FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Dinh, BT Price, SE Majul, A El-Hajj, M Morozov, V Hrabie, JA Davies, KM AF Dinh, Bach T. Price, Stacy E. Majul, Amr El-Hajj, Mazen Morozov, Victor Hrabie, Joseph A. Davies, Keith M. TI Diazeniumdiolate reactivity in model membrane systems SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE diazeniumdiolates; nitric oxide; phospholipid liposomes; vesicle catalysis ID RESPIRATORY-DISTRESS-SYNDROME; NITRIC-OXIDE DONOR; PULMONARY-HYPERTENSION; PHOSPHATIDIC-ACID; REACTION-RATES; LUNG INJURY; VESICLES; DISSOCIATION; AGGREGATION; OXYGENATION AB The effect of small unilamellar phospholipid vesicles on the acid-catalyzed dissociation of nitric oxide from diazeniurridiolate ions, (RR2)-R-1 N[N(O)NO](-), [1: R-1 = (HN)-N-2(CH)(2)](3-), R-2 = H2N(CH2)(3)NH(CH2)(4-); 2: R-1 = R-2 = H2N(CH2)(3-); 3: R-1 = n-butyl-, R-2 = n-butyl- NH2+(CH2)(6-); 4: R-1 = R-2 = nPr-] has been examined at pH 7.4 and 37 degrees C. NO release was catalyzed by anionic liposomes (DPPG, DOPG, DMPS, POPS and DOPA) and by mixed phosphatidylglycerol/phosphatidylcholine (DPPG/DPPC and DOPG/DPPC) covesicles, while cationic liposomes derived from 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) and the zwitterionic liposome DMPC did not significantly affect the dissociation rates of the substrates examined. Enhancement of the dissociation rate constant in DPPG liposome media (0.010 M phosphate buffer, pH 7.4, 37 degrees C) at 10 mM phosphoglycerol levels, ranged from 37 for 1 to 1.2 for the anionic diazeniumdiolate 4, while DOPA effected the greatest rate enhancement, achieving 49-fold rate increases with 1 under similar conditions. The observed catalysis decreases with increase in the bulk concentration of electrolytes in the reaction media. Quantitative analysis of catalytic effects has been obtained through the application of pseudo-phase kinetic models and equilibrium binding constants at different liposome interfaces are compared. The stoichiometry of nitric oxide release from I and 2 in DPPG/DPPC liposome media has been obtained through oxyhemoglobin assay. DPPG = 1,2-dipalmitoyl-sn-glycero-3-[phospho-rac-(1-glycerol)], DOPG = 1,2-dioleoyl-sn-glycero-3-[phospho-rac-(1- -glycerol)], DM PS = 1,2-dimyristoyl-sn-glycero-3-[phospho-L-serine], POPS = 1-palmitoyl-2-oleoyl-sn-glycero-3[phospho-L-serine], DOPA = 1,2-dioleoyl-sn-glycero-3-phosphate; DPPC = 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, DMPC 1,2-dimyristoyl-sn-glycero-3-phospliocholine, DOTAP - 1,2-dioleoyl-3-trimetliylammonium-propane. (C) 2007 Elsevier Inc. All rights reserved. C1 [Dinh, Bach T.; Price, Stacy E.; Majul, Amr; El-Hajj, Mazen; Davies, Keith M.] George Mason Univ, Dept Chem & Biochem, Fairfax, VA 22030 USA. [Morozov, Victor] George Mason Univ, Natl Ctr Biodefense & Infect Dis, Manassas, VA USA. [Hrabie, Joseph A.] NCI, SAIC Frederick Inc, Comparat Carcinogenesis Lab, Basic Res Program, Frederick, MD 21702 USA. RP Davies, KM (reprint author), George Mason Univ, Dept Chem & Biochem, 4400 Univ Dr, Fairfax, VA 22030 USA. EM kdavies@gmu.edu FU Intramural NIH HHS; NCI NIH HHS [N01CO12400, N01-CO-12400]; NHLBI NIH HHS [R15 HL078750, R15-HL078750-01, R15 HL078750-01] NR 38 TC 8 Z9 8 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD MAR PY 2008 VL 18 IS 2 BP 113 EP 121 DI 10.1016/j.niox.2007.11.001 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 262ZR UT WOS:000253187900004 PM 18068133 ER PT J AU Liu, W Dahnke, H Jordan, EK Schaeffter, T Frank, JA AF Liu, Wei Dahnke, Hannes Jordan, E. Kay Schaeffter, Tobias Frank, Joseph A. TI In vivo MRI using positive-contrast techniques in detection of cells labeled with superparamagnetic iron oxide nanoparticles SO NMR IN BIOMEDICINE LA English DT Article DE superparamagnetic iron oxide nanoparticles; cell labeling; positive contrast; susceptibility gradient ID STEM-CELLS; PARTICLES; TRACKING AB Positive-contrast techniques are being developed to increase the detection of magnetically labeled cells in tissues. We evaluated a post-processing positive-contrast technique, susceptibility-gradient mapping (SGM), and compared this approach with two pulse sequences, a gradient-compensation-based "White Marker" technique and an off-resonance-based approach, inversion recovery on-resonance water suppression (IRON), for the detection of superparamagnetic iron oxide (SPIO) nanoparticle-labeled C6 glioma cells implanted in the flanks of nude rats. The SGM, White Marker and IRON positive-contrast images were acquired when the labeled C6 glioma tumors were similar to 5 mm, (small), similar to 10 mm (medium) and similar to 20 mm (large) in diameter along the largest dimension to evaluate their sensitivity to the dilution of the SPIO nanoparticles as the tumor cells proliferated. In vivo MRI demonstrated that all three positive-contrast techniques can produce hyperintensities in areas around the labeled flank tumors against a dark background. The number of positive voxels detected around small and medium tumors was significantly greater with the SGM technique than with the White Marker and IRON techniques. For large tumors, the SGM resulted in a similar number of positive voxels to the White Marker technique, and the IRON approach failed to generate positive-contrast images with a 200 Hz suppression band. This study also reveals that hemorrhage appears as hyperintensities on positive-contrast images and may interfere with the detection of SPIO-labeled cells. Published in 2007 by John Wiley & Sons, Ltd. C1 [Liu, Wei] Philips Res Labs, Briarcliff Manor, NY USA. [Dahnke, Hannes; Schaeffter, Tobias] Philips Res Labs, Hamburg, Germany. [Liu, Wei; Jordan, E. Kay; Frank, Joseph A.] NIH, Expt Neuroimaging Sect, Lab Diagnost Radiol Res, Bethesda, MD 20892 USA. RP Liu, W (reprint author), Philips Res N Amer, 345 Scarborough Rd, Briarcliff Manor, NY 10510 USA. EM Wei.liu_1@philips.com; jafrank@helix.nih.gov OI Schaeffter, Tobias/0000-0003-1310-2631 FU Intramural NIH HHS NR 18 TC 53 Z9 55 U1 4 U2 18 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0952-3480 J9 NMR BIOMED JI NMR Biomed. PD MAR PY 2008 VL 21 IS 3 BP 242 EP 250 DI 10.1002/nbm.1187 PG 9 WC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy SC Biophysics; Radiology, Nuclear Medicine & Medical Imaging; Spectroscopy GA 291YP UT WOS:000255233700006 PM 17566968 ER PT J AU Hyun, M Lee, J Lee, K May, A Bohr, VA Ahn, B AF Hyun, Moonjung Lee, Jihyun Lee, Kyungjin May, Alfred Bohr, Vilhelm A. Ahn, Byungchan TI Longevity and resistance to stress correlate with DNA repair capacity in Caenorhabditis elegans SO NUCLEIC ACIDS RESEARCH LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; LIFE-SPAN; C-ELEGANS; OXIDATIVE STRESS; COCKAYNE-SYNDROME; FAMILY-MEMBER; DAMAGE; GENE; DAF-16; GENOME AB DNA repair is an important mechanism by which cells maintain genomic integrity. Decline in DNA repair capacity or defects in repair factors are thought to contribute to premature aging in mammals. The nematode Caenorhabditis elegans is a good model for studying longevity and DNA repair because of key advances in understanding the genetics of aging in this organism. Long-lived C. elegans mutants have been identified and shown to be resistant to oxidizing agents and UV irradiation, suggesting a genetically determined correlation between DNA repair capacity and life span. In this report, gene-specific DNA repair is compared in wild-type C. elegans and stress-resistant C. elegans mutants for the first time. DNA repair capacity is higher in long-lived C. elegans mutants than in wild-type animals. In addition, RNAi knockdown of the nucleotide excision repair gene xpa-1 increased sensitivity to UV and reduced the life span of long-lived C. elegans mutants. These findings support that DNA repair capacity correlates with longevity in C. elegans. C1 [Hyun, Moonjung; Lee, Jihyun; Lee, Kyungjin; Ahn, Byungchan] Univ Ulsan, Dept Life Sci, Ulsan 680749, South Korea. [May, Alfred; Bohr, Vilhelm A.] NIA, Lab Mol Gerontol, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Ahn, B (reprint author), Univ Ulsan, Dept Life Sci, Ulsan 680749, South Korea. EM bbccahn@mail.ulsan.ac.kr FU Intramural NIH HHS NR 53 TC 31 Z9 35 U1 0 U2 4 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 MAR PY 2008 VL 36 IS 4 BP 1380 EP 1389 DI 10.1093/nar/gkm1161 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 272KD UT WOS:000253857400036 PM 18203746 ER PT J AU Beak, JY Kang, HS Kim, YS Jetten, AM AF Beak, Ju Youn Kang, Hong Soon Kim, Yong-Sik Jetten, Anton M. TI Functional analysis of the zinc finger and activation domains of Glis3 and mutant Glis3(NDH1) SO NUCLEIC ACIDS RESEARCH LA English DT Article ID NUCLEAR-LOCALIZATION SIGNAL; MOLECULAR-PROPERTIES; PROTEIN; IDENTIFICATION; IMPORT; GENE; DIFFERENTIATION; TRANSCRIPTION; MUTATIONS; REPRESSOR AB The Kruppel-like zinc finger protein Gli-similar 3 (Glis3) plays a critical role in pancreatic development and has been implicated in a syndrome with neonatal diabetes and hypothyroidism (NDH). In this study, we examine three steps critical in the mechanism of the transcriptional regulation by Glis3: its translocation to the nucleus, DNA binding and transcriptional activity. We demonstrate that the putative bipartite nuclear localization signal is not required, but the tetrahedral configuration of the fourth zinc finger is essential for the nuclear localization of Glis3. We identify (G/C)TGGGGGGT(A/C) as the consensus sequence of the optimal, high-affinity Glis3 DNA-binding site (Glis-BS). All five zinc finger motifs are critical for efficient binding of Glis3 to Glis-BS. We show that Glis3 functions as a potent inducer of (Glis-BS)-dependent transcription and contains a transactivation function at its C-terminus. A mutation in Glis3 observed in NDH1 patients results in a frameshift mutation and a C-terminal truncated Glis3. We demonstrate that this truncation does not effect the nuclear localization but results in the loss of Glis3 transactivating activity. The loss in Glis3 transactivating function may be responsible for the abnormalities observed in NDH1. C1 [Beak, Ju Youn; Kang, Hong Soon; Kim, Yong-Sik; Jetten, Anton M.] NIEHS, Cell Biol Sect, LRB, Div Intramural Res,NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, LRB, Div Intramural Res,NIH, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU Intramural NIH HHS NR 31 TC 25 Z9 28 U1 1 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD MAR PY 2008 VL 36 IS 5 BP 1690 EP 1702 DI 10.1093/nar/gkn009 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278NY UT WOS:000254294800034 PM 18263616 ER PT J AU Irimia, M Roy, SW AF Irimia, Manuel Roy, Scott William TI Spliceosomal introns as tools for genomic and evolutionary analysis SO NUCLEIC ACIDS RESEARCH LA English DT Review ID PARALOGOUS GENE FAMILIES; EUKARYOTIC EVOLUTION; PROCESSED PSEUDOGENES; POSITIVE SELECTION; SYNONYMOUS SITES; MAMMALIAN GENES; EXON STRUCTURE; CODON USAGE; GAIN; RNA AB Over the past 5 years, the availability of dozens of whole genomic sequences from a wide variety of eukaryotic lineages has revealed a very large amount of information about the dynamics of intron loss and gain through eukaryotic history, as well as the evolution of intron sequences. Implicit in these advances is a great deal of information about the structure and evolution of surrounding sequences. Here, we review the wealth of ways in which structures of spliceosomal introns as well as their conservation and change through evolution may be harnessed for evolutionary and genomic analysis. First, we discuss uses of intron length distributions and positions in sequence assembly and annotation, and for improving alignment of homologous regions. Second, we review uses of introns in evolutionary studies, including the utility of introns as indicators of rates of sequence evolution, for inferences about molecular evolution, as signatures of orthology and paralogy, and for estimating rates of nucleotide substitution. We conclude with a discussion of phylogenetic methods utilizing intron sequences and positions. C1 [Roy, Scott William] Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. [Irimia, Manuel] Univ Barcelona, Dept Genet, Barcelona, Spain. RP Roy, SW (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM scottwroy@gmail.com RI Irimia, Manuel/E-3040-2010; OI Irimia, Manuel/0000-0002-2179-2567 NR 115 TC 55 Z9 59 U1 0 U2 7 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 MAR PY 2008 VL 36 IS 5 BP 1703 EP 1712 DI 10.1093/nar/gkn012 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 278NY UT WOS:000254294800035 PM 18263615 ER PT J AU Joshi, BV Melman, A Mackman, RL Jacobson, KA AF Joshi, Bhalchandra V. Melman, Artem Mackman, Richard L. Jacobson, Kenneth A. TI Synthesis of ethyl (1S,2R,3S,4S,5S)-2,3-O-(isopropylidene)-4-hydroxy-bicyclo[3.1.0]hexane-c arboxylate from L-ribose: A versatile chiral synthon for preparation of adenosine and P2 receptor ligands SO NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS LA English DT Article DE G protein-coupled receptor; nucleosides; nucleotides; purines; pyrimidines; iodination ID P2Y(1) RECEPTOR; SUGAR RING; NUCLEOSIDES; AGONISTS; CONFORMATION; DISCRIMINATE; NUCLEOTIDES; POTENCY; ANALOGS; PUCKER AB Substitution of the ribose moiety of various nucleosides and nucleotides with the (N)-methanocarba ring system increases the potency and selectivity as ligands at certain subtypes of adenosine and P2 receptors. We have prepared a key intermediate in the synthesis of these derivatives, ethyl (1S,2R,3S,4S,5S)-Z3-O-(isopropylidene)-4-hydroxybicyclo[3.1.0]hexane-carboxylate (15), starting from L-ribose (8) as a readily available, enantiopure building block. L-ribose was converted to the corresponding 5'-iodo derivative (9), which was cleaved reductively with Zn. Improvements were made in subsequent steps corresponding to a published route to biologically important (N)-methanocarba 5'-uronamido nucleosides, and new steps were added to prepare related 5'-nucleotides. C1 [Joshi, Bhalchandra V.; Melman, Artem; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, NIH, Bioorgan Chem Lab, Bethesda, MD 20892 USA. [Mackman, Richard L.] Gilead Sci Inc, Foster City, CA 94404 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, NIH, Bioorgan Chem Lab, Bldg 8A,Rm B1A-19, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS NR 17 TC 15 Z9 16 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1525-7770 J9 NUCLEOS NUCLEOT NUCL JI Nucleosides Nucleotides Nucleic Acids PD MAR PY 2008 VL 27 IS 3 BP 279 EP 291 DI 10.1080/15257770701845253 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 271SL UT WOS:000253808900005 PM 18260011 ER PT J AU Hakami, R Mohtadinia, J Etemadi, A Kamangar, F Nemati, M Pourshams, A Islami, F Nasrollahzadeh, D Saberi-Firoozi, M Birkett, N Boffetta, P Malekzadeh, R AF Hakami, Roya Mohtadinia, Javad Etemadi, Arash Kamangar, Farin Nemati, Mahboob Pourshams, Akram Islami, Farhad Nasrollahzadeh, Dariush Saberi-Firoozi, Mehdi Birkett, Nicholas Boffetta, Paolo Malekzadeh, Reza TI Dietary intake of benzo(a)pyrene and risk of esophageal cancer in North of Iran SO NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; FOOD; CONTRIBUTE AB One etiologic factor for high incidence of esophageal squamous cell carcinoma (ESCC) in Golestan (Northeastern Iran) might be exposure to polycyclic aromatic hydrocarbons. We examined whether food and water are major sources of benzo(a)pyrene (BaP) exposure in this population. We used a dietary questionnaire to assess the daily intake of staple food (rice and bread) and water in 3 groups: 40 ESCC Golestan cases, 40 healthy subjects from the same area, and 40 healthy subjects from a low-risk area in Southern Iran. We measured, by high-performance liquid chromatography combined with fluorescence detection, the BaP concentration of bread, rice, and water in samples obtained from these 3 groups and calculated the daily intake of BaR Mean BaP concentration of staple foods and water was similar and within standard levels in both areas, but the daily intake of BaP was higher in controls from the high-risk area than in controls from the low-risk area (91.4 vs. 70.6 ng/day, P < 0.01). In the multivariate regression analysis, having ESCC had no independent effect on BaP, whereas residence in the low-risk area was associated with a significant decrease in total BaP intake. Polycyclic aromatic hydrocarbons might, along with other risk factors, contribute to the high risk of ESCC in Golestan. C1 [Hakami, Roya; Etemadi, Arash; Pourshams, Akram; Islami, Farhad; Nasrollahzadeh, Dariush; Malekzadeh, Reza] Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran 14114, Iran. [Hakami, Roya; Mohtadinia, Javad] Tabriz Univ Med Sci, Sch Hlth & Nutr, Tabriz, Iran. [Etemadi, Arash] Univ Tehran Med Sci, Sch Publ Hlth, Tehran, Iran. [Kamangar, Farin] Natl Canc Inst, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD USA. [Nemati, Mahboob] Tabriz Univ Med Sci, Drug Appl Res Ctr, Tabriz, Iran. [Saberi-Firoozi, Mehdi] Shiraz Univ Med Sci, Dept Med, Shiraz, Iran. [Saberi-Firoozi, Mehdi] Shiraz Univ Med Sci, Gastroenterol Res Ctr, Shiraz, Iran. [Birkett, Nicholas] Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON, Canada. [Boffetta, Paolo] Int Agcy Res Canc, Lyon, France. RP Malekzadeh, R (reprint author), Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, N Kargar Ave, Tehran 14114, Iran. EM malek@ams.ac.ir RI Etemadi, Arash/C-1386-2016; OI Etemadi, Arash/0000-0002-3458-1072; Malekzadeh, Reza/0000-0003-1043-3814 NR 20 TC 29 Z9 30 U1 0 U2 2 PU LAWRENCE ERLBAUM ASSOC INC-TAYLOR & FRANCIS PI PHILADELPHIA PA 325 CHESTNUT STREET, STE 800, PHILADELPHIA, PA 19106 USA SN 0163-5581 J9 NUTR CANCER JI Nutr. Cancer PD MAR-APR PY 2008 VL 60 IS 2 BP 216 EP 221 DI 10.1080/01635580701684831 PG 6 WC Oncology; Nutrition & Dietetics SC Oncology; Nutrition & Dietetics GA 287ND UT WOS:000254922900010 PM 18444153 ER PT J AU Pinnick, KE Collins, SC Londos, C Gauguier, D Clark, A Fielding, BA AF Pinnick, Katherine E. Collins, Stephan C. Londos, Constantine Gauguier, Dominique Clark, Anne Fielding, Barbara A. TI Pancreatic ectopic fat is characterized by adipocyte infiltration and altered lipid composition SO OBESITY LA English DT Article ID STIMULATED INSULIN-SECRETION; BETA-CELL; ADIPOSE-TISSUE; GLUCOSE-METABOLISM; DIABETES-MELLITUS; ARACHIDONIC-ACID; RAT; ISLETS; LIPOTOXICITY; EXPOSURE AB Objective: Sustained exposure to lipids is deleterious for pancreatic islet function. This could be mediated through increased pancreatic fat following increased dietary fat and in obesity, which has implications for the onset of type 2 diabetes. The aims of this study were to determine changes in extent and composition of pancreatic, hepatic, and visceral fat in mice fed a high-fat diet (HFD, 40% by weight) compared with a control diet (5% fat) of similar fatty acid composition, and to compare composition and extent of pancreatic fat in human type 2 diabetes. Methods and Procedures: Mice were fed HFD for 3 or 15 weeks. Human postmortem pancreas was examined from subjects with type 2 diabetes (n = 9) and controls (n = 7). Tissue lipid content and composition were determined by gas chromatography and pancreatic adipocyte infiltration quantified by morphometry. Results: Pancreatic triacylglycerol (TG) content was 20 x greater (P < 0.05) in HFD mice and there were more pancreatic perilipin-positive adipocytes compared with controls after 15 weeks. The proportions of 18:1n-9 and 18:2n-6 in pancreatic TG and the 20:4n-6/18:2n-6 ratio in phospholipids, were higher (both P < 0.05) after HFD compared with controls. Human pancreatic TG content was correlated with the proportion of pancreatic perilipin-positive adipocytes (r = 0.64, P < 0.05) and associated with unsaturated fatty acid enrichment (P < 0.05). Discussion: Adipocyte infiltration in pancreatic exocrine tissue is associated with high-fat feeding in mice and pancreatic TG content in humans. This alters the fatty acid milieu of the islet which could contribute to islet dysfunction. C1 [Pinnick, Katherine E.; Collins, Stephan C.; Clark, Anne; Fielding, Barbara A.] Churchill Hosp, Oxford Ctr Diabetes Endocrinol & Metab, Oxford OX3 7LJ, England. [Londos, Constantine] NIH, NIDDK, Bethesda, MD 20892 USA. [Gauguier, Dominique] Wellcom Trust Ctr Human Genet, Oxford, England. RP Fielding, BA (reprint author), Churchill Hosp, Oxford Ctr Diabetes Endocrinol & Metab, Oxford OX3 7LJ, England. EM barbara.fielding@oxlip.ox.ac.uk RI Pinnick, Katherine/B-7209-2012; collins, stephan/P-4409-2016 OI Pinnick, Katherine/0000-0002-2422-248X; collins, stephan/0000-0002-1533-3380 FU Medical Research Council; Wellcome Trust [057733] NR 49 TC 53 Z9 56 U1 1 U2 3 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 MAR PY 2008 VL 16 IS 3 BP 522 EP 530 DI 10.1038/oby.2007.110 PG 9 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 271YA UT WOS:000253823400004 PM 18239594 ER PT J AU Sciscione, AC Landon, MB Leveno, KJ Spong, CY MacPherson, C Varner, MW Rouse, DJ Moawad, AH Caritis, SN Harper, M Sorokin, Y Miodovnik, M Marshall, C Peaceman, AM O'Sullivan, MJ Sibai, BM Langer, O Thorp, JM Ramin, SM Mercer, BM AF Sciscione, Anthony C. Landon, Mark B. Leveno, Kenneth J. Spong, Catherine Y. MacPherson, Cora Varner, Michael W. Rouse, Dwight J. Moawad, Atef H. Caritis, Steve N. Harper, Margaret Sorokin, Yoram Miodovnik, Menachem Marshall, Carpenter Peaceman, Alan M. O'Sullivan, Mary J. Sibai, Baha M. Langer, Oded Thorp, John M. Ramin, Susan M. Mercer, Brian M. CA NICHD MFMU TI Previous preterm cesarean delivery and risk of subsequent uterine rupture SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID INFECTION; TRIAL; BIRTH; LABOR; INTERLEUKIN-6; CYTOKINES; MORBIDITY; INCISIONS; SEGMENT AB OBJECTIVE: To determine if women with a history of a previous preterm cesarean delivery experienced an increased risk of subsequent uterine rupture compared with women who had a previous nonclassic term cesarean delivery. METHODS: A prospective observational study was performed in singleton gestations that had a previous nonclassic cesarean delivery from 1999 to 2002. Women with a history of a previous preterm cesarean delivery were compared with women who had a previous term cesarean delivery. Women who had both a preterm and term cesarean delivery were included in the preterm group. RESULTS: A prior preterm cesarean delivery was significantly associated with an increased risk of subsequent uterine rupture (0.58% compared with 0.28%, P<.001). When women who had a subsequent elective cesarean delivery were removed (remaining n=26,454) women with a previous preterm cesarean delivery were still significantly more likely to sustain a uterine rupture (0.79% compared with 0.46%, P=.001). However, when only women who had a subsequent trial of labor were included, there was still an absolute increased risk of uterine rupture, but it was not statistically significant (1.00% compared with 0.68%, P=.081). in a multivariable analysis controlling for confounding variables (oxytocin use, two or more previous cesarean deliveries, a cesarean delivery within the past 2 years, and preterm delivery in the current pregnancy), patients with a previous preterm cesarean delivery remained at an increased risk of subsequent uterine rupture (P=.043, odds ratio 1.6, 95% confidence interval 1.01-2.50) compared with women with previous term cesarean delivery. CONCLUSION: Women who have had a previous preterm cesarean delivery are at a minimally increased risk for uterine rupture in a subsequent pregnancy when compared with women who have had previous term cesarean deliveries. C1 Ohio State Univ, Columbus, OH 43210 USA. Christiana Care Hlth Syst, Dept Obstet, Newark, DE 19713 USA. Christiana Care Hlth Syst, Dept Gynecol, Newark, DE 19713 USA. Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. NICHHD, Bethesda, MD 20892 USA. George Washington Univ, Ctr Biostat, Washington, DC USA. Univ Utah, Salt Lake City, UT USA. Univ Alabama, Birmingham, AL USA. Univ Chicago, Chicago, IL 60637 USA. Univ Pittsburgh, Pittsburgh, PA USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Wayne State Univ, Detroit, MI USA. Univ Cincinnati, Cincinnati, OH USA. Columbia Univ, New York, NY USA. Brown Univ, Providence, RI 02912 USA. Northwestern Univ, Chicago, IL 60611 USA. Univ Miami, Miami, FL 33152 USA. Univ Tennessee, Memphis, TN USA. Univ Texas San Antonio, San Antonio, TX USA. Univ N Carolina, Chapel Hill, NC USA. Univ Texas Houston, Houston, TX USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Sciscione, AC (reprint author), Christiana Care Hlth Syst, Dept Mat Fetal Med, 4755 Ogletown Stanton Rd,Suite 1905, Newark, DE 19713 USA. EM asciscione@christianacare.org RI Varner, Michael/K-9890-2013; OI caritis, steve/0000-0002-2169-0712; Varner, Michael/0000-0001-9455-3973; Peaceman, Alan/0000-0002-4515-4850 FU NICHD NIH HHS [HD21414, HD21410, HD27860, HD27861, HD27869, HD27905, HD27915, HD27917, HD34116, HD34122, HD34136, HD34208, HD34210, HD36801, HD40485, HD40500, HD40512, HD40544, HD40545, HD40560, U10 HD040544] NR 21 TC 25 Z9 27 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 MAR PY 2008 VL 111 IS 3 BP 648 EP 653 DI 10.1097/AOG.0b013e318163cd3e PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 270RW UT WOS:000253738900009 PM 18310367 ER PT J AU Mahadevan, R Yan, B Postier, B Nevin, KP Woodard, TL O'Neil, R Coppi, MV Methe, BA Krushkal, J AF Mahadevan, Radhakrishnan Yan, Bin Postier, Brad Nevin, Kelly P. Woodard, Trevor L. O'Neil, Regina Coppi, Maddalena V. Methe, Barbara A. Krushkal, Julia TI Characterizing regulation of metabolism in Geobacter sulfurreducens through genome-wide expression data and sequence analysis SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Article ID ESCHERICHIA-COLI K-12; SINGULAR-VALUE DECOMPOSITION; ENGINEERING GENE NETWORKS; FACTOR-BINDING SITES; FE(III) REDUCTION; MESSENGER-RNA; TRANSCRIPTIONAL REGULATION; SACCHAROMYCES-CEREVISIAE; REDUCING MICROORGANISMS; MICROARRAY DATA AB Geobacteraceae are a family of metal reducing bacteria with important applications in bioremediation and electricity generation. G. sulfurreducens is a representative of Geobacteraceae that has been extensively studied with the goal of extending the understanding of this family of organisms for optimizing their practical applications. Here, we have analyzed gene expression data from 10 experiments involving environmental and genetic perturbations and have identified putative transcription factor binding sites (TFBS) involved in regulating key aspects of metabolism. Specifically, we considered data from both a subset of 10 microarray experiments (7 of 10) and all 10 experiments. The expression data from these two sets were independently clustered, and the upstream regions of genes and operons from the clusters in both sets were used to identify TFBS using the AlignACE program. This analysis resulted in the identification of motifs upstream of several genes involved in central metabolism, sulfate assimilation, and energy metabolism, as well as genes potentially encoding acetate permease. Further, similar TFBS were identified from the analysis of both sets, suggesting that these TFBS are significant in the regulation of metabolism in G. sulfurreducens. In addition, we have utilized microarray data to derive condition specific constraints on the capacity of key enzymes in central metabolism. We have incorporated these constraints into the metabolic model of G. sulfurreducens and simulated Fe(II)-limited growth. The resulting prediction was consistent with data, suggesting that regulatory constraints are important for simulating growth phenotypes in nonoptimal environments. C1 [Mahadevan, Radhakrishnan] Univ Toronto, Dept Chem Engn & Appl Chem, Inst Biomat & Biomed Engn, Toronto, ON, Canada. [Yan, Bin; Krushkal, Julia] Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. [Mahadevan, Radhakrishnan; Postier, Brad; Nevin, Kelly P.; Woodard, Trevor L.; O'Neil, Regina; Coppi, Maddalena V.] Univ Massachusetts, Dept Microbiol, Amherst, MA 01003 USA. [Methe, Barbara A.] Inst Genom Res, Rockville, MD USA. RP Mahadevan, R (reprint author), NIDCD, NIH, Bldg 10,Magnuson CC,Room 5D55,10 Ctr Dr, Bethesda, MD 20892 USA. RI Mahadevan, Radhakrishnan/A-8502-2008 OI Mahadevan, Radhakrishnan/0000-0002-1270-9063 NR 78 TC 16 Z9 16 U1 0 U2 3 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1536-2310 J9 OMICS JI OMICS PD MAR PY 2008 VL 12 IS 1 BP 33 EP + DI 10.1089/omi.2007.0043 PG 27 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 275JD UT WOS:000254066800003 PM 18266557 ER PT J AU Martin, D Galisteo, R Ji, Y Montaner, S Gutkind, JS AF Martin, D. Galisteo, R. Ji, Y. Montaner, S. Gutkind, J. S. TI An NF-kappa B gene expression signature contributes to Kaposi's sarcoma virus vGPCR-induced direct and paracrine neoplasia SO ONCOGENE LA English DT Article DE G proteins; signal transduction; G protein coupled receptors; angiosarcoma; endothelial cell; angiogenesis ID PROTEIN-COUPLED-RECEPTOR; LYMPHOMA-CELLS; HERPESVIRUS; CANCER; ANGIOGENESIS; INFECTION; CYTOKINES; SURVIVAL; PROMOTE; DEATH AB Kaposi's sarcoma (KS) is the most frequent AIDS-associated malignancy, etiologically linked to the infection with the human herpesvirus 8 (HHV-8/KSHV). This member of the gamma-herpesviridae family encodes 81 open reading frames, several bearing oncogenic potential. A constitutively active virally encoded G protein-coupled receptor (vGPCR) readily induces KS-like lesions when expressed in endothelial cells in vivo, and unmasks the oncogenic potential of other HHV-8 genes in a paracrine fashion. How vGPCR causes endothelial cell transformation is still not fully understood. Using full-genome microarray analysis we show here that the expression of nuclear factor-kappa B (NF-kappa B)regulated genes is a prominent feature triggered by vGPCR in cells expressing this viral oncogene and in cells exposed to vGPCR-induced secretions, thus mimicking its paracrine effect. Indeed, vGPCR activates the NF-kappa B pathway potently, and NF-kappa B activation is a hallmark of both human and experimental KS. Of interest, whereas constitutive NF-kappa B signaling is not sufficient to promote endothelial cells transformation, NF-kappa B function is strictly required for vGPCR-induced direct and paracrine neoplasia. Taken together, these results strongly support the role of NF-kappa B regulated genes in KS pathogenesis, thus providing the rationale for the development of novel mechanism-based therapies for this angioproliferative disease. C1 [Martin, D.; Galisteo, R.; Gutkind, J. S.] Natl Inst Dent & Craniofacial Res, NIH, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. [Ji, Y.; Montaner, S.] Univ Maryland, Dept Diagnost Sci & Pathol, Baltimore, MD 21201 USA. [Ji, Y.; Montaner, S.] Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Oral & Pharyngeal Canc Branch, 30 Convent Dr,Bldg 30,Room 211, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009 FU Intramural NIH HHS NR 27 TC 55 Z9 57 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 MAR PY 2008 VL 27 IS 13 BP 1844 EP 1852 DI 10.1038/sj.onc.1210817 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 276NZ UT WOS:000254150600004 PM 17934524 ER PT J AU Vikram, B AF Vikram, Bhadrasain TI Treating prostate cancer: Costs and benefits SO ONCOLOGY-NEW YORK LA English DT Letter ID RANDOMIZED CONTROLLED-TRIAL; RADIATION-THERAPY; ANDROGEN SUPPRESSION; LOCALIZED ADENOCARCINOMA; CONFORMAL PROTONS; RADIOTHERAPY; DEPRIVATION; IRRADIATION; PHOTONS C1 NCI, Clin Radiat Oncol Branch, Bethesda, MD 20892 USA. RP Vikram, B (reprint author), NCI, Clin Radiat Oncol Branch, Bethesda, MD 20892 USA. NR 17 TC 0 Z9 0 U1 0 U2 0 PU UBM MEDICA PI NORWALK PA 535 CONNECTICUT AVE, STE 300, NORWALK, CT 06854 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD MAR PY 2008 VL 22 IS 3 BP 254 EP + PG 2 WC Oncology SC Oncology GA 333SG UT WOS:000258172000001 PM 18494353 ER PT J AU Kirk, KL AF Kirk, Kenneth L. TI Fluorination in medicinal chemistry: Methods, strategies, and recent developments SO ORGANIC PROCESS RESEARCH & DEVELOPMENT LA English DT Review ID CATALYTIC ENANTIOSELECTIVE FLUORINATION; ORGANOCATALYTIC ALPHA-FLUORINATION; FLUOROPYRIDINIUM SALT SYSTEM; SOLID-PHASE SYNTHESIS; ELECTROPHILIC FLUORINATION; ACETYL HYPOFLUORITE; ELEMENTAL FLUORINE; CARBONYL-COMPOUNDS; ORGANIC-SYNTHESIS; BETA-KETOESTERS AB Methods for introducing fluorine into organic molecules are reviewed, with an emphasis on preparation of compounds designed for biomedicinal applications. Electrophilic fluorination, nucleophilic fluorination, and enantioselective monofluorination procedures are discussed. This is followed by a review of the development of nucleophilic and electrophilic trifluoromethylation procedures. The final sections highlight recent applications of fluorine chemistry in drug development with selected examples. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Kirk, KL (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NR 114 TC 611 Z9 616 U1 20 U2 204 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1083-6160 EI 1520-586X J9 ORG PROCESS RES DEV JI Org. Process Res. Dev. PD MAR-APR PY 2008 VL 12 IS 2 BP 305 EP 321 DI 10.1021/op700134j PG 17 WC Chemistry, Applied; Chemistry, Organic SC Chemistry GA 280EP UT WOS:000254408400026 ER PT J AU Umehara, A Kawakami, Y Araki, J Uchida, A AF Umehara, Azusa Kawakami, Yasushi Araki, Jun Uchida, Akhiko TI Multiplex PCR for the identification of Anisakis simplex sensu stricto, Anisakis pegreffii and the other anisakid nematodes SO PARASITOLOGY INTERNATIONAL LA English DT Article DE Anisakis; Pseudoterranova; Contracaecum; Hysterothylacium; multiplex; polymerase chain reaction ID RIBOSOMAL DNA-SEQUENCES; MOLECULAR CHARACTERIZATION; SPECIES NEMATODA; MARINE; FISH; ASCARIDOIDEA; MAMMALS; COMPLEX; WATERS; REGION AB A multiplex PCR method was established for the rapid identification of Anisakis simplex sensu stricto, A. pegreffii, A. physeteris, Pseudoterranova decipiens, Contracaecum osculatum and Hysterothylacium aduncum. The sequence alignment of the internal transcribed spacer 1 region (ITS-1) between A. simplex s. str. and A. pegreffii showed a high degree of similarity, but only two C-T transitions were observed. To differentiate A. simplex s. str. from A. pegreffii, an intentional mismatch primer with an artificial mismatched base at the second base from the primer 3' end was constructed. This intentional mismatch primer, which produced a PCR band only from A. pegreffii DNA, was able to differentiate the two morphologically indistinguishable sibling species of A. simplex. Specific forward primers for other anisakid species were also designed based on the nucleotide sequences of the ITS region. The multiplex PCR using these primers yielded distinct PCR products for each of the anisakid nematodes. The multiplex PCR established in this study would be a useful tool for identifying anisakid nematodes rapidly and accurately. (C) 2007 Elsevier Ireland Ltd. All rights reserved. C1 [Umehara, Azusa] NIAID, Dept Parasitol, Shinjuku Ku, Tokyo 1628640, Japan. [Umehara, Azusa; Kawakami, Yasushi; Uchida, Akhiko] Azabu Univ, Coll Environm Hlth, Lab Med Zool, Kanagawa 2298501, Japan. [Araki, Jun] Meguro Parasitol Museum, Meguro Ku, Tokyo 1530064, Japan. RP Umehara, A (reprint author), NIAID, Dept Parasitol, Shinjuku Ku, 1-23-1 Toyama, Tokyo 1628640, Japan. EM umeazu@nih.go.jp NR 24 TC 40 Z9 45 U1 2 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1383-5769 J9 PARASITOL INT JI Parasitol. Int. PD MAR PY 2008 VL 57 IS 1 BP 49 EP 53 DI 10.1016/j.parint.2007.08.003 PG 5 WC Parasitology SC Parasitology GA 253GL UT WOS:000252506600007 PM 17962067 ER PT J AU Arora, NK AF Arora, Neeraj K. TI Advancing research on patient-centered cancer communication SO PATIENT EDUCATION AND COUNSELING LA English DT Editorial Material C1 NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Arora, NK (reprint author), NCI, Outcomes Res Branch, Appl Res Program, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7344,Exectuu Plaza N 4005, Bethesda, MD 20892 USA. EM aroran@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 3 TC 6 Z9 6 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0738-3991 J9 PATIENT EDUC COUNS JI Patient Educ. Couns. PD MAR PY 2008 VL 70 IS 3 BP 301 EP 302 DI 10.1016/j.pec.2008.01.001 PG 2 WC Public, Environmental & Occupational Health; Social Sciences, Interdisciplinary SC Public, Environmental & Occupational Health; Social Sciences - Other Topics GA 279SB UT WOS:000254373800001 PM 18242936 ER PT J AU Maris, JM Courtright, J Houghton, PJ Morton, CL Gorlick, R Kolb, EA Lock, R Tajbakhsh, M Reynolds, CP Keir, ST Wu, JR Smith, MA AF Maris, John M. Courtright, Joshua Houghton, Peter J. Morton, Christopher L. Gorlick, Richard Kolb, E. Anders Lock, Richard Tajbakhsh, Mayamin Reynolds, C. Patrick Keir, Stephen T. Wu, Jianrong Smith, Malcolm A. TI Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program SO PEDIATRIC BLOOD & CANCER LA English DT Article DE AZD2171; developmental therapeutics; preclinical testing ID ACUTE LYMPHOBLASTIC-LEUKEMIA; ENDOTHELIAL GROWTH-FACTOR; ANTIANGIOGENIC THERAPY; HUMAN NEUROBLASTOMA; TUMOR ANGIOGENESIS; CANCER MODELS; IN-VIVO; CHEMOTHERAPY; DORMANCY; POTENT AB Background. Inhibition of vascular endothelial growth factor mediated signaling shows promise as an antiangiogenic strategy for solid tumors. AZD2171 is a potent and relatively selective inhibitor of the vascular endothelial growth factor (VEGF) receptor family that is orally bioavailable. This Study was designed to screen for antitumor activity of AZD2171 against the in vitro and in vivo childhood cancer preclinical models of the Pediatric Preclinical Testing Program (PPTP). Procedures. AZD2171 was tested at concentrations from 0.1 nM to 1.0 mu M against the in vitro panel and was tested against the in Vivo tumor panels using a 6-week exposure to daily gavage administration of AZD2171 (3 or 6 mg/kg) or vehicle. Results. One of 22 cell lines evaluated was sensitive to AZD2171 in vitro (maximum concentration 1 mu M). Evidence of in vivo antitumor activity (primarily turner growth delay) was observed in 78% of solid tumor xenografts (3/3 rhabdoid, 2/3 Wilms', 3/3 Ewing's, 5/5 rhabdomyosarcoma, 1/3 medulloblastoma, 2/4 glioblastoma, 5/6 neuroblastoma, 4/5 osteosarcoma). Objective responses (both complete responses) were observed in two of 32 (6%) solid tumor xenografts (a rhabdoid xenograft and an osteosarcoma xenograft). No activity was observed against 7 acute lymphoblastic leukemia models. Conclusions. AZD2171 demonstrated broad tumor growth inhibition against the PPTP's solid tumor xenografts and much less commonly induced tumor regression. This pattern of in vivo activity, combined with the disassociation of in vitro and in vivo efficacy, are consistent with AZD2171 inhibiting growth of the PPTP's solid tumor xenografts primarily through an anti-angiogenesis mechanism of action. C1 [Maris, John M.; Courtright, Joshua] Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. [Houghton, Peter J.; Morton, Christopher L.; Wu, Jianrong] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Lock, Richard; Tajbakhsh, Mayamin] Childrens Canc Inst Australia Med Res, Randwick, NSW, Australia. [Reynolds, C. Patrick] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Maris, John M.; Courtright, Joshua] Abramson Family Canc Res Inst, Philadelphia, PA USA. [Keir, Stephen T.] Duke Univ, Med Ctr, Durham, NC USA. [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Maris, JM (reprint author), Univ Penn, Childrens Hosp Philadelphia, Sch Med, Philadelphia, PA 19104 USA. EM maris@chop.edu RI Houghton, Peter/E-3265-2011; Lock, Richard/G-4253-2013; OI Reynolds, C. Patrick/0000-0002-2827-8536 FU NCI NIH HHS [N01-CM-42216] NR 26 TC 76 Z9 80 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAR PY 2008 VL 50 IS 3 BP 581 EP 587 DI 10.1002/pbc.21232 PG 7 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 254LE UT WOS:000252587300013 PM 17457854 ER PT J AU Smith, MA Morton, CL Phelps, D Girtman, K Neale, G Houghton, PJ AF Smith, Malcolm A. Morton, Christopher L. Phelps, Doris Girtman, Kevin Neale, Geoffrey Houghton, Peter J. TI SK-NEP-1 and Rhl are Ewing family tumor lines SO PEDIATRIC BLOOD & CANCER LA English DT Article DE developmental therapeutics; Ewing tumors; preclinical testing; Wilms tumor ID PRIMITIVE NEUROECTODERMAL TUMOR; WILMS-TUMOR; CELL-LINES; RHABDOMYOSARCOMA CELLS; INDUCED APOPTOSIS; DISTINCT ENTITY; KIDNEY; GROWTH; EXPRESSION; INHIBITION AB The utility of preclinical models of childhood cancers is contingent upon reliably classifying them with their corresponding clinical Counterparts. Molecular tools such as gene expression profiling allow researchers to confirm the similarity between clinical tumors and preclinical models. We describe the use of gene expression profiling to show that SK-NEP-1, a cell line previously thought to represent anaplastic Wilms tumor, is instead related to Ewing sarcoma. RT-PCR confirmed that SK-NEP-1 expresses EWSFL1 gene fusion transcripts characteristic of Ewing sarcoma, and DNA sequencing demonstrated the joining of exon 7 of EWS with exon 5 of FLI1 for these transcripts. Rh1, which was previously categorized as an alveolar rhabdomyosarcoma cell line, also has a gene expression profile Suggestive of Ewing sarcoma and expresses EWS-FLI1 fusion transcripts in which exon 7 of EWS is joined with exon 6 of FLI1. These examples illustrate the importance of molecularly characterizing pediatric preclinical models used for testing new agents. C1 [Smith, Malcolm A.] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. [Morton, Christopher L.; Phelps, Doris; Girtman, Kevin; Neale, Geoffrey; Houghton, Peter J.] St Jude Childrens Hosp, Memphis, TN 38105 USA. RP Smith, MA (reprint author), NCI, Canc Therapy Evaluat Program, 6130 Execut Blvd,Room 7025, Bethesda, MD 20892 USA. EM smithm@ctep.nci.nih.gov RI Houghton, Peter/E-3265-2011 FU NCI NIH HHS [N01CM42216] NR 29 TC 35 Z9 36 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD MAR PY 2008 VL 50 IS 3 BP 703 EP 706 DI 10.1002/pbc.21099 PG 4 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 254LE UT WOS:000252587300052 PM 17154184 ER PT J AU Onyekwere, OC Campbell, A Teshome, M Onyeagoro, S Sylvan, C Akintilo, A Hutchinson, S Ensing, G Gaskin, P Kato, G Rana, S Kwagyan, J Gordeuk, V Williams, J Castro, O AF Onyekwere, O. C. Campbell, A. Teshome, M. Onyeagoro, S. Sylvan, C. Akintilo, A. Hutchinson, S. Ensing, G. Gaskin, P. Kato, G. Rana, S. Kwagyan, J. Gordeuk, V. Williams, J. Castro, O. TI Pulmonary hypertension in children and adolescents with sickle cell disease SO PEDIATRIC CARDIOLOGY LA English DT Article DE hemolysis; pulmonary disease; sickle cell disease; tricuspid valve regurgitation ID CHRONIC LUNG-DISEASE; COR-PULMONALE; DEATH; RISK; PATHOGENESIS; INSIGHTS; ANEMIA; HEART AB The prevalence of pulmonary hypertension (PHTN) in the pediatric sickle cell disease (SCD) population is not known despite its high prevalence in adult patients. Our hypothesis was that increased pulmonary artery pressures (PAPs) would be found in SCD children and adolescents, especially those with a history of pulmonary complications: acute chest syndrome, obstructive sleep apnea, asthma, and reactive airway disease. Fifty-two SCD children, 23 of whom had underlying pulmonary disease, were screened for PHTN, which was defined as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/s. Twenty-four (46.15%) SCD patients had increased PAP (i.e., TRV >= 2.5 m/s), and 6 (11.5%) had significant PHTN (i.e., TRV >= 3.0 m/s). Pulmonary disease was marginally associated with PHTN (odds ratio 2.80 and confidence interval 0.88 to 8.86; p = 0.0795). As in adult SCD patients with PHTN, this complication was correlated with the degree of hemolysis as manifested by significantly higher lactate dehydrogenase and bilirubin, lower hemoglobin and hematocrit levels, and a strong association with Hb-SS phenotype. However, after statistical adjustment for age and sex, increased serum LDH was not associated with the development of PHTN. Further studies are needed to clarify the prevalence and mechanisms of PHTN in pediatric and adolescent patients with SCD. C1 [Onyekwere, O. C.; Onyeagoro, S.; Sylvan, C.; Akintilo, A.; Gordeuk, V.; Castro, O.] Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. [Kwagyan, J.; Gordeuk, V.] Howard Univ, Gen Clin Res Ctr, Washington, DC 20059 USA. [Campbell, A.; Teshome, M.; Hutchinson, S.; Ensing, G.; Williams, J.] Univ Michigan, Ctr Sickle Cell Dis, Ann Arbor, MI 48109 USA. [Gaskin, P.] Univ Maryland, Baltimore, MD 21201 USA. [Kato, G.] NHLBI, Vasc Therapeut Sect, Bethesda, MD 20892 USA. [Kato, G.] NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Onyekwere, OC (reprint author), Howard Univ, Ctr Sickle Cell Dis, Washington, DC 20059 USA. EM oonyekwere@howard.edu RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [ZIA HL006014-01, ZIA HL006014-02] NR 19 TC 46 Z9 48 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0172-0643 J9 PEDIATR CARDIOL JI Pediatr. Cardiol. PD MAR PY 2008 VL 29 IS 2 BP 309 EP 312 DI 10.1007/s00246-007-9018-x PG 4 WC Cardiac & Cardiovascular Systems; Pediatrics SC Cardiovascular System & Cardiology; Pediatrics GA 274IO UT WOS:000253995200010 PM 17680298 ER PT J AU Chasela, C Chen, YQ Fiscus, S Hoffman, I Young, A Valentine, M Emel, L Taha, TE Goldenberg, RL Read, JS AF Chasela, Charles Chen, Ying Qing Fiscus, Susan Hoffman, Irving Young, Alicia Valentine, Megan Emel, Lynda Taha, Taha E. Goldenberg, Robert L. Read, Jennifer S. TI Risk factors for late postnatal transmission of human immunodeficiency virus type 1 in sub-Saharan Africa SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE breast-feeding; mother-to-child transmission of HIV-1; risk factors; sub-Saharan Africa ID MOTHER-TO-CHILD; PERINATAL HIV-1 TRANSMISSION; BREAST-MILK; METAANALYSIS; ZIDOVUDINE; TRIAL AB Background: We conducted secondary data analyses of a clinical trial (HIVNET 024) to assess risk factors for late postnatal transmission (LPT) of human immunodeficiency virus type 1 (HIV-1) through breast-feeding. Methods: Data regarding live born, singleton infants of HIV-1infected mothers were analyzed. The timing of HIV-1 transmission through 12 months after birth was defined as: in utero (positive HIV-1 RNA results at birth), perinatal/early postnatal (negative results at birth, positive at 4-6 week visit), or LPT (negative results through the 4-6 week visit, but positive assays thereafter through the 12-month visit). HIV-1-uninfected infants were those with negative HIV-1 enzyme immunoassay results at 12 months of age, or infants with negative HIV-1 RNA results throughout follow-up. Results: Of 2292 HIV-1-infected enrolled women, 2052 mother/ infant pairs met inclusion criteria. Of 1979 infants with HIV- I tests, 404 were HIV-1-infected, and 382 had known timing of infection (LPT represented 22% of transmissions). Further analyses of LPT included infants who were breast-feeding at the 4-6 week visit (with negative HIV-1 results at that visit) revealed 6.9% of 1317 infants acquired HIV-1 infection through LPT by 12 months of age. More advanced maternal HIV-1 disease at enrollment (lower CD4(+) counts, higher plasma viral loads) were the factors associated with LPT in adjusted analyses. Conclusions: In this breast-feeding population, 6.9% of infants uninfected at 6 weeks of age acquired HIV-1 infection by 12 months. Making interventions to decrease the risk of LPT of HIV-1 available and continuing research regarding the mechanisms of LPT (so as to develop improved interventions to reduce such transmission) remain essential. C1 [Chasela, Charles] Univ N Carolina UNC Project, Tidziew Ctr, Kamuzu Cent Hosp, Lilongwe, Malawi. [Chen, Ying Qing; Young, Alicia; Emel, Lynda] Fred Hutchinson Canc Res Ctr, SCHARP, Seattle, WA 98104 USA. [Fiscus, Susan; Hoffman, Irving] Univ N Carolina, Chapel Hill, NC USA. [Valentine, Megan] Family Hlth Int, Durham, NC USA. [Taha, Taha E.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. [Goldenberg, Robert L.] Drexel Coll Med, Dept Obstet & Gynecol, Philadelphia, PA USA. [Read, Jennifer S.] NICHD, NIH, DHHS, CRMC,Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. RP Chasela, C (reprint author), Univ N Carolina UNC Project, Tidziew Ctr, Kamuzu Cent Hosp, Private Bag A-104, Lilongwe, Malawi. EM charles.chasea@ucd.ie FU NIAID NIH HHS [N01 AI035173, N01 AI045200, N01-AI-35173-117/412, P30 AI-50410, P30 AI050410, U01 AI047972, U01 AI048005, U01 AI048006, U01 AI068619, U01 AI068619-03, U01-AI-47972, U01-AI-48005, U01-AI-48006] NR 17 TC 14 Z9 14 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD MAR PY 2008 VL 27 IS 3 BP 251 EP 256 DI 10.1097/INF.0b013e31815b4960 PG 6 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 269PN UT WOS:000253661500011 PM 18277935 ER PT J AU Rau, R Fitzhugh, CD Baird, K Cortez, KJ Li, L Fischer, SH Cowen, EW Balow, JE Walsh, TJ Cohen, JI Wayne, AS AF Rau, Rachel Fitzhugh, Courtney D. Baird, Kristin Cortez, Karroll J. Li, Li Fischer, Steven H. Cowen, Edward W. Balow, James E. Walsh, Thomas J. Cohen, Jeffrey I. Wayne, Alan S. TI Triad of severe abdominal pain, inappropriate antidiuretic hormone secretion, and disseminated varicella-zoster virus infection preceding cutaneous manifestations after hematopoietic stem cell transplantation - Utility of PCR for early recognition and therapy SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE varicella zoster virus infection; immunocompromised host; hematopoietic stem cell transplantation; syndrome of inappropriate diuretic hormone; abdominal pain ID BONE-MARROW-TRANSPLANTATION; HERPES-ZOSTER; VISCERAL VARICELLA; RISK-FACTORS; MYELOID-LEUKEMIA; DIAGNOSIS; PATIENT; CHILDREN AB A hematopoietic stem cell transplant recipient developed abdominal pain, pneumatosis intestinalis, hepatitis, pancreatitis, and inappropriate antidiuretic hormone secretion. Blood for varicella-zoster virus (VZV) DNA polymerase chain reaction was positive. She was treated with acyclovir and subsequently developed VZV antigen-positive zoster. Detection of VZV DNA in blood may be useful for early diagnosis in immunocompromised hosts who present with zoster without skin lesions. C1 [Rau, Rachel; Fitzhugh, Courtney D.; Baird, Kristin; Cortez, Karroll J.; Walsh, Thomas J.; Wayne, Alan S.] NCI, NIH, Ctr Canc Res, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Li, Li; Fischer, Steven H.] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Cowen, Edward W.] NCI, NIH, Canc Res Ctr, Dermatol Branch, Bethesda, MD 20892 USA. [Balow, James E.] NIDDKD, NIH, Kidney Dis Branch, Bethesda, MD 20892 USA. [Cohen, Jeffrey I.] NIAID, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Wayne, AS (reprint author), NCI, NIH, Ctr Canc Res, Pediat Oncol Branch, Bldg 10,Room 1W-3750,9000 Rockville Pike,MSC-1104, Bethesda, MD 20892 USA. EM waynea@mail.nih.gov OI Rau, Rachel/0000-0003-4096-6603 FU Intramural NIH HHS NR 17 TC 13 Z9 13 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD MAR PY 2008 VL 27 IS 3 BP 265 EP 268 DI 10.1097/INF.0b013e31815cb239 PG 4 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 269PN UT WOS:000253661500014 PM 18277922 ER PT J AU Marsh, RA Lucky, AW Walsh, TJ Pacheco, MC Rinaldi, MG Mailler-Savage, E Puel, A Casanova, JL Bleesing, JJ Filippi, MD Williams, DA Daines, MO Filipovich, AH AF Marsh, Rebecca A. Lucky, Anne W. Walsh, Thomas J. Pacheco, M. Cristina Rinaldi, Michael G. Mailler-Savage, Erica Puel, Anne Casanova, Jean-Laurent Bleesing, Jack J. Filippi, Marie-Dominique Williams, David A. Daines, Michael O. Filipovich, Alexandra H. TI Cutaneous infection with Metarhizium anisopliae in a patient with hypohidrotic ectodermal dysplasia and immune deficiency SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Letter ID METARRHIZIUM-ANISOPLIAE C1 [Marsh, Rebecca A.; Bleesing, Jack J.; Filipovich, Alexandra H.] Cincinnati Childrens Hosp, Div Hematol Oncol, Med Ctr, Cincinnati, OH USA. [Lucky, Anne W.] Cincinnati Childrens Hosp, Med Ctr, Div Dermatol, Cincinnati, OH USA. [Walsh, Thomas J.] NCI, Pediat Oncol Branch, Immunocompromised Host Sect, Bethesda, MD 20892 USA. [Pacheco, M. Cristina] Childrens Hosp, Minneapolis, MN USA. [Pacheco, M. Cristina] Clin Minnesota, Minneapolis, MN USA. [Rinaldi, Michael G.] Univ Texas Hlth Sci Ctr San Antonio, Audie L Murphy Mem Vet Hosp, Lab Serv, San Antonio, TX 78229 USA. [Mailler-Savage, Erica] Univ Cincinnati, Dept Dermatol, Cincinnati, OH USA. [Puel, Anne] Univ Paris 05, INSERM, Lab Human Genet Infect Dis, Necker Med Sch, Paris, France. [Casanova, Jean-Laurent] Univ Paris 05, INSERM, Lab Human Genet Infect Dis & Pediat Hematol Immun, Necker Med Sch, Paris, France. [Filippi, Marie-Dominique; Williams, David A.] Cincinnati Childrens Hosp, Med Ctr, Cincinnati Childrens Res Fdn, Div Expt Hematol, Cincinnati, OH USA. [Daines, Michael O.] Univ Arizona, Med Ctr, Dept Pediat, Tucson, AZ 85721 USA. RP Marsh, RA (reprint author), Cincinnati Childrens Hosp, Div Hematol Oncol, Med Ctr, Cincinnati, OH USA. OI Daines, Michael/0000-0003-2464-9034 NR 5 TC 6 Z9 6 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD MAR PY 2008 VL 27 IS 3 BP 283 EP 284 PG 2 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 269PN UT WOS:000253661500023 PM 18277915 ER PT J AU Kim, SH Csaky, KG Wang, NS Lutz, RJ AF Kim, Stephanie H. Csaky, Karl G. Wang, Nam Sun Lutz, Robert J. TI Drug elimination kinetics following subconjunctival injection using dynamic contrast-enhanced magnetic resonance imaging SO PHARMACEUTICAL RESEARCH LA English DT Article DE drug transport barrier; magnetic resonance imaging; ocular pharmacokinetics; subconjunctival injection; transscleral drug delivery ID BLOOD-RETINAL BARRIER; POSITRON-EMISSION-TOMOGRAPHY; PHARMACOKINETIC ANALYSIS; ABSORPTION; LYMPHOSCINTIGRAPHY; QUANTIFICATION; TRIAMCINOLONE; LYMPHEDEMA; TRANSPORT; DELIVERY AB Purpose. To determine the elimination rates of subconjunctivally injected model drugs using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Methods. Gadolinium-diethylenetriaminopentaacetic acid (Gd-DTPA) and gadolinium-albumin (Gd-albumin) were injected in rabbits. Experiments were performed in vivo and post mortem and injection volumes of 200 and 600 mu l were administered. Signal intensity values from MR images were converted to concentration of contrast agent to determine the mass clearance rates from subconjunctival space. Results. Injection volume did not have a significant effect on clearance rate for both Gd-DTPA and Gd-albumin. The clearance rate of Gd-DTPA in vivo was about nine times faster than that post mortem. The in vivo and post mortem clearance rates of Gd-albumin were not significantly different. The in vivo half-life of Gd-DTPA was about 22 min while that of Gd-albumin was about 5.3 h. Conclusions. DCE-MRI was used to quantitatively compare the subconjunctival clearance rates of Gd-DTPA and Gd-albumin. Dynamic clearance mechanisms present in vivo significantly reduced the subconjunctival concentration of Gd-DTPA but not Gd-albumin. Lymphatic clearance does not seem to be as significant as clearance by blood, as evidenced by data from Gd-albumin injections. Larger injection volumes may allow for longer retention times and prolonged release of drug. C1 [Kim, Stephanie H.; Wang, Nam Sun] Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. [Lutz, Robert J.] NIH, Natl Inst Hlth Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. [Csaky, Karl G.] NIH, NEI, Bethesda, MD 20892 USA. RP Kim, SH (reprint author), Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. EM kimstep@mail.nih.gov RI Wang, Nam Sun/E-4253-2016 NR 34 TC 22 Z9 25 U1 2 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0724-8741 J9 PHARM RES JI Pharm. Res. PD MAR PY 2008 VL 25 IS 3 BP 512 EP 520 DI 10.1007/s11095-007-9408-z PG 9 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 271CG UT WOS:000253765900004 PM 17674155 ER PT J AU Jensen, RT Battey, JF Spindel, ER Benya, RV AF Jensen, R. T. Battey, J. F. Spindel, E. R. Benya, R. V. TI International union of pharmacology. LXVIII. Mammalian bombesin receptors: Nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states SO PHARMACOLOGICAL REVIEWS LA English DT Review ID GASTRIN-RELEASING-PEPTIDE; NEUROMEDIN-B-RECEPTOR; SMALL-CELL LUNG; PROTEIN-KINASE-C; SWISS 3T3 CELLS; BRONCHIAL EPITHELIAL-CELLS; PANCREATIC ACINAR-CELLS; GROWTH-FACTOR RECEPTOR; FOCAL ADHESION KINASE; HUMAN ORPHAN RECEPTOR AB The mammalian bombesin receptor family comprises three G protein-coupled heptahelical receptors: the neuromedin B (NMB) receptor (BB1), the gastrin-releasing peptide (GRP) receptor (BB2), and the orphan receptor bombesin receptor subtype 3 (BRS-3) (BB3). Each receptor is widely distributed, especially in the gastrointestinal (GI) tract and central nervous system (CNS), and the receptors have a large range of effects in both normal physiology and pathophysiological conditions. The mammalian bombesin peptides, GRP and NMB, demonstrate a broad spectrum of pharmacological/ biological responses. GRP stimulates smooth muscle contraction and GI motility, release of numerous GI hormones/neurotransmitters, and secretion and/or hormone release from the pancreas, stomach, colon, and numerous endocrine organs and has potent effects on immune cells, potent growth effects on both normal tissues and tumors, potent CNS effects, including regulation of circadian rhythm, thermoregulation; anxiety/fear responses, food intake, and numerous CNS effects on the GI tract as well as the spinal transmission of chronic pruritus. NMB causes contraction of smooth muscle, has growth effects in various tissues, has CNS effects, including effects on feeding and thermoregulation, regulates thyroid-stimulating hormone release, stimulates various CNS neurons, has behavioral effects, and has effects on spinal sensory transmission. GRP, and to a lesser extent NMB, affects growth and/or differentiation of various human tumors, including colon, prostate, lung, and some gynecologic cancers. Knockout studies show that BB3 has important effects in energy balance, glucose homeostasis, control of body weight, lung development and response to injury, tumor growth, and perhaps GI motility. This review summarizes advances in our understanding of the biology/pharmacology of these receptors, including their classification, structure, pharmacology, physiology, and role in pathophysiological conditions. C1 [Jensen, R. T.] NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. [Battey, J. F.] Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD USA. [Spindel, E. R.] Oregon Reg Primate Res Ctr, Div Neurosci, Beaverton, OR 97006 USA. [Benya, R. V.] Univ Illinois, Div Med & Pharmacol, Chicago Vet Adm Med Ctr, Chicago, IL USA. RP Jensen, RT (reprint author), NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov FU Intramural NIH HHS [Z01 DK053100-19, Z01 DK053101-19]; NCI NIH HHS [CA-094346, R01 CA094346] NR 498 TC 230 Z9 237 U1 1 U2 23 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0031-6997 J9 PHARMACOL REV JI Pharmacol. Rev. PD MAR PY 2008 VL 60 IS 1 BP 1 EP 42 DI 10.1124/pr.107.07108 PG 42 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 276FR UT WOS:000254127200001 PM 18055507 ER PT J AU Tang, XW Kim, AL Kopelovich, L Bickers, DR Athar, M AF Tang, Xiuwei Kim, Arianna L. Kopelovich, Levy Bickers, David R. Athar, Mohammad TI Cyclooxygenase-2 inhibitor nimesulide blocks ultraviolet B-induced photocarcinogenesis in SKH-1 hairless mice SO PHOTOCHEMISTRY AND PHOTOBIOLOGY LA English DT Article ID NONMELANOMA SKIN-CANCER; ORNITHINE-DECARBOXYLASE; EXPRESSION; CELECOXIB; MURINE; APOPTOSIS; COX-2; CHEMOPREVENTION; CARCINOGENESIS; MUTATIONS AB Cyclooxygenase-2 (COX-2) inhibition can inhibit UVB-induced carcinogenesis in the skin. We have shown that COX-2 is overexpressed in UVB-induced squamous cell carcinomas (SCCs). Celecoxib, a specific inhibitor of COX-2, blocks UVB-induced papillomas and carcinomas in murine skin. However, as COX-2 inhibitors of this type are associated with an increased risk of adverse cardiovascular events, we decided to study nimesulide, a different class of COX-2 inhibitor, an N-arylmethanesulfonamide derivative not known to have these untoward effects. To assess the antitumor-promoting effects of nimesulide, 90 mice were equally divided into three groups. Group I animals received no test agent or UVB and served as age-matched controls; group II animals were irradiated with UVB (180 mJ cm(-2), twice weekly for 35 weeks) and group III animals received 300 p.p.m. nimesulide in drinking water and were irradiated with UVB as described for group-II. Nimesulide treatment reduced the growth of UVB-induced tumors both in terms of tumor number and tumor volume. By weeks 25, 30 and 35, the tumor numbers in the nimesulide-treated group were 79%, 49% and 53% less than the number occurring in UVB-treated animals whereas tumor volume was reduced 69%, 54% and 53%, respectively, compared to the UVB-irradiated control group. Nimesulide also inhibited the malignant progression of SCCs. The reduction in tumorigenesis was paralleled by a decrease in cell cycle regulatory proteins (cyclins A, B1, D1, E, CDK2/4/6) and the antiapoptotic protein (Bcl2); concomitantly there was an increase in proapoptotic markers, poly (ADPribose) polymerase (PARP) and caspase-3. Nimesulide also decreased ornithine decarboxylase expression and the nuclear accumulation of nuclear factor kappa B transcriptionally active protein complexes. These results show that alternative classes of COX-2 inhibitors may likely be efficacious as cancer chemopreventive agents and may have an improved therapeutic index. C1 [Tang, Xiuwei; Kim, Arianna L.; Bickers, David R.; Athar, Mohammad] Columbia Univ, Coll Phys & Surg, Dept Dermatol, New York, NY 10027 USA. [Kopelovich, Levy] NCI, Chemoprevent Branch, Bethesda, MD 20892 USA. RP Athar, M (reprint author), Columbia Univ, Coll Phys & Surg, Dept Dermatol, New York, NY 10027 USA. EM mathar@uab.cdu FU NCI NIH HHS [CA097249, R01 CA105136]; NIAMS NIH HHS [K01 AR048582]; NIEHS NIH HHS [R01 ES015323] NR 31 TC 18 Z9 18 U1 0 U2 0 PU AMER SOC PHOTOBIOLOGY PI AUGUSTA PA BIOTECH PARK, 1021 15TH ST, SUITE 9, AUGUSTA, GA 30901-3158 USA SN 0031-8655 J9 PHOTOCHEM PHOTOBIOL JI Photochem. Photobiol. PD MAR-APR PY 2008 VL 84 IS 2 BP 522 EP 527 DI 10.1111/j.1751-1097.2008.00303.x PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 270UZ UT WOS:000253747000033 PM 18266822 ER PT J AU Achard, S Bassett, DS Meyer-Lindenberg, A Bullmore, ET AF Achard, Sophie Bassett, Danielle S. Meyer-Lindenberg, Andreas Bullmore, Edward T. TI Fractal connectivity of long-memory networks SO PHYSICAL REVIEW E LA English DT Article ID SMALL-WORLD NETWORKS; HUMAN BRAIN; COMPLEX NETWORKS; TIME-SERIES; WAVELET ANALYSIS AB Using the multivariate long memory (LM) model and Taylor expansions, we find the conditions for convergence of the wavelet correlations between two LM processes on an asymptotic value at low frequencies. These mathematical results, and a least squares estimator of LM parameters, are validated in simulations and applied to neurophysiological (human brain) and financial market time series. Both brain and market systems had multivariate LM properties including a "fractal connectivity" regime of scales over which wavelet correlations were invariantly close to their asymptotic value. This analysis provides efficient and unbiased estimation of long-term correlations in diverse dynamic networks. C1 [Achard, Sophie; Bassett, Danielle S.; Bullmore, Edward T.] Univ Cambridge, Brain Mapping Unit, Cambridge CB2 2QQ, England. [Achard, Sophie; Bassett, Danielle S.; Bullmore, Edward T.] Univ Cambridge, Behav & Clin Neurosci Inst, Cambridge CB2 2QQ, England. [Achard, Sophie] CNRS, UMR 5216, GIPSA Lab, Grenoble, France. [Bassett, Danielle S.; Meyer-Lindenberg, Andreas] NIMH, NIH, Bethesda, MD 20892 USA. [Bassett, Danielle S.] Univ Cambridge, Cavendish Lab, Dept Phys, Cambridge CB3 0HE, England. RP Bullmore, ET (reprint author), Univ Cambridge, Brain Mapping Unit, Cambridge CB2 2QQ, England. EM sa428@cam.ac.uk; dp317@cam.ac.uk; andreasm@mail.nih.gov; etb23@cam.ac.uk RI Achard, Sophie/L-5231-2014; 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 Medical Research Council [, G0001354]; Wellcome Trust NR 36 TC 56 Z9 56 U1 1 U2 8 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 EI 1550-2376 J9 PHYS REV E JI Phys. Rev. E PD MAR PY 2008 VL 77 IS 3 AR 036104 DI 10.1103/PhysRevE.77.036104 PN 2 PG 12 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 282AL UT WOS:000254539900012 PM 18517458 ER PT J AU Buchete, NV Hummer, G AF Buchete, Nicolae-Viorel Hummer, Gerhard TI Peptide folding kinetics from replica exchange molecular dynamics SO PHYSICAL REVIEW E LA English DT Article ID BAYESIAN-ANALYSIS; EXPLICIT SOLVENT; HYDROGEN-BONDS; NETWORK MODEL; SIMULATIONS; EQUILIBRIUM; TRANSITION; DIFFUSION; ENSEMBLE; SYSTEMS AB We show how accurate kinetic information, such as the rates of protein folding and unfolding, can be extracted from replica-exchange molecular dynamics (REMD) simulations. From the brief and continuous trajectory segments between replica exchanges, we estimate short-time propagators in conformation space and use them to construct a master equation. For a helical peptide in explicit water, we determine the rates of transitions both locally between microscopic conformational states and globally for folding and unfolding. We show that accurate rates in the similar to 1/(100 ns) to similar to/(1 ns) range can be obtained from REMD with exchange times of 5 ps, in excellent agreement with results from long equilibrium molecular dynamics. C1 [Buchete, Nicolae-Viorel; Hummer, Gerhard] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Buchete, NV (reprint author), Univ Coll Dublin, Sch Phys, Dublin 4, Ireland. EM gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013; Buchete, Nicolae-Viorel/C-6200-2015 OI Hummer, Gerhard/0000-0001-7768-746X; Buchete, Nicolae-Viorel/0000-0001-9861-1157 FU Intramural NIH HHS NR 30 TC 66 Z9 66 U1 0 U2 20 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD MAR PY 2008 VL 77 IS 3 AR 030902 DI 10.1103/PhysRevE.77.030902 PN 1 PG 4 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 282AJ UT WOS:000254539700012 PM 18517321 ER PT J AU Hassan, SA AF Hassan, Sergio A. TI Morphology of ion clusters in aqueous electrolytes SO PHYSICAL REVIEW E LA English DT Article ID SIDE-CHAIN INTERACTIONS AB Formation of ion clusters in aqueous NaCl solutions at 25 C is investigated with dynamics simulations in the 0.1-3M concentration range. The medium is found to be highly structured even at moderate concentrations, and clusters of over 20 ions are observed above similar to 2M. The medium can be viewed as a multicomponent fluid, composed of reacting particles with well-defined average populations, shapes, sizes, and charge distributions. Clusters show substantial morphological variations that are here characterized by their hydrodynamic radii and internal charge distributions. Clusters can be described as prolate spheroids in the subnanometer length scale. The hydrodynamic radius and the radius of gyration follow simple power laws with the number of ions in the cluster. Dipole moment distributions show characteristic peaks in the similar to 10-60 debye range that reflect conformational preferences modulated by electrostatic and liquid-structure forces. C1 [Hassan, Sergio A.] NIH, DCB CIT, Ctr Mol Modeling, Bethesda, MD 20892 USA. RP Hassan, SA (reprint author), NIH, DCB CIT, Ctr Mol Modeling, Bldg 10, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 CT999999] NR 19 TC 17 Z9 18 U1 3 U2 12 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD MAR PY 2008 VL 77 IS 3 AR 031501 DI 10.1103/PhysRevE.77.031501 PN 1 PG 5 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 282AJ UT WOS:000254539700073 PM 18517382 ER PT J AU Blank, V Hirsch, E Challis, JRG Romero, R Lye, SJ AF Blank, V. Hirsch, E. Challis, J. R. G. Romero, R. Lye, S. J. TI Cytokine signaling, inflammation, innate immunity and preterm labour - A workshop report SO PLACENTA LA English DT Editorial Material DE inflammation; infection; innate immunity; cytokines; preterm labour ID TOLL-LIKE RECEPTOR-2; CHORIOAMNIONITIS; PARTURITION; MEMBRANES; DELIVERY; CELLS C1 [Blank, V.] Lady Davis Inst Med Res, Montreal, PQ H3T1 E2, Canada. [Blank, V.] McGill Univ, Dept Med, Montreal, PQ, Canada. [Hirsch, E.] Evanston NW Healthcare, Dept Obstet & Gynecol, Evanston, IL USA. [Hirsch, E.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Challis, J. R. G.] Univ Toronto, Dept Physiol, Toronto, ON, Canada. [Romero, R.] NICHHD, Perinatal Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Romero, R.] Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. [Lye, S. J.] Univ Toronto, Dept Obstet & Gynecol, Toronto, ON, Canada. RP Blank, V (reprint author), Lady Davis Inst Med Res, 3755 Cote St Catherine Rd, Montreal, PQ H3T1 E2, Canada. EM volker.blank@mcgill.ca; lye@mshri.on.ca RI Lye, Stephen/E-7269-2013; Challis, John/E-7419-2014 FU Intramural NIH HHS NR 10 TC 22 Z9 22 U1 1 U2 4 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD MAR PY 2008 VL 29 SU A BP S102 EP S104 DI 10.1016/j.placenta.2007.10.011 PG 3 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 283IF UT WOS:000254629200021 PM 18082255 ER PT J AU Knofler, M Simmons, DG Lash, GE Harris, LK Armant, DR AF Knoefler, M. Simmons, D. G. Lash, G. E. Harris, L. K. Armant, D. R. TI Regulation of trophoblast invasion - A workshop report SO PLACENTA LA English DT Article; Proceedings Paper CT 13th International-Federation-of-Placenta-Association Meeting CY AUG 17-22, 2007 CL Queens Univ, Kingston, CANADA SP Int Federat Placenta Assoc HO Queens Univ DE trophoblast giant cells; extravillous trophoblast; invasion; uterine NK cell; spiral artery ID GROWTH-FACTOR; CELLS; EXPRESSION AB Trophoblast invasion during placental development helps to establish efficient physiological exchange between maternal and fetal circulatory systems. Trophoblast stem cells differentiate into multiple subtypes, including some that are highly invasive. Signalling to the trophoblast from decidua, uterine natural killer cells and vascular smooth muscle can regulate extravillous trophoblast differentiation. Important questions remain about how these cellular interactions promote trophoblast invasion and the signalling pathways that are involved. New and established biological models are being used to experimentally examine these interactions and the underlying molecular mechanisms. (C) 2007 Published by IFPA and Elsevier Ltd. C1 [Armant, D. R.] Wayne State Univ, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, Sch Med, Detroit, MI 48201 USA. [Knoefler, M.] Med Univ Vienna, Reprod Biol Unit, Dept Obstet & Fetal Maternal Med, Vienna, Austria. [Simmons, D. G.] Univ Calgary, Dept Comparat Biol & Expt Med, Calgary, AB T2N 1N4, Canada. [Lash, G. E.] Univ Newcastle, Uterine Cell Signalling Grp, Inst Cellular Med, Newcastle Upon Tyne, Tyne & Wear, England. [Harris, L. K.] Univ Manchester, Maternal & Fetal Hlth Res Grp, Manchester M13 9PL, Lancs, England. [Armant, D. R.] NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. RP Armant, DR (reprint author), Wayne State Univ, CS Mott Ctr Human Growth & Dev, Dept Obstet & Gynecol, Sch Med, 275 E Hancock Ave, Detroit, MI 48201 USA. EM darmant@med.wayne.edu RI Simmons, David/C-5983-2009; OI Simmons, David/0000-0002-4115-9371; Harris, Lynda/0000-0001-7709-5202; Armant, D. Randall/0000-0001-5904-9325 FU Intramural NIH HHS [Z99 HD999999] NR 9 TC 12 Z9 12 U1 0 U2 3 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD MAR PY 2008 VL 29 SU A BP S26 EP S28 DI 10.1016/j.placenta.2007.11.008 PG 3 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 283IF UT WOS:000254629200007 PM 18083227 ER PT J AU Than, NG Romero, R Hillermann, R Cozzi, V Nie, G Huppertz, B AF Than, N. G. Romero, R. Hillermann, R. Cozzi, V. Nie, G. Huppertz, B. TI Prediction of preeclampsia - A workshop report SO PLACENTA LA English DT Editorial Material DE prediction; preeclampsia; microRNA; PP13; PTX3; HtrA3 ID SERUM; HTRA3 AB Understanding the mechanisms of disease responsible for the syndrome of preeclampsia as well as early risk assessment is still a major challenge. The concentrations of circulating proteins in maternal blood such as placental growth factor, soluble vascular endothelial growth factor receptor-1 and soluble endoglin are altered weeks before the onset of clinical symptoms of the syndrome. Recently, other proteins in maternal serum, such as activin A, inhibin A, PAPP-A, and PP13 have been suggested to be of value in first trimester risk assessment. Since preeclampsia is a syndrome, it seems unlikely that a single test will predict all forms of preeclampsia. This realization has led to the formulation of a new conceptual framework suggesting that a combination of markers (biochemical and/or biophysical) may be required to conduct comprehensive risk assessment for the syndrome. (C) 2007 Published by IFPA and Elsevier Ltd. C1 [Than, N. G.; Romero, R.] Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp,Intramural Div, Detroit, MI 48201 USA. [Than, N. G.] Semmelweis Univ, Dept Obstet & Gynecol 1, H-1085 Budapest, Hungary. [Romero, R.] Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. [Hillermann, R.] Univ Stellenbosch, Dept Genet, ZA-7600 Stellenbosch, South Africa. [Cozzi, V.] Univ Milan, Dept Obstet & Gynecol, IRCCS POMARE, I-20122 Milan, Italy. [Nie, G.] Prince Henrys Inst Med Res, Melbourne, Vic, Australia. [Huppertz, B.] Med Univ Graz, Inst Cell Biol Histol & Embryol, Graz, Austria. RP Than, NG (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD, NIH,DHHS,Hutzel Womens Hosp,Intramural Div, 3990 John R St,Box 4, Detroit, MI 48201 USA. EM nthan@med.wayne.edu FU Intramural NIH HHS [Z01 HD002400-16] NR 10 TC 38 Z9 38 U1 0 U2 6 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD MAR PY 2008 VL 29 SU A BP S83 EP S85 DI 10.1016/j.placenta.2007.10.008 PG 3 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 283IF UT WOS:000254629200017 PM 18061661 ER PT J AU Avisar, D Prokhnevsky, AI Makarova, KS Koonin, EV Dolja, VV AF Avisar, Dror Prokhnevsky, Alexey I. Makarova, Kira S. Koonin, Eugene V. Dolja, Valerian V. TI Myosin XI-K is required for rapid trafficking of Golgi stacks, peroxisomes, and mitochondria in leaf cells of Nicotiana benthamiana SO PLANT PHYSIOLOGY LA English DT Article ID ENDOPLASMIC-RETICULUM; ACTIN CYTOSKELETON; ARABIDOPSIS-THALIANA; PLANT-CELLS; ORGANELLE TRAFFICKING; ROOT HAIR; MOVEMENT; EVOLUTION; TRANSPORT; APPARATUS AB A prominent feature of plant cells is the rapid, incessant movement of the organelles traditionally defined as cytoplasmic streaming and attributed to actomyosin motility. We sequenced six complete Nicotiana benthamiana cDNAs that encode class XI and class VIII myosins. Phylogenetic analysis indicates that these two classes of myosins diverged prior to the radiation of green algae and land plants from a common ancestor and that the common ancestor of land plants likely possessed at least seven myosins. We further report here that movement of Golgi stacks, mitochondria, and peroxisomes in the leaf cells of N. benthamiana is mediated mainly by myosin XI-K. Suppression of myosin XI-K function using dominant negative inhibition or RNA interference dramatically reduced movement of each of these organelles. When similar approaches were used to inhibit functions of myosin XI-2 or XI-F, only moderate to marginal effects were observed. Organelle trafficking was virtually unaffected in response to inhibition of each of the three class VIII myosins. Interestingly, none of the tested six myosins appears to be involved in light-induced movements of chloroplasts. Taken together, these data strongly suggest that myosin XI-K has a major role in trafficking of Golgi stacks, mitochondria, and peroxisomes, whereas myosins XI-2 and XI-F might perform accessory functions in this process. In addition, our analysis of thousands of individual organelles revealed independent movement patterns for Golgi stacks, mitochondria, and peroxisomes, indicating that the notion of coordinated cytoplasmic streaming is not generally applicable to higher plants. C1 [Avisar, Dror; Prokhnevsky, Alexey I.; Dolja, Valerian V.] Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. [Avisar, Dror; Prokhnevsky, Alexey I.; Dolja, Valerian V.] Oregon State Univ, Ctr Genome Res & Biocomp, Corvallis, OR 97331 USA. [Makarova, Kira S.; Koonin, Eugene V.] Natl Inst Hlth, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Dolja, VV (reprint author), Oregon State Univ, Dept Bot & Plant Pathol, Corvallis, OR 97331 USA. EM doljav@science.oregonstate.edu FU NIGMS NIH HHS [GM 053190] NR 56 TC 139 Z9 145 U1 0 U2 16 PU AMER SOC PLANT BIOLOGISTS PI ROCKVILLE PA 15501 MONONA DRIVE, ROCKVILLE, MD 20855 USA SN 0032-0889 J9 PLANT PHYSIOL JI Plant Physiol. PD MAR PY 2008 VL 146 IS 3 BP 1098 EP 1108 DI 10.1104/pp.107.113647 PG 11 WC Plant Sciences SC Plant Sciences GA 308TF UT WOS:000256412200035 PM 18178670 ER PT J AU Pardini, MI Jamal, LF Durigon, EL Massad, E Perez, JF Pinho, JR Holmes, EC Zanotto, PM AF de Moura Campos Pardini, Maria Ines Jamal, Leda Fatima Durigon, Edison Luiz Massad, Eduardo Perez, Jose Fernando Rebello Pinho, Joao Renato Holmes, Edward C. de Andrade Zanotto, Paolo Marinho TI Boosting virology in Brazil SO PLOS BIOLOGY LA English DT Editorial Material C1 [Durigon, Edison Luiz; Massad, Eduardo; Rebello Pinho, Joao Renato; de Andrade Zanotto, Paolo Marinho] Univ Sao Paulo, Sao Paulo, Brazil. [de Moura Campos Pardini, Maria Ines] Univ Sao Paulo State, Sao Paulo, Brazil. [Jamal, Leda Fatima] STD AIDS Reference & Training Ctr Sao Paulo, Sao Paulo, Brazil. [Holmes, Edward C.] Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Zanotto, PM (reprint author), Univ Sao Paulo, Sao Paulo, Brazil. EM pzanotto@usp.br RI Massad, Eduardo/H-6143-2011; Massad, Eduardo/B-1169-2012; Pinho, Joao/G-2850-2012; OI Massad, Eduardo/0000-0002-7200-2916; Pinho, Joao/0000-0003-3999-0489; Durigon, Edison/0000-0003-4898-6553; Holmes, Edward/0000-0001-9596-3552 NR 3 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 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD MAR PY 2008 VL 6 IS 3 BP 428 EP 429 AR e57 DI 10.1371/journal.pbio.0060057 PG 2 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 287PI UT WOS:000254928600002 PM 18336070 ER PT J AU Chow, CC Hall, KD AF Chow, Carson C. Hall, Kevin D. TI The dynamics of human body weight change SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID 24-HOUR ENERGY-EXPENDITURE; RESTING METABOLIC-RATE; HIGH-FAT DIET; SUBSTRATE UTILIZATION; PROTEIN-METABOLISM; FREE MASS; OBESITY; MODEL; EXERCISE; CARBOHYDRATE AB An imbalance between energy intake and energy expenditure will lead to a change in body weight ( mass) and body composition ( fat and lean masses). A quantitative understanding of the processes involved, which currently remains lacking, will be useful in determining the etiology and treatment of obesity and other conditions resulting from prolonged energy imbalance. Here, we show that a mathematical model of the macronutrient flux balances can capture the long-term dynamics of human weight change; all previous models are special cases of this model. We show that the generic dynamic behavior of body composition for a clamped diet can be divided into two classes. In the first class, the body composition and mass are determined uniquely. In the second class, the body composition can exist at an infinite number of possible states. Surprisingly, perturbations of dietary energy intake or energy expenditure can give identical responses in both model classes, and existing data are insufficient to distinguish between these two possibilities. Nevertheless, this distinction has important implications for the efficacy of clinical interventions that alter body composition and mass. C1 [Chow, Carson C.; Hall, Kevin D.] NIDDK, Lab Biol Modelling, NIH, Bethesda, MD 20892 USA. RP Chow, CC (reprint author), NIDDK, Lab Biol Modelling, NIH, Bethesda, MD 20892 USA. EM carsonc@mail.nih.gov RI Chow, Carson/A-7970-2009; Hall, Kevin/F-2383-2010 FU Intramural NIH HHS NR 46 TC 54 Z9 55 U1 1 U2 13 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD MAR PY 2008 VL 4 IS 3 AR e1000045 DI 10.1371/journal.pcbi.1000045 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 294MM UT WOS:000255410100010 PM 18369435 ER PT J AU Biacsi, R Kumari, D Usdin, K AF Biacsi, Rea Kumari, Daman Usdin, Karen TI SIRT1 inhibition alleviates gene silencing in fragile X mental retardation syndrome SO PLOS GENETICS LA English DT Article ID SMALL-MOLECULE INHIBITOR; FULLY EXPANDED MUTATION; FMR1 GENE; HISTONE DEACETYLASE; MINIMAL METHYLATION; HUNTINGTONS-DISEASE; DNA DEMETHYLATION; MOUSE MODEL; CELLS; REACTIVATION AB Expansion of the CGG.CCG-repeat tract in the 5' UTR of the FMR1 gene to > 200 repeats leads to heterochromatinization of the promoter and gene silencing. This results in Fragile X syndrome ( FXS), the most common heritable form of mental retardation. The mechanism of gene silencing is unknown. We report here that a Class III histone deacetylase, SIRT1, plays an important role in this silencing process and show that the inhibition of this enzyme produces significant gene reactivation. This contrasts with the much smaller effect of inhibitors like trichostatin A ( TSA) that inhibit Class I, II and IV histone deacetylases. Reactivation of silenced FMR1 alleles was accompanied by an increase in histone H3 lysine 9 acetylation as well as an increase in the amount of histone H4 that is acetylated at lysine 16 (H4K16) by the histone acetyltransferase, hMOF. DNA methylation, on the other hand, is unaffected. We also demonstrate that deacetylation of H4K16 is a key downstream consequence of DNA methylation. However, since DNA methylation inhibitors require DNA replication in order to be effective, SIRT1 inhibitors may be more useful for FMR1 gene reactivation in post-mitotic cells like neurons where the effect of the gene silencing is most obvious. C1 [Biacsi, Rea; Kumari, Daman; Usdin, Karen] Natl Inst Hlth, Sect Genom Struct & Funct, Mol & Cellular Biol Lab, NIDDK, Bethesda, MD 20892 USA. [Biacsi, Rea] Eotvos Lorand Univ, Dept Genet, Doctorate Sch Biol Class & Mol Genet Branch, Budapest, Hungary. RP Biacsi, R (reprint author), Natl Inst Hlth, Sect Genom Struct & Funct, Mol & Cellular Biol Lab, NIDDK, Bethesda, MD 20892 USA. EM ku@helix.nih.gov FU Intramural NIH HHS NR 44 TC 45 Z9 45 U1 0 U2 0 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 MAR PY 2008 VL 4 IS 3 AR e1000017 DI 10.1371/journal.pgen.1000017 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 294LK UT WOS:000255407300015 PM 18369442 ER PT J AU Oliver, TR Feingold, E Yu, K Cheung, V Tinker, S Yadav-Shah, M Masse, N Sherman, SL AF Oliver, Tiffany Renee Feingold, Eleanor Yu, Kai Cheung, Vivian Tinker, Stuart Yadav-Shah, Maneesha Masse, Nirupama Sherman, Stephanie L. TI New insights into human nondisjunction of chromosome 21 in oocytes SO PLOS GENETICS LA English DT Article ID MATERNAL MEIOSIS I; MEIOTIC RECOMBINATION; DOWN-SYNDROME; DNA POLYMORPHISMS; AGE; SEGREGATION; TRISOMY-21; DROSOPHILA; PATTERNS; ORIGIN AB Nondisjunction of chromosome 21 is the leading cause of Down syndrome. Two risk factors for maternal nondisjunction of chromosome 21 are increased maternal age and altered recombination. In order to provide further insight on mechanisms underlying nondisjunction, we examined the association between these two well established risk factors for chromosome 21 nondisjunction. In our approach, short tandem repeat markers along chromosome 21 were genotyped in DNA collected from individuals with free trisomy 21 and their parents. This information was used to determine the origin of the nondisjunction error and the maternal recombination profile. We analyzed 615 maternal meiosis I and 253 maternal meiosis II cases stratified by maternal age. The examination of meiosis II errors, the first of its type, suggests that the presence of a single exchange within the pericentromeric region of 21q interacts with maternal age-related risk factors. This observation could be explained in two general ways: 1) a pericentromeric exchange initiates or exacerbates the susceptibility to maternal age risk factors or 2) a pericentromeric exchange protects the bivalent against age-related risk factors allowing proper segregation of homologues at meiosis I, but not segregation of sisters at meiosis II. In contrast, analysis of maternal meiosis I errors indicates that a single telomeric exchange imposes the same risk for nondisjunction, irrespective of the age of the oocyte. Our results emphasize the fact that human nondisjunction is a multifactorial trait that must be dissected into its component parts to identify specific associated risk factors. C1 [Oliver, Tiffany Renee; Tinker, Stuart; Yadav-Shah, Maneesha; Masse, Nirupama; Sherman, Stephanie L.] Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. [Feingold, Eleanor] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Human Genet, Pittsburgh, PA USA. [Feingold, Eleanor] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA USA. [Yu, Kai] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA. Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. RP Oliver, TR (reprint author), Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. EM toliver@genetics.emory.edu OI Feingold, Eleanor/0000-0003-2898-6484 FU NCATS NIH HHS [UL1 TR000454]; NCRR NIH HHS [M01 RR000039, MO-1-RR00039]; NHGRI NIH HHS [R01 HG01880, R01 HG001880]; NICHD NIH HHS [R01 HD038979, R01 HD38979]; NIGMS NIH HHS [5F31GM078751-02, F31 GM078751] NR 37 TC 69 Z9 75 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 MAR PY 2008 VL 4 IS 3 AR e1000033 DI 10.1371/journal.pgen.1000033 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 294LK UT WOS:000255407300018 PM 18369452 ER PT J AU Gousset, K Ablan, SD Coren, LV Ono, A Soheilian, F Nagashima, K Ott, DE Freed, EO AF Gousset, Karine Ablan, Sherimay D. Coren, Lori V. Ono, Akira Soheilian, Ferri Nagashima, Kunio Ott, David E. Freed, Eric O. TI Real-time visualization of HIV-1 GAG trafficking in infected macrophages SO PLOS PATHOGENS LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 MATRIX PROTEIN; MONOCYTE-DERIVED MACROPHAGES; TO-CELL TRANSMISSION; PLASMA-MEMBRANE; IMMUNOLOGICAL SYNAPSE; DENDRITIC CELLS; LIFE-CYCLE; BIOLOGICAL APPLICATIONS; TERMINAL REGION AB HIV-1 particle production is driven by the Gag precursor protein Pr55(Gag). Despite significant progress in defining both the viral and cellular determinants of HIV-1 assembly and release, the trafficking pathway used by Gag to reach its site of assembly in the infected cell remains to be elucidated. The Gag trafficking itinerary in primary monocyte-derived macrophages is especially poorly understood. To define the site of assembly and characterize the Gag trafficking pathway in this physiologically relevant cell type, we have made use of the biarsenical-tetracysteine system. A small tetracysteine tag was introduced near the C-terminus of the matrix domain of Gag. The insertion of the tag at this position did not interfere with Gag trafficking, virus assembly or release, particle infectivity, or the kinetics of virus replication. By using this in vivo detection system to visualize Gag trafficking in living macrophages, Gag was observed to accumulate both at the plasma membrane and in an apparently internal compartment that bears markers characteristic of late endosomes or multivesicular bodies. Significantly, the internal Gag rapidly translocated to the junction between the infected macrophages and uninfected T cells following macrophage/T-cell synapse formation. These data indicate that a population of Gag in infected macrophages remains sequestered internally and is presented to uninfected target cells at a virological synapse. C1 [Gousset, Karine; Ablan, Sherimay D.; Freed, Eric O.] NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. [Coren, Lori V.; Ott, David E.] NCI, AIDS Vacc Program, SAIC Frederick Inc, Frederick, MD 21701 USA. [Ono, Akira] Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Soheilian, Ferri; Nagashima, Kunio] NCI, SAIC Frederick, Adv Technol Program, Image Anal Lab, Frederick, MD 21701 USA. RP Gousset, K (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21701 USA. EM efreed@nih.gov OI Ono, Akira/0000-0001-7841-851X; Gousset, Karine/0000-0002-0988-2332 FU Intramural NIH HHS [Z01 BC010775-01]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 78 TC 122 Z9 122 U1 0 U2 9 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 MAR PY 2008 VL 4 IS 3 AR e1000015 DI 10.1371/journal.ppat.1000015 PG 14 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 294PJ UT WOS:000255417700018 PM 18369466 ER PT J AU Thompson, RW Pesce, JT Ramalingam, T Wilson, MS White, S Cheever, AW Ricklefs, SM Porcella, SF Li, L Ellies, LG Wynn, TA AF Thompson, Robert W. Pesce, John T. Ramalingam, Thirumalai Wilson, Mark S. White, Sandy Cheever, Allen W. Ricklefs, Stacy M. Porcella, Stephen F. Li, Lili Ellies, Lesley G. Wynn, Thomas A. TI Cationic amino acid transporter-2 regulates immunity by modulating arginase activity SO PLOS PATHOGENS LA English DT Article ID NITRIC-OXIDE SYNTHASE; ALTERNATIVELY ACTIVATED MACROPHAGES; MARROW-DERIVED MACROPHAGES; L-ARGININE METABOLISM; SCHISTOSOMA-MANSONI; TH2 CYTOKINES; GRANULOMATOUS PATHOLOGY; DIFFERENTIAL REGULATION; MURINE MACROPHAGES; HEPATIC-FIBROSIS AB Cationic amino acid transporters (CAT) are important regulators of NOS2 and ARG1 activity because they regulate L-arginine availability. However, their role in the development of Th1/Th2 effector functions following infection has not been investigated. Here we dissect the function of CAT2 by studying two infectious disease models characterized by the development of polarized Th1 or Th2-type responses. We show that CAT2(-/-) mice are significantly more susceptible to the Th1-inducing pathogen Toxoplasma gondii. Although T. gondii infected CAT2(-/-) mice developed stronger IFN-gamma responses, nitric oxide (NO) production was significantly impaired, which contributed to their enhanced susceptibility. In contrast, CAT2(-/-) mice infected with the Th2-inducing pathogen Schistosoma mansoni displayed no change in susceptibility to infection, although they succumbed to schistosomiasis at an accelerated rate. Granuloma formation and fibrosis, pathological features regulated by Th2 cytokines, were also exacerbated even though their Th2 response was reduced. Finally, while IL-13 blockade was highly efficacious in wild-type mice, the development of fibrosis in CAT2(-/-) mice was largely IL-13-independent. Instead, the exacerbated pathology was associated with increased arginase activity in fibroblasts and alternatively activated macrophages, both in vitro and in vivo. Thus, by controlling NOS2 and arginase activity, CAT2 functions as a potent regulator of immunity. C1 [Thompson, Robert W.; Pesce, John T.; Ramalingam, Thirumalai; Wilson, Mark S.; White, Sandy; Wynn, Thomas A.] NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. [Cheever, Allen W.] Biomed Res Inst, Rockville, MD USA. [Ricklefs, Stacy M.; Porcella, Stephen F.] NIAID, Rocky Mt Labs, Genom Unit, Technol Sect, Hamilton, MT 59840 USA. [Ellies, Lesley G.] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA. [Li, Lili] Centocor Inc, Malvern, PA USA. RP Thompson, RW (reprint author), NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twynn@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU Intramural NIH HHS; NCI NIH HHS [CA118182, K22 CA118182] NR 66 TC 36 Z9 40 U1 1 U2 4 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 MAR PY 2008 VL 4 IS 3 AR e1000023 DI 10.1371/journal.ppat.1000023 PG 17 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 294PJ UT WOS:000255417700012 PM 18369473 ER PT J AU Hall, KL Rossi, JS AF Hall, Kara L. Rossi, Joseph S. TI Meta-analytic examination of the strong and weak principles across 48 health behaviors SO PREVENTIVE MEDICINE LA English DT Review DE transtheoretical model; stages of change; decisional balance; pros and cons; behavior change ID DECISIONAL BALANCE MEASURE; RANDOM-EFFECTS MODELS; TRANSTHEORETICAL MODEL; SELF-EFFICACY; CONDOM USE; SMOKING-CESSATION; PHYSICAL-ACTIVITY; MOTIVATIONAL READINESS; EXERCISE; STAGE AB Objective. The strong and weak principles of change state that progress from the precontemplation to the action stage of change is associated with a one standard deviation increase in the pros and a one-half standard deviation decrease in the cons of change. In this study these relationships, originally developed by Prochaska [Prochaska, J.O., 1994. Strong and weak principles for progressing from precontemplation to action on the basis of 12 problem behaviors. Health Psychology, 13, 47-51] based on an examination of 12 studies of 12 different behaviors, were re-examined using many more datasets and much more rigorous statistical methods. Methods. The current study analyzes 120 datasets from studies conducted between 1984 and 2003 across and within 48 health behaviors, including nearly 50,000 participants from 10 countries. The datasets were primarily analyzed utilizing meta-analytic techniques. Results. Despite the range of behaviors and populations, the results were remarkably consistent with the original results (pros=1.00 standard deviation, cons=0.56 standard deviation). Few potential moderators showed any impact on effect size distributions. Conclusions. This updated and enhanced examination of two important principles of behavior change is a significant contribution to the field of multiple health risk behaviors, as it clearly demonstrates the consistency of the theoretical principles across multiple behaviors, which has implications for developing multiple health risk behavior interventions. (c) 2007 Elsevier Inc. All rights reserved. C1 [Hall, Kara L.; Rossi, Joseph S.] Univ Rhode Isl, Kingston, RI 02881 USA. RP Hall, KL (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7326,Execut Plaza N,Room 512, Bethesda, MD 20892 USA. EM hallka@mail.nih.gov; jsrossi@uri.edu NR 104 TC 85 Z9 89 U1 4 U2 13 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0091-7435 J9 PREV MED JI Prev. Med. PD MAR PY 2008 VL 46 IS 3 BP 266 EP 274 DI 10.1016/j.ypmed.2007.11.006 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 298EA UT WOS:000255668000014 PM 18242667 ER PT J AU Danforth, KN Rodriguez, C Hayes, RB Sakoda, LC Huang, WY Yu, K Calle, EE Jacobs, EJ Chen, BE Andriole, GL Figueroa, JD Yeager, M Platz, EA Michaud, DS Chanock, SJ Thun, MJ Hsing, AW AF Danforth, Kim N. Rodriguez, Carmen Hayes, Richard B. Sakoda, Lori C. Huang, Wen-Yi Yu, Kai Calle, Eugenia E. Jacobs, Eric J. Chen, Bingshu E. Andriole, Gerald L. Figueroa, Jonine D. Yeager, Meredith Platz, Elizabeth A. Michaud, Dominique S. Chanock, Stephen J. Thun, Michael J. Hsing, Ann W. TI TNF polymorphisms and prostate cancer risk SO PROSTATE LA English DT Article DE tumor necrosis factor; inflammation; genetic susceptibility; prostate cancer ID TUMOR-NECROSIS-FACTOR; GENE POLYMORPHISMS; LINKAGE PHASE; ALPHA GENE; TESTS; ASSOCIATION; CARCINOGENESIS; INFLAMMATION AB BACKGROUND. Inflammation has been hypothesized to increase prostate cancer risk. Tumor necrosis factor (TNF) is an important mediator of the inflammatory process, but the relationship between TNF variants and prostate cancer remains unclear. METHODS. We examined associations between six TNF single nucleotide polymorphisms (SNPs) (rs1799964, rs1800630, rs1799724, rs1800629, rs361525, rs1800610) and prostate cancer risk among 2,321 cases and 2,560 controls from two nested case-control studies within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, n = 2,561, 5 SNPs) and the Cancer Prevention Study 11 Nutrition Cohort (Nutrition Cohort, n = 2,320, 6 SNPs). Odds ratios and 95% confidence intervals were estimated for individual SNPs and haplotypes in each cohort separately and in pooled analyses. RESULTS. No TNF SNP was associated with prostate cancer risk in PLCO (P-trend >= 0.16), while in the Nutrition Cohort, associations were significant for 2 highly correlated variants (rs1799724, 1800610, r(2) = 0.95; P-trend=0.04 and 0.02, respectively). In pooled analyses, no single SNP was associated with prostate cancer risk (P-trend >= 0.08). After adjustment for multiple testing, no SNP was associated with prostate cancer risk in either cohort individually or in the pooled analysis (P-trend all >= 0.10). Haplotypes based on 5 TNF SNPs did not vary by case/control status in PLCO, but showed marginal associations in the Nutrition Cohort (global P = 0.06) and the pooled analysis (global P = 0.05). CONCLUSIONS. Despite somewhat suggestive haplotype results, overall our study does not support an association between TNF variants and prostate cancer risk. C1 [Danforth, Kim N.; Hayes, Richard B.; Huang, Wen-Yi; Yu, Kai; Figueroa, Jonine D.; Chanock, Stephen J.; Hsing, Ann W.] Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD USA. [Rodriguez, Carmen; Calle, Eugenia E.; Jacobs, Eric J.; Thun, Michael J.] Amer Canc Soc, Dept Epidemiol & Surveillance Res, Atlanta, GA 30329 USA. [Sakoda, Lori C.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [Chen, Bingshu E.] Concordia Univ, Dept Math & Stat, Montreal, PQ H4B 1R6, Canada. [Andriole, Gerald L.] Washington Univ, Sch Med, Div Urol Surg, St Louis, MO 63110 USA. [Figueroa, Jonine D.] Natl Canc Inst, Div Canc Prevent, NIH, DHHS, Bethesda, MD USA. [Yeager, Meredith; Chanock, Stephen J.] SAIC Frederick Inc, Core Genotyping Facil, Div Canc Epidemiol & Genet, Adv Technol Program, Frederick, MD USA. [Platz, Elizabeth A.] Johns Hopkins Bloomberg, Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Michaud, Dominique S.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Chanock, Stephen J.] Ctr Canc Res, Natl Canc Inst, NIH, DHHS, Bethesda, MD USA. RP Danforth, KN (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,Suite 550,MSC 7234, Rockville, MD 20852 USA. EM danfortk@mail.nih.gov RI Michaud, Dominique/I-5231-2014; OI Hayes, Richard/0000-0002-0918-661X FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 29 TC 26 Z9 29 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD MAR 1 PY 2008 VL 68 IS 4 BP 400 EP 407 DI 10.1002/pros.20694 PG 8 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 272TM UT WOS:000253882900006 PM 18196539 ER PT J AU Woo, JH Liu, JS Kang, SH Singh, R Park, SK Su, YP Ortiz, J Neville, DM Willingham, MC Frankel, AE AF Woo, Jung Hee Liu, Jen-Sing Kang, Soo Hyun Singh, Ravibhushan Park, Seong Kyu Su, Yunpeng Ortiz, Janelle Neville, David M., Jr. Willingham, Mark C. Frankel, Arthur E. TI GMP production and characterization of the bivalent anti-human T cell immunotoxin, A-dmDT390-bisFv(UCHTl) for phase I/II clinical trials SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE diphtheria toxin; UCHT1; CD3 positive; Pichia pastoris ID PICHIA-PASTORIS; CHAIN IMMUNOTOXIN; DIPHTHERIA-TOXIN; EFFICACY; LYMPHOMA; PROTEIN; SECRETION; DEPLETION; TOXICITY; MUTANTS AB The bivalent anti-T cell immunotoxin, A-dmDT390-bisFv(UCHT1), was developed for treatment of T-cell leukemia, autoimmune diseases and tolerance induction for transplantation. To obtain clinical grade bivalent anti-T cell immunotoxin for phase I/II clinical trials, a single batch of 120 L bioreactor culture was performed using the Pichia pastoris mutEF2JC307-8(2) strain expressing the bivalent anti-T cell immunotoxin. After 162 h induction of the culture by methanol, the culture medium was harvested by a 0.1 mu m hollow-fiber microfiltration step. The recombinant protein was purified by a 3-step purification procedure (Butyl 650 M capturing step, borate anion exchange step and final Poros anion exchange step). The final material was filter sterilized, aseptically vialed, and stored at -80 degrees C. Expression level was 207 mg/L of culture supernatant and the final production yield was 69.6% or 144.2 mg/L of culture supernatant. The final product was characterized by multiple assays. Vialed product was sterile. The drug concentration was 0.8 mg/mL in 150 mM NaCl, 5% glycerol, 1 mM EDTA, and 5 mM Tris (pH 8.0). Purity by SDS-PAGE was 98%. Aggregates by Superdex 200 HPLC were < 1%. Potency revealed a 20 h IC50 of 17 fM on Jurkat cells. Endotoxin level was 0.02 U/mg. Chemical and biologic assays confirmed the purity, composition, and functional activities of the molecule. The drug did not react with tested frozen human tissue sections except for T cells. LD10 in mice was between 500 and 750 mu g/kg. There was no evidence of loss of solubility, proteolysis, aggregation, or loss of potency over 1.5 year at -80 degrees C. The scalable synthesis of this protein drug should be useful for production for phase I/II clinical trials and can be applicable for other diphtheria toxin fusion drugs for clinical development. (c) 2007 Elsevier Inc. All rights reserved. C1 [Woo, Jung Hee; Liu, Jen-Sing; Kang, Soo Hyun; Singh, Ravibhushan; Park, Seong Kyu; Su, Yunpeng; Ortiz, Janelle; Frankel, Arthur E.] Scott & White Mem Hosp & Clin, Scott & White Canc Res Inst, Temple, TX 76502 USA. [Neville, David M., Jr.] NIMH, Biophys Chem Sect, Mol Biol Lab, Bethesda, MD 20892 USA. [Willingham, Mark C.] Wake Forest Univ, Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. RP Woo, JH (reprint author), Scott & White Mem Hosp & Clin, Scott & White Canc Res Inst, 5701 S Airport Rd, Temple, TX 76502 USA. EM jwoo@swmail.sw.org NR 28 TC 14 Z9 17 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD MAR PY 2008 VL 58 IS 1 BP 1 EP 11 DI 10.1016/j.pep.2007.11.006 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 268GW UT WOS:000253568700001 PM 18160309 ER PT J AU Emekli, U Schneidman-Duhovny, D Wolfson, HJ Nussinov, R Haliloglu, T AF Emekli, Ugur Schneidman-Duhovny, Dina Wolfson, Haim J. Nussinov, Ruth Haliloglu, Turkan TI HingeProt: Automated prediction of hinges in protein structures SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article ID NORMAL-MODE ANALYSIS; ELASTIC NETWORK MODEL; CONFORMATIONAL-CHANGES; DOMAIN MOVEMENTS; LIGAND DOCKING; DYNAMICS; FLEXIBILITY; DATABASE; MOTIONS; MECHANISMS AB Proteins are highly flexible molecules. Prediction of molecular flexibility aids in the comprehension and prediction of protein function and in providing details of functional mechanisms. The ability to predict the locations, directions, and extent Of molecular movements can assist in fitting atomic resolution structures to low-resolution EM density maps and in predicting the complex structures of interacting molecules (docking). There are several types of molecular movements. In this work, we focus on the prediction of hinge movements. Given a single protein structure, the method automatically divides it into the rigid parts and the hinge regions connecting them. The method employs the Elastic Network Model, which is very efficient and was validated against a large data set of proteins. The output can be used in applications such as flexible protein-protein and protein-ligand docking, flexible docking of protein structures into cryo-EM maps, and refinement of low-resolution EM structures. The web server of HingeProt provides convenient visualization of the results and is available with two mirror sites at http://www.prc.boun. edu.tr/appserv/prc/HingeProt3 and http:// bioinfo3d.cs.tau.ac.il/HingeProt/. C1 [Emekli, Ugur; Haliloglu, Turkan] Bogazici Univ, Polymer Res Ctr, TR-34342 Istanbul, Turkey. [Emekli, Ugur; Haliloglu, Turkan] Bogazici Univ, Dept Chem Engn, TR-34342 Istanbul, Turkey. [Schneidman-Duhovny, Dina; Wolfson, Haim J.] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Nussinov, Ruth] NCI, Basic Res Program, SAIC Frederick Inc, 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 Haliloglu, T (reprint author), Bogazici Univ, Polymer Res Ctr, TR-34342 Istanbul, Turkey. EM halilogt@boun.edu.tr RI Wolfson, Haim/A-1837-2011 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400]; PHS HHS [1UC1AIO67231] NR 46 TC 111 Z9 111 U1 1 U2 11 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 MAR PY 2008 VL 70 IS 4 BP 1219 EP 1227 DI 10.1002/prot.21613 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 268GN UT WOS:000253567400012 PM 17847101 ER PT J AU Ishima, R Louis, JM AF Ishima, Rieko Louis, John M. TI A diverse view of protein dynamics from NMR studies of HIV-1 protease flaps SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE dynamics; molecular dynamics; AIDS; retrovirus; relaxation ID MOLECULAR-DYNAMICS; DRUG-RESISTANCE; SIMULATIONS; RELAXATION; INHIBITOR; MECHANISM; MONOMER; BINDING; CONFORMATIONS; FLUCTUATIONS AB Internal motion in proteins fulfills a multitude of roles in biological processes. NMR spectroscopy has been applied to elucidate protein dynamics at the atomic level, albeit at a low resolution, and is often complemented by molecular dynamics simulation. However, it is critical to justify the consistency between simulation results and conclusions often drawn from multiple experiments in which uncertainties arising from assumed motional models may not be explicitly evaluated. To understand the role of the flaps of HIV-1 protease dimer in substrate recognition and protease function, many molecular dynamics simulations have been performed. The simulations have resulted in various proposed models of the flap dynamics, some of which are more consistent than others with our working model previously derived from experiments. However, using the working model to discriminate among the simulation results is not straightforward because the working model was derived from a combination of NMR experiments and crystal structure data. In this study, we use the NMR chemical shifts and relaxation data of the protease "monomer" rather than structural data to narrow down the possible conformations of the flaps of the "dimer". For the first time, we show that the tips of the flaps in the unliganded protease dimer interact with each other in solution. Accordingly, we discuss the consistency of the simulations with the model derived from all experimental data. C1 [Ishima, Rieko] Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15260 USA. [Louis, John M.] NIDDKD, Natl Inst Hlth, Chem Phys Lab, Bethesda, MD 20892 USA. RP Ishima, R (reprint author), Rm 1037,Biomed Sci Tower 3,3501 5th Ave, Pittsburgh, PA 15260 USA. EM ishima@pitt.edu FU Intramural NIH HHS [Z99 DK999999] NR 33 TC 25 Z9 25 U1 0 U2 6 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD MAR PY 2008 VL 70 IS 4 BP 1408 EP 1415 DI 10.1002/prot.21632 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 268GN UT WOS:000253567400029 PM 17894346 ER PT J AU Wiener, LS Steffen-Smith, E Battles, HB Wayne, A Love, CP Fry, T AF Wiener, Lori S. Steffen-Smith, Emilie Battles, Haven B. Wayne, Alan Love, Cynthia P. Fry, Terry TI Sibling stem cell donor experiences at a single institution SO PSYCHO-ONCOLOGY LA English DT Article DE hematopoietic stem cell transplantation; bone marrow and peripheral blood stem cell transplantation; pediatric sibling donors; psychosocial adjustment ID BONE-MARROW TRANSPLANTATION; PEDIATRIC BLOOD; COLLECTION; CHILDREN; MEMORY AB Allogeneic bone marrow (BM) and cytokine mobilized peripheral blood stem cell (PBSC) transplantation can be curative for patients with malignant and nonmalignant hematologic diseases. Siblings are most often selected as a donor match; however, research on sibling donors is limited and has focused primarily on conventional BM donors. This exploratory study describes the experiences of PBSC sibling donors at a single institution. Through retrospective interviews, 14 sibling donors shared their perceived needs and concerns before and after their stem cell. collection. Donors identified fears about the donation procedure, and expressed the need for more information about transplant outcome and complications. The inclusion of the sibling donors themselves, rather than the report of their parents or health-care providers and the qualitative nature of the structured design allowed sibling donors to describe their concerns and thoughts without being restrained by the beliefs of the participant's parents, researcher or sibling's medical team. Suggestions for visual educational tools, psychosocial interventions and future research are provided. Published in 2007 by John Wiley & Sons, Ltd. C1 [Wiener, Lori S.; Steffen-Smith, Emilie; Battles, Haven B.; Wayne, Alan; Love, Cynthia P.; Fry, Terry] NCI, Pediat Oncol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Wiener, LS (reprint author), NCI, Pediat Psychosocial Support & Res Program, SE Pediat Clin 1, 9000 Rockville Pike Bldg 10,Rm 6466, Bethesda, MD 20892 USA. EM wienel@mail.nih-gov FU Intramural NIH HHS [Z99 CA999999] NR 14 TC 29 Z9 29 U1 0 U2 4 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 MAR PY 2008 VL 17 IS 3 BP 304 EP 307 DI 10.1002/pon.1222 PG 4 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 280GJ UT WOS:000254413400013 PM 17534868 ER PT J AU Brennan, T Wiener, L Ballard, E Pao, M Battles, H AF Brennan, T. Wiener, L. Ballard, E. Pao, M. Battles, H. TI The development of an advanced care planning tool for adolescents and young adults with high risk cancer or HIV disease SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 [Brennan, T.; Wiener, L.; Battles, H.] NCI, Bethesda, MD 20892 USA. [Ballard, E.; Pao, M.] NIMH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 2 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 MAR PY 2008 VL 17 IS 3 SU S BP S31 EP S32 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 281PG UT WOS:000254509900056 ER PT J AU Kwak, K Putnick, DL Bornstein, MH AF Kwak, Keumjoo Putnick, Diane L. Bornstein, Marc H. TI Child and mother play in South Korea: A longitudinal study across the second year of life SO PSYCHOLOGIA LA English DT Article DE Korea; play; mother-infant interaction ID SYMBOLIC PLAY; PRETENSE PLAY; LANGUAGE; PSYCHOLOGY; STABILITY; TODDLERS; CONTEXT AB Play is a predominant individual and social activity of early childhood and has been related to young children's early cognitive growth, social development, and preparation for formal schooling. We examined individual differences and developmental changes in South Korean child and mother exploratory and symbolic play longitudinally when children were 13 and 20 months of age. Children engaged in less exploratory and more symbolic play when playing collaboratively with their mothers than when playing alone. Children engaged in more symbolic play at 20 months than 13 months. Child solitary and collaborative symbolic play were modestly stable across time, but child exploratory play and maternal play were not. Child solitary and collaborative symbolic play were correlated across the two ages. Child and mother play were regularly associated at the two ages, and 13-month maternal play predicted 20-month child collaborative play. The cross-cultural validity of play is affirmed, and individual differences and age-related changes in child and mother play are partly mediated by matched partner play and partly motivated by processes independent of partner play. C1 [Putnick, Diane L.; Bornstein, Marc H.] NICHHD, NIH, Bethesda, MD 20892 USA. [Kwak, Keumjoo] Seoul Natl Univ, Seoul 151, South Korea. RP Bornstein, MH (reprint author), NICHHD, NIH, Suite 8030,6705 Rockledge Dr, Bethesda, MD 20892 USA. EM Marc_H_Bornstein@nih.gov RI Putnick, Diane/B-1707-2009 FU Intramural NIH HHS [Z99 HD999999] NR 44 TC 1 Z9 1 U1 1 U2 5 PU PSYCHOLOGIA SOC PI KYOTO PA DEPT EDUC PSYCHOL FAC EDUC KYOTO UNIV, KYOTO, 606, JAPAN SN 0033-2852 J9 PSYCHOLOGIA JI Psychologia PD MAR PY 2008 VL 51 IS 1 BP 14 EP 27 DI 10.2117/psysoc.2008.14 PG 14 WC Psychology, Multidisciplinary SC Psychology GA 290ML UT WOS:000255126800002 PM 21197419 ER PT J AU Spiller, K Xi, ZX Peng, XQ Newman, AH Ashby, CR Heidbreder, C Gaal, J Gardner, EL AF Spiller, Krista Xi, Zheng-Xiong Peng, Xiao-Qing Newman, Amy H. Ashby, Charles R., Jr. Heidbreder, Christian Gaal, Jozsef Gardner, Eliot L. TI The selective dopamine D-3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D-3 receptor agonist BP-897 attenuate methamphetamine-enhanced brain stimulation reward in rats SO PSYCHOPHARMACOLOGY LA English DT Article DE methamphetamine; dopamine; D-3 receptor; brain reward; SB-277011A; NGB 2904; BP-897 ID COCAINE-SEEKING BEHAVIOR; SELF-STIMULATION; INDUCED REINSTATEMENT; PROGRESSIVE-RATIO; PLACE PREFERENCE; D3 RECEPTORS; NICOTINE; NEUROTOXICITY; SENSITIZATION; INHIBITION AB Rationale We have previously reported that selective antagonism of brain D-3 receptors by SB-277011A or NGB 2904 significantly attenuates cocaine- or nicotine-enhanced brain stimulation reward (BSR). Objective In the present study, we investigated whether the selective D-3 receptor antagonists SB-277011A and NGB 2904 and the putative partial D-3 agonist BP-897 similarly reduce methamphetamine (METH)-enhanced BSR. Materials and methods Rats were trained to respond for rewarding electrical self-stimulation of the medial forebrain bundle. To assess the degree of drug-induced changes in BSR, a rate-frequency curve shift paradigm was used to measure brain-reward threshold (theta(0)). Results METH (0.1-0.65 mg/kg, i.p.) dose-dependently lowered (similar to 10-50%) BSR thresholds, producing an enhancement of BSR. Pretreatment with SB-277011A (12 mg/kg, but not 24 mg/kg, i.p.) significantly attenuated METH-enhanced BSR. NGB 2904 (0.1-1.0 mg/kg, but not 10 mg/kg) also attenuated METH-enhanced BSR. SB-277011A or NGB 2904 alone, at the doses tested, had no effect on BSR. Pretreatment with BP-897 (0.1-5 mg/kg) dose-dependently attenuated METH-enhanced BSR. However, when the dose was increased to 10 mg/kg, BP-897 shifted the stimulation-response curve to the right (inhibited BSR itself) in the presence or absence of METH. Conclusions Selective antagonism of D-3 receptors by SB-277011A or NGB 2904 attenuates METH-enhanced BSR in rats, while the METH-enhanced BSR attenuation produced by BP-897 may involve both D-3 and non-D-3 receptors. These findings support a potential use of selective D-3 receptor antagonists for the treatment of METH addiction. C1 [Spiller, Krista; Xi, Zheng-Xiong; Peng, Xiao-Qing; Newman, Amy H.; Gardner, Eliot L.] Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. [Ashby, Charles R., Jr.] St Johns Univ, Dept Pharmaceut Sci, Jamaica, NY 11439 USA. [Heidbreder, Christian] GlaxoSmithKline Inc, Ctr Psychiat Excellence Drug Discovery, Verona, Italy. [Gaal, Jozsef] MegaPharma Kft, Budapest, Hungary. RP Xi, ZX (reprint author), Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. EM zxi@intra.nida.nih.gov OI PENG, XIAOQING/0000-0002-7272-5428 FU Intramural NIH HHS [Z99 DA999999] NR 52 TC 47 Z9 49 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2008 VL 196 IS 4 BP 533 EP 542 DI 10.1007/s00213-007-0986-6 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 263FF UT WOS:000253202300004 PM 17985117 ER PT J AU Arbab, AS Frank, JA AF Arbab, Ali S. Frank, Joseph A. TI Cellular MRI and its role in stem cell therapy SO REGENERATIVE MEDICINE LA English DT Review DE cellular MRI; ferumoxides-protamine sulfate; magnetic cell labeling; SPIO; stem cell tracking ID HEMATOPOIETIC PROGENITOR CELLS; SODIUM-IODIDE SYMPORTER; IN-VIVO TRACKING; POSITRON-EMISSION-TOMOGRAPHY; ACUTE MYOCARDIAL-INFARCTION; TUMOR INFILTRATING LYMPHOCYTES; MAGNETIC-RESONANCE TRACKING; CENTRAL-NERVOUS-SYSTEM; MODIFIED CD34(+) CELLS; SPINAL-CORD-INJURY AB Hematopoietic, stromal and organ-specific stem cells are under evaluation for therapeutic efficacy in cell-based therapies of cardiac, neurological and other disorders. It is critically important to track the location of directly transplanted or infused cells that can serve as gene carrier/delivery vehicles for the treatment of disease processes and be able to noninvasively monitor the temporal and spatial homing of these cells to target tissues. Moreover, it is also necessary to determine their engraftment efficiency and functional capability following transplantation. There are various in vivo imaging modalities used to track the movement and incorporation of administered cells. Tagging stem cells with different contrast agents can make these cells probes for different imaging modalities. Recent reports have shown that stem cells labeled with iron oxides can be used as cellular MRI probes demonstrating the cell trafficking to target tissues. In this review, we will discuss the status and future prospect of stem cell tracking by cellular MRI for cell-based therapy. C1 [Arbab, Ali S.] Henry Ford Hosp, Cellular & Mol Imaging Lab, Dept Radiol, Detroit, MI 48202 USA. [Frank, Joseph A.] NIH, Bethesda, MD 20892 USA. RP Arbab, AS (reprint author), Henry Ford Hosp, Cellular & Mol Imaging Lab, Dept Radiol, 1 Ford Pl,2F, Detroit, MI 48202 USA. EM saali@rad.hfh.edu FU Intramural NIH HHS NR 193 TC 53 Z9 55 U1 0 U2 27 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0751 J9 REGEN MED JI Regen. Med. PD MAR PY 2008 VL 3 IS 2 BP 199 EP 215 DI 10.2217/17460751.3.2.199 PG 17 WC Cell & Tissue Engineering; Engineering, Biomedical SC Cell Biology; Engineering GA 331EH UT WOS:000257995000014 PM 18307404 ER PT J AU Barr-Anderson, DJ Neumark-Sztainer, D Schmitz, KH Ward, DS Conway, TL Pratt, C Baggett, CD Lytle, L Pate, RR AF Barr-Anderson, Daheia J. Neumark-Sztainer, Dianne Schmitz, Kathryn H. Ward, Dianne S. Conway, Terry L. Pratt, Charlotte Baggett, Chris D. Lytle, Leslie Pate, Russell R. TI But I like PE: Factors associated with enjoyment of physical education class in middle school girls SO RESEARCH QUARTERLY FOR EXERCISE AND SPORT LA English DT Article DE adolescents; physical activity; school climate; self-efficacy ID ADOLESCENT GIRLS; SELF-EFFICACY; ACTIVITY INTERVENTION; CHILDREN; YOUTH; QUESTIONNAIRES; DETERMINANTS; PROMOTION; OBESITY; TRIAL AB The current study examined associations between physical education (PE) class enjoyment and sociodemographic, personal, and perceived school environment factors among early adolescent girls. Participants included 1,511 sixth-grade girls who completed baseline assessments for the Trial of Activity in Adolescent Girls, with 50 % indicating they enjoyed PE class a lot. Variables positively associated with PE class enjoyment included physical activity level, perceived benefits of physical activity, self-efficacy for leisure time physical activity, and perceived school climate for girls' physical activity as influenced by teachers, while body mass index was inversely associated with PE class enjoyment. After adjusting for all variables in the model, PE class enjoyment was significantly greater in Blacks than in Whites. In model testing, with mutual adjustment for all variables, self-efficacy was the strongest correlate of PE class enjoyment, followed by perceived benefits, race/ethnicity, and teachers' support for girls' physical activity, as compared to boys, at school. The overall model explained 11% of the variance in PE class enjoyment. Findings suggest that efforts to enhance girls' self-efficacy and perceived benefits and to provide a supportive PE class environment that promotes gender equality can potentially increase PE class enjoyment among young girls. C1 [Barr-Anderson, Daheia J.; Neumark-Sztainer, Dianne; Lytle, Leslie] Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. [Schmitz, Kathryn H.] Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. [Ward, Dianne S.] Univ N Carolina, Dept Nutr, Chapel Hill, NC USA. [Conway, Terry L.] San Diego State Univ, Grad Sch Publ Hlth, San Diego, CA 92182 USA. [Pratt, Charlotte] NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD USA. [Baggett, Chris D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. [Pate, Russell R.] Univ S Carolina, Dept Exercise Sci, Columbia, SC 29208 USA. RP Barr-Anderson, DJ (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300 S 2nd St,Suite 300, Minneapolis, MN 55454 USA. EM barranderson@epi.umn.edu RI Schmitz, Kathryn/B-7154-2011; Neumark-Sztainer, Dianne/D-8574-2011; OI Neumark-Sztainer, Dianne/0000-0001-9435-1669 FU NHLBI NIH HHS [U01 HL066845, U01 HL066845-06, U01 HL066852, U01 HL066853, U01 HL066855, U01 HL066856, U01 HL066857, U01 HL066858, U01HL66845, U01HL66852, U01HL66853, U01HL66855, U01HL66856, U01HL66858] NR 39 TC 40 Z9 42 U1 2 U2 9 PU AMER ALLIANCE HEALTH PHYS EDUC REC & DANCE PI RESTON PA 1900 ASSOCIATION DRIVE, RESTON, VA 22091 USA SN 0270-1367 J9 RES Q EXERCISE SPORT JI Res. Q. Exerc. Sport PD MAR PY 2008 VL 79 IS 1 BP 18 EP 27 PG 10 WC Hospitality, Leisure, Sport & Tourism; Psychology, Applied; Psychology; Sport Sciences SC Social Sciences - Other Topics; Psychology; Sport Sciences GA 282AR UT WOS:000254540500003 PM 18431947 ER PT J AU Horvath, A Stratakis, CA AF Horvath, Anelia Stratakis, Constantine A. TI Clinical and molecular genetics of acromegaly: MEN1, Carney complex, McCune-Albright syndrome, familial acromegaly and genetic defects in sporadic tumors SO REVIEWS IN ENDOCRINE & METABOLIC DISORDERS LA English DT Review DE pituitary tumors; multiple endocrine neoplasia; Carney complex; growth factors; oncogenes; tumor-suppressor genes ID MULTIPLE ENDOCRINE NEOPLASIA; HUMAN PITUITARY-TUMORS; HISTONE METHYLTRANSFERASE COMPLEX; SPOTTY SKIN PIGMENTATION; GROWTH-HORMONE EXCESS; PROTEIN-KINASE-C; REGULATORY SUBUNIT; TYPE-1 GENE; GS-ALPHA; INTERACTING PROTEIN AB Pituitary tumors are among the most common neoplasms in man; they account for approximately 15% of all primary intracranial lesions (Jagannathan et al., Neurosurg Focus, 19:E4, 2005). Although almost never malignant and rarely clinically expressed, pituitary tumors may cause significant morbidity in affected patients. First, given the critical location of the gland, large tumors may lead to mass effects, and, second, proliferation of hormone-secreting pituitary cells leads to endocrine syndromes. Acromegaly results from oversecretion of growth hormone (GH) by the proliferating somatotrophs. Despite the significant efforts made over the last decade, still little is known about the genetic causes of common pituitary tumors and even less is applied from this knowledge therapeutically. In this review, we present an update on the genetic syndromes associated with pituitary adenomas and discuss the related genetic defects. We next review findings on sporadic, non-genetic, pituitary tumors with an emphasis on pathways and animal models of pituitary disease. In conclusion, we attempt to present an overall, integrative approach to the human molecular genetics of both familiar and sporadic pituitary tumors. C1 [Horvath, Anelia; Stratakis, Constantine A.] NICHHD, SEGEN, PDEGEN, NIH, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHHD, SEGEN, PDEGEN, NIH, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov NR 114 TC 44 Z9 47 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1389-9155 J9 REV ENDOCR METAB DIS JI Rev. Endocr. Metab. Disord. PD MAR PY 2008 VL 9 IS 1 BP 1 EP 11 DI 10.1007/s11154-007-9066-9 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 260FK UT WOS:000252996000001 PM 18200440 ER PT J AU O'Donnel, CJ Elosua, R AF O'Donnel, Christopher J. Elosua, Roberto TI Cardiovascular risk factors. Insights from Framingham Heart Study SO REVISTA ESPANOLA DE CARDIOLOGIA LA Spanish DT Review DE cardiovascular disease; coronary heart disease; epidemiology; prevention; risk factor ID DENSITY-LIPOPROTEIN-CHOLESTEROL; BODY-MASS INDEX; AMERICAN-DIABETES-ASSOCIATION; LONG-TERM CORONARY; BLOOD-PRESSURE; PHYSICAL-ACTIVITY; SERUM-CHOLESTEROL; FOLLOW-UP; SYSTOLIC HYPERTENSION; SCIENTIFIC STATEMENT AB Epidemiology involves the study of disease frequency and its determinants within the population. Cardiovascular epidemiology began in the 1930s as a result of changes observed in the causes of death. In the 1950s, several epidemiological studies were set in motion with the aim of clarifying the cause of cardiovascular disease. Four years after the Framingham Heart Study started, researchers had identified high cholesterol and high blood pressure levels as important factors in the development of cardiovascular disease. In subsequent years, the Framingham study and other epidemiological studies have helped to identify other risk factors, which are now considered classical risk factors. By coining the expression << risk factor >>, the Framingham Heart Study helped to bring about a change in the way medicine is practiced. Today, a risk factor is defined as a measurable characteristic that is causally associated with increased disease frequency and that is a significant independent predictor of an increased risk of presenting with the disease. This wide-ranging overview describes some of the most important insights into the causes of cardiovascular disease to have come from the Framingham Heart Study. The emphasis is on the identification of risk factors, and the assessment of their predictive ability and their implications for disease prevention. C1 [O'Donnel, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. [O'Donnel, Christopher J.] Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol, Boston, MA USA. [Elosua, Roberto] Inst Municipal Invest Med, Hosp Mar, Unidad Lipidos Epidemiol Cardiovasc, E-08003 Barcelona, Spain. [Elosua, Roberto] CIBERESP, Barcelona, Spain. RP O'Donnel, CJ (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. OI ELOSUA, ROBERTO/0000-0001-8235-0095 NR 116 TC 55 Z9 70 U1 2 U2 17 PU EDICIONES DOYMA S A PI BARCELONA PA TRAV DE GRACIA 17-21, 08021 BARCELONA, SPAIN SN 0300-8932 J9 REV ESP CARDIOL JI Rev. Esp. Cardiol. PD MAR PY 2008 VL 61 IS 3 BP 299 EP 310 DI 10.1016/S1885-5857(08)60118-8 PG 12 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 278DV UT WOS:000254265000012 PM 18361904 ER PT J AU Kamala, T AF Kamala, T. TI An optimized immunomagnetic bead-based negative selection protocol for CD4 T-cell isolation from mouse lymph nodes and spleen SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Article ID LYMPHOCYTES; SEPARATION; MOBILITY AB This study describes an immunomagnetic bead-based methodology for optimal purification of mouse CD4(+) T cells. It reproducibly yields highly pure CD4(+) T cells from mouse lymph nodes (95-99%) and spleen (93-96%) with no residual antigen-presenting cell (APC) function in the purified population. The recovery of the starting CD4(+) T-cell population is consistently high (> 70%) and many samples can be simultaneously processed in a short period of time. The key factors responsible for improved purity are combinations of monoclonal antibodies that were found, through trial and error, to yield T cells of maximal purity achievable by non-flow sort-based negative selection. These cocktails efficiently target unwanted cell subsets with antibodies against multiple surface markers expressed by non-CD4(+) T cells. Because immunomagnetic bead-based protocols do not require the expensive and cumbersome processes required by flow sort-based purification, the methodology described here should find widespread use. C1 [Kamala, T.] NIAID, Sect T Cell Tolerance & Memory Ghost Lab, LCMI, NIH, Bethesda, MD 20892 USA. RP Kamala, T (reprint author), Bldg 4,Rm 111,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tkamala@niaid.nih.gov FU Intramural NIH HHS NR 16 TC 2 Z9 2 U1 1 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD MAR PY 2008 VL 67 IS 3 BP 285 EP 294 DI 10.1111/j.1365-3083.2007.02066.x PG 10 WC Immunology SC Immunology GA 258WU UT WOS:000252901600010 PM 18261040 ER PT J AU Arango, C Moreno, C Martinez, S Parellada, M Desco, M Moreno, D Fraguas, D Gogtay, N James, A Rapoport, J AF Arango, Celso Moreno, Carmen Martinez, Salvador Parellada, Mara Desco, Manuel Moreno, Dolores Fraguas, David Gogtay, Nitin James, Anthony Rapoport, Judith TI Longitudinal brain changes in early-onset psychosis SO SCHIZOPHRENIA BULLETIN LA English DT Article DE early-onset; MRI; children; adolescents; psychosis; neurodevelopment ID GRAY-MATTER DEFICITS; PREFRONTAL CORTEX; 1ST-EPISODE SCHIZOPHRENIA; EARLY ADULTHOOD; CORTICAL DEVELOPMENT; SEXUAL-DIMORPHISM; GENE-EXPRESSION; GROWTH-FACTOR; VOLUME LOSS; CHILDHOOD AB Progressive losses of cortical gray matter volumes and increases in ventricular volumes have been reported in patients with childhood-onset schizophrenia (COS) during adolescence. Longitudinal studies suggest that the rate of cortical loss seen in COS during adolescence plateaus during early adulthood. Patients with first-episode adolescent-onset schizophrenia show less marked progressive changes, although the number of studies in this population is small. Some studies show that, although less exaggerated, progressive changes are also present in nonschizophrenia early-onset psychosis. The greater loss of brain tissue seen in COS, even some years after the first episode, as compared to adolescent- or adult-onset schizophrenia may be due to variables such as sample bias (more severe, treatment refractory sample of childhood-onset patients studied), a process uniquely related to adolescent development in COS, differential brain effects of drug treatment in this population, clinical outcome, or interactions among these variables. Findings from both cross-sectional studies of first-episode patients and longitudinal studies in COS and adolescent onset support the concept of early-onset schizophrenia as a progressive neurodevelopmental disorder with both early and late developmental abnormalities. Future studies should look for correlates at a cellular level and for pathophysiological explanations of volume changes in these populations. The association of risk genes involved in circuitries associated with schizophrenia and their relationship to developmental trajectories is another promising area of future research. C1 [Arango, Celso; Moreno, Carmen; Parellada, Mara; Fraguas, David] Hosp Gen Univ Gregorio Maranon, Dept Psychiat, Adolescent Unit, Madrid, Spain. [Martinez, Salvador] Univ Miguel Hernandez, Inst Neurociencias, Alicante, Spain. [Desco, Manuel] Hosp Gen Univ Gregorio Maranon, Unidad Med & Cirugia Expt, Madrid, Spain. [Gogtay, Nitin; Rapoport, Judith] NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. [James, Anthony] Warneford Hosp, Highfield Adolescent Unit, Oxford OX3 7JX, England. RP Arango, C (reprint author), Univ Maryland, Maryland Psychiat Res Ctr, College Pk, MD 20742 USA. EM Carango@mprc.umaryland.edu RI Gogtay, Nitin/A-3035-2008; Arango Lopez, Celso/H-6433-2015; Desco, Manuel/D-2822-2009; OI Arango Lopez, Celso/0000-0003-3382-4754; Desco, Manuel/0000-0003-0989-3231; Moreno, Carmen/0000-0003-0541-4846; Martinez, Salvador/0000-0002-9320-4103; Martinez, Salvador/0000-0002-2910-8926 NR 75 TC 58 Z9 59 U1 6 U2 14 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD MAR PY 2008 VL 34 IS 2 BP 341 EP 353 DI 10.1093/schbul/sbm157 PG 13 WC Psychiatry SC Psychiatry GA 272KX UT WOS:000253859400024 PM 18234701 ER PT J AU Swartz, MS Wagner, HR Swanson, JW Stroup, IS McEvoy, JP Reimherr, F Miller, DD Mcgee, M Khan, A Canive, JM Davis, SM Hsiao, JK Lieberman, JA Adler, L Bari, M Belz, I Bland, R Blocher, T Bolyard, B Buffenstein, A Burruss, J Byerly, M Canive, J Caroff, S Casat, C Chavez-Rice, E Csernansky, J Delgado, P Douyon, R D'Souza, C Glick, I Goff, D Gratz, S Grossberg, GT Hale, M Hamner, M Jaffe, R Jeste, D Kablinger, A Khan, A Lamberti, S Levy, MT Lieberman, J Maguire, G Manschreck, T McEvoy, J McGee, M Meltzer, H Miller, A Miller, DD Nasrallah, H Nemeroff, C Olson, S Oxenkrug, GF Patel, J Reimher, F Riggio, S Risch, S Saltz, B Simpatico, T Simpson, G Smith, M Sommi, R Steinbook, RM Stevens, M Torres, R Weiden, P Wolberg, J AF Swartz, Marvin S. Wagner, H. Ryan Swanson, Jeffrey W. Stroup, I. Scott McEvoy, Joseph P. Reimherr, Fred Miller, Del D. McGee, Mark Khan, Ahsan Canive, Jose M. Davis, Sonia M. Hsiao, John K. Lieberman, Jeffrey A. Adler, Lawrence Bari, Mohammed Belz, Irving Bland, Raymond Blocher, Thomas Bolyard, Brent Buffenstein, Alan Burruss, John Byerly, Matthew Canive, Jose Caroff, Stanley Casat, Charles Chavez-Rice, Eugenio Csernansky, John Delgado, Pedro Douyon, Richard D'Souza, Cyril Glick, Ira Goff, Donald Gratz, Silvia Grossberg, George T. Hale, Mahlon Hamner, Mark Jaffe, Richard Jeste, Dilip Kablinger, Anita Khan, Ahsan Lamberti, Steve Levy, Michael T. Lieberman, Jeffrey Maguire, Gerald Manschreck, Theo McEvoy, Joseph McGee, Mark Meltzer, Herbert Miller, Alexander Miller, Del D. Nasrallah, Henry Nemeroff, Charles Olson, Stephen Oxenkrug, Gregory F. Patel, Jayendra Reimher, Frederick Riggio, Silvana Risch, Samuel Saltz, Bruce Simpatico, Thomas Simpson, George Smith, Michael Sommi, Roger Steinbook, Richard M. Stevens, Michael Torres, Rafael Weiden, Peter Wolberg, James CA CATIE Investigators TI The effectiveness of antipsychotic medications in patients who use or avoid illicit substances: Results from the CATIE study SO SCHIZOPHRENIA RESEARCH LA English DT Article DE schizophrenia; antipsychotics; substance abuse; dual disorders ID INTERVENTION EFFECTIVENESS CATIE; SEVERE MENTAL-ILLNESS; CHRONIC-SCHIZOPHRENIA; USE DISORDERS; NIMH CATIE; DUAL DIAGNOSIS; ABUSE; TRIAL; RISPERIDONE; PREVALENCE AB Objective: This double-blind study compared a second generation (atypical) antipsychotic drugs compared to a representative older agent for patients with schizophrenia who use or avoid illicit substances. Methods: Schizophrenic subjects were recruited at 57 U.S. sites and randomly assigned to olanzapine, perphenazine, quetiapine, risperidone or ziprasidone for up to 18 months. The primary aim of this analysis was to delineate differences between the overall effectiveness of these five treatments among patients who used or did not use illicit substances. Results: There were no significant differences between treatment groups in time to all-cause treatment discontinuation among patients who use illicit drugs (median 3.3 to 6.8 months). Among non-users time to treatment discontinuation was significantly longer for patients treated with olanzapine (median 13.0 months) than perphenazine (5.9 months), risperidone(5.6 months), or quetiapine(5.0 months); time to discontinuation for ziprasidone(4.3 months) was even shorter, although the latter difference was not significant. The difference between risperidone and quetiapine, although small, was significant. All remaining differences were non-significant. Similar results were found for discontinuation due to inefficacy. There were no differences between illicit users and non-users in symptom reduction and global improvement, after adjustment for differential duration of treatment. Differences in discontinuation results were attenuated by non-compliance, but the trends persisted after controlling for treatment compliance. Conclusions: Among patients with chronic schizophrenia who avoid use of illicit drugs, olanzapine was more effective than other antipsychotics as reflected by longer time to all-cause discontinuation, but illicit substance abuse attenuated this advantage, reinforcing the need for concurrent substance abuse treatment. (C) 2007 Elsevier B.V. All rights reserved. C1 [Swartz, Marvin S.] Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Med Ctr, Durham, NC 27710 USA. [Stroup, I. Scott] Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. [Reimherr, Fred] Univ Utah, Med Ctr, Dept Psychiat, Salt Lake City, UT USA. [McGee, Mark] Appalachian Behav Healthcare Syst, Athens, OH USA. [Davis, Sonia M.] Quintiles Inc, Res Triangle Pk, NC USA. [Miller, Del D.] Univ Iowa, Sch Med, Dept Psychiat, Iowa City, IA 52242 USA. [Khan, Ahsan] Inst Psychiat Res, Wichita, KS USA. [Canive, Jose M.] Albuquerque Vet Adm, Med Ctr, Dept Psychiat, Albuquerque, NM USA. [Canive, Jose M.] Univ New Mexico, Albuquerque, NM 87131 USA. [Hsiao, John K.] NIMH, NIH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Lieberman, Jeffrey A.] Columbia Univ, Coll Phys & Surg, New York State Psychiat Inst, Dept Psychiat, New York, NY USA. [Adler, Lawrence] Clin Insights, Glen Burnie, MD USA. [Bari, Mohammed] Synergen Clin Res, Chula Vista, CA USA. [Belz, Irving] Tri Cty MHMR, Conroe, TX USA. [Bland, Raymond] So Illinois Univ, Sch Med, Springfield, IL USA. [Blocher, Thomas] MHMRA Harris Cty, Houston, TX USA. [Bolyard, Brent] Cox N Hosp, Springfield, MO USA. [Burruss, John] Baylor Coll Med, Houston, TX 77030 USA. [Buffenstein, Alan] Queens Med Ctr, Honolulu, HI USA. [Byerly, Matthew] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Canive, Jose] Albuquerque VA Med Ctr, Albuquerque, NM USA. [Caroff, Stanley] Behav Hlth Serv, Philadelphia, PA USA. [Casat, Charles] Behav Hlth Ctr, Charlotte, NC USA. [Chavez-Rice, Eugenio] El Paso Community MHMR Ctr, El Paso, TX USA. [Csernansky, John] Washington Univ, Sch Med, St Louis, MO USA. [Douyon, Richard] VA Med Ctr, Miami, FL USA. [D'Souza, Cyril] Connecticut Mental Hlth Ctr, New Haven, CT USA. [Glick, Ira] Stanford Univ, Sch Med, Stanford, CA 94305 USA. [Goff, Donald] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Gratz, Silvia] Eastern Penn Psychiat Inst, Philadelphia, PA USA. [Grossberg, George T.] St Louis Univ, Sch Med, Wohl Inst, St Louis, MO USA. [Hale, Mahlon] New Britain Gen Hosp, New Britain, CT USA. [Hamner, Mark] Med Univ S Carolina, Charleston, SC 29425 USA. [Hamner, Mark] Vet Affairs Med Ctr, Charleston, SC 29403 USA. [Jaffe, Richard] Belmont Ctr Comprehens Treatment, Philadelphia, PA USA. [Jeste, Dilip] Univ Calif San Diego, VA Med Ctr, San Diego, CA USA. [Kablinger, Anita] Louisiana State Univ, Hlth Sci Ctr, Shreveport, LA USA. [Khan, Ahsan] Univ Kansas, Sch Med, Wichita, KS 67214 USA. [Lamberti, Steve] Univ Rochester, Med Ctr, Rochester, NY 14642 USA. [Levy, Michael T.] Staten Isl Univ Hosp, Staten Isl, NY USA. [Lieberman, Jeffrey] Univ N Carolina, Sch Med, Chapel Hill, NC USA. [Maguire, Gerald] Univ Calif Irvine, Orange, CA 92668 USA. [Manschreck, Theo] Corrigan Mental Hlth Ctr, Fall River, MA USA. [McEvoy, Joseph] Duke Univ, Med Ctr, Durham, NC USA. [McGee, Mark] Appalachian Behav Healthcare, Athens, OH USA. [Meltzer, Herbert] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Miller, Alexander] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Miller, Del D.] Univ Iowa, Iowa City, IA USA. [Nasrallah, Henry] Univ Cincinnati, Med Ctr, Cincinnati, OH 45267 USA. [Nemeroff, Charles] Emory Univ, Sch Med, Atlanta, GA USA. [Olson, Stephen] Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. [Oxenkrug, Gregory F.] St Elizabeths Med Ctr, Boston, MA USA. [Patel, Jayendra] Univ Mass Hlth CAre, Worcester, MA USA. [Reimher, Frederick] Univ Utah, Med Ctr, Salt Lake City, UT USA. [Riggio, Silvana] Bronx VA Med Ctr, Mt Sinai Med Ctr, Bronx, NY USA. [Risch, Samuel] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Saltz, Bruce] Henderson Mental Hlth Ctr, Boca Raton, FL USA. [Simpatico, Thomas] Northwestern Univ, Chicago, IL 60611 USA. [Simpson, George] Univ So Calif, Med Ctr, Los Angeles, CA USA. [Smith, Michael] Harbor UCLA Med Ctr, Torrance, CA 90509 USA. [Sommi, Roger] Univ Missouri, Kansas City, MO 64110 USA. [Steinbook, Richard M.] Univ Miami, Sch Med, Miami, FL USA. [Stevens, Michael] Valley Mental Hlth, Salt Lake City, UT USA. [Torres, Rafael] Univ Mississippi, Jackson, MS 39216 USA. [Weiden, Peter] SUNY Downstate Med Ctr, Brooklyn, NY 11203 USA. [Wolberg, James] Mt Sinai Med Ctr, New York, NY 10029 USA. RP Swartz, MS (reprint author), Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Med Ctr, DUMC Box 3173, Durham, NC 27710 USA. EM swart001@mc.duke.edu RI Meltzer, Herbert/E-8131-2013; Stroup, Thomas/F-9188-2014 OI Adler, Lawrence/0000-0002-6619-2493; Stroup, Thomas/0000-0002-3123-0672 FU NCRR NIH HHS [M01 RR000046]; NIMH NIH HHS [N01 MH90001] NR 46 TC 27 Z9 27 U1 2 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 MAR PY 2008 VL 100 IS 1-3 BP 39 EP 52 DI 10.1016/j.schres.2007.11.034 PG 14 WC Psychiatry SC Psychiatry GA 284RB UT WOS:000254722400004 PM 18191383 ER PT J AU van Raalten, TR Ramsey, NF Jansma, JM Jager, G Kahn, RS AF van Raalten, Tamar R. Ramsey, Nick F. Jansma, J. Martijn Jager, Gerry Kahn, Rene S. TI Automatization and working memory capacity in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Article DE functional MRI; schizophrenia; working memory; automatization; dual-task ID DUAL-TASK PERFORMANCE; DORSOLATERAL PREFRONTAL CORTEX; VAL(108/158) MET GENOTYPE; HUMAN BRAIN; N-ACETYLASPARTATE; FMRI; DYSFUNCTION; ACTIVATION; SYMPTOMS; INTERFERENCE AB Working memory (WM) dysfunction in schizophrenia is characterized by inefficient WM recruitment and reduced capacity, but it is not yet clear how these relate to one another. In controls practice of certain cognitive tasks induces automatization, which is associated with reduced WM recruitment and increased capacity of concurrent task performance. We therefore investigated whether inefficient function and reduced capacity in schizophrenia was associated with a failure in automatization. FMRI data was acquired with a verbal WM task with novel and practiced stimuli in 18 schizophrenia patients and 18 controls. Participants performed a dual-task outside the scanner to test WM capacity. Patients showed intact performance on the WM task, which was paralleled by excessive WM activity. Practice improved performance and reduced WM activity in both groups. The difference in WM activity after practice predicted performance cost in controls but not in patients. In addition, patients showed disproportionately poor dual-task performance compared to controls, especially when processing information that required continuous adjustment in WM. Our findings support the notion of inefficient WM function and reduced capacity in schizophrenia. This was not related to a failure in automatization, but was evident when processing continuously changing information. This suggests that inefficient WM function and reduced capacity may be related to an inability to process information requiring frequent updating. (C) 2007 Elsevier B.V. All rights reserved. C1 [van Raalten, Tamar R.; Jager, Gerry; Kahn, Rene S.] Univ Med Ctr Utrecht, Dept Psychiat, Rudolf Magnus Inst Neurosci, NL-3584 CX Utrecht, Netherlands. [Ramsey, Nick F.] Univ Med Ctr Utrecht, Dept Neurol & Neurosurg, Rudolf Magnus Inst Neurosci, NL-3584 CX Utrecht, Netherlands. [Jansma, J. Martijn] NINDS, NIH, LFMI, Bethesda, MD 20892 USA. RP van Raalten, TR (reprint author), Univ Med Ctr Utrecht, Dept Psychiat, Rudolf Magnus Inst Neurosci, A01-126 Heidelberglaan 100, NL-3584 CX Utrecht, Netherlands. EM t.vanraalten@umcutrecht.nl NR 53 TC 19 Z9 19 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR PY 2008 VL 100 IS 1-3 BP 161 EP 171 DI 10.1016/j.schres.2007.10.035 PG 11 WC Psychiatry SC Psychiatry GA 284RB UT WOS:000254722400015 PM 18155446 ER PT J AU Chong, VZ Thompson, M Beltaifa, S Webster, MJ Law, AJ Weickert, CS AF Chong, Victor Z. Thompson, Mia Beltaifa, Senda Webster, Maree J. Law, Amanda J. Weickert, Cynthia Shannon TI Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients SO SCHIZOPHRENIA RESEARCH LA English DT Article DE Stanley consortium; schizophrenia; immunoblotting; cytoplasm; nucleus; prefrontal cortex; neuregulin-1; ErbB4 ID NUCLEAR-LOCALIZATION; RECEPTOR ERBB-4; WHITE-MATTER; HUMAN BRAIN; EXPRESSION; CELLS; GENE; SUSCEPTIBILITY; ISOFORM; NEURONS AB Neuregulin-1 (NRG1) and its receptor, ErbB4, have been implicated in schizophrenia at both gene and transcript levels. The present investigation compared NRG1 and ErbB4 protein levels in prefrontal cortical (PFC) cytoplasmic and nuclear fractions among normal, schizophrenic, bipolar and major depressed subjects from the Stanley Consortium. We used immunoblotting procedures to examine potential NRG1 and Erb134 immunoreactive bands, but specifically quantified NRG1 immunoreactive signals at 42, 48 and 53 kDa and ErbB4 immunoreactive signals at 21, 55, 60 and 180 kDa. PFC cytoplasmic 53 kDa NRG1 protein levels were significantly increased (similar to 20%) in schizophrenic patients relative to each of the other subject groups. We also detected diagnostic effects on PFC cytoplasmic full-length (180 kDa) ErbB4 protein levels, and post hoc tests revealed that these quantities were significantly increased (similar to 30%) in schizophrenic patients relative to normal and to depressed subjects. In addition, we examined the levels of potential ErbB4 cleavage products at 21, 55 and 60 kDa relative to those of full-length ErbB4 in the PFC fractions. We detected trends for diagnostic effects on PFC cytoplasmic 21 kDa/1 80 kDa and 55 kDa/1 80 kDa ratios, and post hoc tests revealed that these ratios were significantly reduced in schizophrenic patients relative to normal individuals. Our investigation suggests that schizophrenia-associated NRG1 and ErbB4 mRNA elevations also occur at the protein level and may be specific to schizophrenia. We hypothesize that ErbB4 proteolytic processing may also be altered in schizophrenia, yielding altered ratios of functionally distinct forms of ErbB4. Published by Elsevier B.V. C1 [Chong, Victor Z.; Thompson, Mia; Beltaifa, Senda; Weickert, Cynthia Shannon] NIMH, MiNDS Unit, CBDB, NIH, Bethesda, MD 20892 USA. [Webster, Maree J.] Uniform Serv Univ Hlth Sci, Stanley Lab Brain Res, Dept Psychiat, Bethesda, MD 20892 USA. [Law, Amanda J.] Univ Oxford, Dept Psychiat, Warneford Hosp, Oxford OX3 7JX, England. [Weickert, Cynthia Shannon] Univ New S Wales, Schizophrenia Res Inst, Dept Psychiat, Prince Wales Med Res Inst, Randwick, NSW 2031, Australia. RP Weickert, CS (reprint author), NIMH, MiNDS Unit, CBDB, NIH, 10 Ctr Dr,Bldg 10, Bethesda, MD 20892 USA. EM c.weickert@powmri.edu.au RI Shannon Weickert, Cynthia/G-3171-2011; Law, Amanda/G-6372-2012; OI Law, Amanda/0000-0002-2574-1564 FU Intramural NIH HHS [NIH0010048825]; Medical Research Council [G120/997]; PHS HHS [NIH0010048825] NR 44 TC 98 Z9 101 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR PY 2008 VL 100 IS 1-3 BP 270 EP 280 DI 10.1016/j.schres.2007.12.474 PG 11 WC Psychiatry SC Psychiatry GA 284RB UT WOS:000254722400027 PM 18243664 ER PT J AU Gaydos, CA Wright, C Wood, BJ Waterfield, G Hobson, S Quinn, TC AF Gaydos, Charlotte A. Wright, Catherine Wood, Billie Jo Waterfield, Gerry Hobson, Sharon Quinn, Thomas C. TI Chlamydia trachomatis reinfection rates among female adolescents seeking rescreening in school-based health Centers SO SEXUALLY TRANSMITTED DISEASES LA English DT Article; Proceedings Paper CT 105th General Meeting of the American-Society-for-Microbiology CY JUN 05-09, 2005 CL Atlanta, GA SP Amer Soc Microbiol ID SEXUALLY-TRANSMITTED-DISEASES; ADMINISTERED VAGINAL SWABS; NEISSERIA-GONORRHOEAE; DNA AMPLIFICATION; ARMY RECRUITS; YOUNG-WOMEN; INFECTIONS; URINE; PREVALENCE; SETTINGS AB Background: Chlamydia trachomatis (CT) infections are common among adolescents attending high and middle schools. The study objective was to determine the reinfection rates of CT for females attending school-based health centers. Methods: Adolescents attending school-based health centers who reported they were sexually active were screened for CT using nucleic acid amplification tests on cervical or urine samples. Between 1996 and 2003, 10,609 female students were tested. The overall annual prevalence for unduplicated students in a calendar year ranged from 15.1% to 19.5%. Reinfection was defined as a positive test result occurring between 30 and 365 days after an initial positive result. Results: There were 897 female students who tested positive for CT and returned for at least I subsequent test between 30 and 365 days later. Of these, 236 had 1 or more subsequent positive tests for a cumulative incidence of reinfection in I year of 26.3% (95% confidence interval = 23.4-29.2%). Young age at first infection was significantly associated with increased risk of subsequent infection (P < 0.01). Across sites, the cumulative incidence of reinfection in these female students ranged from 14.3% to 38.9%. Conclusions: The chlamydia cumulative incidence of reinfection in these female adolescents attending high and middle schools was high and supports the Centers for Disease Control and Prevention recommendation to screen adolescents frequently, especially those with a history of a previous chlamydia infection. C1 [Gaydos, Charlotte A.; Wood, Billie Jo; Quinn, Thomas C.] Johns Hopkins Univ, Baltimore, MD USA. [Wright, Catherine] Family Planning Council, Philadelphia, PA USA. [Waterfield, Gerry; Hobson, Sharon] Baltimore City Dept Hlth, Baltimore, MD USA. [Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. RP Gaydos, CA (reprint author), 1159 Ross Res Bldg,720 Rutland Ave, Baltimore, MD 21205 USA. EM cgaydos@jhmi.edu RI Gaydos, Charlotte/E-9937-2010 FU Intramural NIH HHS [Z01 AI000358-25]; NIAID NIH HHS [U01 AI068613, U01 AI068613-02] NR 39 TC 24 Z9 24 U1 0 U2 1 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 MAR PY 2008 VL 35 IS 3 BP 233 EP 237 DI 10.1097/OLO.0b013e31815c11fe PG 5 WC Infectious Diseases SC Infectious Diseases GA 268NI UT WOS:000253586100004 PM 18490866 ER PT J AU Prins, GS Korach, KS AF Prins, Gail S. Korach, Kenneth S. TI The role of estrogens and estrogen receptors in normal prostate growth and disease SO STEROIDS LA English DT Review DE prostate; prostate cancer; estrogens; estradiol estrogen receptor ID BETA ER-BETA; GUINEA-PIG PROSTATE; RAT PROSTATE; DIFFERENTIAL EXPRESSION; ANDROGEN RECEPTOR; NEONATAL ESTROGEN; GENE-EXPRESSION; CANCER RISK; TRANSGENIC ADENOCARCINOMA; METASTATIC CARCINOMA AB Estrogens have significant direct and indirect effects on prostate gland development and homeostasis and have been long suspected in playing a role in the etiology of prostatic diseases. Direct effects are mediated through prostatic estrogen receptors alpha (ER alpha) and beta (ER beta) with expression levels changing over time and with disease progression. The present review examines the evidence for a role of estrogens and specific estrogen receptors in prostate growth, differentiation and disease states including prostatitis, benign prostatic hyperplasia (BPH) and cancer and discusses potential therapeutic strategies for growth regulation via these pathways. (C) 2007 Elsevier Inc. All rights reserved. C1 [Prins, Gail S.] Univ Illinois, Dept Urol, Chicago, IL 60612 USA. [Korach, Kenneth S.] NIEHS, NIH, Reprod & Dev Toxicol Lab, Environm Dis & Med Program, Res Triangle Pk, NC 27709 USA. RP Prins, GS (reprint author), Univ Illinois, Dept Urol, 820 S Wood St, Chicago, IL 60612 USA. EM gprins@uic.edu; korach@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU NIDDK NIH HHS [R01 DK040890, R01 DK040890-17]; NIEHS NIH HHS [R01 ES015584] NR 141 TC 152 Z9 159 U1 4 U2 19 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0039-128X J9 STEROIDS JI Steroids PD MAR PY 2008 VL 73 IS 3 BP 233 EP 244 DI 10.1016/j.steroids.2007.10.013 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 268NK UT WOS:000253586300001 PM 18093629 ER PT J AU Sutton-Tyrrell, K Venkitachalam, L Kanaya, AM Boudreau, R Harris, T Thompson, T Mackey, RH Visser, M Vaidean, GD Newman, AB AF Sutton-Tyrrell, Kim Venkitachalam, Lakshmi Kanaya, Alka M. Boudreau, Robert Harris, Tamara Thompson, Trina Mackey, Rachel H. Visser, Marjolein Vaidean, Georgeta D. Newman, Anne B. CA Hlth Aging Body Compostion Study TI Relationship of ankle blood pressures to cardiovascular events in older adults SO STROKE LA English DT Article DE age; mortality; peripheral artery disease; stroke ID PERIPHERAL ARTERIAL-DISEASE; BRACHIAL INDEX; ARM INDEX; ALL-CAUSE; MORTALITY; HEALTH; RISK; PREDICTOR; THERAPY; STROKE AB Background and Purpose - Low values of ankle-arm systolic blood pressure ratio predict mortality and cardiovascular events. High values, associated with arterial calcification, also carry risk for mortality. We focus on the extent to which low and high ankle - arm index values as well as noncompressible arteries are associated with mortality and cardiovascular events, including stroke in older adults. Methods - We followed 2886 adults aged 70 to 79 for a mean of 6.7 years for vital status and cardiovascular events ( coronary heart disease, stroke, and congestive heart failure). Results - Normal ankle - arm index values of 0.91 to 1.3 were found in 80%, low values of <= 0.9 were found in 13%, high values of > 1.3 were obtained in 5%, and noncompressible arteries were found in 2% of the group. Increased mortality was associated with both low and high ankle - arm index values beginning at levels of < 1.0 or >= 1.4. Subjects with low ankle - arm index values or noncompressible arteries had significantly higher event rates than those with normal ankle blood pressures for all end points. For coronary heart disease, hazard ratios associated with a low ankle - arm index, high ankle - arm index, and noncompressible arteries were 1.4, 1.5, and 1.7 ( P < 0.05 for all) after controlling for age, gender, race, prevalent cardiovascular disease, diabetes, and major cardiovascular risk factors. Noncompressible arteries carried a particularly high risk of stroke and congestive heart failure ( hazard ratio = 2.1 and 2.4, respectively). Conclusions - Among older adults, low and high ankle - arm index values carry elevated risk for cardiovascular events. Noncompressible leg arteries carry elevated risk for stroke and congestive heart failure specifically. C1 [Sutton-Tyrrell, Kim; Venkitachalam, Lakshmi; Boudreau, Robert; Thompson, Trina; Mackey, Rachel H.; Newman, Anne B.] Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. [Kanaya, Alka M.] Univ Calif San Francisco, Div Gen Internal Med, San Francisco, CA 94143 USA. [Kanaya, Alka M.] UCSF Womens Hlth Clin Res Ctr, San Francisco, CA USA. [Harris, Tamara] NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. [Visser, Marjolein] Vrije Univ Amsterdam, Fac Earth & Life Sci, Inst Hlth Sci, Amsterdam, Netherlands. [Visser, Marjolein] EMGO Inst, VU Med Ctr, Amsterdam, Netherlands. [Vaidean, Georgeta D.] Univ Tennessee, Dept Prevent Med, Memphis, TN USA. RP Sutton-Tyrrell, K (reprint author), Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, GSPH-505A Parran Hall 130 DeSoto St, Pittsburgh, PA 15261 USA. EM Tyrrell@edc.pitt.edu RI Venkitachalam, Lakshmi/B-5618-2008; Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Boudreau, Robert/0000-0003-0162-5187; Venkitachalam, Lakshmi/0000-0003-0703-3932; Mackey, Rachel/0000-0001-6088-2664 FU Intramural NIH HHS; NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 20 TC 54 Z9 56 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2008 VL 39 IS 3 BP 863 EP 869 DI 10.1161/STROKEAHA.107.487439 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 267XP UT WOS:000253542800021 PM 18258843 ER PT J AU Buch, E Weber, C Cohen, LG Braun, C Dimyan, MA Ard, T Mellinger, J Caria, A Soekadar, S Fourkas, A Birbaumer, N AF Buch, Ethan Weber, Cornelia Cohen, Leonardo G. Braun, Christoph Dimyan, Michael A. Ard, Tyler Mellinger, Jurgen Caria, Andrea Soekadar, Surjo Fourkas, Alissa Birbaumer, Niels TI Think to move: a neuromagnetic brain-computer interface (BCI) system for chronic stroke SO STROKE LA English DT Article DE brain-computer interface; MEG; motor; plasticity; stroke ID MOTOR IMAGERY; COMMUNICATION; RECOVERY; DEVICES; SCALE; MEG AB Background and Purpose - Stroke is a leading cause of long-term motor disability among adults. Present rehabilitative interventions are largely unsuccessful in improving the most severe cases of motor impairment, particularly in relation to hand function. Here we tested the hypothesis that patients experiencing hand plegia as a result of a single, unilateral subcortical, cortical or mixed stroke occurring at least 1 year previously, could be trained to operate a mechanical hand orthosis through a brain-computer interface (BCI). Methods - Eight patients with chronic hand plegia resulting from stroke (residual finger extension function rated on the Medical Research Council scale = 0/5) were recruited from the Stroke Neurorehabilitation Clinic, Human Cortical Physiology Section of the National Institute for Neurological Disorders and Stroke (NINDS) (n = 5) and the Clinic of Neurology of the University of Tubingen (n = 3). Diagnostic MRIs revealed single, unilateral subcortical, cortical or mixed lesions in all patients. A magnetoencephalography-based BCI system was used for this study. Patients participated in between 13 to 22 training sessions geared to volitionally modulate mu rhythm amplitude originating in sensorimotor areas of the cortex, which in turn raised or lowered a screen cursor in the direction of a target displayed on the screen through the BCI interface. Performance feedback was provided visually in real-time. Successful trials (in which the cursor made contact with the target) resulted in opening/closing of an orthosis attached to the paralyzed hand. Results - Training resulted in successful BCI control in 6 of 8 patients. This control was associated with increased range and specificity of mu rhythm modulation as recorded from sensors overlying central ipsilesional (4 patients) or contralesional (2 patients) regions of the array. Clinical scales used to rate hand function showed no significant improvement after training. Conclusions - These results suggest that volitional control of neuromagnetic activity features recorded over central scalp regions can be achieved with BCI training after stroke, and used to control grasping actions through a mechanical hand orthosis. C1 [Buch, Ethan; Weber, Cornelia; Cohen, Leonardo G.; Dimyan, Michael A.; Ard, Tyler; Fourkas, Alissa] NINDS, Human Cort Physiol Sect, Stroke Neurorehabil Clin, NIH, Bethesda, MD 20892 USA. [Buch, Ethan] Univ Oxford, Dept Expt Psychol, Oxford OX1 2JD, England. [Weber, Cornelia; Braun, Christoph; Mellinger, Jurgen; Caria, Andrea; Soekadar, Surjo; Fourkas, Alissa; Birbaumer, Niels] Univ Tubingen, MEG Ctr, Inst Med Psychol & Behav Neurobiol, D-72074 Tubingen, Germany. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, Stroke Neurorehabil Clin, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov RI Braun, Christoph/E-4561-2010; Buch, Ethan/G-1981-2011; Dimyan, Michael/B-1715-2012; Braun, Christoph/J-4160-2014; OI Braun, Christoph/0000-0002-7836-4010; Braun, Christoph/0000-0002-7836-4010; Soekadar, Surjo R./0000-0003-1280-5538; Dimyan, Michael/0000-0002-9715-9741 FU Intramural NIH HHS NR 31 TC 216 Z9 230 U1 7 U2 34 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2008 VL 39 IS 3 BP 910 EP 917 DI 10.1161/STROKEAHA.107.505313 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 267XP UT WOS:000253542800028 PM 18258825 ER PT J AU Kleindorfer, D Lindsell, CJ Brass, L Koroshetz, W Broderick, JP AF Kleindorfer, Dawn Lindsell, Christopher J. Brass, Lawrence Koroshetz, Walter Broderick, Joseph P. TI National US estimates of recombinant tissue plasminogen activator use - ICD-9 codes substantially underestimate SO STROKE LA English DT Article DE acute stroke treatment; epidemiology; tPA ID ACUTE ISCHEMIC-STROKE; T-PA; POPULATION; EXPERIENCE; CENTERS; CARE AB Background and Purpose - Current US estimates of recombinant tissue plasminogen activator (rt-PA) use have been based either on extrapolation of regional studies or on administrative database estimates, both of which may have inherent biases. We sought to compare the utilization of rt-PA in acute ischemic stroke in the MEDPAR database to another national hospital database with drug utilization information. Methods - Cases were defined as DRG 14,15, and 524 and ICD-9 code 99.1, which indicates cerebral thrombolysis, for fiscal year 2001 to 2004. Additionally, the Premier database was queried for rt-PA utilization documented in pharmacy records in those patients admitted for stroke. Change over time and difference between databases were tested using Poisson regression. Results - When comparing databases, rt-PA use, as identified by ICD-9 code 99.1, was only documented in 0.95% of stroke cases in 2004 in MEDPAR, and 1.2% in the Premier database, which slightly increased by 0.04% to 0.09% over time. Analysis of pharmacy billing records increased the estimate to 1.82%. Exclusion of cases younger than 65years excluded 43% of cases treated with rt-PA. In 2004, 12.7% of cases receiving thrombolytic had either a TIA or a hemorrhagic stroke ICD-9 code. Conclusions - We estimate the rate of rt-PA use in the United States to be 1.8% to 2.1% of ischemic stroke patients. The rate of thrombolytic use for ischemic stroke was slightly increasing between 2001 and 2004 at a rate of 0.04% to 0.09% per year. A significant proportion of patients treated with rt-PA are likely miscoded as either TIA or hemorrhagic stroke. We conservatively estimate that 10 800 to 12 600 patients received rt-PA in 2004. C1 [Kleindorfer, Dawn; Lindsell, Christopher J.; Broderick, Joseph P.] Univ Cincinnati, Dept Neurol, Coll Med, Cincinnati, OH 45267 USA. [Brass, Lawrence] Yale Univ, New Haven, CT USA. [Koroshetz, Walter] Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. RP Kleindorfer, D (reprint author), Univ Cincinnati, Dept Neurol, Coll Med, 231 Albert Sabin Way ML 0525, Cincinnati, OH 45267 USA. EM dawn.kleindorfer@uc.edu OI Lindsell, Christopher/0000-0002-3297-2811 NR 14 TC 181 Z9 188 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2008 VL 39 IS 3 BP 924 EP 928 DI 10.1161/STROKEAHA.107.490375 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 267XP UT WOS:000253542800030 PM 18239184 ER PT J AU Guindon, KA Foley, JF Maronpot, RR Massey, TE AF Guindon, Katherine A. Foley, Julie F. Maronpot, Robert R. Massey, Thomas E. TI Failure of catalase to protect against aflatoxin B-1-induced mouse lung tumorigenicity SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Article DE aflatoxin B-1; catalase; mouse lung; carcinogenesis; K-ras ID OXIDATIVE DNA-DAMAGE; KI-RAS ACTIVATION; MAMMALIAN CATALASE; IN-VIVO; MICE; B-1; TUMORS; REPAIR; CELLS; 8-HYDROXYDEOXYGUANOSINE AB The carcinogenic mycotoxin aflatoxin B-1(AFB(1)) induces 8-hydroxy-2'-deoxyguanosine (8-OHdG) formation in mouse lung, an effect that can be prevented by treatment with polyethylene glycol-conjugated catalase (PEG-CAT). G -> 4 T transversion mutation in K-ras, an early event in AFB(1)-induced mouse lung carcinogenesis, is thought to result from AFB(1)-8,9-exo-epoxide binding to DNA to form AFB(1)-N-7-guanine, but may also result from formation of 8-OHdG. Therefore, oxidative DNA damage may be important in AFB(1) carcinogenicity. The objective of this study was to determine whether PEG-CAT would prevent AFB(1) tumorigenicity. Mouse lung tumorigenesis was assessed following treatment of female A/J mice with 300 kU/kg PEG-CAT ip and/or 50 mg/kg AFB(1). Mice were killed 7 months post-treatment and tumors greater than 1 mm in diameter were excised. Unexpectedly, the mean number of tumors per mouse in the PEG-CAT+AFB(1) group (8.81 +/- 3.64, n=47) was greater than that of the group treated with AFB(1) alone (7.05 +/- 3.45, n=42) (P<0.05). The tumors obtained from mice treated with PEG-CAT+AFB(1) were larger than those from mice treated with AFB(1) alone (P<0.05). There was no difference in K-ras exon 1 mutation spectrum or in the histological diagnosis of tumors between AFB(1) and PEG-CAT+AFB(1) groups (P>0.05). In vitro incubation with mouse liver catalase (CAT) resulted in conversion of [H-3]AFB(1) into a DNA-binding species, a possible explanation for the results observed in vivo. These results demonstrate that PEG-CAT is not protective against AFB(1) carcinogenicity in mouse lung despite preventing DNA oxidation. (C) 2007 Elsevier Inc. All rights reserved. C1 [Guindon, Katherine A.; Massey, Thomas E.] Queens Univ, Dept Pharmacol & Toxicol, Kingston, ON K7L 3N6, Canada. [Foley, Julie F.; Maronpot, Robert R.] NIEHS, Res Triangle Pk, NC 27709 USA. RP Massey, TE (reprint author), Queens Univ, Dept Pharmacol & Toxicol, Kingston, ON K7L 3N6, Canada. EM masseyt@queensu.ca FU Intramural NIH HHS NR 27 TC 5 Z9 5 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD MAR 1 PY 2008 VL 227 IS 2 BP 179 EP 183 DI 10.1016/j.taap.2007.10.015 PG 5 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 266KU UT WOS:000253434900002 PM 18155117 ER PT J AU Shimada, H Yasutake, A Hirashima, T Takamure, Y Kitano, T Waalkes, MP Imamura, Y AF Shimada, Hideaki Yasutake, Akira Hirashima, Takaomi Takamure, Yasutaka Kitano, Takeshi Waalkes, Michael P. Imamura, Yorishige TI Strain difference of cadmium accumulation by liver slices of inbred Wistar-Imamichi and Fischer 344 rats SO TOXICOLOGY IN VITRO LA English DT Article DE cadmium accumulation; rat liver slice; strain difference; zinc transport system ID MAMMALIAN ZINC TRANSPORTERS; INDUCED HEPATOTOXICITY; METALLOTHIONEIN-NULL; MICE; RESISTANCE; TOXICITY; TESTIS; GENE AB Strain difference in the accumulation of cadmium (Cd) by liver slices was examined in inbred Cd-resistant Wistar-Imamichi (WI) and Cd-sensitive Fischer 344 (F344) rats. The accumulation of Cd by liver slices of WI rats was significantly lower than that of F344 rats, suggesting strain-related differences in the transport of Cd into the liver cells of these two rat strains. In addition, a similar strain difference was observed in the accumulation of zinc (Zn) by liver slices from WI and F344 rats. Cd accumulation by F344 liver slices decreased when Zn was added to the medium in combination with Cd. Furthermore, in F344 liver slices, Zn accumulation was significantly decreased when Cd was added to the medium. These results suggest that the accumulation of Cd by the liver is probably mediated, at least in part, by Zn transport systems. However, we found no strain difference in hepatic ZnT3 or ZIP3 transcript levels between WI and F344 rats. Further work is in progress to identify the transporter that causes the strain differences in hepatic Cd accumulation seen with WI and F344 rats. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Shimada, Hideaki; Hirashima, Takaomi; Takamure, Yasutaka] Kumamoto Univ, Fac Educ, Kumamoto 8608555, Japan. [Yasutake, Akira] Natl Inst Minamata Dis, Biochem Sect, Kumamoto 8670008, Japan. [Kitano, Takeshi] Kumamoto Univ, Grad Sch Sci & Technol, Kumamoto 8608555, Japan. [Waalkes, Michael P.] NIEHS, Natl Canc Inst, Comparat Carcinogenesis Lab, Inorgan Carcinogenesis Sect, Res Triangle Pk, NC 27709 USA. [Imamura, Yorishige] Kumamoto Univ, Grad Sch Pharmaceut Sci, Kumamoto 8620973, Japan. RP Shimada, H (reprint author), Kumamoto Univ, Fac Educ, 2-40-1 Kurokami, Kumamoto 8608555, Japan. EM hshimada@gpo.kumamoto-u.ac.jp NR 23 TC 7 Z9 7 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0887-2333 J9 TOXICOL IN VITRO JI Toxicol. Vitro PD MAR PY 2008 VL 22 IS 2 BP 338 EP 343 DI 10.1016/j.tiv.2007.09.013 PG 6 WC Toxicology SC Toxicology GA 284GI UT WOS:000254694500008 PM 17980552 ER PT J AU Harel, A Wu, F Mattson, MP Morris, CM Yao, PJ AF Harel, Asaff Wu, Fangbai Mattson, Mark P. Morris, Christa M. Yao, Pamela J. TI Evidence for CALM in directing VAMP2 trafficking SO TRAFFIC LA English DT Article DE clathrin; endocytosis; flow cytometry; siRNA; SNARE proteins ID SYNAPTIC VESICLE ENDOCYTOSIS; CLATHRIN ASSEMBLY PROTEIN; MEDIATED ENDOCYTOSIS; ALPHA-BUNGAROTOXIN; MEMBRANE-PROTEINS; BINDING-SITE; AP180; DOMAIN; EXOCYTOSIS; NETWORK AB Clathrin assembly lymphoid myeloid leukemia protein (CALM) is a clathrin assembly protein with a domain structure similar to the neuron-specific assembly protein AP180. We have previously found that CALM is expressed in neurons and present in synapses. We now report that CALM has a neuron-related function: it facilitates the endocytosis of the synaptic vesicle protein VAMP2 from the plasma membrane. Overexpression of CALM leads to the reduction of cell surface VAMP2, whereas knockdown of CALM by RNA interference results in the accumulation of surface VAMP2. The AP180 N-terminal homology (ANTH) domain of CALM is required for its effect on VAMP2 trafficking, and the ANTH domain itself acts as a dominant-negative mutant. Thus, our results reveal a role for CALM in directing VAMP2 trafficking during endocytosis. C1 [Harel, Asaff; Wu, Fangbai; Mattson, Mark P.; Yao, Pamela J.] NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. [Morris, Christa M.] NIA, Intramural Res Program, Flow Cytometry Lab, Baltimore, MD 21224 USA. RP Yao, PJ (reprint author), NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. EM yaopa@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU Intramural NIH HHS NR 43 TC 82 Z9 83 U1 1 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-9219 J9 TRAFFIC JI Traffic PD MAR PY 2008 VL 9 IS 3 BP 417 EP 429 DI 10.1111/j.1600-0854.2007.00694.x PG 13 WC Cell Biology SC Cell Biology GA 257CK UT WOS:000252776600012 PM 18182011 ER PT J AU Roman, JJG Garay, GO Saenz, P Escuredo, K Ibayondo, CS Gutkind, S Junquera, C Simon, L Martinez, A Luna, JLF Val-Bernal, JF AF Gomez Roman, J. Javier Ochoa Garay, Gorka Saenz, Pilar Escuredo, Kepa Sanz Ibayondo, Cristina Gutkind, Silvio Junquera, Corina Simon, Laureano Martinez, Antonio Fernandez Luna, Jose Luis Val-Bernal, J. Fernando TI Plexin Bl is downregulated in renal cell carcinomas and modulates cell growth SO TRANSLATIONAL RESEARCH LA English DT Article ID RAS GAP ACTIVITY; R-RAS; RECEPTOR PLEXIN-B1; RHO; EXPRESSION; ANGIOGENESIS; ACTIVATION; MIGRATION; MET; CLASSIFICATION AB Plexins are a family of transmembrane receptors that interact with the repulsive axon guidance molecules (Semaphorins) in neural tissues. In extraneural tissues, plexins are involved in other cellular functions often altered in neoplastic cells, such as adhesion, migration, and apoptosis. Plexin Bl has been implicated in the regulation of Akt, which is an activated pathway in renal cell neoplasms, and only I report has emphasized its role as an oncogenic factor. Furthermore, plexin Bl is located in 3p2l, which is a chromosomal region deleted frequently in renal cell carcinomas. In accordance with a hypothetical oncogenic role for plexin Bl, we have shown by reverse transcription-polymerase chain reaction that plexin Bl is expressed in nonneoplastic renal tissue, and it is severely downregulated in clear cell renal carcinomas. We have also demonstrated by immunohistochernistry on tissue microarrays that plexin Bl protein is absent in more than 80% of renal cell carcinomas (1169 in 209 carcinomas examined). Otherwise, all kinds of renal tubules showed strong membrane reactivity. Moreover, when we have induced plexin Bl expression with an expression vector in the renal adenocarcinoma cell line ACHN, a marked reduction in proliferation rate was produced. Altogether, this evidence suggests a possible role for plexin Bl in renal oncogenesis. C1 [Gomez Roman, J. Javier] Univ Cantabria, Fac Med, Hosp Univ Marques de Valdecilla, Dept Anat Patol,Serv Cantabro Salud, E-39008 Santander, Cantabria, Spain. SL Parque Tecnol Zamudio, SA Medplant Genet, Progenika, Derio, Vizcaya, Spain. Hosp Univ Marques de Valdecilla, Unidad Genet Mol, Santander, Spain. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Roman, JJG (reprint author), Univ Cantabria, Fac Med, Hosp Univ Marques de Valdecilla, Dept Anat Patol,Serv Cantabro Salud, Avda Valdecilla S-N, E-39008 Santander, Cantabria, Spain. EM apagrj@humv.es RI Gutkind, J. Silvio/A-1053-2009; OI Gomez-Roman, Jose Javier/0000-0002-2849-9435 NR 29 TC 23 Z9 23 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1931-5244 J9 TRANSL RES JI Transl. Res. PD MAR PY 2008 VL 151 IS 3 BP 134 EP 140 DI 10.1016/j.trsl.2007.12.003 PG 7 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 265VJ UT WOS:000253389500004 ER PT J AU McCloskey, DJ Postolache, TT Vittone, BJ Nghiem, KL Monsale, JL Wesley, RA Rick, ME AF McCloskey, Donna Jo Postolache, Teodor T. Vittone, Bernard J. Nghiem, Khanh L. Monsale, Jude L. Wesley, Robert A. Rick, Margaret E. TI Selective serotonin reuptake inhibitors: measurement of effect on platelet function SO TRANSLATIONAL RESEARCH LA English DT Article ID RISK; ANTIDEPRESSANTS; POPULATION; ASSOCIATION; DYSFUNCTION; PAROXETINE; ASPIRIN; SSRIS AB Selective serotonin reuptake inhibitors (SSRIs) reduce platelet serotonin and are associated with increased gastrointestinal bleeding, an effect that is enhanced when taken with NSAIDs or aspirin. The best method to evaluate hemorrhagic events in patients taking SSRIs has not been determined. Platelet aggregation, which is not widely available, shows SSRI inhibition of platelet function; we tested whether a platelet function analyzer could detect SSRI inhibition of platelet function. Two groups of outpatients with mood disorders were recruited; each patient was taking a stable dose of either an SSRI or bupropion for at least 6 weeks. They were tested using the platelet function analyzer-100 (PFA- 100; Dade International Inc, Miami, Fla) concomitantly with platelet aggregation. Fifty-eight patients were analyzed. We detected significant differences between the groups using aggregation methods with arachidonic acid (aggregation, P = 0.00001; release, P = 0.009) and collagen (aggregation, P = 0.016; release, P = 0.006). The PFA-100 did not detect differences between the groups or results outside the reference range. The PFA-100 does not detect the inhibitory effects of SSRIs on platelet function, but it can be used to direct evaluation of bleeding in a patient taking an SSRI. Abnormal PFA- 100 results suggest additional evaluation for von Willebrand disease, other platelet inhibitory medications, or underlying intrinsic platelet dysfunction. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Lab Med, Bethesda, MD 20892 USA. Univ Maryland, Baltimore, MD 21201 USA. Natl Ctr Treatment Phobias Anxiety & Depress, Washington, DC USA. RP McCloskey, DJ (reprint author), Democracy 1,Room 921, Bethesda, MD 20892 USA. EM mccloskd@mail.nih.gov FU Intramural NIH HHS [Z99 RR999999] NR 20 TC 36 Z9 37 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1931-5244 J9 TRANSL RES JI Transl. Res. PD MAR PY 2008 VL 151 IS 3 BP 168 EP 172 DI 10.1016/j.trsl.2007.10.004 PG 5 WC Medical Laboratory Technology; Medicine, General & Internal; Medicine, Research & Experimental SC Medical Laboratory Technology; General & Internal Medicine; Research & Experimental Medicine GA 265VJ UT WOS:000253389500008 PM 18279816 ER PT J AU Kravitz, DJ Vinson, LD Baker, CI AF Kravitz, Dwight J. Vinson, Latrice D. Baker, Chris I. TI How position dependent is visual object recognition? SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID INFERIOR TEMPORAL CORTEX; INFEROTEMPORAL CORTEX; OCCIPITAL CORTEX; INDIVIDUAL VARIABILITY; PATTERN-RECOGNITION; NEURONAL RESPONSES; SHAPE-RECOGNITION; RECEPTIVE-FIELDS; MACAQUE MONKEY; REPRESENTATION AB Visual object recognition is often assumed to be insensitive to changes in retinal position, leading to theories and formal models incorporating position-independent object representations. However, recent behavioral and physiological evidence has questioned the extent to which object recognition is position independent. Here, we take a computational and physiological perspective to review the current behavioral literature. Although numerous studies report reduced object recognition performance with translation, even for distances as small as 0.5 degrees of visual angle, confounds in many of these studies make the results difficult to interpret. We conclude that there is little evidence to support position-independent object recognition and the precise role of position in object recognition remains unknown. C1 [Kravitz, Dwight J.; Vinson, Latrice D.; Baker, Chris I.] NIMH, Lab Brain & Cognit, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Baker, CI (reprint author), NIMH, Lab Brain & Cognit, Natl Inst Hlth, Bethesda, MD 20892 USA. EM bakerchris@mail.nih.gov RI Kravitz, Dwight/B-8430-2012; OI Baker, Chris/0000-0001-6861-8964 NR 89 TC 60 Z9 60 U1 0 U2 10 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD MAR PY 2008 VL 12 IS 3 BP 114 EP 122 DI 10.1016/j.tics.2007.12.006 PG 9 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 296EU UT WOS:000255527100007 PM 18262829 ER PT J AU Larracuente, AM Sackton, TB Greenberg, AJ Wong, A Singh, ND Sturgill, D Zhang, Y Oliver, B Clark, AG AF Larracuente, Amanda M. Sackton, Timothy B. Greenberg, Anthony J. Wong, Alex Singh, Nadia D. Sturgill, David Zhang, Yu Oliver, Brian Clark, Andrew G. TI Evolution of protein-coding genes in Drosophila SO TRENDS IN GENETICS LA English DT Review ID HILL-ROBERTSON INTERFERENCE; AMINO-ACID SITES; NATURAL-SELECTION; MOLECULAR EVOLUTION; EXPRESSION PATTERN; SUBSTITUTION RATES; CODON USAGE; NUCLEOTIDE SUBSTITUTION; DELETERIOUS MUTATIONS; ADAPTIVE EVOLUTION AB Several contributing factors have been implicated in evolutionary rate heterogeneity among proteins, but their evolutionary mechanisms remain poorly characterized. The recently sequenced 12 Drosophila genomes provide a unique opportunity to shed light on these unresolved issues. Here, we focus on the role of natural selection in shaping evolutionary rates. We use the Drosophila genomic data to distinguish between factors that increase the strength of purifying selection on proteins and factors that affect the amount of positive selection experienced by proteins. We confirm the importance of translational selection in shaping protein evolution in Drosophila and show that factors such as tissue bias in expression, gene essentiality, intron number, and recombination rate also contribute to evolutionary rate variation among proteins. C1 [Larracuente, Amanda M.; Greenberg, Anthony J.; Wong, Alex; Singh, Nadia D.; Clark, Andrew G.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. [Sackton, Timothy B.; Clark, Andrew G.] Cornell Univ, Field Ecol & Evolutionary Biol, Ithaca, NY 14853 USA. [Sturgill, David; Zhang, Yu; Oliver, Brian] NIDDK, Cellular & Dev Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Larracuente, AM (reprint author), Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY 14853 USA. EM aml69@cornell.edu OI Sackton, Timothy/0000-0003-1673-9216 FU Intramural NIH HHS [Z01 DK015600-12] NR 75 TC 139 Z9 139 U1 2 U2 29 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD MAR PY 2008 VL 24 IS 3 BP 114 EP 123 DI 10.1016/j.tig.2007.12.001 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 275FV UT WOS:000254058200004 PM 18249460 ER PT J AU Howard, DB Powers, K Wang, Y Harvey, BK AF Howard, Douglas B. Powers, Kathleen Wang, Yun Harvey, Brandon K. TI Tropism and toxicity of adeno-associated viral vector serotypes 1, 2, 5, 6, 7, 8, and 9 in rat neurons and glia in vitro SO VIROLOGY LA English DT Article DE AAV; adeno-associated virus; gene therapy; serotype; tropism; toxicity; neuron; glia ID CENTRAL-NERVOUS-SYSTEM; VIRUS TYPE-2 INFECTION; MEDIATED GENE-TRANSFER; GROWTH-FACTOR RECEPTOR; MOUSE-BRAIN; EFFICIENT TRANSDUCTION; AAV SEROTYPES; EXPRESSION; CELLS; VIVO AB Recombinant adeno-associated viral (rAAV) vectors are frequently used for gene delivery to the central nervous system and are capable of transducing neurons and glia in vitro. In this study, seven serotypes of a rAAV vector expressing green fluorescent protein (GFP) were characterized for tropism and toxicity in primary cortical cells derived from embryonic rat brain. At 2 days after transduction, serotypes 1 and 5 through 8 expressed GFP predominately in glia, but by 6 days post-transduction expression was neuronal except for AAV5. AAV2 and 9 produced minimal GFP expression. Using cell viability assays, toxicity was observed at higher multiplicities of infection (MOI) for all serotypes except AAV2 and 9. The toxicity of AAV1 and 5-8 affected mostly glia as indicated by a loss of glial-marker immunoreactivity. A frameshift mutation in the GFP gene reduced overall toxicity for serotypes 1, 5 and 6, but not 7 and 8 suggesting that the toxicity was not solely due to the overexpression of GFP. Collectively, a differential tropism and toxicity was observed among the AAV serotypes on primary cortical cultures with an overall preferential glial transduction and toxicity. Published by Elsevier Inc. C1 [Howard, Douglas B.; Powers, Kathleen; Wang, Yun; Harvey, Brandon K.] NIDA, NIH, Mol Neuropsychiat Branch, Neural Protect & Regenerat Sect, Baltimore, MD 21224 USA. RP Harvey, BK (reprint author), NIDA, NIH, Mol Neuropsychiat Branch, Neural Protect & Regenerat Sect, Room 362,Bldg C, Baltimore, MD 21224 USA. EM bharvey@intra.nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 51 TC 63 Z9 64 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 1 PY 2008 VL 372 IS 1 BP 24 EP 34 DI 10.1016/j.virol.2007.10.007 PG 11 WC Virology SC Virology GA 264YC UT WOS:000253325300003 PM 18035387 ER PT J AU Hoshino, Y Qin, J Follmann, D Cohen, JI Straus, SE AF Hoshino, Yo Qin, Jing Follmann, Dean Cohen, Jeffrey I. Straus, Stephen E. TI The number of herpes simplex virus-infected neurons and the number of viral genome copies per neuron correlate with the latent viral load in ganglia SO VIROLOGY LA English DT Article DE HSV-2; latent viral load; number of HSV-infected neurons; number of HSV genome copies per infected cells; Poisson distribution; Poisson-Poisson model ID LASER-CAPTURE MICRODISSECTION; SINGLE-CELL LEVEL; CD8(+) T-CELLS; TRIGEMINAL GANGLIA; SENSORY NEURONS; COPY NUMBER; TRANSCRIPT EXPRESSION; GENITAL HERPES; REACTIVATION; TYPE-1 AB The latent viral load is the most important factor that predicts reactivation rates of animals latently infected with herpes simplex virus (HSV). To estimate the latent viral load, individual latently infected mouse trigeminal ganglia were dispersed into single cell suspensions and plated into 96-well real-time PCR plates, and HSV-2 genome copies were measured. By assuming a Poisson distribution for both the number of HSV-2 infected cells per well and the number of HSV-2 genome copies per infected cell, the numbers of infected cells and mean genome copies per infected cell were determined. Both the number of HSV-2 infected cells and the mean HSV-2 genome copy per infected cell significantly correlated with the latent viral load (p < 10(-4)), indicating that both factors are responsible for the increase in the latent viral load. Published by Elsevier Inc. C1 [Hoshino, Yo; Cohen, Jeffrey I.; Straus, Stephen E.] NIAID, NIH, Med Virol Sect, Lab Clin Infect Dis, Bethesda, MD USA. [Qin, Jing; Follmann, Dean] NIAID, NIH, Biostat Branch, Bethesda, MD USA. RP Cohen, JI (reprint author), NIH, 10 Ctr Dr,Bldg 10,Room 234, Bethesda, MD 20892 USA. EM JCOHEN@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000978-02] NR 24 TC 17 Z9 17 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 1 PY 2008 VL 372 IS 1 BP 56 EP 63 DI 10.1016/j.virol.2007.10.031 PG 8 WC Virology SC Virology GA 264YC UT WOS:000253325300006 PM 18045638 ER PT J AU Golla-Gaur, R Khan, MA Miyagi, E Kao, S Opi, S Takeuchi, H Strebel, K AF Golla-Gaur, Ritu Khan, Mohammad A. Miyagi, Eri Kao, Sandra Opi, Sandrine Takeuchi, Hiroaki Strebel, Klaus TI HIV-1 Vif promotes the formation of high molecular mass APOBEC3G complexes SO VIROLOGY LA English DT Article DE Vif; APOBEC3G; high molecular mass complexes; protein degradation ID IMMUNODEFICIENCY-VIRUS TYPE-1; VIRION INFECTIVITY FACTOR; EDITING ENZYME APOBEC3G; CD4 T-CELLS; ANTIVIRAL ACTIVITY; ALU RETROTRANSPOSITION; STRESS GRANULES; PROTEIN; DEGRADATION; RNA AB HIV-1 Vif inhibits the antiviral activity of APOBEC3G (APO3G) by inducing proteasomal degradation. Here, we studied the effects of Vif on APO3G in vitro. In this system, Vif did not cause APO3G degradation. Instead, Vif induced changes in APO3G that affected immunoprecipitation of the native protein. This effect required wt Vif and was reversed by heat denaturation of APO3G. Sucrose gradient analysis demonstrated that wt Vif induced the gradual transition of APO3G translated in vitro or expressed in HeLa cells from a low molecular mass conformation to puromycin-sensitive high molecular mass (HMM) complexes. In the absence of Vif or the presence of biologically inactive Vif APO3G failed to form HMM complexes. Our results expose a novel function of Vif that promotes the assembly of APO3G into presumably packaging-incompetent HMM complexes and may explain how Vif can overcome the APO3G-imposed block to HIV replication under conditions of no or inefficient APO3G degradation. Published by Elsevier Inc. C1 [Golla-Gaur, Ritu; Khan, Mohammad A.; Miyagi, Eri; Kao, Sandra; Opi, Sandrine; Takeuchi, Hiroaki; Strebel, Klaus] NIAID, NIH, Viral Biochem Sect, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIAID, NIH, Viral Biochem Sect, Mol Microbiol Lab, Bethesda, MD 20892 USA. EM kstrebel@nih.gov RI Takeuchi, Hiroaki/F-9728-2012 FU Intramural NIH HHS [Z01 AI000669-15] NR 43 TC 4 Z9 4 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 1 PY 2008 VL 372 IS 1 BP 136 EP 146 DI 10.1016/j.virol.2007.10.017 PG 11 WC Virology SC Virology GA 264YC UT WOS:000253325300014 PM 18023836 ER PT J AU Connaughton, VP Nelson, R Bender, AM AF Connaughton, Victoria P. Nelson, Ralph Bender, Anna M. TI Electrophysiological evidence of GABA(A) and GABA(C) receptors on zebrafish retinal bipolar cells SO VISUAL NEUROSCIENCE LA English DT Article DE retina; bipolar cells; GABA; zebrafish; inhibition ID GAMMA-AMINOBUTYRIC-ACID; TIGER SALAMANDER RETINA; OUTER PLEXIFORM LAYER; WHITE PERCH RETINA; AXON TERMINALS; HORIZONTAL CELLS; AMACRINE CELLS; MOUSE RETINA; RAT RETINA; GOLDFISH RETINA AB To refine inhibitory circuitry models for ON and OFF pathways in zebrafish retina, GABAergic properties of zebrafish bipolar cells were studied with two techniques: whole cell patch responses to GABA puffs in retinal slice, and voltage probe responses in isolated cells. Retinal slices documented predominantly axon terminal responses; isolated cells revealed mainly soma-dendritic responses. In the slice, GABA elicited a conductance increase, GABA responses were more robust at axon terminals than dendrites, and E(rev) varied with [Cl(-)](in). Axon terminals of ON- and OFF-type cells were similarly sensitive to GABA (30-40 pA peak current); axotomized cells were unresponsive. Bicuculline-sensitive, picrotoxin-sensitive, and picrotoxin-insensitive components were identified. Muscimol was as effective as GABA; baclofen was ineffective. Isolated bipolar cells were either intact or axotomized. Even in cells without an axon, GABA or muscimol (but not baclofen) hyperpolarized dendritic and somatic regions, suggesting significant distal expression. Median fluorescence change for GABA was -0.22 log units (similar to - 16 mV); median half-amplitude dose was 0.4 mu M. Reduced [Cl(-)](out) blocked GABA responses. GABA hyperpolarized isolated ON-bipolar cells; OFF-cells were either unresponsive or depolarized. Hyperpolarizing GABA responses in isolated cells were bicuculline and TPMPA insensitive, but blocked or partially blocked by picrotoxin or zinc. In summary, axon terminals contain bicuculline-sensitive GABA(A) receptors and both picrotoxin-sensitive and insensitive GABA(C) receptors. Dendritic processes express zinc-and picrotoxin-sensitive GABA(C) receptors. C1 [Connaughton, Victoria P.] American Univ, Dept Biol, Washington, DC 20016 USA. [Nelson, Ralph; Bender, Anna M.] NINDS, Bas Neurosci Program, NIH, Bethesda, MD 20892 USA. RP Connaughton, VP (reprint author), American Univ, Dept Biol, 4400 Massachusetts NW, Washington, DC 20016 USA. EM vconn@american.edu FU Intramural NIH HHS [Z01 NS002631-24] NR 90 TC 8 Z9 9 U1 0 U2 1 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0952-5238 J9 VISUAL NEUROSCI JI Visual Neurosci. PD MAR-APR PY 2008 VL 25 IS 2 BP 139 EP 153 DI 10.1017/S0952523808080322 PG 15 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 297EF UT WOS:000255599200003 PM 18442437 ER PT J AU Nelson, R Bender, AM Connaughton, VP AF Nelson, Ralph Bender, Anna M. Connaughton, Victoria P. TI Transporter-mediated GABA responses in horizontal and bipolar cells of zebrafish retina SO VISUAL NEUROSCIENCE LA English DT Article DE outer plexiform; layer; ATPase; GABA transporter; baclofen; glycine; horizontal cell; bipolar cell ID TIGER SALAMANDER RETINA; GAMMA-AMINOBUTYRIC-ACID; GABAERGIC AMACRINE CELLS; GOLDFISH RETINA; CAT RETINA; IMMUNOCYTOCHEMICAL LOCALIZATION; GLUTAMATE RECEPTORS; INDUCED CURRENTS; FUNCTIONAL-ROLE; MONKEY RETINA AB GABA-mediated interactions between horizontal cells (HCs) and bipolar cells (BCs) transform signals within the image-processing circuitry of distal retina. To further understand this process, we have studied the GABA-driven membrane responses from isolated retinal neurons. Papain-dissociated retinal cells from adult zebrafish were exposed to GABAergic ligands while transmembrane potentials were monitored with a fluorescent voltage-sensitive dye (oxonol, DiBaC(4)(5)). In HCs hyperpolarizing, ionotropic GABA responses were almost never seen, nor were responses to baclofen or glycine. A GABA-induced depolarization followed by after hyperpolarization (dep/AHP) occurred in 38% of HCs. The median fluorescence increase (dep component) was 0.17 log units, about 22 mV. HC dep/AHP was not blocked by bicuculline or picrotoxin. Muscimol rarely evoked dep/AHP responses. In BCs picrotoxin sensitive, hyperpolarizing, ionotropic GABA and muscimol responses occurred in most cells. A picrotoxin insensitive dep/AHP response was seen in about 5% of BCs. The median fluorescence increase (dep component) was 0.18 log units, about 23 mV. Some BCs expressed both muscimol-induced hyperpolarizations and GABA-induced dep/AHP responses. For all cells, the pooled Hill fit to median dep amplitudes, in response to treatments with a GABA concentration series, gave an apparent k of 0.61 mu M and an n of 1.1. The dep/A.HP responses of all cells required both extracellular Na+ and Cl-, as dep/AHP was blocked reversibly by Li+ substituted for Na+ and irreversibly by isethionate substituted for Cl-. All cells with dep/AHP responses in zebrafish have the membrane physiology of neurons expressing GABA transporters. These cells likely accumulate GABA, a characteristic of GABAergic neurons. We suggest Na+ drives GABA into these cells, depolarizing the plasma membrane and triggering Na+, K+-dependent ATPase. The ATPase activity generates AHP. In addition to a GABA clearance function, these large-amplitude transporter responses may provide an outer plexiform layer GABA sensor mechanism. C1 [Nelson, Ralph; Bender, Anna M.] NINDS, Bas Neurosci Program, NIH, Bethesda, MD 20892 USA. [Connaughton, Victoria P.] American Univ, Dept Biol, Washington, DC 20016 USA. RP Nelson, R (reprint author), NINDS, Bas Neurosci Program, NIH, 5625 Fishers Lane,Room TS-09, Bethesda, MD 20892 USA. EM nelsonr@ninds.nih.gov FU Intramural NIH HHS [Z01 NS002631-24] NR 65 TC 5 Z9 5 U1 0 U2 3 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0952-5238 EI 1469-8714 J9 VISUAL NEUROSCI JI Visual Neurosci. PD MAR-APR PY 2008 VL 25 IS 2 BP 155 EP 165 DI 10.1017/S0952523808080310 PG 11 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 297EF UT WOS:000255599200004 PM 18442438 ER PT J AU Urquhart, NE Capildeo, KD Sargeant, LA Wharfe, G Hisada, M Hanchard, B AF Urquhart, N. E. Capildeo, K. D. Sargeant, L. A. Wharfe, G. Hisada, M. Hanchard, B. TI White blood cell counts in healthy Jamaican adults SO WEST INDIAN MEDICAL JOURNAL LA English DT Article ID GENETIC NEUTROPENIA; LEUKOCYTE COUNT; LEUKOPENIA; AFRICANS; VALUES; SEX AB The investigation of presumed neutropenia places a. burden on the health services, especially those of developing countries, including Jamaica. This may be because the normal ranges used in the laboratory are based on the values generatedfrom the Caucasian population. Previous studies looking at African and Afro-Caribbean groups have found lower counts for these populations compared with Caucasians. To address this issue, 195 healthy adults donating blood at the National Public Health Laboratory and the University Hospital of the West Indies blood banks in Kingston, Jamaica, were screened for complete blood count (CBQ differentials between June 2001 and June 2006. The geometric means for the neutrophil counts were found to be 2.4 x 1091L for men and 2.7 x 1091L for women, with 95% confidence intervals of 2.2-2.8 x 1091L and 2.5-3.1 x 1091L respectively. Valuesfor the Jamaican population were similar to those of other Afro-Caribbean groups. Based on this distribution, 14% of healthy Jamaicans wouldfall below the normal ranges derivedfrom Caucasians and therefore presumed to have neutropenia. We recommend that the lower reference ranges obtainedfor Afro-Caribbean adults be adoptedfor that population. C1 [Urquhart, N. E.; Capildeo, K. D.; Wharfe, G.; Hanchard, B.] Univ W Indies, Dept Pathol, Kingston 7, Jamaica. [Sargeant, L. A.] Univ W Indies, Epidemiol Res Unit, Res Inst Trop Med, Kingston 7, Jamaica. [Hisada, M.] NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Urquhart, NE (reprint author), Univ W Indies, Dept Pathol, Kingston 7, Jamaica. EM urkie@cwjamaica.com FU CIT NIH HHS [N01-CT-40548] NR 14 TC 4 Z9 4 U1 0 U2 0 PU UNIV WEST INDIES FACULTY MEDICAL SCIENCES PI KINGSTON PA MONA CAMPUS, KINGSTON 7, JAMAICA SN 0043-3144 J9 W INDIAN MED J JI West Ind. Med. J. PD MAR PY 2008 VL 57 IS 2 BP 147 EP 151 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 331VM UT WOS:000258040700013 PM 19565958 ER PT J AU Kwak, T Yufit, T Butmarc, J Kim, SJ Falanga, V AF Kwak, T. Yufit, T. Butmarc, J. Kim, S-J Falanga, V. TI Development of transgenic mice that inducibly express beta IG-H3 in the epidermis SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Kwak, T.; Yufit, T.; Butmarc, J.; Falanga, V.] Roger Williams Med Ctr, Dept Dermatol & Skin Surg, Providence, RI USA. [Kwak, T.; Yufit, T.; Butmarc, J.] Roger Williams Med Ctr, NIH, Ctr Biomed Res Excellence, Providence, RI USA. [Falanga, V.] Boston Univ, Dept Dermatol & Biochem, Boston, MA 02215 USA. [Kim, S-J] NIH, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR-APR PY 2008 VL 16 IS 2 MA 122 BP A42 EP A42 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 271AJ UT WOS:000253761000142 ER PT J AU Yufit, TY Carson, P Butmarc, J Kwak, T Falanga, V AF Yufit, T. Y. Carson, P. Butmarc, J. Kwak, T. Falanga, V. TI Developing an IND for clinical trials in tissue repair SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Yufit, T. Y.; Carson, P.; Butmarc, J.; Kwak, T.; Falanga, V.] Roger Williams Med Ctr, Dept Dermatol & Skin Surg, Providence, RI USA. [Yufit, T. Y.; Carson, P.; Butmarc, J.; Kwak, T.] Roger Williams Med Ctr, NIH, Ctr Biomed Res Excellence, Providence, RI USA. [Falanga, V.] Boston Univ, Dept Dermatol & Biochem, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD MAR-APR PY 2008 VL 16 IS 2 MA 119 BP A41 EP A41 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 271AJ UT WOS:000253761000139 ER PT J AU Wu, WW Wang, GH Liang, XJ Park, JK Shen, RF AF Wu, Wells W. Wang, Guanghui Liang, Xing-Jie Park, John K. Shen, Rong-Fong TI Covalent modification of stathmin by CCNU determined by FTMS analysis of modified proteins and tryptic peptides SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE RP-HPLC; Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS or FTMS); 1-(2-chloroethyl)-3-cyclohexyl-l-nitroso-urea (CCNU); stathmin; stoichiometry ID HYDROPHILIC-INTERACTION CHROMATOGRAPHY; MASS-SPECTROMETRY; SIZE-EXCLUSION; LABEL-FREE; QUANTIFICATION; LIBRARIES AB Chemical modification of proteins is often carried out to generate protein-small molecule conjugates for various applications. The high resolution and mass accuracy of a Fourier transform mass spectrometer is particularly useful for assessing the extent or sites of covalent modifications. As protein-small molecule reactions often produce products with variable numbers of the compound incorporated at different sites, a direct mass analysis of the reaction products at times yields mass spectra hard to interpret. Chromatographic separation at protein level could reduce the complexity of a sample, thus allowing more accurate mass spectrometric analysis. In this report, we demonstrate the utility of reversed-phase protein chromatography and FT-ICR mass spectrometry in analyzing CCNU (lomustine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitroso-urea, MW: 233.7 Da) modification of stathmin. With this combined approach, we determined the stoichiometry as well as sites of CCNU incorporation into the protein, demonstrating differential reactivity of several lysyl residues to CCNU alkylation. Published by Elsevier Inc. C1 [Wu, Wells W.; Wang, Guanghui; Shen, Rong-Fong] NHLBI, NIH, Proteom Core Facil, Bethesda, MD 20892 USA. [Liang, Xing-Jie; Park, John K.] NINDS, NIH, Bethesda, MD 20892 USA. RP Shen, RF (reprint author), NHLBI, NIH, Proteom Core Facil, Bldg 10,Room 8C103C,10 Ctr Dr, Bethesda, MD 20892 USA. EM shenr@nhlbi.nih.gov FU Intramural NIH HHS [Z99 OD999999] NR 15 TC 2 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 29 PY 2008 VL 367 IS 1 BP 7 EP 13 DI 10.1016/j.bbrc.2007.12.107 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 254WW UT WOS:000252619700002 PM 18162179 ER PT J AU Koh, KK Quon, MJ Rosenson, RS Chung, WJ Han, SH AF Koh, Kwang Kon Quon, Michael J. Rosenson, Robert S. Chung, Wook-Jin Han, Seung Hwan TI Vascular and metabolic effects of treatment of combined hyperlipidemia: Focus on statins and fibrates SO INTERNATIONAL JOURNAL OF CARDIOLOGY LA English DT Review DE statins; fibrates; endothelial function; insulin resistance; combined hyperlipidemia; safety ID ACTIVATED-RECEPTOR-ALPHA; CORONARY-ARTERY-DISEASE; NITRIC-OXIDE SYNTHASE; C-REACTIVE PROTEIN; FAMILIAL COMBINED HYPERLIPIDEMIA; IMPROVES ENDOTHELIAL FUNCTION; DEPENDENT DIABETES-MELLITUS; PLASMA ADIPONECTIN LEVELS; TISSUE FACTOR EXPRESSION; LOW-DENSITY-LIPOPROTEIN AB Combined hyperlipidemia results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins in association with reduced lipoprotein lipase activity. Thus, this condition is typically characterized by concurrent elevations in total cholesterol and triglycerides with decreased high-density lipoprotein cholesterol. High levels of apolipoprotein B-containing lipoproteins, most prominently carried by low-density lipoprotein (LDL) particles, are an important risk factor for coronary heart disease. Stalin therapy is highly effective at lowering LDL cholesterol. Despite the benefits of statin treatment for lowering total and LDL cholesterol, many statin-treated patients still have initial or recurrent coronary heart disease events. In this regard, combined therapy with statins and fibrates is more effective in controlling atherogenic dyslipidemia in patients with combined hyperlipidemia than either drug alone. Furthermore, statins and fibrates activate PPAR alpha in a synergistic manner providing a molecular rationale for combination treatment in coronary heart disease. Endothelial dysfunction associated with cardiovascular diseases may contribute to insulin resistance so that there may also be additional beneficial metabolic effects of combined statin/fibrates therapy. However, there has been little published evidence that combined therapy is synergistic or even better than monotherapy alone in clinical studies. Therefore, there is a great need to study the effects of combination therapy in patients. When statins are combined with gemfibrozil therapy, this is more likely to be accompanied by myopathy. However, this limitation is not observed when fenofibrate, bezafibrate, or ciprofibrate are used in combination therapy. (c) 2007 Elsevier Ireland Ltd. All rights reserved. C1 [Koh, Kwang Kon; Chung, Wook-Jin; Han, Seung Hwan] Gachon Med Sch, Gil Heart Ctr, Div Cardiol, Vasc Med & Atherosclerosis Unit, Inchon 405760, South Korea. [Quon, Michael J.] NIH, Diabet Unit, Clin Invest Lab, NCCAM, Bethesda, MD 20892 USA. [Rosenson, Robert S.] Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. [Rosenson, Robert S.] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. RP Koh, KK (reprint author), Gachon Med Sch, Gil Heart Ctr, Div Cardiol, Vasc Med & Atherosclerosis Unit, 1198 Kuwol Dong, Inchon 405760, South Korea. EM kwangk@gilhospital.com RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Chung, Wook-Jin/0000-0002-9767-7098; Quon , Michael /0000-0002-5289-3707 FU Intramural NIH HHS [Z01 AT000001-06] NR 109 TC 26 Z9 28 U1 0 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-5273 J9 INT J CARDIOL JI Int. J. Cardiol. PD FEB 29 PY 2008 VL 124 IS 2 BP 149 EP 159 DI 10.1016/j.ijcard.2007.04.080 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 286DF UT WOS:000254825100004 PM 17658632 ER PT J AU Shetty, PK Huang, FL Huang, KP AF Shetty, Pavan K. Huang, Freesia L. Huang, Kuo-Ping TI Ischemia-elicited oxidative modulation of Ca2+/calmodulin-dependent protein kinase II SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LONG-TERM POTENTIATION; RAT-BRAIN NEUROGRANIN/RC3; DISULFIDE S-OXIDE; POSTSYNAPTIC DENSITIES; HIPPOCAMPAL-NEURONS; SELF-ASSOCIATION; CEREBRAL-ISCHEMIA; DENDRITIC SPINES; NITRIC-OXIDE; CAMKII AB Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) plays a critical role in neuronal signal transduction and synaptic plasticity. Here, we showed that this kinase was very susceptible to oxidative modulation. Treatment of mouse brain synaptosomes with H2O2, diamide, and sodium nitroprusside caused aggregation of CaMKII through formation of disulfide and non-disulfide linkages, and partial inhibition of the kinase activity. These CaMKII aggregates were found to associate with the post synaptic density. However, treatment of purified CaMKII with these oxidants did not replicate those effects observed in the synaptosomes. Using two previously identified potential mediators of oxidants in the brain, glutathione disulfide S-monoxide (GS-DSMO) and glutathione disulfide S-dioxide (GS-DSDO), we showed that they oxidized and inhibited CaMKII in a manner partly related to those of the oxidant-treated synaptosomes as well as the ischemia-elicited oxidative stress in the acutely prepared hippocampal slices. Interestingly, the autophosphorylated and activated CaMKII was relatively refractory to GS-DSMO- and GS-DSDO-mediated aggregation. Short term ischemia (10 min) caused a depression of basal synaptic response of the hippocampal slices, and re-oxygenation (after 10 min) reversed the depression. However, oxidation of CaMKII remained at above the pre-ischemic level throughout the treatment. Oxidation of CaMKII also prevented full recovery of CaMKII autophosphorylation after re-oxygenation. Subsequently, the high frequency stimulation-mediated synaptic potentiation in the hippocampal CA1 region was significantly reduced compared with the control without ischemia. Thus, ischemia-evoked oxidation of CaMKII, probably via the action of glutathione disulfide S-oxides or their analogues, may be involved in the suppression of synaptic plasticity. C1 [Shetty, Pavan K.; Huang, Freesia L.; Huang, Kuo-Ping] NICHD, Natl Inst Hlth, Dev Neurobiol Program, Bethesda, MD 20892 USA. RP Huang, KP (reprint author), NIH, Bldg 49,Rm6A10,49 Convent Dr MSC 4510, Bethesda, MD 20892 USA. EM huangk@mail.nih.gov RI SHETTY, PAVAN/B-9804-2012; OI Shetty, Pavan/0000-0002-6484-7417 FU Intramural NIH HHS NR 53 TC 15 Z9 16 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 29 PY 2008 VL 283 IS 9 BP 5389 EP 5401 DI 10.1074/jbc.M708479200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266IC UT WOS:000253426700019 PM 18174165 ER PT J AU Roehrl, J Yang, D Oppenheim, JJ Hehlgans, T AF Roehrl, Johann Yang, De Oppenheim, Joost J. Hehlgans, Thomas TI Identification and biological characterization of mouse beta-defensin 14, the orthologue of human beta-defensin 3 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN BETA-DEFENSINS; IMMATURE DENDRITIC CELLS; ANTIMICROBIAL PEPTIDES; INDUCTION; IMMUNITY; KERATINOCYTES; EXPRESSION; DISCOVERY; INCREASE; INNATE AB beta-Defensins are small antimicrobial polypeptides that are mainly expressed by epithelial cells and play an important role in the antimicrobial innate immune response. In addition to the direct microbicidal effects of these polypeptides, it became evident that certain members of the beta-defensin super family have the capacity to promote local innate inflammatory and systemic adaptive immune responses by interacting with the CC-chemokine receptor CCR6. We have identified mouse beta-defensin 14 (mBD14, Defb14) as an orthologue of human beta-defensin 3 (hBD3 or DEFB103). Based on primary structural analysis, mBD14 demonstrates greater (68%) homology to its human orthologue, containing three conserved cystein linkages, characteristic for the beta-defensin super family. mBD14 is expressed in a wide variety of tissues including spleen, colon, and tissues of the upper and lower respiratory tract. Interestingly, we also detected mBD14 expression in immature CD11c(+) bone marrow-derived dendritic cells. The expression of mBD14 can be induced by Toll-like receptor agonists such as lipopolysaccharide and poly(I:C) and by pro-inflammatory stimuli e. g. tumor necrosis factor and interferon-gamma. Furthermore, expression of mBD14 seems to be regulated by activation of the intracellular pattern recognition receptor NOD2/CARD15 as revealed by reporter gene analysis. We prepared a recombinant mBD14-Ig fusion protein that retained potent antimicrobial activity against several Escherichia coli strains but not against various Gram-positive Staphylococcus aureus strains. hBD3 and also the newly identified mBD14 were chemotactic for cells expressing the mouse CC-chemokine receptor CCR6. In addition, both hBD3 and mBD14 were chemotactic for freshly isolated mouse resident peritoneal cells. Thus, mBD14, based on structural and functional similarities, appears to be an orthologue of hBD3. C1 [Roehrl, Johann; Hehlgans, Thomas] Univ Regensburg, Inst Immunol, D-93042 Regensburg, Germany. [Yang, De; Oppenheim, Joost J.] NIH, NCI, Div Basic Sci, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Hehlgans, T (reprint author), Univ Regensburg, Inst Immunol, Franz-Josef-Str-Allee 11, D-93042 Regensburg, Germany. EM thomas.hehlgans@klinik.regensburg.de NR 27 TC 5 Z9 5 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 FEB 29 PY 2008 VL 283 IS 9 BP 5414 EP 5419 DI 10.1074/jbc.M709103200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266IC UT WOS:000253426700021 ER PT J AU Zou, YL Wu, J Giannone, RJ Boucher, L Du, HS Huang, Y Johnson, DK Liu, Y Wang, YS AF Zou, Yonglong Wu, Jun Giannone, Richard J. Boucher, Lorrie Du, Hansen Huang, Ying Johnson, Dabney K. Liu, Yie Wang, Yisong TI Nucleophosmin/B23 negatively regulates GCN5-dependent histone acetylation and transactivation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CHROMATIN REMODELING ENZYMES; ACETYLTRANSFERASE ACTIVITY; CENTROSOME DUPLICATION; DEPENDENT KINASE; IN-VIVO; PROTEIN; PHOSPHORYLATION; TRANSCRIPTION; GENE; GCN5 AB Nucleophosmin/B23 is a multifunctional phosphoprotein that is overexpressed in cancer cells and has been shown to be involved in both positive and negative regulation of transcription. In this study, we first identified GCN5 acetyltransferase as a B23-interacting protein by mass spectrometry, which was then confirmed by in vivo co-immunoprecipitation. An in vitro assay demonstrated that B23 bound the PCAF-N domain of GCN5 and inhibited GCN5-mediated acetylation of both free and mononucleosomal histones, probably through interfering with GCN5 and masking histones from being acetylated. Mitotic B23 exhibited higher inhibitory activity on GCN5-mediated histone acetylation than interphase B23. Immunodepletion experiments of mitotic extracts revealed that phosphorylation of B23 at Thr(199) enhanced the inhibition of GCN5-mediated histone acetylation. Moreover, luciferase reporter and microarray analyses suggested that B23 attenuated GCN5-mediated transactivation in vivo. Taken together, our studies suggest a molecular mechanism of B23 in the mitotic inhibition of GCN5-mediated histone acetylation and transactivation. C1 [Zou, Yonglong; Wu, Jun; Giannone, Richard J.; Huang, Ying; Johnson, Dabney K.; Wang, Yisong] Oak Ridge Natl Lab, Biosci Div, Oak Ridge, TN 37831 USA. [Boucher, Lorrie] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. [Du, Hansen; Liu, Yie] NIH, NIA, Ctr Gerontol Res, Baltimore, MD 21224 USA. RP Wang, YS (reprint author), Oak Ridge Natl Lab, Biosci Div, Bethel Valley Rd, Oak Ridge, TN 37831 USA. EM ywa@ornl.gov FU Intramural NIH HHS NR 52 TC 6 Z9 7 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 FEB 29 PY 2008 VL 283 IS 9 BP 5728 EP 5737 DI 10.1074/jbc.M709932200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266IC UT WOS:000253426700054 PM 18165222 ER PT J AU Mitobe, J Morita-Ishihara, T Ishihama, A Watanabe, H AF Mitobe, Jiro Morita-Ishihara, Tomoko Ishihama, Akira Watanabe, Haruo TI Involvement of RNA-binding protein Hfq in the post-transcriptional regulation of invE gene expression in Shigella sonnei SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FORM-I PLASMID; ESCHERICHIA-COLI; H-NS; VIRULENCE GENE; HOST FACTOR; MESSENGER-RNA; CHROMOSOMAL GENES; STATIONARY-PHASE; Q-BETA; FLEXNERI AB The temperature-dependent regulation of Shigella virulence genes is believed to be accomplished at the transcriptional stage by the regulators VirF and InvE. Several lines of evidence herein described indicate that post-transcriptional regulation of InvE expression plays a key role in the temperature-dependent regulation of virulence gene expression: (i) a considerable amount of invE mRNA continues to be transcribed under low temperature conditions, where the production of InvE protein is tightly repressed; (ii) the stability of invE mRNA markedly decreases, because its decay rate is significantly increased under the repressing conditions. Strikingly, in the hfq mutant of Shigella sonnei, a considerable amount of InvE protein was produced even at low temperature. This increase in the InvE level was found to be associated with the improved stability of invE mRNA, in agreement with the finding that the RNA chaperon Hfq influences post-transcriptional regulations of various genes. Consistently, overexpression of the Hfq protein decreased the production of InvE protein even under the expressing condition at 37 degrees C. The binding in vitro of purified Hfq protein to invE RNA was shown to be stronger at 30 degrees C than at 37 degrees C in two experiments, gel shift analysis and surface plasmon resonance (Biacore) analysis. These results altogether suggest that Hfq plays an important role in the temperature-dependent regulation of invE expression at the post-transcriptional step. C1 [Mitobe, Jiro; Morita-Ishihara, Tomoko; Watanabe, Haruo] NIAID, Dept Bacteriol, Shinjuku Ku, Tokyo 1628640, Japan. [Ishihama, Akira] Hosei Univ, Dept Frontier Biosci, Tokyo 1848584, Japan. RP Watanabe, H (reprint author), NIAID, Dept Bacteriol, Shinjuku Ku, Tokyo 1628640, Japan. EM haruwata@nih.go.jp NR 53 TC 22 Z9 22 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 29 PY 2008 VL 283 IS 9 BP 5738 EP 5747 DI 10.1074/jbc.M710108200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266IC UT WOS:000253426700055 PM 18156173 ER PT J AU Ganichkin, OM Xu, XM Carlson, BA Mix, H Hatfield, DL Gladyshev, VN Wahl, MC AF Ganichkin, Oleg M. Xu, Xue-Ming Carlson, Bradley A. Mix, Heiko Hatfield, Dolph L. Gladyshev, Vadim N. Wahl, Markus C. TI Structure and catalytic mechanism of eukaryotic