece. [Hirai, H.; Wu, T.; Kingman, A.; Notkins, A. L.] NIDCR, Expt Med Lab, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S791 EP S791 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202180 ER PT J AU Ullrich, KR Zhou, XD Ward, MM Weisman, MH Brown, MA Reveille, JD Xiong, MM AF Ullrich, Korey R. Zhou, Xiaodong Ward, Michael M. Weisman, Michael H. Brown, Matthew A. Reveille, John D. Xiong, Momiao TI Genetic network involving ARTS1, IL23R, ILIA, and HLA-B27 contributes to disease susceptibility in Ankylosing spondylitis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Ullrich, Korey R.; Zhou, Xiaodong; Reveille, John D.; Xiong, Momiao] Univ Houston, Hlth Sci Ctr, Houston, TX USA. [Ward, Michael M.] NIAMS, Bethesda, TX USA. [Weisman, Michael H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Brown, Matthew A.] Univ Queensland, Brisbane, Qld, Australia. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S944 EP S944 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202595 ER PT J AU Vosters, JLG Landek, MA Yin, H Tak, PP Caturegli, P Chiorini, JA AF Vosters, Jelle L. G. Landek, Melissa A. Yin, Hongen Tak, Paul P. Caturegli, Patrizio Chiorini, John A. TI Gender specific Sjogren's syndrome like salivary gland dysfunction after IL-12 overexpression in mice SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Vosters, Jelle L. G.; Tak, Paul P.] Univ Amsterdam, Div Clin Immunol & Rheumatol, Acad Med Ctr, Amsterdam, Netherlands. [Landek, Melissa A.; Caturegli, Patrizio] Johns Hopkins Sch Med, Dept Pathol, Baltimore, MD USA. [Yin, Hongen; Chiorini, John A.] Natl Inst Dent & Craniofacial Res, Mol Physiol & Therapeut Branch, Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S795 EP S796 PG 2 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244202195 ER PT J AU Ward, MM Guthrie, LC AF Ward, Michael M. Guthrie, Lori C. TI Patients' ratings of clinically important changes in pain and physical function in rheumatoid arthritis SO ARTHRITIS AND RHEUMATISM LA English DT Meeting Abstract CT 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals CY OCT 24-29, 2008 CL San Francisco, CA SP Amer Coll Rheumatol, Assoc Rheumatol Hlth Profess C1 [Ward, Michael M.; Guthrie, Lori C.] NIAMSD, NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD SEP PY 2008 VL 58 IS 9 SU S BP S205 EP S205 PG 1 WC Rheumatology SC Rheumatology GA 348XU UT WOS:000259244200124 ER PT J AU Lenas, P Moreno, A Ikonomou, L Mayer, J Honda, H Novellino, A Pizarro, C Nicodemou-Lena, E Rodergas, S Pintor, J AF Lenas, Petros Moreno, Angel Ikonomou, Laertis Mayer, Joerg Honda, Hiroyuki Novellino, Antonio Pizarro, Camilo Nicodemou-Lena, Eleni Rodergas, Silvia Pintor, Jesus TI The complementarity of the technical tools of tissue engineering and the concepts of artificial organs for the design of functional bioartificial tissues SO ARTIFICIAL ORGANS LA English DT Article DE artificial organs; tissue engineering; biomedical engineering; complex systems ID PARKINSONS-DISEASE; INSULIN-RELEASE; LIVER; TRANSPLANTATION; HETEROGENEITY; CARTILAGE; SCAFFOLD; ZONATION; GLUCOSE; METABOLISM AB Although tissue engineering uses powerful biological tools, it still has a weak conceptual foundation, which is restricted at the cell level. The design criteria at the cell level are not directly related with the tissue functions, and consequently, such functions cannot be implemented in bioartificial tissues with the currently used methods. On the contrary, the field of artificial organs focuses on the function of the artificial organs that are treated in the design as integral entities, instead of the optimization of the artificial organ components. The field of artificial organs has already developed and tested methodologies that are based on system concepts and mathematical-computational methods that connect the component properties with the desired global organ function. Such methodologies are needed in tissue engineering for the design of bioartificial tissues with tissue functions. Under the framework of biomedical engineering, artificial organs and tissue engineering do not present competitive approaches, but are rather complementary and should therefore design a common future for the benefit of patients. C1 [Lenas, Petros; Moreno, Angel; Pizarro, Camilo; Nicodemou-Lena, Eleni; Rodergas, Silvia] Univ Complutense, Fac Vet, Dept Biochem & Mol Biol 4, E-28040 Madrid, Spain. [Pintor, Jesus] Univ Complutense, Sch Opt, Dept Biochem & Mol Biol 4, E-28040 Madrid, Spain. [Ikonomou, Laertis] NIDDK NIH, Clin Endocrinol Branch, Recceptors & Hormone Act Sect, Bethesda, MD USA. [Mayer, Joerg] WoodWelding SA, Zug, Switzerland. [Honda, Hiroyuki] Nagoya Univ, Dept Biotechnol, Sch Engn, Nagoya, Aichi 4648601, Japan. [Novellino, Antonio] Ett Srl, Ett R&D Lab, Genoa, Italy. RP Lenas, P (reprint author), PTM, Parque Cient Madrid, C Santiago Grisolia 2, Madrid 28760, Spain. EM plenas@opt.ucm.es RI Ikonomou, Laertis/D-4579-2009 OI Ikonomou, Laertis/0000-0003-0993-6713 FU European project [LSHM-CT-2007-037862] FX The authors would like to thank the reviewers for critical comments that lead to the conclusion that artificial organs methodologies have been incorporated in the tissue engineering methods in a greater degree than initially presented in the article. The partial financial support from the European project LSHM-CT-2007-037862 is gratefully acknowledged. NR 34 TC 5 Z9 6 U1 1 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0160-564X J9 ARTIF ORGANS JI Artif. Organs PD SEP PY 2008 VL 32 IS 9 BP 742 EP 747 DI 10.1111/j.1525-1594.2008.00599.x PG 7 WC Engineering, Biomedical; Transplantation SC Engineering; Transplantation GA 349GU UT WOS:000259270100011 PM 18684202 ER PT J AU Wongtada, N Rice, G AF Wongtada, Nittaya Rice, Gillian TI Multidimensional latent traits of perceived organizational innovation: Differences between Thai and Egyptian employees SO ASIA PACIFIC JOURNAL OF MANAGEMENT LA English DT Article DE item response theory; multidimensional latent regression; employee creativity; organizational innovation; Thailand; Egypt ID WORK-ENVIRONMENT; CREATIVITY; SUPPORT; DETERMINANTS; LEADERSHIP; BEHAVIORS; CONTEXT; MODEL; FIRMS; PERCEPTIONS AB A new approach, the multidimensional latent regression (MLR) approach of item response theory, is employed to evaluate the dimensions of individual employee creativity, workplace atmosphere, and workplace innovative activity. Based on the MLR concept, the relationships among the measurement scales of these variables are tested for their unidimensionality versus multidimensionality. Multidimensionality was found. While workplace atmosphere is closely linked to workplace innovative activity, individual employee creativity forms its own dimension but is still positively linked to the other two measures. To achieve an accurate comparison between the two groups of Thai and Egyptian employees who have the same levels of agreement with the scale items, it is necessary to adjust the scores of Egyptian employees downwards. C1 [Rice, Gillian] Arizona State Univ, Sch Global Management & Leadership, Phoenix, AZ 85069 USA. [Wongtada, Nittaya] NIDA, Grad Sch Business Adm, Bangkok 10240, Thailand. RP Rice, G (reprint author), Arizona State Univ, Sch Global Management & Leadership, POB 37100, Phoenix, AZ 85069 USA. EM Gillian.Rice@asu.edu NR 77 TC 5 Z9 6 U1 5 U2 16 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0217-4561 J9 ASIA PAC J MANAG JI Asia Pac. J. Manag. PD SEP PY 2008 VL 25 IS 3 SI SI BP 537 EP 562 DI 10.1007/s10490-008-9085-4 PG 26 WC Management SC Business & Economics GA 352BL UT WOS:000259470100010 ER PT J AU Fuglesteg, BN Suleman, N Tiron, C Kanhema, T Lacerda, L Andreasen, TV Sack, MN Jonassen, AK Mjos, OD Opie, LH Lecour, S AF Fuglesteg, Britt N. Suleman, Naushaad Tiron, Crina Kanhema, Tambuzai Lacerda, Lydia Andreasen, Thomas V. Sack, Michael N. Jonassen, Anne K. Mjos, Ole D. Opie, Lionel H. Lecour, Sandrine TI Signal transducer and activator of transcription 3 is involved in the cardioprotective signalling pathway activated by insulin therapy at reperfusion SO BASIC RESEARCH IN CARDIOLOGY LA English DT Article DE insulin; myocardial infarction; ischemia; signal transduction; STAT3 ID ACUTE MYOCARDIAL-INFARCTION; JAK2 TYROSINE KINASE; FACTOR-I RECEPTOR; PHOSPHATIDYLINOSITOL 3-KINASE; CELL PROLIFERATION; STAT3 ACTIVATION; CARDIAC MYOCYTE; MYELOMA CELLS; P70S6 KINASE; GROWTH AB Objective To evaluate the significance of the JAK-STAT pathway in insulin-induced cardioprotection from reperfusion injury. Methods In isolated perfused rat hearts subjected to insulin therapy (0.3 mU/ml) +/- AG490 (5 mu M, JAK-STAT inhibitor), the phosphorylation state of STAT3 and Akt was determined after 15 min of reperfusion. Infarct size was measured after 120 min of reperfusion. Isolated cardiac myocytes from wild type (WT) and cardiac specific STAT3 deficient mice were treated with insulin at reoxygenation following simulated ischemia (SI, 26 h). Cell viability was measured after 120 min of reoxygenation following SI, whereas phosphorylation state of Akt was measured after 15 min of reoxygenation following SI. Results Insulin given at reperfusion led to phosphorylation of STAT3 and Akt both of which were inhibited by AG490. AG490 also blocked the insulin-dependent decrease in infarct size, supporting a role for JAK-STAT in cardioprotection. In addition, insulin protection from SI was blocked in myocytes from the STAT3 deficient mice, or in WT mice treated with AG490. Furthermore, insulin failed to phosphorylate Akt in the STAT3 deficient cardiomyocytes. Conclustion Insulin-induced cardioprotection at reperfusion occurs through activation of STAT3. Inhibiting STAT3 by AG490, or STAT3 depletion in cardiac myocytes affects activation of Akt, suggesting close interaction between STAT3 and Akt in the cardioprotective signalling pathway activated by insulin treatment at reperfusion. C1 [Fuglesteg, Britt N.; Andreasen, Thomas V.; Mjos, Ole D.] Univ Tromso, Dept Med Physiol, Fac Med, N-9037 Tromso, Norway. [Suleman, Naushaad; Lacerda, Lydia; Opie, Lionel H.; Lecour, Sandrine] Univ Cape Town, Dept Med, Fac Hlth Sci, Hatter Inst Cardiovasc Res, ZA-7925 Cape Town, South Africa. [Tiron, Crina; Kanhema, Tambuzai; Jonassen, Anne K.] Univ Bergen, Dept Biomed, Fac Med, Bergen, Norway. [Sack, Michael N.] NHLBI, NIH 10, Bethesda, MD 20892 USA. RP Fuglesteg, BN (reprint author), Univ Tromso, Dept Med Physiol, Fac Med, N-9037 Tromso, Norway. EM brittf@fagmed.uit.no FU Norwegian Research Council; Medical Research Council of South Africa; Norwegian Council on Cardiovascular Diseases; The Norwegian National Health Association; South African National Research Foundation; Servier Senior Fellowship in Heart Failure FX This work was supported by the Norwegian Research Council, the SOUTH AFRICA-NORWAY programme on research co-operation, and by the Medical Research Council of South Africa. B.N.F was supported by the Norwegian Council on Cardiovascular Diseases, The Norwegian National Health Association. N.S was supported by the South African National Research Foundation. S.L was supported by a Servier Senior Fellowship in Heart Failure. We thank Shizuo Akira for the flexed STAT3 mouse and Kenneth R Chien for the MLC2V cre-recombinase mice, and Professor Kirsti Ytrehus for helpful comments. NR 50 TC 55 Z9 56 U1 1 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 0300-8428 J9 BASIC RES CARDIOL JI Basic Res. Cardiol. PD SEP PY 2008 VL 103 IS 5 BP 444 EP 453 DI 10.1007/s00395-008-0728-x PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 338VO UT WOS:000258537700005 PM 18500485 ER PT J AU Samuels, JF Bienvenu, OJ Pinto, A Murphy, DL Piacentini, J Rauch, SL Fyer, AJ Grados, MA Greenberg, BD Knowles, JA McCracken, JT Cullen, B Riddle, MA Rasmussen, SA Pauls, DL Liang, KY Hoehn-Saric, R Pulver, AE Nestadt, G AF Samuels, Jack F. Bienvenu, O. Joseph Pinto, Anthony Murphy, Dennis L. Piacentini, John Rauch, Scott L. Fyer, Abby J. Grados, Marco A. Greenberg, Benjamin D. Knowles, James A. McCracken, James T. Cullen, Bernadette Riddle, Mark A. Rasmussen, Steven A. Pauls, David L. Liang, Kung-Yee Hoehn-Saric, Rudolf Pulver, Ann E. Nestadt, Gerald TI Sex-specific clinical correlates of hoarding in obsessive-compulsive disorder SO BEHAVIOUR RESEARCH AND THERAPY LA English DT Article DE obsessive-compulsive disorder; hoarding; comorbidity; personality disorders; personality; sex differences ID OCD COLLABORATIVE GENETICS; FACTOR-ANALYZED SYMPTOM; PERSONALITY-DISORDER; COGNITIVE ASPECTS; SIBLING PAIRS; DIMENSIONS; FAMILY; RATIONALE; SEVERITY AB Little is known about whether the clinical correlates of hoarding behavior are different in men and women with obsessive-compulsive disorder (OCD). In the current study, we evaluated the association of hoarding with categories of obsessions and compulsions, psychiatric disorders, personality dimensions, and other clinical characteristics separately in 151 men and 358 women with OCD who were examined during the OCD Collaborative Genetics Study. We found that, among men but not women, hoarding was associated with aggressive, sexual, and religious obsessions and checking compulsions. In men, hoarding was associated with generalized anxiety disorder and tics whereas, among women, hoarding was associated with social phobia, post-traumatic stress disorder, body dysmorphic disorder, nail biting, and skin picking. In women but not men, hoarding was associated with schizotypal and dependent personality disorder dimensions, and with low conscientiousness. These findings indicate that specific clinical correlates of hoarding in OCD are different in men and women and may reflect sex-specific differences in the course, expression, and/or etiology of hoarding behavior in OCD. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Samuels, Jack F.; Bienvenu, O. Joseph; Grados, Marco A.; Cullen, Bernadette; Riddle, Mark A.; Hoehn-Saric, Rudolf; Pulver, Ann E.; Nestadt, Gerald] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. [Pinto, Anthony; Greenberg, Benjamin D.; Rasmussen, Steven A.] Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. [Murphy, Dennis L.] NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. [Piacentini, John; McCracken, James T.] Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. [Rauch, Scott L.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. [Fyer, Abby J.] Columbia Univ, New York State Psychiat Inst, Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. [Knowles, James A.] Univ So Calif, Sch Med, Dept Psychiat & Behav Sci, Los Angeles, CA 90033 USA. [Pauls, David L.] Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. [Pauls, David L.] Harvard Univ, Sch Med, Boston, MA 02114 USA. [Liang, Kung-Yee] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21287 USA. RP Samuels, JF (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 600 N Wolfe St,Meyer 4-81, Baltimore, MD 21287 USA. EM jacks@jhmi.edu RI Piacentini, John/C-4645-2011; Liang, Kung-Yee/F-8299-2011; Pinto, Anthony/D-2718-2017; OI Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 FU NCRR NIH HHS [RR00052, M01 RR000052]; NIMH NIH HHS [K23 MH064543, K23-MH64543, R01 MH050214, R01 MH050214-09, R01 MH071507, R01 MH079487, R01 MH50214] NR 43 TC 13 Z9 14 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0005-7967 J9 BEHAV RES THER JI Behav. Res. Ther. PD SEP PY 2008 VL 46 IS 9 BP 1040 EP 1046 DI 10.1016/j.brat.2008.06.005 PG 7 WC Psychology, Clinical SC Psychology GA 357FZ UT WOS:000259833000008 PM 18692168 ER PT J AU LaPorte, JL Ren-Patterson, RF Murphy, DL Kalueff, AV AF LaPorte, Justin L. Ren-Patterson, Renee F. Murphy, Dennis L. Kalueff, Allan V. TI Refining psychiatric genetics: from 'mouse psychiatry' to understanding complex human disorders SO BEHAVIOURAL PHARMACOLOGY LA English DT Article; Proceedings Paper CT European-Behavioural-Pharmacology-Society Workshop on Behavioural Genetics and Neuropsychiatric Disorders CY AUG 25-27, 2008 CL Cork, IRELAND SP European Behavioural Pharmacol Soc DE behavioral domains; genetic factors; psychiatric disorders; spectrum nature of pathogenesis ID OBSESSIVE-COMPULSIVE DISORDER; TRANSPORTER KNOCKOUT MICE; SEROTONIN TRANSPORTER; ENVIRONMENT INTERACTIONS; EPIGENETIC REGULATION; SPECTRUM DISORDERS; TOURETTES-SYNDROME; ANXIETY DISORDERS; ANIMAL-MODELS; MUTANT MICE AB Investigating the pathogenesis of psychiatric disorders is a complicated and rigorous task for psychiatric geneticists, as the disorders often involve combinations of genetic, behavioral, personality, and environmental factors. To nurture further progress in this field, a new set of conceptual tools is needed in addition to the currently accepted approaches. Concepts that consider cross-species trait genetics and the interplay between the domains of disorders, as well as the full spectrum of potential symptoms and their place along the pathogenetic continuum, are particularly important to address these needs. Here, we outline recent concepts and approaches that can help refine the field and enable more precise dissection of the genetic mechanisms contributing to psychiatric disorders. C1 [LaPorte, Justin L.; Ren-Patterson, Renee F.; Murphy, Dennis L.; Kalueff, Allan V.] NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. [Kalueff, Allan V.] Georgetown Univ, Sch Med, Dept Physiol & Biophys, Washington, DC 20007 USA. RP Kalueff, AV (reprint author), NIMH, Clin Sci Lab, Bldg 10,Room 3D41,10 Ctr Dr MSC 1264, Bethesda, MD 20892 USA. EM avkalueff@inbox.ru FU Intramural NIH HHS [Z01 MH000332-29] NR 64 TC 20 Z9 20 U1 4 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2008 VL 19 IS 5-6 BP 377 EP 384 DI 10.1097/FBP.0b013e32830dc09b PG 8 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 342DD UT WOS:000258763900003 PM 18690099 ER PT J AU Perona, MTG Waters, S Hall, FS Sora, I Lesch, KP Murphy, DL Caron, M Uhl, GR AF Perona, Maria T. G. Waters, Shonna Hall, Frank Scott Sora, Ichiro Lesch, Klaus-Peter Murphy, Dennis L. Caron, Marc Uhl, George R. TI Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions SO BEHAVIOURAL PHARMACOLOGY LA English DT Article; Proceedings Paper CT European-Behavioural-Pharmacology-Society Workshop on Behavioural Genertics and Neuropsychiatric Disorders CY AUG 25-27, 2008 CL Cork, IRELAND SP European Behavioural Pharmacol Soc DE DAT knockout; forced swim test; mouse; NET knockout; SERT knockout; sucrose intake; tail suspension test ID FORCED SWIMMING TEST; TAIL-SUSPENSION TEST; ANTIDEPRESSANT DRUGS; PLACE PREFERENCE; WISTAR RATS; NORADRENERGIC ANTIDEPRESSANTS; COCAINE REWARD; INBRED STRAINS; IN-VIVO; LACKING AB Antidepressant drugs produce therapeutic actions and many of their side effects via blockade of the plasma membrane transporters for serotonin (SERT/SLC6A2), norepinephrine (NET/SLC6A1), and dopamine (DAT/SLC6A3). Many antidepressants block several of these transporters; some are more selective. Mouse gene knockouts of these transporters provide interesting models for possible effects of chronic antidepressant treatments. To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. To dissociate general activity from potential antidepressant effects three types of behavior were assessed in the FST: immobility, climbing, and swimming. In confirmation of earlier reports, both DAT KO and NET KO mice exhibited less immobility than wild-type littermates whereas SERT KO mice did not. Effects of DAT deletion were not simply because of hyperactivity, as decreased immobility was observed in DAT + / - mice that were not hyperactive as well as in DAT - / - mice that displayed profound hyperactivity. Climbing was increased, whereas swimming was almost eliminated in DAT - / - mice, and a modest but similar effect was seen in NET KO mice, which showed a modest decrease in locomotor activity. Combined increases in climbing and decreases in immobility are characteristic of FST results in antidepressant animal models, whereas selective effects on swimming are associated with the effects of stimulant drugs. Therefore, an effect on climbing is thought to more specifically reflect antidepressant effects, as has been observed in several other proposed animal models of reduced depressive phenotypes. A similar profile was observed in the tail suspension test, where DAT, NET, and SERT knockouts were all found to reduce immobility, but much greater effects were observed in DAT KO mice. However, to further determine whether these effects of DAT KO in animal models of depression may be because of the confounding effects of hyperactivity, mice were also assessed in a sucrose consumption test. Sucrose consumption was increased in DAT KO mice consistent with reduced anhedonia, and inconsistent with competitive hyperactivity; no increases were observed in SERT KO or NET KO mice. In summary, the effects of DAT KO in animal models of depression are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support reevaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade. C1 [Perona, Maria T. G.; Waters, Shonna; Hall, Frank Scott; Uhl, George R.] Natl Inst Drug Abuse, Mol Neurobiol Branch, IRP, NIH, Baltimore, MD 21224 USA. [Sora, Ichiro] Tohoku Univ, Div Psychobiol, Dept Neurosci, Grad Sch Med, Sendai, Miyagi, Japan. [Lesch, Klaus-Peter] Univ Wurzburg, Dept Psychiat, D-97070 Wurzburg, Germany. [Murphy, Dennis L.] NIMH, Clin Sci Lab, IRP, NIH, Bethesda, MD 20892 USA. [Caron, Marc] Duke Univ, Dept Cell Biol, Durham, NC USA. [Caron, Marc] Duke Univ, Dept Med, Durham, NC USA. RP Uhl, GR (reprint author), Natl Inst Drug Abuse, Mol Neurobiol Branch, IRP, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM guhl@intra.nida.nih.gov RI Lesch, Klaus-Peter/J-4906-2013; Hall, Frank/C-3036-2013 OI Lesch, Klaus-Peter/0000-0001-8348-153X; Hall, Frank/0000-0002-0822-4063 FU Intramural NIH HHS [Z99 DA999999] NR 69 TC 81 Z9 87 U1 3 U2 22 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2008 VL 19 IS 5-6 BP 566 EP 574 DI 10.1097/FBP.0b013e32830cd80f PG 9 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 342DD UT WOS:000258763900015 PM 18690111 ER PT J AU Holmes, A Hefner, K Whittle, N Singewald, N AF Holmes, A. Hefner, K. Whittle, N. Singewald, N. TI Exploring the genetic and neural basis of fear extinction using mouse models SO BEHAVIOURAL PHARMACOLOGY LA English DT Meeting Abstract CT European-Behavioural-Pharmacology-Society Workshop on Behavioural Genetics and Neuropsychiatric Disorders CY AUG 25-27, 2008 CL Cork, IRELAND SP European Behavioural Pharmacol Soc C1 [Holmes, A.; Hefner, K.] NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, NIH, Rockville, MD 20852 USA. [Whittle, N.; Singewald, N.] Univ Innsbruck, Dept Pharmacol & Toxicol, Inst Pharm, A-6020 Innsbruck, Austria. [Whittle, N.; Singewald, N.] Univ Innsbruck, Ctr Mol Biosci, A-6020 Innsbruck, Austria. 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 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2008 VL 19 IS 5-6 MA S3 BP 650 EP 651 PG 2 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 342DD UT WOS:000258763900026 ER PT J AU Wultsch, I Popp, S Lesch, KP Wess, J Reif, A AF Wultsch, I. Popp, S. Lesch, K. -P. Wess, J. Reif, A. TI Behavioural phenotyping of M1 muscarinic acetylcholine receptor-knockout mice SO BEHAVIOURAL PHARMACOLOGY LA English DT Meeting Abstract CT European-Behavioural-Pharmacology-Society Workshop on Behavioural Genertics and Neuropsychiatric Disorders CY AUG 25-27, 2008 CL Cork, IRELAND SP European Behavioural Pharmacol Soc C1 [Wultsch, I.; Popp, S.; Lesch, K. -P.; Reif, A.] Univ Wurzburg, Dept Psychiat & Psychotherapy, Wurzburg, Germany. [Wess, J.] NIH, Mol Signalling Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. EM Wultsch_t@klinik.uni-wuerzburg.de NR 0 TC 0 Z9 0 U1 2 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0955-8810 J9 BEHAV PHARMACOL JI Behav. Pharmacol. PD SEP PY 2008 VL 19 IS 5-6 MA S37 BP 661 EP 661 PG 1 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 342DD UT WOS:000258763900060 ER PT J AU Williams, KM Gress, RE AF Williams, Kristen M. Gress, Ronald E. TI Immune reconstitution and implications for immunotherapy following haematopoietic stem cell transplantation SO BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY LA English DT Review DE immune reconstition; cellular immunotherapy; allogene stem cell transplant; thymus ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; REGULATORY T-CELLS; KIR LIGAND INCOMPATIBILITY; RECEPTOR EXCISION CIRCLE; DENDRITIC CELLS; B-CELL; ALLOGENEIC TRANSPLANTATION; HOMEOSTATIC PROLIFERATION; INTENSIVE CHEMOTHERAPY AB Recovery of a fully functional immune system is a slow and often incomplete process following allogen stem cell transplantation. While innate immunity reconstitutes quickly, adaptive B and especially T-cell lymphopoeisis may be compromised for years following transplantation. Ina large part, these immune system deficits are due to the decrease of even absence of thymopoiesis following transplantation. Thereby, T-cell reconstitution initially relies upon expansion of mature donot Tcells a proliferation driven by high cytokine levels and the presence of allo reactive antigens. this peripheral mechanism of T-cell generation may have important clinical consequences. By expanding tumouricidal T cells it may provide a venue to enhance T-cellular immunotherapy following transplantation. Alternatively, decreased thymic function may impair long-term anti-tumour immunity and increase the likelihood of graft-versus-host diseases. C1 [Williams, Kristen M.; Gress, Ronald E.] NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Gress, RE (reprint author), NCI, Expt Transplantat & Immunol Branch, NIH, CRC 3E-3300,10 Ctr Dr, Bethesda, MD 20892 USA. EM gressr@exchange.nih.gov FU Intramural NIH HHS [Z01 BC010525-05, Z99 CA999999] NR 112 TC 34 Z9 35 U1 1 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1521-6926 J9 BEST PRACT RES CL HA JI Best Pract. Res. Clin. Haematol. PD SEP PY 2008 VL 21 IS 3 BP 579 EP 596 DI 10.1016/j.beha.2008.06.003 PG 18 WC Hematology SC Hematology GA 359CL UT WOS:000259963700014 PM 18790456 ER PT J AU Diaz-Gonzalez, R Perez-Pertejo, Y Pommier, Y Balana-Fouce, R Reguera, RM AF Diaz-Gonzalez, Rosario Perez-Pertejo, Yolanda Pommier, Yves Balana-Fouce, Rafael Reguera, Rosa M. TI Mutational study of the "catalytic tetrad" of DNA topoisomerase IB from the hemoflagellate Leishmania donovani: Role of Asp-353 and Asn-221 in camptothecin resistance SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE topoisomerase IB; Leishmania; trypanosomatids; camptothecin; site-directed mutagenesis; tropical diseases ID ACTIVE-SITE TYROSINE; ANTIPROLIFERATIVE ACTIVITY; MECHANISM; INDOLOCARBAZOLE; IDENTIFICATION; TRYPANOSOMES; CHEMOTHERAPY; SENSITIVITY; MUTANTS; BINDING AB Leishmania donovani, the causative organism for visceral leishmaniasis, contains a unique bisubunit DNA-topoisomerase IB (LdTopIB). The catalytically active enzyme is a heterodimer constituted by a large subunit (LdTopIL) containing a non-conserved N-terminal end and the phylogenetically conserved core domain, whereas the small subunit (LdTopIS) harbors the C-terminal domain with the characteristic tyrosine residue in the active site. Site-directed mutagenesis was used to substitute the basic amino acid (Arg-314, Lys-352, Arg-410 and His-453) of the LdTopIL subunit by the neutral amino acid alanine. The expression of these mutants in a topoisomerase-free yeast strain produced inactive proteins. Similarly, when the Tyr-222 from small subunit, involved in DNA cleavage, was substituted by Phe no topoisomerase activity was detected in yeast overexpressing extracts. in addition two substitutions involved in camptothecin inhibition were also analyzed. Asp-353 located in the core domain of the large subunit and Asn-221 which heads Tyr-222 in the small subunit, were replaced by Ala and Ser, respectively. These mutants were insensitive to the inhibitor; despite they displayed significant relaxation activity. (C) 2008 Elsevier Inc. All rights reserved. C1 [Diaz-Gonzalez, Rosario; Perez-Pertejo, Yolanda; Balana-Fouce, Rafael; Reguera, Rosa M.] Univ Leon, Dept Farmacol & Toxicol, INTOXCAL, E-24071 Leon, Spain. [Pommier, Yves] NCI, Mol Pharmacol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Balana-Fouce, R (reprint author), Univ Leon, Dept Farmacol & Toxicol, INTOXCAL, Campus Vegazana S-N, E-24071 Leon, Spain. EM pommier@mail.nih.gov; rbalf@unileon.es OI perez-pertejo, yolanda/0000-0003-2361-3785; Reguera, Rosa M/0000-0001-9148-2997; Balana-Fouce, Rafael/0000-0003-0418-6116 FU MEC [AGL2006-07420/GAN]; Instituto de Salud Carlos III [PI06302]; Ministerio de Educacion y Ciencia (MEC) FX This research was partially supported by MEC (grant AGL2006-07420/GAN) and Instituto de Salud Carlos III (grant PI06302) from Ministerio de Salud y Consumo from the Spanish Kingdom. Rosario Diaz Gonzalez is granted with a FPI scholarship funded by Ministerio de Educacion y Ciencia (MEC). NR 39 TC 8 Z9 8 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 EI 1873-2968 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD SEP 1 PY 2008 VL 76 IS 5 BP 608 EP 619 DI 10.1016/j.bcp.2008.06.019 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 343HI UT WOS:000258843700005 PM 18655776 ER PT J AU Brooks, BE Buchanan, SK AF Brooks, Benjamin E. Buchanan, Susan K. TI Signaling mechanisms for activation of extracytoplasmic function (ECF) sigma factors SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Review DE ECF; sigma factor; anti-sigma factor; sigma E; Fecl ID REGULATED INTRAMEMBRANE PROTEOLYSIS; FERRIC CITRATE TRANSPORT; ESCHERICHIA-COLI SIGMA(E); ENVELOPE-STRESS-RESPONSE; OUTER-MEMBRANE RECEPTOR; LIGHT-INDUCED CAROTENOGENESIS; BACTERIUM MYXOCOCCUS-XANTHUS; PSEUDOMONAS-AERUGINOSA; CRYSTAL-STRUCTURE; CYSTIC-FIBROSIS AB A variety of mechanisms are used to signal extracytoplasmic conditions to the cytoplasm. These mechanisms activate extracytoplasmic function (ECF) sigma factors which recruit RNA-polymerase to specific genes in order to express appropriate proteins in response to the changing environment. The two best understood ECF signaling pathways regulate sigma(E)-mediated expression of periplasmic stress response genes in Escherichia coli and Fecl-mediated expression of iron-citrate transport genes in E. coli. Homologues from other Gram-negative bacteria suggest that these two signaling mechanisms and variations on these mechanisms may be the general schemes by which ECF sigma factors are regulated in Gram-negative bacteria. Published by Elsevier B.V. C1 [Brooks, Benjamin E.; Buchanan, Susan K.] NIDDKD, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Buchanan, SK (reprint author), NIDDKD, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. EM skbuchan@helix.nih.gov FU Intramural Research Program of the NIH, National Institute of Diabetes; Digestive and Kidney Diseases FX We are grateful to Andrew Perry and Jennifer K. Hill for critically reading this review and helpful discussions. This work is supported by the Intramural Research Program of the NIH, National Institute of Diabetes and Digestive and Kidney Diseases. NR 128 TC 46 Z9 47 U1 0 U2 14 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD SEP PY 2008 VL 1778 IS 9 BP 1930 EP 1945 DI 10.1016/j.bbamem.2007.06.005 PG 16 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 357WF UT WOS:000259877200016 PM 17673165 ER PT J AU Kono, M Allende, ML Proia, RL AF Kono, Mari Allende, Maria Laura Proia, Richard L. TI Sphingosine-1-phosphate regulation of mammalian development SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Review DE lysophospholipid; S1P; development; vascular; neural; maternal : fetal interface; decidualization ID SPHINGOSINE 1-PHOSPHATE RECEPTOR; PROTEIN-COUPLED RECEPTOR; LYSOPHOSPHATIDIC ACID; EMBRYO IMPLANTATION; FUNCTIONAL-CHARACTERIZATION; VASCULAR MATURATION; LYMPHOCYTE EGRESS; MOLECULAR-CLONING; MICE DEFICIENT; KINASE TYPE-2 AB Sphingosine-1-phosphate (SIP) was first identified as a lysophospholipid metabolite whose formation is required for the irreversible degradation of sphingolipids. Years later, it was discovered that S1P is a bioactive lipid that provokes varied cell responses by acting through cell-surface receptors to drive cell signaling. More recent findings in model organisms have now established that S1P metabolism and signaling are integrated into many physiological systems. We describe here the surprising breadth of function of S1P in mammalian development and the underlying biologic processes that S1P regulates. (c) 2008 Elsevier B.V. All rights reserved. C1 [Kono, Mari; Allende, Maria Laura; Proia, Richard L.] NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Proia, RL (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, Bldg 10,Room 9D-06,10 Ctr Dr,MSC 1821, Bethesda, MD 20892 USA. EM proia@nih.gov RI Proia, Richard/A-7908-2012 FU Intramural NIH HHS [Z01 DK056016-01, Z01 DK056018-01, Z01 DK056015-01, Z01 DK056019-01, Z01 DK056014-01, Z01 DK056017-01] NR 50 TC 27 Z9 27 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD SEP PY 2008 VL 1781 IS 9 BP 435 EP 441 DI 10.1016/j.bbalip.2008.07.001 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 355MC UT WOS:000259712000003 PM 18675379 ER PT J AU Bryan, L Kordula, T Spiegel, S Milstien, S AF Bryan, Lauren Kordula, Tomasz Spiegel, Sarah Milstien, Sheldon TI Regulation and functions of sphingosine kinases in the brain SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Review DE sphingosine kinase; sphingsosine-1-phosphate; phosphorylation; transcription; post-translational modifications; central nervous system ID NERVE GROWTH-FACTOR; OPERATED CALCIUM-CHANNELS; FACTOR-INDUCED ACTIVATION; RAT SENSORY NEURONS; BREAST-CANCER CELLS; 1-PHOSPHATE RECEPTOR; MULTIPLE-SCLEROSIS; PLASMA-MEMBRANE; GENE-EXPRESSION; S1P RECEPTORS AB it has long been known that sphingolipids, especially sphingomyelin, a principal component of myelin, are highly enriched in the central nervous system and are structural components of all eukaryotic cell membranes. In the last few years, substantial evidence has accumulated from studies of many types of cells demonstrating that in addition to their structural roles, their breakdown products form a new class of signaling molecules with potent and myriad regulatory effects on essentially every cell in the body. While the sphingolipid metabolites sphingosine and its precursor ceramide have been associated with cell growth arrest and apoptosis, sphingosine-1-phosphate (S1P) enhances proliferation, differentiation, and cell survival as well as regulates many physiological and pathological processes. The relative levels of these three interconvertible sphingolipid metabolites, and thus cell fate, are strongly influenced by the activity of sphingosine kinases, of which there are two isoforms, designated SphK1 and SphK2, the enzymes that phosphorylate sphingosine to produce S1P. Not much is yet known of the importance of S1P in the central nervous system. Therefore, this review is focused on current knowledge of regulation of SphK1 and SphK2 on both transcriptional and post-translational levels and the functions of these isozymes and their product S1P and its receptors in the central nervous system. (c) 2008 Elsevier B.V. All rights reserved. C1 [Bryan, Lauren; Kordula, Tomasz; Spiegel, Sarah] Virginia Commonwealth Univ, Sch Med, Dept Biochem & Mol Biol, Richmond, VA 23298 USA. [Bryan, Lauren; Kordula, Tomasz; Spiegel, Sarah] Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Richmond, VA 23298 USA. [Milstien, Sheldon] NIMH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem & Mol Biol, 1101 E Marshall St,2011 Sanger Hall, Richmond, VA 23298 USA. EM sspiegel@vcu.edu FU NIH [R01NS044118 (T.K), R01A150094 (S.S.), R01CA61774 (S.S.), R37GM043880 (S.S.)] FX This work was Supported by NIH grants R01NS044118 (T.K), R01A150094 (S.S.), R01CA61774 (S.S.) and R37GM043880 (S.S.). S.M. was Supported by the Intramural Research Program of the National Institute of Mental Health NR 109 TC 48 Z9 48 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD SEP PY 2008 VL 1781 IS 9 BP 459 EP 466 DI 10.1016/j.bbalip.2008.04.008 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 355MC UT WOS:000259712000006 PM 18485923 ER PT J AU Bhanu, NV Lee, YT Oneal, PA Gantt, NM Aerbajinai, W Noel, P Thomas, CJ Miller, JL AF Bhanu, Natarajan V. Lee, Y. Terry Oneal, Patricia A. Gantt, Nicole M. Aerbajinai, Wulin Noel, Pierre Thomas, Craig J. Miller, Jeffery L. TI Inhibition of erythroblast growth and fetal hemoglobin production by ribofuranose-substituted adenosine derivatives SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE LA English DT Article DE human erythropoiesis; cytokine; HbF inhibition; adenosine derivative; SQ22536; hemoglobinopathy ID GAMMA-GLOBIN GENE; SICKLE-CELL-ANEMIA; HUMAN ERYTHROPOIESIS; DEPENDENT PATHWAY; EXPRESSION AB in vivo, inhibition of fetal hemoglobin (HbF) expression in humans around the time of birth causes the clinical manifestation of sickle cell and beta-thalassemia syndromes. Inhibition of HbF among cultured cells was recently described by the adenosine derivative molecule named SQ22536. Here, a primary cell culture model was utilized to further explore the inhibition of HbF by adenosine derivative molecules. SQ22536 demonstrated down-regulation of growth and HbF expression among erythroblasts Cultured from fetal and adult human blood. The effects upon HbF were noted in a majority of cells, and quantitative PCR analysis demonstrated a transcriptional mechanism. Screening assays demonstrated that two additional molecules named 5'-deoxy adenosine and 2',3'-dideoxyadenosine had effects on HbF comparable to SQ22536. Other adenosine derivative molecules, adenosine receptor binding ligands, and cAMP-signaling regulators failed to inhibit HbF in matched cultures. These results suggest that structurally related ribofuranose-substituted adenosine analogues act through an unknown mechanism to inhibit HbF expression in fetal and adult human erythroblasts. Published by Elsevier B.V. C1 [Bhanu, Natarajan V.; Lee, Y. Terry; Oneal, Patricia A.; Gantt, Nicole M.; Aerbajinai, Wulin; Miller, Jeffery L.] NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. [Noel, Pierre] NIH, Dept Lab Med, Hematol Serv, Bethesda, MD 20892 USA. [Thomas, Craig J.] NIH, Chem Biol Core Lab, Bethesda, MD 20892 USA. RP Miller, JL (reprint author), NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. EM jm7f@nih.gov FU NIH; NIDDK FX We thank the Department of Transfusion Medicine for CD34+ cell collection and processing. This research was supported by the Intramural Research Program of the NIH, NIDDK. NR 23 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0925-4439 J9 BBA-MOL BASIS DIS JI Biochim. Biophys. Acta-Mol. Basis Dis. PD SEP PY 2008 VL 1782 IS 9 BP 504 EP 510 DI 10.1016/j.bbadis.2008.05.004 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 349NK UT WOS:000259287300003 PM 18586086 ER PT J AU Li, H Zhan, M AF Li, Huai Zhan, Ming TI Unraveling transcriptional regulatory programs by integrative analysis of microarray and transcription factor binding data SO BIOINFORMATICS LA English DT Article ID INDEPENDENT COMPONENT ANALYSIS; SACCHAROMYCES-CEREVISIAE; CELL-CYCLE; GENE-EXPRESSION; COMPUTATIONAL IDENTIFICATION; MATRIX FACTORIZATION; NETWORK; MODULES; GENOME; DISCOVERY AB Motivation: Unraveling the transcriptional regulatory program mediated by transcription factors (TFs) is a fundamental objective of computational biology, yet still remains a challenge. Method: Here, we present a new methodology that integrates microarray and TF binding data for unraveling transcriptional regulatory networks. The algorithm is based on a two-stage constrained matrix decomposition model. The model takes into account the non-linear structure in gene expression data, particularly in the TF-target gene interactions and the combinatorial nature of gene regulation by TFs. The gene expression profile is modeled as a linear weighted combination of the activity profiles of a set of TFs. The TF activity profiles are deduced from the expression levels of TF target genes, instead directly from TFs themselves. The TF-target gene relationships are derived from ChIP-chip and other TF binding data. The proposed algorithm can not only identify transcriptional modules, but also reveal regulatory programs of which TFs control which target genes in which specific ways (either activating or inhibiting). Results: In comparison with other methods, our algorithm identifies biologically more meaningful transcriptional modules relating to specific TFs. We applied the new algorithm on yeast cell cycle and stress response data. While known transcriptional regulations were confirmed, novel TF-gene interactions were predicted and provide new insights into the regulatory mechanisms of the cell. C1 [Li, Huai; Zhan, Ming] NIA, Bioinformat Unit, Branch Res Resources, NIH, Baltimore, MD 21224 USA. RP Zhan, M (reprint author), NIA, Bioinformat Unit, Branch Res Resources, NIH, Baltimore, MD 21224 USA. FU Intramural Research Program; National Institute on Aging; NIH FX This study is supported by the Intramural Research Program, National Institute on Aging, NIH. NR 42 TC 20 Z9 21 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD SEP 1 PY 2008 VL 24 IS 17 BP 1874 EP 1880 DI 10.1093/bioinformatics/btn332 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 343NL UT WOS:000258860700007 PM 18586698 ER PT J AU Mattay, VS Goldberg, TE Sambataro, F Weinberger, DR AF Mattay, Venkata S. Goldberg, Terry E. Sambataro, Fabio Weinberger, Daniel R. TI Neurobiology of cognitive aging: Insights from imaging genetics SO BIOLOGICAL PSYCHOLOGY LA English DT Review DE aging; genes; neuroimaging; cognition ID CATECHOL-O-METHYLTRANSFERASE; FACTOR VAL66MET POLYMORPHISM; AGE-RELATED-CHANGES; AFFECTS HUMAN-MEMORY; LONG-TERM-MEMORY; ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; WHITE-MATTER; HUMAN BRAIN; PREFRONTAL CORTEX AB Over the last several years, neuroscientists have been increasingly using neuroimaging techniques to unravel the neurobiology underlying cognitive aging, and in more recent years to explore the role of genes on the variability of the aging process. One of the primary goals of this research is to identify proteins involved in cognitive aging with the hope that this would facilitate the development of novel treatments to combat cognitive impairment. Further, it is likely with early identification of susceptible individuals, early intervention through life-style changes and other methods could increase an individual's resilience to the effects of aging. Published by Elsevier B.V. C1 [Mattay, Venkata S.; Sambataro, Fabio; Weinberger, Daniel R.] NIMH, Genes Cognit & Psychosis Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Goldberg, Terry E.] Feinstein Inst, Litwin Zucker Alzheimers Dis Ctr, Great Neck, NY 11021 USA. RP Mattay, VS (reprint author), NIMH, Genes Cognit & Psychosis Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM vsm@mail.nih.gov RI Sambataro, Fabio/E-3426-2010 OI Sambataro, Fabio/0000-0003-2102-416X FU Intramural NIH HHS [Z01 MH002905-02, Z99 MH999999, ZIC MH002905-03, Z01 MH002905-01] NR 123 TC 38 Z9 41 U1 2 U2 10 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD SEP PY 2008 VL 79 IS 1 BP 9 EP 22 DI 10.1016/j.biopsycho.2008.03.015 PG 14 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 341TU UT WOS:000258738800002 PM 18511173 ER PT J AU Fossella, J Fan, J Liu, X Guise, K Brocki, K Hof, PR Kittappa, R Mckay, R Posner, M AF Fossella, John Fan, Jin Liu, Xun Guise, Kevin Brocki, Karin Hof, Patrick R. Kittappa, Raja McKay, Ronald Posner, Michael TI Provisional hypotheses for the molecular genetics of cognitive development: Imaging genetic pathways in the anterior cingulate cortex SO BIOLOGICAL PSYCHOLOGY LA English DT Review DE genetic; imaging; brain; cingulate; development ID LONG-TERM POTENTIATION; STIMULATED ADENYLYL CYCLASES; FRAGILE-X-SYNDROME; ATTENTIONAL NETWORKS; BEHAVIORAL SENSITIZATION; EXECUTIVE ATTENTION; SOCIAL-INTERACTION; PREFRONTAL CORTEX; DIGIT AMPUTATION; TRANSGENIC MICE AB Brain imaging genetic research involves a multitude of methods and spans many traditional levels of analysis. Given the vast permutations among several million common genetic variants with thousands of brain tissue voxels and a wide array of cognitive tasks that activate specific brain systems, we are prompted to develop specific hypotheses that synthesize converging evidence and state clear predictions about the anatomical sources, magnitude and direction (increases vs. decreases) of allele- and task-specific brain activity associations. To begin to develop a framework for shaping our imaging genetic hypotheses, we focus on previous results and the wider imaging genetic literature. Particular emphasis is placed on converging evidence that links system-level and biochemical studies with models of synaptic function. In shaping our own imaging genetic hypotheses on the development of Attention Networks, we review relevant literature on core models of synaptic physiology and development in the anterior cingulate cortex. (C) 2008 Elsevier B.V. All rights reserved. C1 [Fossella, John; Fan, Jin; Liu, Xun; Guise, Kevin; Brocki, Karin] Mt Sinai Sch Med, Dept Psychiat, New York, NY 10029 USA. [Fan, Jin; Hof, Patrick R.] Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. [Kittappa, Raja; McKay, Ronald] NINDS, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Posner, Michael] Univ Oregon, Dept Psychol, Eugene, OR 97403 USA. RP Fossella, J (reprint author), Mt Sinai Sch Med, Dept Psychiat, 1 Gustave L Levy Pl, New York, NY 10029 USA. EM John.fossella@mssm.edu RI Guise, Kevin/C-1145-2009; Fan, Jin/A-6716-2009; Liu, Xun/C-2400-2009 OI Fan, Jin/0000-0001-9630-8330; Liu, Xun/0000-0003-1366-8926 FU NIMH NIH HHS [K01 MH074573-02, K01 MH074573] NR 87 TC 9 Z9 11 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD SEP PY 2008 VL 79 IS 1 BP 23 EP 29 DI 10.1016/j.biopsycho.2007.12.006 PG 7 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 341TU UT WOS:000258738800003 PM 18261834 ER PT J AU Szeszko, PR Hodgkinson, CA Robinson, DG DeRosse, P Bilder, RM Lencz, T Burdick, KE Napolitano, B Betensky, JD Kane, JA Goldman, D Malhotra, AK AF Szeszko, Philip R. Hodgkinson, Colin A. Robinson, Delbert G. DeRosse, Pamela Bilder, Robert M. Lencz, Todd Burdick, Katherine E. Napolitano, Barbara Betensky, Julia D. Kane, John A. Goldman, David Malhotra, Anil K. TI DISC1 is associated with prefrontal cortical gray matter and positive symptoms in schizophrenia SO BIOLOGICAL PSYCHOLOGY LA English DT Article DE DISC1; leu607phe; MRI; frontal lobes; schizophrenia; gene; polymorphism ID 1ST-EPISODE SCHIZOPHRENIA; AUDITORY HALLUCINATIONS; HIPPOCAMPAL-FORMATION; MAGNETIC-RESONANCE; NEURITE OUTGROWTH; CEREBRAL-CORTEX; CANDIDATE GENE; DISRUPTED-IN-SCHIZOPHRENIA-1; TRANSLOCATION; VOLUME AB Background: DISC1 is considered a susceptibility gene for schizophrenia and schizoaffective disorder, but little is known regarding the potential mechanisms through which it may confer increased risk. Given that DISC1 plays a role in cerebral cortex development, polymorphisms in this gene may have relevance for neurobiological models of schizophrenia that have implicated cortical deficits in its pathophysiology. Methods: We investigated whether the DISC1 leu607phe polymorphism was associated with prefrontal gray matter volumes using magnetic resonance imaging in a cohort of patients with schizophrenia (N = 19) and healthy volunteers (N = 25) and positive and negative symptoms in 200 patients with schizophrenia. Results: Among patients and healthy volunteers, phe carriers (N = 11) had significantly less gray matter in the superior frontal gyrus and anterior cingulate gyrus compared to leu/leu homozygotes (N = 33). Further, among patients left superior frontal gyrus gray matter volume was significantly negatively correlated with severity of hallucinations. In addition, patients who were phe carriers (N = 144) had significantly greater severity of positive symptoms (hallucinations) compared to patients who were leu/leu homozygotes (N = 56). Discussion: These findings implicate DISC1 in variation of prefrontal cortical volume and positive symptoms, thus providing a potential mechanism through which DISC1 may confer increased risk for schizophrenia or schizoaffective disorder. (C) 2007 Elsevier B.V. All rights reserved. C1 [Szeszko, Philip R.; Robinson, Delbert G.; DeRosse, Pamela; Lencz, Todd; Burdick, Katherine E.; Napolitano, Barbara; Betensky, Julia D.; Kane, John A.; Malhotra, Anil K.] Zucker Hillside Hosp, Dept Psychiat Res, Glen Oaks, NY 11004 USA. [Szeszko, Philip R.; Robinson, Delbert G.; Lencz, Todd; Burdick, Katherine E.; Napolitano, Barbara; Kane, John A.; Malhotra, Anil K.] Feinstein Inst Med Res, Manhasset, NY USA. [Szeszko, Philip R.; Robinson, Delbert G.; Lencz, Todd; Burdick, Katherine E.; Kane, John A.; Malhotra, Anil K.] Montefiore Med Ctr, Albert Einstein Coll Med, Dept Psychiat, Bronx, NY USA. [Hodgkinson, Colin A.; Goldman, David] NIAAA, Sect Human Neurogenet, Rockville, MD 20852 USA. [Bilder, Robert M.] Univ Calif Los Angeles, Inst Neuropsychiat, Los Angeles, CA 90024 USA. [Bilder, Robert M.] Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Szeszko, PR (reprint author), Zucker Hillside Hosp, Dept Psychiat Res, 75-59 263rd St, Glen Oaks, NY 11004 USA. EM szeszko@lij.edu RI Burdick, Katherine/G-6124-2012; Szeszko, Philip/G-9336-2013; Bilder, Robert/A-8894-2008; Goldman, David/F-9772-2010; Lencz, Todd/J-3418-2014 OI Bilder, Robert/0000-0001-5085-7852; Goldman, David/0000-0002-1724-5405; Lencz, Todd/0000-0001-8586-338X FU NARSAD; National Institute of Mental Health [MH01990, MH60374, MH01760, MH60575, MH60004]; NSLIJ Research Institute General Clinical Research Center [M01 RR018535] FX This work was supported in part by grants from NARSAD (P.R.S.) and the National Institute of Mental Health to Dr. Szeszko (MH01990), Dr. Bilder (MH60374), Dr. Malhotra (MH01760), Dr. Kane (MH60575), Dr. Robinson (MH60004) and the NSLIJ Research Institute General Clinical Research Center (M01 RR018535). NR 59 TC 59 Z9 62 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-0511 J9 BIOL PSYCHOL JI Biol. Psychol. PD SEP PY 2008 VL 79 IS 1 BP 103 EP 110 DI 10.1016/j.biopsycho.2007.10.011 PG 8 WC Psychology, Biological; Behavioral Sciences; Psychology; Psychology, Experimental SC Psychology; Behavioral Sciences GA 341TU UT WOS:000258738800010 PM 18078707 ER PT J AU Ballen, KK King, RJ Chitphakdithai, P Bolan, CD Agura, E Hartzman, RJ Kernan, NA AF Ballen, Karen K. King, Roberta J. Chitphakdithai, Pintip Bolan, Charles D., Jr. Agura, Edward Hartzman, Robert J. Kernan, Nancy A. TI The National Marrow Donor Program 20 years of unrelated donor hematopoietic cell transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE National Marrow Donor Program; NMDP; unrelated donor; stem cell transplant; transplantation ID ANTILYMPHOCYTE GLOBULIN; APLASTIC-ANEMIA; CYCLOSPORINE; DISEASES; THERAPY AB In the 20 years since the National Marrow Donor Program (NMDP) facilitated the first unrelated donor transplant, the organization has grown to include almost 7 million donors, and has facilitated over 30,000 transplants on 6 continents. This remarkable accomplishment has been facilitated by the efforts of over 600 employees, and an extensive international network including 171 transplant centers, 73 donor centers, 24 cord blood banks, 97 bone marrow collection centers, 91 apheresis centers, 26 HLA typing laboratories, and 26 Cooperative Registries. In this article, we review the history of the NMDP, and cite the major trends in patient demographics, graft sources, and conditioning regimens over the last 20 years. (C) 2008 American Society for Blood and Marrow Transplantation. C1 [Ballen, Karen K.] Massachusetts Gen Hosp, Div Hematol Oncol, Boston, MA 02114 USA. [King, Roberta J.; Chitphakdithai, Pintip] Natl Marrow Donor Program, Minneapolis, MN USA. [Bolan, Charles D., Jr.] NHLBI, Hematol Branch, NIH, Rockville, MD USA. [Agura, Edward] Baylor Univ, Med Ctr, Houston, TX 77030 USA. [Hartzman, Robert J.] USN, Med Res Ctr, CW Bill Young Dept, Def Marrow Donor Program, Rockville, MD USA. [Kernan, Nancy A.] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. RP Ballen, KK (reprint author), Massachusetts Gen Hosp, Div Hematol Oncol, Suite 118, Boston, MA 02114 USA. EM kballen@partners.org OI Kernan, Nancy/0000-0003-1417-1823 FU NMDP FX Financial Disclosure: Drs. King and Chitphakdithai are employees of the NMDP and have a financial relationship with the NMDP, in that capacity as employees. Drs. Ballen, Bolan, Agura, Hartzman, and Kernan have nothing to disclose. NR 16 TC 37 Z9 39 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2008 VL 14 IS 9 SU 3 BP 2 EP 7 DI 10.1016/j.bbmt.2008.05.017 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 352QU UT WOS:000259513100001 PM 18721774 ER PT J AU Karanes, C Nelson, GO Chitphakdithai, P Agura, E Ballen, KK Bolan, CD Porter, DL Uberti, JP King, RJ Confer, DL AF Karanes, Chatchada Nelson, Gene O. Chitphakdithai, Pintip Agura, Edward Ballen, Karen K. Bolan, Charles D. Porter, David L. Uberti, Joseph P. King, Roberta J. Confer, Dennis L. TI Twenty years of unrelated donor hematopoietic cell transplantation for adult recipients facilitated by the National Marrow Donor Program SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE National Marrow Donor Program; NMDP; adult; hematopoietic; stem cell; transplantation ID VERSUS-HOST-DISEASE; BONE-MARROW; CLASS-I; HLA AB For more than 20 years the National Marrow Donor Program has facilitated unrelated donor hematopoietic cell transplants for adult recipients. In this time period, the volunteer donor pool has expanded to nearly 12 million adult donors worldwide, improvements have occurred in the understanding and technology of HLA matching, there have been many changes in clinical practice and supportive care, and the more common graft source has shifted from bone marrow (BM) to peripheral blood stem cells (PBSCs). The percentage of older patients who are receiving unrelated donor transplants is increasing; currently over 1 in 10 adult transplant recipients is over the age of 60 years. Chronic myelogenous leukemia (CML) was previously the most common diagnosis for unrelated donor transplantation, but it now comprises less than 10% of transplants for adult recipients. Transplants for acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and myelodysplastic syndromes (MDS) all outnumber CML. Treatment-related mortality (TRM) has declined significantly over the years, particularly in association with myeloablative transplant preparative regimens. Correspondingly, survival within each disease category has improved. Particularly gratifying are the results in severe aplastic anemia (AA) where 2-year survival has doubled in just 10 years. (C) 2008 American Society for Blood and Marrow Transplantation. C1 [Nelson, Gene O.; Chitphakdithai, Pintip; King, Roberta J.; Confer, Dennis L.] Natl Marro Donor Program, Minneapolis, MN 55413 USA. [Karanes, Chatchada] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Agura, Edward] Baylor Univ, Med Ctr, Dallas, TX USA. [Ballen, Karen K.] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Bolan, Charles D.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Porter, David L.] Univ Penn, Med Ctr, Philadelphia, PA 19104 USA. [Uberti, Joseph P.] Karmanos Canc Inst, Detroit, MI USA. RP Confer, DL (reprint author), Natl Marro Donor Program, 3001 Broadway St NE,Suite 100, Minneapolis, MN 55413 USA. EM dconfer@nmdp.org FU NMDP FX Financial Disclosure: Drs. Nelson, Chitphakdithal, King, and Confer are employees of the NMDP and have a financial relationship with the NMDP, in that capacity as employees. Drs. Karanes, Agura, Ballen, Bolan, Porter, and Uberti have nothing to disclose. NR 16 TC 61 Z9 71 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2008 VL 14 IS 9 SU 3 BP 8 EP 15 DI 10.1016/j.bbmt.2008.06.006 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 352QU UT WOS:000259513100002 PM 18721775 ER PT J AU Bolan, CD Hartzman, RJ Perry, EH Trainor, L Miller, J Miller, R Hanley, L Chitphakdithai, P King, RJ AF Bolan, Charles D. Hartzman, Robert J. Perry, Elizabeth H. Trainor, Lance Miller, John Miller, Rebecca Hanley, Lori Chitphakdithai, Pintip King, Roberta J. TI Donation activities and product integrity in unrelated donor allogeneic hematopoietic transplantation: Experience of the National Marrow Donor Program SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE National Marrow Donor Program; NMDP; unrelated donor; stem cell; transplantation AB Despite many clinical advances in allogeneic hematopoietic cell transplantation (HCT), the one factor that is consistently required to apply HCT to a wide variety of diseases is the successful donation and the safe transport and administration of viable donor cells to the HCT recipient. Since 1987, the National Marrow Donor Program (NMDP) has maintained a registry of volunteer HCT donors for those patients who lack a suitable related donor, facilitated the donor search, and managed the collection and transportation of donor cells to transplant centers for use in increasingly complex therapies. The NMDP has collected data on marrow and peripheral blood stem cell (PBSC) donations as well as additional donations of lymphocytes, whole blood, or platelets. These additional donations are provided for a variety of reasons, including treating post-transplant complications such as graft failure or relapsed disease, supporting immune reconstitution or providing transfusion support. For donor safety, rates of placement of central venous catheters for collecting PBSC are monitored. Data have also been collected on rare events that may affect the integrity of the HCT product (e.g., graft clotting or leaks from the transport bag). Quality assurance and review of these donation processes is an essential component of the transplantation approach. Data from the broad NMDP experience further illuminate factors surrounding the donation process and product integrity. (C) 2008 American Society for Blood and Mat-row Transplantation. C1 [Miller, John; Miller, Rebecca; Hanley, Lori; Chitphakdithai, Pintip; King, Roberta J.] Natl Marrow Donor Program, Minneapolis, MN 55413 USA. [Bolan, Charles D.