selenocysteine synthase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SERINE TRANSFER-RNA; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; SELENOPROTEIN SYNTHESIS; AUTOIMMUNE HEPATITIS; ANGSTROM RESOLUTION; SECONDARY-STRUCTURE; TARGET ANTIGEN; PROTEIN; IDENTIFICATION AB In eukaryotes and Archaea, selenocysteine synthase (SecS) converts O-phospho-L-seryl-tRNA([Ser]Sec) into selenocysteyl-tRNA([Ser]Sec) using selenophosphate as the selenium donor compound. The molecular mechanisms underlying SecS activity are presently unknown. We have delineated a 450-residue core of mouse SecS, which retained full selenocysteyl-tRNA([Ser]Sec) synthesis activity, and determined its crystal structure at 1.65 angstrom resolution. SecS exhibits three domains that place it in the fold type I family of pyridoxal phosphate (PLP)-dependent enzymes. Two SecS monomers interact intimately and together build up two identical active sites around PLP in a Schiff-base linkage with lysine 284. Two SecS dimers further associate to form a homotetramer. The N terminus, which mediates tetramer formation, and a large insertion that remodels the active site set SecS aside from other members of the family. The active site insertion contributes to PLP binding and positions a glutamate next to the PLP, where it could repel substrates with a free alpha-carboxyl group, suggesting why SecS does not act on free O-phospho-L-serine. Upon soaking crystals in phosphate buffer, a previously disordered loop within the active site insertion contracted to form a phosphate binding site. Residues that are strictly conserved in SecS orthologs but variant in related enzymes coordinate the phosphate and upon mutation corrupt SecS activity. Modeling suggested that the phosphate loop accommodates the gamma-phosphate moiety of O-phospho-L-seryl-tRNA([Ser]Sec) and, after phosphate elimination, binds selenophosphate to initiate attack on the proposed aminoacrylyl-tRNA([Ser]Sec) intermediate. Based on these results and on the activity profiles of mechanism-based inhibitors, we offer a detailed reaction mechanism for the enzyme. C1 [Ganichkin, Oleg M.; Wahl, Markus C.] Max Planck Inst Biophys Chem, Zellulare Biochem Makromol Rontgenkristallog, D-37077 Gottingen, Germany. [Xu, Xue-Ming; Carlson, Bradley A.; Hatfield, Dolph L.] NIH, NCI, Canc Res Ctr, Lab Canc Prevent Mol Biol Selenium Sect, Bethesda, MD 20892 USA. [Mix, Heiko; Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RP Wahl, MC (reprint author), Max Planck Inst Biophys Chem, Zellulare Biochem Makromol Rontgenkristallog, Am Fassberg 11, D-37077 Gottingen, Germany. EM mwahl@gwdg.de RI Gladyshev, Vadim/A-9894-2013; Wahl, Markus/D-6365-2017 OI Wahl, Markus/0000-0002-2811-5307 FU Intramural NIH HHS NR 59 TC 29 Z9 30 U1 2 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 29 PY 2008 VL 283 IS 9 BP 5849 EP 5865 DI 10.1074/jbc.M709342200 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266IC UT WOS:000253426700064 PM 18093968 ER PT J AU Binger, KJ Pham, CLL Wilson, LM Bailey, MF Lawrence, LJ Schuck, P Howlett, GJ AF Binger, Katrina J. Pham, Chi L. L. Wilson, Leanne M. Bailey, Michael F. Lawrence, Lynne J. Schuck, Peter Howlett, Geoffrey J. TI Apolipoprotein C-II amyloid fibrils assemble via a reversible pathway that includes fibril breaking and rejoining SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE fibril formation; amyloid; sedimentation velocity; size distribution; kinetic analysis ID SEDIMENTATION-VELOCITY ANALYSIS; PROTEIN-MISFOLDING DISEASES; ALZHEIMERS-DISEASE; SELF-ASSOCIATION; POLYMERIZATION; MECHANISM; BETA(2)-MICROGLOBULIN; MACROMOLECULES; A-BETA(1-40); CONSEQUENCES AB Alzheimer's and several other diseases are characterized by the misfolding and assembly of protein subunits into amyloid fibrils. Current models propose that amyloid fibril formation proceeds via the self-association of several monomers to form a nucleus, which then elongates by the addition of monomer to form mature fibrils. We have examined the concentration-dependent kinetics of apolipoprotein C-II amyloid fibril formation and correlated this with the final size distribution of the fibrils determined by sedimentation velocity experiments. In contrast to predictions of the nucleation-elongation model, the final size distribution of the fibrils was found to be relatively independent of the starting monomer concentration. To explain these results, we extended the nucleation-elongation model to include fibril breaking and rejoining as integral parts of the amyloid fibril assembly mechanism. The system was examined under conditions that affected the stability of the mature fibrils, including the effect of dilution on the free pool of monomeric apolipoprotein C-II and the time-dependent recovery of fibril size following sonication. Antibody-labelling transmission electron microscopy studies provided direct evidence for spontaneous fibril breaking and rejoining. These studies establish the importance of breaking and rejoining in amyloid fibril formation and identify prospective new therapeutic targets in the assembly pathway. (C) 2008 Elsevier Ltd. All rights reserved. C1 [Binger, Katrina J.; Pham, Chi L. L.; Wilson, Leanne M.; Bailey, Michael F.; Howlett, Geoffrey J.] Univ Melbourne, Dept Biochem & Mol Biol, Bio21 Mol Sci & Biotechnol Inst, Parkville, Vic 3010, Australia. [Binger, Katrina J.; Lawrence, Lynne J.] CSIRO Mol Hlth Technol, Parkville, Vic 3052, Australia. [Schuck, Peter] NIH, Bethesda, MD 20892 USA. RP Howlett, GJ (reprint author), Univ Melbourne, Dept Biochem & Mol Biol, Bio21 Mol Sci & Biotechnol Inst, 30 Flemington Rd, Parkville, Vic 3010, Australia. EM ghowlett@unimelb.edu.au RI Waddington, Lynne/H-3500-2013; OI Binger, Katrina/0000-0003-1139-3308; Schuck, Peter/0000-0002-8859-6966 NR 46 TC 44 Z9 44 U1 0 U2 8 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 FEB 29 PY 2008 VL 376 IS 4 BP 1116 EP 1129 DI 10.1016/j.jmb.2007.12.055 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 273HI UT WOS:000253920600018 PM 18206908 ER PT J AU Butan, C Winkler, DC Heymann, JB Craven, RC Steven, AC AF Butan, Carmen Winkler, Dennis C. Heymann, J. Bernard Craven, Rebecca C. Steven, Alasdair C. TI RSV capsid polymorphism correlates with polymerization efficiency and envelope glycoprotein content: Implications that nucleation controls morphogenesis SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE virus maturation; nucleation of assembly; critical concentration; capsid assembly; cryo-electron tomography ID ROUS-SARCOMA-VIRUS; HUMAN-IMMUNODEFICIENCY-VIRUS; CRYOELECTRON MICROSCOPY; 3-DIMENSIONAL STRUCTURE; ELECTRON TOMOGRAPHY; HIV-1 CORE; T-EVEN; CA PROTEIN; IN-VITRO; TYPE-1 AB We used cryo-electron tomography to visualize Rous sarcoma virus, the prototypic alpharetrovirus. Its polyprotein Gag assembles into spherical procapsids, concomitant with budding. In maturation, Gag is dissected into its matrix, capsid protein (CA), and nucleocapsid moieties. CA reassembles into cores housing the viral RNA and replication enzymes. Evidence suggests that a correctly formed core is essential for infectivity. The virions in our data set range from similar to 105 to similar to 175 run in diameter. Their cores are highly polymorphic. " coffin- observe angular cores, including some that are distinctively " for which we propose a novel fullerene geometry; cores with shaped continuous curvature including, rarely, fullerene cones; and tubular cores. Angular cores are the most voluminous and densely packed; tubes and some curved cores contain less material, suggesting incomplete packaging. From the tomograms, we measured the surface areas of cores and, hence, their contents of CA subunits. From the virion diameters, we estimated their original complements of Gag. We find that Rous sarcoma virus virions, like the human immunodeficiency virus, contain unassembled CA subunits and that the fraction of CA that is assembled correlates with core type; angular cores incorporate similar to 80% of the available subunits, and open-ended tubes, similar to 30%. The number of glycoprotein spikes is variable (similar to 0 to 118) and also correlates with core type; virions with angular cores average 82 spikes, whereas those with tubular cores average 14 spikes. These observations imply that initiation of CA assembly, in which interactions of spike endodomains with the Gag layer play a role, is a critical determinant of core morphology. (C) Published by Elsevier Ltd. C1 [Butan, Carmen; Winkler, Dennis C.; Heymann, J. Bernard; Steven, Alasdair C.] NIH, Struct Biol Lab, Natl Inst Arthritis Musculoskeletal & Skin Dis, Bethesda, MD 20892 USA. [Craven, Rebecca C.] Penn State Univ, Coll Med, Dept Microbiol & Immunol, Hershey, PA 17033 USA. RP Steven, AC (reprint author), NIH, Struct Biol Lab, Natl Inst Arthritis Musculoskeletal & Skin Dis, Bldg 50,Room 1517,50 South Dr MSC 8025, Bethesda, MD 20892 USA. EM stevena@mail.nih.gov RI Heymann, Bernard/F-6825-2011; OI Heymann, Bernard/0000-0002-8872-5326 FU Intramural NIH HHS [Z01 AR027002-29, Z99 AR999999]; NCI NIH HHS [CA100322, R01 CA100322, R01 CA100322-05] NR 53 TC 41 Z9 41 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 FEB 29 PY 2008 VL 376 IS 4 BP 1168 EP 1181 DI 10.1016/j.jmb.2007.12.003 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 273HI UT WOS:000253920600022 PM 18206161 ER PT J AU Tanaka, A Youle, RJ AF Tanaka, Atsushi Youle, Richard J. TI A chemical inhibitor of DRP1 uncouples mitochondrial fission and apoptosis SO MOLECULAR CELL LA English DT Editorial Material ID OUTER-MEMBRANE; DYNAMIN; MITOFUSINS; FUSION AB DRP1, a member of the dynamin family of large GTPases, mediates mitochondrial fission. In a recent issue of Developmental Cell, Cassidy-Stone et al. (2008) identified mdivi-1, a new DRP1 inhibitor that prevents mitochondria division and Bax-mediated mitochondrial outer membrane permeabilization during apoptosis. C1 [Tanaka, Atsushi; Youle, Richard J.] NINDS, NIH, Surg Neurol Branch, Biochem Sect, Bethesda, MD 20824 USA. RP Youle, RJ (reprint author), NINDS, NIH, Surg Neurol Branch, Biochem Sect, Bethesda, MD 20824 USA. EM youler@ninds.nih.gov NR 10 TC 98 Z9 105 U1 0 U2 11 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 FEB 29 PY 2008 VL 29 IS 4 BP 409 EP 410 DI 10.1016/j.molcel.2008.02.005 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 270BA UT WOS:000253693600001 PM 18313377 ER PT J AU Hu, JJ Shibata, Y Voss, C Shemesh, T Li, ZL Coughlin, M Kozlov, MM Rapoport, TA Prinz, WA AF Hu, Junjie Shibata, Yoko Voss, Christiane Shemesh, Tom Li, Zongli Coughlin, Margaret Kozlov, Michael M. Rapoport, Tom A. Prinz, William A. TI Membrane proteins of the endoplasmic reticulum induce high-curvature tubules SO SCIENCE LA English DT Article ID MITOCHONDRIAL FUSION; DYNAMIN; DOMAIN; ENDOCYTOSIS; ENDOPHILIN; AMPHIPHYSIN; MECHANISM; FISSION; RINGS AB The tubular structure of the endoplasmic reticulum ( ER) appears to be generated by integral membrane proteins, the reticulons and a protein family consisting of DP1 in mammals and Yop1p in yeast. Here, individual members of these families were found to be sufficient to generate membrane tubules. When we purified yeast Yop1p and incorporated it into proteoliposomes, narrow tubules (similar to 15 to 17 nanometers in diameter) were generated. Tubule formation occurred with different lipids; required essentially only the central portion of the protein, including its two long hydrophobic segments; and was prevented by mutations that affected tubule formation in vivo. Tubules were also formed by reconstituted purified yeast Rtn1p. Tubules made in vitro were narrower than normal ER tubules, due to a higher concentration of tubule- inducing proteins. The shape and oligomerization of the "morphogenic" proteins could explain the formation of the tubular ER. C1 [Hu, Junjie; Shibata, Yoko; Rapoport, Tom A.] Howard Hughes Med Inst, Boston, MA 02115 USA. [Hu, Junjie; Shibata, Yoko; Li, Zongli; Rapoport, Tom A.] Harvard Univ, Sch Med, Dept Cell Biol, Boston, MA 02115 USA. [Voss, Christiane; Prinz, William A.] NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. [Shemesh, Tom; Kozlov, Michael M.] Tel Aviv Univ, Sackler Fac Med, Dept Physiol & Pharmacol, IL-69978 Tel Aviv, Israel. [Coughlin, Margaret] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA. RP Rapoport, TA (reprint author), Howard Hughes Med Inst, 240 Longwood Ave, Boston, MA 02115 USA. EM tom_rapoport@hms.harvard.edu; wprinz@helix.nih.gov RI Hu, Junjie/F-9713-2013; Shemesh, Tom/J-5060-2013 FU Howard Hughes Medical Institute; Intramural NIH HHS NR 24 TC 193 Z9 195 U1 0 U2 38 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 29 PY 2008 VL 319 IS 5867 BP 1247 EP 1250 DI 10.1126/science.1153634 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 267SX UT WOS:000253530600045 PM 18309084 ER PT J AU Nicodemus, KK AF Nicodemus, Kristin K. TI catmap: case-control and TDT meta-analysis package SO BMC BIOINFORMATICS LA English DT Article ID ASSOCIATIONS AB Background: Risk for complex disease is thought to be controlled by multiple genetic risk factors, each with small individual effects. Meta-analyses of several independent studies may be helpful to increase the ability to detect association when effect sizes are modest. Although many software options are available for meta-analysis of genetic case-control data, no currently available software implements the method described by Kazeem and Farrall (2005), which combines data from independent family-based and case-control studies. Results: I introduce the package catmap for the R statistical computing environment that implements fixed- and random-effects pooled estimates for case-control and transmission disequilibrium methods, allowing for the use of genetic association data across study types. In addition, catmap may be used to create forest and funnel plots and to perform sensitivity analysis and cumulative meta-analysis. catmap is available from the Comprehensive R Archive Network http://www.r-project.org. Conclusion: catmap allows researchers to synthesize data to assess evidence for association in studies of genetic polymorphisms, facilitating the use of pooled data analyses which may increase power to detect moderate genetic associations. C1 [Nicodemus, Kristin K.] NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Nicodemus, KK (reprint author), Wellcome Trust Ctr Human Genet, Roosevelt Dr, Oxford OX3 7BN, England. EM kristin.nicodemus@well.ox.ac.uk NR 15 TC 45 Z9 45 U1 0 U2 1 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 FEB 28 PY 2008 VL 9 AR 130 DI 10.1186/1471-2105-9-130 PG 4 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 286QX UT WOS:000254862200001 PM 18307795 ER PT J AU Zhang, WS Zou, S Song, JZ AF Zhang, Wensheng Zou, Sige Song, Jiuzhou TI Term-tissue specific models for prediction of gene ontology biological processes using transcriptional profiles of aging in drosophila melanogaster SO BMC BIOINFORMATICS LA English DT Article ID DIFFERENTIALLY EXPRESSED GENES; COURSE MICROARRAY EXPERIMENTS; LIFE-SPAN; PATTERNS; HSP22 AB Background: Predictive classification on the base of gene expression profiles appeared recently as an attractive strategy for identifying the biological functions of genes. Gene Ontology (GO) provides a valuable source of knowledge for model training and validation. The increasing collection of microarray data represents a valuable source for generating functional hypotheses of uncharacterized genes. Results: This study focused on using support vector machines (SVM) to predict GO biological processes from individual or multiple-tissue transcriptional profiles of aging in Drosophila melanogaster. Ten-fold cross validation was implemented to evaluate the prediction. One-tail Fisher's exact test was conducted on each cross validation and multiple testing was addressed using BH FDR procedure. The results showed that, of the 148 pursued GO biological processes, fifteen terms each had at least one model with FDR-adjusted p-value (Adj. p) < 0.05 and six had the values between 0.05 and 0.25. Furthermore, all these models had the prediction sensitivity (SN) over 30% and specificity (SP) over 80%. Conclusion: We proposed the concept of term-tissue specific models indicating the fact that the major part of the optimized prediction models was trained from individual tissue data. Furthermore, we observed that the memberships of the genes involved in all the three pursued children biological processes on mitochondrial electron transport could be predicted from the transcriptional profiles of aging (Adj. p < 0.01). This finding may be important in biology because the genes of mitochondria play a critical role in the longevity of C. elegans and D. melanogaster. C1 [Zou, Sige] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. [Zhang, Wensheng; Song, Jiuzhou] Univ Maryland, Dept Anim & Avian Sci, College Pk, MD 20742 USA. [Zhang, Wensheng] NIA, NIH, Bioinformat Unit, Branch Res Resources, Baltimore, MD 21224 USA. RP Zou, S (reprint author), NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. EM wzhang19@umd.edu; zous@grc.nia.nih.gov; songj88@umd.edu NR 28 TC 4 Z9 4 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 FEB 28 PY 2008 VL 9 AR 129 DI 10.1186/1471-2105-9-129 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 292RA UT WOS:000255282600001 PM 18307794 ER PT J AU Calton, BA Stolzenberg-Solomon, RZ Moore, SC Schatzkin, A Schairer, C Albanes, D Leitzmann, MF AF Calton, Brook A. Stolzenberg-Solomon, Rachael Z. Moore, Steven C. Schatzkin, Arthur Schairer, Catherine Albanes, Demetrius Leitzmann, Michael F. TI A prospective study of physical activity and the risk of pancreatic cancer among women (United States) SO BMC CANCER LA English DT Article ID LIFE-STYLE FACTORS; BODY-MASS INDEX; GLUCOSE-TOLERANCE; MALE SMOKERS; COHORT; EPIDEMIOLOGY; OBESITY; ANTHROPOMETRY; POPULATION; MORTALITY AB Background: Several epidemiologic studies have examined the association between physical activity and pancreatic cancer risk; however, the results of these studies are not consistent. Methods: This study examined the associations of total, moderate, and vigorous physical activity to pancreatic cancer in a cohort of 33,530 U. S. women enrolled in the Breast Cancer Detection Demonstration Project ( BCDDP). At baseline ( 1987 - 1989), information on physical activity over the past year was obtained using a self-administered questionnaire. Cox proportional hazards regression was used to estimate relative risks ( RR) and 95% confidence intervals of pancreatic cancer risk. Results: 70 incident cases of pancreatic cancer were ascertained during 284,639 person years of follow-up between 1987 - 1989 and 1995 - 1998. After adjustment for age, body mass index, smoking status, history of diabetes, and height, increased physical activity was related to a suggestively decreased risk of pancreatic cancer. The RRs for increasing quartiles of total physical activity were 1.0, 0.80, 0.66, 0.52 ( 95% CI = 0.26, 1.05; P(trend) = 0.05). This association was consistent across subgroups defined by body mass index and smoking status. We also observed statistically nonsignificant reductions in pancreatic cancer risk for women in the highest quartile of moderate ( RR = 0.57; 95% CI = 0.26, 1.26) and highest quartile of vigorous physical activity ( RR = 0.63; 95% CI = 0.31, 1.28) compared to their least active counterparts. Conclusion: Our study provides evidence for a role of physical activity in protecting against pancreatic cancer. C1 [Calton, Brook A.; Stolzenberg-Solomon, Rachael Z.; Moore, Steven C.; Schatzkin, Arthur; Albanes, Demetrius; Leitzmann, Michael F.] NCI, NIH, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. [Schairer, Catherine] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Calton, BA (reprint author), NCI, NIH, Div Canc Epidemiol & Genet, Rockville, MD 20850 USA. EM brook.calton@ucsf.edu; stolzenr@mail.nih.gov; moorest@mail.nih.gov; schatzka@mail.nih.gov; schairec@exchange.nih.gov; albanesd@mail.nih.gov; leitzmann@mail.nih.gov RI Albanes, Demetrius/B-9749-2015; Moore, Steven/D-8760-2016 OI Moore, Steven/0000-0002-8169-1661 NR 28 TC 18 Z9 18 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2407 J9 BMC CANCER JI BMC Cancer PD FEB 28 PY 2008 VL 8 AR 63 DI 10.1186/1471-2407-8-63 PG 9 WC Oncology SC Oncology GA 283DR UT WOS:000254617400001 PM 18307811 ER PT J AU Yavatkar, AS Lin, Y Ross, J Fann, Y Brody, T Odenwald, WF AF Yavatkar, Amarendra S. Lin, Yong Ross, Jermaine Fann, Yang Brody, Thomas Odenwald, Ward F. TI Rapid detection and curation of conserved DNA via enhanced-BLAT and EvoPrinterHD analysis SO BMC GENOMICS LA English DT Article ID CIS-REGULATORY ELEMENTS; GENE-EXPRESSION; DROSOPHILA; CNS; HUNCHBACK; CASTOR; IDENTIFICATION; PROMOTERS; SEQUENCES; ENCODES AB Background: Multi-genome comparative analysis has yielded important insights into the molecular details of gene regulation. We have developed EvoPrinter, a web-accessed genomics tool that provides a single uninterrupted view of conserved sequences as they appear in a species of interest. An EvoPrint reveals with near base-pair resolution those sequences that are essential for gene function. Results: We describe here EvoPrinterHD, a 2(nd)-generation comparative genomics tool that automatically generates from a single input sequence an enhanced view of sequence conservation between evolutionarily distant species. Currently available for 5 nematode, 3 mosquito, 12 Drosophila, 20 vertebrate, 17 Staphylococcus and 20 enteric bacteria genomes, EvoPrinterHD employs a modified BLAT algorithm [enhanced-BLAT (eBLAT)], which detects up to 75% more conserved bases than identified by the BLAT alignments used in the earlier EvoPrinter program. The new program also identifies conserved sequences within rearranged DNA, highlights repetitive DNA, and detects sequencing gaps. EvoPrinterHD currently holds over 112 billion bp of indexed genomes in memory and has the flexibility of selecting a subset of genomes for analysis. An EvoDifferences profile is also generated to portray conserved sequences that are uniquely lost in any one of the orthologs. Finally, EvoPrinterHD incorporates options that allow for (1) re-initiation of the analysis using a different genome's aligning region as the reference DNA to detect species-specific changes in less-conserved regions, (2) rapid extraction and curation of conserved sequences, and (3) for bacteria, identifies unique or uniquely shared sequences present in subsets of genomes. Conclusion: EvoPrinterHD is a fast, high-resolution comparative genomics tool that automatically generates an uninterrupted species-centric view of sequence conservation and enables the discovery of conserved sequences within rearranged DNA. When combined with cis-Decoder, a program that discovers sequence elements shared among tissue specific enhancers, EvoPrinterHD facilitates the analysis of conserved sequences that are essential for coordinate gene regulation. C1 [Ross, Jermaine; Brody, Thomas; Odenwald, Ward F.] NINDS, Neural Cell Fate Determinants Sect, NIH, Bethesda, MD 20892 USA. [Yavatkar, Amarendra S.; Lin, Yong; Fann, Yang] NINDS, Div Intramural Res, Informat Technol Program, NIH, Bethesda, MD 20892 USA. RP Brody, T (reprint author), NINDS, Neural Cell Fate Determinants Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM yavatka@ninds.nih.gov; linyon@ninds.nih.gov; rossje@ninds.nih.gov; Fann@ninds.nih.gov; brodyt@ninds.nih.gov; ward@codon.nih.gov FU Intramural NIH HHS NR 23 TC 18 Z9 18 U1 0 U2 3 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 FEB 28 PY 2008 VL 9 AR 106 DI 10.1186/1471-2164-9-106 PG 12 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 278LB UT WOS:000254286000001 PM 18307801 ER PT J AU Andreani, A Burnelli, S Granaiola, M Leoni, A Locatelli, A Morigi, R Rambaldi, M Varoli, L Calonghi, N Cappadone, C Farruggia, G Zini, M Stefanelli, C Masotti, L Radin, NS Shoemaker, RH AF Andreani, Aldo Burnelli, Silvia Granaiola, Massimiliano Leoni, Alberto Locatelli, Alessandra Morigi, Rita Rambaldi, Mirella Varoli, Lucilla Calonghi, Natalia Cappadone, Concettina Farruggia, Giovanna Zini, Maddalena Stefanelli, Claudio Masotti, Lanfranco Radin, Norman S. Shoemaker, Robert H. TI Potential Antitumor Agents. 42. New antitumor imidazo[2,1-b]thiazole guanylhydrazones and analogues' SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CELL-DEATH; INHIBITORS; APOPTOSIS AB The synthesis of new antitumor 6-substituted imidazothiazole guanylhydrazones is described. Moreover, a series of compounds with a different basic chain at the 5 position were prepared. Finally, the replacement of the thiazole ring in the imidazothiazole system was also considered. All the new compounds prepared were submitted to the NCI cell line screen for evaluation of their antitumor activity. A few selected compounds were submitted to additional biological studies concerning effects on the cell cycle, apoptosis, and mitochondria. C1 [Andreani, Aldo; Burnelli, Silvia; Granaiola, Massimiliano; Leoni, Alberto; Locatelli, Alessandra; Morigi, Rita; Rambaldi, Mirella; Varoli, Lucilla] Univ Bologna, Dipartimento Sci Farmaceut, I-40126 Bologna, Italy. [Calonghi, Natalia; Cappadone, Concettina; Farruggia, Giovanna; Zini, Maddalena; Stefanelli, Claudio; Masotti, Lanfranco] Univ Bologna, Dipartimento Biochim G Moruzzi, I-40126 Bologna, Italy. [Radin, Norman S.] Univ Michigan, Mol & Behav Neurosci Inst, Ann Arbor, MI 48109 USA. [Shoemaker, Robert H.] Natl Canc Inst, Div Canc Treatment & Diagnosis, Dev Therapeut Program, Screening Technol Branch, Ft Detrick, MD 21702 USA. RP Andreani, A (reprint author), Univ Bologna, Dipartimento Sci Farmaceut, Via Belmeloro 6, I-40126 Bologna, Italy. EM aldo.andreani@unibo.it NR 22 TC 65 Z9 65 U1 0 U2 8 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 FEB 28 PY 2008 VL 51 IS 4 BP 809 EP 816 DI 10.1021/jm701246g PG 8 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 265JB UT WOS:000253353800013 PM 18251494 ER PT J AU Nagappan, G Woo, NH Lu, B AF Nagappan, Guhan Woo, Newton H. Lu, Bai TI Ama"Zinc" link between TrkB transactivation and synaptic plasticity SO NEURON LA English DT Editorial Material ID KINDLING MODEL; ACTIVATION; RECEPTOR; EPILEPTOGENESIS AB While Trk receptors can be activated in a neurotrophin-independent manner through "transactivation" by GPCR ligands, its physiological significance in the brain remains unknown. Huang et al. have now identified a novel mechanism of TrkB transactivation. They show that zinc ions can transactivate TrkB independent of neurotrophins and that such a transactivation is important for mossy fiber long-term potentiation (LTP). C1 [Nagappan, Guhan; Woo, Newton H.; Lu, Bai] NICHHD, Sect Neural Dev & Plastic, Natl Inst Hlth, Bethesda, MD 20892 USA. [Lu, Bai] NIMH, Gene Cognit & Psychosis Program, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Lu, B (reprint author), NICHHD, Sect Neural Dev & Plastic, Natl Inst Hlth, 35 Lincoln Dr, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Lu, Bai/A-4018-2012 NR 12 TC 13 Z9 13 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 28 PY 2008 VL 57 IS 4 BP 477 EP 479 DI 10.1016/j.neuron.2008.02.004 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 270EQ UT WOS:000253703600002 PM 18304477 ER PT J AU Monosov, IE Trageser, JC Thompson, KG AF Monosov, Ilya E. Trageser, Jason C. Thompson, Kirk G. TI Measurements of simultaneously recorded spiking activity and local field potentials suggest that spatial selection emerges in the frontal eye field SO NEURON LA English DT Article ID SACCADE TARGET SELECTION; INFERIOR TEMPORAL CORTEX; SOURCE-DENSITY ANALYSIS; VISUAL-SEARCH TASK; PARIETAL CORTEX; TOP-DOWN; EVOKED-POTENTIALS; BOTTOM-UP; MACAQUE; ATTENTION AB The frontal eye field (FEF) participates in selecting the location of behaviorally relevant stimuli for guiding attention and eye movements. We simultaneously recorded local field potentials (LFPs) and spiking activity in the FEF of monkeys performing memory-guided saccade and covert visual search tasks. We compared visual latencies and the time course of spatially selective responses in LFPs and spiking activity. Consistent with the view that LFPs represent synaptic input, visual responses appeared first in the LFPs followed by visual responses in the spiking activity. However, spatially selective activity identifying the location of the target in the visual search array appeared in the spikes about 30 ms before it appeared in the LFPs. Because LFPs reflect dendritic input and spikes measure neuronal output in a local brain region, this temporal relationship suggests that spatial selection necessary for attention and eye movements is computed locally in FEF from spatially nonselective inputs. C1 [Monosov, Ilya E.; Trageser, Jason C.; Thompson, Kirk G.] NIH, Sensorimotor Res Lab, NEI, Bethesda, MD 20892 USA. [Monosov, Ilya E.] Brown NIH Grad Partnership Program, Brown Dept Neurosci, Providence, RI 02906 USA. RP Thompson, KG (reprint author), NIH, Sensorimotor Res Lab, NEI, Bldg 49 Room 2A50, Bethesda, MD 20892 USA. EM kgt@lsr.nei.nih.gov FU Intramural NIH HHS [Z01 EY000389-06, Z99 RG999999] NR 48 TC 54 Z9 54 U1 0 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 FEB 28 PY 2008 VL 57 IS 4 BP 614 EP 625 DI 10.1016/j.neuron.2007.12.030 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 270EQ UT WOS:000253703600015 PM 18304489 ER PT J AU Stout, MD Herbert, RA Kissling, GE Suarez, F Roycroft, JH Chhabra, RS Bucher, JR AF Stout, Matthew D. Herbert, Ronald A. Kissling, Grace E. Suarez, Fernando Roycroft, Joseph H. Chhabra, Rajendra S. Bucher, John R. TI Toxicity and carcinogenicity of methyl isobutyl ketone in F344N rats and B6C3F1 mice following 2-year inhalation exposure SO TOXICOLOGY LA English DT Article DE methyl isobutyl ketone; carcinogenicity; national toxicology program; inhalation; kidney; liver ID N-BUTYL KETONE; HALOALKANE-INDUCED HEPATOTOXICITY; CHRONIC PROGRESSIVE NEPHROPATHY; ZERO DOSE CONTROL; ALPHA-2U-GLOBULIN NEPHROPATHY; RENAL CARCINOGENESIS; ETHYL KETONE; GENE FAMILY; POTENTIATION; METABOLITES AB Methyl isobutyl ketone (MIBK) is primarily used as a denaturant for rubbing alcohol, as a solvent and in the manufacture of methyl amyl alcohol. Inhalation of vapors is the most likely route of exposure in the work place. In order to evaluate the potential of MIBK to induce toxic and carcinogenic effects following chronic exposure, groups of 50 male and 50 female F344/N rats and B6C3F1 mice were exposed to MIBK at concentrations of 0, 450, 900, or 1800 ppm by inhalation, 6 h/day, 5 days per week for 2 years. Survival was decreased in male rats at 1800 ppm. Body weight gains were decreased in male rats at 900 and 1800 ppm and in female mice at 1800 ppm. The primary targets of MIBK toxicity and carcinogenicity were the kidney in rats and the liver in mice. In male rats, there was increased mineralization of the renal papilla at all exposure concentrations. The incidence of chronic progressive nephropathy (CPN) was increased at 1800ppm and the severity was increased in all exposed groups. There were also increases in renal tubule hyperplasia at all exposure concentrations, and in adenoma and adenoma or carcinoma (combined) at 1800ppm; these lesions are thought to represent a continuum in the progression of proliferative lesions in renal tubule epithelium. These increases may have resulted from the increased severity of CPN, either through alpha 2 mu-globulin-dependent or -independent mechanisms. An increase in mononuclear cell leukemia at 1800 ppm was an uncertain finding. Adrenal medulla hyperplasia was increased at 1800ppm, and there was a positive trend for increases in benign or malignant pheochromocytomas (combined). In female rats, there were increases in the incidence of CPN in all exposure concentrations and in the severity at 1800ppm, indicating that CPN was increased by mechanisms in addition to those related to alpha 2 mu-globulin. There were renal mesenchymal tumors, which have not been observed in historical control animals, in two female rats at 1800ppm. The relationship of these tumors to exposure to MIBK was uncertain. Hepatocellular adenomas, and adenoma or carcinoma (combined) were increased in male and female mice exposed to 1800 ppm. There were also treatment-related increases in multiple adenomas in both sexes. Published by Elsevier Ireland Ltd. C1 [Stout, Matthew D.; Suarez, Fernando; Roycroft, Joseph H.; Chhabra, Rajendra S.; Bucher, John R.] NIEHS, Toxicol Operat Branch, Res Triangle Pk, NC 27709 USA. [Herbert, Ronald A.] NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. [Kissling, Grace E.] NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Bucher, JR (reprint author), NIEHS, Toxicol Operat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM stoutm@niehs.nih.gov; herbert1@niehs.nih.gov; kissling@niehs.nih.gov; fernando.suarez@syngenta.com; roycroft@niehs.nih.gov; chhabrar@niehs.nih.gov; bucher@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 51 TC 7 Z9 8 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD FEB 28 PY 2008 VL 244 IS 2-3 BP 209 EP 219 DI 10.1016/j.tox.2007.11.014 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 273PA UT WOS:000253942700012 PM 18178301 ER PT J AU Pandiyan, P Lenardo, MJ AF Pandiyan, Pushpa Lenardo, Michael J. TI The control of CD4(+)CD25(+)Foxp3(+) regulatory T cell survival SO BIOLOGY DIRECT LA English DT Article ID HOMEOSTATIC PROLIFERATION; GAMMA-CHAIN; IN-VIVO; FOXP3; IL-7; INTERLEUKIN-2; CYTOKINES; TOLERANCE; DISEASES; RECEPTOR AB CD4(+)CD25(+)Foxp3(+) regulatory T (T(reg)) cells are believed to play an important role in suppressing autoimmunity and maintaining peripheral tolerance. How their survival is regulated in the periphery is less clear. Here we show that T(reg) cells express receptors for gamma chain cytokines and are dependent on an exogenous supply of these cytokines to overcome cytokine withdrawal apoptosis in vitro. This result was validated in vivo by the accumulation of T(reg) cells in Bim(-/-) and Bcl-2 tg mice which have arrested cytokine deprivation apoptosis. We also found that CD25 and Foxp3 expression were down-regulated in the absence of these cytokines. CD25(+) cells from Scurfy mice do not depend on cytokines for survival demonstrating that Foxp3 increases their dependence on cytokines by suppressing cytokine production in T(reg) cells. Our study reveals that the survival of T(reg) cells is strictly dependent on cytokines and cytokine producing cells because they do not produce cytokines. Our study thus, demonstrates that different gamma chain cytokines regulate T(reg) homeostasis in the periphery by differentially regulating survival and proliferation. These findings may shed light on ways to manipulate T(reg) cells that could be utilized for their therapeutic applications. C1 [Pandiyan, Pushpa; Lenardo, Michael J.] NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM ppandiyan@niaid.nih.gov; lenardo@nih.gov FU Intramural NIH HHS NR 42 TC 50 Z9 53 U1 0 U2 1 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 FEB 27 PY 2008 VL 3 AR 6 DI 10.1186/1745-6150-3-6 PG 12 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 277GP UT WOS:000254201000001 PM 18304352 ER PT J AU Brent, D Emslie, G Clarke, G Wagner, KD Asarnow, JR Keller, M Vitiello, B Ritz, L Iyengar, S Abebe, K Birmaher, B Ryan, N Kennard, B Hughes, C DeBar, L McCracken, J Strober, M Suddath, R Spirito, A Leonard, H Melhem, N Porta, G Onorato, M Zelazny, J AF Brent, David Emslie, Graham Clarke, Greg Wagner, Karen Dineen Asarnow, Joan Rosenbaum Keller, Marty Vitiello, Benedetto Ritz, Louise Iyengar, Satish Abebe, Kaleab Birmaher, Boris Ryan, Neal Kennard, Betsy Hughes, Carroll DeBar, Lynn McCracken, James Strober, Michael Suddath, Robert Spirito, Anthony Leonard, Henrietta Melhem, Nadine Porta, Giovanna Onorato, Matthew Zelazny, Jamie TI Switching to another SSRI or to venlafaxine with or without cognitive behavioral therapy for adolescents with SSRI-resistant depression - The TORDIA randomized controlled trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID SEROTONIN REUPTAKE INHIBITORS; ASTERISK-D REPORT; MAJOR DEPRESSION; DOUBLE-BLIND; ANTIDEPRESSANT TREATMENT; PSYCHOMETRIC PROPERTIES; AFFECTIVE-DISORDERS; SUICIDAL IDEATION; REMISSION RATES; RATING-SCALE AB Context Only about 60% of adolescents with depression will show an adequate clinical response to an initial treatment trial with a selective serotonin reuptake inhibitor ( SSRI). There are no data to guide clinicians on subsequent treatment strategy. Objective To evaluate the relative efficacy of 4 treatment strategies in adolescents who continued to have depression despite adequate initial treatment with an SSRI. Design, Setting, and Participants Randomized controlled trial of a clinical sample of 334 patients aged 12 to 18 years with a primary diagnosis of major depressive disorder that had not responded to a 2- month initial treatment with an SSRI, conducted at 6 US academic and community clinics from 2000- 2006. Interventions Twelve weeks of: ( 1) switch to a second, different SSRI ( paroxetine, citalopram, or fluoxetine, 20- 40 mg); ( 2) switch to a different SSRI plus cognitive behavioral therapy; ( 3) switch to venlafaxine ( 150- 225 mg); or ( 4) switch to venlafaxine plus cognitive behavioral therapy. Main OutcomeMeasures Clinical Global Impressions- Improvement score of 2 or less ( much or very much improved) and a decrease of at least 50% in the Children's Depression Rating Scale- Revised ( CDRS- R); and change in CDRS- R over time. Results Cognitive behavioral therapy plus a switch to either medication regimen showed a higher response rate ( 54.8%; 95% confidence interval [ CI], 47%- 62%) than a medication switch alone ( 40.5%; 95% CI, 33%- 48%; P=. 009), but there was no difference in response rate between venlafaxine and a second SSRI ( 48.2%; 95% CI, 41%-56% vs 47.0%; 95% CI, 40%- 55%; P=. 83). There were no differential treatment effects on change in the CDRS- R, self- rated depressive symptoms, suicidal ideation, or on the rate of harm- related or any other adverse events. There was a greater increase in diastolic blood pressure and pulse and more frequent occurrence of skin problems during venlafaxine than SSRI treatment. Conclusions For adolescents with depression not responding to an adequate initial treatment with an SSRI, the combination of cognitive behavioral therapy and a switch to another antidepressant resulted in a higher rate of clinical response than did a medication switch alone. However, a switch to another SSRI was just as efficacious as a switch to venlafaxine and resulted in fewer adverse effects. Trial Registration clinicaltrials. gov Identifier: NCT00018902. C1 [Brent, David; Iyengar, Satish; Abebe, Kaleab; Birmaher, Boris; Ryan, Neal; Melhem, Nadine; Porta, Giovanna; Onorato, Matthew; Zelazny, Jamie] Univ Pittsburgh, Western Psychiat Inst & Clin, Pittsburgh, PA 15213 USA. [Emslie, Graham; Kennard, Betsy; Hughes, Carroll] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA. [Clarke, Greg; DeBar, Lynn] Kaiser Permanente Ctr Hlth Res, Portland, OR USA. [Wagner, Karen Dineen] Univ Texas Galveston, Med Branch, Galveston, TX 77550 USA. [Asarnow, Joan Rosenbaum; McCracken, James; Strober, Michael; Suddath, Robert] Univ Calif Los Angeles, Los Angeles, CA USA. [Keller, Marty; Spirito, Anthony; Leonard, Henrietta] Brown Univ, Providence, RI 02912 USA. [Vitiello, Benedetto; Ritz, Louise] NIMH, Bethesda, MD 20892 USA. RP Brent, D (reprint author), Univ Pittsburgh, Western Psychiat Inst & Clin, 3811 Ohara St,Room 315 Bellefield Towers, Pittsburgh, PA 15213 USA. EM brentda@upmc.edu RI Melhem, Nadine/G-1510-2013; OI Abebe, Kaleab/0000-0002-3644-8419 FU NIMH NIH HHS [P30 MH066371-05, MH61835, MH61856, MH61864, MH61869, MH61958, MH62014, MH66371, P30 MH066371, P30 MH066371-019001, P30 MH066371-02, P30 MH066371-03, P30 MH066371-04, U01 MH061835, U01 MH061835-01, U01 MH061835-02, U01 MH061835-03, U01 MH061835-04, U01 MH061835-05, U01 MH061835-06, U01 MH061835-07, U01 MH061856, U01 MH061864, U01 MH061869, U01 MH061958, U01 MH062014] NR 80 TC 254 Z9 258 U1 7 U2 36 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 FEB 27 PY 2008 VL 299 IS 8 BP 901 EP 913 DI 10.1001/jama.299.8.901 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 266DZ UT WOS:000253413200019 PM 18314433 ER PT J AU Emanuel, EJ AF Emanuel, Ezekiel J. TI The cost-coverage trade-off - "It's health care costs, stupid" SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID INSURANCE-COVERAGE; DECLINE C1 [Emanuel, Ezekiel J.] NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. RP Emanuel, EJ (reprint author), NIH, Dept Clin Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM eemanuel@cc.nih.gov NR 22 TC 11 Z9 11 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 FEB 27 PY 2008 VL 299 IS 8 BP 947 EP 949 DI 10.1001/jama.299.8.947 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 266DZ UT WOS:000253413200023 PM 18314437 ER PT J AU Koprich, JB Reske-Nielsen, C Mithal, P Isacson, O AF Koprich, James B. Reske-Nielsen, Casper Mithal, Prabhakar Isacson, Ole TI Neuroinflammation mediated by IL-1 beta increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease SO JOURNAL OF NEUROINFLAMMATION LA English DT Article ID TUMOR-NECROSIS-FACTOR; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SINGLE INTRANIGRAL INJECTION; GROWTH-FACTOR-ALPHA; PROGRESSIVE DEGENERATION; RECEPTOR ANTAGONIST; TNF-ALPHA; ENCEPHALITIS LETHARGICA; MICROGLIAL ACTIVATION; JUVENILE PARKINSONISM AB Background: The etiology of Parkinson's disease (PD) remains elusive despite identification of several genetic mutations. It is more likely that multiple factors converge to give rise to PD than any single cause. Here we report that inflammation can trigger degeneration of dopamine (DA) neurons in an animal model of Parkinson's disease. Methods: We examined the effects of inflammation on the progressive 6-OHDA rat model of Parkinson's disease using immunohistochemistry, multiplex ELISA, and cell counting stereology. Results: We show that a non-toxic dose of lipopolysaccharide (LPS) induced secretion of cytokines and predisposed DA neurons to be more vulnerable to a subsequent low dose of 6-hydroxydopamine. Alterations in cytokines, prominently an increase in interleukin-1beta (IL-1 beta), were identified as being potential mediators of this effect that was associated with activation of microglia. Administration of an interleukin-1 receptor antagonist resulted in significant reductions in tumor necrosis factor-alpha and interferon-gamma and attenuated the augmented loss of DA neurons caused by the LPS-induced sensitization to dopaminergic degeneration. Conclusion: These data provide insight into the etiology of PD and support a role for inflammation as a risk factor for the development of neurodegenerative disease. C1 [Koprich, James B.; Reske-Nielsen, Casper; Mithal, Prabhakar; Isacson, Ole] Harvard Univ, Sch Med, Ctr Neuroregenerat Res, McLean Hosp, Belmont, MA 02478 USA. [Koprich, James B.; Reske-Nielsen, Casper; Mithal, Prabhakar; Isacson, Ole] Harvard Univ, Sch Med, Udall Parkinsons Dis Res Ctr Excellence, McLean Hosp, Belmont, MA 02478 USA. [Isacson, Ole] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA. RP Isacson, O (reprint author), Harvard Univ, Sch Med, Ctr Neuroregenerat Res, McLean Hosp, Belmont, MA 02478 USA. EM jkoprich@mclean.harvard.edu; creske@mclean.harvard.edu; pmithal@gmail.com; isacson@hms.harvard.edu FU NINDS NIH HHS [P50 NS039793-09, NS39793, P50 NS039793] NR 82 TC 129 Z9 132 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-2094 J9 J NEUROINFLAMM JI J. Neuroinflamm. PD FEB 27 PY 2008 VL 5 AR 8 DI 10.1186/1742-2094-5-8 PG 12 WC Immunology; Neurosciences SC Immunology; Neurosciences & Neurology GA 292PP UT WOS:000255278900001 PM 18304357 ER PT J AU Pan, BX Vautier, F Ito, W Bolshakov, VY Morozov, A AF Pan, Bing-Xing Vautier, Francois Ito, Wataru Bolshakov, Vadim Y. Morozov, Alexei TI Enhanced cortico-amygdala efficacy and suppressed fear in absence of Rap1 SO JOURNAL OF NEUROSCIENCE LA English DT Article DE amygdala; fear; LTP; Rap1; cortex; thalamus ID LONG-TERM POTENTIATION; LATERAL AMYGDALA; SYNAPTIC PLASTICITY; PRESYNAPTIC ENHANCEMENT; MULTIVESICULAR RELEASE; CONDITIONED-STIMULI; EXPRESSION; RATS; PATHWAY; BRAIN AB Auditory fear conditioning, a model for fear learning, is thought to be mediated by synaptic changes in the cortical and thalamic inputs to the lateral amygdala ( LA); however, the specific roles of both pathways are still debated. Here, we report that a CaMKII-alpha-Cre-mediated knock-out ( KO) of the rap1a and rap1b genes impaired synaptic plasticity and increased basal synaptic transmission in the cortical but not thalamic input to the LA via presynaptic changes: increases in glutamate release probability and the number of glutamate quanta released by a single action potential. Moreover, KO mice with alterations in the cortico-LA pathway had impaired fear learning, which could be rescued by training with a more aversive unconditional stimulus. These results suggest that Rap1-mediated suppression of synaptic transmission enables plasticity in the cortico-amygdala pathway, which is required for fear learning with a moderately aversive unconditional stimulus. C1 [Pan, Bing-Xing; Vautier, Francois; Ito, Wataru; Morozov, Alexei] NIMH, Natl Inst Hlth, Mol Pathophysiol Lab, Unit Behav Genet, Bethesda, MD 20892 USA. [Bolshakov, Vadim Y.] Harvard Univ, Sch Med, Dept Psychiat, McLean Hosp, Belmont, MA 02478 USA. [Pan, Bing-Xing] So Med Univ, Dept Anat & Neurobiol, Sch Basic Med Sci, Guangzhou 510515, Peoples R China. RP Morozov, A (reprint author), NIMH, Natl Inst Hlth, Mol Pathophysiol Lab, Unit Behav Genet, 35 Convert Dr, Bethesda, MD 20892 USA. EM morozova@mail.nih.gov RI PAN, BINGXING/C-7870-2011 FU Intramural NIH HHS; NINDS NIH HHS [NS44185] NR 46 TC 28 Z9 29 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 27 PY 2008 VL 28 IS 9 BP 2089 EP 2098 DI 10.1523/JNEUROSCI.5156-07.2008 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 268AC UT WOS:000253549300011 PM 18305243 ER PT J AU Limb, CJ Braun, AR AF Limb, Charles J. Braun, Allen R. TI Neural Substrates of Spontaneous Musical Performance: An fMRI Study of Jazz Improvisation SO PLOS ONE LA English DT Article AB To investigate the neural substrates that underlie spontaneous musical performance, we examined improvisation in professional jazz pianists using functional MRI. By employing two paradigms that differed widely in musical complexity, we found that improvisation (compared to production of over-learned musical sequences) was consistently characterized by a dissociated pattern of activity in the prefrontal cortex: extensive deactivation of dorsolateral prefrontal and lateral orbital regions with focal activation of the medial prefrontal (frontal polar) cortex. Such a pattern may reflect a combination of psychological processes required for spontaneous improvisation, in which internally motivated, stimulus-independent behaviors unfold in the absence of central processes that typically mediate self-monitoring and conscious volitional control of ongoing performance. Changes in prefrontal activity during improvisation were accompanied by widespread activation of neocortical sensorimotor areas (that mediate the organization and execution of musical performance) as well as deactivation of limbic structures (that regulate motivation and emotional tone). This distributed neural pattern may provide a cognitive context that enables the emergence of spontaneous creative activity. C1 [Limb, Charles J.; Braun, Allen R.] Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD USA. Johns Hopkins Univ, Dept Otolaryngol Head & Neck Surg, Peabody Conservatory Music, Baltimore, MD USA. RP Limb, CJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Language Sect, Voice Speech & Language Branch, NIH, Bethesda, MD USA. EM climb@jhmi.edu FU Division of Intramural Research; National Institute on Deafness and Other Communication Disorders; National Institutes of Health FX This research was funded solely by the Division of Intramural Research, National Institute on Deafness and Other Communication Disorders, National Institutes of Health. NR 43 TC 134 Z9 139 U1 5 U2 43 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 FEB 27 PY 2008 VL 3 IS 2 AR e1679 DI 10.1371/journal.pone.0001679 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 367XS UT WOS:000260586500023 PM 18301756 ER PT J AU Michalski, CW Maier, M Erkan, M Sauliunaite, D Bergmann, F Pacher, P Batkai, S Giese, NA Giese, T Friess, H Kleeff, J AF Michalski, Christoph W. Maier, Milena Erkan, Mert Sauliunaite, Danguole Bergmann, Frank Pacher, Pal Batkai, Sandor Giese, Nathalia A. Giese, Thomas Friess, Helmut Kleeff, Joerg TI Cannabinoids Reduce Markers of Inflammation and Fibrosis in Pancreatic Stellate Cells SO PLOS ONE LA English DT Article AB Background: While cannabinoids have been shown to ameliorate liver fibrosis, their effects in chronic pancreatitis and on pancreatic stellate cells (PSC) are unknown. Methodology/Principal Findings: The activity of the endocannabinoid system was evaluated in human chronic pancreatitis (CP) tissues. In vitro, effects of blockade and activation of cannabinoid receptors on pancreatic stellate cells were characterized. In CP, cannabinoid receptors were detected predominantly in areas with inflammatory changes, stellate cells and nerves. Levels of endocannabinoids were decreased compared with normal pancreas. Cannabinoid-receptor-1 antagonism effectuated a small PSC phenotype and a trend toward increased invasiveness. Activation of cannabinoid receptors, however, induced de-activation of PSC and dose-dependently inhibited growth and decreased IL-6 and MCP-1 secretion as well as fibronectin, collagen1 and alphaSMA levels. De-activation of PSC was partially reversible using a combination of cannabinoid-receptor-1 and -2 antagonists. Concomitantly, cannabinoid receptor activation specifically decreased invasiveness of PSC, MMP-2 secretion and led to changes in PSC phenotype accompanied by a reduction of intracellular stress fibres. Conclusions/Significance: Augmentation of the endocannabinoid system via exogenously administered cannabinoid receptor agonists specifically induces a functionally and metabolically quiescent pancreatic stellate cell phenotype and may thus constitute an option to treat inflammation and fibrosis in chronic pancreatitis. C1 [Michalski, Christoph W.; Erkan, Mert; Sauliunaite, Danguole; Friess, Helmut; Kleeff, Joerg] Tech Univ Munich, Dept Surg, Munich, Germany. [Michalski, Christoph W.; Maier, Milena; Giese, Nathalia A.] Univ Heidelberg, Dept General Surg, Heidelberg, Germany. [Bergmann, Frank] Univ Heidelberg, Inst Pathol, Heidelberg, Germany. [Pacher, Pal; Batkai, Sandor] NIH, NIAAA, Lab Physiol Stud, Sect Oxidative Stress Tissue Injury, Bethesda, MD USA. [Giese, Thomas] Univ Heidelberg, Inst Immunol, Heidelberg, Germany. RP Michalski, CW (reprint author), Tech Univ Munich, Dept Surg, Munich, Germany. EM christoph.michalski@gmx.de RI Batkai, Sandor/G-3889-2010; Pacher, Pal/B-6378-2008; Batkai, Sandor/H-7983-2014; OI Pacher, Pal/0000-0001-7036-8108; Kleeff, Jorg/0000-0003-3432-6669 FU Postdoctoral Research Program, Heidelberg University; Intramural Research Program of the NIH/NIAAA [1Z01AA000375-01] FX This work was supported by a Postdoctoral Research Program grant of Heidelberg University (to C.W.M) and in part by the Intramural Research Program of the NIH/NIAAA (#1Z01AA000375-01) to P.P. The funders had no role in the design and conduct of the study; neither did they influence collection, analysis and interpretation of the data or preparation, review or approval of the manuscript. NR 52 TC 27 Z9 28 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 FEB 27 PY 2008 VL 3 IS 2 AR e1701 DI 10.1371/journal.pone.0001701 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 367XS UT WOS:000260586500045 PM 18301776 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 Use of alternative thresholds defining insulin resistance to predict incident type 2 diabetes mellitus and cardiovascular disease SO CIRCULATION LA English DT Article DE insulin resistance; cardiovascular diseases; diabetes mellitus; risk factors; prospective studies; prognosis ID HOMEOSTASIS MODEL ASSESSMENT; CORONARY-HEART-DISEASE; METABOLIC SYNDROME; ATHEROSCLEROSIS; SENSITIVITY; GLUCOSE; EVENTS; RISK AB Background- The performance characteristics of surrogate insulin resistance (IR) measures, commonly defined as the top 25% of the measure's distribution, used to predict incident type 2 diabetes mellitus (DM) and cardiovascular disease (CVD) have not been critically assessed in community samples. Methods and Results- Baseline IR was assessed among 2720 Framingham Offspring Study subjects by use of fasting insulin, the homeostasis model assessment of IR (HOMA-IR), and the reciprocal of the Gutt insulin sensitivity index, with 7- to 11-year follow-up for incident DM (130 cases) or CVD (235). Area under the receiver operating characteristic curve, sensitivity, specificity, and positive likelihood ratio were estimated at 12 diagnostic thresholds (quantiles) of IR measures. Positive likelihood ratios for DM or CVD increased in relation to IR quantiles; risk gradients were greater for DM than for CVD, with no 9th to 10th quantile (76th centile) threshold effects. IR had better discrimination for incident DM than for CVD (HOMA-IR area under the receiver operating characteristic curve: DM 0.80 versus CVD 0.63). The HOMA-IR >= 76th centile threshold was associated with these test-performance values: sensitivity (DM 68%, CVD 40%), specificity (DM 77%, CVD 76%), and positive likelihood ratio (DM 3.0, CVD 1.7). The HOMA-IR threshold that yielded > 90% sensitivity was the 6th quantile for DM prediction and the 3rd quantile for CVD. Compared with the >= 76th centile threshold, these alternative thresholds yielded lower specificity (DM 43%, CVD 17%) and positive likelihood ratios (DM 1.6, CVD 1.1). Conclusions- Surrogate IR measures have modest performance at the 76th centile, with no threshold effects. Different centile thresholds might be selected to optimize sensitivity versus specificity for DM versus CVD prediction if surrogate IR measures are used for risk prediction. C1 [Rutter, Martin K.] Univ Manchester, Div Cardiovasc & Endocrine Sci, Cardiovasc Res Grp, Manchester, Lancs, England. [Rutter, Martin K.] Manchester Royal Infirm, Manchester Diabet Ctr, Manchester M13 9WL, Lancs, England. [Wilson, Peter W. F.] Emory Univ, Sch Med, Atlanta, GA USA. [Sullivan, Lisa M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. [D'Agostino, Ralph B.] Boston Univ, Dept Math & Stat, Cunsulting Unit, Boston, MA 02215 USA. [Fox, Caroline S.] NHLBI, Framingham, MA USA. [Fox, Caroline S.; Meigs, James B.] Harvard Univ, Brigham & Womens Hosp, Sch Med, Boston, MA 02115 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Dept Endocrinol & Metab, Boston, MA 02115 USA. [Meigs, James B.] Massachusetts Gen Hosp, Dept Med, Dept Med Genet, Boston, MA 02114 USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jmeigs@partners.org OI Rutter, Martin/0000-0001-6380-539X; Sullivan, Lisa/0000-0003-0726-7149 FU NHLBI NIH HHS [N01-HC-25195, N01HC25195]; NIDDK NIH HHS [K24 DK080140, K24 DK080140-01] NR 22 TC 39 Z9 39 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 FEB 26 PY 2008 VL 117 IS 8 BP 1003 EP 1009 DI 10.1161/CIRCULATIONAHA.107.727727 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 267XQ UT WOS:000253542900003 PM 18250267 ER PT J AU Aerts, JM Groener, JE Kuiper, S Donker-Koopman, WE Strijland, A Ottenhoff, R van Roomen, C Mirzaian, M Wijburg, FA Linthorst, GE Vedder, AC Rombach, SM Cox-Brinkman, J Somerharju, P Boot, RG Hollak, CE Brady, RO Poorthuis, BJ AF Aerts, Johannes M. Groener, Johanna E. Kuiper, Sijmen Donker-Koopman, Wilma E. Strijland, Anneke Ottenhoff, Roelof van Roomen, Cindy Mirzaian, Mina Wijburg, Frits A. Linthorst, Gabor E. Vedder, Anouk C. Rombach, Saskia M. Cox-Brinkman, Josanne Somerharju, Pentti Boot, Rolf G. Hollak, Carla E. Brady, Roscoe O. Poorthuis, Ben J. TI Elevated globotriaosylsphingosine is a hallmark of Fabry disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE alpha-galactosiclase A; globotriaosylceramide; smooth muscle cell; lysoglycolipids ID ENZYME REPLACEMENT THERAPY; HUMAN ALPHA-GALACTOSIDASE; CLINICAL-MANIFESTATIONS; AGALSIDASE-BETA; RENAL-TRANSPLANTATION; GAUCHER-DISEASE; NATURAL-HISTORY; GLOBOTRIAOSYLCERAMIDE; ACCUMULATION; PSYCHOSINE AB Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A that affects males and shows disease expression in heterozygotes. The characteristic progressive renal insufficiency, cardiac involvement, and neuropathology usually are ascribed to globotriaosylceramide accumulation in the endothelium. However, no direct correlation exists between lipid storage and clinical manifestations, and treatment of patients with recombinant enzymes does not reverse several key signs despite clearance of lipid from the endothelium. We therefore investigated the possibility that globotriaosylceramide metabolites are a missing link in the pathogenesis. We report that deacylated globotriaosylceramide, globotriaosylsphingosine, and a minor additional metabolite are dramatically increased in plasma of classically affected male Fabry patients and plasma and tissues of Fabry mice. Plasma globotriaosylceramide levels are reduced by therapy. We show that globotriaosylsphingosine is an inhibitor of alpha-galactosidase A activity. Furthermore, exposure of smooth muscle cells, but not fibroblasts, to globotriaosylsphingosine at concentrations observed in plasma of patients promotes proliferation. The increased intima-media thickness in Fabry patients therefore may be related to the presence of this metabolite. Our findings suggest that measurement of circulating globotriaosylsphingosine will be useful to monitor Fabry disease and may contribute to a better understanding of the disorder. C1 [Aerts, Johannes M.; Groener, Johanna E.; Kuiper, Sijmen; Donker-Koopman, Wilma E.; Strijland, Anneke; Ottenhoff, Roelof; van Roomen, Cindy; Mirzaian, Mina; Wijburg, Frits A.; Linthorst, Gabor E.; Vedder, Anouk C.; Rombach, Saskia M.; Cox-Brinkman, Josanne; Boot, Rolf G.; Hollak, Carla E.; Poorthuis, Ben J.] Amsterdam Lysosome Ctr, Dept Med Biochem, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Aerts, Johannes M.; Groener, Johanna E.; Kuiper, Sijmen; Donker-Koopman, Wilma E.; Strijland, Anneke; Ottenhoff, Roelof; van Roomen, Cindy; Mirzaian, Mina; Wijburg, Frits A.; Linthorst, Gabor E.; Vedder, Anouk C.; Rombach, Saskia M.; Cox-Brinkman, Josanne; Boot, Rolf G.; Hollak, Carla E.; Poorthuis, Ben J.] Amsterdam Lysosome Ctr, Dept Internal Med, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Aerts, Johannes M.; Groener, Johanna E.; Kuiper, Sijmen; Donker-Koopman, Wilma E.; Strijland, Anneke; Ottenhoff, Roelof; van Roomen, Cindy; Mirzaian, Mina; Wijburg, Frits A.; Linthorst, Gabor E.; Vedder, Anouk C.; Rombach, Saskia M.; Cox-Brinkman, Josanne; Boot, Rolf G.; Hollak, Carla E.; Poorthuis, Ben J.] Amsterdam Lysosome Ctr, Dept Paediat, Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. [Somerharju, Pentti] Univ Helsinki, Dept Biochem, Inst Biomed, FIN-00014 Helsinki, Finland. [Brady, Roscoe O.] NINCDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Aerts, JM (reprint author), Amsterdam Lysosome Ctr, Dept Med Biochem, Acad Med Ctr, Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM j.m.aerts@amc.uva.nI; rb57v@nih.gov RI Aerts, Johannes/A-1028-2009 NR 42 TC 253 Z9 259 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 26 PY 2008 VL 105 IS 8 BP 2812 EP 2817 DI 10.1073/pnas.0712309105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 268GQ UT WOS:000253567900014 PM 18287059 ER PT J AU Citterio, C Vichi, A Pacheco-Rodriguez, G Aponte, AM Moss, J Vaughan, M AF Citterio, Carmen Vichi, Alessandro Pacheco-Rodriguez, Gustavo Aponte, Angel M. Moss, Joel Vaughan, Martha TI Unfolded protein response and cell death after depletion of brefeldin A-inhibited guanine nucleotide-exchange protein GBF1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ADP-ribosylation factor; ER stress; chaperone; ATF6 ID ADP-RIBOSYLATION FACTOR; ENDOPLASMIC-RETICULUM STRESS; CIS-GOLGI; TETHERING PROTEIN; FREE SYSTEM; ARF; BINDING; DOMAIN; ER; IDENTIFICATION AB Guanine nucleotide-exchange factors (GEFs) activate ADP-ribosylation factor (ARF) GTPases that recruit coat proteins to membranes to initiate transport vesicle formation. Three mammalian GEFs are inhibited by brefeldin A (BFA). GBF1, predominantly associated with cis-Golgi membranes, functions early in the secretory pathway, whereas BIG1 and BIG2 act in trans-Golgi or later sites. Perturbation of endoplasmic reticulum (ER) functions can result in accumulation of unfolded or misfolded proteins that causes ER stress and unfolded protein response (UPR), with accumulation of ER stress response element (ERSE) gene products. BFA treatment of cells causes accumulation of proteins in the ER, ER stress, and ultimately apoptosis. To assess involvement of BFA-sensitive GEFs in the damage resulting from prolonged BFA treatment, HepG2 cells were selectively depleted of BIG1, BIG2, or GBF1 by using specific siRNA. Only GBF1 siRNA dramatically slowed cell growth, led to cell-cycle arrest in G(0)/G(1) phase, and caused dispersion of Golgi markers beta-COP and GM130, whereas ER structure appeared intact. GBF1 depletion also significantly increased levels of ER proteins calreticulin and protein disulfide isomerase (PDI). Proteomic analysis identified ER chaperones involved in the UPR that were significantly increased in amounts in GBF1-depleted cells. Upon ER stress, transcription factor ATF6 translocates from the ER to Golgi, where it is sequentially cleaved by site 1 and site 2 proteases, S1P and S2P, to a 50-kDa form that activates transcription of ERSE genes. Depletion of GBF1, but not BIG1 or BIG2, induced relocation of S2P f rom Golgi to ER with proteolysis of ATF6 followed by up-regulation of ER chaperones, mimicking a UPR response. C1 [Citterio, Carmen; Vichi, Alessandro; Pacheco-Rodriguez, Gustavo; Moss, Joel; Vaughan, Martha] NHLBI, NIH, Translat Med Branch, Bethesda, MD 20892 USA. [Aponte, Angel M.] NHLBI, NIH, Proteom Core Facil, Bethesda, MD 20892 USA. RP Vaughan, M (reprint author), NHLBI, NIH, Translat Med Branch, Bldg 10,Room 5N307, Bethesda, MD 20892 USA. EM vaughanm@nhlbi.nih.gov FU Intramural NIH HHS NR 44 TC 52 Z9 53 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 FEB 26 PY 2008 VL 105 IS 8 BP 2877 EP 2882 DI 10.1073/pnas.0712224105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 268GQ UT WOS:000253567900025 PM 18287014 ER PT J AU Liao, Y Erxleben, C Abramowitz, J Flockerzi, V Zhu, MX Armstrong, DL Birnbaumer, L AF Liao, Yanhong Erxleben, Christian Abramowitz, Joel Flockerzi, Veit Zhu, Michael Xi Armstrong, David L. Birnbaumer, Lutz TI Functional interactions among Orai1, TRPCs, and STIM1 suggest a STIM-regulated heteromeric Orai/TRPC model for SOCE/Icrac channels SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE capacitative calcium entry; signal transduction; store depletion ID STORE-OPERATED CHANNELS; CA2+ ENTRY; PLASMA-MEMBRANE; CALCIUM CURRENT; I-CRAC; ACTIVATION; CELLS; DEPLETION; RECEPTORS; MICE AB Receptor-operated Ca2+ entry (ROCE) and store-operated Ca2+ entry (SOCE) into cells are functions performed by all higher eukaryotic cells, and their impairment is life-threatening. The main molecular components of this pathway appear to be known. However, the molecular make-up of channels mediating ROCE and SOCE is largely unknown. One hypothesis proposes SOCE channels to be formed solely by Orai proteins. Another proposes SOCE channels to be composed of both Orai and C-type transient receptor potential (TRPC) proteins. Both hypotheses propose that the channels are activated by STIM1, a sensor of the filling state of the Ca2+ stores that activates Ca2+ entry when stores are depleted. The role of Orai in SOCE has been proven. Here we show the TRPC-dependent reconstitution of Icrac, the electrophysiological correlate to SOCE, by expression of Orai1; we also show that R91W-Orai1 can inhibit SOCE and ROCE and that Orai1 and STIM1 expression leads to functional expression of Gd-resistant ROCE. Because channels that mediate ROCE are accepted to be formed with the participation of TRPCs, our data show functional interaction between ROCE and SOCE components. We propose that SOCE/Icrac channels are composed of heteromeric complexes that include TRPCs and Orai proteins. C1 [Liao, Yanhong; Erxleben, Christian; Abramowitz, Joel; Armstrong, David L.; Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. [Flockerzi, Veit] Univ Saarland, Inst Expt & Clin Pharmacol & Toxicol, D-66421 Homburg, Germany. [Zhu, Michael Xi] Ohio State Univ, Dept Neurosci, Columbus, OH 43210 USA. [Zhu, Michael Xi] Ohio State Univ, Ctr Mol Neurobiol, Columbus, OH 43210 USA. RP Armstrong, DL (reprint author), Natl Inst Environm Hlth Sci, Neurobiol Lab, Res Triangle Pk, NC 27709 USA. EM armstro3@niehs.nih.gov; brinbau1@niehs.nigh.gov RI Abramowitz, Joel/A-2620-2015 FU Intramural NIH HHS NR 25 TC 160 Z9 165 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 26 PY 2008 VL 105 IS 8 BP 2895 EP 2900 DI 10.1073/pnas.0712288105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 268GQ UT WOS:000253567900028 PM 18287061 ER PT J AU Lin, DYW Tanaka, Y Iwasaki, M Gittis, AG Su, HP Mikami, B Okazaki, T Honjo, T Minato, N Garboczi, DN AF Lin, David Yin-Wei Tanaka, Yoshimasa Iwasaki, Masashi Gittis, Apostolos G. Su, Hua-Poo Mikami, Bunzo Okazaki, Taku Honjo, Tasuku Minato, Nagahiro Garboczi, David N. TI The PD-1/PD-L1 complex resembles the antigen-binding Fv domains of antibodies and T cell receptors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE coreceptor; costimulation; inhibitory receptor ID B7 FAMILY; PD-1; MEMBER; IMMUNORECEPTOR; ACTIVATION; EXPRESSION; TOLERANCE; RESPONSES; MOLECULE; SYSTEM AB Signaling through the programmed death 1 (PD-1) inhibitory receptor upon binding its ligand, PD-L1, suppresses immune responses against autoantigens and tumors and plays an important role in the maintenance of peripheral immune tolerance. Release from PD-1 inhibitory signaling revives "exhausted" virus-specific T cells in chronic viral infections. Here we present the crystal structure of murine PD-1 in complex with human PD-L1. PD-1 and PD-L1 interact through the conserved front and side of their Ig variable (IgV) domains, as do the IgV domains of antibodies and T cell receptors. This places the loops at the ends of the IgV domains on the same side of the PD-1/PD-L1 complex, forming a surface that is similar to the antigen-binding surface of antibodies and T cell receptors. Mapping conserved residues allowed the identification of residues that are important in forming the PD-1/PD-L1 interface. Based on the structure, we show that some reported loss-of-binding mutations involve the PD-1/PD-L1 interaction but that others compromise protein folding. The PD-1/PD-L1 interaction described here may be blocked by antibodies or by designed small-molecule drugs to lower inhibitory signaling that results in a stronger immune response. The immune receptor-like loops offer a new surface for further study and potentially the design of molecules that would affect PD-1/PD-L1 complex formation and thereby modulate the immune response. C1 [Okazaki, Taku; Honjo, Tasuku] Kyoto Univ, Grad Sch Med, Dept Immunol & Genom Med, Sakyo Ku, Kyoto 6068501, Japan. [Tanaka, Yoshimasa; Iwasaki, Masashi; Minato, Nagahiro] Kyoto Univ, Grad Sch Med, Dept Immunol & Cell Biol, Kyoto 6068501, Japan. [Okazaki, Taku] Kyoto Univ, Grad Sch Med, Century Ctr Excellence Format 21, Kyoto 6068501, Japan. [Lin, David Yin-Wei; Gittis, Apostolos G.; Su, Hua-Poo; Garboczi, David N.] NIAID, Struct Biol Sect, Immunogenet Lab, Natl Inst Hlth, Rockville, MD 20852 USA. [Tanaka, Yoshimasa] Japan Sci & Technol Agcy, Precursory Res Embryon Sci & Technol, Kawaguchi, Saitama 1900012, Japan. [Mikami, Bunzo] Kyoto Univ, Grad Sch Agr, Div Appl Life Sci, Lab Appl Struct Biol, Kyoto 6110011, Japan. RP Honjo, T (reprint author), Kyoto Univ, Grad Sch Med, Dept Immunol & Genom Med, Sakyo Ku, Kyoto 6068501, Japan. EM honjo@mfour.med.kyoto-u.ac.jp; dgarbacozi@niaid.nih.gov RI Honjo, Tasuku/N-4470-2016 FU Intramural NIH HHS NR 32 TC 68 Z9 72 U1 2 U2 23 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 FEB 26 PY 2008 VL 105 IS 8 BP 3011 EP 3016 DI 10.1073/pnas.0712278105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 268GQ UT WOS:000253567900048 PM 18287011 ER PT J AU Wu, CJ Ashwell, JD AF Wu, Chuan-Jin Ashwell, Jonathan D. TI NEMO recognition of ubiquitinated Bcl10 is required for T cell receptor-mediated NF-kappa B activation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE I kappa B kinase; T cell signaling; ubiquitination ID GAMMA-DEFICIENT MICE; CARMA1; KINASE; PATHWAY; PROTEIN; MALT1; IKK; TCR; DEGRADATION; BINDING AB The mechanism by which the Carma1-Bcl10-MALT1 (CBM) complex couples T cell antigen receptor (TCR) signaling to I kappa B kinase (IKK) and NF-kappa B activation is not known. Here, we show that Bcl10 undergoes K63-linked polyubiquitination in response to T cell activation and subsequently binds NEMO, the regulatory subunit of IKK. This interaction requires the ubiquitin-binding activity of NEMO. The sites of Bcl10 ubiquitination were mapped to K31 and K63. Mutation of these residues did not affect TCR signaling-induced CBM complex assembly but prevented Bcl10 ubiquitination, NEMO binding, and NF-kappa B activation. Therefore, the regulated ubiquitination of Bcl10 and its recognition by NEMO are a critical link between the CBM complex, IKK recruitment, and NF-kappa B activation. C1 [Wu, Chuan-Jin; Ashwell, Jonathan D.] NCI, Lab Immune Cell Biol, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, Natl Inst Hlth, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU Intramural NIH HHS NR 31 TC 90 Z9 92 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 FEB 26 PY 2008 VL 105 IS 8 BP 3023 EP 3028 DI 10.1073/pnas.0712313105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 268GQ UT WOS:000253567900050 PM 18287044 ER PT J AU Bastrikova, N Gardner, GA Reece, JM Jeromin, A Dudek, SM AF Bastrikova, Natalia Gardner, Gregory A. Reece, Jeff M. Jeromin, Andreas Dudek, Serena M. TI Synapse elimination accompanies functional plasticity in hippocampal neurons SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cortex; critical period; development; long-term depression; schizophrenia ID LONG-TERM DEPRESSION; OCULAR DOMINANCE COLUMNS; VISUAL-CORTEX; DENDRITIC SPINES; STRIATE CORTEX; NMDA RECEPTOR; MORPHOLOGICAL PLASTICITY; BLOCKADE PREVENTS; CA1 NEURONS; DEPRIVATION AB A critical component of nervous system development is synapse elimination during early postnatal life, a process known to depend on neuronal activity. Changes in synaptic strength in the form of long-term potentiation (LTIP) and long-term depression (LTD) correlate with dendritic spine enlargement or shrinkage, respectively, but whether LTD can lead to an actual separation of the synaptic structures when the spine shrinks or is lost remains unknown. Here, we addressed this issue by using concurrent imaging and electrophysiological recording of live synapses. Slices of rat hippocampus were cultured on multielectrode arrays, and the neurons were labeled with genes encoding red or green fluorescent proteins to visualize presynaptic and postsynaptic neuronal processes, respectively. LTD-inducing stimulation led to a reduction in the synaptic green and red colocalization, and, in many cases, it induced a complete separation of the presynaptic bouton from the dendritic spine. This type of synapse loss was associated with smaller initial spine size and greater synaptic depression but not spine shrinkage during LTD. All cases of synapse separation were observed without an accompanying loss of the spine during this period. We suggest that repeated low-frequency stimulation simultaneous with LTD induction is capable of restructuring synaptic contacts. Future work with this model will be able to provide critical insight into the molecular mechanisms of activity and experience-dependent refinement of brain circuitry during development. C1 [Bastrikova, Natalia; Gardner, Gregory A.; Dudek, Serena M.] NIEHS, Neurobiol Lab, NIH, Res Triangle Pk, NC 27709 USA. [Reece, Jeff M.] NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. [Jeromin, Andreas] Allen Inst Brain Sci, Seattle, WA 98103 USA. RP Dudek, SM (reprint author), NIEHS, Neurobiol Lab, NIH, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM dudek@niehs.nih.gov OI Dudek, Serena M./0000-0003-4094-8368 FU Intramural NIH HHS [ZIA ES100221-08] NR 44 TC 108 Z9 109 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 26 PY 2008 VL 105 IS 8 BP 3123 EP 3127 DI 10.1073/pnas.0800027105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 268GQ UT WOS:000253567900067 PM 18287055 ER PT J AU Fenton, RA Moeller, HB Hoffert, JD Yu, MJ Nielsen, S Knepper, MA AF Fenton, Robert A. Moeller, Hanne B. Hoffert, Jason D. Yu, Ming-Jiun Nielsen, Soren Knepper, Mark A. TI Acute regulation of aquaporin-2 phosphorylation at Ser-264 by vasopressin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE concentrating mechanism; immunohistochemistry; kidney; trafficking ID RAT-KIDNEY; MEMBRANE ACCUMULATION; COLLECTING DUCT; WATER CHANNEL; AQP2; ENDOCYTOSIS; LOCALIZATION; TRAFFICKING; CELLS AB By phosphoproteome analysis, we identified a phosphorylation site, serine 264 (pS264), in the COOH terminus of the vasopressin-regulated water channel, aquaporin-2 (AQP2). In this study, we examined the regulation of AQP2 phosphorylated at serine 264 (pS264-AQP2) by vasopressin, using a phospho-specific antibody (anti-pS264). Immunohistochemical analysis showed pS264-AQP2 labeling of inner medullary collecting duct (IMCD) from control mice, whereas AQP2 knockout mice showed a complete absence of labeling. In rat and mouse, pS264-AQP2 was present throughout the collecting duct system, from the connecting tubule to the terminal IMCD. Immunogold electron microscopy, combined with double-labeling confocal immunofluorescence, microscopy with organelle-specific markers, determined that the majority of pS264 resides in compartments associated with the plasma membrane and early endocytic pathways. In Brattleboro rats treated with [deamino-Cys-1, D-Arg-8]vasopressin (dDAVP), the abundance of pS264-AQP2 increased 4-fold over controls. Additionally, dDAVP treatment resulted in a time-dependent change in the distribution of pS264 from predominantly intracellular vesicles, to both the basolateral and apical plasma membranes. Sixty minutes after dDAVP exposure, a proportion of pS264-AQP2 was observed in clathrin-coated vesicles, early endosomal compartments, and recycling compartments, but not lysosomes. Overall, our results are consistent with a dynamic effect of AVP on the phosphorylation and subcellular distribution of AQP2. C1 [Fenton, Robert A.; Moeller, Hanne B.; Nielsen, Soren] Univ Aarhus, Water & Salt Res Ctr, Inst Anat, DK-8000 Aarhus C, Denmark. [Hoffert, Jason D.; Yu, Ming-Jiun; Knepper, Mark A.] NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Fenton, RA (reprint author), Univ Aarhus, Water & Salt Res Ctr, Inst Anat, Bldg 233, DK-8000 Aarhus C, Denmark. EM rofe@ana.au.dk OI YU, MING-JIUN/0000-0003-0393-4696 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [Z01 HL001285] NR 21 TC 67 Z9 69 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 26 PY 2008 VL 105 IS 8 BP 3134 EP 3139 DI 10.1073/pnas.0712338105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 268GQ UT WOS:000253567900069 PM 18287043 ER PT J AU Vaccari, T Lu, H Kanwar, R Fortin, ME Bilder, D AF Vaccari, Thomas Lu, Han Kanwar, Ritu Fortin, Mark E. Bilder, David TI Endosomal entry regulates Notch receptor activation in Drosophila melanogaster SO JOURNAL OF CELL BIOLOGY LA English DT Article ID AMYLOID PRECURSOR PROTEIN; GAMMA-SECRETASE CLEAVAGE; FOLLICLE CELLS; ENDOCYTIC PATHWAY; TUMOR SUPPRESSORS; TRAFFICKING; WINGLESS; COMPLEX; GROWTH; PROLIFERATION AB Signaling through the transmembrane receptor Notch is widely used throughout animal development and is a major regulator of cell proliferation and differentiation. During canonical Notch signaling, internalization and recycling of Notch ligands controls signaling activity, but the involvement of endocytosis in activation of Notch itself is not well understood. To address this question, we systematically assessed Notch localization, processing, and signaling in a comprehensive set of Drosophila melanogaster mutants that block access of cargo to different endocytic compartments. We find that gamma-secretase cleavage and signaling of endogenous Notch is reduced in mutants that impair entry into the early endosome but is enhanced in mutants that increase endosomal retention. In mutants that block endosomal entry, we also uncover an alternative, low-efficiency Notch trafficking route that can contribute to signaling. Our data show that endosomal access of the Notch receptor is critical to achieve physiological levels of signaling and further suggest that altered residence in distinct endocytic compartments could underlie pathologies involving aberrant Notch pathway activation. C1 [Vaccari, Thomas; Lu, Han; Bilder, David] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. [Kanwar, Ritu; Fortin, Mark E.] NCI, Ctr Canc Res, Frederick, MD 21702 USA. RP Bilder, D (reprint author), Univ Calif Berkeley, Dept Mol & Cell Biol, 229 Stanley Hall, Berkeley, CA 94720 USA. EM bilder@berkeley.edu OI vaccari, thomas/0000-0002-6231-7105 FU NIGMS NIH HHS [R01 GM068675-01, R01 GM068675, R01 GM090150] NR 43 TC 154 Z9 155 U1 1 U2 10 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 950 THIRD AVE, 2ND FLR, NEW YORK, NY 10022 USA SN 0021-9525 EI 1540-8140 J9 J CELL BIOL JI J. Cell Biol. PD FEB 25 PY 2008 VL 180 IS 4 BP 755 EP 762 DI 10.1083/jcb.200708127 PG 8 WC Cell Biology SC Cell Biology GA 267FD UT WOS:000253494000026 PM 18299346 ER PT J AU Berkhout, B Gorelick, R Summers, MF Mely, Y Darlix, JL AF Berkhout, Ben Gorelick, Robert Summers, Michael F. Mely, Yves Darlix, Jean-Luc TI 6(th) international symposium on retroviral nucleocapsid SO RETROVIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; HIV-1 REVERSE TRANSCRIPTION; SELECTIVE 2'-HYDROXYL ACYLATION; SINGLE NUCLEOTIDE RESOLUTION; ACID-CHAPERONE ACTIVITY; PRIMER EXTENSION SHAPE; RNA STRUCTURE-ANALYSIS; GENOMIC RNA; ZINC-FINGER AB Retroviruses and LTR-retrotransposons are widespread in all living organisms and, in some instances such as for HIV, can be a serious threat to the human health. The retroviral nucleocapsid is the inner structure of the virus where several hundred nucleocapsid protein (NC) molecules coat the dimeric, genomic RNA. During the past twenty years, NC was found to play multiple roles in the viral life cycle (Fig. 1), notably during the copying of the genomic RNA into the proviral DNA by viral reverse transcriptase and integrase, and is therefore considered to be a prime target for anti-HIV therapy. The 6(th) NC symposium was held in the beautiful city of Amsterdam, the Netherlands, on the 20(th) and 21(st) of September 2007. All aspects of NC biology, from structure to function and to anti-HIV vaccination, were covered during this meeting. C1 [Darlix, Jean-Luc] Ecole Normale Super Lyon, Labretro INSERM 758, IFR Biosci 128, F-69364 Lyon 07, France. [Berkhout, Ben] Univ Amsterdam, Acad Med Ctr, CINIMA,Lab Expt Viriol, Dept Med Microbiol, NL-1105 AZ Amsterdam, Netherlands. [Gorelick, Robert] Inc NCI Frederick, AIDS Vaccine Program SAIC, Ft Detrick, MD 21702 USA. [Summers, Michael F.] Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. [Summers, Michael F.] Univ Maryland Baltimore Cty, Howard Hughes Med Inst, Baltimore, MD 21250 USA. [Mely, Yves] Univ Strasbourg 1, CNRS, Inst Gilbert Laustrait,UMR 7175, Dept Pharmacol & Physico Chem, F-67401 Illkirch Graffenstaden, France. RP Darlix, JL (reprint author), Ecole Normale Super Lyon, Labretro INSERM 758, IFR Biosci 128, F-69364 Lyon 07, France. EM b.berkhout@amc.uva.nl; gorelick@ncifcrf.gov; summers@hhmi.umbc.edu; yves.mely@pharma.u-strasbg.fr; jldarlix@ens-lyon.fr FU NCI NIH HHS [N01CO12400] NR 63 TC 4 Z9 4 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD FEB 25 PY 2008 VL 5 AR 21 DI 10.1186/1742-4690-5-21 PG 9 WC Virology SC Virology GA 280QO UT WOS:000254441500001 PM 18298807 ER PT J AU Sivertsen, A Wilcox, AJ Skjaerven, R Vindenes, HA Abyholm, F Harville, E Lie, RT AF Sivertsen, Ase Wilcox, Allen J. Skjaerven, Rov Vindenes, Hallvard Andreas Abyholm, Frank Harville, Emily Lie, Rolv Terje TI Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relatives SO BRITISH MEDICAL JOURNAL LA English DT Article ID BIRTH-DEFECTS; RECURRENCE; PALATE; LIP; SURVIVAL; GENETICS; CHILDREN AB Objective To estimate the relative risk of recurrence of oral cleft in first degree relatives in relation to cleft morphology. Design Population based cohort study. Setting Data from the medical birth registry of Norway linked with clinical data on virtually all cleft patients treated in Norway over a 35 year period. Participants 2.1 million children born in Norway between 1967 and 2001, 4138 of whom were treated for an oral cleft. Main outcome measure Relative risk of recurrence of isolated clefts from parent to child and between full siblings, for anatomic subgroups of clefts. Results Among first degree relatives, the relative risk of recurrence of cleft was 32 (95% confidence interval 24.6 to 40.3) for any cleft lip and 56 (37.2 to 84.8) for cleft palate only (P difference=0.02). The risk of clefts among children of affected mothers and affected fathers was similar. Risks of recurrence were also similar for parent-offspring and sibling-sibling pairs. The "crossover" risk between any cleft lip and cleft palate only was 3.0 (1.3 to 6.7). The severity of the primary case was unrelated to the risk of recurrence. Conclusions The stronger family recurrence of cleft palate only suggests a larger genetic component for cleft palate only than for any cleft lip. The weaker risk of crossover between the two types of cleft indicates relatively distinct causes. The similarity of mother-offspring, father-offspring, and sibling-sibling risks is consistent with genetic risk that works chiefly through fetal genes. Anatomical severity does not affect the recurrence risk in first degree relatives, which argues against a multifactorial threshold model of causation. C1 [Sivertsen, Ase; Vindenes, Hallvard Andreas] Haukeland Hosp, Dept Plast Surg, NO-5021 Bergen, Norway. [Sivertsen, Ase; Skjaerven, Rov; Lie, Rolv Terje] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, N-5018 Bergen, Norway. [Wilcox, Allen J.] NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. [Abyholm, Frank] Univ Oslo, Rikshosp, Dept Plast Surg, N-0027 Oslo, Norway. [Harville, Emily] Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA. RP Sivertsen, A (reprint author), Haukeland Hosp, Dept Plast Surg, NO-5021 Bergen, Norway. EM ase.sivertsen@isf.uib.no OI Wilcox, Allen/0000-0002-3376-1311 FU Intramural NIH HHS; NIDCR NIH HHS [2R01 DE-11948-04] NR 25 TC 62 Z9 64 U1 0 U2 5 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8146 J9 BRIT MED J JI Br. Med. J. PD FEB 23 PY 2008 VL 336 IS 7641 BP 432 EP 434A DI 10.1136/bmj.39458.563611.AE PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 269QM UT WOS:000253664000039 PM 18250102 ER PT J AU Malchnkhuu, E Sato, K Maehama, T Mogi, C Tomura, H Ishiuchi, S Yoshimoto, Y Kurose, H Okajima, F AF Malchnkhuu, Enkhzol Sato, Koichi Maehama, Tomohiko Mogi, Chihiro Tomura, Hideaki Ishiuchi, Shogo Yoshimoto, Yuhei Kurose, Hitoshi Okajima, Fumikazu TI S1P(2) receptors mediate inhibition of glioma cell migration through Rho signaling pathways independent of PTEN SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE glioma; cell migration; sphingosine-1-phosphate; lysophosphatidic acid; PTEN ID PROTEIN-COUPLED RECEPTOR; TUMOR-SUPPRESSOR PTEN; LYSOPHOSPHATIDIC ACID; SPHINGOSINE-1-PHOSPHATE; KINASE; RAC; REQUIREMENT; DOWNSTREAM; ACTIVATION; MOTILITY AB Sphingosine I-phosphate (SIP) induced the inhibition of glioma cell migration. Here, we characterized the signaling mechanisms involved in the inhibitory action by SIP. In human GNS-3314 glioblastoma cells, the SIP-induced inhibition of cell migration was associated with activation of RhoA and suppression of Rac1. The inhibitory action of S1P was recovered by a small interference RNA specific to S1P(2) receptor, a carboxyl-terminal region of G alpha 12 or G alpha 13, an RGS domain of p115RhoGEF, and a dominant-negative mutant of RhoA. The inhibitory action of S1P through S1P(2) receptors was also observed in both U87MG glioblastoma and 1321N1 astrocytoma cells, which have no protein expression of a phosphatase and tensin homolog deleted on chromosome 10 (PTEN). These results suggest that S1P(2) receptors/G(12/13)-proteins/Rho signaling pathways mediate S1P-induced inhibition of glioma cell migration. However, PTEN, recently postulated as an indispensable molecule for the inhibition of cell migration, may not be critical for the S1P(2) receptor-mediated action in glioma cells. (c) 2007 Elsevier Inc. All rights reserved. C1 [Malchnkhuu, Enkhzol; Sato, Koichi; Mogi, Chihiro; Tomura, Hideaki; Okajima, Fumikazu] Gunma Univ, Inst Mol & Cellular Regulatt, Lab Signal Transduct, Maebashi, Gumma 3718512, Japan. [Maehama, Tomohiko] NIAID, Dept Biochem & Cell Biol, Shinjuku Ku, Tokyo 1628640, Japan. [Yoshimoto, Yuhei] Gunma Univ, Grad Sch Med, Dept Neurosurg, Maebashi, Gumma 3718511, Japan. [Kurose, Hitoshi] Kyushu Univ, Grad Sch Pharmaceut Sci, Dept Pharmacol & Toxicol, Fukuoka 8128582, Japan. RP Sato, K (reprint author), Gunma Univ, Inst Mol & Cellular Regulatt, Lab Signal Transduct, Maebashi, Gumma 3718512, Japan. EM kosato@showa.gunrna-u.ac.jp OI Maehama, Tomohiko/0000-0002-9685-2317 NR 18 TC 31 Z9 31 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 22 PY 2008 VL 366 IS 4 BP 963 EP 968 DI 10.1016/j.bbrc.2007.12.054 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 253IV UT WOS:000252512800017 PM 18088600 ER PT J AU Chen, C Krausz, KW Idle, JR Gonzalez, FJ AF Chen, Chi Krausz, Kristopher W. Idle, Jeffrey R. Gonzalez, Frank J. TI Identification of novel toxicity-associated metabolites by metabolomics and mass isotopomer analysis of acetaminophen metabolism in wild-type and Cyp2e1-null mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOCHONDRIAL PERMEABILITY TRANSITION; ALCOHOL-MEDIATED INCREASES; ACUTE LIVER-FAILURE; OXIDATIVE STRESS; RAT-LIVER; INDUCED HEPATOTOXICITY; CATECHOL METABOLITES; HEPATIC GLUTATHIONE; MOUSE HEPATOCYTES; COVALENT BINDING AB CYP2E1 is recognized as the most important enzyme for initiation of acetaminophen ( APAP)-induced toxicity. In this study, the resistance of Cyp2e1-null mice to APAP treatment was confirmed by comparing serum aminotransferase activities and blood urea nitrogen levels in wild-type and Cyp2e1-null mice. However, unexpectedly, profiling of major known APAP metabolites in urine and serum revealed that the contribution of CYP2E1 to APAP metabolism decreased with increasing APAP doses administered. Measurement of hepatic glutathione and hydrogen peroxide levels exposed the importance of oxidative stress in determining the consequence of APAP overdose. Subsequent metabolomic analysis was capable of constructing a principal components analysis (PCA) model that delineated a relationship between urinary metabolomes and the responses to APAP treatment. Urinary ions high in wild-type mice treated with 400 mg/kg APAP were elucidated as 3-methoxy-APAP glucuronide (VII) and three novel APAP metabolites, including S-(5-acetylamino-2-hydroxyphenyl) mercaptopyruvic acid ( VI, formed by a Cys-APAP transamination reaction in kidney), 3,3'-biacetaminophen (VIII, an APAP dimer), and a benzothiazine compound (IX, originated from deacetylated APAP), through mass isotopomer analysis, accurate mass measurement, tandem mass spectrometry fragmentation, in vitro reactions, and chemical treatments. Dose-, time-, and genotype-dependent appearance of these minor APAP metabolites implied their association with the APAP-induced toxicity and potential biomarker application. Overall, the oxidative stress elicited by CYP2E1-mediated APAP metabolism might significantly contribute to APAP-induced toxicity. The combination of genetically modified animal models, mass isotopomer analysis, and metabolomics provides a powerful and efficient technical platform to characterize APAP-induced toxicity through identifying novel biomarkers and unraveling novel mechanisms. C1 [Chen, Chi; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, NIH, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. [Idle, Jeffrey R.] Charles Univ Prague, Inst Pharmacol, Fac Med 1, Prague 12800, Czech Republic. RP Gonzalez, FJ (reprint author), NCI, NIH, Lab Metab, Ctr Canc Res, 37 Convert Dr, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov RI Chen, Chi/B-4618-2008; OI Idle, Jeff/0000-0002-6143-1520 FU Intramural NIH HHS [Z01 BC005562-19] NR 53 TC 75 Z9 78 U1 1 U2 22 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 FEB 22 PY 2008 VL 283 IS 8 BP 4543 EP 4559 DI 10.1074/jbc.M706299200 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266IA UT WOS:000253426500011 PM 18093979 ER PT J AU Hebbar, PB Archer, TK AF Hebbar, Pratibha B. Archer, Trevor K. TI Altered histone H1 stoichiometry and an absence of nucleosome positioning on transfected DNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR VIRUS PROMOTER; IN-VIVO; LINKER HISTONE; TRANSCRIPTIONAL ACTIVATION; CHROMATIN-STRUCTURE; MMTV PROMOTER; REPLICATION; TEMPLATES; COMPLEXES; MECHANISM AB The packaging of DNA with histones to form chromatin represents an important and powerful mechanism to regulate gene expression. Critical aspects of chromatin-specific contributions to gene regulation have been revealed by the comparison of the activities from DNA regulatory elements examined both as transiently transfected reporters and stably integrated reporters organized as chromatin. Using the mouse mammary tumor virus ( MMTV) promoter as a model, we probed the structural differences between transiently transfected and stably integrated DNA templates. We demonstrated that all four core histones and the linker histone (H1) are associated with the transient template. However, whereas the core histones were present at a similar stoichiometry between the transient and the stable templates, we found that linker histone H1 molecules are fewer on the transient template. By using supercoiling assay, we show that the transient template shows intermediate levels of nucleosomal assembly. Overexpression of H1 resulted in repression of MMTV transcriptional activity and reduced accessibility to restriction endonucleases on the transient MMTV promoter. However, the addition of exogenous H1 failed to impose a normal chromatin structure on the transient template as measured by micrococcal nuclease digestion pattern. Thus, our results suggest that while transiently transfected DNA acquires a full complement of core histones, the underrepresentation of H1 on the transient template is indicative of structural differences between the two templates that may underlie the differences in the mechanisms of activation of the two templates. C1 [Hebbar, Pratibha B.; Archer, Trevor K.] NIEHS, Natl Inst Hlth, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Natl Inst Hlth, Mol Carcinogenesis Lab, 111 Alexander Dr,MD D4-01,POB 12233, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov FU Intramural NIH HHS [Z01 ES071006-09] NR 27 TC 38 Z9 38 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 FEB 22 PY 2008 VL 283 IS 8 BP 4595 EP 4601 DI 10.1074/jbc.M709121200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266IA UT WOS:000253426500016 PM 18156629 ER PT J AU Picard, N Eladari, D El Moghrabi, S Planes, C Bourgeois, S Houillier, P Wang, Q Burnier, M Deschenes, G Knepper, MA Meneton, P Chambrey, R AF Picard, Nicolas Eladari, Dominique El Moghrabi, Soumaya Planes, Carole Bourgeois, Soline Houillier, Pascal Wang, Qing Burnier, Michel Deschenes, Georges Knepper, Mark A. Meneton, Pierre Chambrey, Regine TI Defective ENaC processing and function in tissue kallikrein-deficient mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID EPITHELIAL SODIUM-CHANNEL; CORTICAL COLLECTING DUCT; URINARY KALLIKREIN; XENOPUS-OOCYTES; SERINE PROTEASES; RENIN-ACTIVITY; ANGIOTENSIN-I; ACTIVATION; KIDNEY; HYPERTENSION AB An inverse relationship exists between urinary tissue kallikrein (TK) excretion and blood pressure in humans and rodents. In the kidney TK is synthesized in large amounts in the connecting tubule and is mainly released into the urinary fluid where its function remains unknown. In the present study mice with no functional gene coding for TK (TK-/-) were used to test whether the enzyme regulates apically expressed sodium transporters. Semiquantitative immunoblotting of the renal cortex revealed an absence of the 70-kDa form of gamma-ENaC in TK-/- mice. Urinary Na+ excretion after amiloride injection was blunted in TK-/- mice, consistent with reduced renal ENaC activity. Amiloride-sensitive transepithelial potential difference in the colon, where TK is also expressed, was decreased in TK-/- mice, whereas amiloride-ensitive alveolar fluid clearance in the lung, where TK is not expressed, was unchanged. In mice lacking the B2 receptor for kinins, the abundance of the 70-kDa form of gamma-ENaC was increased, indicating that its absence in TK-/- mice is not kinin-mediated. Incubation of membrane proteins from renal cortex of TK-/- mice with TK resulted in the appearance of the 70-kDa band of the gamma-ENaC, indicating that TK was able to promote gamma-ENaC cleavage in vitro. Finally, in mouse cortical collecting ducts isolated and microperfused in vitro, the addition of TK in the luminal fluid increased significantly intracellular Na+ concentration, consistent with an activation of the luminal entry of the cation. The results demonstrate that TK, like several other proteases, can activate ENaC in the kidney and the colon. C1 [Picard, Nicolas; Eladari, Dominique; El Moghrabi, Soumaya; Bourgeois, Soline; Houillier, Pascal; Meneton, Pierre; Chambrey, Regine] Univ Paris 05, INSERM, U872,Fac Med Rene Descartes, Ctr Rech Cordeliers, F-75006 Paris, France. [Planes, Carole] Univ Paris 07, INSERM, U773 CRB3, UFR Med, F-75018 Paris, France. [Eladari, Dominique] Hop Necker Enfants Malad, Dept Physiol, F-75015 Paris, France. [Wang, Qing; Burnier, Michel] CHU Vaudois, Dept Nephrol, CH-1011 Lausanne, Switzerland. [Deschenes, Georges] UPMC, CNRS, UMR 7134, F-75006 Paris, France. [Knepper, Mark A.] NHLBI, Natl Inst Hlth, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. RP Eladari, D (reprint author), Univ Paris 05, INSERM, U872,Fac Med Rene Descartes, Ctr Rech Cordeliers, 15 Rue Ecole Med, F-75006 Paris, France. EM eladari@ccr.jussieu.fr RI Picard, Nicolas/B-6677-2012 OI Picard, Nicolas/0000-0002-1695-3389 FU Intramural NIH HHS NR 48 TC 60 Z9 61 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 FEB 22 PY 2008 VL 283 IS 8 BP 4602 EP 4611 DI 10.1074/jbc.M705664200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266IA UT WOS:000253426500017 PM 18086683 ER PT J AU Makareeva, E Mertz, EL Kuznetsova, NV Sutter, MB DeRidder, AM Cabral, WA Barnes, AM McBride, DJ Marini, JC Leikin, S AF Makareeva, Elena Mertz, Edward L. Kuznetsova, Natalia V. Sutter, Mary B. DeRidder, Angela M. Cabral, Wayne A. Barnes, Aileen M. McBride, Daniel J. Marini, Joan C. Leikin, Sergey TI Structural heterogeneity of type I collagen triple helix and its role in osteogenesis imperfecta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID AMINO-ACID-SEQUENCE; THERMAL-STABILITY; ELECTRON-MICROGRAPHS; MOLECULAR PACKING; ALPHA-1(I) CHAIN; ALPHA-2(I) CHAIN; DANLOS-SYNDROME; MODEL PEPTIDES; BINDING SITES; MURINE MODEL AB We investigated regions of different helical stability within human type I collagen and discussed their role in intermolecular interactions and osteogenesis imperfecta (OI). By differential scanning calorimetry and circular dichroism, we measured and mapped changes in the collagen melting temperature (Delta T-m) for 41 different Gly substitutions from 47 OI patients. In contrast to peptides, we found no correlations of Delta T-m with the identity of the substituting residue. Instead, we observed regular variations in Delta T-m with the substitution location in different triple helix regions. To relate the Delta T-m map to peptide-based stability predictions, we extracted the activation energy of local helix unfolding (Delta G(double dagger)) from the reported peptide data. We constructed the Delta G(double dagger) map and tested it by measuring the H-D exchange rate for glycine NH residues involved in interchain hydrogen bonds. Based on the Delta T-m and Delta G(double dagger) maps, we delineated regional variations in the collagen triple helix stability. Two large, flexible regions deduced from the Delta T-m map aligned with the regions important for collagen fibril assembly and ligand binding. One of these regions also aligned with a lethal region for Gly substitutions in the alpha 1(I) chain. C1 [Makareeva, Elena; Mertz, Edward L.; Kuznetsova, Natalia V.; Sutter, Mary B.; DeRidder, Angela M.; Leikin, Sergey] NICHD, Sect Phys Biochem, NIH, Bethesda, MD 20892 USA. [Cabral, Wayne A.; Barnes, Aileen M.; Marini, Joan C.] NICHD, Bone & Extracellular Matrix Branch, NIH, Bethesda, MD 20892 USA. [McBride, Daniel J.] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. RP Leikin, S (reprint author), NICHD, Sect Phys Biochem, NIH, Bldg 9,Rm 1E-127, Bethesda, MD 20892 USA. EM leikins@mail.nih.gov RI Leikin, Sergey/A-5518-2008; Makareeva, Elena/F-5183-2011 OI Leikin, Sergey/0000-0001-7095-0739; FU Intramural NIH HHS NR 58 TC 46 Z9 48 U1 0 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 22 PY 2008 VL 283 IS 8 BP 4787 EP 4798 DI 10.1074/jbc.M705773200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266IA UT WOS:000253426500036 PM 18073209 ER PT J AU Nakamura, T de Vega, S Fukumoto, S Jimenez, L Unda, F Yamada, Y AF Nakamura, Takashi de Vega, Susana Fukumoto, Satoshi Jimenez, Lucia Unda, Fernando Yamada, Yoshihiko TI Transcription factor epiprofin is essential for tooth morphogenesis by regulating epithelial cell fate and tooth number SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DEVELOPING MOUSE TOOTH; EPIDERMAL MORPHOGENESIS; MICE; LIMB; PROLIFERATION; EXPRESSION; GROWTH; GENE; ABNORMALITIES; AMELOBLASTIN AB In tooth morphogenesis, the dental epithelium and mesenchyme interact reciprocally for growth and differentiation to form the proper number and shapes of teeth. We previously identified epiprofin (Epfn), a gene preferentially expressed in dental epithelia, differentiated ameloblasts, and certain ectodermal organs. To identify the role of Epfn in tooth development, we created Epfn-deficient mice (Epfn(-/-)). Epfn(-/-) mice developed an excess number of teeth, enamel deficiency, defects in cusp and root formation, and abnormal dentin structure. Mutant tooth germs formed multiple dental epithelial buds into the mesenchyme. In Epfn(-/-) molars, rapid proliferation and differentiation of the inner dental epithelium were inhibited, and the dental epithelium retained the progenitor phenotype. Formation of the enamel knot, a signaling center for cusps, whose cells differentiate from the dental epithelium, was also inhibited. However, multiple premature nonproliferating enamel knot-like structures were formed ectopically. These dental epithelial abnormalities were accompanied by dysregulation of Lef-1, which is required for the normal transition from the bud to cap stage. Transfection of an Epfn vector promoted dental epithelial cell differentiation into ameloblasts and activated promoter activity of the enamel matrix ameloblastin gene. Our results suggest that in Epfn-deficient teeth, ectopic nonproliferating regions likely bud off from the self-renewable dental epithelium, form multiple branches, and eventually develop into supernumerary teeth. Thus, Epfn has multiple functions for cell fate determination of the dental epithelium by regulating both proliferation and differentiation, preventing continuous tooth budding and generation. C1 [Nakamura, Takashi; de Vega, Susana; Fukumoto, Satoshi; Yamada, Yoshihiko] NIDCR, Lab Cell & Dev Biol, Bethesda, MD 20892 USA. [Fukumoto, Satoshi] Kyushu Univ, Fac Dent Sci, Dept Pediat Dent, Fukuoka 8128582, Japan. [Jimenez, Lucia; Unda, Fernando] Univ Basque Country, Fac Med & Dent, Dept Cell Biol & Histol, Vizcaya 48940, Spain. RP Yamada, Y (reprint author), NIDCR, Lab Cell & Dev Biol, Bldg 30,Rm 407,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM yoshi.yamada@nih.gov RI Jimenez, Lucia/K-3377-2012; Nakamura, Takashi/P-7796-2016 OI Nakamura, Takashi/0000-0001-9904-1037 FU Intramural NIH HHS NR 32 TC 37 Z9 39 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 22 PY 2008 VL 283 IS 8 BP 4825 EP 4833 DI 10.1074/jbc.M708388200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266IA UT WOS:000253426500040 PM 18156176 ER PT J AU Beck, EJ Yang, Y Yaemsiri, S Raghuram, V AF Beck, Edward J. Yang, Yu Yaemsiri, Sirin Raghuram, Viswanathan TI Conformational changes in a pore-lining helix coupled to cystic fibrosis transmembrane conductance regulator channel gating SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CFTR CHLORIDE CHANNEL; ACETYLCHOLINE-RECEPTOR CHANNEL; NUCLEOTIDE-BINDING DOMAIN; ABC TRANSPORTER; P-GLYCOPROTEIN; ANION-BINDING; CL-CHANNELS; CYSTEINE; MECHANISM; SITE AB Cystic fibrosis transmembrane conductance regulator (CFTR), the protein dysfunctional in cystic fibrosis, is unique among ATP-binding cassette transporters in that it functions as an ion channel. In CFTR, ATP binding opens the channel, and its subsequent hydrolysis causes channel closure. We studied the conformational changes in the pore-lining sixth transmembrane segment upon ATP binding by measuring state-dependent changes in accessibility of substituted cysteines to methanethiosulfonate reagents. Modification rates of three residues (resides 331, 333, and 335) near the extracellular side were 10-1000-fold slower in the open state than in the closed state. Introduction of a charged residue by chemical modification at two of these positions (resides 331 and 333) affected CFTR single-channel gating. In contrast, modifications of pore-lining residues 334 and 338 were not state-dependent. Our results suggest that ATP binding induces a modest conformational change in the sixth transmembrane segment, and this conformational change is coupled to the gating mechanism that regulates ion conduction. These results may establish a structural basis of gating involving the dynamic rearrangement of transmembrane domains necessary for vectorial transport of substrates in ATP-binding cassette transporters. C1 [Beck, Edward J.; Yang, Yu; Yaemsiri, Sirin; Raghuram, Viswanathan] NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Raghuram, V (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, NIH, 9000 Rockville Pike,Bldg 10,Rm 7D13, Bethesda, MD 20892 USA. EM raghuramv@mail.nih.gov FU Intramural NIH HHS NR 38 TC 29 Z9 29 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 FEB 22 PY 2008 VL 283 IS 8 BP 4957 EP 4966 DI 10.1074/jbc.M702235200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 266IA UT WOS:000253426500053 PM 18056267 ER PT J AU Dong, J Boyd, WA Freedman, JH AF Dong, Jie Boyd, Windy A. Freedman, Jonathan H. TI Molecular characterization of two homologs of the Caenorhabditis elegans cadmium-responsive gene cdr-1: cdr-4 and cdr-6 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE C. elegans; cadmium; transition metal; RNA interference; transcription ID CELL-SPECIFIC EXPRESSION; TRANSCRIPTION FACTOR; METALLOTHIONEIN GENES; MICROARRAY ANALYSIS; PROTEIN-KINASE; GATA-FACTOR; C-ELEGANS; STRESS; ACTIVATION; RESISTANCE AB A novel cadmium-inducible gene, cdr-1, was previously identified and characterized in the nematode Caenorhabditis elegans and found to mediate resistance to cadmium toxicity. Subsequently, six homologs of cdr-1 were identified in C. elegans. Here, we describe two homologs: cdr-4, which is metal inducible, and cdr-6, which is noninducible. Both cdr-4 and cdr-6 mRNAs contain open reading frames of 831 nt and encode predicted 32-kDa integral membrane proteins, which are similar to CDR-1. cdr-4 expression is induced by arsenic, cadmium, mercury, and zinc exposure as well as by hypotonic stress. In contrast, cdr-6 is constitutively expressed at a high level in C. elegans, and expression is not affected by these stressors. Both cdr-4 and cdr-6 are transcribed in postembryonic pharyngeal and intestinal cells in C. elegans. In addition, cdr-4 is transcribed in developing embryos. Like CDR-1, CDR-4 is targeted to intestinal cell lysosomes in vivo. Inhibition of CDR-4 and/or CDR-6 expression does not render C. elegans more susceptible to cadmium toxicity; however, there is a significant decrease in their lifespan in the absence of metal. Although nematodes in which CDR-4 and/or CDR-6 expression is knocked down accumulate fluid in the pseudocoelomic space, exposure to hypertonic conditions did not significantly affect growth or reproduction in these nematodes. These results suggest that CDR expression is required for optimal viability but does not function in osmoregulation. Published by Elsevier Ltd. C1 [Boyd, Windy A.; Freedman, Jonathan H.] NIEHS, Natl Toxicol Program, NIH DHHS, Res Triangle Pk, NC 27709 USA. [Boyd, Windy A.; Freedman, Jonathan H.] NIEHS, Mol Toxicol Lab, NIH DHHS, Res Triangle Pk, NC 27709 USA. [Dong, Jie] Duke Univ, Nicholas Sch Environ & Earth Sci, Durham, NC 27708 USA. RP Freedman, JH (reprint author), NIEHS, Natl Toxicol Program, NIH DHHS, Res Triangle Pk, Res Triangle Pk, NC 27709 USA. EM freedma1@niehs.nih.gov OI Boyd, Windy/0000-0003-3803-3716 FU Intramural NIH HHS [Z01 ES102045-02, Z01 ES102046-02, Z99 ES999999]; NIEHS NIH HHS [ES09949, R01 ES009949, R01 ES009949-01, R01 ES009949-02, R01 ES009949-03, R01 ES009949-04, R01 ES009949-05] NR 61 TC 11 Z9 15 U1 1 U2 3 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 EI 1089-8638 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 22 PY 2008 VL 376 IS 3 BP 621 EP 633 DI 10.1016/j.jmb.2007.11.094 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 265JM UT WOS:000253354900003 PM 18177893 ER PT J AU Das, R Loss, S Li, J Waugh, DS Tarasov, S Wingfield, PT Byrd, RA Altieri, AS AF Das, Ranabir Loss, Sandra Li, Jess Waugh, David S. Tarasov, Sergey Wingfield, Paul T. Byrd, R. Andrew Altieri, Amanda S. TI Structural biophysics of the NusB : NusE antitermination complex SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE anti-termination; NusB; NusE; protein-protein interaction NMR ID TRIPLE-RESONANCE NMR; MACROMOLECULAR STRUCTURE DETERMINATION; SMALL RIBOSOMAL-SUBUNIT; ESCHERICHIA-COLI; TRANSCRIPTION ANTITERMINATION; C-13-LABELED PROTEINS; PHAGE-LAMBDA; MYCOBACTERIUM-TUBERCULOSIS; ANGSTROM RESOLUTION; DIPOLAR COUPLINGS AB In prokaryotic transcription regulation, several host factors form a complex with RNA polymerase and the nascent mRNA. As part of a process known as antitermination, two of these host factors, NusB and NusE, bind to form a heterodimer, which interacts with a specific boxA site on the RNA. The NusB/NusE/boxA RNA ternary complex interacts with the RNA polymerase transcription complex, stabilizing it and allowing transcription past premature termination points. The NusB protein also binds boxA RNA individually and retains all specificity for boxA. However, NusE increases the affinity of RNA to NusB in the ternary complex, which contributes to efficient antitermination. To understand the molecular mechanism of the process, we have determined the structure of NusB from the thermophilic bacterium Aquifex aeolicus and studied the interaction of NusB and NusE. We characterize this binding interaction using NMR, isothermal titration calorimetry, gel filtration, and analytical ultracentrifugation. The binding site of NusE on NusB was determined using NMR chemical shift perturbation studies. We have also determined the NusE binding site in the ternary Escherichia coli NusB/NusE/boxA RNA complex and show that it is very similar to that in the NusB/NusE complex. There is one loop of residues (from 113 to 118 in NusB) affected by NusE binding in the ternary complex but not in the binary complex. This difference may be correlated to an increase in binding affinity of RNA for the NusB/NusE complex. Published by Elsevier Ltd. C1 [Das, Ranabir; Loss, Sandra; Li, Jess; Tarasov, Sergey; Byrd, R. Andrew; Altieri, Amanda S.] NCI, Struct & Biophys Lab, Frederick, MD 21702 USA. [Waugh, David S.] NCI, Macromol Crytallog Lab, Frederick, MD 21702 USA. [Wingfield, Paul T.] NIH, NIAMSD, Prot Express Lab, Bethesda, MD 20892 USA. RP Byrd, RA (reprint author), NCI, Struct & Biophys Lab, Frederick, MD 21702 USA. EM rabyrd@ncifcrf.gov; altieri@ncifcrf.gov RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 FU Intramural NIH HHS [Z01 BC010346-07]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 48 TC 13 Z9 13 U1 0 U2 6 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 FEB 22 PY 2008 VL 376 IS 3 BP 705 EP 720 DI 10.1016/j.jmb.2007.11.022 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 265JM UT WOS:000253354900010 PM 18177898 ER PT J AU Colt, JS Gunier, RB Metayer, C Nishioka, MG Bell, EM Reynolds, P Buffler, PA Ward, MH AF Colt, Joanne S. Gunier, Robert B. Metayer, Catherine Nishioka, Marcia G. Bell, Erin M. Reynolds, Peggy Buffler, Patricia A. Ward, Mary H. TI Household vacuum cleaners vs. the high-volume surface sampler for collection of carpet dust samples in epidemiologic studies of children SO ENVIRONMENTAL HEALTH LA English DT Article ID PESTICIDES; RISK; VALLEY; LEAD AB Background: Levels of pesticides and other compounds in carpet dust can be useful indicators of exposure in epidemiologic studies, particularly for young children who are in frequent contact with carpets. The high-volume surface sampler (HVS3) is often used to collect dust samples in the room in which the child had spent the most time. This method can be expensive and cumbersome, and it has been suggested that an easier method would be to remove dust that had already been collected with the household vacuum cleaner. However, the household vacuum integrates exposures over multiple rooms, some of which are not relevant to the child's exposure, and differences in vacuuming equipment and practices could affect the chemical concentration data. Here, we compare levels of pesticides and other compounds in dust from household vacuums to that collected using the HVS3. Methods: Both methods were used in 45 homes in California. HVS3 samples were collected in one room, while the household vacuum had typically been used throughout the home. The samples were analyzed for 64 organic compounds, including pesticides, polycyclic aromatic hydrocarbons, and polychlorinated biphenyls (PCBs), using GC/MS in multiple ion monitoring mode; and for nine metals using conventional microwave-assisted acid digestion combined with ICP/MS. Results: The methods agreed in detecting the presence of the compounds 77% to 100% of the time (median 95%). For compounds with less than 100% agreement, neither method was consistently more sensitive than the other. Median concentrations were similar for most analytes, and Spearman correlation coefficients were 0.60 or higher except for allethrin (0.15) and malathion (0.24), which were detected infrequently, and benzo(k) fluoranthene (0.55), benzo(a) pyrene (0.55), PCB 105 (0.54), PCB 118 (0.54), and PCB 138 (0.58). Assuming that the HVS3 method is the "gold standard," the extent to which the household vacuum cleaner method yields relative risk estimates closer to unity by increasing random measurement error varies by compound and depends on the method used to calculate relative risk. Conclusion: The household vacuum cleaner method appears to be a reasonable alternative to the HVS3 for detecting, ranking, and quantifying the concentrations of pesticides and other compounds in carpet dust. C1 [Colt, Joanne S.; Ward, Mary H.] NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Gunier, Robert B.; Reynolds, Peggy] No Calif Canc Ctr, Berkeley, CA 94704 USA. [Metayer, Catherine; Buffler, Patricia A.] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Nishioka, Marcia G.] Battelle Mem Inst, Columbus, OH 43201 USA. [Bell, Erin M.] SUNY Albany, Sch Publ Hlth, Dept Epidemiol, Rensselaer, NY 12144 USA. RP Colt, JS (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,MSC 7240, Bethesda, MD 20892 USA. EM coltj@mail.nih.gov; robert.gunier@nccc.org; cmetayer@berkeley.edu; nishiomg@battelle.org; emb05@health.state.ny.us; preynold@nccc.org; pab@berkeley.edu; wardm@mail.nih.gov OI Gunier, Robert/0000-0001-5485-9919 FU Intramural NIH HHS; NCI NIH HHS [5R01CA092683-03, N02CP11015, R01 CA092683]; NIEHS NIH HHS [P-42-ES-04705-18, P42 ES004705, R01 ES009137, R01ES009137] NR 20 TC 35 Z9 35 U1 2 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-069X J9 ENVIRON HEALTH-GLOB JI Environ. Health PD FEB 21 PY 2008 VL 7 AR 6 DI 10.1186/1476-069X-7-6 PG 9 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 272MU UT WOS:000253864300001 PM 18291036 ER PT J AU Lee, YS Pike, VW Hodoscek, M AF Lee, Yong-Sok Pike, Victor W. Hodoscek, Milan TI Identification of the transition states in the inversion of 1,4-benzodiazepines with the ab initio replica path method SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID PERIPHERAL BENZODIAZEPINE-RECEPTOR; PROTEIN 18 KDA; RING INVERSION; CONFORMATIONAL RECOGNITION; ROTATIONAL-ISOMERISM; QUANTUM; TRIFLUORONITROMETHANE; 1,5-BENZODIAZOCINES; ATROPISOMERS; DERIVATIVES AB The inversion of four 1,4-benzodiazepines was investigated with the ab initio "replica path method" with density functional theory at the B3LYP/6-31G* level. The reaction path constructed with this method for the inversion provides an approximate transition state (TS) geometry, which, upon further TS optimization, leads to the TS geometry characterized by a single vibrational frequency. 1,4-Benzodiazepines lacking a 5-phenyl ring have a single reaction path for the inversion with C-s symmetry at the TS. In contrast, the inversion of benzodiazepines with a 5-phenyl ring, such as the peripheral benzodiazepine receptor ligand 4'-chlorodiazepam (Ro5-4864) and its N-1-desmethyl analog (Ro5-2752), can proceed through multiple reaction paths having a TS with or without CS symmetry. Notably, the replica path method found a path connecting two asymmetric TSs of 4'-chlorodiazepam via a symmetrical TS, suggesting that these inversion paths can be readily crossed from one to another. The stabilization energies gained by 4'-chlorodiazepam and its N-1-desmethyl analog from the breaking of C-s symmetry at the TS were calculated to be 0.10 and 0.07 kcal/mol, respectively. The origin of the broken symmetry of C-s was traced to the coupling of the puckering of the diazepine ring with the rotation of the chlorophenyl ring. These results show the advantages of the replica path method for locating the TSs as well as for constructing the reaction paths for the inversion of 1,4-benzodiazepines. C1 [Lee, Yong-Sok] NIH, Ctr Informat Technol, Div Computat Biosci, Ctr Mol Modeling, Bethesda, MD 20892 USA. [Pike, Victor W.] NIMH, NIH, Mol Imaging Branch, Bethesda, MD 20892 USA. [Hodoscek, Milan] NHLBI, NIH, DHHS, Bethesda, MD 20892 USA. [Hodoscek, Milan] Natl Inst Chem, Ljubljana, Slovenia. RP Lee, YS (reprint author), NIH, Ctr Informat Technol, Div Computat Biosci, Ctr Mol Modeling, Bldg 12A,Room 2049, Bethesda, MD 20892 USA. EM Leeys@mail.nih.gov FU Intramural NIH HHS NR 40 TC 6 Z9 6 U1 0 U2 4 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 FEB 21 PY 2008 VL 112 IS 7 BP 1604 EP 1611 DI 10.1021/jp077738o PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 263MV UT WOS:000253222100029 PM 18229901 ER PT J AU Jakobsson, M Scholz, SW Scheet, P Gibbs, JR VanLiere, JM Fung, HC Szpiech, ZA Degnan, JH Wang, K Guerreiro, R Bras, JM Schymick, JC Hernandez, DG Traynor, BJ Simon-Sanchez, J Matarin, M Britton, A van de Leemput, J Rafferty, I Bucan, M Cann, HM Hardy, JA Rosenberg, NA Singleton, AB AF Jakobsson, Mattias Scholz, Sonja W. Scheet, Paul Gibbs, J. Raphael VanLiere, Jenna M. Fung, Hon-Chung Szpiech, Zachary A. Degnan, James H. Wang, Kai Guerreiro, Rita Bras, Jose M. Schymick, Jennifer C. Hernandez, Dena G. Traynor, Bryan J. Simon-Sanchez, Javier Matarin, Mar Britton, Angela van de Leemput, Joyce Rafferty, Ian Bucan, Maja Cann, Howard M. Hardy, John A. Rosenberg, Noah A. Singleton, Andrew B. TI Genotype, haplotype and copy-number variation in worldwide human populations SO NATURE LA English DT Article ID HUMAN GENOME; LINKAGE DISEQUILIBRIUM; GENETIC-STRUCTURE; POLYMORPHISMS; DISTANCE; AFRICA; MODEL AB Genome-wide patterns of variation across individuals provide a powerful source of data for uncovering the history of migration, range expansion, and adaptation of the human species. However, high-resolution surveys of variation in genotype, haplotype and copy number have generally focused on a small number of population groups(1-3). Here we report the analysis of high-quality genotypes at 525,910 single-nucleotide polymorphisms ( SNPs) and 396 copy-number-variable loci in a worldwide sample of 29 populations. Analysis of SNP genotypes yields strongly supported fine-scale inferences about population structure. Increasing linkage disequilibrium is observed with increasing geographic distance from Africa, as expected under a serial founder effect for the out-of-Africa spread of human populations. New approaches for haplotype analysis produce inferences about population structure that complement results based on unphased SNPs. Despite a difference from SNPs in the frequency spectrum of the copy-number variants (CNVs) detected-including a comparatively large number of CNVs in previously unexamined populations from Oceania and the Americas-the global distribution of CNVs largely accords with population structure analyses for SNP data sets of similar size. Our results produce new inferences about inter-population variation, support the utility of CNVs in human population-genetic research, and serve as a genomic resource for human-genetic studies in diverse worldwide populations. C1 [Jakobsson, Mattias; Scheet, Paul; VanLiere, Jenna M.; Szpiech, Zachary A.; Degnan, James H.; Rosenberg, Noah A.] Univ Michigan, Ctr Computat Med & Biol, Ann Arbor, MI 48109 USA. [Jakobsson, Mattias; Degnan, James H.; Rosenberg, Noah A.] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA. [Scheet, Paul; Rosenberg, Noah A.] Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. [Scholz, Sonja W.; Gibbs, J. Raphael; Fung, Hon-Chung; Guerreiro, Rita; Bras, Jose M.; Schymick, Jennifer C.; Hernandez, Dena G.; Traynor, Bryan J.; Simon-Sanchez, Javier; Matarin, Mar; Britton, Angela; van de Leemput, Joyce; Rafferty, Ian; Singleton, Andrew B.] NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. [Scholz, Sonja W.; Gibbs, J. Raphael; van de Leemput, Joyce; Hardy, John A.] UCL, Dept Mol Neurosci, London WC1N 3BG, England. [Scholz, Sonja W.; Gibbs, J. Raphael; van de Leemput, Joyce; Hardy, John A.] UCL, Reta Lila Weston Inst Neurol Studies, Inst Neurol, London WC1N 3BG, England. [Fung, Hon-Chung] Chang Gung Mem Hosp, Dept Neurol, Taipei 10591, Taiwan. [Fung, Hon-Chung] Chang Gung Univ, Coll Med, Taipei 10591, Taiwan. [Wang, Kai; Bucan, Maja] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Guerreiro, Rita; Bras, Jose M.] Univ Coimbra, Fac Med, Ctr Neurosci & Cell Biol, P-3004504 Coimbra, Portugal. [Schymick, Jennifer C.] Univ Oxford, John Radcliffe Hosp, Dept Clin Neurol, Oxford OX3 9DU, England. [Traynor, Bryan J.] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. [Simon-Sanchez, Javier] CSIC, Unidad Genet Mol, Dept Genom & Proteom, Inst Biomed Valencia, Valencia 46010, Spain. [Cann, Howard M.] Ctr Etud Polymorphisme Humain, Fdn Jean Dausset, F-75010 Paris, France. [Singleton, Andrew B.] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA. RP Rosenberg, NA (reprint author), Univ Michigan, Ctr Computat Med & Biol, Ann Arbor, MI 48109 USA. EM rnoah@umich.edu; singleta@mail.nih.gov RI Bras, Jose/D-3366-2009; Guerreiro, Rita/A-1327-2011; Jakobsson, Mattias/A-6116-2011; Gibbs, J. Raphael/A-3984-2010; Singleton, Andrew/C-3010-2009; Traynor, Bryan/G-5690-2010; Bras, Jose/A-1428-2011; Matarin, Mar/F-1771-2016; Hardy, John/C-2451-2009; Degnan, James/A-4489-2008 OI Jakobsson, Mattias/0000-0001-7840-7853; Matarin, Mar/0000-0002-4717-5735; Canzoniero, Jenna/0000-0003-1084-6918; Scholz, Sonja/0000-0002-6623-0429; FU Intramural NIH HHS; Medical Research Council [G0701075, MR/K01417X/1] NR 30 TC 503 Z9 517 U1 13 U2 74 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 21 PY 2008 VL 451 IS 7181 BP 998 EP 1003 DI 10.1038/nature06742 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 264TK UT WOS:000253313100050 PM 18288195 ER PT J AU Miller, FG Emanuel, EJ AF Miller, Franklin G. Emanuel, Ezekiel J. TI Perspective: Quality-improvement research, and informed consent. SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material C1 [Miller, Franklin G.; Emanuel, Ezekiel J.] NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Bioeth, Bldg 10, Bethesda, MD 20892 USA. NR 4 TC 73 Z9 73 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 21 PY 2008 VL 358 IS 8 BP 765 EP 767 DI 10.1056/NEJMp0800136 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 264AN UT WOS:000253257700001 PM 18287598 ER PT J AU Akbari, MR Malekzadeh, R Nasrollahzadeh, D Amanian, D Islami, F Li, S Zandvakili, I Shakeri, R Sotoudeh, M Aghceli, K Salahi, R Pourshams, A Semnani, S Boffetta, P Dawsey, SM Ghadirian, P Narod, SA AF Akbari, M. R. Malekzadeh, R. Nasrollahzadeh, D. Amanian, D. Islami, F. Li, S. Zandvakili, I. Shakeri, R. Sotoudeh, M. Aghceli, K. Salahi, R. Pourshams, A. Semnani, S. Boffetta, P. Dawsey, S. M. Ghadirian, P. Narod, S. A. TI Germline BRCA2 mutations and the risk of esophageal squamous cell carcinoma SO ONCOGENE LA English DT Article DE esophageal squamous cell carcinoma; Turkmen population; BRCA2; K3326X; Fanconi anemia pathway ID POLYMORPHIC STOP CODON; FANCONI-ANEMIA; CANCER SUSCEPTIBILITY; BREAST-CANCER; GENETIC SUSCEPTIBILITY; PANCREATIC-CANCER; ALLELIC LOSS; CROSS-LINKS; DNA-BINDING; IRAN AB The incidence of esophageal squamous cell carcinoma (ESCC) is very high among the Turkmen population of Iran. Family studies suggest a genetic component to the disease. Turkmen are ethnically homogenous and are well suited for genetic studies. A previous study from China suggested that BRCA2 might play a role in the etiology of ESCC. We screened for mutations in the coding region of the BRCA2 gene in the germline DNA of 197 Turkmen patients with ESCC. A nonsense variant, K3326X, was identified in 9 of 197 cases (4.6%) vs 2 of 254 controls (0.8%) (OR = 6.0, 95% CI = 1.3-28; P = 0.01). This mutation leads to the loss of the C-terminal domain of the BRCA2 protein, a part of the region of interaction with the FANCD2 protein. We observed nine other BRCA2 variants in single cases only, including two deletions, and seven missense mutations. Six of these were judged to be pathogenic. In total, a suspicious deleterious BRCA2 variant was identified in 15 of 197 ESCC cases (7.6%). C1 [Akbari, M. R.; Malekzadeh, R.; Nasrollahzadeh, D.; Amanian, D.; Islami, F.; Shakeri, R.; Sotoudeh, M.; Aghceli, K.; Pourshams, A.] Univ Tehran, Shariati Hosp, Digest Dis Res Ctr, Tehran 14114, Iran. [Akbari, M. R.; Li, S.; Zandvakili, I.; Narod, S. A.] Univ Toronto, Womens Coll Res Inst, Toronto, ON, Canada. [Akbari, M. R.] Univ Toronto, Fac Med, Inst Med Sci, Toronto, ON, Canada. [Semnani, S.] Golestan Univ Med Sci, Res Ctr Gastroentrol, Gorgan, Iran. [Boffetta, P.] Int Agcy Res Canc, F-69372 Lyon, France. [Dawsey, S. M.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Ghadirian, P.] Univ Montreal, CHUM Hotel Dieu, Epidemiol Res Unit Res Ctr, Montreal, PQ, Canada. RP Narod, SA (reprint author), Univ Tehran, Shariati Hosp, Digest Dis Res Ctr, Tehran 14114, Iran. EM malek@ams.ac.ir RI Zandvakili, Inuk/C-8496-2011; Semnani, Shahryar/N-2270-2016; OI Semnani, Shahryar/0000-0002-8768-6142; , Ramin/0000-0003-0487-3629; Malekzadeh, Reza/0000-0003-1043-3814 NR 46 TC 25 Z9 27 U1 3 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 21 PY 2008 VL 27 IS 9 BP 1290 EP 1296 DI 10.1038/sj.onc.1210739 PG 7 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 266BT UT WOS:000253407000011 PM 17724471 ER PT J AU Tanegashima, K Zhao, H Dawid, IB AF Tanegashima, Kosuke Zhao, Hui Dawid, Igor B. TI WGEF activates Rho in the Wnt-PCP pathway and controls convergent extension in Xenopus gastrulation SO EMBO JOURNAL LA English DT Article DE convergent extension; gastrulation; GEF; Wnt-PCP; Xenopus ID NUCLEOTIDE-EXCHANGE FACTORS; PLANAR CELL POLARIZATION; VERTEBRATE GASTRULATION; EMBRYONIC-DEVELOPMENT; ACTIN CYTOSKELETON; SIGNALING PATHWAY; MOVEMENTS; GTPASES; LAEVIS; RAC AB The Wnt-PCP (planar cell polarity, PCP) pathway regulates cell polarity and convergent extension movements during axis formation in vertebrates by activation of Rho and Rac, leading to the re-organization of the actin cytoskeleton. Rho and Rac activation require guanine nucleotide-exchange factors ( GEFs), but the identity of the GEF involved in Wnt-PCP-mediated convergent extension is unknown. Here we report the identification of the weak-similarity GEF ( WGEF) gene by a microarray-based screen for notochord enriched genes, and show that WGEF is involved in Wnt-regulated convergent extension. Overexpression of WGEF activated RhoA and rescued the suppression of convergent extension by dominant-negative Wnt-11, whereas depletion of WGEF led to suppression of convergent extension that could be rescued by RhoA or Rho-associated kinase activation. WGEF protein preferentially localized at the plasma membrane, and Frizzled-7 induced colocalization of Dishevelled and WGEF. WGEF protein can bind to Dishevelled and Daam-1, and deletion of the Dishevelled-binding domain generates a hyperactive from of WGEF. These results indicate that WGEF is a component of the Wnt-PCP pathway that connects Dishevelled to Rho activation. C1 [Tanegashima, Kosuke; Zhao, Hui; Dawid, Igor B.] NICHHD, NIH, Genet Mol Lab, Bethesda, MD 20892 USA. RP Dawid, IB (reprint author), NICHHD, NIH, Genet Mol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM idawid@mail.nih.gov RI Zhao, Hui/B-8429-2016 FU Intramural NIH HHS NR 51 TC 56 Z9 59 U1 1 U2 9 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 20 PY 2008 VL 27 IS 4 BP 606 EP 617 DI 10.1038/emboj.2008.9 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 266CP UT WOS:000253409300003 PM 18256687 ER PT J AU Iha, H Peloponese, JM Verstrepen, L Zapart, G Ikeda, F Smith, CD Starost, MF Yedavalli, V Heyninck, K Dikic, I Beyaert, R Jeang, KT AF Iha, Hidekatsu Peloponese, Jean-Marie Verstrepen, Lynn Zapart, Grzegorz Ikeda, Fumiyo Smith, C. Dahlem Starost, Matthew F. Yedavalli, Venkat Heyninck, Karen Dikic, Ivan Beyaert, Rudi Jeang, Kuan-Teh TI Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-kappa B activation SO EMBO JOURNAL LA English DT Article DE A20; NF-kappa B; Tax; TAX1BP1; TRAF6 ID FINGER PROTEIN A20; UBIQUITIN; KINASE; RECEPTOR; BINDS; STRATEGIES; INHIBITOR; REGULATOR; RESPONSES; DOMAINS AB Nuclear factor kappa B (NF-kappa B) is a key mediator of inflammation. Unchecked NF-kappa B signalling can engender autoimmune pathologies and cancers. Here, we show that Tax1-binding protein 1 ( TAX1BP1) is a negative regulator of TNF-alpha- and IL-1 beta-induced NF-kappa B activation and that binding to mono- and polyubiquitin by a ubiquitin-binding Zn finger domain in TAX1BP1 is needed for TRAF6 association and NF-kappa B inhibition. Mice genetically knocked out for TAX1BP1 are born normal, but develop age-dependent inflammatory cardiac valvulitis, die prematurely, and are hypersensitive to low doses of TNF-alpha and IL-1 beta. TAX1BP1(-/-) cells are more highly activated for NF-kappa B than control cells when stimulated with TNF-alpha or IL-1 beta. Mechanistically, TAX1BP1 acts in NF-kappa B signalling as an essential adaptor between A20 and its targets. C1 [Iha, Hidekatsu; Peloponese, Jean-Marie; Yedavalli, Venkat; Jeang, Kuan-Teh] NIAID, NIH, Mol Microbiol Lab, Mol Virol Sect, Bethesda, MD 20892 USA. [Verstrepen, Lynn; Heyninck, Karen; Beyaert, Rudi] Univ Ghent VIB, Dept Mol Biomed Res, Unit Mol Signal Transduct Inflammat, B-9052 Ghent, Belgium. [Ikeda, Fumiyo; Dikic, Ivan] Univ Frankfurt, Sch Med, Inst Biochem 2, Frankfurt, Germany. [Smith, C. Dahlem] SAIC Frederick Inc, NCI FCR, Pathol Histotechnol Lab, Frederick, MD USA. [Starost, Matthew F.] NIH, Div Vet Resources, Bethesda, MD 20892 USA. [Iha, Hidekatsu] Oita Univ, Fac Med, Dept Infect Dis, Hasama Yufu, Japan. RP Jeang, KT (reprint author), NIAID, NIH, Mol Microbiol Lab, Mol Virol Sect, Bldg 4,Room 306,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kjeang@niaid.nih.gov RI Jeang, Kuan-Teh/A-2424-2008; Beyaert, Rudi/B-2589-2009; Dikic, Ivan/O-4650-2015; OI Dikic, Ivan/0000-0001-8156-9511; Iha, Hidekatsu/0000-0002-0999-5636; Ikeda, Fumiyo/0000-0003-0407-2768 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 43 TC 88 Z9 89 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 20 PY 2008 VL 27 IS 4 BP 629 EP 641 DI 10.1038/emboj.2008.5 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 266CP UT WOS:000253409300005 PM 18239685 ER PT J AU Hadley, DW Jenkins, JF Steinberg, SM Liewehr, D Moller, S Martin, JC Calzone, KA Soballe, PW Kirsch, IR AF Hadley, Donald W. Jenkins, Jean F. Steinberg, Seth M. Liewehr, David Moller, Stephanie Martin, Jean C. Calzone, Kathleen A. Soballe, Peter W. Kirsch, Ilan R. TI Perceptions of cancer risks and predictors of colon and endometrial cancer screening in women undergoing genetic testing for Lynch syndrome SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID NONPOLYPOSIS COLORECTAL-CANCER; INHERITED PREDISPOSITION; FOLLOW-UP; HEREDITARY; RECOMMENDATIONS; INDIVIDUALS; MUTATIONS; CARE AB Purpose Lynch syndrome poses multiple cancer risks, yet attention has focused on screening for colorectal cancer. Estimated risks for endometrial cancer equal risks for colorectal cancer. This study (1) evaluated women's perceived risks for cancers, (2) compared endometrial cancer screening and colonoscopy, and (3) identified predictors of screening before and after genetic testing. Patients and Methods Sixty-five adult women at 50% risk for carrying a cancer-predisposing mutation, without a history of endometrial cancer or hysterectomy, participated in genetic counseling and received unequivocal genetic test results for Lynch syndrome. Participants completed questionnaires before and after receipt of genetic results. Results Pretest, perceived risks for colon cancer were significantly higher than for extracolonic cancers (P<.0001). Use of colonoscopy was significantly higher (P=.006) than endometrial cancer screening. Post-test, carriers demonstrated a significant (P<.0001) increase in their perceived risk for extracolonic cancers and increased both colonoscopy (P=.79) and endometrial cancer screening (P=.11). Mutation status, age, perceived likelihood of carrying a mutation, and communication of test results to their physician independently predicted cancer screening at follow-up. Conclusion Women in families with Lynch syndrome are less aware of their risks for extracolonic cancers and undergo endometrial cancer screening significantly less often than colonoscopy before genetic counseling. Given the significantly increased risks for endometrial and ovarian cancers and the mortality associated with ovarian cancer, additional efforts to inform families of cancer risks and screening recommendations seem prudent. Physicians play a critical role in ensuring appropriate cancer screening in women with Lynch syndrome. C1 [Hadley, Donald W.] Natl Inst Hlth, Ctr Canc Res, Natl Canc Inst, Biostat & Data Management Sect, Bethesda, MD 20892 USA. Social & Behav Res Branch, Bethesda, MD USA. NHGRI, Off Director, Bethesda, MD USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. RP Hadley, DW (reprint author), Natl Inst Hlth, Ctr Canc Res, Natl Canc Inst, Biostat & Data Management Sect, 31 Ctr Dr,MSC 2073,Bldg 31,Room B1B37F, Bethesda, MD 20892 USA. EM dhadley@mail.nih.gov FU Intramural NIH HHS NR 18 TC 21 Z9 21 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2008 VL 26 IS 6 BP 948 EP 954 DI 10.1200/JCO.2007.13.055 PG 7 WC Oncology SC Oncology GA 276XU UT WOS:000254177800023 PM 18281669 ER PT J AU Eberhard, DA Giaccone, G Johnson, BE AF Eberhard, David A. Giaccone, Giuseppe Johnson, Bruce E. TI Biomarkers of response to epidermal growth factor receptor inhibitors in non-small-cell lung cancer working group: Standardization for use in the clinical trial setting SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID IN-SITU-HYBRIDIZATION; HER-2/NEU GENE AMPLIFICATION; SOUTHWEST-ONCOLOGY-GROUP; PHASE-II TRIAL; BREAST-CANCER; COPY NUMBER; EGFR MUTATIONS; BRONCHIOLOALVEOLAR-CARCINOMA; PROTEIN OVEREXPRESSION; INCREASED SENSITIVITY AB The body of literature on the correlations between molecular assessments and patient outcomes after treatment with epidermal growth factor receptor (EGFR) inhibitors continues to grow. It will be important in the future to determine how to most effectively integrate molecular assays that assess the likelihood of therapeutic benefit into clinical practice. Although EGFR-targeted therapies such as erlotinib have been approved for use without molecular testing, immunohistochemistry, fluorescence in situ hybridization, and mutational analyses of the EGFR gene have all been proposed as candidates to help predict response or survival benefit from EGFR-targeted therapy in patients with non-small-cell lung cancer (NSCLC). Further prospective validation from ongoing randomized studies will be needed to fully determine which assays are best to help predict patient outcome. In addition, it will be critical for these assays to undergo standardization before widespread clinical use. The Molecular Assays in NSCLC Working Group, under the sponsorship of Genentech Inc, Roche Pharmaceuticals, and OSI Pharmaceuticals, Inc, was convened to evaluate the available molecular assays for use in the clinical trial setting and provide recommendations for application and interpretation of these tests for future clinical trials. Recommendations of the Molecular Assays in NSCLC Working Group for the use of EGFR molecular assays are presented and include guidelines for tissue storage, handling, and processing. Recommendations for the standardization of molecular assays are also discussed. C1 [Johnson, Bruce E.] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. RP Johnson, BE (reprint author), Dana Farber Canc Inst, Dept Med Oncol, 44 Binney St,Dana 1234, Boston, MA 02115 USA. EM bejohnson@partners.org RI Giaccone, Giuseppe/E-8297-2017 OI Giaccone, Giuseppe/0000-0002-5023-7562 NR 74 TC 209 Z9 221 U1 0 U2 4 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2008 VL 26 IS 6 BP 983 EP 994 DI 10.1200/JCO.2007.12.9858 PG 12 WC Oncology SC Oncology GA 276XU UT WOS:000254177800027 PM 18281673 ER PT J AU Landen, CN Birrer, MJ Sood, AK AF Landen, Charles N., Jr. Birrer, Michael J. Sood, Anil K. TI Early events in the pathogenesis of epithelial ovarian cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID ENDOTHELIAL GROWTH-FACTOR; VASCULAR-PERMEABILITY FACTOR; GENE-EXPRESSION PROFILES; FALLOPIAN-TUBE CARCINOMA; INTERFERING RNA DELIVERY; K-RAS PROTOONCOGENE; ALPHA-V-INTEGRIN; SEROUS CARCINOMA; LOW-GRADE; PRIMARY PERITONEAL AB Ovarian carcinogenesis, as in most cancers, involves multiple genetic alterations. A great deal has been learned about proteins and pathways important in the early stages of malignant transformation and metastasis, as derived from studies of individual tumors, microarray data, animal models, and inherited disorders that confer susceptibility. However, a full understanding of the earliest recognizable events in epithelial ovarian carcinogenesis is limited by the lack of a well-defined premalignant state common to all ovarian subtypes and by the paucity of data from early-stage cancers. Evidence suggests that ovarian cancers can progress both through a stepwise mutation process (low-grade pathway) and through greater genetic instability that leads to rapid metastasis without an identifiable precursor lesion (high-grade pathway). In this review, we discuss many of the genetic and molecular disorders in each key process that is altered in cancer cells, and we present a model of ovarian pathogenesis that incorporates the role of tumor cell mutations and factors in the host microenvironment important to tumor initiation and progression. C1 [Sood, Anil K.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. [Sood, Anil K.] Univ Texas Houston, MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Sood, AK (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Dept Gynecol Oncol, 1155 Herman Pressler,Unit 1362, Houston, TX 77030 USA. EM asood@mdanderson.org FU Intramural NIH HHS; NCI NIH HHS [CA 10929801, CA 11079301, P50 CA083639]; NICHD NIH HHS [5K12HD00849] NR 148 TC 245 Z9 250 U1 1 U2 24 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2008 VL 26 IS 6 BP 995 EP 1005 DI 10.1200/JCO.2006.07.9970 PG 11 WC Oncology SC Oncology GA 276XU UT WOS:000254177800028 PM 18195328 ER PT J AU Li, PX Evans, CD Wu, YZ Cao, B Hamel, E Joullie, MM AF Li, Pixu Evans, Cory D. Wu, Yongzhong Cao, Bin Hamel, Ernest Joullie, Madeleine M. TI Evolution of the total syntheses of ustiloxin natural products and their analogues SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ASYMMETRIC ALLYLIC ALKYLATION; 14-MEMBERED CYCLOPEPTIDE ALKALOIDS; RING-OPENING REACTION; FALSE SMUT BALLS; ARYL ETHERS; PHOMOPSIN-A; HEXAPEPTIDE MYCOTOXIN; MICROTUBULE DYNAMICS; ANTIMITOTIC AGENTS; PHENOL DERIVATIVES AB dUstiloxins A-F are antimitotic heterodetic cyclopeptides containing a 13-membered cyclic core structure with a synthetically challenging chiral tertiary alkyl-aryl ether linkage. The first total synthesis of ustiloxin D was achieved in 31 linear steps using an S(N)Ar reaction. An NOE study of this synthetic product showed that ustiloxin D existed as a single atropisomer. Subsequently, highly concise and convergent syntheses of ustiloxins D and F were developed by utilizing a newly discovered ethynyl aziridine ring-opening reaction in a longest linear sequence of 15 steps. The approach was further optimized to achieve a better macrolactamization strategy. Ustiloxins D, F, and eight analogues (14-MeO-ustiloxin D, four analogues with different amino acid residues at the C-6 position, and three (9R, 10S)-epi-ustiloxin analogues) were prepared via the second-gene ration route. Evaluation of these compounds as inhibitors of tubulin polymerization demonstrated that variation at the C-6 position is tolerated to a certain extent. In contrast, the S configuration of the C-9 methylamino group and a free phenolic hydroxyl group are essential for inhibition of tubulin polymerization. C1 [Li, Pixu; Evans, Cory D.; Wu, Yongzhong; Cao, Bin; Joullie, Madeleine M.] Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. [Hamel, Ernest] NIH, NCI, Div Canc Treatment & Diag, Dev Therapeut Program,Toxicol & Pharmacol Branch, Frederick, MD 21702 USA. RP Joullie, MM (reprint author), Univ Penn, Dept Chem, 231 S 34th St, Philadelphia, PA 19104 USA. FU NCI NIH HHS [CA-40081, R01 CA040081, R01 CA040081-19] NR 76 TC 32 Z9 41 U1 3 U2 32 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 FEB 20 PY 2008 VL 130 IS 7 BP 2351 EP 2364 DI 10.1021/ja710363p PG 14 WC Chemistry, Multidisciplinary SC Chemistry GA 262UK UT WOS:000253173300052 PM 18229928 ER PT J AU Edgerly, M Fojo, T AF Edgerly, Maureen Fojo, Tito TI Is there room for improvement in adverse event reporting in the era of targeted therapies? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material AB The Common Terminology Criteria for Adverse Events (CTCAE), version 3.0, and its predecessors, the Common Toxicity Criteria (CTC) versions 1.0 and 2.0, were developed under the direction of the Cancer Therapy Evaluation Program of the National Cancer Institute (NCI) in an effort to provide standard language for reporting adverse events that occur in NCI-sponsored clinical trials. Each successive version of the CTC has improved the accuracy, precision, and completeness of the criteria in an effort to standardize reporting. We believe that the current version of the CTCAE cannot adequately code the subacute adverse events that commonly occur with today's targeted therapies. C1 [Edgerly, Maureen; Fojo, Tito] Natl Canc Ctr, Canc Res Ctr, Bethesda, MD USA. RP Fojo, T (reprint author), Bldg 10,Rm 12N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov NR 5 TC 32 Z9 34 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 FEB 20 PY 2008 VL 100 IS 4 BP 240 EP 242 DI 10.1093/jnci/djm324 PG 3 WC Oncology SC Oncology GA 271OB UT WOS:000253796600006 PM 18270340 ER PT J AU Landi, MT Dracheva, T Rotunno, M Figueroa, JD Liu, H Dasgupta, A Mann, FE Fukuoka, J Hames, M Bergen, AW Murphy, SE Yang, P Pesatori, AC Consonni, D Bertazzi, PA Wacholder, S Shih, JH Caporaso, NE Jen, J AF Landi, Maria Teresa Dracheva, Tatiana Rotunno, Melissa Figueroa, Jonine D. Liu, Huaitian Dasgupta, Abhijit Mann, Felecia E. Fukuoka, Junya Hames, Megan Bergen, Andrew W. Murphy, Sharon E. Yang, Ping Pesatori, Angela C. Consonni, Dario Bertazzi, Pier Alberto Wacholder, Sholom Shih, Joanna H. Caporaso, Neil E. Jen, Jin TI Gene Expression Signature of Cigarette Smoking and Its Role in Lung Adenocarcinoma Development and Survival SO PLOS ONE LA English DT Article AB Background: Tobacco smoking is responsible for over 90% of lung cancer cases, and yet the precise molecular alterations induced by smoking in lung that develop into cancer and impact survival have remained obscure. Methodology/Principal Findings: We performed gene expression analysis using HG-U133A Affymetrix chips on 135 fresh frozen tissue samples of adenocarcinoma and paired noninvolved lung tissue from current, former and never smokers, with biochemically validated smoking information. ANOVA analysis adjusted for potential confounders, multiple testing procedure, Gene Set Enrichment Analysis, and GO-functional classification were conducted for gene selection. Results were confirmed in independent adenocarcinoma and non-tumor tissues from two studies. We identified a gene expression signature characteristic of smoking that includes cell cycle genes, particularly those involved in the mitotic spindle formation (e. g., NEK2, TTK, PRC1). Expression of these genes strongly differentiated both smokers from non-smokers in lung tumors and early stage tumor tissue from non-tumor tissue (p<0.001 and fold-change >1.5, for each comparison), consistent with an important role for this pathway in lung carcinogenesis induced by smoking. These changes persisted many years after smoking cessation. NEK2 (p<0.001) and TTK (p = 0.002) expression in the noninvolved lung tissue was also associated with a 3-fold increased risk of mortality from lung adenocarcinoma in smokers. Conclusions/Significance: Our work provides insight into the smoking-related mechanisms of lung neoplasia, and shows that the very mitotic genes known to be involved in cancer development are induced by smoking and affect survival. These genes are candidate targets for chemoprevention and treatment of lung cancer in smokers. C1 [Landi, Maria Teresa; Rotunno, Melissa; Figueroa, Jonine D.; Dasgupta, Abhijit; Bergen, Andrew W.; Wacholder, Sholom; Caporaso, Neil E.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. [Dracheva, Tatiana; Mann, Felecia E.; Fukuoka, Junya; Hames, Megan; Jen, Jin] NCI, Ctr Canc Res, NIH, DHHS, Bethesda, MD USA. [Figueroa, Jonine D.] NIH, NCI, Canc Prevent Fellowship, DHHS, Bethesda, MD USA. [Liu, Huaitian; Shih, Joanna H.] NCI, Div Canc Treatment & Diagnosis, NIH, DHHS, Bethesda, MD USA. [Murphy, Sharon E.] Univ Minnesota, Canc Ctr, Minneapolis, MN USA. [Yang, Ping] Mayo Clin, Dept Hlth Sci, Rochester, MN USA. [Pesatori, Angela C.; Consonni, Dario; Bertazzi, Pier Alberto] Univ Milan, Fdn OM Policlin, Milan, Italy. RP Landi, MT (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. EM landim@mail.nih.gov RI bertazzi, pietro alberto/D-5039-2017; OI bertazzi, pietro alberto/0000-0003-3475-2449; Bergen, Andrew/0000-0002-1237-7644; pesatori, angela/0000-0002-0261-3252 FU Intramural Research Program, NIH; National Cancer Institute, Division of Cancer Epidemiology and Genetics [NIH-R01-84354, Cancer Prevention Fellowship]; Center for Cancer Research FX This study was supported by the Intramural Research Program of NIH, National Cancer Institute, Division of Cancer Epidemiology and Genetics and the Center for Cancer Research, and from the NIH-R01-84354 grant to P.Y. J.F. was supported by the Cancer Prevention Fellowship Program, National Cancer Institute. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 30 TC 212 Z9 218 U1 1 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 20 PY 2008 VL 3 IS 2 AR e1651 DI 10.1371/journal.pone.0001651 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 367XR UT WOS:000260586400044 PM 18297132 ER PT J AU Lee, JY Muenzberg, H Gavrilova, O Reed, JA Berryman, D Villanueva, EC Louis, GW Leinninger, GM Bertuzzi, S Seeley, RJ Robinson, GW Myers, MG Hennighausen, L AF Lee, Ji-Yeon Muenzberg, Heike Gavrilova, Oksana Reed, Jacquelyn A. Berryman, Darlene Villanueva, Eneida C. Louis, Gwendolyn W. Leinninger, Gina M. Bertuzzi, Stefano Seeley, Randy J. Robinson, Gertraud W. Myers, Martin G., Jr. Hennighausen, Lothar TI Loss of Cytokine-STAT5 Signaling in the CNS and Pituitary Gland Alters Energy Balance and Leads to Obesity SO PLOS ONE LA English DT Article AB Signal transducers and activators of transcription (STATs) are critical components of cytokine signaling pathways. STAT5A and STAT5B (STAT5), the most promiscuous members of this family, are highly expressed in specific populations of hypothalamic neurons in regions known to mediate the actions of cytokines in the regulation of energy balance. To test the hypothesis that STAT5 signaling is essential to energy homeostasis, we used Cre-mediated recombination to delete the Stat5 locus in the CNS. Mutant males and females developed severe obesity with hyperphagia, impaired thermal regulation in response to cold, hyperleptinemia and insulin resistance. Furthermore, central administration of GM-CSF mediated the nuclear accumulation of STAT5 in hypothalamic neurons and reduced food intake in control but not in mutant mice. These results demonstrate that STAT5 mediates energy homeostasis in response to endogenous cytokines such as GM-CSF. C1 [Lee, Ji-Yeon; Robinson, Gertraud W.; Hennighausen, Lothar] NIDDK, Lab Genet & Physiol, Natl Inst Hlth, Bethesda, MD 20892 USA. [Muenzberg, Heike; Villanueva, Eneida C.; Louis, Gwendolyn W.; Leinninger, Gina M.; Myers, Martin G., Jr.] Univ Michigan, Dept Med & Mol & Integrat Physiol, Ann Arbor, MI 48109 USA. [Gavrilova, Oksana] NIDDK, Mouse Metab Core Facil, Natl Inst Hlth, Bethesda, MD USA. [Reed, Jacquelyn A.; Seeley, Randy J.] Univ Cincinnati, Cincinnati, OH USA. [Berryman, Darlene] Ohio Univ, Athens, OH 45701 USA. [Bertuzzi, Stefano] Natl Inst Neurol Disorders & Stroke, Mammalian Dev Sect, Natl Inst Hlth, Bethesda, MD USA. RP Lee, JY (reprint author), NIDDK, Lab Genet & Physiol, Natl Inst Hlth, Bethesda, MD 20892 USA. EM hennighausen@nih.gov RI Robinson, Gertraud/I-2136-2012; OI Seeley, Randy/0000-0002-3721-5625 FU Federal Government of the USA; National Institutes of Health FX This work was funded by the Federal Government of the USA (intramural and extramural programs of the National Institutes of Health). NR 29 TC 40 Z9 45 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 20 PY 2008 VL 3 IS 2 AR e1639 DI 10.1371/journal.pone.0001639 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 367XR UT WOS:000260586400032 PM 18286195 ER PT J AU Onaivi, ES Ishiguro, H Gong, JP Patel, S Meozzi, PA Myers, L Perchuk, A Mora, Z Tagliaferro, PA Gardner, E Brusco, A Akinshola, BE Hope, B Lujilde, J Inada, T Iwasaki, S Macharia, D Teasenfitz, L Arinami, T Uhl, GR AF Onaivi, Emmanuel S. Ishiguro, Hiroki Gong, Jian-Ping Patel, Sejal Meozzi, Paul A. Myers, Lester Perchuk, Alex Mora, Zoila Tagliaferro, Patricia A. Gardner, Eileen Brusco, Alicia Akinshola, B. Emmanuel Hope, Bruce Lujilde, Javier Inada, Toshiya Iwasaki, Shinya Macharia, David Teasenfitz, Lindsey Arinami, Tadao Uhl, George R. TI Brain Neuronal CB2 Cannabinoid Receptors in Drug Abuse and Depression: From Mice to Human Subjects SO PLOS ONE LA English DT Article ID ENDOCANNABINOID SYSTEM; EXPRESSION; GENE; DISORDERS; ALCOHOL; ANXIETY; CELLS; RISK; PAIN AB Background: Addiction and major depression are mental health problems associated with stressful events in life with high relapse and reoccurrence even after treatment. Many laboratories were not able to detect the presence of cannabinoid CB2 receptors (CB2-Rs) in healthy brains, but there has been demonstration of CB2-R expression in rat microglial cells and other brain associated cells during inflammation. Therefore, neuronal expression of CB2-Rs had been ambiguous and controversial and its role in depression and substance abuse is unknown. Methodology/Principal Findings: In this study we tested the hypothesis that genetic variants of CB2 gene might be associated with depression in a human population and that alteration in CB2 gene expression may be involved in the effects of abused substances including opiates, cocaine and ethanol in rodents. Here we demonstrate that a high incidence of (Q63R) but not (H316Y) polymorphism in the CB2 gene was found in Japanese depressed subjects. CB2-Rs and their gene transcripts are expressed in the brains of naive mice and are modulated following exposure to stressors and administration of abused drugs. Mice that developed alcohol preference had reduced CB2 gene expression and chronic treatment with JWH015 a putative CB2-R agonist, enhanced alcohol consumption in stressed but not in control mice. The direct intracerebroventricular microinjection of CB2 anti-sense oligonucleotide into the mouse brain reduced mouse aversions in the plus-maze test, indicating the functional presence of CB2-Rs in the brain that modifies behavior. We report for the using electron microscopy the sub cellular localization of CB2-Rs that are mainly on post-synaptic elements in rodent brain. Conclusions/Significance: Our data demonstrate the functional expression of CB2-Rs in brain that may provide novel targets for the effects of cannabinoids in depression and substance abuse disorders beyond neuro-immunocannabinoid activity. C1 [Onaivi, Emmanuel S.; Patel, Sejal; Meozzi, Paul A.; Myers, Lester; Perchuk, Alex; Mora, Zoila; Gardner, Eileen; Macharia, David; Teasenfitz, Lindsey] William Paterson Univ, Dept Biol, Wayne, NJ 07470 USA. [Onaivi, Emmanuel S.; Ishiguro, Hiroki; Gong, Jian-Ping; Iwasaki, Shinya; Arinami, Tadao; Uhl, George R.] Natl Inst Drug Abuse, Mol Neurobiol Branch, Intramural Res Program, Natl Inst Hlth, Bethesda, MD USA. [Ishiguro, Hiroki] Univ Tsukuba, Dept Med Genet, Inst Basic Med Sci, Tsukuba, Ibaraki 305, Japan. [Tagliaferro, Patricia A.; Brusco, Alicia; Lujilde, Javier] Univ Buenos Aires, Fac Med, Buenos Aires, DF, Argentina. [Akinshola, B. Emmanuel] Howard Univ, Dept Pharmacol, Washington, DC 20059 USA. [Hope, Bruce] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, Natl Inst Hlth, Bethesda, MD USA. [Inada, Toshiya] Teikyo Univ, Chiba Med Ctr, Chiba, Japan. RP Onaivi, ES (reprint author), William Paterson Univ, Dept Biol, Wayne, NJ 07470 USA. EM OnaiviE@wpunj.edu RI Hope, Bruce/A-9223-2010 OI Hope, Bruce/0000-0001-5804-7061 FU NIDA/IRP; William Paterson University center for research; Public interest trust FX This work was supported in part by NIDA/IRP and ESO acknowledges financial support from William Paterson University center for research and the Dean, Dr. DeYoung, student worker fund. HI and TA acknowledge Public interest trust, Research aid fund for stress related diseases with commemoration of Imaikimi. The sponsors or funders had no role in the design and conduct of the study, in the collection, analysis, and interpretation of the data, and in the preparation, review, or approval of the manuscript. NR 36 TC 102 Z9 106 U1 1 U2 13 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 FEB 20 PY 2008 VL 3 IS 2 AR e1640 DI 10.1371/journal.pone.0001640 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 367XR UT WOS:000260586400033 PM 18286196 ER PT J AU Wang, S Kennedy, JS West, K Montefiori, DC Coley, S Lawrence, J Shen, S Green, S Rothman, AL Ennis, FA Arthos, J Pal, R Markham, P Lu, S AF Wang, Shixia Kennedy, Jeffrey S. West, Kim Montefiori, David C. Coley, Scott Lawrence, John Shen, Siyuan Green, Sharone Rothman, Alan L. Ennis, Francis A. Arthos, James Pal, Ranajit Markham, Phillip Lu, Shan TI Cross-subtype antibody and cellular immune responses induced by a polyvalent DNA prime-protein boost HIV-1 vaccine in healthy human volunteers SO VACCINE LA English DT Article DE HIV-1; DNA vaccine; recombinant protein vaccine; phase I clinical trial; prime-boost ID HUMAN-IMMUNODEFICIENCY-VIRUS; RECOMBINANT GLYCOPROTEIN-120 VACCINE; NEUTRALIZING ANTIBODIES; RHESUS MACAQUES; PLASMID DNA; IMMUNOGENICITY EVALUATION; GENERATE ANTIBODIES; CANDIDATE VACCINE; TYPE-1 INFECTION; PHASE-1 SAFETY AB An optimally effective AIDS vaccine would likely require the induction of both neutralizing antibody and cell-mediated immune responses, which has proven difficult to obtain in previous clinical trials. Here we report on the induction of Human Immunodeficiency Virus Type-1 (HIV-1)-specific immune responses in healthy adult volunteers that received the multi-gene, polyvalent, DNA prime-protein boost HIV-1 vaccine formulation, DP6-001, in a Phase I clinical. trial conducted in healthy adult volunteers of both genders. Robust cross-subtype HIV-1-specific T cell responses were detected in IFN gamma ELISPOT assays. Furthermore, we detected high titer serum antibody responses that recognized a wide range of primary HIV-1 Env antigens and also neutralized pseudotyped viruses that express the primary Env antigens from multiple HIV-1 subtypes. These findings demonstrate that the DNA prime-protein boost approach is an effective immunization method to elicit both humoral and cell-mediated immune responses in humans, and that a potyvatent Env formulation could generate broad immune responses against HIV-1 viruses with diverse genetic backgrounds. (c) 2008 Elsevier Ltd. All rights reserved. C1 [Wang, Shixia; Coley, Scott; Lawrence, John; Shen, Siyuan; Lu, Shan] Univ Massachusetts, Sch Med, Dept Med, Lab Nucle Acid Vaccines, Worcester, MA 01655 USA. [Kennedy, Jeffrey S.; West, Kim; Green, Sharone; Rothman, Alan L.; Ennis, Francis A.] Univ Massachusetts, Sch Med, Dept Med, Ctr Infect Dis & Vaccine Res, Worcester, MA 01655 USA. [Pal, Ranajit; Markham, Phillip] Adv BioSci Labs, Dept Cell Biol, Kensington, MD 20895 USA. [Montefiori, David C.] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. [Arthos, James] NIAID, Immunoregulat Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Lu, S (reprint author), Univ Massachusetts, Sch Med, Dept Med, Lab Nucle Acid Vaccines, Rm 304,Lazare Res Bldg,364 Plantat St, Worcester, MA 01655 USA. EM shan.tu@umassmed.edu OI Lu, Shan/0000-0002-8417-7588 FU Intramural NIH HHS [Z01 AI000883-07]; NIAID NIH HHS [R01 AI065250, R01AI65250, R21 AI046294-02, R29AI40337, R29 AI040337-05, R29 AI040337, R21 AI046294, R01 AI065250-02, N01AI05394, AI46705, AI30034]; NIDDK NIH HHS [P30 DK032520, 5P30DK32520] NR 48 TC 59 Z9 62 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 20 PY 2008 VL 26 IS 8 BP 1098 EP 1110 DI 10.1016/j.vaccine.2007.12.024 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 269JV UT WOS:000253646200010 PM 18243434 ER PT J AU Long, JL Engels, EA Moore, RD Gebo, KA AF Long, Jessica L. Engels, Eric A. Moore, Richard D. Gebo, Kelly A. TI Incidence and outcomes of malignancy in the HAART era in an urban cohort of HIV-infected individuals SO AIDS LA English DT Article; Proceedings Paper CT 45th Annual Meeting of the Infectious-Diseases-Society-of-America CY OCT, 2007 CL San Diego, CA SP Infect Dis Soc Amer DE hIV; malignancy; cancer; HAART; lung cancer ID ACTIVE ANTIRETROVIRAL THERAPY; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; AIDS-RELATED MALIGNANCIES; CANCER-RISK; LUNG-CANCER; VIRUS-INFECTION; DEATH; MORTALITY; ADULTS; OLDER AB Objective: To investigate trends, patient characteristics, and survival associated with AIDS-defining cancer (ADC) and non-AIDS defining cancer (NADC) in the HAART era. Design: Retrospective analysis of all incident malignancies occurring in 1996-2005 among 2566 patients in an urban HIV clinic. Methods: Clinical profiles of NADC were compared with ADC and the general cohort. Incidence was examined by Poisson analysis. Standardized incidence ratios (SIR) compared cancer risk with that in the general population. Survival was analyzed by Kaplan-Meier and Cox proportional hazards models. Results: Between 1996 and 2005, 138 ADC and 115 NADC were diagnosed. ADC rates decreased from 12.5 to 3.5 cases/1000 person-years (P < 0.001 for trend) while NADC rates increased from 3.9 to 7.1 cases/1000person-years (P=0.13 for trend). Incidence of the most common NADC was higher than expected, including cancers of the lung [n = 29; SIR, 5.5; 95% confidence interval (Cl), 3.7-8.01, liver (n = 13, SIR, 16.5; 95% Cl, 8.8-28.2), anus (n = 10; SIR, 39.0; 95% Cl, 18.7-71.7), head and neck (n = 14; SIR, 5.1; 95% Cl, 2.8-8.6), and Hodgkin's lymphoma (n = 8; SIR, 9.8; 95% Cl, 4.2-19.2). Survival after cancer diagnosis did not differ between ADC and NADC. Advanced age was associated with NADC (P < 0.01 for trend) and increased mortality in ADC (age > 50 years adjusted hazard ratio, 2.2 1; 95% Cl, 1.00-4.89). Conclusions: Rates of ADC decreased while NADC increased within this cohort. Several NADC occurred at rates significantly higher than expected. Screening and suspicion for NADC should increase in care for HIV-infected patients. (c) 2008 Wolters Kluwer Health I Lippincott Williams & Wilkins C1 [Long, Jessica L.; Engels, Eric A.; Moore, Richard D.; Gebo, Kelly A.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Engels, Eric A.] NCI, Div Canc Epidemiol & Genet, NIH, Rockville, MD USA. RP Gebo, KA (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, 1830 E Monument St,Room 435, Baltimore, MD 21287 USA. EM kgebo@jhmi.edu FU NIA NIH HHS [R01 AG026250]; NIAAA NIH HHS [R01 AA016893]; NIAID NIH HHS [U01 AI069918]; NIDA NIH HHS [K24 DA000432, K23 DA000523, K23-DA00523, K24 DA000432-09, K24-DA00432, R01 DA011602, R01 DA011602-10, R01-DA-11602] NR 33 TC 85 Z9 86 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 FEB 19 PY 2008 VL 22 IS 4 BP 489 EP 496 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 277XE UT WOS:000254247200006 PM 18301061 ER PT J AU Kearney, M Palmer, S Maldarelli, F Shao, W Polis, MA Mican, J Rock-Kress, D Margolick, JB Coffin, JA Mellors, JW AF Kearney, Mary Palmer, Sarah Maldarelli, Frank Shao, Wei Polis, Michael A. Mican, Joann Rock-Kress, Diane Margolick, Joseph B. Coffin, John A. Mellors, John W. TI Frequent polymorphism at drug resistance sites in HIV-1 protease and reverse transcriptase SO AIDS LA English DT Article DE drug resistance polymorphisms; drug resistance; minority drug-resistant variants; pro-pol diversity; single genome sequencing (SGS); treatment-naive patients ID HUMAN-IMMUNODEFICIENCY-VIRUS; MULTIPLE SEQUENCE ALIGNMENT; IN-VIVO; RECOMBINATION; SENSITIVITY; MUTATIONS; DIVERSITY; SELECTION; THERAPY AB Background: Failure of antiretroviral therapy may result from the selection of preexisting, drug-resistant HIV-1 variants, but the frequency and type of such variants have not been defined. Objective: We used single genome sequencing (SGS) to characterize the frequency of polymorphism at drug resistance sites in protease (PR) and reverse transcriptase (RT) in plasma samples from antiretroviral naive individuals. Methods: A total of 2229 pro-pol sequences in 79 plasma samples from 30 patients were analyzed by SGS. A mean of 28 single genome sequences was obtained from each sample. The frequency of mutations at all PR and RT sites was compared to those associated with drug resistance. Results: We detected polymorphism at one or more drug resistance sites in 27 of 30 (90%) patients. Polymorphism at positions 179 and 215 of RT was most common, both occurring in 23% of patients. Most (68%) of other drug resistance sites were polymorphic with an average of 3.2% of genomes per sample containing at least one variant from wild type. Seven drug resistance sites were polymorphic in more than 1% of genomes: PR position 33; RT positions 69, 98, 118, 179, 210, and 215. Although frequencies of synonymous polymorphism were similar at resistance and nonresistance sites, nonsynonymous polymorphism were significantly less common at drug resistance sites, implying stronger purifying selection at these positions. Conclusions: HIV-1 variants that are polymorphic at drug resistance sites pre-exist frequently as minor species in antiretroviral naive individuals. Standard genotype techniques have grossly underestimated their frequency. (c) 2008 Wolters Kluwer Health I Lippincott Williams & Wilkins. C1 [Kearney, Mary; Palmer, Sarah; Maldarelli, Frank; Coffin, John A.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. [Shao, Wei] Sci Applicat Int Corp, Frederick, MD USA. [Polis, Michael A.; Mican, Joann] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Rock-Kress, Diane] NIAID, Crit Care Med Dept Clin, NIH, Bethesda, MD 20892 USA. [Margolick, Joseph B.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. [Mellors, John W.] Univ Pittsburgh, Div Infect Dis, Pittsburgh, PA USA. RP Kearney, M (reprint author), NCI, HIV Drug Resistance Program, NIH, 1050 Boyles St,Bldg 535,Room 109, Frederick, MD 21702 USA. EM kearneym@ncifcrf.gov OI Polis, Michael/0000-0002-9151-2268 FU Intramural NIH HHS [Z01 BC010819-01, Z01 BC010820-01]; NIAID NIH HHS [AI 41532, U01 AI041532]; PHS HHS [SAIC 20XS190A] NR 11 TC 51 Z9 52 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 FEB 19 PY 2008 VL 22 IS 4 BP 497 EP 501 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 277XE UT WOS:000254247200007 PM 18301062 ER PT J AU Malope, BI MacPhail, P Mbisa, G MacPhail, C Stein, L Ratshikhopha, EM Ndhlovu, L Sitas, F Whitby, D AF Malope, Babatyi I. MacPhail, Patrick Mbisa, Georgina MacPhail, Catherine Stein, Lara Ratshikhopha, Edith M. Ndhlovu, Lewis Sitas, Freddy Whitby, Denise TI No evidence of sexual transmission of Kaposi's sarcoma herpes virus in a heterosexual South African population SO AIDS LA English DT Article DE co-infection; high-risk sexual behavior; human herpes virus 8/Kaposi's sarcoma herpes virus; HIV; sexually transmitted infections grouping ID MOTHER-TO-CHILD; HIV-INFECTED INDIVIDUALS; HUMAN-HERPESVIRUS-8 INFECTION; DNA-SEQUENCES; RISK-FACTORS; TRANSMITTED INFECTIONS; MALE CIRCUMCISION; UGANDAN CHILDREN; PREVALENCE; SEROPREVALENCE AB Background: The transmission of Kaposi's sarcoma herpes virus (KSHV) in men who have sex with men is clearly associated with sexual risk factors, but evidence of heterosexual transmission of KSHV is conflicting. Methods: Sera were obtained from 2103 South African individuals (862 miners, 95 sex workers, 731 female and 415 male township residents; mean age 33.2 years; +/- 10.1). All sera were tested for antibodies to KSHV lytic K8.1 and latent Orf73, HIV, gonococcus, herpes simplex virus type 2 (HSV-2), syphilis and chlamyclia. Information on social, demographic and high-risk sexual behavior was I inked to laboratory data, to evaluate risk factors, expressed as odds ratios (95% confidence interval) for KSHV. Results: Overall KSHV and HIV prevalences were 47.5 and 40%, respectively (P=0.43). The risk of HIV infection was highest in sex workers then female residents and miners, compared with male residents (P < 0.001). HSV-2 infection was highly prevalent (66%) and lower, but still substantial, prevalences (6-8%) were observed for other sexually transmitted infections (STI). No significant difference in KSHV infection was observed among the residential groups (P > 0.05). KSHV was not associated with any of the STI or any measures of sexual behavior (P > 0.05). Conclusion: The pattern of HIV and STI in sex workers suggests high rates of high-risk sexual behavior in this population. The lack of association with high-risk sexual behavior, particularly in sex workers, and with any markers of STI strongly suggest that the sexual mode does not play a significant role in KSHV transmission in this South African population. (c) 2008 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins C1 [Mbisa, Georgina; Whitby, Denise] NCI, Viral Oncol SEct, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21701 USA. [Malope, Babatyi I.; MacPhail, Patrick] Univ Witwatersrand, Fac Hlth Sci, Dept Med, Clin HIV Res Unit, Johannesburg, South Africa. [Malope, Babatyi I.; Stein, Lara; Ratshikhopha, Edith M.; Sitas, Freddy] Natl Hlth Lab Serv, Canc Epidemiol Res Grp, Johannesburg, South Africa. [MacPhail, Catherine] Univ Witwatersrand, Fac Hlth Sci, Sch Publ Hlth, Reprod Hlth Res Unit, Johannesburg, South Africa. [Ndhlovu, Lewis] Populat Council, Johannesburg, South Africa. RP Whitby, D (reprint author), NCI, Viral Oncol SEct, AIDS Vaccine Program, SAIC Frederick, Frederick, MD 21701 USA. EM whitbyd@ncifcrf.gov RI MacPhail, Catherine/N-4234-2014; OI Sitas, Freddy/0000-0001-9679-1481 NR 51 TC 36 Z9 36 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB 19 PY 2008 VL 22 IS 4 BP 519 EP 526 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 277XE UT WOS:000254247200010 PM 18301065 ER PT J AU Mbulaiteye, SM Goedert, JJ AF Mbulaiteye, Sam M. Goedert, James J. TI Transmission of Kaposi sarcoma-associated herpesvirus in sub-Saharan Africa SO AIDS LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN-HERPESVIRUS-8 INFECTION; HOMOSEXUAL-MEN; RISK-FACTORS; AIDS; CANCER; ZAMBIA; EPIDEMIOLOGY; UGANDA; SEROPREVALENCE C1 [Mbulaiteye, Sam M.; Goedert, James J.] NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. RP Mbulaiteye, SM (reprint author), 6120 Execut Blvd,Room 7080, Rockville, MD 20852 USA. EM mbulaits@mail.nih.gov NR 29 TC 5 Z9 5 U1 1 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 FEB 19 PY 2008 VL 22 IS 4 BP 535 EP 537 PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 277XE UT WOS:000254247200013 PM 18301068 ER PT J AU Tchernaenko, V Halvorson, HR Kashlev, M Lutter, LC AF Tchernaenko, Vladimir Halvorson, Herbert R. Kashlev, Mikhail Lutter, Leonard C. TI DNA bubble formation in transcription initiation SO BIOCHEMISTRY LA English DT Article ID COLI RNA-POLYMERASE; LAC UV5 PROMOTER; OPEN COMPLEX-FORMATION; LAMBDA-PR PROMOTER; SINGLE-STRANDED REGIONS; CLOSED CIRCULAR DNA; TRACT BEND ANGLE; ESCHERICHIA-COLI; START SITE; TOPOLOGICAL MEASUREMENT AB The properties of the DNA bubble in the transcription open complex have been characterized by topological analysis of DNA circles containing the lac UV5 promoter or the PR promoter from bacteriophage lambda. Topological analysis is particularly well suited to this purpose since it quantifies the changes in DNA duplex geometry caused by bubble formation as well as by superhelical DNA wrapping. The duplex unwinding that results from bubble formation is detected as a reduction in topological linking number of the DNA circle, and the precision of this measurement has been enhanced in the current study through the use of 8 or 10 promoter copies per circle. Several lines of evidence indicate that the linking number change induced by open complex formation is essentially all due to bubble generation, with very little derived from superhelical wrapping. Accordingly, the linking number change of -1.17 measured for the lac UV5 promoter indicates that the size of the lac UV5 bubble is about 12.3 base pairs, while the change of -0.98 measured for the lambda PR promoter indicates that the lambda PR bubble is 10.3 base pairs. It was also found that the presence or absence of magnesium ion had little effect on the value of the linking number change, a result that resolves the uncertainty associated with use of chemical probes to study the effect of magnesium on bubble size. Finally, the magnitude of linking number change increases progressively when the 3' end of a transcript is extended to +2 and +3 in an abortive initiation complex. This indicates that the transcription bubble expands at its leading edge in the abortive complex, results that confirm and extend the proposal of a DNA "scrunching" mechanism at the onset of transcription. These results are relevant to several models for the structure of DNA in the functional open complex in solution, and provide an important complement to the structural information available from recent crystal structures. C1 [Tchernaenko, Vladimir; Halvorson, Herbert R.; Lutter, Leonard C.] Henry Ford Hosp, Ctr Bone & Joint, Mol Biol Sect, Detroit, MI 48202 USA. [Kashlev, Mikhail] Frederick Canc Res & Dev Ctr, NCI Ctr Canc Res, Mechanisms Transcript Sect, Frederick, MD 21702 USA. RP Lutter, LC (reprint author), Henry Ford Hosp, Ctr Bone & Joint, Mol Biol Sect, Detroit, MI 48202 USA. EM llutterl@hfhs.org FU NIGMS NIH HHS [GM49988, GM56216] NR 88 TC 6 Z9 6 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 19 PY 2008 VL 47 IS 7 BP 1871 EP 1884 DI 10.1021/bi701289g PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 261TD UT WOS:000253102000005 PM 18205393 ER PT J AU Tchernaenko, V Radlinska, M Lubkowska, L Halvorson, HR Kashlev, M Lutter, LC AF Tchernaenko, Vladimir Radlinska, Monika Lubkowska, Lucyna Halvorson, Herbert R. Kashlev, Mikhail Lutter, Leonard C. TI DNA bending in transcription initiation SO BIOCHEMISTRY LA English DT Article ID COLI RNA-POLYMERASE; OPEN COMPLEX-FORMATION; PROMOTER OPEN COMPLEX; LAC UV5 PROMOTER; SIMIAN VIRUS 40; ESCHERICHIA-COLI; TOPOLOGICAL MEASUREMENT; CONFORMATIONAL-CHANGES; ANGSTROM RESOLUTION; ELONGATION COMPLEX AB Electrophoretic mobility shift (bandshift) phasing analysis and rotational variant topological analysis were performed on initiation complexes formed on the bacteriophage lambda PR promoter. Both the open complex and an abortive complex containing a short RNA primer extending to +3 were characterized. The two methods were used to analyze a series of constructs containing tandemly repeated copies of the PR promoter, with the repeat length increased in single base pair increments to progressively change the rotational setting of adjacent copies. The phasing effect observed in bandshift analysis of open complexes formed on this set of constructs provided qualitative evidence for the presence of a bend. Subsequent rotational variant topological analysis confirmed this and quantified the overall bend angle in the open complex as well as in the +3 abortive complex: a bend of 49 degrees +/- 7 degrees was measured for the open complex, while a bend of 47 degrees +/- 11 degrees was measured for the +3 complex, i.e., the two bends are the same. However, the topological results are not consistent with extensive superhelical wrapping of DNA on either complex as has been proposed. The two complexes do differ in the size of the transcription bubble: the open complex contains a 10.4 +/- 0.1 by bubble, while that of the +3 complex is 12.2 +/- 0.1 bp, a result consistent with "DNA scrunching" during the onset of transcription. A model for the overall path of the DNA in the open complex is presented that is consistent with the measured bend angle. Measurement of both bubble size and overall bend angle complements the results of crystal structures in providing an enhanced description of the solution structures of the intact initiation complexes. C1 [Tchernaenko, Vladimir; Radlinska, Monika; Halvorson, Herbert R.; Lutter, Leonard C.] Henry Ford Hosp, Ctr Bone & Joint, Mol Biol Sect, Detroit, MI 48202 USA. [Lubkowska, Lucyna; Kashlev, Mikhail] Frederick Canc Res & Dev Ctr, NCI Ctr Canc Res, Mol Mechanism Transcript Sect, Frederick, MD 21702 USA. RP Lutter, LC (reprint author), Henry Ford Hosp, Ctr Bone & Joint, Mol Biol Sect, Detroit, MI 48202 USA. EM llutterl@hfhs.org FU NIGMS NIH HHS [GM56216, GM49988] NR 64 TC 6 Z9 6 U1 1 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 FEB 19 PY 2008 VL 47 IS 7 BP 1885 EP 1895 DI 10.1021/bi7012883 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 261TD UT WOS:000253102000006 PM 18205392 ER PT J AU Chen, K Bachtair, I Piszczek, G Bouamr, F Carter, C Tjandra, N AF Chen, Kang Bachtair, Indra Piszczek, Grzegorz Bouamr, Fadila Carter, Carol Tjandra, Nico TI Solution NMR characterizations of oligomerization and dynamics of equine infectious anemia virus matrix protein and its interaction with PIP2 SO BIOCHEMISTRY LA English DT Article ID LIQUID-CRYSTALLINE PHASE; HIV-1 GAG; PLASMA-MEMBRANE; CHEMICAL-EXCHANGE; BINDING; SWITCH; MACROMOLECULES; IDENTIFICATION; SPECTROSCOPY; ASSOCIATION AB Budding of retroviruses requires the structural precursor polyprotein, Gag, to target the plasma membrane through its N-terminal matrix (MA) domain. For HIV-1, the interaction between membrane signaling molecule phosphatidylinositol 4,5-diphosphate (PIP2) and MA induces the exposure of myristate and promotes membrane binding. Here we studied oligomerization of the naturally unmyristylated equine infectious anemia virus (EIAV) MA and its interaction with PIP2-C4 primarily using solution NMR spectroscopy. The measured H-1-N-15 residual dipolar coupling agrees with the atomic coordinates from the EIAV MA crystal structure. The analytical ultracentrifugation results show a dominant population of monomeric EIAV MA at a concentration of 63 mu M and 20 degrees C, along with a small trimer and a broad distribution of other oligomers. The monomer-trimer equilibrium model and the quaternary packing of the trimer were further established by the con centration-dependent N-15 spin relaxation rates and chemical shifts. Binding of MA to PIP2-C4 was detected by chemical shift mapping (CSM) with an apparent K-d of 182 +/- 56 mu M, a value similar to that reported for HIV-1 MA. The PIP2 binding site includes the Loop region between Helix2 and Helix3 in the EIAV MA. CSM and spin relaxation dispersion, reveal a coupling of conformational change and submillisecond dynamics, respectively, between the Loop and trimeric Interface Residues due to PIP2 binding. We infer that PIP2 participates in the initial trimer formation of EIAV MA, but more importantly, the concentration effect is dominant in shifting the equilibrium toward trimer, in line with the entropic switch mechanism proposed for myristylated HIV-1 MA. C1 [Chen, Kang; Bachtair, Indra; Tjandra, Nico] Natl Inst Hlth, Natl Heart Lung & Blood Inst, Biochem Lab, Lab Mol Biophys, Bethesda, MD 20892 USA. [Piszczek, Grzegorz; Bouamr, Fadila] Natl Inst Hlth, NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. [Carter, Carol] SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. RP Tjandra, N (reprint author), Natl Inst Hlth, Natl Heart Lung & Blood Inst, Biochem Lab, Lab Mol Biophys, Bethesda, MD 20892 USA. EM ccarter@ms.cc.sunysb.edu; tjandran@nhlbi.nih.gov FU Intramural NIH HHS; NIAID NIH HHS [R01 AI068463, R01 AI068463-04] NR 41 TC 44 Z9 44 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 19 PY 2008 VL 47 IS 7 BP 1928 EP 1937 DI 10.1021/bi701984h PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 261TD UT WOS:000253102000010 PM 18220420 ER PT J AU Viard, M Ablan, SD Zhou, M Veenstra, TD Freed, EO Raviv, Y Blumenthal, R AF Viard, Mathias Ablan, Sherimay D. Zhou, Ming Veenstra, Timothy D. Freed, Eric O. Raviv, Yossef Blumenthal, Robert TI Photoinduced reactivity of the HIV-1 envelope glycoprotein with a membrane-embedded probe reveals insertion of portions of the HIV-1 gp41 cytoplasmic tail into the viral membrane SO BIOCHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; MEDIATED FUSION; BIOLOGICAL-MEMBRANES; CONFORMATIONAL-CHANGES; INHIBITORY-ACTION; 6-HELIX BUNDLE; LIPID BILAYER; PROTEINS; DOMAIN; PEPTIDE AB The interactions of HIV-1 Env (gp120-gp41) with CD4 and coreceptors trigger a barrage of conformational changes in Env that drive the membrane fusion process. Various regions of gp41 have profound effects on HIV entry and budding. However, the precise interactions between gp41 and the membrane have not been elucidated. To examine portions of membrane proteins that are embedded in membrane lipids, we have studied photoinduced chemical reactions in membranes using the lipid bilayer specific probe iodonaphthyl azide (INA). Here we show that in addition to the transmembrane anchor, amphipatic sequences in the cytoplasmic tail (CT) of HIV-1 gp41 are labeled by INA. INA labeling of the HIV-1 gp41 CT was similar whether wild-type or a mutant HIV-1 was used with uncleaved p55 Gag, which does not allow entry. These results shed light on the disposition of the HIV-1 gp41 CT with respect to the membrane. Moreover, our data have general implications for topology of membrane proteins and their in situ interactions with the lipid bilayer. C1 [Viard, Mathias; Raviv, Yossef; Blumenthal, Robert] Natl Inst Hlth, Natl Canc Inst, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Viard, Mathias; Raviv, Yossef] Natl Inst Hlth, Natl Canc Inst, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. [Ablan, Sherimay D.; Freed, Eric O.] Natl Inst Hlth, Natl Canc Inst, Virus Interaction Sect HIV Drug Resistance Progra, Frederick, MD 21702 USA. [Zhou, Ming; Veenstra, Timothy D.] Natl Inst Hlth, Natl Canc Inst, Adv Technol Program, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. RP Blumenthal, R (reprint author), Natl Inst Hlth, Natl Canc Inst, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. EM blumenthalr@mail.nih.gov FU Intramural NIH HHS [Z01 BC010775-01, Z01 BC010776-01]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 50 TC 26 Z9 26 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 19 PY 2008 VL 47 IS 7 BP 1977 EP 1983 DI 10.1021/bi701920f PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 261TD UT WOS:000253102000015 PM 18198900 ER PT J AU Yang, M Lee, JE Padgett, RW Edery, I AF Yang, Maocheng Lee, Jung-Eun Padgett, Richard W. Edery, Isaac TI Circadian regulation of a limited set of conserved microRNAs in Drosophila SO BMC GENOMICS LA English DT Article ID MESSENGER-RNA DEGRADATION; GENE-EXPRESSION; TRANSCRIPTIONAL REPRESSOR; CLOCKWORK-ORANGE; PERIOD PROTEIN; PHOSPHORYLATION; RHYTHMS; TIMELESS; GENOME; PACEMAKER AB Background: MicroRNAs (miRNAs) are short non-coding RNA molecules that target mRNAs to control gene expression by attenuating the translational efficiency and stability of transcripts. They are found in a wide variety of organisms, from plants to insects and humans. Here, we use Drosophila to investigate the possibility that circadian clocks regulate the expression of miRNAs. Results: We used a microarray platform to survey the daily levels of D. melanogaster miRNAs in adult heads of wildtype flies and the arrhythmic clock mutant cyc(01). We find two miRNAs (dme-miR-263a and -263b) that exhibit robust daily changes in abundance in wildtype flies that are abolished in the cyc(01) mutant. dme-miR-263a and -263b reach trough levels during the daytime, peak during the night and their levels are constitutively elevated in cyc(01) flies. A similar pattern of cycling is also observed in complete darkness, further supporting circadian regulation. In addition, we identified several miRNAs that appear to be constitutively expressed but nevertheless differ in overall daily levels between control and cyc(01) flies. Conclusion: The circadian clock regulates miRNA expression in Drosophila, although this appears to be highly restricted to a small number of miRNAs. A common mechanism likely underlies daily changes in the levels of dme-miR-263a and -263b. Our results suggest that cycling miRNAs contribute to daily changes in mRNA and/or protein levels in Drosophila. Intriguingly, the mature forms of dme-miR-263a and -263b are very similar in sequence to several miRNAs recently shown to be under circadian regulation in the mouse retina, suggesting conserved functions. C1 [Yang, Maocheng; Padgett, Richard W.; Edery, Isaac] Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08855 USA. [Yang, Maocheng; Padgett, Richard W.] Rutgers State Univ, Waksman Inst, Piscataway, NJ USA. [Lee, Jung-Eun; Edery, Isaac] Ctr Adv Biotechnol, Piscataway, NJ USA. [Yang, Maocheng] NCI, NIH, Bethesda, MD 20892 USA. RP Edery, I (reprint author), Rutgers State Univ, Dept Mol Biol & Biochem, Piscataway, NJ 08855 USA. EM yangm3@mail.nih.gov; jungeunl@eden.rutgers.edu; padgett@waksman.rutgers.edu; edery@cabm.rutgers.edu RI Lee, Jung-Eun/J-1777-2014 OI Lee, Jung-Eun/0000-0003-0184-3440 FU NINDS NIH HHS [R01 NS034958, NS034958] NR 51 TC 61 Z9 66 U1 1 U2 8 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 FEB 19 PY 2008 VL 9 AR 83 DI 10.1186/1471-2164-9-83 PG 11 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 274GC UT WOS:000253988800001 PM 18284684 ER PT J AU Hurt, EM Kawasaki, BT Klarmann, GJ Thomas, SB Farrar, WL AF Hurt, E. M. Kawasaki, B. T. Klarmann, G. J. Thomas, S. B. Farrar, W. L. TI CD44(+)CD24(-) prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis SO BRITISH JOURNAL OF CANCER LA English DT Article DE prostate cancer; tumour stem cells; genomics; CD44; CD24 ID IN-VITRO PROPAGATION; TUMOR STEM-CELLS; PROSPECTIVE IDENTIFICATION; STEM/PROGENITOR CELLS AB Recent evidence supports the hypothesis that cancer stem cells are responsible for tumour initiation and formation. Using flow cytometry, we isolated a population of CD44(+)CD24(-) prostate cells that display stem cell characteristics as well as gene expression patterns that predict overall survival in prostate cancer patients. CD44(+)CD24(-) cells form colonies in soft agar and form tumours in NOD/SCID mice when as few as 100 cells are injected. Furthermore, CD44(+)CD24(-) cells express genes known to be important in stem cell maintenance, such as BMI-1 and Oct-3/4. Moreover, we can maintain CD44(+)CD24(-) prostate stem-like cells as nonadherent spheres in serum-replacement media without substantially shifting gene expression. Addition of serum results in adherence to plastic and shifts gene expression patterns to resemble the differentiated parental cells. Thus, we propose that CD44(+)CD24(-) prostate cells are stem-like cells responsible for tumour initiation and we provide a genomic definition of these cells and the differentiated cells they give rise to. Furthermore, gene expression patterns of CD44(+)CD24(-) cells have a genomic signature that is predictive of poor patient prognosis. Therefore, CD44(+)CD24(-) LNCaP prostate cells offer an attractive model system to both explore the biology important to the maintenance and differentiation of prostate cancer stem cells as well as to develop the therapeutics, as the gene expression pattern in these cells is consistent with poor survival in prostate cancer patients. C1 [Hurt, E. M.; Kawasaki, B. T.; Farrar, W. L.] NCI, NIH, Ctr Canc Res, Canc Stem Cell Sect,Canc Prevent Lab, Ft Detrick, MD 21702 USA. [Klarmann, G. J.; Thomas, S. B.] SAIC Frederick Inc, NCI, NIH, Basic Res Program, Ft Detrick, MD 21702 USA. RP Hurt, EM (reprint author), NCI, Ctr Canc Res, Canc Prevent Lab, Canc Stem Cell Sect, 1050 Boyles St,Bldg 560,Rm 21-81, Ft Detrick, MD 21702 USA. EM hurte@ncifcrf.gov.or; farrar@mail.ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 26 TC 218 Z9 227 U1 2 U2 22 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 FEB 19 PY 2008 VL 98 IS 4 BP 756 EP 765 DI 10.1038/sj.bjc.6604242 PG 10 WC Oncology SC Oncology GA 263LX UT WOS:000253219700013 PM 18268494 ER PT J AU Lightfoot, JT Turner, MJ Pomp, D Kleeberger, SR Leamy, LJ AF Lightfoot, J. Timothy Turner, Michael J. Pomp, Daniel Kleeberger, Steven R. Leamy, Larry J. TI Quantitative trait loci for physical activity traits in mice SO PHYSIOLOGICAL GENOMICS LA English DT Article DE genetics; locomotion; linkage mapping ID RECOMBINANT INBRED MICE; WHEEL-RUNNING BEHAVIOR; IN-HOUSE MICE; DIFFERENTIAL SENSITIVITY; MULTIPLE COMPARISONS; EXERCISE; MOUSE; MODEL; LOCOMOTION; LOCALIZATION AB The genomic locations and identities of the genes that regulate voluntary physical activity are presently unknown. The purpose of this study was to search for quantitative trait loci (QTL) that are linked with daily mouse running wheel distance, duration, and speed of exercise. F-2 animals (n = 310) derived from high active C57L/J and low active C3H/HeJ inbred strains were phenotyped for 21 days. After phenotyping, genotyping with a fully informative single-nucleotide polymorphism panel with an average intermarker interval of 13.7 cM was used. On all three activity indexes, sex and strain were significant factors, with the F2 animals similar to the high active C57L/J mice in both daily exercise distance and duration of exercise. In the F2 cohort, female mice ran significantly farther, longer, and faster than male mice. QTL analysis revealed no sex-specific QTL but at the 5% experimentwise significance level did identify one QTL for duration, one QTL for distance, and two QTL for speed. The QTL for duration (DUR13.1) and distance (DIST13.1) colocalized with the QTL for speed (SPD13.1). Each of these QTL accounted for similar to 6% of the phenotypic variance, whereas SPD9.1 (chromosome 9, 7 cM) accounted for 11.3% of the phenotypic variation. DUR13.1, DIST13.1, SPD13.1, and SPD9.1 were subsequently replicated by haplotype association mapping. The results of this study suggest a genetic basis of voluntary activity in mice and provide a foundation for future candidate gene studies. C1 [Lightfoot, J. Timothy; Turner, Michael J.] Univ N Carolina, Dept Kinesiol, Charlotte, NC 28223 USA. [Leamy, Larry J.] Univ N Carolina, Dept Biol, Charlotte, NC 28223 USA. [Pomp, Daniel] Univ N Carolina, Dept Nutr & Cell, Chapel Hill, NC USA. [Pomp, Daniel] Univ N Carolina, Dept Mol Physiol, Chapel Hill, NC USA. [Kleeberger, Steven R.] NIEHS, Lab Resp Biol, Durham, NC USA. RP Lightfoot, JT (reprint author), Univ N Carolina, Dept Kinesiol, 9201 Univ City Blvd, Charlotte, NC 28223 USA. EM tlightfoot@uncc.edu FU Intramural NIH HHS; NCI NIH HHS [U01 CA105417-04, U01 CA105417]; NIA NIH HHS [AG-022417, R15 AG022417]; NIAMS NIH HHS [AR-050085, R01 AR050085]; NIDDK NIH HHS [DK-61635, R01 DK076050-02, DK-076050, R01 DK076050, R15 DK061635] NR 39 TC 57 Z9 58 U1 0 U2 6 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD FEB 19 PY 2008 VL 32 IS 3 BP 401 EP 408 DI 10.1152/physiolgenomics.00241.2007 PG 8 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 314NO UT WOS:000256816300013 PM 18171721 ER PT J AU Pearson, KJ Lewis, KN Price, NL Chang, JW Perez, E Cascajo, MV Tamashiro, KL Poosala, S Csiszar, A Ungvari, Z Kensler, TW Yamamoto, M Egan, JM Longo, DL Ingram, DK Navas, P de Cabo, R AF Pearson, Kevin J. Lewis, Kaitlyn N. Price, Nathan L. Chang, Joy W. Perez, Evelyn Victoria Cascajo, Maria Tamashiro, Kellie L. Poosala, Suresh Csiszar, Anna Ungvari, Zoltan Kensler, Thomas W. Yamamoto, Masayuki Egan, Josephine M. Longo, Dan L. Ingram, Donald K. Navas, Placido de Cabo, Rafael TI Nrf2 mediates cancer protection but not prolongevity induced by caloric restriction SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aging; carcinogenesis; oxidative stress ID OXIDATIVE STRESS; CAENORHABDITIS-ELEGANS; DIETARY RESTRICTION; NF-E2-RELATED FACTOR-2; TRANSCRIPTION FACTOR; HEME OXYGENASE-1; MOUSE SKIN; LIFE-SPAN; ENZYME GENES; C-ELEGANS AB Caloric restriction (CR) is the most potent intervention known to both protect against carcinogenesis and extend lifespan in laboratory animals. A variety of anticarcinogens and CR mimetics induce and activate the NF-E2-related factor 2 (Nrf2) pathway. Nrf2, in turn, induces a number of antioxidative and carcinogendetoxifying enzymes. Thus, Nrf2 offers a promising target for anticarcinogenesis and antiaging interventions. We used Nrf2-disrupted (KO) mice to examine its role on the biological effects of CR. Here, we show that Nrf2 is responsible for most of the anticarcinogenic effects of CR, but is dispensable for increased insulin sensitivity and lifespan extension. Nrf2-deficient mice developed tumors more readily in response to carcinogen exposure than did WT mice, and CR was ineffective in suppressing tumors in the KO mice. However, CR extended lifespan and increased insulin sensitivity similarly in KO and WT mice. These findings identify a molecular pathway that dissociates the prolongevity and anticarcinogenic effects of CR. C1 [Pearson, Kevin J.; Lewis, Kaitlyn N.; Price, Nathan L.; Chang, Joy W.; Perez, Evelyn; Ingram, Donald K.; de Cabo, Rafael] NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. [Egan, Josephine M.] NIA, Clin Invest Lab, NIH, Baltimore, MD 21224 USA. [Longo, Dan L.] NIA, Immunol Lab, NIH, Baltimore, MD 21224 USA. [Poosala, Suresh] NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. [Victoria Cascajo, Maria; Navas, Placido] Univ Pablo Olavide Consejo Super Invest Cient, Ctr Andaluz Biol Desarrollo, Seville 41013, Spain. [Victoria Cascajo, Maria; Navas, Placido] Inst Salud Carlos III, Ctr Invest Biomed Red Enfermedades Raras, Seville 41013, Spain. [Tamashiro, Kellie L.] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Csiszar, Anna; Ungvari, Zoltan] New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. [Kensler, Thomas W.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21202 USA. [Yamamoto, Masayuki] Univ Tsukuba, Ctr Tsukuka Adv Res Alliance, Tsukuba, Ibaraki 3058577, Japan. [Ingram, Donald K.] Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutrit Neurosci & Aging Lab, Baton Rouge, LA 70808 USA. RP Cascajo, MV (reprint author), NIA, Lab Expt Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM decabora@grc.nia.nih.gov RI de Cabo, Rafael/E-7996-2010; Yamamoto, Masayuki/A-4873-2010; Kensler, Thomas/D-8686-2014; de Cabo, Rafael/J-5230-2016; OI Kensler, Thomas/0000-0002-6676-261X; de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 FU Intramural NIH HHS; NICHD NIH HHS [K99 HD055030, HD055030, R00 HD055030]; NIDDK NIH HHS [DK077623, R01 DK077623] NR 43 TC 113 Z9 116 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 19 PY 2008 VL 105 IS 7 BP 2325 EP 2330 DI 10.1073/pnas.0712162105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266XB UT WOS:000253469900016 PM 18287083 ER PT J AU Zurita, AR Birnbaumer, L AF Zurita, Adolfo R. Birnbaumer, Lutz TI The same mutation in Gs alpha and transducin alpha reveals behavioral differences between these highly homologous G protein alpha-subunits SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE adenylyl cyclase; beta-adrenergic receptor; GTP shift; GTPase; crystal ID BETA-ADRENERGIC-RECEPTOR; HETEROTRIMERIC G-PROTEIN; SIMPLE 2-STATE MODEL; S49 LYMPHOMA-CELLS; ADENYLYL-CYCLASE; CRYSTAL-STRUCTURE; SIGNAL-TRANSDUCTION; REGULATORY COMPONENT; GUANINE-NUCLEOTIDE; GUANYL NUCLEOTIDES AB Mutating Arg-238 to Glu (R238E) in the switch 3 region of a transducin alpha(*T alpha) in which 27 aa of the GTPase domain have been replaced with those of the a-subunit of the inhibitory G protein 1 (Gil alpha), was reported to create an alpha-subunit that is resistant to activation by GTP gamma S, is devoid of resident nucleotide, and has dominant negative (DN) properties. In an attempt to create a DN stimultory G protein a (Gs alpha) with a single mutation we created Gs alpha-R265E, equivalent to *T alpha-R238E. Gs alpha-R265E has facilitated activation by GTP gamma S, a slightly facilitated activation by GTP but much reduced receptor plus GTP stimulated activation, and an apparently unaltered ability to interact with receptor as seen in ligand binding studies. Further, the activity profile of Gs alpha-R265E is that of an alpha-subunit with unaltered or increased GTPase activity. The only change in Gs alpha that is similar to that in *T alpha is that the apparent affinity for guanine nucleotides is decreased in both proteins. The molecular basis of the changed properties are discussed based on the known crystal structure of Gs alpha and the changes introduced by the same mutation in a *T alpha (Gt alpha*) with only 23 aa from Gil alpha. Gt alpha*-R238E, with four fewer mutations in switch 3, was reported to show no evidence of DN properties, is activated by GTP gamma S, and has reduced GTPase activity. The data highlight a critical role for the switch 3 region in setting overall properties of signal-transducing GTPases. C1 [Zurita, Adolfo R.; Birnbaumer, Lutz] Natl Inst Environm Hlth Sci, Neurobiol Lab, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. RP Birnbaumer, L (reprint author), Natl Inst Environm Hlth Sci, Neurobiol Lab, Div Intramural Res, NIH, Bldg 101,Room F180,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM birnbau1@niehs.nih.gov FU Intramural NIH HHS NR 34 TC 5 Z9 5 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 19 PY 2008 VL 105 IS 7 BP 2363 EP 2368 DI 10.1073/pnas.0712261105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266XB UT WOS:000253469900023 PM 18258741 ER PT J AU Wickner, RB Dyda, F Tycko, R AF Wickner, Reed B. Dyda, Fred Tycko, Robert TI Amyloid of Rnq1p, the basis of the [PIN+] prion, has a parallel in-register beta-sheet structure SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID SOLID-STATE NMR; DE-NOVO APPEARANCE; HET-S PRION; SACCHAROMYCES-CEREVISIAE; EXPERIMENTAL CONSTRAINTS; PSI+ PRION; YEAST; FIBRILS; PROTEIN; PEPTIDE AB The [PIN+] prion, a self-propagating amyloid form of Rnq1p, increases the frequency with which the [PSI+] or [URE3] prions arise de novo. Like the prion domains of Sup35p and Ure2p, Rnq1p is rich in IN and Q residues, but rnq1 Delta strains have no known phenotype except for inability to propagate the [PIN+] prion. We used solid-state NMR methods to examine amyloid formed in vitro from recombinant Rnq1 prion domain (residues 153-405) labeled with Tyr-1-C-13 (14 residues), Leu-1-C-13 (7 residues), or Ala-3-13C (13 residues). The carbonyl chemical shifts indicate that most Tyr and Leu residues are in beta-sheet conformation. Experiments designed to measure the distance from each labeled residue to the next nearest labeled carbonyl showed that almost all Tyr and Leu carboryl carbon atoms were approximate to 0.5 nm from the next nearest Tyr and Leu residues, respectively. This result indicates that the Rnq1 prion domain forms amyloid consisting of parallel beta-strands that are either in register or,are at most one amino acid out of register. Similar experiments with Ala-3-C-13 indicate that the beta-strands are indeed in-register. The parallel in-register structure, now demonstrated for each of the yeast prions, explains the faithful templating of prion strains, and suggests as well a mechanism for the rare hetero-priming that is [PIN+]'s defining characteristic. C1 [Wickner, Reed B.] NIDDKD, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. [Dyda, Fred] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. [Tycko, Robert] NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDKD, Lab Biochem & Genet, NIH, Bldg 8,Room 225,8 Ctr Dr,MSC 0830, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov; robertty@mail.nih.gov FU Intramural NIH HHS NR 43 TC 95 Z9 97 U1 2 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 19 PY 2008 VL 105 IS 7 BP 2403 EP 2408 DI 10.1073/pnas.0712032105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266XB UT WOS:000253469900030 PM 18268327 ER PT J AU Tang, Y Kitisin, K Jogunoori, W Li, C Deng, CX Mueller, SC Ressom, HW Rashid, A He, AR Mendelson, JS Jessup, JM Shetty, K Zasloff, M Mishra, B Reddy, EP Johnson, L Mishra, L AF Tang, Yi Kitisin, Krit Jogunoori, Wilma Li, Cuiling Deng, Chu-Xia Mueller, Susette C. Ressom, Habtom W. Rashid, Asif He, Aiwu Ruth Mendelson, Jonathan S. Jessup, John M. Shetty, Kirti Zasloff, Michael Mishra, Bibhuti Reddy, E. P. Johnson, Lynt Mishra, Lopa TI Progenitor/stem cells give rise to liver cancer due to aberrant TGF-beta and IL-6 signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID HEPATOCELLULAR-CARCINOMA; EXPRESSION; GROWTH; STAT3; MICE; REGENERATION; DISRUPTION; INFLAMMATION; HYPERPLASIA; INDUCTION AB Cancer stem cells (CSCs) are critical for the initiation, propagation, and treatment resistance of multiple cancers. Yet functional interactions between specific signaling pathways in solid organ "cancer stem cells," such as those of the liver, remain elusive. We report that in regenerating human liver, two to four cells per 30,000-50,000 cells express stem cell proteins Stat3, Oct4, and Nanog, along with the prodifferentiation proteins TGF-beta-receptor type 11 (TBRII) and embryonic liver fodrin (ELF). Examination of human hepatocellular cancer (HCC) reveals cells that label with stem cell markers that have unexpectedly lost TBRII and ELF. elf(+/-) mice spontaneously develop HCC; expression analysis of these tumors highlighted the marked activation of the genes involved in the IL-6 signaling pathway, including IL-6 and Stat3, suggesting that HCC could arise from an IL-6-driven transformed stem cell with inactivated TGF-beta signaling. Similarly, suppression of IL-6 signaling, through the generation of mouse knockouts involving a positive regulator of IL-6, Inter-alpha-trypsin inhibitor-heavy chain-4 (ITIH4), resulted in reduction in HCC in elf(+/-) mice. This study reveals an unexpected functional link between IL-6, a major stem cell signaling pathway, and the TGF-beta signaling pathway in the modulation of mammalian HCC, a lethal cancer of the foregut. These experiments suggest an important therapeutic role for targeting IL-6 in HCCs lacking a functional TGF-beta pathway. C1 [Tang, Yi; Kitisin, Krit; Jogunoori, Wilma; Mendelson, Jonathan S.; Shetty, Kirti; Zasloff, Michael; Mishra, Bibhuti; Johnson, Lynt; Mishra, Lopa] Georgetown Univ, Canc Genet Digest Dis & Dev Mol Biol, Washington, DC 20007 USA. [Kitisin, Krit; Johnson, Lynt] Georgetown Univ, Inst Transplant Surg, Dept Surg, Washington, DC 20007 USA. [Mueller, Susette C.; Ressom, Habtom W.; Mishra, Lopa] Georgetown Univ, Vincent T Lombardi Canc Res Ctr, Washington, DC 20007 USA. [He, Aiwu Ruth] Georgetown Univ, Dept Med Oncol, Washington, DC 20007 USA. [Li, Cuiling; Deng, Chu-Xia] NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. [Rashid, Asif] Univ Texas Houston, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. [Mishra, Lopa] Dept Vet Affairs Med Ctr, Washington, DC 20422 USA. [Reddy, E. P.; Mishra, Lopa] Temple Univ, Fels Inst Canc Res & Mol Biol, Philadelphia, PA 19140 USA. [Jessup, John M.] NCI, Canc Diag Program, Rockville, MD 20852 USA. RP Shetty, K (reprint author), Georgetown Univ, Canc Genet Digest Dis & Dev Mol Biol, 3900 Reservoir Rd, Med Dent Bldg, Washington, DC 20007 USA. EM kirti.shetty@medstar.net; lynt.johnson@medstar.net; lm229@georgetown.edu RI Reddy, E. Premkumar/F-6233-2011; deng, chuxia/N-6713-2016 FU NCI NIH HHS [R01 CA042857, R01 CA042857-18A1, R01 CA106614, R01 CA106614-01A2, R01 CA106614A, R01 CA4285718A]; NIDDK NIH HHS [R01 DK056111, R01 DK056111-01, R01 DK56111, R01 DK58637] NR 43 TC 189 Z9 198 U1 4 U2 21 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 19 PY 2008 VL 105 IS 7 BP 2445 EP 2450 DI 10.1073/pnas.0705395105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266XB UT WOS:000253469900037 PM 18263735 ER PT J AU Puri, N Roche, PA AF Puri, Niti Roche, Paul A. TI Mast cells possess distinct secretory granule subsets whose exocytosis is regulated by different SNARE isoforms SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE serotonin; histamine; VAMP-8 ID LYSOSOMES; SNAP-23; RELEASE AB Mast cells degranulate and release the contents of intracellular secretory granules in response to the cross-linking of Fc epsilon RI by multivalent antigens. These granules contain a variety of biologically active inflammatory mediators; however, it is not clear whether these granules are homogenous or whether there is heterogeneity within the secretory granule population in mast cells. By using genetically altered mice lacking specific vesicle-associated SNARE membrane fusion proteins, we found that VAMP-8-deficient mast cells exhibited defects in Fc epsilon RI-regulated exocytosis, whereas synaptobrevin 2- or VAMP-3-deficient mast cells did not. Surprisingly, the defect in secretion in VAMP-8-deficient mice was limited to the subpopulation of mast cell secretory granules containing serotonin and cathepsin D, whereas regulated exocytosis of secretory granules containing histamine and TNF-alpha was normal. Confocal microscopy confirmed that serotonin and histamine were present in distinct intracellular granules and that most serotonin-containing granules were VAMP-8-positive. Thus, this study demonstrates that mast cells do indeed possess distinct subsets of secretory granules and that these subsets use different SNARE isoforms for exocytosis. C1 [Puri, Niti; Roche, Paul A.] NCI, Natl Inst Hlth, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Roche, PA (reprint author), NCI, Natl Inst Hlth, Expt Immunol Branch, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. EM paul.roche@nih.gov FU Intramural NIH HHS NR 20 TC 103 Z9 105 U1 2 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 FEB 19 PY 2008 VL 105 IS 7 BP 2580 EP 2585 DI 10.1073/pnas.0707854105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 266XB UT WOS:000253469900060 PM 18250339 ER PT J AU Jacobson-Kram, D Mattison, D Shelby, M Slikker, W Tice, R Witt, K AF Jacobson-Kram, David Mattison, Donald Shelby, Michael Slikker, William Tice, Raymond Witt, Kristine TI Methylphenidate and chromosome damage SO CANCER LETTERS LA English DT Letter ID ABERRATIONS; CHILDREN; CANCER; RISK C1 [Jacobson-Kram, David] US FDA, Ctr Drug Evaluat & Res, Off New Drug, Silver Spring, MD 20993 USA. [Mattison, Donald] Natl Inst Child Hlth & Dev, NIH, Rockville, MD 20892 USA. [Shelby, Michael; Tice, Raymond; Witt, Kristine] NIEHS, NIH, Res Triangle Pk, NC 27709 USA. [Slikker, William] US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. RP Jacobson-Kram, D (reprint author), US FDA, Ctr Drug Evaluat & Res, Off New Drug, Silver Spring, MD 20993 USA. EM david.jacobsonkram@fda.hhs.gov RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013 OI Mattison, Donald/0000-0001-5623-0874 NR 8 TC 8 Z9 8 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 FEB 18 PY 2008 VL 260 IS 1-2 BP 216 EP 218 DI 10.1016/j.canlet.2007.10.017 PG 3 WC Oncology SC Oncology GA 264HM UT WOS:000253278400025 PM 18055105 ER PT J AU DeLeo, FR Otto, M AF DeLeo, Frank R. Otto, Michael TI An antidote for Staphylococcus aureus pneumonia? SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID PANTON-VALENTINE LEUKOCIDIN; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; UNITED-STATES; PHAGOCYTOSIS; INFECTIONS; POLYSACCHARIDE; OPSONIZATION; NEUTROPHILS; ANTIBODIES; SURVIVAL AB Methicillin-resistant Staphylococcus aureus (MRSA) is the leading cause of bacterial infections in the United States. Severe invasive MRSA infections, which include pneumonia, are difficult to treat because the bacteria are resistant to antibiotics. A new report now shows that immunization against alpha-hemolysin (Hla), a cytolytic toxin secreted by most S. aureus strains, protects mice against lethal pneumonia. This finding represents the first successful vaccine strategy for the treatment of staphylococcal pneumonia. C1 [DeLeo, Frank R.; Otto, Michael] NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, Natl Inst Hlth, Hamilton, MT 59840 USA. RP DeLeo, FR (reprint author), NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, Natl Inst Hlth, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov OI DeLeo, Frank/0000-0003-3150-2516; Otto, Michael/0000-0002-2222-4115 FU Intramural NIH HHS NR 30 TC 37 Z9 39 U1 0 U2 5 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 FEB 18 PY 2008 VL 205 IS 2 BP 271 EP 274 DI 10.1084/jem.20080167 PG 4 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 263XR UT WOS:000253250300004 PM 18268043 ER PT J AU Hume, JCC Barnish, G Mangal, T Armazio, L Streat, E Bates, I AF Hume, Jen C. C. Barnish, Guy Mangal, Tara Armazio, Luiz Streat, Elizabeth Bates, Imelda TI Household cost of malaria overdiagnosis in rural Mozambique SO MALARIA JOURNAL LA English DT Article ID ECONOMIC COST; SRI-LANKA; TANZANIA AB Background: It is estimated that over 70% of patients with suspected malaria in sub-Saharan Africa, diagnose and manage their illness at home without referral to a formal health clinic. Of those patients who do attend a formal health clinic, malaria overdiagnosis rates are estimated to range between 30-70%. Methods: This paper details an observational cohort study documenting the number and cost of repeat consultations as a result of malaria overdiagnosis at two health care providers in a rural district of Mozambique. 535 adults and children with a clinical diagnosis of malaria were enrolled and followed over a 21 day period to assess treatment regimen, symptoms, number and cost of repeat visits to health providers in patients misdiagnosed with malaria compared to those with confirmed malaria (determined by positive bloodfilm reading). Results: Diagnosis based solely on clinical symptoms overdiagnosed 23% of children (< 16y) and 31% of adults with malaria. Symptoms persisted (p = 0.023) and new ones developed (p < 0.001) in more adults than children in the three weeks following initial presentation. Adults overdiagnosed with malaria had more repeat visits (67% v 46%, p = 0.01-0.06) compared to those with true malaria. There was no difference in costs between patients correctly or incorrectly diagnosed with malaria. Median costs over three weeks were $0.28 for those who had one visit and $0.76 for >= 3 visits and were proportionally highest among the poorest (p < 0.001) Conclusion: Overdiagnosis of malaria results in a greater number of healthcare visits and associated cost for adult patients. Additionally, it is clear that the poorest individuals pay significantly more proportionally for their healthcare making it imperative that the treatment they receive is correct in order to prevent wastage of limited economic resources. Thus, investment in accurate malaria diagnosis and appropriate management at primary level is critical for improving health outcomes and reducing poverty. C1 [Hume, Jen C. C.; Barnish, Guy; Mangal, Tara; Bates, Imelda] Univ Liverpool, Liverpool Sch Trop Med, Dis Control Strategy Grp, Liverpool L3 5QA, Merseyside, England. [Hume, Jen C. C.] NIAID, NIH, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Streat, Elizabeth] Maputo Province Directorate Hlth, LSDI Malaria Program, Matola, Maputo, Mozambique. RP Bates, I (reprint author), Univ Liverpool, Liverpool Sch Trop Med, Dis Control Strategy Grp, Liverpool L3 5QA, Merseyside, England. EM humej@niaid.nih.gov; gbarnish@liv.ac.uk; tmangal@liv.ac.uk; eastreat@gmail.com; ibates@liv.ac.uk NR 18 TC 23 Z9 23 U1 0 U2 1 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 FEB 18 PY 2008 VL 7 AR 33 DI 10.1186/1475-2875-7-33 PG 8 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 283MD UT WOS:000254639400001 PM 18282270 ER PT J AU Klionsky, DJ Abeliovich, H Agostinis, P Agrawal, DK Aliev, G Askew, DS Baba, M Baehrecke, EH Bahr, BA Ballabio, A Bamber, BA Bassham, DC Bergamini, E Bi, XN Biard-Piechaczyk, M Blum, JS Breclesen, DE Brodsky, JL Brumell, JH Brunk, UT Bursch, W Camougrand, N Cebollero, E Cecconi, F Chen, YY Chin, LS Choi, A Chu, CT Chung, JK Clarke, PGH Clark, RSB Clarke, SG Clave, C Cleveland, JL Codogno, P Colombo, MI Coto-Montes, A Cregg, JM Cuervo, AM Debnath, J Demarchi, F Dennis, PB Dennis, PA Deretic, V Devenish, RJ Di Sano, F Dice, JF DiFiglia, M Dinesh-Kumar, S Distelhorst, CW Djavaheri-Mergny, M Dorsey, FC Droge, W Dron, M Dunn, WA Duszenko, M Eissa, NT Elazar, Z Esclatine, A Eskelinen, EL Fesues, L Finley, KD Fuentes, JM Fueyo, J Fujisaki, K Galliot, B Gao, FB Gewirtz, DA Gibson, SB Gohla, A Goldberg, AL Gonzalez, R Gonzalez-Estevez, C Gorski, S Gottlieb, RA Haussinger, D He, YW Heidenreich, K Hill, JA Hoyer-Hansen, M Hu, X Huang, WP Iwasaki, A Jaattela, M Jackson, WT Jiang, X Jin, SK Johansen, T Jung, JU Kadowaki, M Kang, C Kelekar, A Kessel, DH Kiel, JAKW Kim, HP Kimchi, A Kinsella, TJ Kiselyov, K Kitamoto, K Knecht, E Komatsu, M Kominami, E Konclo, S Kovacs, AL Kroemer, G Kuan, CY Kumar, R Kundu, M Landry, J Laporte, M Le, WD Lei, HY Lenardo, MJ Levine, B Lieberman, A Lim, KL Lin, FC Liou, W Liu, LF Lopez-Berestein, G Lopez-Otin, C Lu, B Macleod, KF Malorni, W Martinet, W Matsuoka, K Mautner, J Meijer, AJ Melendez, A Michels, P Miotto, G Mistiaen, WP Mizushima, N Mograbi, B Monastyrska, I Moore, MN Moreira, PI Moriyasu, Y Motyl, T Munz, C Murphy, LO Naqvi, NI Neufeld, TP Nishino, I Nixon, RA Noda, T Nurnberg, B Ogawa, M Oleinick, NL Olsen, LJ Ozpolat, B Paglin, S Palmer, GE Papassideri, I Parkes, M Perlmutter, DH Perry, G Piacentini, M Pinkas-Kramarski, R Prescott, M Proikas-Cezanne, T Raben, N Rami, A Reggiori, F Rohrer, B Rubinsztein, DC Ryan, KM Sadoshima, J Sakagami, H Sakai, Y Sandri, M Sasakawa, C Sass, M Schneider, C Seglen, PO Seleverstov, O Settleman, J Shacka, JJ Shapiro, IM Sibirny, A Silva-Zacarin, ECM Simon, HU Simone, C Simonsen, A Smith, MA Spanel-Borowski, K Srinivas, V Steeves, M Stenmark, H Stromhaug, PE Subauste, CS Sugimoto, S Sulzer, D Suzuki, T Swanson, MS Takeshita, F Talbot, NJ Talloczy, Z Tanaka, K Tanaka, K Tanida, I Taylor, GS Taylor, JP Terman, A Tettamanti, G Thompson, CB Thumm, M Tolkovsky, AM Tooze, SA Truant, R Tumanovska, LV Uchiyama, Y Ueno, T Uzcategui, NL van der Klei, I Vaquero, EC Vellai, T Vogel, MW Wang, HG Webster, P Wiley, JW Xi, ZJ Xiao, G Yahalom, J Yang, JM Yap, G Yin, XM Yoshimori, T Yu, L Yue, ZY Yuzaki, M Zabirnyk, O Zheng, XX Zhu, X Deter, RL Tabas, I AF Klionsky, Daniel J. Abeliovich, Hagai Agostinis, Patrizia Agrawal, Devendra K. Aliev, Giumrakch Askew, David S. Baba, Misuzu Baehrecke, Eric H. Bahr, Ben A. Ballabio, Andrea Bamber, Bruce A. Bassham, Diane C. Bergamini, Ettore Bi, Xiaoning Biard-Piechaczyk, Martine Blum, Janice S. Breclesen, Dale E. Brodsky, Jeffrey L. Brumell, John H. Brunk, Ulf T. Bursch, Wilfried Camougrand, Nadine Cebollero, Eduardo Cecconi, Francesco Chen, Yingyu Chin, Lih-Shen Choi, Augustine Chu, Charleen T. Chung, Jongkyeong Clarke, Peter G. H. Clark, Robert S. B. Clarke, Steven G. Clave, Corinne Cleveland, John L. Codogno, Patrice Colombo, Maria I. Coto-Montes, Ana Cregg, James M. Cuervo, Ana Maria Debnath, Jayanta Demarchi, Francesca Dennis, Patrick B. Dennis, Phillip A. Deretic, Vojo Devenish, Rodney J. Di Sano, Federica Dice, J. Fred DiFiglia, Marian Dinesh-Kumar, Savithramma Distelhorst, Clark W. Djavaheri-Mergny, Mojgan Dorsey, Frank C. Droege, Wulf Dron, Michel Dunn, William A., Jr. Duszenko, Michael Eissa, N. Tony Elazar, Zvulun Esclatine, Audrey Eskelinen, Eeva-Liisa Fesues, Laszlo Finley, Kim D. Fuentes, Jose M. Fueyo, Juan Fujisaki, Kozo Galliot, Brigitte Gao, Fen-Biao Gewirtz, David A. Gibson, Spencer B. Gohla, Antje Goldberg, Alfred L. Gonzalez, Ramon Gonzalez-Estevez, Cristina Gorski, Sharon Gottlieb, Roberta A. Haussinger, Dieter He, You-Wen Heidenreich, Kim Hill, Joseph A. Hoyer-Hansen, Maria Hu, Xun Huang, Wei-Pang Iwasaki, Akiko Jaattela, Marja Jackson, William T. Jiang, Xuejun Jin, Shengkan Johansen, Terje Jung, Jae U. Kadowaki, Motoni Kang, Chanhee Kelekar, Ameeta Kessel, David H. Kiel, Jan A. K. W. Kim, Hong Pyo Kimchi, Adi Kinsella, Timothy J. Kiselyov, Kirill Kitamoto, Katsuhiko Knecht, Erwin Komatsu, Masaaki Kominami, Eiki Konclo, Seiji Kovacs, Attila L. Kroemer, Guido Kuan, Chia-Yi Kumar, Rakesh Kundu, Mondira Landry, Jacques Laporte, Marianne Le, Weidong Lei, Huan-Yao Lenardo, Michael J. Levine, Beth Lieberman, Andrew Lim, Kah-Leong Lin, Fu-Cheng Liou, Willisa Liu, Leroy F. Lopez-Berestein, Gabriel Lopez-Otin, Carlos Lu, Bo Macleod, Kay F. Malorni, Walter Martinet, Wim Matsuoka, Ken Mautner, Josef Meijer, Alfred J. Melendez, Alicia Michels, Paul Miotto, Giovanni Mistiaen, Wilhelm P. Mizushima, Noboru Mograbi, Baharia Monastyrska, Iryna Moore, Michael N. Moreira, Paula I. Moriyasu, Yuji Motyl, Tomasz Muenz, Christian Murphy, Leon O. Naqvi, Naweed I. Neufeld, Thomas P. Nishino, Ichizo Nixon, Ralph A. Noda, Takeshi Nuernberg, Bernd Ogawa, Michinaga Oleinick, Nancy L. Olsen, Laura J. Ozpolat, Bulent Paglin, Shoshana Palmer, Glen E. Papassideri, Issidora Parkes, Miles Perlmutter, David H. Perry, George Piacentini, Mauro Pinkas-Kramarski, Ronit Prescott, Mark Proikas-Cezanne, Tassula Raben, Nina Rami, Abdelhaq Reggiori, Fulvio Rohrer, Baerbel Rubinsztein, David C. Ryan, Kevin M. Sadoshima, Junichi Sakagami, Hiroshi Sakai, Yasuyoshi Sandri, Marco Sasakawa, Chihiro Sass, Miklos Schneider, Claudio Seglen, Per O. Seleverstov, Oleksandr Settleman, Jeffre Shacka, John J. Shapiro, Irving M. Sibirny, Andrei Silva-Zacarin, Elaine C. M. Simon, Hans-Uwe Simone, Cristiano Simonsen, Anne Smith, Mark A. Spanel-Borowski, Katharina Srinivas, Vickram Steeves, Meredith Stenmark, Harald Stromhaug, Per E. Subauste, Carlos S. Sugimoto, Seiichiro Sulzer, David Suzuki, Toshihiko Swanson, Michele S. Takeshita, Fumihiko Talbot, Nicholas. J. Talloczy, Zsolt Tanaka, Keiji Tanaka, Kozo Tanida, Isei Taylor, Graham S. Taylor, J. Paul Terman, Alexei Tettamanti, Gianluca Thompson, Craig B. Thumm, Michael Tolkovsky, Aviva M. Tooze, Sharon A. Truant, Ray Tumanovska, Lesya V. Uchiyama, Yasuo Ueno, Takashi Uzcategui, Nestor L. van der Klei, Ida Vaquero, Eva C. Vellai, Tibor Vogel, Michael W. Wang, Hong-Gang Webster, Paul Wiley, John W. Xi, Zhijun Xiao, Gutian Yahalom, Joachim Yang, Jin-Ming Yap, George Yin, Xiao-Min Yoshimori, Tamotsu Yu, Li Yue, Zhenyu Yuzaki, Michisuke Zabirnyk, Olga Zheng, Xiaoxiang Zhu, Xiongwei Deter, Russell L. Tabas, Ira TI Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes SO AUTOPHAGY LA English DT Review DE autolysosome; autophagosome; flux; lysosome; phagophore; stress; vacuole ID GLUCAGON-INDUCED AUTOPHAGY; MURINE PANCREATIC ACINAR; ISOLATED RAT HEPATOCYTES; SEMINAL-VESICLE CELLS; DROSOPHILA FAT-BODY; BETAINE HOMOCYSTEINE METHYLTRANSFERASE; VINBLASTINE-INDUCED AUTOPHAGOCYTOSIS; ELECTRON MICROSCOPIC EXAMINATION; CHAPERONE-MEDIATED AUTOPHAGY; STARVATION-INDUCED AUTOPHAGY AB Research in autophagy continues to accelerate,1 and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response. C1 [Klionsky, Daniel J.] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. [Klionsky, Daniel J.] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Klionsky, Daniel J.] Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA. 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[Clarke, Steven G.] Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90024 USA. [Clave, Corinne] Univ Bordeaux 2, Inst Biochim & Genet Cellulaires, Lab Genet Mol Champignons, F-33076 Bordeaux, France. [Codogno, Patrice; Djavaheri-Mergny, Mojgan; Esclatine, Audrey] Univ Paris 11, Chatenay Malabry, France. [Codogno, Patrice; Djavaheri-Mergny, Mojgan; Esclatine, Audrey] INSERM, U756, Chatenay Malabry, France. [Cleveland, John L.; Steeves, Meredith] Scripps Res Inst, Dept Canc Biol, Jupiter, FL USA. [Colombo, Maria I.] Univ Nacl Cuyo, CONICET, Lab Biol Celular & Mol, Inst Histol & Embryol, RA-5500 Mendoza, Argentina. [Coto-Montes, Ana] Univ Oviedo, Dept Morfol & Biol Celular, E-33006 Oviedo, Spain. [Cregg, James M.] Keck Grad Inst Appl Sci, Claremont, CA USA. [Cuervo, Ana Maria] Albert Einstein Coll Med, Marion Bessin Liver Res Ctr, Dept Anat & Struct Biol & Dev & Mol Biol, Bronx, NY 10467 USA. [Debnath, Jayanta] Univ Calif San Francisco, Dept Pathol, San Francisco, CA USA. [Demarchi, Francesca] Lab Nazl Consorzio Interuniv Biotecnol, Trieste, Italy. [Demarchi, Francesca] Univ Cincinnati, Dept Genome Sci, Cincinnati, OH USA. [Dennis, Phillip A.] USN Med Oncol, NCI, Med Oncol Branch, Bethesda, MD 20892 USA. [Deretic, Vojo] Univ New Mexico, Hlth Sci Ctr, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. [Devenish, Rodney J.] Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic 3004, Australia. [Devenish, Rodney J.] Monash Univ, ARC Ctr Excellence Struct & Funct Microbial Genom, Melbourne, Vic 3004, Australia. [Di Sano, Federica] Univ Roma Tor Vergata, Dipartimento Biol, I-00173 Rome, Italy. [Dice, J. Fred] Tufts Univ, Dept Physiol, Boston, MA 02111 USA. [DiFiglia, Marian] Massachusetts Gen Hosp, Dept Neurol, Charlestown, MA USA. [Dinesh-Kumar, Savithramma] Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT USA. [Distelhorst, Clark W.] Case Western Reserve Univ, Ctr Comprehens Canc, Dept Med, Cleveland, OH 44106 USA. 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[Michels, Paul] Catholic Univ Louvain, Duve Inst, Trop Dis Res Unit, Brussels, Belgium. [Michels, Paul] Catholic Univ Louvain, Biochem Lab, Brussels, Belgium. [Miotto, Giovanni] Univ Padua, Dept Biol Chem, Padua, Italy. [Mistiaen, Wilhelm P.] Univ Coll Antwerp, Dept Healthcare Sci, Antwerp, Belgium. [Mizushima, Noboru] Tokyo Med & Dent Univ, Dept Physiol & Cell Biol, Tokyo, Japan. [Mograbi, Baharia] INSERM, ERI 21, Nice, France. [Mograbi, Baharia] IFR 50, Lab Pathol Clin & Expt, Nice, France. [Monastyrska, Iryna; Reggiori, Fulvio] Univ Utrecht, Med Ctr, Dept Cell Biol, Utrecht, Netherlands. [Moore, Michael N.] Plymouth Marine Lab, Plymouth, Devon, England. [Moreira, Paula I.] Ctr Neurosci & Cell Biol, Inst Physiol, Coimbra, Portugal. [Moriyasu, Yuji] Saitama Univ, Grad Sch Sci & Engn, Div Life Sci, Saitama, Japan. [Motyl, Tomasz] Agr Univ Warsaw, Dept Physiol Sci, Warsaw, Poland. [Muenz, Christian] Rockefeller Univ, Lab Viral Immunobiol, New York, NY 10021 USA. [Murphy, Leon O.] Novartis Inst Biomed Res, Cambridge, MA USA. [Naqvi, Naweed I.] Natl Univ Singapore, Temasek Life Sci Lab, Fungal Pathobiol Grp, Singapore 117548, Singapore. [Nishino, Ichizo] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Dept Neuromuscular Res, Kodaira, Tokyo 187, Japan. [Nixon, Ralph A.] NYU, Sch Med, Nathan Kline Inst, Orangeburg, NY USA. [Noda, Takeshi; Yoshimori, Tamotsu] Osaka Univ, Res Inst Microbial Dis, Dept Cellular Regulat, Osaka, Japan. [Nuernberg, Bernd] Univ Dusseldorf, Inst Biochem & Mol Biol 2, Dusseldorf, Germany. [Ogawa, Michinaga] Univ Tokyo, Dept Microbiol & Immunol, Tokyo, Japan. [Oleinick, Nancy L.] Case Western Reserve Univ, Dept Radiat Oncol, Cleveland, OH USA. [Oleinick, Nancy L.] Case Western Reserve Univ, Dept Biochem, Cleveland, OH 44106 USA. [Oleinick, Nancy L.] Case Western Reserve Univ, Dept Environm Hlth Sci, Cleveland, OH 44106 USA. [Oleinick, Nancy L.] Case Western Reserve Univ, Case Comprehens Canc Ctr, Cleveland, OH 44106 USA. [Olsen, Laura J.] Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. [Paglin, Shoshana] Chaim Sheba Med Ctr, Dept Oncol, Ramat Gan, Israel. [Palmer, Glen E.] Louisiana State Univ, Hlth Sci Ctr, Sch Dent, Dept Oral & Craniofacial Biol, New Orleans, LA USA. [Papassideri, Issidora] Dept Cell Biol & Biophys, Athens, Greece. [Parkes, Miles] Univ Cambridge, Addenbrookes Hosp, Inflammatory Bowel Dis Res Grp, Cambridge CB2 2QQ, England. [Perlmutter, David H.] Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15261 USA. [Perlmutter, David H.] Childrens Hosp Pittsburgh, Pittsburgh, PA 15213 USA. [Piacentini, Mauro] Univ Roma Tor Vergata, Dipartimento Biol, I-00173 Rome, Italy. [Pinkas-Kramarski, Ronit] Tel Aviv Univ, Dept Neurobiochem, IL-69978 Tel Aviv, Israel. [Prescott, Mark] Monash Univ, Dept Biochem & Mol Biol, Melbourne, Vic 3004, Australia. [Proikas-Cezanne, Tassula] Univ Tubingen, Dept Mol Biol, Tubingen, Germany. [Raben, Nina] NIAMSD, Natl Inst Hlth, Arthritis & Rheumatism Branch, Bethesda, MD USA. [Rami, Abdelhaq] Clin JWG Univ, Inst Cellular & Mol Anat, Frankfurt, Germany. [Rohrer, Baerbel] Med Univ S Carolina, Ophthalmol & Neurosci Div, Charleston, SC 29425 USA. [Rubinsztein, David C.] Cambridge Inst Med Res, Dept Med Genet, Cambridge, England. [Ryan, Kevin M.] Beatson Inst Canc Res, Tumor Cell Death Lab, Glasgow G61 1BD, Lanark, Scotland. [Sadoshima, Junichi] Univ Med & Dent New Jersey, Sch Med, Cardiovasc Res Inst, Dept Cell Biol & Mol Med, Newark, NJ 07103 USA. [Sakagami, Hiroshi] Meikai Univ, Sch Dent, Dept Diagnost & Therapeut Sci, Sakado, Saitama 35002, Japan. [Sakai, Yasuyoshi] Kyoto Univ, Div Appl Life Sci, Kyoto, Japan. [Sakai, Yasuyoshi] JST, CREST, Kyoto, Japan. [Sandri, Marco] Univ Padua, Dept Biomed Sci, Padua, Italy. [Sandri, Marco] Venetan Inst Mol Med, Dulbecco Telethon Inst, Padua, Italy. [Sasakawa, Chihiro] Univ Tokyo, Dept Microbiol & Immunol, Tokyo, Japan. [Sass, Miklos] Univ Oslo, Rikshosp, Radiumhosp HF, Inst Canc Res,Dept Cell Biol, N-0027 Oslo, Norway. [Seleverstov, Oleksandr] Univ Oslo, Dept Mol Biosci, N-0027 Oslo, Norway. [Seglen, Per O.] Univ Wyoming, Dept Anim Sci, Laramie, WY 82071 USA. [Brodsky, Jeffrey L.] Massachusetts Gen Hosp, Ctr Canc, Charlestown, MA USA. [Shacka, John J.] Univ Alabama Birmingham, Dept Pathol, Birmingham, AL 35294 USA. [Shapiro, Irving M.; Srinivas, Vickram] Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. [Sibirny, Andrei] Natl Acad Sci Ukraine, Inst Cell Biol, Lvov, Ukraine. [Silva-Zacarin, Elaine C. M.] Univ Fed Sao Carlos, Sorocaba, Brazil. [Simon, Hans-Uwe] Univ Bern, Dept Pharmacol, Bern, Switzerland. [Simone, Cristiano] Ist Ric Farmacol Mario Negri, Consorzio Mario Negri Sud, Dept Translat Pharmacol, I-66030 Santa Maria Imbaro, Italy. [Simonsen, Anne] Univ Oslo, Ctr Canc Biomed, Oslo, Norway. [Simonsen, Anne; Stenmark, Harald] Norwegian Radium Hosp, Dept Biochem, Oslo, Norway. [Smith, Mark A.; Zhu, Xiongwei] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA. [Spanel-Borowski, Katharina] Univ Leipzig, Inst Anat, Leipzig, Germany. [Stromhaug, Per E.] Univ Missouri, Div Biol, Columbia, MO USA. [Subauste, Carlos S.] Case Western Reserve Univ, Sch Med, Inst Pathol, Dept Ophthalmol, Cleveland, OH USA. [Subauste, Carlos S.] Case Western Reserve Univ, Sch Med, Inst Pathol, Dept Med, Cleveland, OH USA. [Sugimoto, Seiichiro] Natl Hosp Org, Miyazaki Higashi Hosp, Dept Neurol, Miyazaki, Japan. [Sulzer, David; Talloczy, Zsolt] Columbia Univ, Dept Neurol, New York, NY USA. [Sulzer, David; Talloczy, Zsolt] Columbia Univ, Dept Psychiat, New York, NY USA. [Suzuki, Toshihiko] Univ Ryukyus, Dept Microbiol, Okinawa, Japan. [Swanson, Michele S.] Univ Michigan, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. [Tabas, Ira] Columbia Univ, Dept Med, New York, NY USA. [Takeshita, Fumihiko] Yokohama City Univ, Grad Sch Med, Dept Mol Biodef Res, Yokohama, Kanagawa 232, Japan. [Talbot, Nicholas. J.] Univ Exeter, Sch Biosci, Exeter, Devon, England. [Tanaka, Kozo] Tohoku Univ, Ctr Res Strategy & Support, Inst Dev Aging & Canc, Sendai, Miyagi 980, Japan. [Tanida, Isei] Natl Inst Infect Dis, Dept Biochem & Cell Biol, Tokyo, Japan. [Taylor, Graham S.] Univ Birmingham, CRUK Inst Canc Studies, Birmingham, W Midlands, England. [Taylor, J. Paul] Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. [Terman, Alexei] Linkoping Univ, Fac Hlth Sci, Div Geriatr Med, Linkoping, Sweden. [Tettamanti, Gianluca] Univ Insubria, Dept Struct & Funct Biol, Varese, Italy. [Thumm, Michael] Univ Gottingen, Zentrum Biochem & Mol Zellbiol, Gottingen, Germany. [Tolkovsky, Aviva M.] Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England. [Tooze, Sharon A.] Canc Res UK London Res Inst, Secretory Pathways Lab, London, England. [Truant, Ray] McMaster Univ, Hamilton, ON, Canada. [Tumanovska, Lesya V.] AA Bogomolets Physiol Inst, Dept Gen & Mol Pathophysiol, UA-252601 Kiev, Ukraine. [Uchiyama, Yasuo] Osaka Univ, Grad Sch Med, Dept Cell Biol & Neurosci, Osaka, Japan. [Uzcategui, Nestor L.] Cent Univ Venezuela, Escuela Bioanal, Caracas, Venezuela. [Vaquero, Eva C.] Hosp Clin Barcelona, Div Gastroenterol, Barcelona, Catalonia, Spain. [Vellai, Tibor] Eotvos Lorand Univ, Dept Genet, Budapest, Hungary. [Vogel, Michael W.] Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA. [Wang, Hong-Gang] H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. [Webster, Paul] House Ear Res Inst, Ahmanson Ctr Adv Elect Microscopy & Imaging, Los Angeles, CA USA. [Wiley, John W.] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. [Xi, Zhijun] Peking Univ, Hosp 1, Dept Urol, Beijing 100871, Peoples R China. [Xiao, Gutian] Univ Pittsburgh, Sch Med, Dept Microbiol & Mol Genet, Pittsburgh, PA USA. [Yang, Jin-Ming] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Canc Inst New Jersey, New Brunswick, NJ USA. [Yap, George] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Med, Newark, NJ 07103 USA. [Yin, Xiao-Min] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA. [Yue, Zhenyu] Mt Sinai Sch Med, Dept Neurol & Neurosci, New York, NY USA. [Yuzaki, Michisuke] Keio Univ, Sch Med, Dept Neurophysiol, Tokyo, Japan. [Zabirnyk, Olga] NCI, Ctr Canc Res, Comparat Carcinogenesis Lab, Metab & Canc Susceptibil Sect, Frederick, MD USA. [Zabirnyk, Olga] Natl Inst Hlth, Frederick, MD USA. [Zheng, Xiaoxiang] Zhejiang Univ, Dept Biomed Engn, Zhejiang, Peoples R China. [Deter, Russell L.] Baylor Univ, Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. [Distelhorst, Clark W.] Case Western Reserve Univ, Ctr Comprehens Canc, Dept Pathol, Cleveland, OH 44106 USA. RP Klionsky, DJ (reprint author), Univ Michigan, Inst Life Sci, Rm 6036,210 Washtenaw Ave, Ann Arbor, MI 48109 USA. EM klionsky@umich.edu RI van der Klei, Ida/D-1919-2012; Tettamanti, Gianluca/E-5465-2012; Chu, Charleen/B-1601-2008; Gonzalez-Estevez, Cristina/I-9326-2012; Kroemer, Guido/B-4263-2013; Codogno, Patrice/G-1384-2013; Galliot, Brigitte/I-7051-2013; Mizushima, Noboru/C-3635-2009; Knecht, Erwin/A-9366-2014; Tang, Macy/B-9798-2014; Liao, Yung-Feng/A-9761-2011; Gorski, Sharon/E-9375-2012; Fuentes, Jose/H-9490-2014; Matsuoka, Ken/E-3215-2010; Kominami, Eiki/D-3802-2009; Noda, Takeshi/B-7240-2008; Dinesh-Kumar, Savithramma/E-1153-2011; Gonzalez, Ramon/G-9281-2011; Gonzalez, Ramon/B-7843-2008; Stenmark, Harald/B-8868-2008; Michels, Paul/A-5637-2009; Smith, Mark/A-9053-2009; Zhu, Xiongwei/A-9629-2009; Moreira, Paula/B-3608-2009; Tanida, Isei/C-8277-2009; Perry, George/A-8611-2009; lu, bo/G-4573-2010; Talbot, Nicholas/I-9584-2014; Knecht, Erwin/K-2432-2014; Yuzaki, Michisuke/K-5328-2013; Wang, Hong-Gang/A-3018-2015; Thumm, Michael/A-8033-2015; Martinet, Wim/I-7375-2015; Johansen, Terje/N-2971-2015; Malorni, Walter/G-5874-2016; Lopez-Otin, Carlos/C-6657-2013; Mistiaen, Wilhelm/C-3187-2017; Miotto, Giovanni/S-1903-2016; OI Tettamanti, Gianluca/0000-0002-0665-828X; Chu, Charleen/0000-0002-5052-8271; Codogno, Patrice/0000-0002-5492-3180; Mizushima, Noboru/0000-0002-6258-6444; Gorski, Sharon/0000-0002-3821-8289; Fuentes, Jose/0000-0001-6910-2089; Noda, Takeshi/0000-0003-3581-7961; Gonzalez, Ramon/0000-0001-7388-1660; Moreira, Paula/0000-0001-5177-6747; Perry, George/0000-0002-6547-0172; Deretic, Vojo/0000-0002-3624-5208; Subauste, Carlos/0000-0002-5602-1439; BALLABIO, Andrea/0000-0003-1381-4604; Nishino, Ichizo/0000-0001-9452-112X; HUANG, WEI-PANG/0000-0001-8410-6555; Mograbi, Baharia/0000-0002-1025-3429; Van der Klei, Ida J./0000-0001-7165-9679; Vogel, Michael/0000-0002-8402-1495; Gibson, Spencer/0000-0003-0119-732X; Simon, Hans-Uwe/0000-0002-9404-7736; Demarchi, Francesca/0000-0003-1565-3162; Talbot, Nicholas/0000-0001-6434-7757; Knecht, Erwin/0000-0002-7208-3832; Yuzaki, Michisuke/0000-0002-5750-3544; Johansen, Terje/0000-0003-1451-9578; Lopez-Otin, Carlos/0000-0001-6964-1904; Mistiaen, Wilhelm/0000-0001-8583-2524; Miotto, Giovanni/0000-0002-4278-4873; SIMONE, Cristiano/0000-0002-2628-7658 FU Biotechnology and Biological Sciences Research Council [BB/E01030X/1]; Medical Research Council [G0600194, G0600194(77639), G0601133]; NCI NIH HHS [R01 CA023378, R01 CA023378-29]; NIA NIH HHS [R01 AG026389, R01 AG026389-01A2]; NIAID NIH HHS [P01 AI056097, R01 AI079065]; NIAMS NIH HHS [R01 AR055255, R01 AR055255-02]; NIGMS NIH HHS [GM53396, R01 GM053396, R01 GM062509, R01 GM075061, R01 GM075061-03]; Telethon [TCR04004]; Wellcome Trust [064354] NR 207 TC 1507 Z9 1604 U1 64 U2 436 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 530 WALNUT STREET, STE 850, PHILADELPHIA, PA 19106 USA SN 1554-8627 EI 1554-8635 J9 AUTOPHAGY JI Autophagy PD FEB 16 PY 2008 VL 4 IS 2 BP 151 EP 175 PG 25 WC Cell Biology SC Cell Biology GA 260KI UT WOS:000253008800003 PM 18188003 ER PT J AU Hsia, J Jablonski, KA Rice, MM Sabatine, MS Zabalgoitia, M Maggioni, A Cuddy, TE Domanski, MJ Geller, NL Flaker, G Solomon, S Omland, T Rouleau, JL AF Hsia, Judith Jablonski, Kathleen A. Rice, Madeline Murguia Sabatine, Marc S. Zabalgoitia, Miguel Maggioni, Aldo Cuddy, Thomas E. Domanski, Michael J. Geller, Nancy L. Flaker, Greg Solomon, Scott Omland, Torbjorn Rouleau, Jean L. CA Behalf Peace Investigators TI Sudden cardiac death in patients with stable coronary artery disease and preserved left ventricular systolic function SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CONVERTING-ENZYME-INHIBITION; ACUTE MYOCARDIAL-INFARCTION; HEART-FAILURE; RISK SCORE; EVENTS; DYSFUNCTION; PREDICTION; MORTALITY; SURVIVORS; TRIALS AB Although sudden cardiac death (SCD) has been extensively studied in patients with coronary artery disease (CAD) and low ejection fraction, prediction of SCD among individuals with preserved left ventricular systolic function is less well understood. We randomized 8,290 patients with stable CAD with preserved left ventricular systolic function to trandolapril or placebo in a secondary coronary prevention trial, and we used Cox proportional hazards models to identify independent baseline predictors of SCD during 4.8 year follow-up (median). Using a risk scoring algorithm based on simple, clinical characteristics, we were able to distinguish individuals at higher risk for SCD. Independent determinants of SCD included age (p <0.001), current angina pectoris (p = 0.002), ejection fraction >40% to <50% (as opposed to >50%) (p <0.001), and diuretic (p <0.001) and digitalis use (p <0.001). Negative predictors included having prior coronary revascularization (p = 0.01) and being female (p = 0.02) or Caucasian (p = 0.006). Trandolapril neither increased nor decreased SCD. Thus, among patients with stable CAD with preserved left ventricular systolic function receiving current standard-of-care including coronary revascularization, clinical characteristics can identify individuals at higher risk for SCD. (C) 2008 Elsevier Inc. C1 [Hsia, Judith] George Washington Univ, Dept Med, Washington, DC USA. [Jablonski, Kathleen A.; Rice, Madeline Murguia] George Washington Univ, Ctr Biostat, Washington, DC USA. [Jablonski, Kathleen A.; Rice, Madeline Murguia] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Hsia, Judith] George Washington Univ, Dept Med, Rockville, MD USA. [Sabatine, Marc S.; Solomon, Scott] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA. [Sabatine, Marc S.; Solomon, Scott] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Zabalgoitia, Miguel] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, San Antonio, TX 78229 USA. [Maggioni, Aldo] AMNCO Fdn, Florence, Italy. [Cuddy, Thomas E.] Univ Manitoba, Winnipeg, MB, Canada. [Domanski, Michael J.; Geller, Nancy L.] NHLBI, Clin Trials Grp, Bethesda, MD 20892 USA. [Flaker, Greg] Univ Missouri, Dept Med, Columbia, MO USA. [Omland, Torbjorn] Akershus Univ Hosp, Lorenskog, Norway. [Rouleau, Jean L.] Univ Montreal, Montreal, PQ, Canada. RP Hsia, J (reprint author), George Washington Univ, Dept Med, Washington, DC USA. EM judith.hsia@astrazeneca.com FU NHLBI NIH HHS [N01HC65149] NR 21 TC 10 Z9 10 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 2008 VL 101 IS 4 BP 457 EP 461 DI 10.1016/j.amjcard.2007.09.107 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262UQ UT WOS:000253173900008 PM 18312757 ER PT J AU Kannel, WB Vasan, RS Keyes, MJ Sullivan, LM Robins, SJ AF Kannel, William B. Vasan, Ramachandran S. Keyes, Michelle J. Sullivan, Lisa M. Robins, Sander J. TI Usefulness of the triglyceride-high-density lipoprotein versus the cholesterol-high-density lipoprotein ratio for predicting insulin resistance and cardiometabolic risk (from the Framingham offspring cohort) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ISCHEMIC-HEART-DISEASE; GLUCOSE-TOLERANCE; ATHEROGENIC INDEX; PLASMA; HYPERINSULINEMIA; INDIVIDUALS; MARKERS; EVENTS AB Increased triglycerides (TG) and decreased high-density lipoprotein (HDL) cholesterol are key metabolic abnormalities in patients with insulin resistance (IR) states, including diabetes mellitus. The TG/HDL cholesterol ratio was advocated as a simple clinical indicator of IR, but studies yielded inconsistent results. The total cholesterol/HDL cholesterol ratio was widely used to assess lipid atherogenesis, but its utility for assessing IR or its associated coronary heart disease (CHD) risk was unknown. TG/HDL cholesterol and total cholesterol/HDL cholesterol ratios were related to IR (top quartile of the homeostasis model assessment-IR) in 3,014 patients (mean age 54 years; 55% women). Logistic regression was used to construct receiver-operator characteristic curves for predicting IR, with lipid ratios as predictors. Multivariable Cox regression was used to evaluate whether adjusting for lipid ratios attenuated the association of IR with CHD. Cross sectionally, age-and gender-adjusted correlations of IR were 0.46 with TG/HDL cholesterol ratio and 0.38 with total/HDL cholesterol ratio. IR prevalence increased across tertiles of lipid ratios (p <0.0001). The area under the receiver-operator characteristic curves for predicting IR with TG/HDL cholesterol ratio was 0.745, slightly higher than that for total/HDL cholesterol ratio (0.707; p <0.001 for comparison). On follow-up (mean 6.4 years), 112 patients experienced initial CHD events. IR was associated with CHD risk (multivariable-adjusted hazards ratio 2.71, 95% confidence interval 1.79 to 4.11), which remained significant even after adjustment for lipid ratios. In conclusion, our observations suggested that the TG/HDL cholesterol ratio was an imperfect surrogate for IR and its associated CHD risk, and it was only slightly better than the total/HDL cholesterol ratio for this purpose. (D 2008 Elsevier Inc. All rights reserved. C1 [Kannel, William B.; Vasan, Ramachandran S.; Keyes, Michelle J.; Sullivan, Lisa M.; Robins, Sander J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Kannel, William B.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Boston, MA 02118 USA. [Keyes, Michelle J.] Boston Univ, Dept Math, Boston, MA 02215 USA. [Sullivan, Lisa M.] Boston Univ, Dept Biostat, Boston, MA 02215 USA. RP Kannel, WB (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM billkannel@yahoo.com OI Ramachandran, Vasan/0000-0001-7357-5970; Sullivan, Lisa/0000-0003-0726-7149 FU NHLBI NIH HHS [K24 HL004334, 2K24HL04334, K24 HL004334-01A1, N01 HC025195, N01-HC-251595, N01HC25195] NR 20 TC 62 Z9 67 U1 0 U2 4 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 2008 VL 101 IS 4 BP 497 EP 501 DI 10.1016/j.amjcard.2007.09.109 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 262UQ UT WOS:000253173900016 PM 18312765 ER PT J AU Wilcox, AJ Skjaerven, R Lie, RT AF Wilcox, Allen J. Skjaerven, Rolv Lie, Rolv Terje TI Familial patterns of preterm delivery: Maternal and fetal contributions SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE family characteristics; genetics; premature birth ID BIRTH-WEIGHT; PATERNAL INFLUENCES; GENETIC-VARIATION; GESTATIONAL-AGE; RISK; POLYMORPHISMS; GENERATIONS; PREECLAMPSIA; ASSOCIATION; RECURRENCE AB Women who deliver preterm (< 37 completed weeks' gestation) are at high risk for recurrence. This has prompted exploration of candidate genes (both maternal and fetal) associated with preterm delivery. Epidemiologists can use recurrence patterns of preterm delivery across generations to assess the relative contributions of maternal and fetal genes. The authors used data from the Medical Birth Registry of Norway (1967-2004) to identify 191,282 mothers and 127,830 fathers who subsequently had at least one singleton offspring. The authors stratified parents according to whether or not they had been born preterm and calculated the risk of preterm delivery among their firstborn. Mothers born preterm had a relative risk for preterm delivery of 1.54 (95% confidence interval (CI): 1.42, 1.67). This association was weaker for fathers born preterm (relative risk (RR) = 1.12, 95% CI: 1.01, 1.25). Among early preterm births (< 35 weeks), the effect became stronger for mothers (RR = 1.85, 95% CI: 1.52, 2.27) and weaker for fathers (RR = 1.06, 95% CI: 0.77, 1.44). These data suggest that paternal genes have little, if any, effect on preterm delivery risk. This argues against major contributions of fetal genes inherited from either parent. The increased risk of preterm delivery among mothers born preterm is consistent with heritable maternal phenotypes that confer a propensity to deliver preterm. C1 [Wilcox, Allen J.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Skjaerven, Rolv; Lie, Rolv Terje] Univ Bergen, Fac Med, Dept Publ Hlth & Primary Care Hlth, Bergen, Norway. RP Wilcox, AJ (reprint author), NIEHS, Epidemiol Branch, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM wilcox@niehs.nih.gov OI Wilcox, Allen/0000-0002-3376-1311 FU Intramural NIH HHS NR 31 TC 65 Z9 66 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 15 PY 2008 VL 167 IS 4 BP 474 EP 479 DI 10.1093/aje/kwm319 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 263WC UT WOS:000253246200013 PM 18048376 ER PT J AU Boyles, AL Wilcox, AJ Taylor, JA Meyer, K Fredriksen, A Ueland, PM Drevon, CA Vollset, SE Lie, RT AF Boyles, Abee L. Wilcox, Allen J. Taylor, Jack A. Meyer, Klaus Fredriksen, Ase Ueland, Per Magne Drevon, Christian A. Vollset, Stein Emil Lie, Rolv Terje TI Folate and one-carbon metabolism gene polymorphisms and their associations with oral facial clefts SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE alleles; cleft lip; cleft palate; dietary supplements; folic acid; metabolism; humans; single nucleotide polymorphisms ID NEURAL-TUBE DEFECTS; METHYLENETETRAHYDROFOLATE REDUCTASE POLYMORPHISMS; COLORECTAL-CANCER RISK; OROFACIAL CLEFTS; SPINA-BIFIDA; CANDIDATE GENES; GENOTYPE CONTRIBUTES; METHIONINE SYNTHASE; C677T MUTATION; MTHFR GENOTYPE AB Folare metabolism plays a critical role in embryonic development. Prenatal folate supplementation reduces the risk of neural tube defects and probably oral facial clefts. Previous studies of related metabolic genes have associated polymorphisms in cystathionine-beta-synthase (CBS) and 5,10-methylenetetrahydrofolate reductase (MTHFR) with cleft risk. We explored associations between genes related to one-carbon metabolism and clefts in a Norwegian population-based study that included 362 families with cleft lip with Or without cleft palate (CUP) and 191 families with cleft palate only, (CPO). We previously showed a 39% reduction in risk of CUP with folic acid supplementation in this population. In the present study we genotyped 12 polymorphisms in nine genes related to one-carbon metabolism and looked for associations of clefting risk with fetal polymorphisms, maternal polymorphisms, as well as parent-of-origin effects, using combined likelihood-ratio tests (LRT). We also stratified by maternal periconceptional intake of folic acid (> 400 mu g) to explore gene-exposure interactions. We found a reduced risk of CUP with mothers who carried the CBS C699T variant (rs234706); relative risk was 0.94 with one copy of the T allele (95% Cl 0.63-1.4) and 0.50 (95% Cl 0.26-0.96) with two copies (P=0.008). We found no evidence of interaction of this variant with folate status. We saw no evidence of risk from the MTHFR C677T variant (rs1801133) either overall or after stratifying by maternal folate intake. No associations were found between any of the polymorphisms and CPO. Genetic variations in the nine metabolic genes examined here do not confer a substantial degree of risk for clefts. Published 2008 Wiley-Liss. Inc.(dagger) C1 [Boyles, Abee L.; Wilcox, Allen J.; Taylor, Jack A.] NIEHS, NIH, Epidemiol Branch, Durham, NC 27709 USA. [Meyer, Klaus; Fredriksen, Ase; Ueland, Per Magne] Univ Bergen, Pharmacol Sect, Inst Med, Bergen, Norway. [Meyer, Klaus; Fredriksen, Ase; Ueland, Per Magne] Haukeland Hosp, N-5021 Bergen, Norway. [Drevon, Christian A.] Univ Oslo, Inst Basic Med Sci, Dept Nutr, Fac Med, Oslo, Norway. [Vollset, Stein Emil; Lie, Rolv Terje] Univ Bergen, Dept Publ Hlth & Primary Hlth Care, Sect Epidemiol & Med Stat, Bergen, Norway. RP Boyles, AL (reprint author), NIEHS, NIH, Epidemiol Branch, Mail Drop A3-05,POB 12233, Durham, NC 27709 USA. EM boylesa@niehs.nih.gov RI Drevon, Christian /F-6012-2010; Ueland, Per/C-7340-2013; OI Boyles, Abee/0000-0002-8711-2077; Wilcox, Allen/0000-0002-3376-1311; taylor, jack/0000-0001-5303-6398 FU Intramural NIH HHS [Z99 ES999999] NR 70 TC 38 Z9 42 U1 0 U2 8 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD FEB 15 PY 2008 VL 146A IS 4 BP 440 EP 449 DI 10.1002/ajmg.a.32162 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 258CM UT WOS:000252846000005 PM 18203168 ER PT J AU Marszall, MP Moaddel, R Jozwiak, K Bernier, M Wainer, IW AF Marszall, Michal P. Moaddel, Ruin Jozwiak, Krzysztof Bernier, Michel Wainer, Irving W. TI Initial synthesis and characterization of an immobilized heat shock protein 90 column for online determination of binding affinities SO ANALYTICAL BIOCHEMISTRY LA English DT Article DE Hsp90; online screening; affinity chromatography; inhibitors ID ACETYLCHOLINE-RECEPTOR; LIQUID-CHROMATOGRAPHY; NONCOMPETITIVE INHIBITORS; STATIONARY-PHASE; SPECTROMETRY; CHAPERONE; CANCER AB Heat shock protein 90 alpha (Hsp90 alpha) was immobilized on aminopropyl silica via the N terminus to create the Hsp90 alpha(NT) column or via the C terminus to create the Hsp90 alpha(CT) column. Binding to the exposed C terminus on the Hsp90a(NT) column was characterized using frontal chromatography and the C-terminus ligands cournermycin A(1) (CA1) and novobiocin (NOVO). The calculated K-d values were 220 +/- 110 nM (CA1) and 100 +/- 20 nM (NOVO). Nonlinear chromatography was used to determine the association and dissociation rate constants associated with the NOVO-Hsp90 alpha complex: 22.2 +/- 8.8 mu M-1 s(-1) and 2.7 +/- 0.6 s(-1), respectively. Binding to the exposed N terminus on the Hsp90 alpha(CT) column was characterized using frontal chromatography. The K-d values of the N-terminus ligands geldanamycin (GM, 90 +/- 50 nM), 17-allylamino-17-demethoxygeldanamycin (17-AAG, 210 +/- 50 nM), and radicicol (RAD, 20 +/- 9 nM) were consistent with previously reported values. The effect of the immobilization on ATPase activity was investigated through the determination of IC50 values for inhibition of ATPase activity on the Hsp90 alpha(CT) column. The IC50 for GM was 2.80 +/- 0.18 mu M, and the relative IC50 values were 17-AAG > GM > RAD, in agreement with previously reported values and indicating that immobilization had not affected ATPase activity or sensitivity to inhibition. (C) 2007 Elsevier Inc. All rights reserved. C1 [Marszall, Michal P.; Moaddel, Ruin; Bernier, Michel; Wainer, Irving W.] NIA, Natl Inst Hlth, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Jozwiak, Krzysztof] Med Univ Lublin, Dept Chem, PL-20081 Lublin, Poland. RP Wainer, IW (reprint author), NIA, Natl Inst Hlth, Gerontol Res Ctr, Baltimore, MD 21224 USA. EM wainerir@grc.nia.nih.gov RI Marszall, Michal/G-8936-2014; OI Bernier, Michel/0000-0002-5948-368X FU Intramural NIH HHS [Z01 AG000296-06] NR 20 TC 15 Z9 15 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 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD FEB 15 PY 2008 VL 373 IS 2 BP 313 EP 321 DI 10.1016/j.ab.2007.11.001 PG 9 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 253JI UT WOS:000252514100017 PM 18047824 ER PT J AU Ward, MM AF Ward, Michael M. TI Avoidable hospitalizations in patients with systemic lupus erythematosus SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID CARE SENSITIVE CONDITIONS; PREVENTABLE HOSPITALIZATIONS; SOCIOECONOMIC-STATUS; HEALTH-CARE; MORTALITY; ADMISSION; DISEASE; ACCESS; RATES AB appropriate outpatient treatment. Avoidable hospitalizations thus serve as an indicator of poor access to, or underutilization of, medical care. This study examined risk factors for avoidable hospitalizations among patients with systemic lupus erythematosus (SLE). Methods. Data were obtained on acute-care hospitalizations in a population-based sample of 8,670 patients with SLE age >= 18 years hospitalized in New York state in 2000, 2001, and 2002. Hospitalizations were classified as avoidable based on the principal indication for hospitalization. Patient demographic and hospital characteristics were examined as risk factors. Results. Of 16,751 hospitalizations, 2,123 (12.7%) were for avoidable conditions, most commonly pneumonia, congestive heart failure, and cellulitis. The likelihood of avoidable hospitalizations increased progressively with age, was higher among patients with Medicare than among those with other types of medical insurance, and was higher among those of lower socioeconomic status. Hospitalizations for avoidable conditions were less likely at hospitals that admitted larger numbers of patients with SLE than at hospitals that admitted fewer patients with SLE. Conclusion. Avoidable hospitalizations occur more commonly among older and poorer patients, suggesting that these patients have more difficulty accessing care. The lower risk of avoidable hospitalizations at centers that admit large numbers of patients with SLE may be due to patient selection or may represent better outpatient care by physicians at these centers. C1 [Ward, Michael M.] IRP, NIAMS, NIH, Bethesda, MD 20892 USA. [Ward, Michael M.] NIAMSD, Intramural Res Program, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), IRP, NIAMS, NIH, Bldg 10 CRC,Room 4-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS NR 32 TC 21 Z9 23 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 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD FEB 15 PY 2008 VL 59 IS 2 BP 162 EP 168 DI 10.1002/art.23346 PG 7 WC Rheumatology SC Rheumatology GA 262UI UT WOS:000253173100003 PM 18240192 ER PT J AU Huber, AM Dugan, EM Lachenbruch, PA Feldman, BM Perez, MD Zemel, LS Lindsley, CB Rennebohm, RM Wallace, CA Passo, MH Reed, AM Bowyer, SL Ballinger, SH Miller, FW Rider, LG AF Huber, Adam M. Dugan, Elizabeth M. Lachenbruch, Peter A. Feldman, Brian M. Perez, Maria D. Zemel, Lawrence S. Lindsley, Carol B. Rennebohm, Robert M. Wallace, Carol A. Passo, Murray H. Reed, Ann M. Bowyer, Suzanne L. Ballinger, Susan H. Miller, Frederick W. Rider, Lisa G. CA Juvenile Dermatomyositis Dis Activ TI Preliminary validation and clinical meaning of the cutaneous assessment tool in juvenile dermatomyositis SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article ID IDIOPATHIC INFLAMMATORY MYOPATHIES; MYOSITIS ASSESSMENT SCALE; QUALITY-OF-LIFE; DISEASE-ACTIVITY; SKIN INVOLVEMENT; MUSCLE FUNCTION; DAMAGE INDEXES; RELIABILITY; CHILDREN AB Objective. To provide preliminary validation of the Cutaneous Assessment Tool (CAT), a new tool to assess cutaneous manifestations of juvenile dermatomyositis (DM), and to explore the clinical meaning of CAT scores. Methods. Children with juvenile DM (n = 113) were assessed at baseline and 7-9 months later (n = 94). Internal consistency, redundancy, construct validity, and responsiveness of the CAT were examined. CAT scores corresponding to ordinal global assessments were determined. Results. Item-total correlations ranged from 0.27-0.67 for activity lesions present in >= 10% of patients; item-domain and domain-total correlations ranged from 0.25-0.99. Cronbach's alpha was 0.79 for the CAT activity score and 0.74 for the CAT damage score. As predicted, the CAT activity score correlated strongly with both global disease activity and skin disease activity and moderately with the Childhood Myositis Assessment Scale, whereas the CAT damage score correlated moderately with the physician global disease and skin disease damage scores. Median CAT activity scores of 1, 7, 13, 18, and 31 corresponded to absent, mild, moderate, severe, and extremely severe skin disease activity, respectively. Median CAT damage scores of 0, 1, 2, and 5 correlated with the same descriptions of damage (severe and extremely severe combined). Conclusion. Preliminary validation of the CAT demonstrated good internal consistency, nonredundancy, good construct validity, and appropriate responsiveness. The CAT is a comprehensive, semiquantitative assessment tool for skin disease in juvenile DM. C1 [Huber, Adam M.] IWK Hlth Ctr, Div Pediat Rheumatol, Halifax, NS B3K 6R8, Canada. [Huber, Adam M.] Dalhousie Univ, Halifax, NS B3H 3J5, Canada. [Dugan, Elizabeth M.] Washington Hosp Ctr, Washington, DC 20010 USA. [Lachenbruch, Peter A.] Ctr Biol Evaluat & Res, Rockville, MD USA. [Feldman, Brian M.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Feldman, Brian M.] Univ Toronto, Toronto, ON M5G 1X8, Canada. [Perez, Maria D.] Baylor Univ, Texas Childrens Hosp, Houston, TX 77030 USA. [Perez, Maria D.] Baylor Coll Med, Houston, TX 77030 USA. [Zemel, Lawrence S.] Univ Connecticut, Connecticut Childrens Med Ctr, Hartford, CT 06112 USA. [Zemel, Lawrence S.] Univ Connecticut, Hartford, CT 06112 USA. [Lindsley, Carol B.] Univ Kansas, Kansas City, KS 66045 USA. [Rennebohm, Robert M.] Ohio State Univ, Columbus Childrens Hosp, Columbus, OH 43210 USA. [Rennebohm, Robert M.] Ohio State Univ, Columbus, OH 43210 USA. [Wallace, Carol A.] Univ Washington, Childrens Hosp, Seattle, WA 98195 USA. [Wallace, Carol A.] Univ Washington, Seattle, WA 98195 USA. [Passo, Murray H.] Univ Cincinnati, Childrens Hosp, Cincinnati, OH USA. [Passo, Murray H.] Univ Cincinnati, Cincinnati, OH USA. [Reed, Ann M.] Mayo Clin, Rochester, MN USA. [Bowyer, Suzanne L.; Ballinger, Susan H.] Indiana Univ Sch Med, Riley Children Hosp, Indianapolis, IN USA. [Bowyer, Suzanne L.; Ballinger, Susan H.] Indiana Univ Sch Med, Indianapolis, IN USA. [Miller, Frederick W.; Rider, Lisa G.] Natl Inst Environm Hlth Sci, NIH, Environm Autoimmun Grp, Bethesda, MD USA. RP Huber, AM (reprint author), IWK Hlth Ctr, Div Pediat Rheumatol, 5850 Univ Ave, Halifax, NS B3K 6R8, Canada. EM adam.huber@iwk.nshealth.ca RI Feldman, Brian/A-8586-2011; OI Rider, Lisa/0000-0002-6912-2458; Miller, Frederick/0000-0003-2831-9593 FU Intramural NIH HHS NR 19 TC 20 Z9 23 U1 1 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD FEB 15 PY 2008 VL 59 IS 2 BP 214 EP 221 DI 10.1002/art.23340 PG 8 WC Rheumatology SC Rheumatology GA 262UI UT WOS:000253173100011 PM 18240194 ER PT J AU Isenberg, JS Yu, C Roberts, DD AF Isenberg, Jeff S. Yu, Christine Roberts, David D. TI Differential effects of ABT-510 and a CD36-binding peptide derived from the type 1 repeats of thrombospondin-1 on fatty acid uptake, nitric oxide signaling, and caspase activation in vascular cells SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE thrombospondin-1; nitric oxide; CD36; ABT-510; cancer; fatty acid uptake ID ANGIOGENESIS INHIBITOR ABT-510; TUMOR-GROWTH; DEPENDENT INHIBITION; ENDOTHELIAL-CELLS; IN-VIVO; PHASE-I; APOPTOSIS; CD47; RESPONSES; PATHWAY AB ABT-510 is a potent mimetic of an anti-angiogenic sequence from the second type 1 repeat of thrombospondin-1. ABT-510 and the original D-Ile mimetic from which it was derived, GDGV(DI)TRIR, are similarly active for inhibiting vascular outgrowth in a B16 melanoma explant assay. Because GDGV(DI)TRIR and thrombospondin-1 modulate nitric oxide signaling by inhibiting the fatty translocase activity of CD36, we examined the ability ABT-510 to modulate fatty acid uptake into vascular cells and downstream nitric oxide/cGMP signaling. Remarkably, ABT-510 is less active than GDGV(DI)TRIR for inhibiting myristic acid uptake into both endothelial and vascular smooth muscle cells. Correspondingly, ABT-510 is less potent than GDGV(DI)TRIR for blocking a myristate-stimulated increase in cell adhesion to Collagen and nitric oxide-driven accumulation of cGMP. ABT-510 at concentrations sufficient to inhibit CD36 fatty acid translocase activity synergizes with thrombin in aggregating platelets and blunts the activity of NO to delay aggregation, but again less than GDGV(DI)TRIR. In contrast, ABT-510 is more potent than GDGV(DI)TRIR for inducing caspase activation in vascular cells. Thus, we propose that ABT-510 is a drug with at least two mechanisms of action, and its potent anti-tumor activity may be in part independent of CD36 fatty acid translocase inhibition. Published by Elsevier Inc. C1 [Isenberg, Jeff S.; Yu, Christine; Roberts, David D.] NIH, Natl Canc Inst, Pathol Lab, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NIH, Natl Canc Inst, Pathol Lab, Bldg 10,Room 2A33,10 Ctr Dr MSC1500, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural NIH HHS [Z01 SC009172-03] NR 39 TC 15 Z9 16 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD FEB 15 PY 2008 VL 75 IS 4 BP 875 EP 882 DI 10.1016/j.bcp.2007.10.025 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 268XP UT WOS:000253614000009 PM 18068687 ER PT J AU Abhiman, S Iyer, LM Aravind, L AF Abhiman, Saraswathi Iyer, Lakshminarayan M. Aravind, L. TI BEN: a novel domain in chromatin factors and DNA viral proteins SO BIOINFORMATICS LA English DT Article ID SEQUENCE ALIGNMENT; REPRESSION; PREDICTION; INTERACTS; LOCUS; SMAR1; NACL AB We report a previously uncharacterized alpha-helical module, the BEN domain, in diverse animal proteins such as BANP/SMAR1, NAC1 and the Drosophila mod(mdg4) isoform C, in the chordopoxvirus virosomal protein E5R and in several proteins of polydnaviruses. Contextual analysis suggests that the BEN domain mediates protein-DNA and protein-protein interactions during chromatin organization and transcription. The presence of BEN domains in a poxviral early virosomal protein and in polydnaviral proteins also suggests a possible role for them in organization of viral DNA during replication or transcription. C1 [Abhiman, Saraswathi; Iyer, Lakshminarayan M.; Aravind, L.] NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. FU Intramural NIH HHS [Z01 LM594244-01, Z99 LM999999] NR 21 TC 40 Z9 40 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2008 VL 24 IS 4 BP 458 EP 461 DI 10.1093/bioinformatics/btn007 PG 4 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 263WD UT WOS:000253246300002 PM 18203771 ER PT J AU Maeng, S Zarate, CA Du, J Schloesser, RJ McCammon, J Chen, G Manji, HK AF Maeng, Sungho Zarate, Carlos A., Jr. Du, Jing Schloesser, Robert J. McCammon, Joseph Chen, Guang Manji, Husseini K. TI Cellular mechanisms underlying the antidepressant effects of ketamine: Role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors SO BIOLOGICAL PSYCHIATRY LA English DT Article DE AMPA; antidepressant; depression; glutamate; ketamine; NMDA; rapid-onset ID METHYL-D-ASPARTATE; PREFRONTAL CORTEX; MOOD DISORDERS; MICE; DEPRESSION; GLUTAMATE; NEUROTRANSMISSION; INHIBITION; ANTAGONIST; MODEL AB Background: Ketamine exerts a robust, rapid, and relatively sustained antidepressant effect in patients with major depression. Understanding the mechanisms underlying the intriguing effects of N-methyl d-aspartate (NMDA) antagonists could lead to novel treatments with a rapid onset of action. Methods: The learned helplessness, forced swim, and passive avoidance tests were used to investigate ketamine's behavioral effects in mice. Additional biochemical and behavioral experiments were undertaken to determine whether the antidepressant-like properties of ketamine and other NMDA antagonists involve alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor throughput. Results: Subanesthetic doses of ketamine treatment caused acute and sustained antidepressant-like effects. At these doses, ketamine did not impair fear memory retention. MK-801 (dizocilpine) and Ro25-6981, an NR2B selective antagonist, also exerted antidepressant-like effects; these effects, however, were not sustained as long as those of ketamine. Pre-treatment with NBQX, an AMPA receptor antagonist, attenuated both ketamine-induced antidepressant-like behavior and regulation of hippocampal phosphorylated GluR1 AMPA receptors. Conclusions: NMDA antagonists might exert rapid antidepressant-like effects by enhancing AMPA relative to NMDA throughput in critical neuronal circuits. C1 [Maeng, Sungho; Zarate, Carlos A., Jr.; Du, Jing; Schloesser, Robert J.; McCammon, Joseph; Chen, Guang; Manji, Husseini K.] NIMH, Mood & Anxiety Disorders Program, NIH, Lab Mol Pathophysiol & Expt Therapeut, Bethesda, MD 20892 USA. [Maeng, Sungho; Zarate, Carlos A., Jr.; Du, Jing; Schloesser, Robert J.; McCammon, Joseph; Chen, Guang; Manji, Husseini K.] Dept Hlth & Human Serv, Bethesda, MD USA. RP Manji, HK (reprint author), NIMH, Mood & Anxiety Disorders Program, NIH, Lab Mol Pathophysiol & Expt Therapeut, Bldg 35,1C-912,35 Convent Dr, Bethesda, MD 20892 USA. EM manji@nih.go RI Du, Jing/A-9023-2012; Chen, Guang/A-2570-2017 FU Intramural NIH HHS NR 19 TC 447 Z9 475 U1 7 U2 86 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2008 VL 63 IS 4 BP 349 EP 352 DI 10.1016/j.biopsych.2007.05.028 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 256YR UT WOS:000252766300002 PM 17643398 ER PT J AU Skoumbourdis, AP Huang, RL Southall, N Leister, W Guo, V Cho, MH Inglese, J Nirenberg, M Austin, CP Xia, MH Thomas, CJ AF Skoumbourdis, Amanda P. Huang, Ruili Southall, Noel Leister, William Guo, Vicky Cho, Ming-Hsuang Inglese, James Nirenberg, Marshall Austin, Christopher P. Xia, Menghang Thomas, Craig J. TI Identification of a potent new chemotype for the selective inhibition of PDE4 SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE PDE4; COPD; 3,4-catechol diether ID PHOSPHODIESTERASE-4 INHIBITOR; RESPIRATORY-DISEASE; CRYSTAL-STRUCTURE; CREB AB A series of substituted 3,6-diphenyl-7H-[1,2,4] triazolo[ 3,4-b][ 1,3,4] thiadiazines were prepared and analyzed as inhibitors of phosphodiesterase 4 (PDE4). Synthesis, structure-activity relationships, and the selectivity of a highly potent analogue against related phosphodiesterase isoforms are presented. Published by Elsevier Ltd. C1 [Skoumbourdis, Amanda P.; Huang, Ruili; Southall, Noel; Leister, William; Cho, Ming-Hsuang; Inglese, James; Austin, Christopher P.; Xia, Menghang; Thomas, Craig J.] NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. [Guo, Vicky; Nirenberg, Marshall] NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Thomas, CJ (reprint author), NHGRI, NIH Chem Genom Ctr, NIH, 9800 Med Ctr Dr,MSC 3370, Bethesda, MD 20892 USA. EM craigt@mail.nih.gov RI Southall, Noel/H-8991-2012 OI Southall, Noel/0000-0003-4500-880X FU Intramural NIH HHS [Z01 HG200319-04, Z99 HG999999] NR 26 TC 19 Z9 19 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 FEB 15 PY 2008 VL 18 IS 4 BP 1297 EP 1303 DI 10.1016/j.bmcl.2008.01.028 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 276YQ UT WOS:000254180000009 PM 18243697 ER PT J AU Rostovtseva, TK Petrache, HI Kazemi, N Hassanzadeh, E Bezrukov, SM AF Rostovtseva, Tatiana K. Petrache, Horia I. Kazemi, Namdar Hassanzadeh, Elnaz Bezrukov, Sergey M. TI Interfacial polar interactions affect gramicidin channel kinetics SO BIOPHYSICAL JOURNAL LA English DT Article ID LIPID-BILAYERS; H-2 NMR; MEMBRANE; DEFORMATION; THICKNESS; LIFETIME AB Critical to biological processes such as secretion and transport, protein-lipid interactions within the membrane and at the membrane-water interface still raise many questions. Here we examine the role of lipid headgroups in these interactions by using gramicidin A(gA) channels in planar bilayers as a probe. We show that although headgroup demethylation from phosphatidylcholine (DOPC) to phosphatidylethanolamine decreases the lifetime of gA channels by an order of magnitude in accordance with the currently accepted hydrophobic mismatch mechanism, our findings with diether-DOPC suggest the importance of the headgroup-peptide interactions. According to our x-ray diffraction measurements, this lipid has the same hydrophobic thickness as DOPC but increases gA lifetime by a factor of 2. Thus we demonstrate that peptide-headgroup interactions may dominate over the effect of hydrophobic mismatch in regulating protein function. C1 [Rostovtseva, Tatiana K.; Kazemi, Namdar; Hassanzadeh, Elnaz; Bezrukov, Sergey M.] NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. [Petrache, Horia I.] Indiana Univ Purdue Univ, Dept Phys, Indianapolis, IN 46202 USA. RP Rostovtseva, TK (reprint author), NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. EM rostovtt@mail.nih.gov FU Intramural NIH HHS NR 20 TC 16 Z9 16 U1 0 U2 1 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 FEB 15 PY 2008 VL 94 IS 4 BP L23 EP L25 DI 10.1529/biophysj.107.120261 PG 3 WC Biophysics SC Biophysics GA 254PE UT WOS:000252597700001 PM 18055540 ER PT J AU Brodsky, RA Young, NS Antonioli, E Risitano, AM Schrezenmeier, H Schubert, J Gaya, A Coyle, L De Castro, C Fu, CL Maciejewski, JP Bessler, M Kroon, HA Rother, RP Hillmen, P AF Brodsky, Robert A. Young, Neal S. Antonioli, Elisabetta Risitano, Antonio M. Schrezenmeier, Hubert Schubert, Jorg Gaya, Anna Coyle, Luke De Castro, Carlos Fu, Chieh-Lin Maciejewski, Jaroslaw P. Bessler, Monica Kroon, Henk-Andre Rother, Russell P. Hillmen, Peter TI Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria SO BLOOD LA English DT Article ID FUNCTIONAL ASSESSMENT; NATURAL-HISTORY; NITRIC-OXIDE; FATIGUE; HEMOLYSIS; MIGRAINE; ANEMIA AB The terminal complement inhibitor eculizumab was recently shown to be effective and well tolerated in patients with paroxysmal nocturnal hemoglobinuria (PNH). Here, we extended these observations with results from an open-label, nonplacebo-controlled, 52-week, phase 3 clinical safety and efficacy study evaluating eculizumab in a broader PNH patient population. Eculizumab was administered by intravenous infusion at 600 mg every 7 +/- 2 days for 4 weeks; 900 mg 7 +/- 2 days later; followed by 900 mg every 14 +/- 2 days for a total treatment period of 52 weeks. Ninety-seven patients at 33 international sites were enrolled. Patients treated with eculizumab responded with an 87% reduction in hemolysis, as measured by lactate dehydrogenase levels (P < .001). Baseline fatigue scores in the FACIT-Fatigue instrument improved by 12.2 +/- 1.1 points (P <.001). Eculizumab treatment led to an improvement in anemia. The increase in hemoglobin level occurred despite a reduction in transfusion requirements from a median of 8.0 units of packed red cells per patient before treatment to 0.0 units per patient during the study (P <.001). Overall, transfusions were reduced 52% from a mean of 12.3 to 5.9 units of packed red cells per patient. Forty-nine patients (51%) achieved transfusion independence for the entire 52-week period. Improvements in hemolysis, fatigue, and transfusion requirements with eculizumab were independent of baseline levels of hemolysis and degree of thrombocytopenia. Quality of life measures were also broadly improved with eculizumab treatment. This study demonstrates that the beneficial effects of eculizumab treatment in patients with PNH are applicable to a broader population of PNH patients than previously studied. This trial is registered at http://clinicaltrials.gov as NCT00130000. C1 [Brodsky, Robert A.] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. [Young, Neal S.] NHLBI, Bethesda, MD 20892 USA. [Antonioli, Elisabetta] Univ Florence, Florence, Italy. [Risitano, Antonio M.] Univ Naples Federico 2, Naples, Italy. [Schrezenmeier, Hubert] Univ Hosp Ulm, Inst Clin Transfus Med & Immunogenet, Inst Transfus Med, Ulm, Germany. [Schubert, Jorg] Univ Saarland, Sch Med, D-6650 Homburg, Germany. [Gaya, Anna] Hosp Clin Barcelona, Inst Invest Biomed Augist Pi & Sunyer, Barcelona, Spain. [Coyle, Luke] Royal N Shore Hosp, St Leonards, NSW 2065, Australia. [Fu, Chieh-Lin] Cleveland Clin, Weston, FL USA. [Maciejewski, Jaroslaw P.] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH 44106 USA. [Bessler, Monica] Washington Univ, St Louis, MO USA. [Kroon, Henk-Andre; Rother, Russell P.] Alexion Pharmaceut, Cheshire, CT USA. [Hillmen, Peter] St James Inst Oncol, Leeds, W Yorkshire, England. RP Brodsky, RA (reprint author), Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. NR 24 TC 216 Z9 223 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 FEB 15 PY 2008 VL 111 IS 4 BP 1840 EP 1847 DI 10.1182/blood-2007-06-094136 PG 8 WC Hematology SC Hematology GA 263XZ UT WOS:000253251100027 PM 18055865 ER PT J AU Ryu, BY Evans-Galea, MV Gray, JT Bodine, DM Persons, DA Nienhuis, AW AF Ryu, Byoung Y. Evans-Galea, Marguerite V. Gray, John T. Bodine, David M. Persons, Derek A. Nienhuis, Arthur W. TI An experimental system for the evaluation of retroviral vector design to diminish the risk for proto-oncogene activation SO BLOOD LA English DT Article ID ADENOASSOCIATED VIRUS VECTORS; SEVERE COMBINED IMMUNODEFICIENCY; BETA-GLOBIN INSULATOR; GENE-THERAPY; LENTIVIRAL VECTOR; INSERTIONAL MUTAGENESIS; CHROMATIN INSULATOR; REGULATORY ELEMENTS; HEMATOPOIETIC-CELLS; CRE RECOMBINASE AB Pathogenic activation of the LMO2 protooncogene by an oncoretroviral vector insertion in a clinical trial for X-linked severe combined immunodeficiency (X-SCID) has prompted safety concerns. We used an adeno-associated virus vector to achieve targeted insertion of a gamma-retroviral long terminal repeat (LTR) driving a GFP expression cassette with flanking loxP sites in a human T-cell line at the precise location of vector integration in one of the patients with X-SCID. The LTR-GFP cassette was inserted into the first intron of the LMO2 gene, resulting in strong activation of LMO2. Cre-mediated cassette exchange was used to replace the original LTR-GFP cassette with one flanked by insulator elements leading to a several fold reduction in LMO2 expression. The LTR-GFP cassette was also replaced with a globin gene regulatory cassette that failed to activate the LMO2 gene in lymphoid cells. A gamma-retroviral vector with 2 intact LTRs resulted in activation of the LMO2 gene when inserted into the first intron, but a self-inactivating lentiviral vector with an internal cellular promoter and flanking insulator elements did not activate the LMO2 gene. Thus, this system is useful for comparing the safety profiles of vector cassettes with various regulatory elements for their potential for proto-oncogene activation. C1 [Ryu, Byoung Y.; Evans-Galea, Marguerite V.; Gray, John T.; Persons, Derek A.; Nienhuis, Arthur W.] St Jude Childrens Res Hosp, Dept Hematol, Memphis, TN 38105 USA. [Bodine, David M.] NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. RP Ryu, BY (reprint author), St Jude Childrens Res Hosp, Dept Hematol, 332 N Lauderdale, Memphis, TN 38105 USA. RI Evans-Galea, Marguerite/A-4673-2013 OI Evans-Galea, Marguerite/0000-0003-1867-9667 FU NHLBI NIH HHS [P01 HL053749, P01 HL53749] NR 44 TC 59 Z9 61 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 FEB 15 PY 2008 VL 111 IS 4 BP 1866 EP 1875 DI 10.1182/blood-2007-04-085506 PG 10 WC Hematology SC Hematology GA 263XZ UT WOS:000253251100031 PM 17991809 ER PT J AU Tailor, P Tamura, T Morse, HC Ozato, K AF Tailor, Prafullakumar Tamura, Tomohiko Morse, Herbert C., III Ozato, Keiko TI The BXH2 mutation in IRF8 differentially impairs dendritic cell subset development in the mouse SO BLOOD LA English DT Article ID REGULATORY FACTOR-4; ADAPTIVE IMMUNITY; CUTTING EDGE; RECOGNITION; INNATE; FAMILY; MICE AB Among dendritic cell (DC) subsets, CD8 alpha(+) DCs and plasmacytoid DCs (pDCs) produce high levels of IL12 and type I interferons (IFNs), respectively, and confer early innate immunity. Development of CD8 alpha(+) DCs and pDCs requires the interferon regulatory factor 8 (IRF8). Recently, a spontaneous point mutation was identified in the Irf8/Icsbp gene in the BXH2 mouse, which exhibits an immunodeficient phenotype similar to the IRF8 knockout (KO) mouse. We show that this mutation, designated IRF8(R294c), abolishes the development of CD8 alpha(+) DCs without impairing pDC development, and eliminates production of IL12p40, while retaining that of type I IFNs. Electrophoretic mobility shift and chromatin immunoprecipitation assays indicated that IRF8(R294c) failed to interact with partner transcription factors and did not bind certain promoters that require partner interactions. Together, this work indicates that IRF8-partner interactions play different roles in CD8 alpha(+) DCs and pDCs, revealing a mechanistic separation that underlies development of these DC subsets. C1 [Tailor, Prafullakumar; Tamura, Tomohiko; Ozato, Keiko] NIH, NICHHD, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. [Morse, Herbert C., III] NIH, NIAID, Immunopathol Lab, Bethesda, MD 20892 USA. RP Tailor, P (reprint author), NIH, NICHHD, Lab Mol Growth Regulat, Bldg 10, Bethesda, MD 20892 USA. OI Morse, Herbert/0000-0002-9331-3705 FU Intramural NIH HHS NR 23 TC 86 Z9 87 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 FEB 15 PY 2008 VL 111 IS 4 BP 1942 EP 1945 DI 10.1182/blood-2007-07-100750 PG 4 WC Hematology SC Hematology GA 263XZ UT WOS:000253251100039 PM 18055870 ER PT J AU Dimberg, A Rylova, S Dieterich, LC Olsson, AK Schiller, P Wikner, C Bohman, S Botling, J Lukinius, A Wawrousek, EF Claesson-Welsh, L AF Dimberg, Anna Rylova, Svetlana Dieterich, Lothar C. Olsson, Anna-Karin Schiller, Petter Wikner, Charlotte Bohman, Svante Botling, Johan Lukinius, Agneta Wawrousek, Eric F. Claesson-Welsh, Lena TI alpha B-crystallin promotes tumor angiogenesis by increasing vascular survival during tube morphogenesis SO BLOOD LA English DT Article ID HEAT-SHOCK-PROTEIN; ENDOTHELIAL-CELLS; INDUCED APOPTOSIS; PHOSPHORYLATION; ACTIVATION; STRESS; DIFFERENTIATION; INDUCTION; CASPASE-3; KINASE AB Selective targeting of endothelial cells in tumor vessels requires delineation of key molecular events in formation and survival of blood vessels within the tumor microenvironment. To this end, proteins transiently up-regulated during vessel morphogenesis were screened for their potential as targets in antiangiogenic tumor therapy. The molecular chaperone alpha B-crystallin was identified as specifically induced with regard to expression level, modification by serine phosphorylation, and subcellular localization during tubular morphogenesis of endothelial cells. Small interfering RNA-mediated knockdown of alpha B-crystallin expression did not affect endothelial proliferation but led to attenuated tubular morphogenesis, early activation of proapoptotic caspase-3, and increased apoptosis. alpha B-crystallin was expressed in a subset of human tumor vessels but not in normal capillaries. Tumors grown in alpha B-crystallin(-/-) mice were significantly less vascularized than wild-type tumors and displayed increased areas of apoptosis/necrosis. Importantly, tumor vessels in alpha B-crystallin(-/-) mice were leaky and showed signs of caspase-3 activation and extensive apoptosis. Ultrastructural analyses showed defective vessels partially devoid of endothelial lining. These data strongly implicate alpha B-crystallin as an important regulator of tubular morphogenesis and survival of endothelial cell during tumor angiogenesis. Hereby we identify the small heat shock protein family as a novel class of anglogenic modulators. C1 [Dimberg, Anna; Rylova, Svetlana; Dieterich, Lothar C.; Olsson, Anna-Karin; Schiller, Petter; Wikner, Charlotte; Bohman, Svante; Botling, Johan; Lukinius, Agneta; Claesson-Welsh, Lena] Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden. [Wawrousek, Eric F.] NIH, NEI, Bethesda, MD 20892 USA. RP Dimberg, A (reprint author), Uppsala Univ, Dept Genet & Pathol, Uppsala, Sweden. NR 45 TC 58 Z9 64 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 15 PY 2008 VL 111 IS 4 BP 2015 EP 2023 DI 10.1182/blood-2007-04-087841 PG 9 WC Hematology SC Hematology GA 263XZ UT WOS:000253251100048 PM 18063749 ER PT J AU Harry, GJ Funk, JA d'Hellencourt, CL McPherson, CA Aoyama, M AF Harry, G. Jean Funk, Jason A. d'Hellencourt, Christian Lefebvre McPherson, Christopher A. Aoyama, Mineyoshi TI The type 1 interleukin 1 receptor is not required for the death of murine hippocampal dentate granule cells and microglia activation SO BRAIN RESEARCH LA English DT Article DE neurotoxicity; inflammation; IL-1; cytokine; trimethyltin; hippocampus ID CENTRAL-NERVOUS-SYSTEM; CEREBRAL-ARTERY OCCLUSION; FIBRILLARY ACIDIC PROTEIN; LONG-TERM POTENTIATION; ISCHEMIC BRAIN-DAMAGE; NECROSIS-FACTOR-ALPHA; TRANSFORMING GROWTH-FACTOR-BETA-1; NEURONAL DAMAGE; MESSENGER-RNA; GROWTH-FACTOR AB Alterations in inflammatory process, neuronal death, and glia response have been observed under manipulation of interleukin-1 (IL-1) and subsequent signaling through the type 1 IL-1 receptor (IL-1R1). To investigate the influence of IL-1R1 activation in the pathophysiology of a chemical-induced injury to the murine hippocampus, we examined the level and pattern of neuronal death and neuroinflammation in male weanling mice exposed to trimethyltin hydroxide (2.0 mg TMT/kg, i.p.). Dentate granule cell death occurred at 6 h post-TMT as detected by active caspase 3 immunostaining and presence of lectin positive microglia. The severity of neuronal death and microglia response increased by 12-24 h with elevations in mRNA levels for TNF alpha and IL-1 alpha. In IL-1R1 null (IL-1R1(-/-)) mice, the pattern and severity of neuronal death at 24 or 72 h post-TMT was similar as compared to wildtype (WT) mice. In both groups, mRNA levels for TNF alpha and MIP-1 alpha were elevated, no significant change was seen in either IL-1 alpha or IL-beta, and the early activation of microglia, including their ability to progress to a phagocytic phenotype, was maintained. Compared to WT mice, IL-1R1(-/-) mice displayed a limited glial fibrillary acidic protein (GFAP) astrocytic response, as well as a preferential induction in mRNA levels of Fas signaling components. Cumulatively, these results indicate that IL-1R1 activation is not necessary for TMT-induced death of dentate granule neurons or local activation of microglia; however, IL-1R1 signaling is involved in mediating the structural response of astrocytes to injury and may regulate apoptotic mechanisms via Fas signaling components. Published by Elsevier B.V. C1 [Harry, G. Jean; Funk, Jason A.; d'Hellencourt, Christian Lefebvre; McPherson, Christopher A.; Aoyama, Mineyoshi] NIEHS, Dept Hlth & Human Serv, Neurobiol Lab, Neurotoxicol Grp,Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. [d'Hellencourt, Christian Lefebvre] Univ Reunion, Fac Sci, Lab Biochim & Genet Mol, St Denis, Reunion. [Aoyama, Mineyoshi] Nagoya City Univ, Dept Mol Neurobiol, Mizuho Ku, Nagoya, Aichi 4678601, Japan. RP Harry, GJ (reprint author), NIEHS, Dept Hlth & Human Serv, Neurobiol Lab, Neurotoxicol Grp,Natl Inst Hlth, POB 12233,MD C1-04, Res Triangle Pk, NC 27709 USA. EM harry@niehs.nih.gov FU Intramural NIH HHS [Z01 ES101623-05, Z01 ES021164-11] NR 66 TC 16 Z9 16 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 15 PY 2008 VL 1194 BP 8 EP 20 DI 10.1016/j.brainres.2007.11.076 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 274ML UT WOS:000254005300002 PM 18191113 ER PT J AU Dobie, SA Warren, JL Matthews, B Schwartz, D Baldwin, LM Billingsley, K AF Dobie, Sharon A. Warren, Joan L. Matthews, Barbara Schwartz, David Baldwin, Laura-Mae Billingsley, Kevin TI Survival benefits and trends in use of adjuvant therapy among elderly stage II and III rectal cancer patients in the general population SO CANCER LA English DT Article DE rectal cancer; adjuvant therapy; chemotherapy; radiation therapy; cancer mortality ID TOTAL MESORECTAL EXCISION; COMBINED-MODALITY THERAPY; RADIATION-THERAPY; POSTOPERATIVE CHEMORADIOTHERAPY; COLORECTAL-CANCER; UNITED-STATES; COLON-CANCER; CHEMOTHERAPY; CARCINOMA; MEDICARE AB BACKGROUND. This study examined elderly stage II and III rectal cancer patients' adjuvant chemoradiation therapy adherence, trends in adherence over time, and the relation of levels of adherence to mortality. METHODS. The authors studied 2886 stage II and III rectal cancer patients who had surgical resection and who appeared in 1992-1999 linked SEER-Medicare claims data. The authors compared measures of adjuvant radiation and chemotherapy receipt and completion between stage II and III patients. Adjusted risk of cancer-related 5-year mortality was calculated by multivariate logistic regression for different levels of chemoradiation adherence among stage II and III patients. RESULTS. Of the 2886 patients, 45.4% received both adjuvant radiation and chemotherapy. Stage III patients were more likely to receive chemoradiation than stage II patients. The receipt of chemoradiation by stage II patients increased significantly from 1992 to 1999. Stage III patients were more likely to complete radiation therapy (96.6%), chemotherapy (68.2%), and both modalities (67.5%) than stage II patients (91.5%, 49.8%, 47.6%, respectively). Only a complete course of both radiation and chemotherapy for both stage II (relative risk [RR] 0.74; 95% Cl, 0.54, 0.97) and III (RR 0.80; 95% CI, 0.65, 0.96) decreased the adjusted 5-year cancer mortality risk compared with counterparts with no adjuvant therapy. CONCLUSIONS. Even though stage II rectal cancer patients were less likely than stage III patients to receive and complete adjuvant chemoradiation, both patient groups in the general population had lower cancer-related mortality if they completed chemoradiation. These patients deserve support and encouragement to complete treatment. C1 [Dobie, Sharon A.; Matthews, Barbara; Baldwin, Laura-Mae] Univ Washington, Dept Family Med, Seattle, WA 98195 USA. [Warren, Joan L.] NCI, Bethesda, MD 20892 USA. [Schwartz, David] Univ Texas MD Anderson Canc Ctr, Div Radiat Oncol, Houston, TX USA. [Billingsley, Kevin] Oregon Hlth & Sci Univ, Dept Surg, Portland, OR 97201 USA. RP Dobie, SA (reprint author), Univ Washington, Dept Family Med, Box 356390, Seattle, WA 98195 USA. EM dob@u.washington.edu FU NCI NIH HHS [R01 CA089544, R01 CA089544-01, R01CA089544] NR 48 TC 32 Z9 35 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 15 PY 2008 VL 112 IS 4 BP 789 EP 799 DI 10.1002/cncr.23244 PG 11 WC Oncology SC Oncology GA 260PZ UT WOS:000253023700007 PM 18189291 ER PT J AU Bowles, EJA Tuzzio, L Wiese, CJ Kirlin, B Greene, SM Clauser, SB Wagner, EH AF Bowles, Erin J. Aiello Tuzzio, Leah Wiese, Cheryl J. Kirlin, Beth Greene, Sarah M. Clauser, Steven B. Wagner, Edward H. TI Understanding high-quality cancer care - A summary of expert perspectives SO CANCER LA English DT Article DE quality of cancer care; coordination; standardization; patient-centered; diagnostic delays; cancer treatment efficiency; equitable care ID STAGE BREAST-CANCER; INFORMATION NEEDS; PATIENT; THERAPY; PREFERENCES; MORTALITY; DECISIONS; SUPPORT; IMPROVE; TRIAL AB BACKGROUND. The Institute of Medicine (IOM) report Crossing the Quality Chasm proposed 6 aims for high-quality healthcare: effective, safe, timely, efficient, equitable, and patient-centered, and emphasized care coordination. Through interviews with nationally recognized experts in healthcare quality, perspectives on barriers and facilitators to achieving these aims for cancer patients were elicited. METHODS. In all, 23 peer-nominated experts with diverse backgrounds in policy, healthcare, patient advocacy, and research were individually interviewed. They were asked about barriers and facilitators to achieving high-quality cancer care, and information technology or other innovations that might improve the quality of cancer diagnosis, treatment, and surveillance. Interviews were tape-recorded and transcribed. Two analysts independently reviewed and coded each transcript using ethnographic software to elucidate key themes. RESULTS. The major perceived barrier to providing high-quality cancer care was unnecessary variation in cancer care because of lack of standardization or adherence to guidelines during diagnosis, treatment, and surveillance. Additional barriers included insufficient teamwork and communication among multidisciplinary care teams, lack of patient awareness and empowerment, diagnostic delays during provider transitions, and excessive reimbursement for treatment. Experts suggested improving cancer patients' experiences by standardizing care, adhering to guidelines, and using "patient navigators" and an interoperable electronic medical record accessible to patients and providers at multiple facilities. CONCLUSIONS. Some of these solutions have been developed and tested, whereas others have not. It is hoped that these suggestions provide impetus for new research, accelerating progress toward achieving the IOM's vision for high-quality cancer care. C1 [Bowles, Erin J. Aiello; Tuzzio, Leah; Wiese, Cheryl J.; Kirlin, Beth; Greene, Sarah M.; Wagner, Edward H.] Grp Hlth Ctr Hlth Studies, Grp Hlth Cooperat, Seattle, WA 98103 USA. [Clauser, Steven B.