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Hartzman, Robert J.] USN, Med Res Ctr, CW Bill Young Dept, Def Marrow Donor Program, Rockville, MD USA. [Perry, Elizabeth H.] Mem Blood Ctr, St Paul, MN USA. [Trainor, Lance] William Beaumont Hosp, Royal Oak, MI 48072 USA. RP King, RJ (reprint author), Natl Marrow Donor Program, 3001 Broadway St NE,Suite 100, Minneapolis, MN 55413 USA. EM rking@nmdp.org FU NMDP FX Financial Disclosure: Drs. J. Miller, R. Miller, Hanley, Chitphakdithai, and King are employees of the NMDP and have a financial relationship with the NMDP, in that capacity as employees. Drs. Bolan, Hartzman, Perry, and Trainor have nothing to disclose. NR 0 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2008 VL 14 IS 9 SU 3 BP 23 EP 28 DI 10.1016/j.bbmt.2008.06.001 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 352QU UT WOS:000259513100004 PM 18721777 ER PT J AU Miller, JP Perry, EH Price, TH Bolan, CD Karanes, C Boyd, TM Chitphakdithai, P King, RJ AF Miller, John P. Perry, Elizabeth H. Price, Thomas H. Bolan, Charles D., Jr. Karanes, Chatchada Boyd, Theresa M. Chitphakdithai, Pintip King, Roberta J. TI Recovery and safety profiles of marrow and PBSC donors: Experience of the National Marrow Donor Program SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE National Marrow Donor Program; NMDP; unrelated donor; bone marrow donor; stem cell donor; PBSC AB The National Marrow Donor Program (NMDP) has been facilitating hematopoietic cell transplants since 1987. Volunteer donors listed on the NMDP Registry may be asked to donate either bone marrow (BM) or peripheral blood stem cells (PBSC); however, since 2003, the majority of donors (72% in 2007) have been asked to donate PBSC. From the donor's perspective these stem cell sources carry different recovery and safety profiles. The majority of BM and PBSC donors experienced symptoms during the course of their donation experience. Pain is the number 1 symptom for both groups of donors. BM donors most often reported pain at the collection site (82% back or hip pain) and anesthesia-related pain sites (33% throat pain; 17% post-anesthesia headache), whereas PBSC donors most often reported bone pain (97%) at various sites during filgrastim administration. Fatigue was the second most reported symptom by both BM and PBSC donors (59% and 70%, respectively). PBSC donors reported a median time to recovery of I week compared to a median time to recovery of 3 weeks for BM donors. Both BM and PBSC donors experienced transient changes in their WBC, platelet, and hemoglobin counts during the donation process, with most counts returning to baseline values by I month post-donation and beyond. Serious adverse events are uncommon, but these events occurred more often in BM donors than PBSC donors (1.34% in BM donors, 0.6% in PBSC donors) and a few BM donors may have long-term complications. NMDP donors are currently participating in a randomized clinical trial that will formally compare the clinical and quality-of-life outcomes of BM and PBSC donors and their graft recipients. (C) 2008 American Society for Blood and Marrow Transplantation. C1 [Miller, John P.; Chitphakdithai, Pintip; King, Roberta J.] Natl Marrow Donor Program, Minneapolis, MN 55413 USA. [Perry, Elizabeth H.] Mem Blood Ctr, St Paul, MN USA. [Price, Thomas H.] Puget Sound Blood Ctr, Seattle, WA 98104 USA. [Bolan, Charles D., Jr.] NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Karanes, Chatchada] City Hope Natl Med Ctr, Duarte, CA 91010 USA. [Boyd, Theresa M.] Amer Red Cross, Washington, DC 20006 USA. RP King, RJ (reprint author), Natl Marrow Donor Program, 3001 Broadway St NE,Suite 100, Minneapolis, MN 55413 USA. EM rking@nmdp.org FU NMDP FX Financial Disclosure: Drs. Miller, Chitphakdithai, and King are employees of the NMDP and have a financial relationship with the NMDP, in that capacity as employees. Dr. Price is an employee of the NMDP Donor Center, Apheresis Center, and Cord Blood Bank, and has a financial relationship, in that capacity as an employee. Drs. Perry, Bolan, Karanes, and Boyd have nothing to disclose. NR 0 TC 44 Z9 44 U1 2 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2008 VL 14 IS 9 SU 3 BP 29 EP 36 DI 10.1016/j.bbmt.2008.05.018 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 352QU UT WOS:000259513100005 PM 18721778 ER PT J AU Foley, JE Mariotti, J Ryan, K Eckhaus, M Fowler, DH AF Foley, Jason E. Mariotti, Jacopo Ryan, Kaitlyn Eckhaus, Michael Fowler, Daniel H. TI Th2 cell therapy of established acute graft-versus-host disease requires IL-4 and IL-10 and is abrogated by IL-2 or host-type antigen-presenting cells SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE Th2; GVHD; IL-2; APC ID REGULATORY T-CELLS; BONE-MARROW-TRANSPLANTATION; MINOR HISTOCOMPATIBILITY ANTIGENS; SECRETION IN-VITRO; STEM-CELLS; CD8(+) TC1; INTERLEUKIN-10; VIVO; PROLIFERATION; TOLERANCE AB Delayed donor Th2 cell infusion permits a graft-versus-tumor (GVT) effect to occur with subsequent amelioration of established graft-versus-host disease (GVHD). Relative to GVHD controls (B6-into-BALB/c model), recipients of delayed Th2 cells (day 14 post-BMT) had increased survival (3/3 experiments [exp]; each exp P < .0001) and reduced GVHD by histology analysis 5 days post-Th2 infusion without increased tumor burden (3 of 3 exp; each exp P <= .02). Th2 cell-mediated amelioration of GVHD was associated with greatly reduced allospecific IFN-gamma secretion, in vivo augmentation of allospecific IL-4 and IL-10 secretion, and reduction in donor CD8(+) T cell number post-BAIT (3 of 3 exp; each comparison, P <= .003). To better understand the molecular mechanism of this GVHD therapy, Th2 cells were generated from wild-type (WT), IL-4 deficient (KO), or IL-10 KO donors: remarkably, recipients of IL-4 or IL-10 KO Th2 cells had no survival advantage, no improvement in GVHD by histology, no reduction in CD8+ T cell expansion post-BMT, and no in vivo shift toward type II cytokines. We reasoned that IL-2 and alloantigen availability may be limiting factors for Th2 cell therapy, and as such, evaluated whether coadministration of IL-2 or coinfusion of host-type antigen-presenting cells (APC) might intensify the anti-GVHD effect. However, contrary to these hypotheses, concomitant IL-2 therapy or APC administration fully abrogated the Th2 cell-mediated survival advantage and histology-defined GVHD reduction, reduced Th2 cell expansion in vivo while promoting CD8(+) T cell expansion from cells originating from the initial allograft, and impaired type H polarization in vivo. In conclusion, Th2 cell therapy can rapidly ameliorate severe GVHD via IL-4 and IL-10 mediated mechanisms, and potentially, via IL-2 consumption and APC modulation mechanisms. (C) 2008 American Society for Blood and Marrow Transplantation. C1 [Foley, Jason E.; Mariotti, Jacopo; Ryan, Kaitlyn; Fowler, Daniel H.] NIH, Ctr Canc Res, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Eckhaus, Michael] NIH, Natl Ctr Res Resources, Bethesda, MD 20892 USA. RP Fowler, DH (reprint author), NIH, Ctr Canc Res, Expt Transplantat & Immunol Branch, 10 Ctr Dr,Bldg 10,CRC,3 EAST Labs,3-3330, Bethesda, MD 20892 USA. EM dhfowler@helix.nih.gov FU Intramural NIH HHS [Z01 SC010288-10] NR 42 TC 28 Z9 31 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2008 VL 14 IS 9 BP 959 EP 972 DI 10.1016/j.bbmt.2008.06.007 PG 14 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 352QT UT WOS:000259513000002 PM 18721759 ER PT J AU Savani, BN Stratton, P Shenoy, A Kozanas, E Goodman, S Barrett, AJ AF Savani, Bipin N. Stratton, Pamela Shenoy, Aarthi Kozanas, Eleftheria Goodman, Stacey Barrett, A. John TI Increased risk of cervical dysplasia in long-term survivors of allogeneic stem cell transplantation - Implications for screening and HPV vaccination SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE cervical dysplasia; HPV; long-term survivors; stems cell transplantation ID BONE-MARROW-TRANSPLANTATION; PAPILLOMA-VIRUS INFECTION; LESIONS; CANCER; PERSISTENCE; RECIPIENTS; WORLDWIDE; HEAD AB As more women survive allogeneic stem cell transplantation (SCT), the development of genital human papilloma virus (HPV)-related squamous intraepithelial lesions (SIL) warrants study. Thirty-five of 38 females followed prospectively long-term after SCT for hematological malignancies (median 7 years posttransplant) were adults and had cervical cytology testing. Acute graft-versus-host-disease (aGVHD) occurred in 9 and chronic (cGVHD) in 34 patients. Six (17%) continued receiving systemic immunosuppressive therapy (IST) for cGVHD >3 years after SCT. Of 15 (43%) with abnormal cytology, 12 (34%) patients had HPV-related SIL (median time to SIL 51 months, range: 22-108) including high-grade SIL in 7 (20%). Patients requiring continued IST had the highest risk (odds ratio [OR] 4.6, 95% confidence interval [CI] 1.1-16.4; P = .019). This high incidence of SIL in long-term SCT survivors underscores the importance of gynecologic assessment after transplantation, especially in those requiring IST. This may portend an increased risk of genital or other HPV-related malignancies. (C) 2008 American Society for Blood and Marrow Transplantation. C1 [Savani, Bipin N.; Shenoy, Aarthi; Kozanas, Eleftheria; Barrett, A. John] NHLBI, Stem Cell Transplantat Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. [Savani, Bipin N.; Goodman, Stacey] Vet Affairs Med Ctr, Nashville, TN 37212 USA. [Savani, Bipin N.; Goodman, Stacey] Vanderbilt Univ, Transplant Program, Nashville, TN USA. [Stratton, Pamela] NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. RP Barrett, AJ (reprint author), NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH, Bldg 10,Hatfield CRC,Room 3-5330,10 Ctr Dr,MSC 12, Bethesda, MD 20892 USA. EM barrettj@nhlbi.nih.gov FU NHLBI; NICHD FX This work was supported by the intramural research program of the NHLBI. and NICHD B.N.S designed and wrote the study and wrote the manuscript. P.S. performed gyn examinations, treated patients, and wrote the manuscript. A.S. made a critical analysis of results and the manuscript, and treated patients. E.K. made data collection and patient recruitment. S.G. made critical analysis of the results and the manuscript. A.J.B., senior author, supervised the study, study design discussion, and wrote the manuscript. NR 24 TC 34 Z9 35 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 EI 1523-6536 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD SEP PY 2008 VL 14 IS 9 BP 1072 EP 1075 DI 10.1016/j.bbmt.2008.07.005 PG 4 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 352QT UT WOS:000259513000014 PM 18721771 ER PT J AU Nakamura, N Miranda-Vizuete, A Miki, K Mori, C Eddy, EM AF Nakamura, Noriko Miranda-Vizuete, Antonio Miki, Kiyoshi Mori, Chisato Eddy, Edward M. TI Cleavage of disulfide bonds in mouse spermatogenic cell-specific type 1 hexokinase isozyme is associated with increased hexokinase activity and initiation of sperm motility SO BIOLOGY OF REPRODUCTION LA English DT Article DE disulfide bond reduction; epididymis; fibrous sheath; glycolysis; sperm; sperm activation; sperm capacitation; sperm maturation; sperm motility and transport ID RABBIT EPIDIDYMAL SPERMATOZOA; MAMMALIAN SPERMATOZOA; HYDROGEN-PEROXIDE; CRYSTAL-STRUCTURE; GENE-EXPRESSION; GLUCOSE; PROTEIN; CAPACITATION; THIOREDOXIN; BRAIN AB During epididymal transit, sperm acquire the ability to initiate rapid forward progressive motility on release into the female reproductive tract or physiological media. Glycolysis is the primary source of the ATP necessary for this motility in the mouse, and several novel glycolytic enzymes have been identified that are localized to the principal piece region of the flagellum. One of these is the spermatogenic cell-specific type 1 hexokinase isozyme (HK1S), the only member of the hexokinase enzyme family detected in sperm. Hexokinase activity was found to be lower in immotile sperm immediately after removal from the cauda epididymis (quiescent) than in sperm incubated in physiological medium for 5 min and showing rapid forward progressive motility (activated). However, incubating sperm in medium containing diamide, an inhibitor of disulfide bond reduction, resulted in lower motility and HK activity than in controls. HK1S was present in dimer and monomer forms in extracts of quiescent sperm but mainly as a monomer in motile sperm. A dimer-size band detected in quiescent sperm with phosphotyrosine antibody was not detected in activated sperm, and the monomer-size band was enhanced. In addition, the general protein oxido-reductase thioredoxin-1 was able to catalyze the in vitro conversion of HK1S dimers to the monomeric form. These results strongly suggest that cleavage of disulfide bonds in HK1S dimers contributes to the increases in HK activity and motility that occur when mouse sperm become activated. C1 [Nakamura, Noriko; Eddy, Edward M.] NIEHS, NIH, Reprod & Dev Toxicol Lab, Gamete Biol Sect, Res Triangle Pk, NC 27709 USA. [Miranda-Vizuete, Antonio] Univ Pablo Olavide, Dept Fisiol Anat & Biol Celular, CABD, CSIC, Seville 41013, Spain. [Miki, Kiyoshi] Univ N Carolina, Sch Med, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA. [Mori, Chisato] Chiba Univ, Grad Sch Med, Dept Bioenvironm Med, Chiba 2608670, Japan. RP Eddy, EM (reprint author), NIEHS, NIH, Reprod & Dev Toxicol Lab, Gamete Biol Sect, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eddy@niehs.nih.gov RI Miranda-Vizuete, Antonio/D-6927-2012; IBIS, FISIOLOGIA/O-9485-2015 OI Miranda-Vizuete, Antonio/0000-0002-6856-5396; FU Intramural NIH HHS NR 50 TC 18 Z9 19 U1 0 U2 2 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 SEP PY 2008 VL 79 IS 3 BP 537 EP 545 DI 10.1095/biolreprod.108.067561 PG 9 WC Reproductive Biology SC Reproductive Biology GA 339LV UT WOS:000258580000017 PM 18509164 ER PT J AU Lobach, I Carroll, RJ Spinka, C Gail, MH Chatterjee, N AF Lobach, Iryna Carroll, Raymond J. Spinka, Christine Gail, Mitchell H. Chatterjee, Nilanjan TI Haplotype-based regression analysis and inference of case-control studies with unphased genotypes and measurement errors in environmental exposures SO BIOMETRICS LA English DT Article DE EM algorithm; errors in variables; gene-environment independence; gene-environment interactions; likelihood-ratio tests in misspecified models; inferences in measurement error models; profile likelihood; semiparametric methods ID LIKELIHOOD; MODELS; ASSOCIATION; RISK AB It is widely believed that risks of many complex diseases are determined by genetic susceptibilities, environmental exposures, and their interaction. Chatterjee and Carroll (2005, Biometrika 92, 399-418) developed an efficient retrospective maximum-likelihood method for analysis of case-control studies that exploits an assumption of gene-environment independence and leaves the distribution of the environmental covariates to be completely nonparametric. Spinka, Carroll, and Chatterjee (2005, Genetic Epidemiology 29, 108-127) extended this approach to studies where certain types of genetic information, such as haplotype phases, may be missing on some subjects. We further extend this approach to situations when some of the environmental exposures are measured with error. Using a polychotomous logistic regression model, we allow disease status to have K + 1 levels. We propose use of a pseudolikelihood and a related EM algorithm for parameter estimation. We prove consistency and derive the resulting asymptotic covariance matrix of parameter estimates when the variance of the measurement error is known and when it is estimated using replications. Inferences with measurement error corrections are complicated by the fact that the Wald test often behaves poorly in the presence of large amounts of measurement error. The likelihood-ratio (LR) techniques are known to be a good alternative. However, the LR tests are not technically correct in this setting because the likelihood function is based on an incorrect model, i.e., a prospective model in a retrospective sampling scheme. We corrected standard asymptotic results to account for the fact that the LR test is based on a likelihood-type function. The performance of the proposed method is illustrated using simulation studies emphasizing the case when genetic information is in the form of haplotypes and missing data arises from haplotype-phase ambiguity. An application of our method is illustrated using a population-based case-control study of the association between calcium intake and the risk of colorectal adenoma. C1 [Lobach, Iryna; Carroll, Raymond J.] Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. [Spinka, Christine] Univ Missouri, Dept Stat, Columbia, MO 65211 USA. [Gail, Mitchell H.; Chatterjee, Nilanjan] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. RP Lobach, I (reprint author), Texas A&M Univ, Dept Stat, College Stn, TX 77843 USA. EM carroll@stat.tamu.edu FU NCI NIH HHS [R37 CA057030-20, CA57030, CA90301, R01 CA057030, R25 CA090301, R37 CA057030, U01 CA057030]; NIEHS NIH HHS [P30 ES009106, P30-ES09106] NR 23 TC 9 Z9 9 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2008 VL 64 IS 3 BP 673 EP 684 DI 10.1111/j.1541-0420.2007.00930.x PG 12 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 337YE UT WOS:000258470600001 PM 18047538 ER PT J AU Mukherjee, B Chatterjee, N AF Mukherjee, Bhramar Chatterjee, Nilanjan TI Exploiting gene-environment independence for analysis of case-control studies: An empirical bayes-type shrinkage estimator to trade-off between bias and efficiency SO BIOMETRICS LA English DT Article DE case-only designs; gene-environment interaction; profile likelihood; retrospective analysis; semiparametrics ID MAXIMUM-LIKELIHOOD; CIGARETTE-SMOKING; INFERENCE; RISK; ASSOCIATIONS; INFORMATION; GENOTYPE; EXPOSURE; DESIGNS; MODELS AB Standard prospective logistic regression analysis of case-control data often leads to very imprecise estimates of gene-environment interactions due to small numbers of cases or controls in cells of crossing genotype and exposure. In contrast, under the assumption of gene-environment independence, modern "retrospective" methods, including the "case-only" approach, can estimate the interaction parameters much more precisely, but they can be seriously biased when the underlying assumption of gene-environment independence is violated. In this article, we propose a novel empirical Bayes-type shrinkage estimator to analyze case-control data that can relax the gene-environment independence assumption in a data-adaptive fashion. In the special case, involving a binary gene and a binary exposure, the method leads to an estimator of the interaction log odds ratio parameter in a simple closed form that corresponds to an weighted average of the standard case-only and case-control estimators. We also describe a general approach for deriving the new shrinkage estimator and its variance within the retrospective maximum-likelihood framework developed by Chatterjee and Carroll (2005, Biometrika 92, 399-418). Both simulated and real data examples suggest that the proposed estimator strikes a balance between bias and efficiency depending on the true nature of the gene-environment association and the sample size for a given study. C1 [Mukherjee, Bhramar] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Chatterjee, Nilanjan] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Mukherjee, B (reprint author), Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. EM bhramar@umich.edu; chattern@mail.nih.gov FU Intramural NIH HHS NR 27 TC 103 Z9 103 U1 0 U2 7 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2008 VL 64 IS 3 BP 685 EP 694 DI 10.1111/j.1541-0420.2007.00953.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 337YE UT WOS:000258470600002 PM 18162111 ER PT J AU Vexler, A Liu, AY Eliseeva, E Schisterman, EF AF Vexler, Albert Liu, Aiyi Eliseeva, Ekaterina Schisterman, Enrique F. TI Maximum likelihood ratio tests for comparing the discriminatory ability of biomarkers subject to limit of detection SO BIOMETRICS LA English DT Article DE area under curve (AUC); censoring; hypothesis testing; limit of detection (LOD); maximum likelihood; receiver operating characteristics (ROC) ID BIOSPECIMENS; STATISTICS; INFERENCE; EXPOSURE; SAMPLE; MODELS AB In this article, we consider comparing the areas under correlated receiver operating characteristic (ROC) curves of diagnostic biomarkers whose measurements are subject to a limit of detection (LOD), a source of measurement error from instruments' sensitivity in epidemiological studies. We propose and examine the likelihood ratio tests with operating characteristics that are easily obtained by classical maximum likelihood methodology. C1 [Vexler, Albert; Liu, Aiyi; Eliseeva, Ekaterina; Schisterman, Enrique F.] NICHD, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. [Vexler, Albert] SUNY Buffalo, Dept Biostat, Buffalo, NY 14214 USA. [Eliseeva, Ekaterina] Univ Chicago, Chicago, IL 60637 USA. RP Vexler, A (reprint author), NICHD, Div Epidemiol Stat & Prevent Res, NIH, Rockville, MD 20852 USA. EM avexler@buffalo.edu OI Liu, Aiyi/0000-0002-6618-5082; Schisterman, Enrique/0000-0003-3757-641X FU Intramural NIH HHS [Z01 HD008761-05] NR 19 TC 27 Z9 27 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD SEP PY 2008 VL 64 IS 3 BP 895 EP 903 DI 10.1111/j.1541-0420.2007.00941.x PG 9 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 337YE UT WOS:000258470600026 PM 18047527 ER PT J AU Chen, YD Wang, SK Sherman, A AF Chen, Yi-der Wang, Shaokun Sherman, Arthur TI Identifying the targets of the amplifying pathway for insulin secretion in pancreatic beta-cells by kinetic modeling of granule exocytosis SO BIOPHYSICAL JOURNAL LA English DT Article ID SENSITIVE-K+-CHANNELS; ADRENAL CHROMAFFIN CELLS; MATHEMATICAL-MODEL; CYTOPLASMIC CA2+; MEMBRANE-FUSION; CALCIUM INFLUX; VESICLE POOLS; B-CELLS; GLUCOSE; RELEASE AB A kinetic model for insulin secretion in pancreatic beta-cells is adapted from a model for fast exocytosis in chromaffin cells. The fusion of primed granules with the plasma membrane is assumed to occur only in the "microdomain" near voltage-sensitive L-type Ca2+-channels, where [Ca2+] can reach micromolar levels. In contrast, resupply and priming of granules are assumed to depend on the cytosolic [Ca2+]. Adding a two-compartment model to handle the temporal distribution of Ca2+ between the microdomain and the cytosol, we obtain a unified model that can generate both the fast granule fusion and the slow insulin secretion found experimentally in response to a step of membrane potential. The model can simulate the potentiation induced in islets by preincubation with glucose and the reduction in second-phase insulin secretion induced by blocking R-type Ca2+-channels (Ca(V)2.3). The model indicates that increased second-phase insulin secretion induced by the amplifying signal is controlled by the "resupply" step of the exocytosis cascade. In contrast, enhancement of priming is a good candidate for amplification of first-phase secretion by glucose, cyclic adenosine 3':5'-cyclic monophosphate, and protein kinase C. Finally, insulin secretion is enhanced when the amplifying signal oscillates in phase with the triggering Ca2+-signal. C1 [Chen, Yi-der; Sherman, Arthur] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Wang, Shaokun] Shandong Univ, Sch Chem & Chem Engn, Jinan 250100, Shandong, Peoples R China. RP Sherman, A (reprint author), NIDDK, Lab Biol Modeling, NIH, 12 South Dr,Rm 4007,MSC 5621, Bethesda, MD 20892 USA. EM asherman@nih.gov FU Intramural NIH HHS NR 60 TC 33 Z9 33 U1 1 U2 3 PU BIOPHYSICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD SEP 1 PY 2008 VL 95 IS 5 BP 2226 EP 2241 DI 10.1529/biophysj.107.124990 PG 16 WC Biophysics SC Biophysics GA 337ZJ UT WOS:000258473900010 PM 18515381 ER PT J AU Manley, S Horton, MR Lecszynski, S Gast, AP AF Manley, Suliana Horton, Margaret R. Lecszynski, Szymon Gast, Alice P. TI Sorting of streptavidin protein coats on phase-separating model membranes SO BIOPHYSICAL JOURNAL LA English DT Article ID LIPID RAFTS; FLUORESCENCE MICROSCOPY; CELL-MEMBRANES; LIQUID-PHASES; VESICLES; CHOLESTEROL; DOMAINS; CURVATURE; PHOSPHOLIPIDS; MONOLAYERS AB Heterogeneities in cell membranes due to the ordering of lipids and proteins are thought to play an important role in enabling protein and lipid trafficking throughout the secretory pathway and in maintaining cell polarization. Protein-coated vesicles provide a major mechanism for intracellular transport of select cargo, which may be sorted into lipid microdomains; however, the mechanisms and physical constraints for lipid sorting by protein coats are relatively unexplored. We studied the influence of membrane-tethered protein coats on the sorting, morphology, and phase behavior of liquid-ordered lipid domains in a model system of giant unilamellar vesicles composed of dioleoylphosphatidylcholine, sphingomyelin, and cholesterol. We created protein-coated membranes by forming giant unilamellar vesicles containing a small amount of biotinylated lipid, thereby creating binding sites for streptavidin and avidin proteins in solution. We found that individual tethered proteins colocalize with the liquid-disordered phase, whereas ordered protein domains on the membrane surface colocalize with the liquid-ordered phase. These observations may be explained by considering the thermodynamics of this coupled system, which maximizes its entropy by cosegregating ordered protein and lipid domains. In addition, protein ordering inhibits lipid domain rearrangement and modifies the morphology and miscibility transition temperature of the membrane, most dramatically near the critical point in the membrane phase diagram. This observation suggests that liquid-ordered domains are stabilized by contact with ordered protein domains; it also hints at an approach to the stabilization of lipid microdomains by cross-linked protein clusters or ordered protein coats. C1 [Manley, Suliana; Horton, Margaret R.; Lecszynski, Szymon; Gast, Alice P.] MIT, Dept Chem Engn, Cambridge, MA 02139 USA. RP Manley, S (reprint author), NIH, Cell Biol & Metab Branch, Bldg 18T,Rm 101,18 Lib Dr, Bethesda, MD 20892 USA. EM manleysu@mail.nih.gov RI Manley, Suliana/D-3818-2012 OI Manley, Suliana/0000-0002-4755-4778 NR 36 TC 10 Z9 10 U1 1 U2 12 PU BIOPHYSICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD SEP 1 PY 2008 VL 95 IS 5 BP 2301 EP 2307 DI 10.1529/biophysj.107.124024 PG 7 WC Biophysics SC Biophysics GA 337ZJ UT WOS:000258473900017 PM 18502811 ER PT J AU Waybright, T Gillette, WK Esposito, D Stephens, RM Lucas, DA Hartley, JL Veenstra, TD AF Waybright, Timothy Gillette, William K. Esposito, Dominic Stephens, Robert M. Lucas, David A. Hartley, James L. Veenstra, Timothy D. TI Identification of highly expressed, soluble proteins using an improved, high-throughput pooled ORF expression technology SO BIOTECHNIQUES LA English DT Article ID HUMAN ORFEOME; PROTEOMICS; PEPTIDES AB This article describes an improved pooled open reading frame (ORF) expression technology (POET) that users recombinational cloning and solution-based tandem mass spectrometry (MS/MS) to identify ORFs that yield high levels of soluble, purified protein when expressed in Escherichia coli. Using this method, three identical pools of 512 human ORFs were subcloned, purified, and transfected into three separate E. coli cultures. After bulk expression and purification, the proteins from the three separate pools were digested into tryptic peptides. Each of these samples was subsequently analyzed in triplicate using reversed-phase high-performance liquid chromatography (LC) coupled directly online with MS/MS. The abundance of each protein was determined by calculating the average exponentially modified protein abundance index (emPAI) of each protein across the three protein pools. Human proteins that consistently gave high emPAI values were subjected to small-scale expression and purification. These clones showed high levels of expression of soluble protein. Conversely, proteins that were not observed by LC-MS/MS did not show any detectable soluble expression in small-scale validation studies. Using this improved POET method allows the expression characteristics of hundreds of proteins to be quickly determined in a single experiment. C1 [Veenstra, Timothy D.] NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Prot Express Lab, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Adv Biomed Comp Ctr, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Veenstra, TD (reprint author), NCI, Lab Prote & Analyt Technol, Adv Technol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov FU National Cancer Institute, National Institutes of Health [NO1-CO-12400] FX The authors wish to thank Chacko S. Chakiath and Earl W. Bere III for technical assistance on this project. This project has been funded in whole or in part with federal funds front the National Cancer Institute, National Institutes of Health, under Contract NO1-CO-12400. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the U.S. Government. This paper is subject to the NIH Public Access Policy. NR 18 TC 6 Z9 6 U1 0 U2 2 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD SEP PY 2008 VL 45 IS 3 BP 307 EP 315 DI 10.2144/000112916 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 411GU UT WOS:000263638100021 PM 18778254 ER PT J AU Kim, MJ Kang, KH Kim, CH Choi, SY AF Kim, Min Jung Kang, Kyung Ho Kim, Cheol-Hee Choi, Seok-Yong TI Real-time imaging of mitochondria in transgenic zebrafish expressing mitochondrially targeted GFP SO BIOTECHNIQUES LA English DT Article ID CELL-DEATH; APOPTOSIS; DYNAMICS; FUSION; FISH AB Mitochondria maintain a web-shaped network in cells through a balance between fusion and fission. Under certain physiological and pathological conditions, this balance is breached, and as a result, change in mitochondrial morphology ensues. Real-time monitoring of such change is of significant importance for studying mitochondrial physiology and pathology, such its apoptosis, aging, and neurodegeneration. Numerous studies have been conducted in animal cell culture systems concerning mitochondrial morphology change. Howevey, very little is known to date about file real-time changes in mitochondrial morphology it the organism level due to difficulties in observation and administration of mitochondria-disrupting drugs. Here we report the generation of transgenic zebrafish (Danio rerio) expressing mitochondrially targeted green fluorescent protein (GFP). The transparency Of transgenic zebrafish embryos make it possible to monitor mitochondrial morphology in real time and in vivo. Since zebrafish inhabit fresh water, incubating zebrafish in drug-dissolved water sufficed to administer drugs to the zebrafish. We observed real-time and in vivo frag-mentation of mitochondria in the transgenic embryos upon incubation in water with the following apoptosis-inducing drugs: valinomycin, carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone (FCCP), and staurosporine. Thus, the transgenic zebrafish we generated could provide a platform for research on apoptosis and mitochondrial physiology and a screen for apoptosis-modulating drugs. It could also facilitate study of the pathogenesis of apoptosis-related diseases. C1 [Kim, Min Jung; Choi, Seok-Yong] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. [Kim, Min Jung] Sookmyung Womens Univ, Dept Biol Sci, Seoul, South Korea. [Kang, Kyung Ho; Choi, Seok-Yong] Chonnam Natl Univ, Sch Med, Med Res Ctr Gene Regulat, Kwangju, South Korea. [Kim, Cheol-Hee] Chungnam Natl Univ, Dept Biol, Taejon, South Korea. RP Choi, SY (reprint author), Chonnam Med Sch, Dept Biomed Sci, Rm A411,Bldg 1,Hak Dong, Kwangju 501746, South Korea. EM zebrafish@chonnam.ac.kr FU Intramural NIH HHS NR 19 TC 24 Z9 24 U1 0 U2 6 PU INFORMA HEALTHCARE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD SEP PY 2008 VL 45 IS 3 BP 331 EP 334 DI 10.2144/000112909 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 411GU UT WOS:000263638100025 PM 18778258 ER PT J AU Mills, JL Molloy, AM Parle-McDermott, A Troendle, JF Brody, LC Conley, MR Cox, C Pangilinan, F Orr, DJA Earley, M McKiernan, E Lynn, EC Doyle, A Scott, JM Kirke, PN AF Mills, James L. Molloy, Anne M. Parle-McDermott, Anne Troendle, James F. Brody, Lawrence C. Conley, Mary R. Cox, Christopher Pangilinan, Faith Orr, David J. A. Earley, Michael McKiernan, Eamon Lynn, Ena C. Doyle, Anne Scott, John M. Kirke, Peadar N. TI Folate-related gene polymorphisms as risk factors for cleft lip and cleft palate SO BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY LA English DT Article DE cleft lip; cleft palate; oral clefts; folate; folate genes; vitamin B12; transcobalamin gene ID NEURAL-TUBE DEFECTS; METHYLENETETRAHYDROFOLATE REDUCTASE GENE; FOLIC-ACID SUPPLEMENTATION; INFANT C677T MUTATION; OROFACIAL CLEFTS; ORAL CLEFTS; BIRTH-DEFECTS; MTHFR GENE; GENOTYPE CONTRIBUTES; COMMON MUTATION AB BACKGROUND: Cleft lip with or without cleft palate (CLP) and cleft palate only (CPO) have an inherited component and, many studies suggest, a relationship with folate. Attempts to find folate-related genes associated with clefts have, however, often been inconclusive. This study examined four SNPS related to folate metabolism (MTHFR 677 C -> T, MTHFR 1298 A -> C, MTHFD1 1958 G -> A, and TC II 776 C -> G) in a large Irish population to clarify their relationship with clefts. METHODS: Cases and their parents were recruited from major surgical centers performing cleft repairs in Ireland and a support organization. Data on risk factors, medical history, and DNA were collected. Controls were pregnant women from the greater Dublin area (n = 1,599). RESULTS: CLP cases numbered 536 and CPO cases 426 after exclusions. CPO mothers were significantly more likely than controls to be MTHFR 677 TT, OR 1.50 (95% CI: 1.05-2.16; p = .03). Log-linear analysis showed a borderline association (p =.07). Isolated CPO case mothers were significantly more likely than controls to be homozygous for the MTHFD1 1958 G -> A. variant, OR 1.50 (95%CI: 1.08-2.09; p = .02). When multiple cases were added, both CPO cases and cast, mothers were significantly more likely to be AA (p = .02 and p = .007, respectively). The CLP case-control and mother-control analyses also showed significant effects, ORs 1.38 (95% CI: 1.05-1.82; p =.03) and 1.39 (95%, CI: 1.04-1.85; p =.03), respectively. CONCLUSIONS: Associations were found for both CPO and CLP and MTHFD1 1958 G -> A in cases and case mothers. MTHFR 677 C -> T could be a maternal risk factor for clefts but the association was not strong. Because multiple comparisons were made, these findings require additional investigation. Given the known association between MTHFD1 1958 G -> A and NTDs, these findings should be explored in more detail. C1 [Mills, James L.; Troendle, James F.; Conley, Mary R.; Cox, Christopher] Eunice Kennedy Shriver Natl Inst Child Hlth & Hum, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Molloy, Anne M.; Scott, John M.] Trinity Coll Dublin, Sch Immunol & Biochem, Dublin, Ireland. [Parle-McDermott, Anne] Dublin City Univ, Sch Biotechnol, Dublin 9, Ireland. [Brody, Lawrence C.; Pangilinan, Faith] NHGRI, NIH, Dept Hlth & Human Serv, Genome Technol Branch, Bethesda, MD 20892 USA. [Orr, David J. A.; Earley, Michael; McKiernan, Eamon] St James Hosp, Dublin Cleft Ctr, Dublin 8, Ireland. [Orr, David J. A.; Earley, Michael; McKiernan, Eamon] Our Ladys Childrens Hosp, Dublin, Ireland. [Lynn, Ena C.; Doyle, Anne; Kirke, Peadar N.] Hlth Res Board Ireland, Child Hlth Epidemiol Unit, Dublin, Ireland. RP Mills, JL (reprint author), NICHD, NIH, 6100 Bldg,Room7B03, Bethesda, MD 20892 USA. EM jamesmills@nih.gov OI Molloy, Anne/0000-0002-1688-9049; Orr, David/0000-0002-1935-1412 FU Intramural NIH HHS [Z01 HD002502-15] NR 37 TC 38 Z9 45 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1542-0752 EI 1542-0760 J9 BIRTH DEFECTS RES A JI Birth Defects Res. Part A-Clin. Mol. Teratol. PD SEP PY 2008 VL 82 IS 9 BP 636 EP 643 DI 10.1002/bdra.20491 PG 8 WC Developmental Biology; Toxicology SC Developmental Biology; Toxicology GA 355MS UT WOS:000259713600005 PM 18661527 ER PT J AU Sharifi, N Hamada, A Sissung, T Danesi, R Venzon, D Baum, C Gulley, JL Price, DK Dahut, WL Figg, WD AF Sharifi, Nima Hamada, Akinobu Sissung, Tristan Danesi, Romano Venzon, David Baum, Caitlin Gulley, James L. Price, Douglas K. Dahut, William L. Figg, William D. TI A polymorphism in a transporter of testosterone is a determinant of androgen independence in prostate cancer SO BJU INTERNATIONAL LA English DT Editorial Material DE prostate cancer; androgen independence; testosterone; androgen deprivation; hormonal therapy; transporter ID RECEPTOR; BIOLOGY C1 [Sharifi, Nima; Hamada, Akinobu; Sissung, Tristan; Baum, Caitlin; Price, Douglas K.; Dahut, William L.; Figg, William D.] NCI, Clin Pharmacol Program, Bethesda, MD 20892 USA. [Sharifi, Nima; Gulley, James L.; Dahut, William L.; Figg, William D.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Danesi, Romano] Univ Pisa, Pisa, Italy. RP Sharifi, N (reprint author), Univ Texas SW Med Ctr Dallas, Div Hematol Oncol, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM nima.sharifi@utsouthwestern.edu RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; FU Intramural NIH HHS [Z01 BC010453-06] NR 13 TC 33 Z9 36 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1464-4096 J9 BJU INT JI BJU Int. PD SEP PY 2008 VL 102 IS 5 BP 617 EP 621 DI 10.1111/j.1464-410X.2008.07629.x PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 333LI UT WOS:000258153600018 PM 18537956 ER PT J AU Zhu, JF Paul, WE AF Zhu, Jinfang Paul, William E. TI CD4 T cells: fates, functions, and faults SO BLOOD LA English DT Review ID GROWTH-FACTOR-BETA; INTERFERON-REGULATORY FACTOR-4; LOCUS-CONTROL REGION; HYPER-IGE SYNDROME; ROR-GAMMA-T; ALLERGIC DISREGULATION SYNDROME; IMMUNOLOGICAL SELF-TOLERANCE; TRANSCRIPTION FACTOR GATA-3; DEVELOPING TH1 CELLS; HELPER TYPE-1 CELLS AB In 1986, Mosmann and Coff man identified 2 subsets of activated CD4 Tcells, Th1 and Th2 cells, which differed from each other in their pattern of cytokine production and their functions. Our understanding of the importance of the distinct differentiated forms of CD4 T cells and of the mechanisms through which they achieve their differentiated state has greatly expanded over the past 2 decades. Today at least 4 distinct CD4 T-cell subsets have been shown to exist, Th1, Th2, Th17, and iTreg cells. Here we summarize much of what is known about the 4 subsets, including the history of their discovery, their unique cytokine products and related functions, their distinctive expression of cell surface receptors and their characteristic transcription factors, the regulation of their fate determination, and the consequences of their abnormal activation. C1 [Zhu, Jinfang; Paul, William E.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Zhu, JF (reprint author), NIAID, Immunol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Zhu, Jinfang/B-7574-2012 FU Division of Intramural Research; National Institute of Allergy and Infectious Diseases; National Institutes of Health [Z01 A1000493-22-L1] FX We thank Dr Hidehiro Yamane for insightful discussions in preparation of this review. We apologize to those authors whose related work is not appropriately cited because of the limitations of the space and/or our knowledge.; This work was supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, under project Z01 A1000493-22-L1. NR 179 TC 609 Z9 656 U1 12 U2 80 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 SEP 1 PY 2008 VL 112 IS 5 BP 1557 EP 1569 DI 10.1182/blood-2008-05-078154 PG 13 WC Hematology SC Hematology GA 344VU UT WOS:000258956200009 PM 18725574 ER PT J AU Farrar, JE Nater, M Caywood, E McDevitt, MA Kowalski, J Takemoto, CM Talbot, CC Meltzer, P Esposito, D Beggs, AH Schneider, HE Grabowska, A Ball, SE Niewiadomska, E Sieff, CA Vlachos, A Atsidaftos, E Ellis, SR Lipton, JM Gazda, HT Areci, RJ AF Farrar, Jason E. Nater, Michelle Caywood, Emi McDevitt, Michael A. Kowalski, Jeanne Takemoto, Clifford M. Talbot, C. Conover, Jr. Meltzer, Paul Esposito, Diane Beggs, Alan H. Schneider, Hal E. Grabowska, Agnieszka Ball, Sarah E. Niewiadomska, Edyta Sieff, Colin A. Vlachos, Adrianna Atsidaftos, Eva Ellis, Steven R. Lipton, Jeffrey M. Gazda, Hanna T. Areci, Robert J. TI Abnormalities of the large ribosomal subunit protein, Rp135a, in Diamond-Blackfan anemia SO BLOOD LA English DT Article ID SACCHAROMYCES-CEREVISIAE; RNA INTERFERENCE; GENE; RPS19; CELLS; IDENTIFICATION; EXPRESSION; MUTATIONS; STRESS; S19 AB Diamond-Blackfan anemia (DBA) is an inherited bone marrow failure syndrome characterized by anemia, congenital abnormalities, and cancer predisposition. Small ribosomal subunit genes RPS19, RPS24, and RPS17 are mutated in approximately one-third of patients. We used a candidate gene strategy combining high-resolution genomic mapping and gene expression microarray in the analysis of 2 DBA patients with chromosome 3q deletions to identify RPL35A as a potential DBA gene. Sequence analysis of a cohort of DBA probands confirmed involvement RPL35A in DBA. shRNA inhibition shows that Rp135a is essential for maturation of 28S and 5.8S rRNAs, 60S subunit biogenesis, normal proliferation, and cell survival. Analysis of pre-rRNA processing in primary DBA lymphoblastoid cell lines demonstrated similar alterations of large ribosomal subunit rRNA in both RPL35A-mutated and some RPL35A wild-type patients, suggesting additional large ribosomal subunit gene defects are likely present in some cases of DBA. These data demonstrate that alterations of large ribosomal subunit proteins cause DBA and support the hypothesis that DBA is primarily the result of altered ribosomal function. The results also establish that haploinsufficiency of large ribosomal subunit proteins contributes to bone marrow failure and potentially cancer predisposition. C1 [Farrar, Jason E.; Nater, Michelle; Caywood, Emi; Areci, Robert J.] Johns Hopkins Univ, Sch Med, Div Pediat Oncol, Dept Oncol,Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA. [McDevitt, Michael A.] Johns Hopkins Univ, Sch Med, Div Hematol, Dept Med, Baltimore, MD USA. [Kowalski, Jeanne] Johns Hopkins Univ, Sch Med, Div Oncol Biostat, Dept Oncol,Kimmel Comprehens Canc Ctr, Baltimore, MD USA. [Takemoto, Clifford M.] Johns Hopkins Univ, Sch Med, Div Pediat Hematol, Dept Pediat, Baltimore, MD USA. [Talbot, C. Conover, Jr.] Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD USA. [Meltzer, Paul] Natl Human Genome Res Inst, Canc Genet Branch, Natl Inst Hlth, Bethesda, MD USA. [Esposito, Diane] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Beggs, Alan H.; Schneider, Hal E.; Grabowska, Agnieszka; Gazda, Hanna T.] Childrens Hosp, Div Genet, Boston, MA 02115 USA. [Beggs, Alan H.; Schneider, Hal E.; Grabowska, Agnieszka; Gazda, Hanna T.] Childrens Hosp, Program Genom, Boston, MA 02115 USA. [Beggs, Alan H.; Sieff, Colin A.; Gazda, Hanna T.] Harvard Univ, Sch Med, Boston, MA USA. [Ball, Sarah E.] Univ London St Georges Hosp, Dept Cellular & Mol Med, London, England. [Niewiadomska, Edyta] Univ Med Sch, Dept Pediat Hematol Oncol, Warsaw, Poland. [Sieff, Colin A.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Sieff, Colin A.] Childrens Hosp, Div Pediat Hematol, Boston, MA 02115 USA. [Vlachos, Adrianna; Atsidaftos, Eva; Lipton, Jeffrey M.] Schneider Childrens Hosp, Div Hematol Oncol & Stem Cell Transplantat, New Hyde Pk, NY USA. Feinstein Inst Med Res, Manhasset, NY USA. [Ellis, Steven R.] Univ Louisville, Dept Biochem & Mol Biol, Louisville, KY 40292 USA. RP Farrar, JE (reprint author), Johns Hopkins Univ, Sch Med, Div Pediat Oncol, Dept Oncol,Kimmel Comprehens Canc Ctr, Baltimore, MD 21218 USA. OI Farrar, Jason/0000-0003-2148-5839 FU Children's Cancer Foundation; Lyles Parachini Fund; Michael Corb Fund; Michael Garil Leukemia Survivors Program; Pediatric Cancer Foundation; Alex's Lemonade Stand Foundation; ASCO Foundatio; Diamond Blackfan Anemia Foundation; National Institutes of Health [HL079583, HL079571, M01RR0918535, CA120535]; Ruth L. Kirschstein National Research Service Award [CA60441] FX The authors thank the patients and families for their participation in this Study, Drs Gita Massey and Nancy Dunn for the identification of the second deletion patient, Dr Joseph Palumbo for caring for the first deletion patient, and Amanda Black for computational microarray assistance.; This work was supported in part by grants from the Children's Cancer Foundation (R.J.A.), the Lyles Parachini Fund (R.J.A.), the Michael Corb Fund (R.J.A.), file Michael Garil Leukemia Survivors Program (R.J.A.), the Pediatric Cancer Foundation (J.M.L.), Alex's Lemonade Stand Foundation (J.E.F.), ASCO Foundation (J.E.F), the Diamond Blackfan Anemia Foundation (H.T.G.) and National Institutes of Health (NIH) grants HL079583 (S.R.E.), HL079571 (J.M.L.), GCRC Grant M01RR0918535 (J.M.L., A.V., E.A.), and CA120535 (R.J.A.). I.E.F. also received NIH Support under Ruth L. Kirschstein National Research Service Award CA60441. NR 52 TC 120 Z9 123 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2008 VL 112 IS 5 BP 1582 EP 1592 DI 10.1182/blood-2008-02-140012 PG 11 WC Hematology SC Hematology GA 344VU UT WOS:000258956200011 PM 18535205 ER PT J AU Chae, JJ Wood, G Richard, K Jaffe, H Colburn, NT Masters, SL Gumucio, DL Shoham, NG Kastner, DL AF Chae, Jae Jin Wood, Geryl Richard, Katharina Jaffe, Howard Colburn, Nona T. Masters, Seth L. Gumucio, Deborah L. Shoham, Nitza G. Kastner, Daniel L. TI The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappa B through its N-terminal fragment SO BLOOD LA English DT Article ID TUMOR-NECROSIS-FACTOR; CONTAINING APAF1-LIKE PROTEIN; NUCLEAR EXPORT SIGNAL; IFN-GAMMA PRODUCTION; REGULATES ACTIVATION; ASC; APOPTOSIS; DOMAIN; ALPHA; GENE AB Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by mutations in MEFV which encodes a 781-amino acid protein denoted pyrin. We have previously shown that pyrin regulates caspase-1 activation and IL-1 beta production through interaction of its N-terminal PYD motif with the ASC adapter protein, and also modulates IL-1 beta production by interaction of its C-terminal B30.2 domain with the catalytic domains of caspase-1. We now asked whether pyrin might itself be a caspase-1 substrate, and found that pyrin is cleaved by caspase-1 at Asp330, a site remote from the B30.2 domain. Pyrin variants harboring FMF-associated B30.2 mutations were cleaved more efficiently than wild-type pyrin. The N-terminal cleaved fragment interacted with the p65 subunit of NF-kappa B and with I kappa B-alpha through its 15-aa bZIP basic domain and adjacent sequences, respectively, and translocated to the nucleus. The interaction of the N-terminal fragment with p65 enhanced entrance of p65 into the nucleus. The interaction of N-terminal pyrin with I kappa B-alpha induced calpain-mediated degradation of I kappa B-alpha, thus potentiating NF-kappa B activation. Absolute and relative quantities of cleaved pyrin and I kappa B-alpha degradation products were substantially increased in leukocytes from FMF patients compared with healthy controls. Our data support a new pyrin/caspase-1 pathway for NF-kappa B activation. C1 [Chae, Jae Jin; Wood, Geryl; Richard, Katharina; Colburn, Nona T.; Masters, Seth L.; Shoham, Nitza G.; Kastner, Daniel L.] NIAMSD, Genet & Genom Branch, Bethesda, MD 20892 USA. [Jaffe, Howard] Natl Inst Neurol Disorders & Stroke, Prot Peptide Sequencing Facil, Bethesda, MD 20892 USA. [Gumucio, Deborah L.] Univ Michigan, Sch Med, Dept Cell & Dev Biol, Ann Arbor, MI USA. RP Chae, JJ (reprint author), NIAMS, NIH, GGB, Bldg 10,Room 9N-214,10 Ctr Dr MSC 1820, Bethesda, MD 20892 USA. EM chaej@exchange.nih.gov OI masters, seth/0000-0003-4763-576X FU National Institute of Arthritis and Muculoskeletal and Skill Diseases (Bethesda, MD) FX This work was supported by the Intramural Research Program of the National Institute of Arthritis and Muculoskeletal and Skill Diseases (Bethesda, MD). NR 65 TC 74 Z9 79 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2008 VL 112 IS 5 BP 1794 EP 1803 DI 10.1182/blood-2008-01-134932 PG 10 WC Hematology SC Hematology GA 344VU UT WOS:000258956200036 PM 18577712 ER PT J AU Cohen, PA Koski, GK Czerniecki, BJ Bunting, KD Fu, XY Wang, ZQ Zhang, WJ Carter, CS Awad, M Distel, CA Nagem, H Paustian, CC Johnson, TD Tisdale, JF Shu, SY AF Cohen, Peter A. Koski, Gary K. Czerniecki, Brian J. Bunting, Kevin D. Fu, Xin-Yuan Wang, Zhengqi Zhang, Wen-Jun Carter, Charles S. Awad, Mohamed Distel, Christopher A. Nagem, Hassan Paustian, Christopher C. Johnson, Terrence D. Tisdale, John F. Shu, Suyu TI STAT3- and STAT5-dependent pathways competitively regulate the pan-differentiation of CD34(pos) cells into tumor-competent dendritic cells SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; HEMATOPOIETIC PROGENITOR CELLS; CD8(+) T-CELLS; FLT3 LIGAND; BONE-MARROW; PERIPHERAL-BLOOD; IN-VIVO; ADOPTIVE IMMUNOTHERAPY; ANTITUMOR-ACTIVITY; CD34(+) CELLS AB The clinical outcomes of dendritic cell (DC)based immunotherapy remain disappointing, with DCs often displaying a tenuous capacity to complete maturation and DC1 polarization in the tumor host. Surprisingly, we observed that the capacity for successful DC1 polarization, including robust IL12p70 production, could be regulated by STAT-dependent events even prior to DC differentiation. Exposure of CD34(pos) cells to single-agent granulocyte-macrophage colony-stimulating factor (GMCSF) induced multilineage, STAT5-dependent differentiation, including DCs that failed to mature in the absence of further exogenous signals. In contrast, FIt3L induced nearly global differentiation of CD34(pos) cells into spontaneously maturing DCs. IL-6 synergized with FIt3L to produce explosive, STAT3-dependent proliferation of phenotypically undifferentiated cells that nevertheless functioned as committed DC1 precursors. Such precursors not only resisted many tumor-associated immunosuppressants, but also responded to tumor contact or TGF beta with facilitated DC maturation and IL12p70 production, and displayed a superior capacity to reverse tumor-induced T-cell tolerance. GMCSF preempted FIt3L or FIt3L plus IL-6 licensing by blocking STAT3 activation and promoting STAT5-dependent differentiation. Paradoxically, following overt DC differentiation, STAT5 enhanced whereas STAT3 inhibited DC1 polarization. Therefore, nonoverlapping, sequential activation of STAT3 and STAT5, achievable by sequenced exposure to FIt3L plus IL-6, then GMCSF, selects for multilog expansion, programming, and DC1 polarization of tumor-competent DCs from CD34(pos) cells. C1 [Cohen, Peter A.; Koski, Gary K.; Awad, Mohamed; Distel, Christopher A.; Nagem, Hassan; Paustian, Christopher C.; Johnson, Terrence D.; Shu, Suyu] Cleveland Clin Fdn, Surg Res Ctr, Lerner Res Inst, Cleveland, OH 44195 USA. [Cohen, Peter A.; Koski, Gary K.; Bunting, Kevin D.; Wang, Zhengqi; Shu, Suyu] Case Comprehens Canc Ctr, Cleveland, OH USA. [Czerniecki, Brian J.] Univ Penn, Med Ctr, Dept Surg, Philadelphia, PA 19104 USA. [Fu, Xin-Yuan; Zhang, Wen-Jun] Indiana Univ, Sch Med, Walther Oncol Ctr, Indianapolis, IN 46202 USA. [Fu, Xin-Yuan; Zhang, Wen-Jun] Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. [Tisdale, John F.] Natl Inst Diabet & Digest & Kidney Dis, NIH, Bethesda, MD USA. [Carter, Charles S.] NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Cohen, PA (reprint author), Cleveland Clin Fdn, Surg Res Ctr, Lerner Res Inst, NE6,9500 Euclid Ave, Cleveland, OH 44195 USA. EM cohenp@ccf.org FU National Institutes of Health (NIH, Bethesda, MD) [R01-CA089511, R01-CA103946, ROI-CA129815] FX This work is supported by National Institutes of Health (NIH, Bethesda, MD) grants R01-CA089511, R01-CA103946, and ROI-CA129815. NR 50 TC 32 Z9 33 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 SEP 1 PY 2008 VL 112 IS 5 BP 1832 EP 1843 DI 10.1182/blood-2007-12-130138 PG 12 WC Hematology SC Hematology GA 344VU UT WOS:000258956200040 PM 18577706 ER PT J AU Segarra, M Williams, CK Sierra, MD Bernardo, M McCormick, PJ Maric, D Regino, C Choyke, P Tosato, G AF Segarra, Marta Williams, Cassin Kimmel Sierra, Maria de la Luz Bernardo, Marcelino McCormick, Peter J. Maric, Dragan Regino, Celeste Choyke, Peter Tosato, Giovanna TI Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth SO BLOOD LA English DT Article ID ENDOTHELIAL-CELL FUNCTION; LIGAND DELTA-LIKE-4; UP-REGULATION; ANGIOGENESIS; VEGF; VASCULATURE; EXPRESSION; PROLIFERATION; NORMALIZATION; LETHALITY AB Gene targeting experiments have shown that Delta-like 4 (Dll4) is a vascular-specific Notch ligand critical to normal vascular development. Recent studies have demonstrated that inhibition of Dll4/Notch signaling in tumor-bearing mice resulted in excessive, yet nonproductive tumor neovascularization and unexpectedly reduced tumor growth. Because nonfunctional blood vessels have the potential to normalize, we explored the alternative approach of stimulating Notch signaling in the tumor vasculature to inhibit tumor growth. Here we show that retrovirus-induced over-expression of Dll4 in tumor cells activates Notch signaling in cocultured endothelial cells and limits vascular endothelial growth factor (VEGF)-induced endothelial cell growth. Tumors produced in mice by injection of human and murine tumor cells transduced with Dll4 were significantly smaller, less vascularized and more hypoxic than controls, and displayed evidence of Notch activation. In addition, tumor blood perfusion was reduced as documented by vascular imaging. These results demonstrate that Notch activation in the tumor micro-environment reduces tumor neovascularization and blood perfusion, and suggest that Dll4-induced Notch activation may represent an effective therapeutic approach for the treatment of solid tumors. C1 [Segarra, Marta; Williams, Cassin Kimmel; Sierra, Maria de la Luz; McCormick, Peter J.; Tosato, Giovanna] NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bernardo, Marcelino; Regino, Celeste; Choyke, Peter] NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Bernardo, Marcelino] NCI Frederick, SAIC Frederick, Lab Anim Sci Program, Frederick, MD USA. [Maric, Dragan] NINDS, Flow Cytometry Core Facil, NIH, Bethesda, MD USA. RP Segarra, M (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, 37 Ctr Dr,Bldg 37,Room 4124, Bethesda, MD 20892 USA. EM segarram@mail.nih.gov RI McCormick, Peter/E-7387-2012 OI McCormick, Peter/0000-0002-2225-5181 FU Intramural NIH HHS; NCI NIH HHS [N01CO12400, N01-CO-12400] NR 36 TC 31 Z9 32 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2008 VL 112 IS 5 BP 1904 EP 1911 DI 10.1182/blood-2007-11-126045 PG 8 WC Hematology SC Hematology GA 344VU UT WOS:000258956200048 PM 18577711 ER PT J AU Slape, C Liu, LY Beachy, S Aplan, PD AF Slape, Christopher Liu, Leah Y. Beachy, Sarah Aplan, Peter D. TI Leukemic transformation in mice expressing a NUP98-HOXD13 transgene is accompanied by spontaneous mutations in Nras, Kras, and Cbl SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; MYELODYSPLASTIC SYNDROME; BETHESDA PROPOSALS; C-CBL; GENES; IDENTIFICATION; CLASSIFICATION; CBFB-MYH11; NEOPLASMS; CANCER AB The NUP98-HOXD13(NHD13) fusion gene occurs in patients with myelodysplastic syndrome (MDS) and acute nonlymphocytic leukemia (ANLL). We reported that transgenic mice expressing NHD13 develop MDS, and that more than half of these mice eventually progress to acute leukemia. The latency period suggests a requirement for at least I complementary event before leukemic transformation. We conducted a candidate gene search for complementary events focused on genes that are frequently mutated in human myeloid leukemia. We investigated 22 ANLL samples and found a high frequency of Nras and Kras mutations, an absence of Npm1, p53, Runx1, Kit and Flt3 mutations, and a single Cbl mutation. Our findings support a working hypothesis that predicts that ANLL cases have one mutation which inhibits differentiation, and a complementary mutation which enhances proliferation or inhibit apoptosis. In addition, we provide the first evidence for spontaneous collaborating mutations in a genetically engineered mouse model of ANLL. C1 [Slape, Christopher; Liu, Leah Y.; Beachy, Sarah; Aplan, Peter D.] NCI, NIH, CCR, Genet Branch, Bethesda, MD 20889 USA. RP Aplan, PD (reprint author), NCI, NIH, CCR, Genet Branch, Navy 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM aplanp@mail.nih.gov RI Slape, Christopher/H-8586-2016; Aplan, Peter/K-9064-2016 OI Slape, Christopher/0000-0002-8407-3092; FU Intramural Research Program of the NIH and NCI FX We are grateful to our colleagues Ying-Wei Lin, Helge Hartung, Yangjo Chung, and Chul Won Choi for significant discussion and technical assistance.; This research was supported by the Intramural Research Program of the NIH and NCI. NR 22 TC 32 Z9 33 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 SEP 1 PY 2008 VL 112 IS 5 BP 2017 EP 2019 DI 10.1182/blood-2008-01-135186 PG 3 WC Hematology SC Hematology GA 344VU UT WOS:000258956200060 PM 18566322 ER PT J AU Zhu, BM McLaughlin, SK Na, R Liu, J Cui, Y Martin, C Kimura, A Robinson, GW Andrews, NC Hennighausen, L AF Zhu, Bing-Mei McLaughlin, Sara K. Na, Risu Liu, Jie Cui, Yongzhi Martin, Cyril Kimura, Akiko Robinson, Gertraud W. Andrews, Nancy C. Hennighausen, Lothar TI Hematopoietic-specific Stat5-null mice display microcytic hypochromic anemia associated with reduced transferrin receptor gene expression SO BLOOD LA English DT Article ID MESSENGER-RNA EXPRESSION; STAT5A(-/-)5B(-/-) MICE; CELL-PROLIFERATION; ERYTHROID-CELLS; TRANSGENIC MICE; BINDING-SITES; JAK2; ERYTHROPOIETIN; IDENTIFICATION; PROGENITORS AB Iron is essential for all cells but is toxic in excess, so iron absorption and distribution are tightly regulated. Serum iron is bound to transferrin and enters erythroid cells primarily via receptor-mediated endocytosis of the transferrin receptor (Tfr1). Tfr1 is essential for developing erythrocytes and reduced Tfr1 expression is associated with anemia. The transcription factors STAT5A/B are activated by many cytokines, including erythropoietin. Stat5a/b(-/-) mice are severely anemic and die perinatally, but no link has been made to iron homeostasis. To study the function of STAT5A/B in vivo, we deleted the floxed Stat5a/b locus in hematopoietic cells with a Tie2-Cre transgene. These mice exhibited microcytic, hypochromic anemia, as did lethally irradiated mice that received a transplant of Stat5a/b fetal liver cells. Flow cytometry and RNA analyses of erythroid cells from mutant mice revealed a 50% reduction in Tfr1 binding sites in the first intron of the Tfr1 gene and found that expression of constitutively active STAT5A in an erythroid cell line increased Tfr1 levels. Chromatin immunoprecipitation experiments confirmed the binding of STAT5A/B to these sites. We conclude that STAT5A/B is an important regulator of iron update in erythroid progenitor cells via its control of Tfr1 transcription. C1 [Zhu, Bing-Mei; Na, Risu; Cui, Yongzhi; Martin, Cyril; Kimura, Akiko; Robinson, Gertraud W.; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. [McLaughlin, Sara K.; Andrews, Nancy C.] Childrens Hosp, Boston, MA 02115 USA. [McLaughlin, Sara K.; Andrews, Nancy C.] Harvard Univ, Sch Med, Boston, MA USA. [Liu, Jie] NIAID, ImmunoTechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Zhu, BM (reprint author), NIDDK, Lab Genet & Physiol, NIH, Bldg 8,Room 101,8 Ctr Dr, Bethesda, MD 20892 USA. EM bingmei@mail.nih.gov; lotharh@mail.nih.gov RI Robinson, Gertraud/I-2136-2012; OI Andrews, Nancy/0000-0003-0243-4462 FU NIDDK; NIAID; NIH [R01 HL51057, T32 HL07623] FX The authors thank Susanne Pechhold for cell sorting and Ann Dean for providing MEL cells. We also thank Toshio Kitamura for providing the constitutively active Stat5A construct and Weiping Chen and Maggie Cam for microarray analysis.; This study was supported by the intramural research programs of NIDDK and NIAID, NIH, by NIH R01 HL51057 (N.C.A.) and NIH T32 HL07623 (S.K.M.). NR 30 TC 53 Z9 56 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2008 VL 112 IS 5 BP 2071 EP 2080 DI 10.1182/blood-2007-12-127480 PG 10 WC Hematology SC Hematology GA 344VU UT WOS:000258956200068 PM 18552213 ER PT J AU Vasu, S Leitman, SF Tisdale, JF Hsieh, MM Childs, RW Barrett, AJ Fowler, DH Bishop, MR Kang, EM Malech, HL Dunbar, CE Khuu, HM Wesley, R Yau, YY Bolan, CD AF Vasu, Sumithira Leitman, Susan F. Tisdale, John F. Hsieh, Matthew M. Childs, Richard W. Barrett, A. John Fowler, Daniel H. Bishop, Michael R. Kang, Elizabeth M. Malech, Harry L. Dunbar, Cynthia E. Khuu, Hanh M. Wesley, Robert Yau, Yu Y. Bolan, Charles D. TI Donor demographic and laboratory predictors of allogeneic peripheral blood stem cell mobilization in an ethnically diverse population SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; BONE-MINERAL DENSITY; LARGE-VOLUME LEUKAPHERESIS; PROGENITOR CELLS; HEALTHY DONORS; G-CSF; AUTOMATED PLATELETPHERESIS; GRANULOCYTE-MACROPHAGE; HOST-DISEASE; TRANSPLANTATION AB A reliable estimate of peripheral blood stem cell (PBSC) mobilization response to granulocyte colony-stimulating factor (G-CSF) may identify donors at risk for poor mobilization and help optimize transplantation approaches. We studied 639 allogeneic PBSC collections performed in 412 white, 75 black, 116 Hispanic, and 36 Asian/Pacific adult donors who were prescribed G-CSF dosed at either 10 or 16 mu g/kg per day for 5 days followed by large-volume leukapheresis (LVL). Additional LVL (mean, 11 L) to collect lymphocytes for donor lymphocyte infusion (DLI) and other therapies was performed before G-CSF administration in 299 of these donors. Day 5 preapheresis blood CD34(+) cell counts after mobilization were significantly lower in whites compared with blacks, Hispanics, and Asian/Pacific donors (79 vs 104, 94, and 101 cells/mu L, P <.001). In addition, donors who underwent lymphapheresis before mobilization had higher CD34(+) cell counts than donors who did not (94 vs 79 cells/mu L, P <.001). In multivariate analysis, higher post-G-CSF CD34(+) cell counts were most strongly associated with the total amount of G-CSIF received, followed by the pre-G-CSF platelet count, pre-G-CSF mononuclear count, and performance of prior LVL for DLI collection. Age, white ethnicity, and female gender were associated with significantly lower post-G-CSF CD34(+) cell counts. C1 [Childs, Richard W.; Barrett, A. John; Dunbar, Cynthia E.; Bolan, Charles D.] NHLBI, Hematol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Vasu, Sumithira; Leitman, Susan F.; Khuu, Hanh M.; Yau, Yu Y.] NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. [Tisdale, John F.; Hsieh, Matthew M.] NIDDK, Mol Hematol Sect, Bethesda, MD 20892 USA. [Fowler, Daniel H.; Bishop, Michael R.] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. [Kang, Elizabeth M.; Malech, Harry L.] NIAID, Host Def Lab, Bethesda, MD 20892 USA. [Wesley, Robert] NIH, Bethesda, MD 20892 USA. [Wesley, Robert] Biostat & Clin Epidemiol Serv, Bethesda, MD USA. RP Bolan, CD (reprint author), NHLBI, Hematol Branch, Natl Inst Hlth, Bldg 10,CRC Room 4-5140,MSC 1202, Bethesda, MD 20892 USA. EM cbolan@nhlbi.nih.gov OI Malech, Harry/0000-0001-5874-5775 FU National Institutes of Health FX The authors thank Gail Birmingham, Karen Diggs, De Gladden, and the Outstanding staff of the Dowling Apheresis Clinic for the care of the donors during the performance of the apheresis procedures, Dr Harvey Klein for his Support For the conduct of the Study and preparation of the manuscript, and the research nurses, clinical fellows, and staff of the clinical teams of National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of Diabetes, Digestive and Kidney Diseases, and National Institute of Allerguy and Infectious Diseases for their evaluation, management, and recruitment of donors.; This work was supported by the National Institutes of Health.; The views expressed in this paper are those of the authors and are not to be construed as the official position of the United States Department of Health and Human Services or the United States Public Health Service. NR 49 TC 60 Z9 61 U1 2 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD SEP 1 PY 2008 VL 112 IS 5 BP 2092 EP 2100 DI 10.1182/blood-2008-03-143677 PG 9 WC Hematology SC Hematology GA 344VU UT WOS:000258956200071 PM 18523146 ER PT J AU Haviernik, P Diaz, MT Haviernikova, E Tse, W Stetler-Stevenson, WG Bunting, KD AF Haviernik, Peter Diaz, Maria T. Haviernikova, Eleonora Tse, William Stetler-Stevenson, William G. Bunting, Kevin D. TI Hematopoiesis in mice is extremely resilient to wide variation in TIMP/MMP balance SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Article DE matrix metalloproteinase; hematopoiesis; retroviral vector; bone marrow; hematopoietic progenitor mobilization ID TIMP-1 TRANSGENIC MICE; TISSUE INHIBITOR; TUMOR-GROWTH; BONE-MARROW; MATRIX METALLOPROTEINASES; PANCREATIC-CANCER; CELL MOBILIZATION; TERMINAL DOMAIN; GELATINASE-B; NUDE-MICE AB Tissue inhibitos of matrix metalloproteinases (TIMPs) are natural inhibitors of matrix metalloproteinases (MMPs) and are associated with normal and pathologic extracellular matrix turnover. Because the microenvironment is critical for normal hematopoietic stem/progenitor cell function, we aimed to determine whether alterations in the TIMP/MMP balance impact upon normal hematopoiesis in mice. We have used both overexpression and knockout mouse models to determine whether early hematopoiesis is susceptible to potentially pathologic changes in TIMP/MMP level. These studies used TIMP-1(-/-) mice and retroviral vectors co-expressing human TIMP-1 or TIMP-2 linked with the green fluorescent protein (GFP) transduced into bone marrow (BM) cells and transplanted into lethally-irradiated recipient mice. Loss of TIMP-1 in knockout mice or retroviral overexpression of TIMP-1 or TIMP-2 did not alter hematopoietic stem/progenitor function during steady-state hematopoiesis. Surprisingly, even when applying hematopoietic stress through mobilization, chemotaxis, or myelosuppression, murine hematopoiesis was not adversely affected by TIMP-1 or TIMP-2 level. We Conclude that TIMP/MMP balance alone does not exert significant influence on blood cell development and homeostasis. An important corollary of these studies is that specific modulation using MMP inhibitors for cancer or immunologic therapy is unlikely to have adverse hematopoietic side effects. (C) 2008 Elsevier Inc. All rights reserved. C1 [Haviernik, Peter; Haviernikova, Eleonora; Tse, William; Bunting, Kevin D.] Case Western Reserve Univ, Dept Med, Div Hematol Oncol, Cleveland, OH 44106 USA. [Diaz, Maria T.; Stetler-Stevenson, William G.] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD USA. [Tse, William; Bunting, Kevin D.] Case Comphrehens Canc Ctr, Cleveland, OH USA. [Tse, William; Bunting, Kevin D.] Ctr Stem Cell & Regenerat Med, Cleveland, OH USA. RP Bunting, KD (reprint author), Case Western Reserve Univ, Dept Med, Div Hematol Oncol, WRB 2-131, Cleveland, OH 44106 USA. EM Kevin.Bunting@case.edu RI Stetler-Stevenson, William/H-6956-2012 OI Stetler-Stevenson, William/0000-0002-5500-5808 FU NCI NIH HHS [P30 CA043703]; NHLBI NIH HHS [R01 HL073738, R01 HL073738-04]; NIDDK NIH HHS [R01 DK059380] NR 45 TC 5 Z9 5 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD SEP-OCT PY 2008 VL 41 IS 2 BP 179 EP 187 DI 10.1016/j.bcmd.2008.03.005 PG 9 WC Hematology SC Hematology GA 338XP UT WOS:000258543000008 PM 18487063 ER PT J AU Hyde, TM Deep-Soboslay, A Iglesias, B Callicott, JH Gold, JM Meyer-Lindenberg, A Honea, RA Bigelow, LB Egan, MF Emsellem, EM Weinberger, DR AF Hyde, Thomas M. Deep-Soboslay, Amy Iglesias, Bianca Callicott, Joseph H. Gold, James M. Meyer-Lindenberg, Andreas Honea, Robyn A. Bigelow, Llewellyn B. Egan, Michael F. Emsellem, Esther M. Weinberger, Daniel R. TI Enuresis as a premorbid developmental marker of schizophrenia SO BRAIN LA English DT Article DE schizophrenia; enuresis; development; neuroimaging; frontal lobes ID NOCTURNAL BLADDER CONTROL; VOXEL-BASED MORPHOMETRY; FRONTAL-LOBE LESIONS; BRAIN ACTIVATION; WORKING-MEMORY; VERBAL FLUENCY; FOLLOW-UP; ADULT SCHIZOPHRENIA; BEHAVIORAL-PROBLEMS; AFFECTIVE PSYCHOSES AB There is comparatively little information about premorbid maturational brain abnormalities in schizophrenia (SCZ). We investigated whether a history of childhood enuresis, a well-established marker of neurodevelopmental delay, is associated with SCZ and with measures of brain abnormalities also associated with SCZ. A Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) based history of enuresis, volumetric brain MRI scans and neuropsychological testing were obtained in patients with SCZ, their non-psychotic siblings (SIB) and non-psychiatric controls (NC). The subjects were 211 patients (79.6% male), 234 of their SIB (43.2% male) and 355 controls (39.2% male). Frequency of enuresis was compared across groups and correlated with cognitive measures. Total and regional brain volumes were determined using voxel-based morphometry onmatched subsets of probands (n = 82) with or without enuresis (n = 16, n = 66, respectively) and controls (n = 102) with or without enuresis (n = 11, n = 91, respectively). Patients with SCZ had higher rates of childhood enuresis (21%) compared with SIB (11%; chi(2) = 6.42, P = 0.01) or controls (7%; chi(2) = 23.65, P < 0.0001) and relative risk for enuresis was increased in SIB (lambda(S) = 2.62). Patients with enuresis performed worse on two frontal lobe cognitive tests [Letter Fluency (t = 1.97, P = 0.05, df = 200) and Category Fluency (t = 2.15, P = 0.03, df = 200)] as compared with non-enuretic patients. Voxel-based morphometry analysis revealed grey matter volume reductions in several frontal regions (right BA 9, right BA 10 and bilateral BA 45) and right superior parietal cortex (BA 7) in patients with a history of enuresis as compared with non-enuretic patients (all t > 3.57, all P < 0.001). The high frequency of childhood enuresis associated with SCZ and abnormalities in prefrontal function and structure in patients with a childhood history of enuresis suggest that childhood enuresis may be a premorbid marker for neurodevelopmental abnormalities related to SCZ. These findings add to the evidence implicating prefrontal dysmaturation in this disorder, potentially related to genetic risk factors. C1 [Hyde, Thomas M.; Deep-Soboslay, Amy; Iglesias, Bianca; Callicott, Joseph H.; Honea, Robyn A.; Bigelow, Llewellyn B.; Egan, Michael F.; Emsellem, Esther M.] Univ Maryland, Clin Brain Disorders Branch, Baltimore, MD 21201 USA. [Gold, James M.] Univ Maryland, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. [Meyer-Lindenberg, Andreas; Weinberger, Daniel R.] NIMH, DIRP, NIH, Genes Cognit & Psychosis Program, Bethesda, MD 20892 USA. RP Hyde, TM (reprint author), NIMH, DIRP, NIH, Clin Brain Disorders Branch, 10 Ctr Dr,MSC 1385, Bethesda, MD 20892 USA. EM hydet@mail.nih.gov RI Callicott, Joseph/C-9102-2009; Meyer-Lindenberg, Andreas/H-1076-2011 OI Callicott, Joseph/0000-0003-1298-3334; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU NIMH Intramural Research Program, NIH FX This study was supported by the NIMH Intramural Research Program, NIH. We acknowledge all the individuals and their families who participated in this study. We acknowledge Joann Berkson, RN, MEd, and Mary Weirich, MSW, for assistance in data collection and John Meyers, BS, for data management. NR 64 TC 11 Z9 13 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD SEP PY 2008 VL 131 BP 2489 EP 2498 DI 10.1093/brain/awn167 PN 9 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 343OA UT WOS:000258862200023 PM 18669483 ER PT J AU Drevets, WC Price, JL Furey, ML AF Drevets, Wayne C. Price, Joseph L. Furey, Maura L. TI Brain structural and functional abnormalities in mood disorders: implications for neurocircuitry models of depression SO BRAIN STRUCTURE & FUNCTION LA English DT Review ID MEDIAL PREFRONTAL CORTEX; ANTERIOR CINGULATE CORTEX; POSITRON-EMISSION-TOMOGRAPHY; UNIPOLAR MAJOR DEPRESSION; VAGUS NERVE-STIMULATION; CEREBRAL-BLOOD-FLOW; MAGNETIC-RESONANCE SPECTROSCOPY; TREATMENT-RESISTANT DEPRESSION; CORTICOTROPIN-RELEASING-FACTOR; SEROTONIN TRANSPORTER BINDING AB The neural networks that putatively modulate aspects of normal emotional behavior have been implicated in the pathophysiology of mood disorders by converging evidence from neuroimaging, neuropathological and lesion analysis studies. These networks involve the medial prefrontal cortex (MPFC) and closely related areas in the medial and caudolateral orbital cortex (medial prefrontal network), amygdala, hippocampus, and ventromedial parts of the basal ganglia, where alterations in grey matter volume and neurophysiological activity are found in cases with recurrent depressive episodes. Such findings hold major implications for models of the neurocircuits that underlie depression. In particular evidence from lesion analysis studies suggests that the MPFC and related limbic and striato-pallido-thalamic structures organize emotional expression. The MPFC is part of a larger "default system" of cortical areas that include the dorsal PFC, mid- and posterior cingulate cortex, anterior temporal cortex, and entorhinal and parahippocampal cortex, which has been implicated in self-referential functions. Dysfunction within and between structures in this circuit may induce disturbances in emotional behavior and other cognitive aspects of depressive syndromes in humans. Further, because the MPFC and related limbic structures provide forebrain modulation over visceral control structures in the hypothalamus and brainstem, their dysfunction can account for the disturbances in autonomic regulation and neuroendocrine responses that are associated with mood disorders. This paper discusses these systems together with the neurochemical systems that impinge on them and form the basis for most pharmacological therapies. C1 [Drevets, Wayne C.; Furey, Maura L.] NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, DIRP, Bethesda, MD 20892 USA. [Price, Joseph L.] Washington Univ, Dept Anat & Neurobiol, Sch Med, St Louis, MO 63110 USA. RP Drevets, WC (reprint author), NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, DIRP, 15K N Dr,Room 210, Bethesda, MD 20892 USA. EM drevetsw@mail.nih.gov RI Furey, Maura/H-5273-2013 NR 247 TC 803 Z9 839 U1 31 U2 192 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD SEP PY 2008 VL 213 IS 1-2 BP 93 EP 118 DI 10.1007/s00429-008-0189-x PG 26 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA 340OC UT WOS:000258653900009 PM 18704495 ER PT J AU Colantuoni, C Hyde, TM Mitkus, S Joseph, A Sartorius, L Aguirre, C Creswell, J Johnson, E Deep-Soboslay, A Herman, MM Lipska, BK Weinberger, DR Kleinman, JE AF Colantuoni, Carlo Hyde, Thomas M. Mitkus, Shruti Joseph, Andrew Sartorius, Leah Aguirre, Claudia Creswell, Johanna Johnson, Elizabeth Deep-Soboslay, Amy Herman, Mary M. Lipska, Barbara K. Weinberger, Daniel R. Kleinman, Joel E. TI Age-related changes in the expression of schizophrenia susceptibility genes in the human prefrontal cortex SO BRAIN STRUCTURE & FUNCTION LA English DT Article DE aging; disease onset; schizophrenia; gene expression; susceptibility; postmortem; prefrontal cortex ID BIPOLAR-AFFECTIVE-DISORDER; MESSENGER-RNA EXPRESSION; AMINO-ACID TRANSPORTER-2; MAJOR MENTAL-ILLNESS; SIB-PAIR FAMILIES; LINKAGE DISEQUILIBRIUM; CHINESE POPULATION; TRANSMISSION DISEQUILIBRIUM; FUNCTIONAL-ANALYSIS; NEUREGULIN-1 GENE AB The molecular basis of complex neuropsychiatric disorders most likely involves many genes. In recent years, specific genetic variations influencing risk for schizophrenia and other neuropsychiatric disorders have been reported. We have used custom DNA microarrays and qPCR to investigate the expression of putative schizophrenia susceptibility genes and related genes of interest in the normal human brain. Expression of 31 genes was measured in Brodmann's area 10 (BA10) in the prefrontal cortex of 72 postmortem brain samples spanning half a century of human aging (18-67 years), each without history of neuropsychiatric illness, neurological disease, or drug abuse. Examination of expression across age allowed the identification of genes whose expression patterns correlate with age, as well as genes that share common expression patterns and that possibly participate in common cellular mechanisms related to the emergence of schizophrenia in early adult life. The expression of GRM3 and RGS4 decreased across the entire age range surveyed, while that of PRODH and DARPP-32 was shown to increase with age. NRG1, ERBB3, and NGFR show expression changes during the years of greatest risk for the development of schizophrenia. Expression of FEZ1, GAD1, and RGS4 showed especially high correlation with one another, in addition to the strongest mean levels of absolute correlation with all other genes studied here. All microarray data are available at http://www.ncbi.nlm.nih.gov/geo/ (accession #: TBA). C1 [Colantuoni, Carlo; Hyde, Thomas M.; Mitkus, Shruti; Joseph, Andrew; Sartorius, Leah; Aguirre, Claudia; Creswell, Johanna; Deep-Soboslay, Amy; Herman, Mary M.; Lipska, Barbara K.; Weinberger, Daniel R.; Kleinman, Joel E.] NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, IRP,NIH, Bethesda, MD 20892 USA. [Colantuoni, Carlo; Johnson, Elizabeth] Johns Hopkins Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. RP Colantuoni, C (reprint author), NIMH, Clin Brain Disorders Branch, Genes Cognit & Psychosis Program, IRP,NIH, Bethesda, MD 20892 USA. EM carlo@illuminatoart.com FU Intramural Research Program of the National Institute of Mental Health FX This research was supported by funding solely provided by the Intramural Research Program of the National Institute of Mental Health. The authors would also like to thank Llewellyn B. Bigelow, MD., Vesna Imamovic, Yeva Snitkovsky, and Jewell King for their contributions to the collection and diagnosis of the brain specimens used in this research, the Offices of the Chief Medical Examiner of Washington DC and of Northern Virginia, as well as families of the deceased whose donation of this tissue made this research possible. NR 97 TC 37 Z9 36 U1 0 U2 3 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1863-2653 J9 BRAIN STRUCT FUNCT JI Brain Struct. Funct. PD SEP PY 2008 VL 213 IS 1-2 BP 255 EP 271 DI 10.1007/s00429-008-0181-5 PG 17 WC Anatomy & Morphology; Neurosciences SC Anatomy & Morphology; Neurosciences & Neurology GA 340OC UT WOS:000258653900021 PM 18470533 ER PT J AU Vlachos, A Ball, S Dahl, N Alter, BP Sheth, S Ramenghi, U Meerpohl, J Karlsson, S Liu, JM Leblanc, T Paley, C Kang, EM Leder, EJ Atsidaftos, E Shimamura, A Bessler, M Glader, B Lipton, JM AF Vlachos, Adrianna Ball, Sarah Dahl, Niklas Alter, Blanche P. Sheth, Sujit Ramenghi, Ugo Meerpohl, Joerg Karlsson, Stefan Liu, Johnson M. Leblanc, Thierry Paley, Carole Kang, Elizabeth M. Leder, Eva Judmann Atsidaftos, Eva Shimamura, Akiko Bessler, Monica Glader, Bertil Lipton, Jeffrey M. CA Sixth Annual Daniella Maria Arturi TI Diagnosing and treating Diamond Blackfan anaemia: results of an international clinical consensus conference SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review DE Diamond Blackfan anaemia; bone marrow failure; cancer predisposition; genetics; treatment ID RIBOSOMAL-PROTEIN S19; BONE-MARROW TRANSPLANTATION; STEM-CELL TRANSPLANTATION; ORAL MEGADOSE METHYLPREDNISOLONE; RECOMBINANT HUMAN INTERLEUKIN-3; TRANSFUSIONAL IRON OVERLOAD; BETA-THALASSEMIA; ERYTHROID DEVELOPMENT; PARVOVIRUS INFECTION; CYCLOSPORINE THERAPY AB Diamond Blackfan anaemia (DBA) is a rare, genetically and clinically heterogeneous, inherited red cell aplasia. Classical DBA affects about seven per million live births and presents during the first year of life. However, as mutated genes have been discovered in DBA, non-classical cases with less distinct phenotypes are being described in adults as well as children. In caring for these patients it is often difficult to have a clear understanding of the treatment options and their outcomes because of the lack of complete information on the natural history of the disease. The purpose of this document is to review the criteria for diagnosis, evaluate the available treatment options, including corticosteroid and transfusion therapies and stem cell transplantation, and propose a plan for optimizing patient care. Congenital anomalies, mode of inheritance, cancer predisposition, and pregnancy in DBA are also reviewed. Evidence-based conclusions will be made when possible; however, as in many rare diseases, the data are often anecdotal and the recommendations are based upon the best judgment of experienced clinicians. The recommendations regarding the diagnosis and management described in this report are the result of deliberations and discussions at an international consensus conference. C1 [Vlachos, Adrianna; Liu, Johnson M.; Atsidaftos, Eva; Lipton, Jeffrey M.] Schneider Childrens Hosp, Albert Einstein Coll Med, New Hyde Pk, NY 11042 USA. [Vlachos, Adrianna; Liu, Johnson M.; Leder, Eva Judmann; Lipton, Jeffrey M.] Feinstein Inst Med Res, Manhasset, NY USA. [Ball, Sarah] Univ London St Georges Hosp, Sch Med, London SW17 0RE, England. [Dahl, Niklas] Uppsala Univ, Sch Med, Dept Genet, Uppsala, Sweden. [Dahl, Niklas] Uppsala Univ, Sch Med, Dept Pathol, Uppsala, Sweden. [Alter, Blanche P.] NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Sheth, Sujit] Columbia Univ, New York, NY USA. [Ramenghi, Ugo] Univ Turin, Turin, Italy. [Meerpohl, Joerg] Univ Freiburg Klinikum, Zentrum Kinderheilkunde & Jugendmed, Freiburg, Germany. [Karlsson, Stefan] Lund Univ, Lund, Sweden. [Leblanc, Thierry] Hop St Louis, Paris, France. [Paley, Carole] Novartis, E Hanover, NJ USA. [Kang, Elizabeth M.] NIAID, NIH, Bethesda, MD 20892 USA. [Shimamura, Akiko] Childrens Hosp, Boston, MA 02115 USA. [Bessler, Monica] Washington Univ, St Louis, MO USA. [Glader, Bertil] Stanford Univ, Palo Alto, CA 94304 USA. RP Vlachos, A (reprint author), Schneider Childrens Hosp, Albert Einstein Coll Med, 269-01 76th Ave, New Hyde Pk, NY 11042 USA. EM avlachos@lij.edu RI Meerpohl, Joerg/J-4224-2013 OI Meerpohl, Joerg/0000-0002-1333-5403 FU Daniella Maria Arturi Foundation; Diamond Blackfan Anemia Foundation; Pediatric Cancer Foundation; Association Francaise de la maladie de Blackfan-Diamond; National Institutes of Health [RO1 HL 079571, 5R01-HL079567-02, R21 DK075443, RO1 CA10532]; Feinstein Institute for Medical Research General Clinical Research Center [MO1 RR018535]; National Institutes of Health and the National Cancer Institute; Division of Intramural Research of National Institute of Allergy and Infectious Diseases/ National Institutes of Health; Children's Cancer Foundation of Sweden; Ministero Italiano dell'Universita e Ricerca FX This work was supported by grants from the Daniella Maria Arturi Foundation, Diamond Blackfan Anemia Foundation, Pediatric Cancer Foundation (J.M. Lipton), Association Francaise de la maladie de Blackfan-Diamond (T.L.), National Institutes of Health RO1 HL 079571 (J.M. Lipton, A.V., E.A.), 5R01-HL079567-02 (N.D.), R21 DK075443 (M.B.) and RO1 CA10532 (M.B.), The Feinstein Institute for Medical Research General Clinical Research Center MO1 RR018535 (J.M. Lipton, A.V., E.A.), the Intramural Research Program of the National Institutes of Health and the National Cancer Institute (B.P.A.), the Division of Intramural Research of National Institute of Allergy and Infectious Diseases/ National Institutes of Health (E.M.K.), Children's Cancer Foundation of Sweden (N.D.), Ministero Italiano dell'Universita e Ricerca (U.R.). Dr. J. M. Liu is a consultant for Alexion Pharmaceuticals.; A.V. and J.M. Lipton wrote, reviewed and revised the manuscript. E.J.L. recorded conference discussions. E.A. recorded conference discussions and assisted with technical preparation of the manuscript. S.B., N.D., B.P.A., S.S., U.R., J.M., S.K., J.M. Liu, T.L., C.P., E.M.K. and B.G. wrote their designated sections and reviewed the manuscript. A.S. and M.B. reviewed the manuscript and contributed to various sections.; We are indebted to David G. Nathan, Gil Tchernia and George Buchanan for their critical review of the manuscript. NR 139 TC 154 Z9 163 U1 1 U2 16 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD SEP PY 2008 VL 142 IS 6 BP 859 EP 876 DI 10.1111/j.1365-2141.2008.07269.x PG 18 WC Hematology SC Hematology GA 339VA UT WOS:000258604200001 PM 18671700 ER PT J AU Barrett, AJ AF Barrett, A. John TI Understanding and harnessing the graft-versus-leukaemia effect SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Review DE graft-versus-leukaemia; leukaemia; bone marrow transplantation ID STEM-CELL TRANSPLANTATION; BONE-MARROW-TRANSPLANTATION; ACUTE MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; REGULATORY T-CELLS; MINOR HISTOCOMPATIBILITY ANTIGENS; DONOR LYMPHOCYTE INFUSIONS; ACUTE LYMPHOBLASTIC-LEUKEMIA; WT1 PEPTIDE VACCINATION; UMBILICAL-CORD BLOOD AB The graft-versus-leukaemia (GVL) effect is a central component of the stem cell allograft's ability to cure haematological malignancies. The GVL effect is mediated by donor-derived natural killer cells and T lymphocytes, which have distinct mechanisms of recognizing and targeting the recipient's malignant cells. After transplantation the cytokine milieu is favourable to the early establishment of a GVL effect, but the need to prevent graft-versus-host disease limits the full potential of this process. Clinical studies have identified some critical components of the transplant preparation, donor selection, stem cell source (peripheral blood versus bone marrow) and post-transplant management that can be manipulated to optimize the GVL effect. However, further developments focusing on the selective depletion of unwanted alloreactivity with preservation of GVL effects, and the use of vaccines or the adoptive transfer of leukaemia-specific lymphocytes, will be required to enhance the GVL effect to reliably eradicate more resistant leukaemias. C1 [Barrett, A. John] NHLBI, Chief Allogene Stem Cell Sect, Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Barrett, AJ (reprint author), NHLBI, Clin Res Ctr, NIH, Rm 3-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM barrettj@nhlbi.nih.gov FU National Heart, Lung and Blood Institute FX This work was supported by the Intramural Research Program of the National Heart, Lung and Blood Institute. NR 99 TC 40 Z9 42 U1 0 U2 9 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD SEP PY 2008 VL 142 IS 6 BP 877 EP 888 DI 10.1111/j.1365-2141.2008.07260.x PG 12 WC Hematology SC Hematology GA 339VA UT WOS:000258604200002 PM 18564358 ER PT J AU Mack, AK McGowan, VR Tremonti, CK Ackah, D Barnett, C Machado, RF Gladwin, MT Kato, GJ AF Mack, A. Kyle McGowan, Vicki R., II Tremonti, Carole K. Ackah, Diana Barnett, Christopher Machado, Roberto F. Gladwin, Mark T. Kato, Gregory J. TI Sodium nitrite promotes regional blood flow in patients with sickle cell disease: a phase I/II study SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE sickle cell; nitrite; blood flow; nitroprusside; vasodilation ID ISCHEMIA-REPERFUSION INJURY; PULMONARY-HYPERTENSION; OXIDE BIOAVAILABILITY; MEDIATED VASODILATION; HEMOLYSIS; NO; HEMOGLOBIN; PRIAPISM; MODEL; MICE AB In addition to vaso-occlusion by sickled erythrocytes, the pathophysiology of sickle cell disease (SCD) is compounded by the diminished bioavailability of nitric oxide (NO), associated with vasoconstriction, endothelial activation and cell adhesion. We tested the ability of sodium nitrite, which can be converted to NO by deoxyhaemoglobin at acid pH and low oxygen tension, to improve blood flow in patients with SCD. In a phase I/II clinical trial, sodium nitroprusside, NG-monomethyl-L-arginine, and sodium nitrite were infused sequentially into the brachial artery in 14 patients at steady state. In a dose-dependent manner, sodium nitrite infusion rates of 0.4, 4 and 40 mu mol/min into the brachial artery augmented mean venous plasma nitrite concentrations (P < 0.0001) and stimulated forearm blood flow up to 77 +/- 11% above baseline (P < 0.0001), measured by venous occlusion strain gauge plethysmography. This nitrite response was blunted significantly compared to controls without SCD, as previously seen with other NO donors. Sodium nitrite infusions were well tolerated without hypotension, clinically significant methaemoglobinaemia or other untoward events. The unique pharmacological properties of nitrite as a hypoxia-potentiated vasodilator and cytoprotective agent in the setting of ischaemia-reperfusion injury make this anion a plausible NO donor for future clinical trials in SCD. C1 [Mack, A. Kyle; McGowan, Vicki R., II; Tremonti, Carole K.; Ackah, Diana; Machado, Roberto F.; Gladwin, Mark T.; Kato, Gregory J.] NHLBI, Pulm & Vasc Med Branch, NIH, Bethesda, MD 20892 USA. [Mack, A. Kyle] NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Tremonti, Carole K.; Barnett, Christopher; Machado, Roberto F.; Gladwin, Mark T.; Kato, Gregory J.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kato, GJ (reprint author), NHLBI, Pulm & Vasc Med Branch, NIH, 10 Ctr Dr,MSC 1476, Bethesda, MD 20892 USA. EM gkato@mail.nih.gov RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Division of Intramural Research of the National Institutes of Health, Bethesda, MD FX The authors are grateful to Mary K. Hall for protocol management and to Christine Hon for helpful discussions. The study was funded by the Division of Intramural Research of the National Institutes of Health, Bethesda, MD, including a Bench to Bedside award (A.K.M. and G.J.K.). M.T.G. is a participant on a pending U. S. patent, filed on October 14, 2003 through NIH (patent no. 60/511, 244), regarding the use of sodium nitrite in cardiovascular disease. He and the other co-authors declare no other competing financial interests. A.K.M., G.J.K. and M.T.G. designed the research, A.K.M., C.B. and R.F.M. performed the blood flow studies, D.A. performed the nitrite measurements, C.K.T. and V.R.M. recruited patients and collected data, A.K.M. and G.J.K. analyzed and interpreted the data, and drafted the manuscript. NR 30 TC 37 Z9 37 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD SEP PY 2008 VL 142 IS 6 BP 971 EP 978 DI 10.1111/j.1365-2141.2008.07259.x PG 8 WC Hematology SC Hematology GA 339VA UT WOS:000258604200011 PM 18671702 ER PT J AU Chen, Z Arendell, L Aickin, M Cauley, J Lewis, CE Chlebowski, R Nabel, E Rossouw, J Ludlam, S Pottern, L McGowan, J Ford, L Geller, N Prentice, R Anderson, G LaCroix, A Kooperberg, CL Patterson, RE McTiernan, A Shumaker, S Stein, E Cummings, S Wassertheil-Smoller, S Hays, J Manson, J Assaf, AR Phillips, L Beresford, S Hsia, J Chlebowski, R Whitlock, E Caan, B Howard, BV Van Horn, L Black, H Stefanick, ML Lane, D Jackson, R Lewis, CE Bassford, T Wactawski-Wende, J Robbins, J Hubbell, FA Judd, H Langer, RD Gass, M Limacher, M Curb, D Wallace, R Ockene, J Lasser, N O'Sullivan, MJ Margolis, K Brunner, R Heiss, G Kuller, L Johnson, KC Brzyski, R Santo, GE Bonds, D Henddx, S Kotchen, JM AF Chen, Zhao Arendell, Leslie Aickin, Mikel Cauley, Jane Lewis, Cora E. Chlebowski, Rowan Nabel, Elizabeth Rossouw, Jacques Ludlam, Shari Pottern, Linda McGowan, Joan Ford, Leslie Geller, Nancy Prentice, Ross Anderson, Garnet LaCroix, Andrea Kooperberg, Charles L. Patterson, Ruth E. McTiernan, Anne Shumaker, Sally Stein, Evan Cummings, Steven Wassertheil-Smoller, Sylvia Hays, Jennifer Manson, Joann Assaf, Annlouise R. Phillips, Lawrence Beresford, Shirley Hsia, Judith Chlebowski, Rowan Whitlock, Evelyn Caan, Bette Howard, Barbara V. Van Horn, Linda Black, Henry Stefanick, Marcia L. Lane, Dorothy Jackson, Rebecca Lewis, Cora E. Bassford, Tamsen Wactawski-Wende, Jean Robbins, John Hubbell, F. Allan Judd, Howard Langer, Robert D. Gass, Margery Limacher, Marian Curb, David Wallace, Robert Ockene, Judith Lasser, Norman O'Sullivan, Mary Jo Margolis, Karen Brunner, Robert Heiss, Gerardo Kuller, Lewis Johnson, Karen C. Brzyski, Robert Santo, Gloria E. Bonds, Denise Henddx, Susan Kotchen, Jane Morley TI Hip bone density predicts breast cancer risk independently of gail score - Results from the women's health initiative SO CANCER LA English DT Article DE breast cancer; postmenopausal women; Gail score; bone mineral density; Women's Health Initiative; receiver operator characteristic ID MINERAL DENSITY; POSTMENOPAUSAL WOMEN; MODEL; VALIDATION AB BACKGROUND. The Gail model has been commonly used to estimate a woman's risk of breast cancer within a certain time period. High bone mineral density (BNID) is also a significant risk factor For breast cancer, but it appears to play no role in the Gail model. The objective of the current: study was to investigate whether hip BMD predicts postmenopausal breast cancer risk independently of the Gail score. METHODS. In this prospective Study, 9941 postmenopausal women who had a baseline hip BMD and Gail score from the Women's Health Initiative were included in the analysis. Their average age %vas 63.0 +/- 7.4 years at baseline. RESULTS. After an average of 8.43 years of follow-Lip, 327 incident breast cancer cases were reported and adjudicated. In a multivariate Cox proportional hazards model, the hazards ratios (95% confidence interval [95% CI]) for incident breast cancer were 1.35 (95% Cl, 1.05-1.73) for high Gail score (>= 1.67%) and 1.25 (95% Cl, 1.11-1.40) for each unit of increase in the total hip BMD T-score. Restricting the analysis to women with both BMD and a Gail score above the median, a sharp increase in incident breast cancer for women with the highest BNID and Gail scores was found (P <.05). CONCLUSIONS. The contribution of BMD to the prediction of incident postmenopausal breast cancer across the entire population was found to be independent of the Gail score. However, among women with both high BMD and a high Gail score, there appears to be an interaction between these 2 factors. These findings suggest that BMD and Gail score may be used together to better quantify the risk of breast cancer. C1 [Chen, Zhao; Arendell, Leslie] Univ Arizona, Coll Publ Hlth, Div Epidemiol & Biostat, Tucson, AZ 85721 USA. [Aickin, Mikel] Univ Arizona, Dept Family & Community Med, Tucson, AZ USA. [Cauley, Jane] Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. [Lewis, Cora E.] Univ Alabama, Sch Med, Div Prevent Med, Birmingham, AL USA. [Chlebowski, Rowan] Univ Calif Los Angeles, Med Ctr LABioMed, Los Angeles Biomed Res Inst Harbor, Torrance, CA USA. [Nabel, Elizabeth; Rossouw, Jacques; Ludlam, Shari; Pottern, Linda; McGowan, Joan; Ford, Leslie; Geller, Nancy] NHLBI, Program Off, Bethesda, MD 20892 USA. [Prentice, Ross; Anderson, Garnet; LaCroix, Andrea; Kooperberg, Charles L.; Patterson, Ruth E.; McTiernan, Anne] Fred Hutchinson Canc Res Ctr, Clin Coordinating Ctr, Seattle, WA 98104 USA. [Shumaker, Sally; Bonds, Denise] Wake Forest Univ, Bowman Gray Sch Med, Winston Salem, NC USA. [Stein, Evan] Med Res Labs, Highland Hts, KY USA. [Cummings, Steven] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Wassertheil-Smoller, Sylvia] Albert Einstein Coll Med, Ctr Clin, Bronx, NY 10467 USA. [Hays, Jennifer] Baylor Coll Med, Houston, TX 77030 USA. [Manson, Joann] Harvard Univ, Sch Med, Womens Hosp, Boston, MA USA. [Assaf, Annlouise R.] Brown Univ, Providence, RI 02912 USA. [Phillips, Lawrence] Emory Univ, Atlanta, GA 30322 USA. [Beresford, Shirley] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Hsia, Judith] George Washington Univ, Med Ctr, Washington, DC 20037 USA. [Chlebowski, Rowan] Harbor Univ Calif Los Angeles, Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA 90509 USA. [Whitlock, Evelyn] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Caan, Bette] Kaiser Permanente, Div Res, Oakland, CA USA. [Kotchen, Jane Morley] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Howard, Barbara V.] Howard Univ, MedStar Res Inst, Washington, DC 20059 USA. [Van Horn, Linda] Northwestern Univ, Chicago, IL 60611 USA. [Black, Henry] Rush Presbyterian St Lukes Med Ctr, Chicago, IL 60612 USA. [Stefanick, Marcia L.] Stanford Prevent Res Ctr, Stanford, CA USA. [Lane, Dorothy] SUNY Stony Brook, Stony Brook, NY 11794 USA. [Jackson, Rebecca] Ohio State Univ, Columbus, OH 43210 USA. [Lewis, Cora E.] Univ Alabama, Birmingham, AL USA. [Bassford, Tamsen] Univ Arizona, Tucson, AZ USA. [Wactawski-Wende, Jean] SUNY Coll Buffalo, Buffalo, NY 14222 USA. [Robbins, John] Univ Calif Davis, Sacramento, CA 95817 USA. [Hubbell, F. Allan] Univ Calif Irvine, Irvine, CA USA. [Judd, Howard] Univ Calif Los Angeles, Los Angeles, CA USA. [Langer, Robert D.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Gass, Margery] Univ Cincinnati, Cincinnati, OH USA. [Limacher, Marian] Univ Florida, Jacksonville, FL USA. [Curb, David] Univ Hawaii, Honolulu, HI 96822 USA. [Wallace, Robert] Univ Iowa, Iowa City, IA USA. [Ockene, Judith] Univ Massachusetts, Fallon Clin, Worcester, MA 01605 USA. [Lasser, Norman] Univ Med & Dent New Jersey, Newark, NJ 07103 USA. [O'Sullivan, Mary Jo] Univ Miami, Miami, FL USA. [Margolis, Karen] Univ Minnesota, Minneapolis, MN USA. [Brunner, Robert] Univ Nevada, Reno, NV 89557 USA. [Heiss, Gerardo] Univ N Carolina, Chapel Hill, NC USA. [Kuller, Lewis] Univ Pittsburgh, Pittsburgh, PA USA. [Johnson, Karen C.] Univ Tennessee, Memphis, TN USA. [Brzyski, Robert] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Santo, Gloria E.] Univ Wisconsin, Madison, WI USA. [Henddx, Susan] Wayne State Univ, Sch Med, Hutzel Hosp, Detroit, MI USA. RP Chen, Z (reprint author), Univ Arizona, Coll Publ Hlth, Div Epidemiol & Biostat, Tucson, AZ 85721 USA. RI Cauley, Jane/N-4836-2015 OI Cauley, Jane/0000-0003-0752-4408 FU Eli Lilly FX Funded by Eli Lilly. NR 21 TC 36 Z9 40 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 1 PY 2008 VL 113 IS 5 BP 907 EP 915 DI 10.1002/cncr.23674 PG 9 WC Oncology SC Oncology GA 346LC UT WOS:000259069000007 PM 18666209 ER PT J AU Cobb, N Wingo, PA Edwards, BK AF Cobb, Nathaniel Wingo, Phyllis A. Edwards, Brenda K. TI Introduction to the supplement on cancer in the American Indian and Alaska Native populations in the United States SO CANCER LA English DT Editorial Material DE cancer incidence; American Indian; Alaska Native; race; misclassification; disparities ID PATTERNS; WHITES; RATES AB The collection of papers in this Supplement combines cancer incidence data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results program, enhanced by record linkages and geographic factors, to provide a comprehensive description of the cancer burden in the American Indian/Alaska Native population in the United States. Cancer incidence rates among this population varied widely, sometimes more than 5-fold, by geographic region. C1 [Cobb, Nathaniel] Indian Hlth Serv, Div Epidemiol & Dis Prevent, Albuquerque, NM 87110 USA. [Wingo, Phyllis A.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30333 USA. [Edwards, Brenda K.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Cobb, N (reprint author), Indian Hlth Serv, Div Epidemiol & Dis Prevent, 3500 Homestead NE, Albuquerque, NM 87110 USA. EM nathaniel.cobb@ihs.gov FU NCCDPHP CDC HHS [U50 DP424071-04] NR 37 TC 12 Z9 12 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 1 PY 2008 VL 113 IS 5 SU S BP 1113 EP 1116 DI 10.1002/cncr.23729 PG 4 WC Oncology SC Oncology GA 346LH UT WOS:000259069500001 PM 18720369 ER PT J AU Espey, DK Wiggins, CL Jim, MA Miller, BA Johnson, CJ Becker, TM AF Espey, David K. Wiggins, Charles L. Jim, Melissa A. Miller, Barry A. Johnson, Christopher J. Becker, Tom M. TI Methods for improving cancer surveillance data in American Indian and Alaska Native populations SO CANCER LA English DT Article DE cancer; incidence; American Indian; Alaska Native; misclassification; National Program of Cancer Registries; Surveillance, Epidemiology, and End Results; United States; health disparity ID RATES; RACE; EPIDEMIOLOGY; ETHNICITY; MORTALITY; PATTERNS; MONTANA; WHITES AB BACKGROUND. The misclassification of race decreases the accuracy of cancer incidence data for American Indians and Alaska Natives (AI/ANs) in some central cancer registries. This article describes the data sources and methods that were used to address this misclassification and to produce the cancer Statistics Used by most of the articles in this supplement. METHODS. Records from United States cancer registries were linked with Indian Health Service (IHS) records to identify AI/AN cases that were misclassified as non-AI/AN. Data were available from 47 registries that linked their data with IHS, met quality criteria, and agreed to participate. Analyses focused on cases among AI/AN residents in IHS Contract Health Service Delivery Area (CHSDA) counties in 33 states. Cancer incidence and stage data were compiled for non-Hispanic whites (NHWs) and AI/ANs across 6 IHS regions of the United States For 1999 through 2004. RESULTS. Misclassification of AI/AN race as normative in central cancer registries ranged from 85 individuals in Alaska (3.4%) to 5297 individuals in the Southern Plains (44.5%). Cancer incidence rates among AI/ANs for all cancers combined were lower than for NHWs, hot incidence rates varied by geographic region For AI/ANs. Restricting the rate calculations to CHSDA counties generally resulted in higher rates than those obtained for all counties combined. CONCLUSIONS. The classification of race for AI/AN cases in cancer registries can be improved by linking records to the IHS and stratifying by CHSDA counties. Cancer in the AI/AN population is clarified further by describing incidence rates by geographic region. Improved cancer surveillance data for AI/AN communities should aid in the planning, implementation, and evaluation of more effective cancer control and should reduce health disparities in this population. C1 [Espey, David K.; Jim, Melissa A.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Albuquerque, NM 87110 USA. [Wiggins, Charles L.] Univ New Mexico, New Mexico Tumor Registry, Albuquerque, NM 87131 USA. [Miller, Barry A.] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Johnson, Christopher J.] Canc Data Registry Idaho, Boise, ID USA. [Becker, Tom M.] Oregon Hlth & Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. RP Espey, DK (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, 5300 Homestead NE, Albuquerque, NM 87110 USA. EM david.espey@ihs.gov FU Centers for Disease Control and Prevention, Division of Cancer Prevention and Control [U50 DP424071-04] FX This supplement was sponsored by Cooperative Agreement Number U50 DP424071-04 from the Centers for Disease Control and Prevention, Division of Cancer Prevention and Control. NR 55 TC 54 Z9 54 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 1 PY 2008 VL 113 IS 5 SU S BP 1120 EP 1130 DI 10.1002/cncr.23724 PG 11 WC Oncology SC Oncology GA 346LH UT WOS:000259069500003 PM 18720372 ER PT J AU Wiggins, CL Espey, DK Wingo, PA Kaur, JS Wilson, RT Swan, J Miller, BA Jim, MA Kelly, JJ Lanier, AR AF Wiggins, Charles L. Espey, David K. Wingo, Phyllis A. Kaur, Judith S. Wilson, Robin Taylor Swan, Judith Miller, Barry A. Jim, Melissa A. Kelly, Janet J. Lanier, Anne P. TI Cancer among American Indians and Alaska Natives in the United States, 1999-2004 SO CANCER LA English DT Article DE cancer; incidence; American Indian; Alaska Native; misclassification; National Program of Cancer Registries; Surveillance, Epidemiology, End Results; United States; health disparity ID NEW-MEXICO; MORTALITY; PATTERNS; EPIDEMIOLOGY; SURVEILLANCE; REGISTRY; WHITES; TRENDS; RATES AB BACKGROUND. Cancer incidence rates vary among American Indian and Alaska Native (AI/AN) populations and often differ from rates among non-Hispanic whites (NHWs). However, the misclassification of race for AI/AN cancer cases in central cancer registries may have led to underestimates of the AI/AN cancer burden in previous reports. METHODS. Cases diagnosed during 1999 through 2004 were identified from population-based cancer registries in the United States. Age-adjusted rates were calculated for the 25 most common sites for AI/ANs and NHWs. To minimize the misclassification of race, cancer registry records were linked with patient registration files from the Indian Health Service (IHS). Analyses were restricted to Contract Health Service Delivery Area (CHSDA) Counties and were stratified by IHS region. RESULTS. In CHSDA counties, cancer incidence rates among AI/ANs varied widely by region, whereas rates among NHWs did not. For all cancer sites combined, AI/AN rates were higher than NHW rates among both males and females in the Northern and Southern Plains, and among Alaska Native Females; AI/AN rates were lower than NHW rates in the Southwest, the Pacific Coast, and the Fast. Lung cancer and colorectal cancer rates for AI/ANs exceeded rates for NHWs in Alaska and the Northern Plains. Rates for stomach, gallbladder, kidney, and liver cancer were higher among AI/ANs than among NHWs overall, in Alaska, in the Plains regions, and in the Southwest. CONCLUSIONS. Regional differences in cancer incidence rates among AI/AN Populations were not obvious from nationwide data and highlighted opportunities for cancer control and prevention. It is unlikely that such differences are explained by Face misclassification. C1 [Wiggins, Charles L.] Univ New Mexico, New Mexico Tumor Registry, Albuquerque, NM 87131 USA. [Kaur, Judith S.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Wilson, Robin Taylor] Mayo Clin, Native Amer Programs, Rochester, MN USA. [Swan, Judith; Miller, Barry A.] Penn State Univ, Coll Med, Dept Publ Hlth Sci, Hershey, PA USA. [Kelly, Janet J.; Lanier, Anne P.] NCI, Div Canc Control & Populat Sci, Surveillance Res Program, Bethesda, MD 20892 USA. [Espey, David K.; Wingo, Phyllis A.; Jim, Melissa A.] Alaska Native Tribal Hlth Consortium, Alaska Native Epidemiol Ctr, Anchorage, AK USA. RP Wiggins, CL (reprint author), Univ New Mexico, New Mexico Tumor Registry, MSC-11 6020,1 Univ New Mexico, Albuquerque, NM 87131 USA. EM cwiggins@salud.unm.edu FU National Cancer Institute (NCI) [N01-PC-35138]; University of New Mexico Cancer Center; NCI Cancer Support [P30-CA118100] FX Preparation of this article was supported, in part, by National Cancer Institute (NCI) Contract N01-PC-35138 and by the University of New Mexico Cancer Center, a recipient of NCI Cancer Support Grant P30-CA118100. NR 39 TC 62 Z9 63 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 1 PY 2008 VL 113 IS 5 SU S BP 1142 EP 1152 DI 10.1002/cncr.23734 PG 11 WC Oncology SC Oncology GA 346LH UT WOS:000259069500005 PM 18720375 ER PT J AU Wingo, PA King, J Swan, J Coughlin, SS Kaur, JS Erb-Alvarez, JA Jackson-Thompson, J Solomon, TGA AF Wingo, Phyllis A. King, Jessica Swan, Judith Coughlin, Steven S. Kaur, Judith S. Erb-Alvarez, Julie A. Jackson-Thompson, Jeannette Solomon, Teshia G. Arambula TI Breast cancer incidence among American Indian and Alaska Native women: US, 1999-2004 SO CANCER LA English DT Article DE incidence; breast cancer; American Indian/Alaska Native; National Program of Cancer Registries; Surveillance, Epidemiology, and End Results ID UNITED-STATES; RISK-FACTORS; CERVICAL-CANCER; NEW-MEXICO; DIAGNOSIS; PATTERNS; RATES; STAGE; EPIDEMIOLOGY; ETHNICITY AB BACKGROUND. Breast cancer is a leading cause of cancer morbidity and mortality among American Indian and Alaska Native (AI/AN) women. Although published Studies have Suggested that breast cancer rates among AI/AN women are lower than those among other racial and ethnic populations, accurate determinations of the breast cancer burden have been hampered by misclassification of AI/AN race. METHODS. Cancer incidence data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results Program were combined to estimate age-adjusted rates for the diagnosis years 1999 through 2004. Several steps were taken to reduce the misclassification of AI/AN race: linking cases to Indian Health Service (IHS) patient services database, restricting analyses to Contract Health Service Delivery Area Counties, and stratifying results by IHS region. RESULTS. Breast cancer incidence rates among AI/AN women varied nearly 3-fold across IHS regions. The highest rates were in Alaska (134.8) and the Plains (Northern, 115.9; Southern, 115.7), and the lowest rates were in the Southwest (50.8). The rate in Alaska was similar to the rate among non-Hispanic white (NHW) women in Alaska. Overall, AI/AN women had lower rates of breast cancer than NHW women, but AI/AN women were more likely to be diagnosed with late-stage disease. CONCLUSIONS. To the authors' knowledge, this report provides the most comprehensive breast cancer incidence data for AI/AN women to date. The wide regional variation indicates an important need for etiologic and health services research, and the large percentage of AI/AN women with late-stage disease demands innovative approaches for increasing access to screening. C1 [Wingo, Phyllis A.; King, Jessica; Coughlin, Steven S.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Ctr Dis Control, Atlanta, GA 30341 USA. [Swan, Judith] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Kaur, Judith S.] Mayo Clin, Div Med Oncol, Coll Med, Rochester, MN USA. [Erb-Alvarez, Julie A.] So Plains Inter Tribal Epidemiol Ctr, Oklahoma City, OK USA. [Jackson-Thompson, Jeannette] Univ Missouri, Missouri Canc Registry, Columbia, MO USA. [Jackson-Thompson, Jeannette] Univ Missouri, Dept Hlth Management & Informat, Columbia, MO USA. [Solomon, Teshia G. Arambula] Univ Arizona, Dept Family & Community Med, Tucson, AZ USA. RP Coughlin, SS (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Ctr Dis Control, 4770 Buford Highway NE,MS K55, Atlanta, GA 30341 USA. EM sic9@cdc.gov FU Centers for Disease Control and Prevention, Division of Cancer Prevention and Control [U50 DP424071-04] FX This supplement was sponsored by Cooperative Agreement Number U50 DP424071-04 from the Centers for Disease Control and Prevention, Division of Cancer Prevention and Control. NR 64 TC 34 Z9 34 U1 1 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 1 PY 2008 VL 113 IS 5 SU S BP 1191 EP 1202 DI 10.1002/cncr.23725 PG 12 WC Oncology SC Oncology GA 346LH UT WOS:000259069500009 PM 18720389 ER PT J AU Reichman, ME Kelly, JJ Kosary, CL Coughlin, SS Jim, MA Lanier, AP AF Reichman, Marsha E. Kelly, Janet J. Kosary, Carol L. Coughlin, Steven S. Jim, Melissa A. Lanier, Anne P. TI Incidence of cancers of the oral cavity and pharynx among American Indians and Alaska Natives, 1999-2004 SO CANCER LA English DT Article DE cancer; incidence; oral cavity; pharynx; American Indian/Alaska Native; NPCR; SEER ID NASOPHARYNGEAL CARCINOMA; UNITED-STATES; ALCOHOL-DRINKING; TOBACCO SMOKING; CHINA; RISK AB BACKGROUND. Previous studies identified disparities in incidence rates of cancers of the oral cavity and pharynx between American Indians/Alaska Natives (AI/AN) and non-Hispanic whites (NHW) and differences between various AI/AN populations. Reporting among AI/AN has been hampered by: 1) heterogeneity among various anatomic sites of oral cavity mid pharyngeal cancers obscuring unique patterns of individual anatomic sites; 2) race misclassification and underreporting of AI/AN; and 3) sparseness of data needed to identify regional variations. METHODS. To improve race classification of AI/AN, data from US central cancer registries were linked with Indian Health Service (IHS) records. AI/AN incidence data from 1999 to 2004 were stratified by sex, age, stage at diagnosis, and anatomic subsite for 6 IHS geographic regions and compared with NHW populations. RESULTS. For all oral cavity and pharynx cancers combined, among residents of Contract Health Service Delivery Area counties, AI/AN overall had significantly lower incidence rates than NHW (8.5 vs 11.0). However, AI/AN rates were significantly higher in the Northern Plains (13.9 vs 10.5) and Alaska (16,3 vs 10.6), significantly lower in the Pacific Coast (7.7 vs 11.6) and Southwest (3.3 vs 10.4), and similar in the Southern Plains (11.4). Overall AI/AN males had higher incidence rates than AI/AN women. Nasopharyngeal cancer was more frequent (1.1 AI/AN vs 0.4 NHW), and tongue cancer less frequent (1.6 AI/AN vs 2.9 NHW) in AI/AN than NHW populations; however, rates varied by region. Stage distribution was modestly less favorable for AI/AN compared with NHW populations. CONCLUSIONS. Variation by region, anatomic site, and sex indicates a need for research into etiologic factors and attention to regional risk factor profiles when planning cancer control programs. C1 [Reichman, Marsha E.; Kosary, Carol L.] NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Kelly, Janet J.; Lanier, Anne P.] Alaska Native Tribal Hlth Consortium, Alaska Native Epidemiol Ctr, Anchorage, AK USA. [Coughlin, Steven S.; Jim, Melissa A.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA USA. [Jim, Melissa A.] Indian Hlth Serv, Div Epidemiol & Dis Prevent, Albuquerque, NM USA. RP Reichman, ME (reprint author), NCI, Surveillance Res Program, Div Canc Control & Populat Sci, 6116 Execut Blvd,Suite 504, Bethesda, MD 20892 USA. EM ReichmaM@mail.nih.gov FU Centers for Disease Control and Prevention, Division of Cancer Prevention and Control [U50 DP424071-04] FX This supplement was sponsored by Cooperative Agreement Number U50 DP424071-04 from the Centers for Disease Control and Prevention, Division of Cancer Prevention and Control. NR 31 TC 7 Z9 7 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD SEP 1 PY 2008 VL 113 IS 5 SU S BP 1256 EP 1265 DI 10.1002/cncr.23735 PG 10 WC Oncology SC Oncology GA 346LH UT WOS:000259069500015 PM 18720381 ER PT J AU Lemrow, SM Perdue, DG Stewart, SL Richardson, LC Jim, MA French, HT Swan, J Edwards, BK Wiggins, C Dickie, L Espey, DK AF Lemrow, Shannon M. Perdue, David G. Stewart, Sherri L. Richardson, Lisa C. Jim, Melissa A. French, Helen T. Swan, Judith Edwards, Brenda K. Wiggins, Charles Dickie, Lois Espey, David K. TI Gallbladder cancer incidence among American Indians and Alaska Natives, US, 1999-2004 SO CANCER LA English DT Article DE American Indian/Alaska Native; surveillance; gallbladder cancer; regional stage; distant stage ID UNITED-STATES; RISK-FACTORS; BILE-DUCT; DISEASE; EPIDEMIOLOGY; CARCINOMA; PREVALENCE; GALLSTONES; EXPERIENCE; PATTERNS AB BACKGROUND. Gallbladder cancer (GBC) is rare; however, it disproportionately affects the American Indian and Alaska Natives (AI/AN) population. The purpose of the study was to characterize GBC among AI/AN in the US population. METHODS. Cases of GBC diagnosed between 1999 and 2004 and collected by state-based cancer registries were included. Registry records were linked with Indian Health Service (IHS) administration records to decrease race misclassification of AI/AN. GBC rates and/or percent distributions for AI/AN and non-Hispanic whites (NHW) were calculated by sex, IHS region, age, and stage for all US counties and IHS Contract Health Service Delivery Area (CHSDA) Counties, in which approximately 56% of US AI/AN individuals reside. RESULTS. In CHSDA Counties, the GBC incidence rate among AI/AN was 3.3 per 100,000, which was significantly higher than that among NHW (P < .05). Rates varied widely among IHS regions and ranged from 1.5 in the East to 5.5 in Alaska. Rates were higher among AI/AN females than males in all regions, except the Northern Plains. Higher percentages of GBC were diagnosed among AI/AN aged <65 years compared with NHW. GBC was most often diagnosed at the regional stage among AI/AN, whereas GBC was most often diagnosed at regional or distant stages among NHW. CONCLUSIONS. To the authors' knowledge to date, this is the most comprehensive study of GBC incidence among AI/AN in the US. The accurate characterization of GBC in this population could help inform the development of interventions aimed at reducing morbidity and mortality from this disease. C1 [Stewart, Sherri L.; Richardson, Lisa C.; Jim, Melissa A.; Espey, David K.] Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. [Lemrow, Shannon M.; French, Helen T.; Swan, Judith; Edwards, Brenda K.; Dickie, Lois] NCI, Div Canc Control & Populat, Bethesda, MD 20892 USA. [Perdue, David G.] Univ Minnesota, Div Gastroenterol & Hepatol, Ctr Canc, Minneapolis, MN USA. [Perdue, David G.] Univ Minnesota, Program Hlth Dispar Res, Minneapolis, MN USA. [Perdue, David G.] Minnesota Gasteroenterol PA, Minneapolis, MN USA. [Jim, Melissa A.; Espey, David K.] IHS, Div Epidemiol & Dis Prevent, Albuquerque, NM USA. [Wiggins, Charles] Univ New Mexico, Ctr Canc, New Mexico Tumor Registry, Albuquerque, NM 87131 USA. RP Stewart, SL (reprint author), Ctr Dis Control & Prevent, Div Canc Prevent & Control, Natl Ctr Chron Dis Prevent & Hlth Promot, 4770 Buford Highway,K-57, Atlanta, GA 30341 USA. EM sstewart2@cdc.gov FU Centers for Disease Control and Prevention, Division of Cancer Prevention and Control [U50 DP424071-04] FX This supplement was sponsored by Cooperative Agreement Number U50 DP424071-04 from the Centers for Disease Control and Prevention, Division of Cancer Prevention and Control. NR 34 TC 18 Z9 18 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0008-543X J9 CANCER-AM CANCER SOC JI Cancer PD SEP 1 PY 2008 VL 113 IS 5 SU S BP 1266 EP 1273 DI 10.1002/cncr.23737 PG 8 WC Oncology SC Oncology GA 346LH UT WOS:000259069500016 PM 18720382 ER PT J AU Brown, AP Citrin, DE Camphausen, KA AF Brown, Aaron P. Citrin, Deborah E. Camphausen, Kevin A. TI Clinical biomarkers of angiogenesis inhibition SO CANCER AND METASTASIS REVIEWS LA English DT Review DE cancer; angiogenesis; biomarker; imaging ID ENDOTHELIAL GROWTH-FACTOR; CELL LUNG-CANCER; POSITRON-EMISSION-TOMOGRAPHY; METASTATIC COLORECTAL-CANCER; CONTRAST-ENHANCED MRI; PHASE-I TRIAL; HIGH-DOSE CHEMOTHERAPY; ADVANCED BREAST-CANCER; ADVANCED SOLID TUMORS; INTERCELLULAR-ADHESION MOLECULE-1 AB Introduction An expanding understanding of the importance of angiogenesis in oncology and the development of numerous angiogenesis inhibitors are driving the search for biomarkers of angiogenesis. We review currently available candidate biomarkers and surrogate markers of anti-angiogenic agent effect. Discussion A number of invasive, minimally invasive, and non-invasive tools are described with their potential benefits and limitations. Diverse markers can evaluate tumor tissue or biological fluids, or specialized imaging modalities. Conclusions The inclusion of these markers into clinical trials may provide insight into appropriate dosing for desired biological effects, appropriate timing of additional therapy, prediction of individual response to an agent, insight into the interaction of chemotherapy and radiation following exposure to these agents, and perhaps most importantly, a better understanding of the complex nature of angiogenesis in human tumors. While many markers have potential for clinical use, it is not yet clear which marker or combination of markers will prove most useful. C1 [Citrin, Deborah E.; Camphausen, Kevin A.] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Brown, Aaron P.] NIH, Bethesda, MD 20892 USA. RP Citrin, DE (reprint author), NCI, Radiat Oncol Branch, 10 CRC,B2-3500, Bethesda, MD 20892 USA. EM citrind@mail.nih.gov FU NIH; NCI FX This research was supported by the Intramural Research Program of the NIH, NCI. This research year was made possible through the Clinical Research Training Program, a public-private partnership supported jointly by the NIH and Pfizer Inc (via a grant to the Foundation for NIH from Pfizer Inc). DC, KC: This research was supported by the Intramural Research Program of the NIH, NCI. NR 294 TC 35 Z9 37 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-7659 EI 1573-7233 J9 CANCER METAST REV JI Cancer Metastasis Rev. PD SEP PY 2008 VL 27 IS 3 BP 415 EP 434 DI 10.1007/s10555-008-9143-x PG 20 WC Oncology SC Oncology GA 339QS UT WOS:000258592700009 PM 18414993 ER PT J AU Chau, CH Wang, WX Figg, WD AF Chau, Cindy H. Wang, Weixin Figg, William D. TI Combining mTOR inhibition with metronomic chemotherapy in targeting angiogenesis SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE mTOR; HIF-1 alpha; everolimus; cyclophosphamide; metronomic chemotherapy; gastric cancer ID GASTRIC-CANCER; TUMOR-GROWTH; RAPAMYCIN; THERAPY; PATHWAY C1 [Chau, Cindy H.; Wang, Weixin; Figg, William D.] NCI, Mol Pharmacol Sect, Med Oncol Branch, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Med Oncol Branch, Canc Res Ctr,NIH, Bldg 10,Rm 5A01,MSC 1910,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 14 TC 0 Z9 0 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD SEP PY 2008 VL 7 IS 9 BP 1388 EP 1389 PG 2 WC Oncology SC Oncology GA 350EX UT WOS:000259336500013 ER PT J AU Zhang, XH Rao, M Loprieato, JA Hong, JA Zhao, M Chen, GZ Humphries, AE Nguyen, DM Trepel, JB Yu, XD Schrump, DS AF Zhang, Xu-Hui Rao, Mahadev Loprieato, Joseph A. Hong, Julie A. Zhao, Ming Chen, Guo-Zhu Humphries, Ashley E. Nguyen, Dao M. Trepel, Jane B. Yu, Xiaodan Schrump, David S. TI Aurora A, aurora B and survivin are novel targets of transcriptional regulation by histone deacetylase inhibitors in non-small cell lung cancer SO CANCER BIOLOGY & THERAPY LA English DT Article DE FK228; TSA; lung cancer; aurora kinase; survivin; mitotic catastrophe ID CYCLE-DEPENDENT REGULATION; CHROMOSOMAL PASSENGERS; M-PHASE; EXPRESSION; KINASES; OVEREXPRESSION; CARCINOMA; COMPLEX; GENE; APOPTOSIS AB Background: Analysis of biopsies from a recent clinical trial suggested that Depsipeptide FK228 (DP) inhibits Aurora kinase expression in lung cancer cells. The present study was undertaken to confirm and extend these observations. Results: Aurora A and B mRNA levels in lung cancer cells were considerably higher than levels in normal pulmonary epithelia. DP, TSA and SAHA inhibited Aurora A, Aurora B and survivin expression with kinetics that were remarkably similar within individual cell lines, and appeared to coincide with p53 expression status. These effects were not observed following treatment with geldanamycins. Inhibition of Aurora B transcription coincided with decreased H3K9Ac and H3K4Me2 activation marks, and accumulation of H3K9Me3, as well as MBD1, MBD2 and MBD3 repression marks within the minimal Aurora B promoter. Knockdown of MBD1, -2 or -3 did not reproducibly abrogate inhibition of Aurora or survivin expression by DP or TSA. DP and TSA decreased expression and altered localization of Aurora kinases and survivin, resulting in mitotic catastrophe in lung cancer cells. Methods: Aurora A, and Aurora B levels in lung cancer cells and normal respiratory epithelia were assessed using quantitative RT-PCR techniques. These methods, as well as as Western blots were used to examine expression of Auroras A/B, and several related genes/proteins in lung cancer cells exposed to DP, TSA, SAHA and geldanamycins. Transient transfection promoter-reporter assays, and chromatin immunoprecipitation (ChIP) techniques were used to examine DP-mediated changes in activity and chromatin structure of the Aurora B promoter. Confocal imaging techniques were used to examine the effects of DP and TSA on mitotic progression in lung cancer cells. Conclusions: Novel transcriptional regulatory mechanisms involving Aurora kinase and survivin appear to contribute to cytotoxicity mediated by HDAC inhibitors in lung cancer cells. C1 [Rao, Mahadev; Loprieato, Joseph A.; Hong, Julie A.; Zhao, Ming; Humphries, Ashley E.; Nguyen, Dao M.; Schrump, David S.] NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Trepel, Jane B.] NCI, Thorac Oncol Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Zhang, Xu-Hui; Chen, Guo-Zhu; Yu, Xiaodan] Chinese Acad Med Sci, Inst Basic Med Sci, Dept Pathol, Beijing 100730, Peoples R China. RP Schrump, DS (reprint author), NCI, Thorac Oncol Sect, Surg Branch, Ctr Canc Res,NIH, Bldg 10,Rm 4-3940,10 Ctr Dr MSC1201, Bethesda, MD 20892 USA. EM David_Schrump@nih.gov FU National Natural Science Foundation of China [30330620, 30672404] FX Supported in part by the National Natural Science Foundation of China (Grant No. 30330620 and 30672404 to XD Yu). NR 50 TC 5 Z9 5 U1 0 U2 3 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD SEP PY 2008 VL 7 IS 9 BP 1390 EP 1399 PG 10 WC Oncology SC Oncology GA 350EX UT WOS:000259336500014 ER PT J AU Murphy, G Sansbury, LB Cross, AJ Stolzenberg-Solomon, R Laiyemo, A Albert, PS Wang, ZQ Schatzkin, A Lehman, T Kalidindi, A Modali, R Lanza, E AF Murphy, Gwen Sansbury, Leah B. Cross, Amanda J. Stolzenberg-Solomon, Rachael Laiyemo, Adeyinka Albert, Paul S. Wang, Zhuoqiao Schatzkin, Arthur Lehman, Teresa Kalidindi, Aravind Modali, Rama Lanza, Elaine TI Folate and MTHFR: risk of adenoma recurrence in the Polyp Prevention Trial SO CANCER CAUSES & CONTROL LA English DT Article DE folate; methlylenetetrahydrofolate reductase; adenoma ID METHYLENETETRAHYDROFOLATE REDUCTASE; COLORECTAL-CANCER; COLON-CANCER; GENETIC POLYMORPHISMS; COMMON MUTATION; DIET; SURVEILLANCE; GENOTYPE; ALCOHOL; CARCINOGENESIS AB Background Low dietary folate intake has been associated with colorectal cancer risk and adenoma recurrence. A C/T transition at position 677 in the gene encoding methlylenetetrahydrofolate reductase (MTHFR C677T) has been reported to interact with folate intake to modulate colorectal adenoma recurrence or cancer risk. Methods We investigated the association between MTHFR, total folate, and the risk of colorectal adenoma recurrence in the Polyp Prevention Trial. We compared 625 individuals with any adenoma recurrence after 4 years (266 individuals with multiple (>= 2) recurrent adenomas and 101 individuals with advanced adenoma recurrence) to 978 individuals with no adenoma recurrence. Odds ratios (OR) and 95% confidence intervals (CI) for risk of adenoma recurrence were calculated using unconditional logistic regression. We also investigated effect modification of the MTHFR genotype associations by total folate intake. Results In general, no statistically significant associations were found between quartile of folate intake (dietary or total) and adenoma recurrence. The MTHFR CT genotype was associated with a significantly increased risk of multiple adenoma recurrence (OR: 1.34, 95% CI: 1.00, 1.81). No significant interaction was noted for total folate and MTHFR genotype, though an increased risk of recurrence noted for the MTHFR CT genotype was statistically significant only for those individuals with below median intake of total folate. Conclusion We report that the MTHFR 677 CT genotype was associated with increased risk of adenoma recurrence (specifically multiple adenoma recurrence) 4 years after polypectomy. C1 [Murphy, Gwen] Natl Canc Inst, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. [Lehman, Teresa; Kalidindi, Aravind; Modali, Rama] Bioserve Biotechnol Ltd, Laurel, MD USA. [Wang, Zhuoqiao] Informat Management Serv Inc, Rockville, MD USA. [Albert, Paul S.] Natl Canc Inst, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD USA. [Cross, Amanda J.; Stolzenberg-Solomon, Rachael; Schatzkin, Arthur] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Murphy, Gwen; Sansbury, Leah B.; Laiyemo, Adeyinka; Lanza, Elaine] Natl Canc Inst, Ctr Canc Res, Bethesda, MD USA. [Murphy, Gwen; Sansbury, Leah B.; Laiyemo, Adeyinka] Off Prevent Oncol, Canc Prevent Fellowship Program, Bethesda, MD USA. RP Murphy, G (reprint author), Natl Canc Inst, Infect & Immunoepidemiol Branch, Div Canc Epidemiol & Genet, 6120 Executive Blvd,EPS 7067, Rockville, MD 20892 USA. EM murphygw@mail.nih.gov RI Murphy, Gwen/G-7443-2015 FU Intramural NIH HHS NR 39 TC 6 Z9 7 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 EI 1573-7225 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD SEP PY 2008 VL 19 IS 7 BP 751 EP 758 DI 10.1007/s10552-008-9137-6 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 330BH UT WOS:000257913800009 PM 18322814 ER PT J AU Gamblin, TC Egorin, MJ Zuhowski, EG Lagattuta, TF Herscher, LL Russo, A Libutti, SK Alexander, HR Dedrick, RL Bartlett, DL AF Gamblin, T. Clark Egorin, Merrill J. Zuhowski, Eleanor G. Lagattuta, Theodore F. Herscher, Laurie L. Russo, Angelo Libutti, Steven K. Alexander, H. Richard Dedrick, Robert L. Bartlett, David L. TI Intraperitoneal gemcitabine pharmacokinetics: a pilot and pharmacokinetic study in patients with advanced adenocarcinoma of the pancreas SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE intraperitoneal chemotherapy; pharmacokinetics; gemcitabine; pancreatic cancer ID SINGLE-AGENT GEMCITABINE; UROTHELIAL CANCER; MODALITY THERAPY; OVARIAN-CANCER; CHEMOTHERAPY; CARCINOMA; 2',2'-DIFLUORODEOXYCYTIDINE; RADIOTHERAPY; 5-FLUOROURACIL; CONCURRENT AB Background The pyrimidine analogue gemcitabine (2', 2'-difluorodeoxycitidine, dFdC) is active against pancreatic cancer, and its high clearance (CL(tb)) and low incidence of local toxicity make it an excellent candidate for evaluation as intraperitoneal (IP) therapy. We designed a dosing schema that used multiple sequential exchanges of a peritoneal dialysate containing dFdC in an effort to produce prolonged IP dFdC exposure. Methods As part of a study involving multi-modality therapy for advanced pancreatic adenocarcinoma, patients were treated with four 6-h IP dwells of dFdC (50 mg/m(2) in 21) over a 24-h period. A second 24-h cycle of IP dFdC therapy was repeated 1 week later. Each exchange of dialysate contained 50 mg/m(2) dFdC in 21 of commercial 1.5% dextrose dialysis solution. Plasma and peritoneal fluid were analyzed by HPLC to determine concentrations of dFdC and its inactive metabolite 2', 2' difluorodeoxyuridine (dFdU). Clinical data were recorded to note drug toxicity and response. Results Nine patients underwent IP dFdC therapy, and eight were able to receive two cycles. There were no recorded significant toxicities. Low plasma dFdC concentrations (< 1 mu g/ml) were present transiently in seven of nine patients, and dFdC was not detectable in the plasma of the other two. Plasma dFdU concentrations were low but increased gradually until 12 h and then declined little if any. IP dFdC concentrations declined rapidly, and dFdC was seldom measurable prior to administration of the next scheduled 6-h dwell. dFdU concentrations in peritoneal fluid were very low (< 0.5 mu g/ml) throughout treatment. The mean area under the concentration versus time curve (AUC) for dFdC in peritoneal fluid was 182 mu g/ml x h, which was approximately 70x the AUC of dFdC reported in the ascites of a patient undergoing systemic dFdC therapy. Conclusions IP dFdC was well tolerated, and no significant toxicities were noted. The rapid decrease in peritoneal dFdC concentrations and low concentrations of IP dFdU imply almost total absorption of IP-administered dFdC. Little, if any, dFdC could be detected in plasma, but the steady-state plasma dFdU concentrations also imply absorption and inactivation of virtually all IP-administered dFdC. These findings are consistent with the known high CL(tb) and low incidence of local toxicity of dFdC and argue for its further evaluation as a drug for IP therapy. C1 [Gamblin, T. Clark] UPMC, Montefiore Hosp, Liver Canc Ctr, Pittsburgh, PA 15213 USA. [Dedrick, Robert L.] NIH, Div Bioengn & Phys Sci, Off Res Serv, Bethesda, MD 20892 USA. [Libutti, Steven K.; Alexander, H. Richard; Bartlett, David L.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. [Herscher, Laurie L.; Russo, Angelo] NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. [Egorin, Merrill J.; Zuhowski, Eleanor G.; Lagattuta, Theodore F.] Univ Pittsburgh, Inst Canc, Mol Therapeut Drug Discovery Program, Pittsburgh, PA 15213 USA. [Egorin, Merrill J.] Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15213 USA. [Egorin, Merrill J.] Univ Pittsburgh, Sch Med, Dept Med, Div Hematol Oncol, Pittsburgh, PA 15213 USA. [Gamblin, T. Clark; Bartlett, David L.] Univ Pittsburgh, Sch Med, Dept Surg, Div Transplantat, Pittsburgh, PA 15213 USA. [Gamblin, T. Clark] Univ Pittsburgh, Sch Med, Dept Surg, Div Surg Oncol, Pittsburgh, PA 15213 USA. RP Gamblin, TC (reprint author), UPMC, Montefiore Hosp, Liver Canc Ctr, 7 South,3459 5th Ave, Pittsburgh, PA 15213 USA. EM gamblintc@upmc.edu FU NCI NIH HHS [P30CA 47904]; NICHD NIH HHS [K12 HD049109] NR 34 TC 9 Z9 9 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD SEP PY 2008 VL 62 IS 4 BP 647 EP 653 DI 10.1007/s00280-007-0647-9 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 327FJ UT WOS:000257714700009 PM 18040687 ER PT J AU Kang, HJ Kim, HJ Kwon, SH Kang, BD Eling, TE Lee, SH Bae, I AF Kang, Hyo Jin Kim, Hee Jeong Kwon, Sang Hoon Kang, Brian DongHoon Eling, Thomas E. Lee, Sang Han Bae, Insoo TI BRCA1 modulates sensitivity to 5F-203 by regulating xenobiotic stress-inducible protein levels and EROD activity SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE BRCA1; 5F-203; AhR; CYP1A1; P53; EROD activity ID ARYL-HYDROCARBON RECEPTOR; BREAST-CANCER CELLS; GENE-EXPRESSION; IN-VIVO; 2-(4-AMINO-3-METHYLPHENYL)-5-FLUOROBENZOTHIAZOLE; REPRESSOR; COMPLEX; GROWTH AB Purpose We have investigated the effects of BRCA1 over-expression and knockdown on 5F-203-induced gene expression and cytotoxicity in human breast cancer cells. 5F-203 is a chemotherapeutic prodrug that both induces a p450 enzyme, CYP1A1, and is metabolically activated by CYP1A1. Methods We used several molecular biological techniques to confirm our findings. BRCA1 regulates sensitivity to 5F-203 by regulating the expression of CYP1A1 mRNA and its EROD activity. XRE-Luc reporter assays, semi-quantitative RT-PCR, Western blot analysis, EROD activity measurements, gene knockdown and MTT cell survival assays were used for this study. Results Our results show that the ability of 5F-203 treatments to increase CYP1A1 mRNA level and CYP1A1 enzymatic activity (EROD activity) are affected by BRCA1 protein levels. In addition, the ability of 5F-203 treatments to induce proteins, P53 and P53 target genes such as P21, is significantly decreased in BRCA1 knockdown cells, suggesting that BRCA1-related effects could at least partially explain why BRCA1 knockdown increases resistance to 5F-203-mediated cytotoxicity. We also observed altered expression of the two major transcription factors (AhR and ARNT) that affect CYP1A1 expression when BRCA1 protein levels are altered. Conclusion BRCA1 is an important protein, which affects 5F-203-mediated cytotoxicity. Our findings are potentially clinically significant; they suggest that those patients most likely to respond to this new prodrug will have tumors containing normal amounts of BRCA1. C1 [Kang, Hyo Jin; Kim, Hee Jeong; Kwon, Sang Hoon; Lee, Sang Han; Bae, Insoo] Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Bae, Insoo] Georgetown Univ, Dept Radiat Med, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. [Kwon, Sang Hoon] Keimyung Univ, Sch Med, Dept Obstet & Gynecol, Taegu, South Korea. [Kang, Brian DongHoon] Univ Michigan, Dept Biochem, Ann Arbor, MI 48109 USA. [Eling, Thomas E.] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Lee, Sang Han] Soonchunhyang Univ, Coll Med, Dept Biochem, Cheonan, South Korea. RP Bae, I (reprint author), Georgetown Univ, Dept Oncol, Lombardi Comprehens Canc Ctr, 3970 Reservoir Rd NW, Washington, DC 20057 USA. EM ib42@georgetown.edu FU NIEHS NIH HHS [ES01440-01] NR 20 TC 5 Z9 5 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD SEP PY 2008 VL 62 IS 4 BP 689 EP 697 DI 10.1007/s00280-007-0657-7 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 327FJ UT WOS:000257714700015 PM 18074135 ER PT J AU Hartman, AM Thun, MJ Ballard-Barbash, R AF Hartman, Anne M. Thun, Michael J. Ballard-Barbash, Rachel CA Organizing Comm TI Linking tobacco control policies and practices to early cancer endpoints: Surveillance as an agent for change SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID CONTROL PROGRAMS; UNITED-STATES; SMOKING AB State tobacco control programs provide an important laboratory for the development, implementation, and evaluation of comprehensive tobacco control interventions. Studies have shown that states and municipalities with aggressive tobacco control programs have experienced more rapid decreases in per capita cigarette sales, smoking prevalence, lung cancer, and heart disease than entities without such programs. Despite strong evidence that population-level interventions are critical in achieving large and sustained reductions in tobacco use, states do not fund tobacco control efforts at levels recommended by the Centers for Disease Control and Prevention. Research on the effectiveness and cost effectiveness of these activities is essential to inform and strengthen tobacco control at the state level. A workshop, co-organized by the American Cancer Society, the National Cancer Institute, the American Association for Cancer Research, and the Centers for Disease Control and Prevention, was held in Philadelphia in December, 2007, to discuss the topic "Linking tobacco control policies and practices to early cancer endpoints: surveillance as an agent for change." Participants represented three different disciplines. Tobacco surveillance researchers described the data currently collected on state-level tobacco control policies, pro-tobacco countermeasures by the industry, public attitudes toward tobacco use, and measures of smoking prevalence and consumption. Cancer registry experts described the geographic coverage of high quality, population-based cancer registries. Mathematical modeling experts discussed various modeling approaches that can be used to relate upstream tobacco promotion and control activities to downstream measures such as public attitudes, changes in tobacco use, and trends in tobacco-related diseases. The most important recommendation of the Workshop was a call for national leadership to enhance the collection and integration of data from multiple sources as a resource to further study and strengthen the scientific basis for tobacco control. C1 [Hartman, Anne M.] NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Thun, Michael J.] Amer Canc Soc, Dept Epidemiol & Surveillance Res, Atlanta, GA 30329 USA. RP Hartman, AM (reprint author), NCI, Risk Factor Monitoring & Methods Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM Anne-Hartman@nih.gov FU National Cancer Institute; American Cancer Society; American Association for Cancer Research FX Grant support: Financial and staff support for this meeting were provided by the National Cancer Institute, the American Cancer Society and the American Association for Cancer Research. NR 26 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 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2008 VL 17 IS 9 BP 2215 EP 2219 DI 10.1158/1055-9965.EPI-08-0563 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 348LG UT WOS:000259211400004 PM 18768485 ER PT J AU Huang, WY Hayes, R Pfeiffer, R Viscidi, RP Lee, FK Wang, YF Reding, D Whitby, D Papp, JR Rabkin, CS AF Huang, Wen-Yi Hayes, Richard Pfeiffer, Ruth Viscidi, Raphael P. Lee, Francis K. Wang, Yun F. Reding, Douglas Whitby, Denise Papp, John R. Rabkin, Charles S. TI Sexually transmissible infections and prostate cancer risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SIMPLEX-VIRUS TYPE-2; CHLAMYDIA-TRACHOMATIS; HUMAN-PAPILLOMAVIRUS; UNITED-STATES; HUMAN-HERPESVIRUS-8 INFECTION; TRANSMITTED-DISEASES; PLASMA ANTIBODIES; OVARIAN-CANCER; SEROPREVALENCE; CYTOMEGALOVIRUS AB Background: Sexually transmissible infections (STI) have been variably associated with increased risks of prostate cancer, largely in case-control studies. Methods: In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we examined risk of prostate cancer in relation to serum antibodies to Chlamydia trachomatis, human papillomavirus-16 and -18, herpes simplex virus-2, cytomegalovirus, and human herpesvirus-8 in 868 cases (765 Whites and 103 Blacks) and 1,283 controls matched by race, age, time since initial screening, and year of blood draw; all blood samples were collected at least 1 year before prostate cancer diagnosis, except for 43 Black cases. We also assessed risk associated with self-reported history of syphilis and gonorrhea. Results: Prevalences of the 7 STIs among controls were weakly correlated, and all were more frequent among Blacks than Whites, except for human herpesvirus-8. Among Whites, prostate cancer risk was not significantly associated with the individual infections or with their number (P-trend = 0.1); however, men with one or more STI had slightly higher risk (odds ratio, 1.3; 95% confidence interval, 1.0-1.6). Among Blacks, excess risk was associated with IgA antibody to C. trachomatis (odds ratio, 2.1; 95% confidence interval, 1.2-3.6). Conclusion: This large prospective study of prostate cancer shows no consistent association with specific STIs and a borderline association with any versus none. Whether a shared response or correlated infection not directly measured underlies the weak association requires further study. C1 [Huang, Wen-Yi; Hayes, Richard; Pfeiffer, Ruth; Whitby, Denise; Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Viscidi, Raphael P.] Johns Hopkins Univ, Sch Med, Stanley Div Dev Neurovirol, Baltimore, MD USA. [Lee, Francis K.] Emory Univ, Sch Med, Div Infect Dis Epidemiol & Immunol, Atlanta, GA 30322 USA. [Wang, Yun F.] Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. [Papp, John R.] Ctr Dis Control & Prevent, Chlamydia Lab, Atlanta, GA USA. [Reding, Douglas] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI 54449 USA. [Whitby, Denise] NCI, Viral Oncol Sect, AIDS Vaccine program, Sci Applicat Int Corp, Frederick, MD 21701 USA. RP Huang, WY (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 8110,MSC 7240, Bethesda, MD 20892 USA. EM huangw@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 FU Intramural Research Program of the Division of Cancer Epidemiology; Genetics and Division of Cancer Prevention; National Cancer Institute; NIH; Department of Health and Human services FX Intramural Research Program of the Division of Cancer Epidemiology and Genetics and Division of Cancer Prevention, National Cancer Institute, NIH, Department of Health and Human services. NR 71 TC 29 Z9 33 U1 2 U2 5 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 SEP PY 2008 VL 17 IS 9 BP 2374 EP 2381 DI 10.1158/1055-9965.EPI-08-0173 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 348LG UT WOS:000259211400027 PM 18768506 ER PT J AU Levine, AJ Wallace, K Tsang, S Haile, RW Saibil, F Ahnen, D Cole, BF Barry, EL Munroe, DJ Ali, IU Ueland, P Baron, JA AF Levine, A. Joan Wallace, Kristin Tsang, Shirley Haile, Robert W. Saibil, Fred Ahnen, Dennis Cole, Bernard F. Barry, Elizabeth L. Munroe, David J. Ali, Iqbal U. Ueland, Per Baron, John A. TI MTHFR genotype and colorectal adenoma recurrence: Data from a double-blind placebo-controlled clinical trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID METHYLENETETRAHYDROFOLATE REDUCTASE POLYMORPHISM; GENETIC POLYMORPHISMS; C677T POLYMORPHISM; FOLATE METABOLISM; COMMON MUTATION; RISK-FACTOR; FOLIC-ACID; CANCER; METHIONINE; HOMOCYSTEINE AB Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. We assessed the association between two common MTHFR variants, 677C > T and 1298A > C, and adenoma recurrence in the context of a randomized double-blind clinical trial of aspirin use and folate supplementation. We used generalized linear regression to estimate risk ratios and 95% confidence intervals (95% CI) for recurrence, adjusting for age, sex, clinical center, follow-up time, and treatment status. Neither MTHFR polymorphism was associated with overall or advanced adenoma recurrence. Compared with those with two wild-type alleles, the relative risk for advanced adenoma was 0.75 (95% CI, 0.36-1.55) for the MTHFR 677 TT genotype and 1.16 (95% CI, 0.58-2.33) for the MTHFR 1298 CC genotype. The effect of folate supplementation on recurrence risk did not differ by genotype. Our findings indicate that the MTHFR genotype does not change adenoma risk in a manner similar to its effect on colorectal cancer, and does not modify the effect of folate supplementation on metachronous adenoma risk. C1 [Levine, A. Joan; Haile, Robert W.] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. [Wallace, Kristin; Barry, Elizabeth L.; Baron, John A.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Community & Family Med, Hanover, NH 03756 USA. [Baron, John A.] Dartmouth Coll, Hitchcock Med Ctr, Dartmouth Med Sch, Dept Med, Hanover, NH 03756 USA. [Ali, Iqbal U.] SAIC Frederick Inc, NCI, Lab Mol Technol, Adv Technol Program, Frederick, MD USA. [Saibil, Fred] Univ Toronto, Dept Med, Toronto, ON, Canada. [Ahnen, Dennis] Univ Colorado, Hlth Sci Ctr, Dept Med, Denver, CO 80262 USA. [Ueland, Per] Univ Bergen, Pharmacol Sect, Inst Med, Bergen, Norway. [Ueland, Per] Haukeland Hosp, N-5021 Bergen, Norway. [Cole, Bernard F.] Univ Vermont, Dept Math & Stat, Coll Engn & Math Sci, Burlington, VT 05405 USA. RP Levine, AJ (reprint author), Univ So Calif, Keck Sch Med, Dept Prevent Med, Topping Tower,1441 Eastlake Ave, Los Angeles, CA 90033 USA. EM ajoanlev@usc.edu RI Ueland, Per/C-7340-2013 FU National Cancer Institute, NIH [N01-CO-12400, 5 RO1 CA059005, U54 CA 100971] FX National Cancer Institute, NIH, under contract N01-CO-12400 and grants 5 RO1 CA059005 and U54 CA 100971 from the NIH. 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 35 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 SEP PY 2008 VL 17 IS 9 BP 2409 EP 2415 DI 10.1158/1055-9965.EPI-07-2670 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 348LG UT WOS:000259211400032 PM 18768511 ER PT J AU Moore, SC Peters, TM Ahn, J Park, Y Schatzkin, A Albanes, D Ballard-Barbash, R Hollenbeck, A Leitzmann, MF AF Moore, Steven C. Peters, Tricia M. Ahn, Jiyoung Park, Yikyung Schatzkin, Arthur Albanes, Demetrius Ballard-Barbash, Rachel Hollenbeck, Albert Leitzmann, Michael F. TI Physical activity in relation to total, advanced, and fatal prostate cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID RISK UNITED-STATES; HEALTH-PROFESSIONALS; DIETARY-INTAKE; LARGE COHORT; FOLLOW-UP; INSULIN; MEN; ASSOCIATION; HORMONES; CHINA AB Physical activity has been inconsistently related to total prostate cancer and few studies have examined whether this association varies by disease aggressiveness. We examined physical activity in relation to total, advanced, and fatal prostate cancer in the NIH-AARP Diet and Health Study. At baseline (1995-1996), 293,902 men ages 50 to 71. years completed a questionnaire inquiring about current frequency of vigorous exercise of at least 20 min of duration, as well as frequency of exercise during adolescence (ages 15-18). We used proportional hazards regression to calculate multivariate relative risks (RR) and 95% confidence intervals (95% CI). During up to 8.2 years of follow-up, 17,872 prostate cancer cases were identified, including 1,942 advanced and 513 fatal cases. Comparing frequent (5+ times per week) versus infrequent (less than once per week) vigorous exercise, exercise at baseline was not associated with risk of total prostate cancer (RR, 1.01; 95% CI, 0.96-1.07; P-trend = 0.78), advanced prostate cancer (RR, 1.14; 95% CI, 0.97-1.33; P-trend = 0.25), or fatal prostate cancer (RR, 0.90; 95% CI, 0.67-1.20; P-trend = 0.12). Increasing level of vigorous exercise during adolescence was associated with a small 3% reduction in total prostate cancer risk (frequent versus infrequent exercise during adolescence: RR, 0.97; 95% CI, 0.91-1.03; P-trend = 0.03) but was not associated with risk of advanced prostate cancer (RR, 0.95; 95% CI, 0.78-1.14; P-trend = 0.18) or fatal prostate cancer (RR, 0.96; 95% CI, 0.67-1.36; P-trend = 0.99). Neither vigorous exercise at baseline nor exercise during adolescence was related to risk of total, advanced, or fatal prostate cancer in this large prospective cohort. C1 [Moore, Steven C.; Peters, Tricia M.; Ahn, Jiyoung; Park, Yikyung; Schatzkin, Arthur; Albanes, Demetrius; Leitzmann, Michael F.] NCI, Div Canc Epidemiol, Bethesda, MD 20892 USA. [Moore, Steven C.; Peters, Tricia M.; Ahn, Jiyoung; Park, Yikyung; Schatzkin, Arthur; Albanes, Demetrius; Leitzmann, Michael F.] NCI, Div Genet, Bethesda, MD 20892 USA. [Hollenbeck, Albert] Amer Assoc Retired Persons, Washington, DC USA. RP Moore, SC (reprint author), NCI, Div Canc Epidemiol, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM moorest@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Moore, Steven/D-8760-2016; OI Moore, Steven/0000-0002-8169-1661; Park, Yikyung/0000-0002-6281-489X FU NIH, National Cancer Institute [TU2CA105666] FX Intramural Research Program of the NIH, National Cancer Institute, and grant TU2CA105666. NR 38 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 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD SEP PY 2008 VL 17 IS 9 BP 2458 EP 2466 DI 10.1158/1055-9965.EPI-08-0403 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 348LG UT WOS:000259211400039 PM 18725512 ER PT J AU Toubaji, A Achtar, M Provenzano, M Herrin, VE Behrens, R Hamilton, M Bernstein, S Venzon, D Gause, B Marincola, F Khleif, SN AF Toubaji, Antoun Achtar, Moujahed Provenzano, Maurizio Herrin, Vincent E. Behrens, Robert Hamilton, Michael Bernstein, Sarah Venzon, David Gause, Barry Marincola, Francesco Khleif, Samir N. TI Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE mutant ras; adjuvant; immunotherapy; pancreatic cancer; colorectal cancer ID ACTIVE SPECIFIC IMMUNOTHERAPY; COLONY-STIMULATING FACTOR; SECRETING TUMOR VACCINE; BLOOD MONONUCLEAR-CELLS; CD8(+) T-CELLS; K-RAS; IMMUNE-RESPONSE; SOLID TUMORS; MUTATION; ADENOCARCINOMA AB Introduction There is mounting evidence describing the immunosuppressive role of bulky metastatic disease, thus countering the therapeutic effects of tumor vaccine. Therefore, adjuvant immunotherapy may have a better impact on clinical outcome. In this phase II clinical trial, we aimed to test the feasibility of using a specific mutant ras peptide vaccine as an adjuvant immunotherapy in pancreatic and colorectal cancer patients. Materials and methods Twelve patients with no evidence of disease (NED), five pancreatic and seven colorectal cancer patients were vaccinated subcutaneously with 13-mer mutant ras peptide, corresponding to their tumor's ras mutation. Vaccinations were given every 4 weeks, up to a total of six vaccines. Results No serious acute or delayed systemic side effects were seen. We detected specific immune responses to the relevant mutant ras peptide by measuring IFN-gamma mRNA expression by quantitative real-time PCR. Five out of eleven patients showed a positive immune response. Furthermore, the five pancreatic cancer patients have shown a mean disease-free survival (DFS) of 35.2+ months and a mean overall survival (OS) of 44.4+ months. The seven colorectal cancer patients have shown a mean disease-free survival (DFS) of 27.2+ months and a mean overall survival (OS) of 41.5+ months. Conclusion In this study, we found that it is feasible to use mutant ras vaccine in the adjuvant setting. This vaccine is safe, can induce specific immune responses, and it appears to have a positive outcome in overall survival. Therefore, we believe that such an approach warrants further investigation in combination with other therapies. C1 [Toubaji, Antoun; Achtar, Moujahed; Behrens, Robert; Khleif, Samir N.] NNMC, Canc Vaccine Sect, Vaccine Branch, NCI,NIH, Bethesda, MD 20889 USA. [Provenzano, Maurizio; Marincola, Francesco] NIH, Immunogenet Sect, DTM, CC, Bethesda, MD 20892 USA. [Herrin, Vincent E.] Natl Naval Med Ctr, Dept Hematol Oncol, Bethesda, MD USA. [Hamilton, Michael; Bernstein, Sarah; Gause, Barry] MOCRU NNMC, Bethesda, MD USA. [Venzon, David] NCI, Biostat & Data Management Sect, CCR, NIH, Bethesda, MD 20892 USA. RP Khleif, SN (reprint author), NNMC, Canc Vaccine Sect, Vaccine Branch, NCI,NIH, Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM khleif@nih.gov NR 25 TC 47 Z9 47 U1 0 U2 3 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 SEP PY 2008 VL 57 IS 9 BP 1413 EP 1420 DI 10.1007/s00262-008-0477-6 PG 8 WC Oncology; Immunology SC Oncology; Immunology GA 316PT UT WOS:000256962900014 PM 18297281 ER PT J AU Chow, WH Devesa, SS AF Chow, Wong-Ho Devesa, Susan S. TI Contemporary epidemiology of renal cell cancer SO CANCER JOURNAL LA English DT Review DE renal cell cancer; incidence trends; cohort studies; smoking; obesity; hypertension; diet; occupation; genetic polymorphism; somatic mutation ID HIPPEL-LINDAU GENE; POPULATION-BASED COHORT; BODY-MASS INDEX; OCCUPATIONAL RISK-FACTORS; TUMOR-SUPPRESSOR GENE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; RANDOMIZED CONTROLLED-TRIAL; CARCINOMA UNITED-STATES; COPY NUMBER ALTERATIONS; HOGG-DUBE-SYNDROME AB We analyzed renal cell cancer incidence patterns in the United States and reviewed recent epidemiologic evidence with regard to environmental and host genetic determinants of renal cell cancer risk. Renal cell cancer incidence rates continued to rise among all racial/ethnic groups in the United States, across all age groups, and for all tumor sizes, with the most rapid increases for localized stage disease and small tumors. Recent cohort studies confirmed the association of smoking, excess body weight, and hypertension with an elevated risk of renal cell cancer, and suggested that these factors can be modified to reduce the risk. There is increasing evidence for an inverse association between renal cell cancer risk and physical activity and moderate intake of alcohol. Occupational exposure to trichloroethylene has been positively associated with renal cell cancer risk in several recent studies, but its link with somatic mutations of the von Hippel-Lindau gene has not been confirmed. Studies of genetic polymorphisms in relation to renal cell cancer risk have produced mixed results. but genome-wide association studies with larger sample size and a more comprehensive approach are underway. Few epidemiologic studies have evaluated risk factors by subtypes of renal cell cancer defined by somatic mutations and other tumor markers. C1 [Chow, Wong-Ho; Devesa, Susan S.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Chow, WH (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8100, Bethesda, MD 20892 USA. EM choww@mail.nih.gov FU SEER program; IMS, Inc; Intramural Research Program of the National Institutes of Health FX This work was supported by the Intramural Research Program of the National Institutes of Health. NR 204 TC 110 Z9 112 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-9117 EI 1540-336X J9 CANCER J JI Cancer J. PD SEP-OCT PY 2008 VL 14 IS 5 BP 288 EP 301 PG 14 WC Oncology SC Oncology GA 358KR UT WOS:000259916200003 PM 18836333 ER PT J AU Yoo, CB Chuang, JC Byun, HM Egger, G Yang, AS Dubeau, L Long, T Laird, PW Marquez, VE Jones, PA AF Yoo, Christine B. Chuang, Jody C. Byun, Hyang-Min Egger, Gerda Yang, Allen S. Dubeau, Louis Long, Tiffany Laird, Peter W. Marquez, Victor E. Jones, Peter A. TI Long-term Epigenetic Therapy with Oral Zebularine Has Minimal Side Effects and Prevents Intestinal Tumors in Mice SO CANCER PREVENTION RESEARCH LA English DT Article ID DNA METHYLTRANSFERASE INHIBITOR; CPG-ISLAND HYPERMETHYLATION; HEPATIC ALDEHYDE OXIDASE; HUMAN MAMMARY EPITHELIA; METHYLATION INHIBITOR; EXPRESSION DATA; CANCER-CELLS; IN-VIVO; MOUSE; HYPOMETHYLATION AB Recent successes in the application of epigenetic drugs for the treatment of myelodysplastic syndrome have raised questions on the safety of long-term administration of DNA methylation inhibitors. We treated preweaned cancer prone Apc(Min/+) (Min) mice continuously with the DNA methylation inhibitor zebularine in their drinking water to determine the effects of the drug on normal mouse development as well as cancer prevention. Zebularine caused a tissue-specific reduction in DNA methylation at B1 short interspersed nucleotide elements in the small and large intestines of female Min mice but not in other organs examined after chronic oral treatment. No significant difference in the average weights of mice was observed during the treatment. In addition, analysis of global gene expression of colonic epithelial cells from the females indicated that only 3% to 6% of the genes were affected in their expression. We did not detect toxicity and abnormalities from the histopathologic analysis of liver and intestinal tissues. Lastly, we tested whether prevention of tumorigenesis can be achieved with chronic oral administration of zebularine in Min mice. The average number of polyps in Min females decreased from 58 to 1, whereas the average polyp number remained unaffected in Min males possibly due to differential activity of aldehyde oxidase. Taken together, our results show for the first time that long-term oral administration of zebularine causes a gender-specific abrogation of intestinal tumors while causing a tissue-specific DNA demethylation. Importantly, prolonged treatment of mice with epigenetic drugs resulted in only minor developmental and histologic changes. C1 [Egger, Gerda; Yang, Allen S.; Dubeau, Louis; Long, Tiffany; Laird, Peter W.; Jones, Peter A.] Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, Los Angeles, CA 90033 USA. [Yoo, Christine B.; Chuang, Jody C.; Laird, Peter W.; Jones, Peter A.] Univ So Calif, Dept Biochem & Mol Biol, Keck Sch Med, Los Angeles, CA 90033 USA. [Jones, Peter A.] Univ So Calif, Dept Urol, Keck Sch Med, Los Angeles, CA 90033 USA. [Long, Tiffany; Laird, Peter W.] Univ So Calif, Dept Surg, Keck Sch Med, Los Angeles, CA 90033 USA. [Byun, Hyang-Min; Yang, Allen S.] Univ So Calif, Dept Hematol, Keck Sch Med, Los Angeles, CA 90033 USA. [Byun, Hyang-Min; Dubeau, Louis] Univ So Calif, Dept Pathol, Keck Sch Med, Los Angeles, CA 90033 USA. [Marquez, Victor E.] NCI, Ctr Canc Res, Med Chem Lab, Frederick, MD 21701 USA. RP Jones, PA (reprint author), Univ So Calif, Kenneth Norris Jr Comprehens Canc Ctr, Keck Sch Med, 1441 Eastlake Ave,Room 8302L,Mail Stop 83, Los Angeles, CA 90033 USA. EM jones_p@ccnt.hsc.usc.edu RI Egger, Gerda/B-7177-2013; Laird, Peter/G-8683-2012; OI Egger, Gerda/0000-0003-2489-155X; Byun, Hyang-Min/0000-0002-6278-3165 NR 46 TC 49 Z9 52 U1 0 U2 4 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 SEP PY 2008 VL 1 IS 4 BP 233 EP 240 DI 10.1158/1940-6207.CAPR-07-0008 PG 8 WC Oncology SC Oncology GA 420MH UT WOS:000264293400005 PM 19138966 ER PT J AU Loeb, LA Harris, CC AF Loeb, Lawrence A. Harris, Curtis C. TI Advances in chemical carcinogenesis: A historical review and prospective SO CANCER RESEARCH LA English DT Editorial Material ID GENE-EXPRESSION PATTERNS; CULTURED HUMAN BRONCHI; DNA-POLYMERASE ETA; DEOXYRIBONUCLEIC-ACID; HUMAN CANCER; LUNG-CANCER; HEPATOCELLULAR-CARCINOMA; SV40-TRANSFORMED CELLS; MOLECULAR EPIDEMIOLOGY; TRANSLESION SYNTHESIS C1 [Loeb, Lawrence A.] Univ Washington, Dept Pathol, Gottstein Mem Canc Res Lab, Seattle, WA 98195 USA. [Harris, Curtis C.] NCI, Human Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Loeb, LA (reprint author), Univ Washington, Dept Pathol, Gottstein Mem Canc Res Lab, Box 357470,1959 N E Pacific Ave,Room K072, Seattle, WA 98195 USA. EM laloeb@u.washington.edu; curtis_harris@nih.gov FU Intramural NIH HHS [Z01 BC005480-22]; NCI NIH HHS [CA115802, CA77852, P01 CA077852, R01 CA115802]; NIA NIH HHS [P01 AG001751, AG01751] NR 177 TC 109 Z9 114 U1 0 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2008 VL 68 IS 17 BP 6863 EP 6872 DI 10.1158/0008-5472.CAN-08-2852 PG 10 WC Oncology SC Oncology GA 346PF UT WOS:000259080300002 PM 18757397 ER PT J AU Squarize, CH Castilho, RM Gutkind, JS AF Squarize, Cristiane H. Castilho, Rogerio M. Gutkind, J. Silvio TI Chemoprevention and treatment of experimental Cowden's disease by mTOR inhibition with rapamycin SO CANCER RESEARCH LA English DT Article ID LHERMITTE-DUCLOS-DISEASE; SQUAMOUS-CELL CARCINOMA; TUMOR-SUPPRESSOR GENE; NEGATIVE REGULATION; GERMLINE MUTATIONS; PTEN(+/-) MICE; BREAST-CANCER; SOMA SIZE; PTEN; NEOPLASIA AB Cowden's disease is an autosomal dominant disorder characterized by the development of multiple mucocutaneous lesions and benign tumors, and enhanced cancer predisposition. Most Cowden's disease patients harbor inactivating mutations in the PTEN tumor suppressor gene which encodes a lipid phosphatase, PTEN, which restrains the phosphatidylinositol 3-kinase-Akt signaling pathway. We observed that the epithelial-specific deletion of Pten in mice causes multiple hyperproliferative and tumor lesions that strikingly resemble Cowden's disease. This animal model system provided an opportunity to explore novel therapeutic approaches in Cowden's disease. Indeed, we show here that rapamycin administration, which inhibits a key downstream target of Akt, mammalian target of rapamycin (mTOR), promotes the rapid regression of advanced mucocutaneous lesions. Furthermore, when administered before disease manifestation, rapamycin can halt the development of Cowden's disease-like lesions, thereby prolonging animal survival. These findings suggest that mTOR inhibition with rapamycin may represent a suitable therapeutic option for the chemoprevention and treatment of Cowden disease patients and others tumor syndromes that involve defective PTEN function. C1 [Squarize, Cristiane H.; Castilho, Rogerio M.; Gutkind, J. Silvio] Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Room 211, Bethesda, MD 20892 USA. EM gutkind@dir.nidcr.nih.gov RI Gutkind, J. Silvio/A-1053-2009; Castilho, Rogerio/E-4987-2010 FU Intramural Research Program of NIH; National Institute of Dental, and Craniofacial Research FX Intramural Research Program of NIH, National Institute of Dental, and Craniofacial Research. NR 50 TC 54 Z9 54 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2008 VL 68 IS 17 BP 7066 EP 7072 DI 10.1158/0008-5472.CAN-08-0922 PG 7 WC Oncology SC Oncology GA 346PF UT WOS:000259080300027 PM 18757421 ER PT J AU Martin-Manso, G Galli, S Ridnour, LA Tsokos, M Wink, DA Roberts, DD AF Martin-Manso, Gema Galli, Susana Ridnour, Lisa A. Tsokos, Maria Wink, David A. Roberts, David D. TI Thrombospondin 1 promotes tumor macrophage recruitment and enhances tumor cell cytotoxicity of differentiated U937 cells SO CANCER RESEARCH LA English DT Article ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; ANGIOGENESIS IN-VIVO; HUMAN-NEUTROPHILS; EXTRACELLULAR-MATRIX; BONE-MARROW; GROWTH; INTEGRIN; EXPRESSION; RECEPTOR; MONOCYTES AB Inhibition of tumor growth by thrombospondin (TSP) 1 is generally attributed to its antiangiogenic activity, but effects on tumor immunity should also be considered. We show that overexpression of TSP1 in melanoma cells increases macrophage recruitment into xenograft tumors grown in nude or beige/nude mice. In vitro, TSP1 acutely induces expression of plasminogen activator inhibitor-1 (PAI-1) by monocytic cells, suggesting that TSPI-induced macrophage recruitment is at least. partially mediated by PAI-1. Tumor-associated macrophages (TAM) can either promote or limit tumor progression. 'The percentage of M1-polarized macrophages expressing inducible nitric oxide synthase is increased in TSP1-expressing tumors. Furthermore, soluble TSPI stimulates killing of breast carcinoma and melanoma cells by IFN-gamma-differentiated U937 cells in vitro via release of reactive oxygen species. TSPI causes a significant increase in phorbol ester-mediated superoxide generation from differentiated monocytes by interaction with alpha(6)beta(1) integrin through its NH2-terminal region. The NH2-terminal domain of TSP2 also stimulates monocyte superoxide production. Extracellular calcium is required for the TSP1-induced macrophage respiratory burst. Thus, TSP1 may play an important role in antitumor immunity by enhancing recruitment and activation of TAMs, which provides an additional selective pressure for loss of TSP1 and TSP2 expression during tumor progression. C1 [Martin-Manso, Gema; Galli, Susana; Tsokos, Maria; Roberts, David D.] Natl Canc Inst, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ridnour, Lisa A.; Wink, David A.] Natl Canc Inst, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), Natl Canc Inst, Pathol Lab, Ctr Canc Res, NIH, Bldg 10,Room 2A33,10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. EM droberts@hclix.nih.gov RI Roberts, David/A-9699-2008; Martin Manso, Maria Gema/D-4612-2013 OI Roberts, David/0000-0002-2481-2981; FU Intramural Research Program of the NIH; NCI; Center for Cancer Research; Institute tie Salad Carlo III (Spanish Ministry of Heath) FX Intramural Research Program of the NIH, NCI, Center for Cancer Research (M. Tsokos. D.A. Wink, and D.D. Roberts). G Martin-Manso is a recipient of a grant BEFI from Institute tie Salad Carlo III (Spanish Ministry of Heath). NR 49 TC 57 Z9 59 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 SEP 1 PY 2008 VL 68 IS 17 BP 7090 EP 7099 DI 10.1158/0008-5472.CAN-08-0643 PG 10 WC Oncology SC Oncology GA 346PF UT WOS:000259080300030 PM 18757424 ER PT J AU Hussain, SP He, P Subleski, J Hofseth, LJ Trivers, GE Mechanic, L Hofseth, AB Bernard, M Schwank, J Nguyen, G Mathe, E Djurickovic, D Haines, D Weiss, J Back, T Gruys, E Laubach, VE Wiltrout, RH Harris, CC AF Hussain, S. Perwez He, Peijun Subleski, Jeffery Hofseth, Lorne J. Trivers, Glenwood E. Mechanic, Leah Hofseth, Anne B. Bernard, Mark Schwank, Jonathan Nguyen, Giang Mathe, Ewy Djurickovic, Draginja Haines, Diana Weiss, Jonathan Back, Timothy Gruys, Eilene Laubach, Victor E. Wiltrout, Robert H. Harris, Curtis C. TI Nitric oxide is a key component in inflammation-accelerated tumorigenesis SO CANCER RESEARCH LA English DT Article ID REGULATORY T-CELLS; DENDRITIC CELLS; IFN-GAMMA; SYNTHASE EXPRESSION; CYCLIC-GMP; APOPTOSIS; CANCER; IL-6; CYTOKINES; ACTIVATION AB Nitric oxide (NO center dot), an important signaling molecule and it component of inflammatory response, is involved in tumorigenesis. However, the quantity of NO center dot and the cellular micro-environment influences the role of NO center dot in tumor development. We used a genetic strategy to test the hypothesis that an inflammatory microenvironment with an enhanced level of NO center dot accelerates spontaneous tumor development. C. parvum-induced inflammation and increased NO center dot synthase-2 (NOS2) expression coincided with accelerated spontaneous tumor development, mostly lymphomas, in p53-/-NOS2+/+ C57BL6 mice when compared with the controls (P = 0.001). However, p53-/-NOS2-/- mice did not show any difference in tumor latency between C. parvum-treated and control groups. In C. parvum-treated p53-/-NOS2+/+ mice, tumor development was preceded by a higher expression of NOS2 and phosphorylated Akt-Ser(473) (pAkt-Ser473) in spleen, increased cell proliferation measured by Ki-67 IHC in spleen and thymus, and a lower apoptotic index and CD95-L expression in spleen and thymus. C. parvum-treated p53-/-NOS2+/+ mice showed an increase in the number of Foxp3(+) T-reg cells, dendritic cells (I)Q, as well as increased CD80(+), CD86(+), CD40(+), and CD83(+) on DC in the spleen. Regulatory T-cells (T-reg) and the maturation of DC may modulate tumorigenesis. An increase in the FoxP3(+)T-reg cells in C. parvum-treated p53-/-NOS2+/+ mice indicates a role of NO center dot in the regulation of T-reg cells that may contribute to a protumor shift of the immune environment favoring an accelerated tumor development. These data provide genetic and mechanistic evidence that an inflammatory microenvironment and an increased level of NO center dot can accelerate tumor development. C1 [Hussain, S. Perwez; He, Peijun] NCI, Human Carcinogenesis Lab, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. [Nguyen, Giang] NIH, Howard Hughes Med Inst, Bethesda, MD 20892 USA. [Subleski, Jeffery; Weiss, Jonathan; Back, Timothy; Gruys, Eilene; Wiltrout, Robert H.] NCI, Expt Immunol Lab, Canc Inflammat Program, Ctr Canc Res, Frederick, MD 21701 USA. [Haines, Diana] Frederick Canc Res & Dev Ctr, Sci Applicat Int Corp, Frederick, MD USA. [Hofseth, Lorne J.; Hofseth, Anne B.] Univ S Carolina, Dept Basic Pharm Sci, Coll Pharm, Columbia, SC 29208 USA. [Laubach, Victor E.] Univ Virginia, Hlth Sci Ctr, Charlottesville, VA USA. [Mechanic, Leah] WESTAT Corp, Rockville, MD 20850 USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Ctr Canc Res, Bldg 37,Room 3068, Bethesda, MD 20892 USA. EM harrisc@mail.nih.gov RI Laubach, Victor/E-8818-2015 OI Laubach, Victor/0000-0001-9673-5383 FU Intramural Research Program of the NIH; National Cancer institute; Center for Cancer Research FX Intramural Research Program of the NIH, National Cancer institute, Center for Cancer Research. NR 50 TC 49 Z9 52 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD SEP 1 PY 2008 VL 68 IS 17 BP 7130 EP 7136 DI 10.1158/0008-5472.CAN-08-0410 PG 7 WC Oncology SC Oncology GA 346PF UT WOS:000259080300034 PM 18757428 ER PT J AU Asami, Y Kakeya, H Komi, Y Kojima, S Nishikawa, K Beebe, K Neckers, L Osada, H AF Asami, Yukihiro Kakeya, Hideaki Komi, Yusuke Kojima, Soichi Nishikawa, Kiyohiro Beebe, Kristin Neckers, Len Osada, Hiroyuki TI Azaspirene, a fungal product, inhibits angiogenesis by blocking Raf-1 activation SO CANCER SCIENCE LA English DT Article ID RECEPTOR TYROSINE KINASES; BLOOD-VESSEL FORMATION; ANTIANGIOGENIC ACTIVITY; MOLECULAR-MECHANISMS; SIGNAL-TRANSDUCTION; ENDOTHELIAL-CELLS; ERK ACTIVATION; VEGF RECEPTORS; DNA-SYNTHESIS; GROWTH AB Angiogenesis is an inevitable event in tumor progression and metastasis, and thus has been a compelling target for cancer therapy in recent years. Effective inhibition of tumor progression and metastasis could become a promising way to treat tumor-induced angiogenesis. We discovered that a fungus, Neosartorya sp., isolated from a soil sample, produced a new angiogenesis inhibitor, which we designated azaspirene. Azaspirene was previously shown to inhibit human umbilical vein endothelial cell (HUVEC) migration induced by vascular endothelial growth factor (VEGF) at an effective dose, 100% of 27 mu mol/L without significant cell toxicity. In the present study, we investigated the antiangiogenic activity of azaspirene in vivo. Azaspirene treatment reduced the number of tumor-induced blood vessels. Administration of azaspirene at 30 mu g/egg resulted in inhibition of angiogenesis (23.6-45.3% maximum inhibition relative to the controls) in a chicken chorioallantoic membrane assay. Next, we elucidated the molecular mechanism of antiangiogenesis of azaspirene. We investigated the effects of azaspirene on VEGF-induced activation of the mitogen-activated protein kinase signaling pathway in HUVEC. In vitro experiments indicated that azaspirene suppressed Raf-1 activation induced by VEGF without affecting the activation of kinase insert domain-containing receptor/fetal liver kinase 1 (VEGF receptor 2). Additionally, azaspirene preferentially inhibited the growth of HUVEC but not that of the non-vascular endothelial cells NIH3T3, HeLa, MSS31, and MCF-7. Taken together, these results demonstrate that azaspirene is a novel inhibitor of angiogenesis and Raf-1 activation that contains a unique carbon skeleton in its molecular structure. C1 [Asami, Yukihiro; Kakeya, Hideaki; Osada, Hiroyuki] RIKEN, Adv Sci Inst, Antibiot Lab, Wako, Saitama 3510198, Japan. [Komi, Yusuke; Kojima, Soichi] RIKEN, Mol Cellular Pathol Res Unit, Wako, Saitama 3510198, Japan. [Nishikawa, Kiyohiro] Nippon Kayaku Co Ltd, Pharmaceut Grp, R & D Div, Kita Ku, Tokyo 1158588, Japan. [Beebe, Kristin; Neckers, Len] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Osada, H (reprint author), RIKEN, Adv Sci Inst, Antibiot Lab, 2-1 Hirosawa, Wako, Saitama 3510198, Japan. EM hisyo@riken.jp RI Osada, Hiroyuki/N-4305-2014; Kojima, Soichi/N-7104-2015 OI Kojima, Soichi/0000-0002-5252-1612 FU Ministry of Education, Culture, Sports, Science, and Technology of Japan; Ministry of Health, Labour, and Welfare of Japan; RIKEN; Special Postdoctoral Researchers Program FX This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan, by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labour, and Welfare of Japan, by the Chemical Biology Project (RIKEN), and by funding from the Special Postdoctoral Researchers Program (to Y. A.). The authors thank the Screening Committee of New Anticancer Agents, which is supported by a Grant-in-Aid for Scientific Research on the Priority Area 'Cancer' from The Ministry of Education, Culture, Sports, Science, and Technology of Japan. We are grateful to Ms. K. Kawai, Dr. Y. Tamura, Dr. S. Takahashi, and Dr. S. Simizu (RIKEN) for suggestions concerning the western blotting and immunoprecipitation experiments. NR 39 TC 12 Z9 12 U1 2 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1347-9032 J9 CANCER SCI JI Cancer Sci. PD SEP PY 2008 VL 99 IS 9 BP 1853 EP 1858 DI 10.1111/j.1349-7006.2008.00890.x PG 6 WC Oncology SC Oncology GA 339VE UT WOS:000258604600023 PM 18637013 ER PT J AU Beuten, J Gelfond, JAL Byrne, JJ Balic, I Crandall, AC Johnson-Pais, TL Thompson, IM Price, DK Leach, RJ AF Beuten, Joke Gelfond, Jonathan A. L. Byrne, John J. Balic, Ivana Crandall, AnaLisa C. Johnson-Pais, Teresa L. Thompson, Ian M. Price, Douglas K. Leach, Robin J. TI CYP1B1 variants are associated with prostate cancer in non-Hispanic and Hispanic Caucasians SO CARCINOGENESIS LA English DT Article ID CYTOCHROME P4501B1 VARIANTS; MESSENGER-RNA; DIFFERENTIAL EXPRESSION; FUNCTIONAL-ANALYSIS; GENE POLYMORPHISM; P450CYP1B1; ESTRADIOL; CDNA; RISK; METABOLISM AB Cytochrome P450 1B1 (CYP1B1) is involved in the activation of many carcinogens and in the metabolism of steroid hormones. We compared allele, genotype and haplotype frequencies of six single-nucleotide polymorphisms (SNPs) within CYP1B1 among non-Hispanic Caucasians (496 cases and 498 controls) and Hispanic Caucasians (153 cases and 240 controls). In the Hispanic Caucasians, the GG genotype for rs1056836 decreased the risk for prostate cancer (PCa) when compared with the CC genotype [odds ratio (OR) = 0.31, P = 0.04, 95% confidence interval (CI) = 0.10-0.96]. Among non-Hispanic Caucasian men with more aggressive PCa, the prevalence of several SNPs (rs2567206, rs2551188, rs2617266, rs10012 and rs1056836) was significantly associated with the disease status. A common C-G-C-C-G-A haplotype for rs2567206-rs2551188-rs2617266-rs10012-rs1056836-rs1800440 showed an inverse association with PCa risk in Hispanic Caucasians (OR = 0.19, P = 0.04, 95% CI = 0.04-0.95) and with aggressive disease status (i.e. Gleason score >= 7) in non-Hispanic Caucasian cases (OR = 0.64, P = 0.008, 95% CI = 0.47-0.89). In the non-Hispanic Caucasian cases, a second major haplotype T-A-T-G-C-A was positively associated with the high-grade disease status (OR = 1.77, P = 0.002, 95% CI = 1.24-2.53). Our findings suggest that genetic polymorphisms in CYP1B1 may modify the risk for PCa and support the role of CYP1B1 as a candidate gene for PCa. C1 [Beuten, Joke; Byrne, John J.; Crandall, AnaLisa C.; Leach, Robin J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. [Gelfond, Jonathan A. L.] Univ Texas Hlth Sci Ctr San Antonio, Dept Epidemiol & Biostat, San Antonio, TX 78229 USA. [Balic, Ivana] Univ Texas Hlth Sci Ctr San Antonio, Dept Psychiat, San Antonio, TX 78229 USA. [Johnson-Pais, Teresa L.; Leach, Robin J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Pediat, San Antonio, TX 78229 USA. [Thompson, Ian M.; Leach, Robin J.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX 78229 USA. [Price, Douglas K.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Leach, RJ (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. EM leach@uthscsa.edu FU San Antonio Cancer Institute; National Cancer Institute [5U01CA086402]; American Cancer Society [TURSG-03-152-01-CCE] FX San Antonio Cancer Institute; Early Detection Research Network of the National Cancer Institute (# 5U01CA086402); American Cancer Society (# TURSG-03-152-01-CCE, 'The Role of Genetic Variation in Prostate Cancer among Hispanics and Blacks'). NR 47 TC 28 Z9 30 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD SEP PY 2008 VL 29 IS 9 BP 1751 EP 1757 DI 10.1093/carcin/bgm300 PG 7 WC Oncology SC Oncology GA 344XS UT WOS:000258961200011 PM 18544568 ER PT J AU Elkouby-Naor, L Abassi, Z Lagziel, A Gow, A Ben-Yosef, T AF Elkouby-Naor, Liron Abassi, Zaid Lagziel, Ayala Gow, Alexander Ben-Yosef, Tamar TI Double gene deletion reveals lack of cooperation between claudin 11 and claudin 14 tight junction proteins SO CELL AND TISSUE RESEARCH LA English DT Article DE tight junction; claudin 11; claudin 14; knockout mouse ID RECESSIVE DEAFNESS DFNB29; OUTER HAIR CELLS; STRIA VASCULARIS; INNER-EAR; DIFFERENTIAL EXPRESSION; MICE; BARRIER; STRANDS; MUTATIONS; TRICELLULIN AB Members of the claudin family of proteins are the main components of tight junctions (TJs), the major selective barrier of the paracellular pathway between epithelial cells. The selectivity and specificity of TJ strands are determined by the type of claudins present. An understanding of the cooperation between different claudins in various tissues is thus important. To study the possible cooperation between claudin 11 and claudin 14, we have generated claudin 11/claudin 14 double-deficient mice, which exhibit a combination of the phenotypes found in each of the singly deficient mutants, including deafness, neurological deficits, and male sterility. These two claudins have distinct and partially overlapping expression patterns in the kidney. Claudin 11 is located in both the proximal and distal convoluted tubules, whereas claudin 14 occurs in both the thin descending and thick ascending limbs of the loop of Henle and in the proximal convoluted tubules. Although daily urinary excretion of Mg(++), and to a lesser extent of Ca(++), tends to be higher in claudin 11/claudin 14 double mutants, these changes do not reach statistical significance compared with wild-type animals. Thus, under normal conditions, co-deletion of claudin 11 and claudin 14 does not affect kidney function or ion balance. Our data demonstrate that, despite the importance of each of these claudins, there is probably no functional cooperation between them. Generation of additional mouse models in which different claudins are abolished should provide further insight into the complex interactions between claudin proteins in various physiological systems. C1 [Ben-Yosef, Tamar] Technion Israel Inst Technol, Rappaport Fac Med, Dept Genet, IL-31096 Haifa, Israel. [Gow, Alexander] Wayne State Univ, Dept Neurol, Carman & Ann Adams Dept Pediat, Ctr Mol Med & Genet, Detroit, MI USA. [Lagziel, Ayala] Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, Natl Inst Hlth, Rockville, MD USA. [Abassi, Zaid] Technion Israel Inst Technol, Fac Med, Rappaport Family Inst Res Med Sci, Dept Physiol & Biophys, Haifa, Israel. [Elkouby-Naor, Liron; Ben-Yosef, Tamar] Technion Israel Inst Technol, Fac Med, Rappaport Family Inst Res Med Sci, Dept Genet, Haifa, Israel. RP Ben-Yosef, T (reprint author), Technion Israel Inst Technol, Rappaport Fac Med, Dept Genet, POB 9649, IL-31096 Haifa, Israel. EM benyosef@tx.technion.ac.il FU Intramural NIH HHS; NIDCD NIH HHS [Z01-DC-00039-11, R01 DC006262-05, Z01 DC000039, R01 DC006262] NR 50 TC 25 Z9 27 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0302-766X J9 CELL TISSUE RES JI Cell Tissue Res. PD SEP PY 2008 VL 333 IS 3 BP 427 EP 438 DI 10.1007/s00441-008-0621-9 PG 12 WC Cell Biology SC Cell Biology GA 338SE UT WOS:000258528200007 PM 18663477 ER PT J AU Kuwano, Y Gorospe, M AF Kuwano, Yuki Gorospe, Myriam TI Protecting the stress response, guarding the MKP-1 mRNA SO CELL CYCLE LA English DT Article DE mRNA-binding protein; ribonucleoprotein complex; mRNA turnover; translational control; ELAV; MAP kinase; ERK; JNK; p38 ID BINDING PROTEIN HUR; KINASE PHOSPHATASE-1; MAP KINASE; TRANSLATIONAL CONTROL; EPITHELIAL-CELLS; EXPRESSION; STABILITY; STABILIZATION; GENE; PHOSPHORYLATION AB The RNA-binding protein (RBP) HuR plays a vital role in the mammalian stress response, effecting changes in the proliferation and survival of damaged cells. HuR prominently influences the stress response by regulating the stability and translation of mRNAs encoding stress-response proteins. Recently, HuR was found to affect mitogen-activated protein kinase (MAPK) signaling, at least in part by post-transcriptionally promoting the expression of MAPK phosphatase-1 (MKP-1). As anticipated for a pivotal regulator of the MAPKs c-jun N-terminal kinase (JNK) and p38, MKP-1 expression is tightly regulated transcriptionally, post-transcriptionally and post-translationally. HuR's influence on MKP-1 expression helps to ensure the appropriate abundance of MKP-1 and consequently the appropriate cellular response to stress stimuli. C1 [Kuwano, Yuki; Gorospe, Myriam] Natl Inst Aging IRP, Cellular & Mol Biol Lab, NIH, Baltimore, MD USA. RP Gorospe, M (reprint author), 251 Bayview Blvd, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov 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. NR 38 TC 14 Z9 16 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD SEP 1 PY 2008 VL 7 IS 17 BP 2640 EP 2642 DI 10.4161/cc.7.17.6534 PG 3 WC Cell Biology SC Cell Biology GA 343CK UT WOS:000258830000007 PM 18728392 ER PT J AU Lee, MY Kim, HJ Kim, MA Jee, HJ Kim, AJ Bae, YS Park, JI Chung, JH Yun, J AF Lee, Min-Young Kim, Hyun-Ju Kim, Myoung-Ae Jee, Hye Jin Kim, Ae Jeong Bae, Yoe-Sik Park, Joo-In Chung, Jay H. Yun, Jeanho TI Nek6 is involved in G(2)/M phase cell cycle arrest through DNA damage-induced phosphorylation SO CELL CYCLE LA English DT Article DE nek6; DNA damage checkpoint; G(2)/M arrest; protein phosphorylation; chk1; chk2 ID NIMA FAMILY KINASES; MURINE KINASES; IDENTIFICATION; CHK1; INHIBITION; EXPRESSION AB Nek6 is a recently identified NIMA-related kinase that is required for mitotic cell cycle progression. In the present study, we examined the role of Nek6 in the DNA damage response. We found that Nek6 is phosphorylated upon IR and UV irradiation through the DNA damage checkpoint in vivo. Nek6 is also directly phosphorylated by the checkpoint kinases Chk1 and Chk2 in vitro. Notably, Nek6 activation during mitosis is completely abolished by IR and UV irradiation. Moreover, the ectopic expression of Nek6 overrides DNA damage-induced G(2)/M arrest. These results suggest that Nek6 is a novel target of the DNA damage checkpoint and that the inhibition of Nek6 activity is required for proper cell cycle arrest in the G(2)/M phase upon DNA damage. C1 [Lee, Min-Young; Kim, Hyun-Ju; Kim, Myoung-Ae; Jee, Hye Jin; Kim, Ae Jeong; Bae, Yoe-Sik; Park, Joo-In; Yun, Jeanho] Dong A Univ, Coll Med, Dept Biochem, Pusan 602714, South Korea. [Chung, Jay H.] NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Yun, J (reprint author), Dong A Univ, Coll Med, Dept Biochem, 3-1 Dongdaesin Dong, Pusan 602714, South Korea. EM yunj@dau.ac.kr FU Korean Government [KRF-2006-331-E00026]; KOSEF (Korea Science and Engineering Foundation) [M1075604000107N560400110] FX We thank to Joseph Avruch for providing Flag-Nek6 plasmid. This work was supported by the Korea Research Foundation Grant funded by the Korean Government (MOEHRD, Basic Research Promotion Fund) (KRF-2006-331-E00026) and Research Program of dual regulation mechanisms of aging and cancer from KOSEF (Korea Science and Engineering Foundation) (M1075604000107N560400110). NR 19 TC 27 Z9 30 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD SEP 1 PY 2008 VL 7 IS 17 BP 2705 EP 2709 DI 10.4161/cc.7.17.6551 PG 5 WC Cell Biology SC Cell Biology GA 343CK UT WOS:000258830000016 PM 18728393 ER PT J AU Lu, SJ Horowits, R AF Lu, Shajia Horowits, Robert TI Role of nonmuscle myosin IIB and N-RAP in cell spreading and myofibril assembly in primary mouse cardiomyocytes SO CELL MOTILITY AND THE CYTOSKELETON LA English DT Article DE myofibrillogenesis; RNA interference; heart; sarcomere ID CULTURED CHICK CARDIOMYOCYTES; NEBULIN-RELATED PROTEIN; TIME QUANTITATIVE PCR; CARDIAC MYOFIBRILLOGENESIS; PRECARDIAC MESODERM; INTERCALATED DISKS; STRIATED-MUSCLE; SKELETAL-MUSCLE; GENE-EXPRESSION; HEART AB We investigated the role of nonmuscle myosin heavy chain (NMHC) IIB in cultured embryonic mouse cardiomyocytes by specific knockdown using RNA interference. NMHC IIB protein levels decreased 90% compared with mock-transfected cells by 3 days post transfection. NMHC IIB knockdown resulted in a slow decrease in N-RAP protein levels over 6 days with no change in N-RAP transcript levels. N-RAP is a scaffold for alpha-actinin and actin assembly during myofibrillogenesis, and we quantitated myofibril accumulation by morphometric analysis of a-actinin organization. Between 3 and 6 days, NMHC IIB knockdown was accompartied by the abolishment of cardiomyocyte spreading. During this period the rate of myofibril accumulation steadily decreased, correlating with the slowly decreasing levels of N-RAP. Between 6 and 8 days NMHC IIB and N-RAP protein levels recovered, and cardiomyocyte spreading and myofibril accumulation resumed. Inhibition of proteasome function using MG132 led to accumulation of excess NRAP, and the secondary decrease in N-RAP that otherwise accompanied NMHC IIB knockdown was abolished. The results show that NMHC IIB knockdown led to decreased N-RAP levels through proteasome-mediated degradation. Furthermore, these proteins have distinct functional roles, with NMHC IIB playing a role in cardiomyocyte spreading and N-RAP functioning in myofibril assembly. C1 [Lu, Shajia; Horowits, Robert] NIAMSD, Natl Inst Hlth, Dept Hlth & Human Serv, Muscle Biol Lab, Bethesda, MD 20892 USA. RP Horowits, R (reprint author), NIAMSD, Natl Inst Hlth, Dept Hlth & Human Serv, Muscle Biol Lab, Bldg 50,Room 1154,MSC 8024, Bethesda, MD 20892 USA. EM horowits@helix.nih.gov FU Intramural Research Program; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institutes of Health FX This research was supported by the Intramural Research Program, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health. NR 47 TC 5 Z9 6 U1 1 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0886-1544 J9 CELL MOTIL CYTOSKEL JI Cell Motil. Cytoskeleton PD SEP PY 2008 VL 65 IS 9 BP 747 EP 761 DI 10.1002/cm.20299 PG 15 WC Cell Biology SC Cell Biology GA 343PZ UT WOS:000258867400005 PM 18615632 ER PT J AU Jong, A Wu, CH Prasadarao, NV Kwon-Chung, KJ Chang, YC Ouyang, Y Shackleford, GM Huang, SH AF Jong, Ambrose Wu, Chun-Hua Prasadarao, Nemani V. Kwon-Chung, Kyung J. Chang, Yun C. Ouyang, Yannan Shackleford, Gregory M. Huang, Sheng-He TI Invasion of Cryptococcus neoformans into human brain microvascular endothelial cells requires protein kinase C-alpha activation SO CELLULAR MICROBIOLOGY LA English DT Article ID CAPSULE-ASSOCIATED GENE; ACTIN CYTOSKELETON; VIRULENCE; BARRIER; LOCALIZATION; ASSOCIATION; INFECTION; DYNAMICS; BIOLOGY; CPS1 AB Pathogenic fungus Cryptococcus neoformans has a predilection for the central nervous system causing devastating meningoencephalitis. Traversal of C. neoformans across the blood-brain barrier (BBB) is a crucial step in the pathogenesis of C. neoformans. Our previous studies have shown that the CPS1 gene is required for C. neoformans adherence to the surface protein CD44 of human brain microvascular endothelial cells (HBMEC), which constitute the BBB. In this report, we demonstrated that C. neoformans invasion of HBMEC was blocked in the presence of G109203X, a protein kinase C (PKC) inhibitor, and by overexpression of a dominant-negative form of PKC alpha in HBMEC. During C. neoformans infection, phosphorylation of PKC alpha was induced and the PKC enzymatic activity was detected in the HBMEC membrane fraction. Our results suggested that the PKC alpha isoform might play a crucial role during C. neoformans invasion. Immunofluorescence microscopic images showed that induced phospho-PKC alpha colocalized with beta-actin on the membrane of HBMEC. In addition, cytochalasin D (an F-filament-disrupting agent) inhibited fungus invasion into HBMEC in a dose-dependent manner. Furthermore, blockage of PKC alpha function attenuated actin filament activity during C. neoformans invasion. These results suggest a significant role of PKC alpha and downstream actin filament activity during the fungal invasion into HBMEC. C1 [Jong, Ambrose; Wu, Chun-Hua; Ouyang, Yannan; Shackleford, Gregory M.] Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA. [Prasadarao, Nemani V.; Huang, Sheng-He] Childrens Hosp Los Angeles, Div Infect Dis, Los Angeles, CA 90027 USA. [Kwon-Chung, Kyung J.; Chang, Yun C.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Jong, A (reprint author), Childrens Hosp Los Angeles, Div Hematol Oncol, Los Angeles, CA 90027 USA. EM ajong@chla.usc.edu FU Intramural NIH HHS [Z01 AI000057-34]; NIAID NIH HHS [R01 AI040635, R01-AI40635]; NINDS NIH HHS [R01 NS047599-04, R01-NS047599, R01 NS047599] NR 31 TC 34 Z9 39 U1 0 U2 1 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD SEP PY 2008 VL 10 IS 9 BP 1854 EP 1865 DI 10.1111/j.1462-5822.2008.01172.x PG 12 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 334DL UT WOS:000258202400010 PM 18489726 ER EF