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Bowles, EJA (reprint author), Grp Hlth Ctr Hlth Studies, Grp Hlth Cooperat, 1730 Minor Ave,Suite 1600, Seattle, WA 98103 USA. EM aiello.e@ghc.org NR 41 TC 51 Z9 52 U1 3 U2 12 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 15 PY 2008 VL 112 IS 4 BP 934 EP 942 DI 10.1002/cncr23250 PG 9 WC Oncology SC Oncology GA 260PZ UT WOS:000253023700024 ER PT J AU Amornphimoltham, P Patel, V Leelahavanichkul, K Abraham, RT Gutkind, JS AF Amornphimoltham, Panomwat Patel, Vyomesh Leelahavanichkul, Kantima Abraham, Robert T. Gutkind, J. Silvio TI A retroinhibition approach reveals a tumor cell-autonomous response to rapamycin in head and neck cancer SO CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; MAMMALIAN TARGET; MTOR; CARCINOMA; THERAPY; AKT; ANGIOGENESIS; INHIBITORS; PATHWAY; GENE AB Emerging evidence supporting the activation of the Akt-mammalian target of rapamycin (mTOR) signaling network in head and neck squamous cell carcinoma (HNSCC) progression has provided the rationale for exploring the therapeutic potential of inhibiting this pathway for HNSCC treatment. Indeed, rapamycin, a clinically relevant mTOR inhibitor, promotes the rapid regression of HNSCC-tumor xenografts in mice. However, rapamycin does not affect the growth of HNSCC cells in vitro, thus raising the possibility that, as for other cancer types, rapamycin may not target cancer cells directly but may instead act on a component of the tumor microenvironment, such as tumor-associated vasculature. Here, we used a retroinhibition approach to assess the contribution of cancer cell-autonomous actions of rapamycin to its antitumor activity in HNSCC. A rapamycin-resistant form of mTOR (mTOR-RR) was expressed in HNSCC cells while retaining the wild-type (rapamycin-sensitive) mTOR (mTOR-WT) alleles in host-derived endothelial and stromal cells. Expression of mTOR-RR prevented the decrease in phospho-S6 levels caused by rapamycin through mTOR in HNSCC cells but not in stromal cells, and rendered HNSCC xenografts completely resistant to the antitumoral activity of rapamycin. This reverse pharmacology strategy also enabled monitoring the direct consequences of inhibiting mTOR in cancer cells within the complex tumor microenvironment, which revealed that mTOR controls the accumulation of hypoxia-inducible factor-1 alpha (HIF-1 alpha) and the consequent expression of vascular endothelial growth factor and a glucose transporter, Glut-1, in HNSCC cells. These findings indicate that HNSCC cells are the primary target of rapamycin in vivo, and provide evidence that its antiangiogenic effects may represent a downstream consequence of mTOR inhibition in HNSCC cells. C1 [Amornphimoltham, Panomwat; Patel, Vyomesh; Leelahavanichkul, Kantima; Gutkind, J. Silvio] NIH, Natl Inst Dent & Cranofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. [Abraham, Robert T.] Wyeth Pharmaceut, Oncol Discovery Res, Pearl River, NY USA. RP Gutkind, JS (reprint author), NIH, Natl Inst Dent & Cranofacial Res, Oral & Pharyngeal Canc Branch, 30 Convent Dr,Bldg 30,Rm 211, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009 FU Intramural NIH HHS [Z01 DE000558-17] NR 50 TC 30 Z9 31 U1 0 U2 4 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 FEB 15 PY 2008 VL 68 IS 4 BP 1144 EP 1153 DI 10.1158/0008-5472.CAN-07-1756 PG 10 WC Oncology SC Oncology GA 263YH UT WOS:000253251900025 PM 18281490 ER PT J AU El-Bizri, N Wang, L Merklinger, SL Guignabert, C Desai, T Urashima, T Sheikh, AY Knutsen, RH Mecham, RP Mishina, Y Rabinovitch, M AF El-Bizri, Nesrine Wang, Lingli Merklinger, Sandra L. Guignabert, Christophe Desai, Tushar Urashima, Takashi Sheikh, Ahmad Y. Knutsen, Russell H. Mecham, Robert P. Mishina, Yuji Rabinovitch, Marlene TI Smooth muscle protein 22 alpha-mediated patchy deletion of Bmpr1a impairs cardiac contractility but protects against pulmonary vascular remodeling SO CIRCULATION RESEARCH LA English DT Article DE Bmpr1a (Alk3); pulmonary hypertension; hypoxia; smooth muscle cell; pericyte; transgenic mice ID BONE MORPHOGENETIC PROTEIN-4; TRANSGENIC MICE; II RECEPTOR; HYPERTENSION; MOUSE; GENE; GASTRULATION; EXPRESSION; PRESSURE; DEFECTS AB Vascular expression of bone morphogenetic type IA receptor (Bmpr1a) is reduced in lungs of patients with pulmonary arterial hypertension, but the significance of this observation is poorly understood. To elucidate the role of Bmpr1a in the vascular pathology of pulmonary arterial hypertension and associated right ventricular ( RV) dysfunction, we deleted Bmpr1a in vascular smooth muscle cells and in cardiac myocytes in mice using the SM22 alpha; TRE-Cre/LoxP; R26R system. The LacZ distribution reflected patchy deletion of Bmpr1a in the lung vessels, aorta, and heart of SM22 alpha; TRE-Cre; R26R; Bmpr1a(flox/+) and flox/flox mutants. This reduction in BMPR-IA expression was confirmed by Western immunoblot and immunohistochemistry in the flox/flox group. This did not affect pulmonary vasoreactivity to acute hypoxia (10% O-2) or the increase in RV systolic pressure and RV hypertrophy following 3 weeks in chronic hypoxia. However, both SM22 alpha; TRE-Cre; R26R; Bmpr1a(flox/+) and flox/flox mutant mice had fewer muscularized distal pulmonary arteries and attenuated loss of peripheral pulmonary arteries compared with age-matched control littermates in hypoxia. When Bmpr1a expression was reduced by short interference RNA in cultured pulmonary arterial smooth muscle cells, serum-induced proliferation was attenuated explaining decreased hypoxia-mediated muscularization of distal vessels. When Bmpr1a was reduced in cultured microvascular pericytes by short interference RNA, resistance to apoptosis was observed and this could account for protection against hypoxia-mediated vessel loss. The similar elevation in RV systolic pressure and RV hypertrophy, despite the attenuated remodeling with chronic hypoxia in the flox/flox mutants versus controls, was not a function of elevated left ventricular end diastolicpressure but was associated with increased periadventitial deposition of elastin and collagen, potentially influencing vascular stiffness. C1 [El-Bizri, Nesrine; Wang, Lingli; Merklinger, Sandra L.; Guignabert, Christophe; Rabinovitch, Marlene] Stanford Univ, Sch Med, Cardiopulm Res Program, Stanford, CA 94305 USA. [El-Bizri, Nesrine; Wang, Lingli; Merklinger, Sandra L.; Guignabert, Christophe; Urashima, Takashi; Rabinovitch, Marlene] Stanford Univ, Sch Med, Vera Moultan Wall Ctr Pulm Vasc Dis, Dept Pediat, Stanford, CA 94305 USA. [Desai, Tushar] Stanford Univ, Sch Med, Dept Biochem, Stanford, CA 94305 USA. [Desai, Tushar] Stanford Univ, Sch Med, Dept Pulm & Crit Care Med, Stanford, CA 94305 USA. [Sheikh, Ahmad Y.] Stanford Univ, Sch Med, Dept Cardiothorac Surg, Stanford, CA 94305 USA. [Knutsen, Russell H.; Mecham, Robert P.] Washington Univ, Sch Med, Dept Cell Biol, St Louis, MO 63110 USA. [Mishina, Yuji] NIEHS, Reprod & Dev Toxicol Lab, Mol Dev Biol Grp, Res Triangle Pk, NC 27709 USA. RP Rabinovitch, M (reprint author), Stanford Univ, Sch Med, Cardiopulm Res Program, CCSR 2245B,269 Campus Dr, Stanford, CA 94305 USA. EM marlener@stanford.edu FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL074186, R01 HL074186-01A1, R01 HL074186-02, R01 HL074186-03, R01 HL074186-04] NR 43 TC 28 Z9 28 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD FEB 15 PY 2008 VL 102 IS 3 BP 380 EP 388 DI 10.1161/CIRCRESAHA.107.161059 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 263CG UT WOS:000253194600018 PM 18079409 ER PT J AU Patel, V Hood, BL Molinolo, A Lee, NH Conrads, TP Braisted, JC Krizman, DB Veenstra, TD Gutkind, JS AF Patel, Vyomesh Hood, Brian L. Molinolo, Alfredo A. Lee, Norman H. Conrads, Thomas P. Braisted, John C. Krizman, David B. Veenstra, Timothy D. Gutkind, J. Silvio TI Proteomic analysis of laser-captured paraffin-embedded tissues: A molecular portrait of head and neck cancer progression SO CLINICAL CANCER RESEARCH LA English DT Article ID SQUAMOUS-CELL CARCINOMAS; MASS-SPECTROMETRY; GENE; EXPRESSION; TARGET; ACTIVATION; GROWTH; IDENTIFICATION; TUMORIGENESIS; METASTASIS AB Purpose: Squamous cell carcinoma of the head and neck (HNSCC), the sixth most prevalent cancer among men worldwide, is associated with poor prognosis, which has improved only marginally over the past three decades. A proteomic analysis of HNSCC lesions may help identify novel molecular targets for the early detection, prevention, and treatment of HNSCC. Experimental Design: Laser capture microdissection was combined with recently developed techniques for protein extraction from formalin-fixed paraffin-embedded (FFPE) tissues and a novel proteomics platform. Approximately 20,000 cells procured from FFPE tissue sections of normal oral epithelium and well, moderately, and poorly differentiated HNSCC were processed for mass spectrometry and bioinformatic analysis. Results: A large number of proteins expressed in normal oral epithelium and HNSCC, including cytokeratins, intermediate filaments, differentiation markers, and proteins involved in stem cell maintenance, signal transduction, migration, cell cycle regulation, growth and angiogenesis, matrix degradation, and proteins with tumor suppressive and oncogenic potential, were readily detected. Of interest, the relative expression of many of these molecules followed a distinct pattern in normal squamous epithelia and well, moderately, and poorly differentiated HNSCC tumor tissues. Representative proteins were further validated using immunohistochemical studies in HNSCC tissue sections and tissue microarrays. Conclusions: The ability to combine laser capture microdissection and in-depth proteomic analysis of FFPE tissues provided a wealth of information regarding the nature of the proteins expressed in normal squamous epithelium and during HNSCC progression, which may allow the development of novel biomarkers of diagnostic and prognostic value and the identification of novel targets for therapeutic intervention in HNSCC. C1 [Patel, Vyomesh; Molinolo, Alfredo A.; Gutkind, J. Silvio] NIH, Oral & Pharyngeal Canc Branch, Natl Inst Dent & Cranofac Res, Bethesda, MD 20892 USA. [Hood, Brian L.; Conrads, Thomas P.; Veenstra, Timothy D.] NCI, Sci Applicat Int Corp Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD USA. [Krizman, David B.] Express Pathol Inc, Gaithersburg, MD USA. [Lee, Norman H.] George Washington Univ, Med Ctr, Dept Physiol & Pharmacol, Washington, DC 20037 USA. [Braisted, John C.] J Craig Venter Inst, Pathogen Funct Genom Resource Ctr, Rockville, MD USA. RP Gutkind, JS (reprint author), NIH, Oral & Pharyngeal Canc Branch, Natl Inst Dent & Cranofac Res, 30 Convent Dr,Bldg 30,Room 211, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009 FU NCI NIH HHS [N01-CO-12400] NR 43 TC 119 Z9 123 U1 0 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2008 VL 14 IS 4 BP 1002 EP 1014 DI 10.1158/1078-0432.CCR-07-1497 PG 13 WC Oncology SC Oncology GA 266PX UT WOS:000253449700008 PM 18281532 ER PT J AU Yokokawa, J Remondo, C Gulley, JL Arlen, PM Schlom, JR Tsang, KY AF Yokokawa, Junko Remondo, Cinzia Gulley, James L. Arlen, Philip M. Schlom, Jeffrey Tsang, Kwong Y. TI Enhanced functionality of CD4(+)CD25(high)FoxP3(+) regulatory T cells in the peripheral blood of patients with prostate cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; TRANSCRIPTION FACTOR FOXP3; METASTATIC MELANOMA; OVARIAN-CANCER; LUNG-CANCER; IN-VITRO; TUMOR; EXPRESSION; CARCINOMA; CYCLOOXYGENASE-2 AB Purpose: CD4(+)CD25(high)FoxP3(+) regulatory T cells (Treg) have been shown to inhibit the activation and function of T cells that participate in antigen-specific immune responses. Higher levels of Tregs have been reported in the peripheral blood of patients with several types of tumors. In this study, we investigated the number and functionality of CD4(+)CD25(high)FoxP3(+) Tregs in patients with prostate cancer (PCa), and their potential role in inhibiting antitumor immune responses. Experimental Design: Levels of Tregs in the peripheral blood of healthy donors and patients with biochemically progressive, localized, and metastatic PCa were each measured by flow cytometry. The functional activity of Tregs was determined by their ability to suppress the proliferation of CD4(+)CD25(-) T cells. Data were analyzed using Wilcoxon rank sum test and unpaired Student's t test. Results: Although levels of Tregs in the peripheral blood of patients with PCa were not significantly higher than those in healthy donors, Tregs in patients with PCa had significantly greater suppressive functionality than Tregs from healthy donors (P < 0.05). Additionally, there was a direct correlation between the serum levels of prostaglandin E-2 and Treg functionality in patients with localized PCa, using Pearson's product-moment correlation coefficient (R). Conclusions: These findings further show the potential importance of Tregs in modifying immune responses in patients with PCa. Although longer studies are necessary to confirm these findings, these studies also show for the first time the differences in Treg populations in patients with various stages of PCa, and thus, provide a basis for determining which PCa patient populations are best suited for immunotherapy trials involving the inhibition of Tregs. C1 [Yokokawa, Junko; Remondo, Cinzia; Gulley, James L.; Arlen, Philip M.; Schlom, Jeffrey; Tsang, Kwong Y.] NIH, Natl Canc Inst, Ctr Canc Res, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Schlom, JR (reprint author), NIH, Natl Canc Inst, Ctr Canc Res, Tumor Immunol & Biol Lab, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS NR 50 TC 98 Z9 105 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2008 VL 14 IS 4 BP 1032 EP 1040 DI 10.1158/1078-0432.CCR-07-2056 PG 9 WC Oncology SC Oncology GA 266PX UT WOS:000253449700011 PM 18281535 ER PT J AU Liu, WL Li, YQ Zhu, JQ Wright, E Ding, I Rodgers, GP AF Liu, Wenli Li, Yueqin Zhu, Jianqiong Wright, Elizabeth Ding, Ivan Rodgers, Griffin P. TI Reduced hGC-1 protein expression is associated with malignant progression of colon carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID OPEN-ANGLE GLAUCOMA; COLORECTAL-CANCER; GENE-EXPRESSION; MESSENGER-RNA; CELL-ADHESION; OLFACTOMEDIN; METASTASIS; CADHERIN; IDENTIFICATION; OVEREXPRESSION AB Purpose: hGC-1 (human granulocyte colony - stimulating factor - stimulated clone 1) is a gastrointestinal protein that is a member of the olfactomedin glycoprotein family. Its biological function remains poorly understood. Aberrant expression of hGC-1 in some human carcinomas has been recently reported. The purpose of this study was to examine hGC-1 expression in colon carcinoma and explore the relationship between hGC-1 expression and the clinicopathologic features of patients with colon cancer. Experimental Design: The expression of hGC-1 in colon adenocarcinoma tissues was examined by dot-blot analysis, in situ hybridization, and immunohistochemistry. The association of hGC-1 expression pattern with patient differentiation grade, tumor stage, metastasis, and survival were examined. To further investigate the involvement of hGC-1 in colon cancer progression, human colon carcinoma (HT-29) cells overexpressing hGC-1 were established and cell proliferation, adhesion, and migration were studied. Results: Compared with normal colon mucosa, the up-regulation of hGC-1 was more frequently detected in more differentiated colon cancers, whereas down-regulation or no expression was associated with poorly differentiated colon cancers. Interestingly, hGC-1 down-regulation was also found in late tumor-node-metastasis stage, metastasis, and in patients with shorter survival The morphology and cortical actin distribution of HT-29 cells were altered by hGC-1 overexpression. However, this did not change cell proliferation, but decreased cell adhesion and migration. Conclusion: Our findings indicate that hGC-1 is involved in colon cancer adhesion and metastasis, and that hGC-1 may be a useful marker for tumor differentiation and progression of human colon carcinoma. C1 [Liu, Wenli; Li, Yueqin; Zhu, Jianqiong; Rodgers, Griffin P.] NIH, NIDDK, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. [Wright, Elizabeth] NIDDK, Office Director, Bethesda, MD USA. [Ding, Ivan] NCI, Org Syst Branch, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NIH, NIDDK, Mol & Clin Hematol Branch, Bldg 10,Room 9N119,9000 Rockville Pike, Bethesda, MD 20892 USA. EM gr5n@nih.gov NR 36 TC 41 Z9 44 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 FEB 15 PY 2008 VL 14 IS 4 BP 1041 EP 1049 DI 10.1158/1078-0432.CCR-07-4125 PG 9 WC Oncology SC Oncology GA 266PX UT WOS:000253449700012 PM 18281536 ER PT J AU Fox, E Maris, JM Widemann, BC Goodspeed, W Goodwin, A Kromplewski, M Fouts, ME Medina, D Cohn, SL Krivoshik, A Hagey, AE Adamson, PC Balis, FM AF Fox, Elizabeth Maris, John M. Widemann, Brigitte C. Goodspeed, Wendy Goodwin, Anne Kromplewski, Marie Fouts, Molly E. Medina, Diane Cohn, Susan L. Krivoshik, Andrew Hagey, Anne E. Adamson, Peter C. Balis, Frank M. TI A phase I study of ABT-751, an orally bioavailable tubulin inhibitor, administered daily for 21 days every 28 days in pediatric patients with solid tumors SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 41st Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 13-17, 2005 CL Orlando, FL SP Amer Soc Clin Oncol ID ANTIMITOTIC AGENT; SULFONAMIDE; GROWTH; MODELS; E7010; VIVO AB Purpose: To determine the toxicity profile, close-limiting toxicities (DLT), and maximum tolerated dose (MTD) of ABT-751 administered orally once daily for 21 days, repeated every 28 days in a pediatric population. Experimental Design: Patients who were <= 18 years with relapsed or refractory solid tumors and who were able to swallow capsules were eligible. The starting dose was 75 mg/m(2)/d (n = 3) and was escalated to 100 (n = 6),130 (n = 5), and 165 (n = 3) mg/m(2)/d in cohorts of three to six patients. The MTD was determined from DLTs occurring during the first treatment cycle. Results: Nineteen children (median age, 13 years; range, 5-18 years) were enrolled, and 17 were evaluable for toxicity. Diagnoses included neuroblastoma (n = 9), sarcomas (n = 9), and other solid tumors (n = 1). DLTs included fatigue, sensory neuropathy, transient hypertension, neutropenia, thrombocytopenia, nausea, vomiting, dehydration, abdominal pain, and constipation. The MTD of ABT-751 administered daily for 21 days every 28 days was 100 mg/m(2)/d. Non-DLTat the MTD included bone marrow suppression, gastrointestinal toxicities (anorexia, abdominal pain, nausea, vomiting, and constipation), and sensory and motor neuropathies. The median number of cycles administered was one (range, one to five). Tolerance of repeated treatment cycles was poor. Conclusion: Fatigue, hematologic, and gastrointestinal toxicities limited the tolerability of ABT-751 administered to children on the once daily for 21 days every 28 days schedule. The MTD in children with solid tumors (100 mg/m(2)/d daily for 21 days) was similar to the recommended dose in adults with solid tumors (200 mg fixed dose) receiving the same dosing schedule. C1 [Fox, Elizabeth; Widemann, Brigitte C.; Goodspeed, Wendy; Goodwin, Anne; Balis, Frank M.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Maris, John M.; Kromplewski, Marie; Adamson, Peter C.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Maris, John M.; Kromplewski, Marie; Adamson, Peter C.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Maris, John M.; Kromplewski, Marie; Adamson, Peter C.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Fouts, Molly E.; Cohn, Susan L.] Childrens Mem Med Ctr, Chicago, IL USA. [Medina, Diane; Krivoshik, Andrew; Hagey, Anne E.] Abbott Labs, Abbott Pk, IL 60064 USA. RP Fox, E (reprint author), NCI, Pediat Oncol Branch, Bldg 10-CRC,Room 1-5750,10 Ctr Dr, Bethesda, MD 20892 USA. EM foxb@mail.nih.gov OI Cohn, Susan/0000-0001-5749-7650 FU Intramural NIH HHS NR 9 TC 33 Z9 34 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 FEB 15 PY 2008 VL 14 IS 4 BP 1111 EP 1115 DI 10.1158/1078-0432.CCR-07-4097 PG 5 WC Oncology SC Oncology GA 266PX UT WOS:000253449700021 PM 18281544 ER PT J AU Moss, WJ Fisher, C Scott, S Monze, M Ryon, JJ Quinn, TC Griffin, DE Cutts, FT AF Moss, William J. Fisher, Cynthia Scott, Susana Monze, Mwaka Ryon, Judith J. Quinn, Thomas C. Griffin, Diane E. Cutts, Felicity T. TI HIV type 1 infection is a risk factor for mortality in hospitalized Zambian children with measles SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ANTIBODY; HEALTH; IMPACT; SEX AB Background. Measles remains a significant cause of vaccine-preventable mortality in sub-Saharan Africa, yet few studies have investigated risk factors for measles mortality in regions of high human immunodeficiency virus type 1 (HIV-1) prevalence. Methods. Between January 1998 and July 2003, children with clinically diagnosed measles who were hospitalized at the University Teaching Hospital in Lusaka, Zambia, were enrolled in an observational study. Demographic and clinical information was recorded at enrollment and at discharge or death. Measles was confirmed by detection of antimeasles virus immunoglobulin M antibodies, and HIV-1 infection was confirmed by detection of HIV-1 RNA. Results. Of 1474 enrolled children, 1227 (83%) had confirmed measles and known HIV-1 infection status. Almost one-third of the HIV-1-infected children with measles were < 9 months of age, the age of routine measles vaccination, compared with one-fourth of the uninfected children (P <.001). Death occurred during hospitalization in 23 (12.2%) of the HIV-1-infected children and 45 (4.3%) of the HIV-1-uninfected children (P <.001) with measles. After adjusting for age, sex, and measles vaccination status, HIV-1 infection (odds ratio, 2.5; 95% confidence interval, 1.4-4.6),<= 8 years of maternal education (odds ratio, 2.4; 95% confidence interval, 1.2-4.8), and the presence of a desquamating rash (odds ratio, 2.2, 95% confidence interval, 1.3-3.6) were significant predictors of mortality due to measles. Conclusions. In a region of high HIV-1 prevalence, coinfection with HIV-1 more than doubled the odds of death in hospitalized children with measles. Increased mortality among HIV-1-infected children is further evidence that greater efforts are necessary to reduce transmission of the measles virus in regions of high HIV-1 prevalence. C1 [Moss, William J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Moss, William J.; Ryon, Judith J.; Griffin, Diane E.] Johns Hopkins Univ, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Fisher, Cynthia; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Baltimore, MD USA. [Quinn, Thomas C.] NIAID, Natl Inst Hlth, Bethesda, MD USA. [Scott, Susana; Cutts, Felicity T.] London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England. [Monze, Mwaka] Univ Teaching Hosp, Virol Lab, Lusaka, Zambia. RP Moss, WJ (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM wmoss@jhsph.edu FU Intramural NIH HHS; NIAID NIH HHS [AI 23047] NR 29 TC 27 Z9 28 U1 0 U2 3 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 15 PY 2008 VL 46 IS 4 BP 523 EP 527 DI 10.1086/526525 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 254WB UT WOS:000252617600006 PM 18194095 ER PT J AU Mendoza, D Connors, S Lane, C Stehnach, S AF Mendoza, Daniel Connors, Sheila Lane, Clifford Stehnach, Sam TI Liposomal amphotericin B as a cause of pseudohyperphosphatemia SO CLINICAL INFECTIOUS DISEASES LA English DT Letter C1 [Mendoza, Daniel; Lane, Clifford] NIAID, NIH, Bethesda, MD 20892 USA. [Connors, Sheila; Stehnach, Sam] NIH, Dept Lab Med, Bethesda, MD 20892 USA. RP Mendoza, D (reprint author), 4000 Massachusetts Ave NW,Apt 1508, Washington, DC 20016 USA. EM mendozadan@niaid.nih.gov RI Mendoza, Daniel/B-5800-2008; OI Mendoza, Daniel/0000-0002-6362-0771 NR 3 TC 9 Z9 9 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 15 PY 2008 VL 46 IS 4 BP 645 EP 646 DI 10.1086/527041 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 254WB UT WOS:000252617600030 PM 18205543 ER PT J AU DeVido, SK Kwon, D Brown, JL Kassis, JA AF DeVido, Sarah K. Kwon, Deborah Brown, J. Lesley Kassis, Judith A. TI The role of Polycomb-group response elements in regulation of engrailed transcription in Drosophila SO DEVELOPMENT LA English DT Article DE polycomb group genes; polycomb-group response elements (PREs); gene silencing; Drosophila ID CONVEYS EPIGENETIC INHERITANCE; GROUP PROTEIN COMPLEX; IN-SITU DISSECTION; BITHORAX COMPLEX; CELLULAR MEMORY; PCG PROTEINS; DNA-BINDING; GROUP GENES; MELANOGASTER; TRITHORAX AB Polycomb group proteins are required for long-term repression of many genes in Drosophila and all metazoans. In Drosophila, DNA fragments called Polycomb-group response elements (PREs) have been identified that mediate the action of Polycomb-group proteins. Previous studies have shown that a 2 kb fragment located from -2.4 kb to -395 bp upstream of the Drosophila engrailed promoter contains a multipartite PRE that can mediate mini-white silencing and act as a PRE in an Ubx-reporter construct. Here, we study the role of this 2 kb fragment in the regulation of the engrailed gene itself. Our results show that within this 2 kb fragment, there are two subfragments that can act as PREs in embryos. In addition to their role in gene silencing, these two adjacent PRE fragments can facilitate the activation of the engrailed promoter by distant enhancers. The repressive action of the engrailed PRE can also act over a distance. A 181 bp subfragment can act as a PRE and also mediate positive effects in an enhancer-detector construct. Finally, a deletion of 530 bp of the 2 kb PRE fragment within the endogenous engrailed gene causes a loss-of-function phenotype, showing the importance of the positive regulatory effects of this PRE-containing fragment. Our data are consistent with the model that engrailed PREs bring chromatin together, allowing both positive and negative regulatory interactions between distantly located DNA fragments. C1 [DeVido, Sarah K.; Kwon, Deborah; Brown, J. Lesley; Kassis, Judith A.] NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20982 USA. RP Kassis, JA (reprint author), NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20982 USA. EM jk14p@nih.gov OI Kassis, Judith/0000-0001-9268-3213 FU Intramural NIH HHS NR 46 TC 30 Z9 31 U1 0 U2 2 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD FEB 15 PY 2008 VL 135 IS 4 BP 669 EP 676 DI 10.1242/dev.014779 PG 8 WC Developmental Biology SC Developmental Biology GA 255TF UT WOS:000252679600007 PM 18199580 ER PT J AU Uno, S Dragin, N Miller, ML Dalton, TP Gonzalez, FJ Nebert, DW AF Uno, Shigeyuki Dragin, Nadine Miller, Marian L. Dalton, Timothy P. Gonzalez, Frank J. Nebert, Daniel W. TI Basal and inducible CYP1 mRNA quantitation and protein localization throughout the mouse gastrointestinal tract SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE CYP1A1; CYP1A2; CYP1B1; Q-PCR; immunohistochemistry; tongue; Esophagus; stomach; duodenum; jejunum; colon; benzo[a]pyrene; 2,3,7,8-tetrachlorodibenzo-p-dioxin ID RAT SMALL-INTESTINE; CYTOCHROME-P450 EXPRESSION; XENOBIOTIC METABOLISM; ALIMENTARY-TRACT; DRUG-METABOLISM; INDUCTION; ENZYMES; GENES; LIVER; DETOXICATION AB The CYP1A1, CYP1A2, and CYP1B1 enzymes are inducible by benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); metabolism of BaP by these enzymes leads to electrophilic intermediates and genotoxicity. Throughout the gastrointestinal (GI) tract, we systematically compared basal and inducible levels of the CYP1 mRNAs by Q-PCR, and localized the CYP1 proteins by immunohistochemistry. Cyp1(+/+) wild-type were compared with the Cyp1a1(-/-), Cyp1a2(-/-), and Cyp1b1(-/-) single-knockout and Cyp1a1/1b1(-/-) and Cyp1a2/1b1(-/-) double-knockout mice. Oral BaP was compared with intraperitoneal TCDD. In general, maximal CYP1A1 mRNA levels were 3-10 times greater than CYP1B1, which were 3-10 times greater than CYP1A2 mRNA levels. Highest inducible concentrations of CYP1A1 and CYP1A2 occurred in proximal small intestine, whereas the highest basal and inducible levels of CYP1B1 mRNA occurred in esophagus, forestomach, and glandular stomach. Ablation of either Cyp1a2 or Cyp1b1 gene resulted in a compensatory increase in CYP1A1 mRNA - but only in small intestine. Also in small intestine, although BaP- and TCDD-mediated CYP1A1 inductions were roughly equivalent, oral BaP-mediated CYP1A2 mRNA induction was similar to 40-fold greater than TCDD-mediated CYP1A2 induction. CYP1B1 induction by TCDD in Cyp1(+/+) and Cyp1a2(-/-) mice was 4-5 times higher than that by BaP; however, in Cyp1a1(-/-) animals CYP1B1 induction by TCDD or BaP was approximately equivalent. CYP1A1 and CYP1A2 proteins were generally localized nearer to the lumen than CYP1B1 proteins, in both squamous and glandular epithelial cells. These GI tract data suggest that the inducible CYP1A1 enzyme, both in concentration and in location, might act as a "shield" in detoxifying oral BaP and, hence, protecting the animal. (c) 2007 Published by Elsevier Inc. C1 [Uno, Shigeyuki; Dragin, Nadine; Miller, Marian L.; Dalton, Timothy P.; Nebert, Daniel W.] Univ Cincinnati, Med Ctr, Dept Environm Hlth, Cincinnati, OH 45267 USA. [Uno, Shigeyuki; Dragin, Nadine; Miller, Marian L.; Dalton, Timothy P.; Nebert, Daniel W.] Univ Cincinnati, Med Ctr, CEG, Cincinnati, OH 45267 USA. [Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Nebert, DW (reprint author), Univ Cincinnati, Med Ctr, Dept Environm Hlth, POB 670056, Cincinnati, OH 45267 USA. EM dan.nebert@uc.edu FU NIEHS NIH HHS [P30 ES006096-139007, P30 ES06096, P30 ES006096, R01 ES014403-03, R01 ES014403-03S1, P30 ES006096-149007, R01 ES014403, R01 ES008147, R01 ES08147, R01 ES008147-07S1, R01 ES008147-07] NR 37 TC 40 Z9 42 U1 0 U2 2 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 FEB 15 PY 2008 VL 44 IS 4 BP 570 EP 583 DI 10.1016/j.freeradbiomed.2007.10.044 PG 14 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 261OS UT WOS:000253090200009 PM 17997381 ER PT J AU Takizawa, T Gudla, PR Guo, LY Lockett, S Misteli, T AF Takizawa, Takumi Gudla, Prabhakar R. Guo, Liying Lockett, Stephan Misteli, Tom TI Allele-specific nuclear positioning of the monoallelically expressed astrocyte marker GFAP SO GENES & DEVELOPMENT LA English DT Article DE monoallelic expression; spatial gene positioning; nuclear architecture; astrocyte ID SPATIAL GENOME ORGANIZATION; GENE-EXPRESSION; PROBABILISTIC REGULATION; CHROMOSOME TERRITORIES; DNA METHYLATION; FETAL-BRAIN; DIFFERENTIATION; TRANSCRIPTION; CELLS; ARCHITECTURE AB Chromosomes and genes are nonrandomly arranged within the mammalian cell nucleus. However, the functional significance of nuclear positioning in gene expression is unclear. Here we directly probed the relationship between nuclear positioning and gene activity by comparing the location of the active and inactive copies of a monoallelically expressed gene in single cell nuclei. We demonstrate that the astrocyte-specific marker GFAP (glial fibrillary acidic protein) is monoallelically expressed in cortical astrocytes. Selection of the active allele occurs in a stochastic manner and is generally maintained through cell division. Taking advantage of the monoallelic expression of GFAP, we show that the functionally distinct alleles occupy differential radial positions within the cell nucleus and differentially associate with intranuclear compartments. In addition, coordinately regulated astrocyte-specific genes on distinct chromosomes spatially associate in their inactive state and dissociate upon activation. These results provide direct evidence for function-related differential positioning of individual gene alleles within the interphase nucleus. C1 [Takizawa, Takumi; Misteli, Tom] NCI, NIH, Bethesda, MD 20892 USA. [Gudla, Prabhakar R.; Lockett, Stephan] NCI, NIH, Sci Applicat Int Corp Frederick, Frederick, MD 21702 USA. [Lockett, Stephan] NIAID, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU Intramural NIH HHS NR 37 TC 85 Z9 88 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI COLD SPRING HARBOR PA 1 BUNGTOWN RD, COLD SPRING HARBOR, NY 11724 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD FEB 15 PY 2008 VL 22 IS 4 BP 489 EP 498 DI 10.1101/gad.1634608 PG 10 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 266SW UT WOS:000253458300008 PM 18281462 ER PT J AU Michalski, CW Oti, FE Erkan, M Saulitmaite, D Bergmann, F Pacher, P Batkai, S Muller, MW Giese, NA Friess, H Kleeff, J AF Michalski, Christoph W. Oti, Florian E. Erkan, Mert Saulitmaite, Danguole Bergmann, Frank Pacher, Pal Batkai, Sandor Mueller, Michael W. Giese, Nathalia A. Friess, Helmut Kleeff, Joerg TI Cannabinoids in pancreatic cancer: Correlation with survival and pain SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE pancreatic cancer; cannabinoids; pain; survival ID RECEPTOR-INDEPENDENT MECHANISM; ENDOCANNABINOID INACTIVATION; MOLECULAR CHARACTERIZATION; CELL-PROLIFERATION; PROSTATE-CANCER; TUMOR-GROWTH; DELTA-9-TETRAHYDROCANNABINOL; ANGIOGENESIS; INHIBITION; ACTIVATION AB Cannabinoids exert antiproliferative properties in a variety of malignant tumors, including pancreatic ductal adenocarcinoma (PDAC). In our study, we quantitatively evaluated the immunoreactivity for cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptors as well as for the endocannabinoid metabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MGLL). Furthermore, quantitative real-time RT-PCR for CB1, CB2, FAAH and MGLL in normal pancreas and pancreatic cancer tissues was performed. Levels of endocannabinoids were determined by liquid chromatography/mass spectrometry. Immunoreactivity scores and QRT-PCR expression levels were correlated with the clinico-pathological (TNM, survival, pain) status of the patients. Evaluation of endocannabinoid levels revealed that these remained unchanged in PDAC compared to the normal pancreas. Patients with high CB1 receptor levels in enlarged nerves in PDAC had a lower combined pain score (intensity, frequency, duration; p = 0.012). There was a significant relationship between low CB1 receptor immunoreactivity or mRNA expression levels (P = 0.0011 and p = 0.026, respectively), or high FAAH and MGLL cancer cell immunoreactivity (p = 0.036 and p = 0.017, respectively) and longer survival of PDAC patients. These results are underlined by a significant correlation of high pain scores and increased survival (p = 0.0343). CB2 receptor immunoreactivity, CB2 receptor, FAAH and MGLL mRNA expression levels did not correlate with survival. Therefore, changes in the levels of endocannabinoid metabolizing enzymes and cannabinoid receptors on pancreatic cancer cells may affect prognosis and pain status or PDAC patients. (C) 2007 Wiley-Liss. Inc. C1 [Michalski, Christoph W.; Erkan, Mert; Saulitmaite, Danguole; Mueller, Michael W.; Giese, Nathalia A.; Friess, Helmut; Kleeff, Joerg] Tech Univ Munich, Dept Gen Surg, D-81675 Munich, Germany. [Michalski, Christoph W.; Oti, Florian E.; Erkan, Mert; Saulitmaite, Danguole; Mueller, Michael W.; Giese, Nathalia A.; Friess, Helmut; Kleeff, Joerg] Univ Heidelberg, Dept Gen Surg, Heidelberg, Germany. [Bergmann, Frank] Univ Heidelberg, Inst Pathol, D-6900 Heidelberg, Germany. [Pacher, Pal; Batkai, Sandor] NIAAA, NIH, Lab Psychol Studies, Sect Oxidat Stress Tissue Injury, Bethesda, MD USA. RP Michalski, CW (reprint author), Tech Univ Munich, Dept Gen Surg, Ismaningerstr 22, D-81675 Munich, Germany. EM christoph.michalski@gmx.de RI Kleeff, Jorg/B-2124-2009; Batkai, Sandor/G-3889-2010; Pacher, Pal/B-6378-2008; Batkai, Sandor/H-7983-2014 OI Kleeff, Jorg/0000-0003-3432-6669; Pacher, Pal/0000-0001-7036-8108; FU Intramural NIH HHS [Z01 AA000375-02] NR 38 TC 52 Z9 53 U1 1 U2 5 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 FEB 15 PY 2008 VL 122 IS 4 BP 742 EP 750 DI 10.1002/ije.23114 PG 9 WC Oncology SC Oncology GA 253MQ UT WOS:000252522700005 PM 17943729 ER PT J AU Nyante, SJ Gammon, MD Malone, KF Daling, JR Brinton, LA AF Nyante, Sarah J. Gammon, Marilie D. Malone, Kathleen F. Daling, Janet R. Brinton, Louise A. TI The association between oral contraceptive use and lobular and ductal breast cancer in young women SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast cancer; ductal carcinoma; lobular carcinoma; oral contraceptives ID HORMONE REPLACEMENT THERAPY; CARCINOMA IN-SITU; UNITED-STATES; RISK-FACTORS; HISTOLOGIC TYPE; AGE; HISTORIES; REPRODUCIBILITY; OVEREXPRESSION; REGIMENS AB Recent reports indicate that the incidence of lobular breast cancer is increasing at a faster rate than ductal breast cancer, which may be due to the differential effects of exogenous hormones by histology. To address this issue, we examined whether the relationship between oral contraceptive use and incident breast cancer differs between lobular and ductal subtypes in young women. A population-based sample of in situ and invasive breast cancer cases between ages 20 and 44 were recruited from Atlanta, GA; Seattle-Puget Sound, WA and central New Jersey. Controls were sampled from the same areas by random-digit dialing, and were frequency matched to the expected case age distribution. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using polytomous logistic regression. Among the 100 lobular cancers 1,1 41 ductal cancers, and 1,501 controls, the odds ratios for oral contraceptive ever use were 1.10 (95% CI = 0.68-1.78) for lobular cancers and 1.21 (95% CI = 1.01-1.45) for ductal cancers, adjusted for study site, age at diagnosis, and pap screening history. Our results suggest that the magnitude of the association between ever use of oral contraceptives and breast cancer in young women does not vary strongly by histologic subtype. These results are similar to previous studies that report little difference in the effect of oral contraceptive use on breast cancer by histology. (c) 2007 Wilev-Liss, Inc. C1 [Nyante, Sarah J.; Gammon, Marilie D.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [Malone, Kathleen F.; Daling, Janet R.] Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA. [Brinton, Louise A.] NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Nyante, SJ (reprint author), Univ N Carolina, Dept Epidemiol, CB 7435, Chapel Hill, NC 27599 USA. EM nyante@email.unc.edu RI Brinton, Louise/G-7486-2015 OI Brinton, Louise/0000-0003-3853-8562 FU Intramural NIH HHS; NCI NIH HHS [5-T32-CA009330, N01-CN-0532, NCI-NO1-CP-95671]; NIEHS NIH HHS [P30ES10126] NR 47 TC 7 Z9 8 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 FEB 15 PY 2008 VL 122 IS 4 BP 936 EP 941 DI 10.1002/ijc.23163 PG 6 WC Oncology SC Oncology GA 253MQ UT WOS:000252522700032 PM 17957781 ER PT J AU Cook, MB Richiardi, L McGlynn, KA AF Cook, Michael B. Richiardi, Lorenzo McGlynn, Katherine A. TI Birth weight and risk of testicular cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Letter C1 [Cook, Michael B.; McGlynn, Katherine A.] NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Richiardi, Lorenzo] Univ Turin, Dept Biomed Sci & Human Oncol, Canc Epidemiol Unit, I-10124 Turin, Italy. RP Cook, MB (reprint author), NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, EPS Suite 550,6120 Execut Blvd, Bethesda, MD 20892 USA. EM cookmich@mail.nih.gov RI Cook, Michael/A-5641-2009 OI Cook, Michael/0000-0002-0533-7302 FU Intramural NIH HHS [Z99 CA999999] NR 4 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 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2008 VL 122 IS 4 BP 957 EP 957 DI 10.1002/ijc.23129 PG 1 WC Oncology SC Oncology GA 253MQ UT WOS:000252522700036 PM 17943727 ER PT J AU Bergamaschi, C Rosati, M Jalah, R Valentin, A Kulkarni, V Alicea, C Zhang, GM Patel, V Felber, BK Pavlakis, GN AF Bergamaschi, Cristina Rosati, Margherita Jalah, Rashmi Valentin, Antonio Kulkarni, Viraj Alicea, Candido Zhang, Gen-Mu Patel, Vainav Felber, Barbara K. Pavlakis, George N. TI Intracellular interaction of interleukin-15 with its receptor alpha during production leads to mutual stabilization and increased bioactivity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CD8(+) T-CELLS; NATURAL-KILLER-CELLS; MARROW-DERIVED CELLS; IN-VIVO; IL-15 ACTIVITY; CUTTING EDGE; PLASMID DNA; BETA-CHAIN; EXPRESSION; MEMORY AB We show that co-expression of interleukin 15 (IL-15) and IL-15 receptor alpha(IL-15R alpha) in the same cell allows for the intracellular interaction of the two proteins early after translation, resulting in increased stability and secretion of both molecules as a complex. In the absence of co-expressed IL-15R alpha, a large portion of the produced IL-15 is rapidly degraded immediately after synthesis. Co-injection into mice of IL-15 and IL-15R alpha expression plasmids led to significantly increased levels of the cytokine in serum as well as increased biological activity of IL-15. Examination of natural killer cells and T lymphocytes in mouse organs showed a great expansion of both cell types in the lung, liver, and spleen. The presence of IL-15R alpha also increased the number of CD44(high) memory cells with effector phenotype (CD44(high)CD62L-). Thus, mutual stabilization of IL-15 and IL-15R alpha leads to remarkable increases in production, stability, and tissue availability of bioactive IL-15 in vivo. The in vivo data show that the most potent form of IL-15 is as part of a complex with its receptor alpha either on the surface of the producing cells or as a soluble extracellular complex. These results explain the reason for coordinate expression of IL-15 and IL-15R alpha in the same cell and suggest that the IL-15R alpha is part of the active IL-15 cytokine rather than part of the receptor. C1 [Bergamaschi, Cristina; Rosati, Margherita; Valentin, Antonio; Zhang, Gen-Mu; Patel, Vainav; Pavlakis, George N.] NCI, Canc Res Ctr, Vaccine Branch, Human Retrovirus Sect,NIH, Frederick, MD 21702 USA. [Jalah, Rashmi; Kulkarni, Viraj; Alicea, Candido; Zhang, Gen-Mu; Felber, Barbara K.] NCI, Canc Res Ctr, Vaccine Branch, Human Retrovirus Pathogenesis Sect,NIH, Frederick, MD 21702 USA. RP Pavlakis, GN (reprint author), NCI, Canc Res Ctr, Vaccine Branch, Human Retrovirus Sect,NIH, Bldg 535,Rm 210, Frederick, MD 21702 USA. EM pavlakis@ncifcrf.gov FU Intramural NIH HHS NR 56 TC 72 Z9 73 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 FEB 15 PY 2008 VL 283 IS 7 BP 4189 EP 4199 DI 10.1074/jbc.M705725200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 261MO UT WOS:000253083500054 PM 18055460 ER PT J AU Gomes, DA Rodrigues, MA Leite, MF Gomez, MV Varnai, P Balla, T Bennett, AM Nathanson, MH AF Gomes, Dawidson A. Rodrigues, Michele A. Leite, M. Fatima Gomez, Marcus V. Varnai, Peter Balla, Tamas Bennett, Anton M. Nathanson, Michael H. TI C-met must translocate to the nucleus to initiate calcium signals SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; PERFUSED-RAT-LIVER; TYROSINE PHOSPHORYLATION; CELL-PROLIFERATION; DOWN-REGULATION; FACTOR RECEPTOR; BILE SECRETION; CA2+; LOCALIZATION; RELEASE AB Hepatocyte growth factor (HGF) is important for cell proliferation, differentiation, and related activities. HGF acts through its receptor c-Met, which activates downstream signaling pathways. HGF binds to c-Met at the plasma membrane, where it is generally believed that c-Met signaling is initiated. Here we report that c-Met rapidly translocates to the nucleus upon stimulation with HGF. Ca2+ signals that are induced by HGF result from phosphatidylinositol 4,5-bisphosphate hydrolysis and inositol 1,4,5-trisphosphate formation within the nucleus rather than within the cytoplasm. Translocation of c-Met to the nucleus depends upon the adaptor protein Gab1 and importin beta 1, and formation of Ca2+ signals in turn depends upon this translocation. HGF may exert its particular effects on cells because it bypasses signaling pathways in the cytoplasm to directly activate signaling pathways in the nucleus. C1 [Gomes, Dawidson A.; Rodrigues, Michele A.; Nathanson, Michael H.] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA. [Bennett, Anton M.] Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA. [Gomez, Marcus V.] Univ Fed Minas Gerais, Dept Pharmacol, BR-31270901 Belo Horizonte, MG, Brazil. [Gomes, Dawidson A.; Rodrigues, Michele A.; Leite, M. Fatima] Univ Fed Minas Gerais, Dept Physiol & Biophys, BR-31270901 Belo Horizonte, MG, Brazil. [Varnai, Peter; Balla, Tamas] NICHD, Sect Mol Signal Transduct, NIH, Bethesda, MD 20892 USA. RP Nathanson, MH (reprint author), Yale Univ, Sch Med, Dept Internal Med, Rm TAC S241D, New Haven, CT 06520 USA. EM michael.nathanson@yale.edu RI Gomez, Marcus Vinicius/I-4081-2012; Gomes, Dawidson/O-1372-2013; OI Gomes, Dawidson/0000-0001-7714-991X; Balla, Tamas/0000-0002-9077-3335 FU Howard Hughes Medical Institute; NIDDK NIH HHS [DK37989, DK45710, DK57751, P01 DK057751, P01 DK057751-01A1, P30 DK034989, P30 DK034989-169004, R01 DK045710, R01 DK045710-06A2] NR 49 TC 81 Z9 87 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 FEB 15 PY 2008 VL 283 IS 7 BP 4344 EP 4351 DI 10.1074/jbc.M706550200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 261MO UT WOS:000253083500069 PM 18073207 ER PT J AU Kanaani, J Patterson, G Schaufele, F Lippincott-Schwartz, J Baekkeskov, S AF Kanaani, Jamil Patterson, George Schaufele, Fred Lippincott-Schwartz, Jennifer Baekkeskov, Steinunn TI A palmitoylation cycle dynamically regulates partitioning of the GABA-synthesizing enzyme GAD65 between ER-Golgi and post-Golgi membranes SO JOURNAL OF CELL SCIENCE LA English DT Article DE glutamic acid decarboxylase; palmitoylation signals; palmitoylation cycle; membrane trafficking; ER/Golgi trafficking; Golgi/post-Golgi cycling; FRAP analysis ID GLUTAMIC-ACID DECARBOXYLASE; PANCREATIC BETA-CELLS; GAMMA-AMINOBUTYRIC-ACID; ACYL-PROTEIN THIOESTERASE-1; 65-KDA ISOFORM; MICE DEFICIENT; ENDOPLASMIC-RETICULUM; ORGANELLE STRUCTURE; PLASMA-MEMBRANE; CLEFT-PALATE AB GAD65, the smaller isoform of the enzyme glutamic acid decarboxylase, synthesizes GABA for fine-tuning of inhibitory neurotransmission. GAD65 is synthesized as a soluble hydrophilic protein but undergoes a hydrophobic post-translational modification and becomes anchored to the cytosolic face of Golgi membranes. A second hydrophobic modification, palmitoylation of Cys30 and Cys45 in GAD65, is not required for the initial membrane anchoring but is crucial for post-Golgi trafficking of the protein to presynaptic clusters. The mechanism by which palmitoylation directs targeting of GAD65 through and out of the Golgi complex is unknown. Here, we show that prior to palmitoylation, GAD65 anchors to both ER and Golgi membranes. Palmitoylation, however, clears GAD65 from the ER-Golgi, targets it to the trans-Golgi network and then to a post-Golgi vesicular pathway. FRAP analyses of trafficking of GAD65-GFP reveal a rapid and a slow pool of protein replenishing the Golgi complex. The rapid pool represents non-palmitoylated hydrophobic GAD65-GFP, which exchanges rapidly between the cytosol and ER/Golgi membranes. The slow pool represents palmitoylation-competent GAD65-GFP, which replenishes the Golgi complex via a non-vesicular pathway and at a rate consistent with a depalmitoylation step. We propose that a depalmitoylation-repalmitoylation cycle serves to cycle GAD65 between Golgi and post-Golgi membranes and dynamically control levels of enzyme directed to the synapse. C1 [Kanaani, Jamil; Schaufele, Fred; Baekkeskov, Steinunn] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. [Kanaani, Jamil; Schaufele, Fred; Baekkeskov, Steinunn] Univ Calif San Francisco, Ctr Diabet, San Francisco, CA 94143 USA. [Kanaani, Jamil; Baekkeskov, Steinunn] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA. [Patterson, George; Lippincott-Schwartz, Jennifer] NICHHD, Natl Inst Hlth, Cell Biol & Metab Branch, Bethesda, MD 21218 USA. RP Baekkeskov, S (reprint author), Univ Calif San Francisco, Dept Med, 513 Parnassus Ave,HSW 1090, San Francisco, CA 94143 USA. EM s_baekkeskov@biochem.ucsf.edu FU NIDDK NIH HHS [P30 DK 063720] NR 50 TC 33 Z9 33 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD FEB 15 PY 2008 VL 121 IS 4 BP 437 EP 449 DI 10.1242/jcs.011916 PG 13 WC Cell Biology SC Cell Biology GA 266HT UT WOS:000253425800005 PM 18230651 ER PT J AU Gray, TR Shakleya, DM Huestis, MA AF Gray, Teresa R. Shakleya, Diaa M. Huestis, Marilyn A. TI Quantification of nicotine, cotinine, trans-3 '-hydroxycotinine, nornicotine and norcotinine in human meconium by liquid chromatography/tandem mass spectrometry SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE meconium; nicotine; cotinine; trans-3-hydroxycotinine; tobacco ID MATERNAL SMOKING; METABOLITES; PREGNANCY; EXPOSURE; URINE; ANABASINE; CAFFEINE; INFANTS; SMOKERS; MOTHERS AB There are no analytical methods that simultaneously quantify nicotine, cotinine, trans-3'-hydroxycotinine, nornicotine and norcotinine in human meconium. Such a method could improve identification of in utero tobacco exposure, determine if matemal close-meconium concentration relationships exist, and whether nicotine meconium concentrations predict neonatal outcomes. The first liquid chromatography/atmospheric pressure chemical ionization tandem mass spectrometry method for simultaneous quantification of these analytes in meconium was developed and validated. Specimen preparation included homogenization, enzyme hydrolysis and solid phase extraction. The linear range was 1.25 or 5-500 ng/g. Method applicability was evaluated with meconium collected from an in utero tobacco exposed infant. Published by Elsevier B.V. C1 [Gray, Teresa R.; Shakleya, Diaa M.; Huestis, Marilyn A.] Natl Inst Drug Abuse, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, NIH, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000433-08, Z01 DA000412-10] NR 23 TC 43 Z9 43 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD FEB 15 PY 2008 VL 863 IS 1 BP 107 EP 114 DI 10.1016/j.jchromb.2008.01.001 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 268QK UT WOS:000253594100014 PM 18243821 ER PT J AU Kothapalli, N Norton, DD Fugmann, SD AF Kothapalli, Nagarama Norton, Darrell D. Fugmann, Sebastian D. TI A cis-acting DNA element targets AID-mediated sequence diversification to the chicken Ig light chain gene locus SO JOURNAL OF IMMUNOLOGY LA English DT Review ID CYTIDINE DEAMINASE AID; SOMATIC HYPERMUTATION; IMMUNOGLOBULIN; CONVERSION; TRANSCRIPTION; ENHANCER; EXPRESSION; PROMOTER; ENZYME; CELLS AB Somatic hypermutation and gene conversion are two closely related processes that increase the diversity of the primary Ig repertoire. Both processes are initiated by the activation-induced cytidine deaminase that converts cytosine residues to uracils in a transcription-dependent manner; these lesions are subsequently fixed in the genome by direct replication and error-prone DNA repair. Two alternative mechanisms were proposed to explain why this mutagenic activity is targeted almost exclusively to Ig loci:]) specific cis-acting DNA sequences; or 2) very high levels of Ig gene transcription. In this study we now identify a novel 3' regulatory region in the chicken Ig light chain gene containing not only a classical transcriptional enhancer but also cis-acting DNA elements essential for targeting activation-induced cytidine deaminase-mediated sequence diversification to this locus. C1 [Kothapalli, Nagarama; Norton, Darrell D.; Fugmann, Sebastian D.] NIA, Cellular & Mol Biol Lab, Gerontol Res Ctr, Mol Immunol Unit,NIH, Baltimore, MD 21224 USA. RP Fugmann, SD (reprint author), NIA, Cellular & Mol Biol Lab, Gerontol Res Ctr, Mol Immunol Unit,NIH, 5600 Narthan Shock Dr, Baltimore, MD 21224 USA. EM fugmanns@grc.nia.nih.gov RI Kothapalli, Naga Rama/E-5229-2017 OI Kothapalli, Naga Rama/0000-0001-7993-8525 FU Intramural NIH HHS NR 24 TC 39 Z9 40 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2008 VL 180 IS 4 BP 2019 EP 2023 PG 5 WC Immunology SC Immunology GA 260JC UT WOS:000253005600008 PM 18250404 ER PT J AU Kashyap, M Thornton, AM Norton, SK Barnstein, B Macey, M Brenzovich, J Shevach, E Leonard, WJ Ryan, JJ AF Kashyap, Mohit Thornton, Angela M. Norton, Sarah Kennedy Barnstein, Brian Macey, Matthew Brenzovich, Jennifer Shevach, Ethan Leonard, Warren J. Ryan, John J. TI CD4 T cell-mast cell interactions alter IgE receptor expression and signaling SO JOURNAL OF IMMUNOLOGY LA English DT Review ID EPSILON-RI EXPRESSION; SUPPRESSOR FUNCTION; STAT5 EXPRESSION; ASTHMA; IL-10; HYPERREACTIVITY; INFLAMMATION; MODULATION; ACTIVATION; TGF-BETA-1 AB Mast cell activation is associated with atopic and inflammatory diseases, but the natural controls of mast cell homeostasis are poorly understood. We hypothesized that CD4(+) CD25(+) regulatory T cells (Treg) could function in mast cell homeostasis. In this study, we demonstrate that mast cells can recruit both Treg and conventional CD4+ T cells (Tconv). Furthermore, Treg, but not Tconv, suppress mast cell Fc epsilon RI expression. Despite the known inhibitory functions of IL-10 and TGF beta 1, FcFRI suppression was independent of IL-10 and TGF-beta 1 and required cell contact. Surprisingly, coculture with either Treg or Tconv cells suppressed IgE-mediated leukotriene C4 production but enhanced cytokine production by mast cells. This was accompanied by a selective increase in Fc epsilon RI-mediated Stat5 phosphorylation, which is a critical mediator of IgE-mediated cytokine secretion. These data are the first direct demonstration that mast cells can recruit Treg and illustrate that T cell interactions can alter the mast cell response. C1 [Kashyap, Mohit; Norton, Sarah Kennedy; Barnstein, Brian; Macey, Matthew; Brenzovich, Jennifer; Ryan, John J.] Virginia Commonwealth Univ, Dept Biol, Richmond, VA 23284 USA. [Thornton, Angela M.; Shevach, Ethan] NIAID, Immunol Lab, Bethesda, MD 20892 USA. [Leonard, Warren J.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Ryan, JJ (reprint author), Virginia Commonwealth Univ, Dept Biol, Box 842012, Richmond, VA 23284 USA. EM jjryan@saturn.vcu.edu RI Kashyap, Mohit/F-4534-2011 FU NCI NIH HHS [1R01 CA 91839]; NIAID NIH HHS [1R01 AI 059638] NR 32 TC 61 Z9 65 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2008 VL 180 IS 4 BP 2039 EP 2043 PG 5 WC Immunology SC Immunology GA 260JC UT WOS:000253005600012 PM 18250408 ER PT J AU Dubois, S Patel, HJ Zhang, M Waldmann, TA Muller, JR AF Dubois, Sigrid Patel, Hiral J. Zhang, Meili Waldmann, Thomas A. Mueller, Juergen R. TI Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8(+)/CD44(high) T cells and its antitumor action SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; DENDRITIC CELLS; CUTTING EDGE; SELECTIVE STIMULATION; IN-VIVO; MEMORY; TRANS; INTERLEUKIN-15; IMMUNOTHERAPY; ROLES AB In the induction of an immune response, IL-1511 alpha on APCs transpresents IL-15 to NK and CD8(+)/CD44(high) T cells that express the IL-2/15R beta and gamma c subunits only. In this study, we show data mimicking this transpresentation by using IL-15 preassociated with a chimeric protein that is comprised of the extracellular domain of murine IL-1511a and the Fe portion of human IgG1. When tested in vitro, IL-15R alpha-IgG1-Fc strongly increased the IL-15-mediated proliferation of murine NK and CD8(+)/CD44(high) T cells. The effect of IL-15R alpha-IgG1-Fc was dependent on the presence of both IgG1-Fc and IL-15R alpha. When injected into mice, IL-15R alpha-IgG1-Fc enhanced the capacity of IL-15 to expand the number of NK and CD8(+)/CD44(high) T cells. The effect on cell numbers in vivo also depended on Fe receptor binding because reduced expansion was observed in FcR gamma(-/-) mice. NK cells cultured in IL-15/IL-15R alpha-IgG1-Fc complex gained cytotoxic activity toward a number of NK-sensitive targets. When mice bearing the NK-sensitive syngeneic tumor B16 were treated, the presence of IL-15R alpha-IgG1-Fc increased the antitumor activity of IL-15. Thus, a preassociation with IL-15R alpha-IgG1-Fc enhances the activities of IL-15 in vivo and in vitro that may be useful in the treatment of tumors. C1 [Dubois, Sigrid; Patel, Hiral J.; Zhang, Meili; Waldmann, Thomas A.; Mueller, Juergen R.] NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Muller, JR (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bldg 10 Room 4N109,10 Ctr Dr, Bethesda, MD 20892 USA. EM muellerj@mail.nih.gov FU Intramural NIH HHS NR 30 TC 102 Z9 106 U1 2 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2008 VL 180 IS 4 BP 2099 EP 2106 PG 8 WC Immunology SC Immunology GA 260JC UT WOS:000253005600019 PM 18250415 ER PT J AU Ma, HT Peng, Z Hiragun, T Iwaki, S Gilfillan, AM Beaven, MA AF Ma, Hong-Tao Peng, Ze Hiragun, Takaaki Iwaki, Shoko Gilfillan, Alasdair M. Beaven, Michael A. TI Canonical transient receptor potential 5 channel in conjunction with Orai1 and STIM1 allows Sr2+ entry, optimal influx of Ca2+, and degranulation in a rat mast cell line SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CAPACITATIVE CALCIUM-ENTRY; CA2+-PERMEABLE CATION CHANNEL; BASOPHILIC RBL-2H3 CELLS; STORE-OPERATED CHANNEL; PROTEIN-KINASE-C; PLASMA-MEMBRANE; T-LYMPHOCYTES; CRAC CHANNEL; SIMILAR MECHANISMS; TRPC3 CHANNELS AB Degranulation of mast cells in response to Ag or the calcium mobilizing agent, thapsigargin, is dependent on emptying of intracellular stores of Ca2+ and the ensuing influx of external Ca2+, also referred to as store-operated calcium entry. However, it is unlikely that the calcium release-activated calcium channel is the sole mechanism for the entry of Ca2+ because Sr2+ and other 14 divalent cations also permeate and support degranulation in stimulated mast cells. In this study we show that influx of Ca2+ and Sr2+ as well as degranulation are dependent on the presence of the canonical transient receptor potential (TRPC) channel protein TRPC5, in addition to STIM1 and Orai1, as demonstrated by knock down of each of these proteins by inhibitory RNAs in a rat mast cell (RBL-2H3) line. Overexpression of STIM1 and Orai1, which are known to be essential components of calcium release-activated calcium channel, allows entry of Ca2+ but not Sr2+ whereas overexpression of STIM1 and TRPC5 allows entry of both Ca2+ and Sr2+. These and other observations suggest that the Sr2+-permeable TRPC5 associates with STIM1 and Orai1 in a stoichiometric manner to enhance entry of Ca2+ to generate a signal for degranulation. C1 [Ma, Hong-Tao; Peng, Ze; Hiragun, Takaaki; Beaven, Michael A.] NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. [Iwaki, Shoko; Gilfillan, Alasdair M.] NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Beaven, MA (reprint author), NHLBI, Lab Mol Immunol, NIH, Room 8N109,Bldg 10, Bethesda, MD 20892 USA. EM beavenm@nhlbi.nih.gov FU Intramural NIH HHS [Z01 HL000993-21] NR 68 TC 62 Z9 68 U1 1 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 EI 1550-6606 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2008 VL 180 IS 4 BP 2233 EP 2239 PG 7 WC Immunology SC Immunology GA 260JC UT WOS:000253005600034 PM 18250430 ER PT J AU Moir, S Malaspina, A Ho, J Wang, W DiPoto, AC O'Shea, MA Roby, G Mican, JM Kottilil, S Chun, TW Proschan, MA Fauci, AS AF Moir, Susan Malaspina, Angela Ho, Jason Wang, Wei DiPoto, Angela C. O'Shea, Marie A. Roby, Gregg Mican, Joann M. Kottilil, Shyam Chun, Tae-Wook Proschan, Michael A. Fauci, Anthony S. TI Normalization of B cell counts and subpopulations after antiretroviral therapy in chronic HIV disease SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 11th Training Course in the Physics of Strongly Correlated Systems CY OCT 02-13, 2006 CL Salerno, ITALY SP Univ Degli Studi, Salerno, Int Inst Adv Sci Studies, Campania Reg, CNR-INFM, SUPERMAT Reg Lab, COST P16 ID VIRUS TYPE-1 INFECTION; T-CELLS; INFLUENZA VACCINATION; IMMUNE ACTIVATION; RHESUS MACAQUES; RAPID TURNOVER; NK CELLS; CD4(+); LYMPHOCYTES; DEPLETION AB Background. Untreated human immunodeficiency virus (HIV) disease leads to abnormalities in all major lymphocyte populations, including CD4(+) T cells, CD8(+) T cells, and B cells. However, little is known regarding the effect of antiretroviral therapy (ART)-induced decrease in HIV viremia on B cell numbers and subpopulations. Methods. We conducted a longitudinal study to evaluate changes in B cell numbers and subpopulations that occur during the course of 12 months of effective ART in a group of individuals with chronic HIV infection. Results. ART-induced decrease in HIV viremia was associated with a significant increase in B cell counts, similar to increases in CD4(+) T cell counts yet distinct from the lack of increase in CD8(+) T cells. The increase in B cell counts was accompanied by a significant decrease in the frequency of apoptosis-prone B cell subpopulations, namely mature activated and immature transitional B cells, which are overrepresented in untreated HIV disease. The increase in B cell counts was reflected by a significant increase in naive and resting memory B cells, both of which represent populations that are essential for generating adequate humoral immunity. Conclusions. Normalization of B cell counts and subpopulations may help to explain the improvement in humoral immunity reported to occur after an ART-induced decrease in HIV viremia. C1 [Moir, Susan; Malaspina, Angela; Ho, Jason; Wang, Wei; DiPoto, Angela C.; O'Shea, Marie A.; Roby, Gregg; Kottilil, Shyam; Chun, Tae-Wook; Fauci, Anthony S.] NIAID, Immunoregulat Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Mican, Joann M.] NIAID, Div Clin Res, Natl Inst Hlth, Bethesda, MD 20892 USA. [Proschan, Michael A.] NIAID, Biostat Res Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Moir, S (reprint author), NIAID, Immunoregulat Lab, Natl Inst Hlth, Bldg 10 Rm 6A02,9000 Rockville Pike, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov FU Intramural NIH HHS NR 50 TC 89 Z9 92 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2008 VL 197 IS 4 BP 572 EP 579 DI 10.1086/526789 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 263BC UT WOS:000253191600012 PM 18240953 ER PT J AU Gay, EA Giniatullin, R Skorinkin, A Yakel, JL AF Gay, Elaine A. Giniatullin, Rashid Skorinkin, Andrei Yakel, Jerrel L. TI Aromatic residues at position 55 of rat alpha 7 nicotinic acetylcholine receptors are critical for maintaining rapid desensitization SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID LIGAND-BINDING DOMAIN; E-DERIVED PEPTIDES; GATED ION-CHANNEL; AGONIST BINDING; CHARGED RESIDUES; GABA(A) RECEPTOR; ACH RECEPTORS; ACTIVATION; LOOP; COMPLEXES AB The rat alpha 7 nicotinic acetylcholine receptor (nAChR) can undergo rapid onset of desensitization; however, the mechanisms of desensitization are largely unknown. The contribution of a tryptophan (W) residue at position 55 of the rat alpha 7 nAChR subunit, which lies within the beta 2 strand, was studied by mutating it to other hydrophobic and/or aromatic amino acids, followed by voltage-clamp experiments in Xenopus oocytes. When mutated to alanine, the alpha 7-W55A nAChR desensitized more slowly, and recovered from desensitization more rapidly, than wildtype alpha 7 nAChRs. The contribution of desensitization was validated by kinetic modelling. Mutating W55 to other aromatic residues (phenylalanine or tyrosine) had no significant effect on the kinetics of desensitization, whereas mutation to various hydrophobic residues (alanine, cysteine or valine) significantly decreased the rate of onset and increased the rate of recovery from desensitization. To gain insight into possible structural rearrangements during desensitization, we probed the accessibility of W55 by mutating W55 to cysteine (alpha 7-W55C) and testing the ability of various sulfhydryl reagents to react with this cysteine. Several positively charged sulfhydryl reagents blocked ACh-induced responses for alpha 7-W55C nAChRs, whereas a neutral sulfhydryl reagent potentiated responses; residue C55 was not accessible for modification in the desensitized state. These data suggest that W55 plays an important role in both the onset and recovery from desensitization in the rat alpha 7 nAChR, and that aromatic residues at position 55 are critical for maintaining rapid desensitization. Furthermore, these data suggest that W55 may be a potential target for modulatory agents operating via hydrophobic interactions. C1 [Gay, Elaine A.; Yakel, Jerrel L.] NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Giniatullin, Rashid] Scuola Int Super Studi Avanzati, Dept Neurobiol, I-34014 Trieste, Italy. [Skorinkin, Andrei] Russian Acad Sci, Biochem & Biophys Inst, Kazan, Russia. RP Gay, EA (reprint author), NIEHS, Neurobiol Lab, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. OI Giniatullin, Rashid/0000-0002-1580-6280 FU Intramural NIH HHS NR 36 TC 31 Z9 32 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD FEB 15 PY 2008 VL 586 IS 4 BP 1105 EP 1115 DI 10.1113/jphysiol.2007.149492 PG 11 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 267CE UT WOS:000253485300018 PM 18096596 ER PT J AU Yao, HN Etzkorn, LH Virani, S AF Yao, Haining Etzkorn, Letha H. Virani, Shamsnaz TI Automated classification and retrieval of reusable software components SO JOURNAL OF THE AMERICAN SOCIETY FOR INFORMATION SCIENCE AND TECHNOLOGY LA English DT Article AB The authors describe their research which improves software reuse by using an automated approach to semantically search for and retrieve reusable software components in large software component repositories and on the World Wide Web (WWW). Using automation and smart (semantic) techniques, their approach speeds up the search and retrieval of reusable software components, while retaining good accuracy, and therefore improves the affordability of software reuse. A program understanding of software components and natural language understanding of user queries was employed. Then the software component descriptions were compared by matching the resulting semantic representations of the user queries to the semantic representations of the software components to search for software components that best match the user queries. A proof of concept system was developed to test the authors' approach. The results of this proof of concept system were compared to human experts, and statistical analysis was performed on the collected experimental data. The results from these experiments demonstrate that this automated semantic-based approach for software reusable component classification and retrieval is successful when compared to the labor-intensive results from the experts, thus showing that this approach can significantly benefit software reuse classification and retrieval. C1 [Yao, Haining] NIH, Natl Lib Med, Bethesda, MD 20892 USA. [Etzkorn, Letha H.] Univ Alabama, Dept Comp Sci, Huntsville, AL 35899 USA. [Virani, Shamsnaz] Univ Alabama, Dept Ind & Syst Engn & Engn Management, Huntsville, AL 35899 USA. RP Yao, HN (reprint author), NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM hy77t@nih.gov; letzkorn@cs.uah.edu; shamsv@email.uah.edu NR 37 TC 9 Z9 9 U1 0 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1532-2882 J9 J AM SOC INF SCI TEC JI J. Am. Soc. Inf. Sci. Technol. PD FEB 15 PY 2008 VL 59 IS 4 BP 613 EP 627 DI 10.1002/asi.20775 PG 15 WC Computer Science, Information Systems; Information Science & Library Science SC Computer Science; Information Science & Library Science GA 264AP UT WOS:000253257900010 ER PT J AU Guynet, C Hickman, AB Barabas, O Dyda, F Chandler, M Ton-Hoang, B AF Guynet, Catherine Hickman, Alison Burgess Barabas, Orsolya Dyda, Fred Chandler, Michael Ton-Hoang, Bao TI In vitro reconstitution of a single-stranded transposition mechanism of IS608 SO MOLECULAR CELL LA English DT Article ID CONJUGATIVE RELAXASE TRWC; DEINOCOCCUS-RADIODURANS; DNA TRANSPOSASES; PLASMID R388; RECOMBINATION; RECOGNITION; SEQUENCES; ISHP608; PROTEIN; FAMILY AB Bacterial insertion sequences (IS) play an important role in restructuring their host genomes. IS608, from Helicobacter pylori, belongs to a newly recognized and widespread IS group with a unique transposition mechanism. We have reconstituted the entire set of transposition cleavage and strand transfer reactions in vitro and find that, unlike any other known transposition system, they strictly require single-strand DNA. TnpA, the shortest identified transposase, uses a nucleophilic tyrosine for these reactions. It recognizes and cleaves only the IS608 "top strand." The results support a transposition model involving excision of a single-strand circle with abutted left (LE) and right (RE) IS ends. Insertion occurs site specifically 3 ' to conserved and essential TTAC tetranucleotide and appears to be driven by LE. This single-strand transposition mode has important implications not only for dispersion of IS608 but also for the other members of this very large IS family. C1 [Guynet, Catherine; Chandler, Michael; Ton-Hoang, Bao] CNRS, UMR 5100, Lab Microbiol & Genet Mol, F-31062 Toulouse, France. [Hickman, Alison Burgess; Barabas, Orsolya; Dyda, Fred] NIDDK, Mol Biol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Chandler, M (reprint author), CNRS, UMR 5100, Lab Microbiol & Genet Mol, 118 Rte Narbonne, F-31062 Toulouse, France. EM michael.chandler@ibcg.biotoul.fr; bao.tonhoang@ibcg.biotoul.fr RI Guynet, Catherine/A-4815-2011; Barabas, Orsolya/F-3961-2012; OI Barabas, Orsolya/0000-0002-2873-5872; Chandler, Michael/0000-0002-0292-6662 FU Intramural NIH HHS NR 19 TC 36 Z9 36 U1 0 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 FEB 15 PY 2008 VL 29 IS 3 BP 302 EP 312 DI 10.1016/j.molcel.2007.12.008 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 265AG UT WOS:000253330900003 PM 18280236 ER PT J AU Wang, GJ Tomasi, D Backus, W Wang, R Telang, F Geliebter, A Korner, J Bauman, A Fowler, JS Thanos, PK Volkow, ND AF Wang, Gene-Jack Tomasi, Dardo Backus, Walter Wang, Ruiliang Telang, Frank Geliebter, Allan Korner, Judith Bauman, Angela Fowler, Joanna S. Thanos, Panayotis K. Volkow, Nora D. TI Gastric distention activates satiety circuitry in the human brain SO NEUROIMAGE LA English DT Article DE amygdala; fMRI; gastric distention; insula ID TEST-MEAL INTAKE; NEURAL RESPONSES; BULIMIC WOMEN; FOOD-INTAKE; GHRELIN; AMYGDALA; CAPACITY; BEHAVIOR; NUCLEUS; RAT AB Gastric distention during meal ingestion activates vagal afferents, which send signals from the stomach to the brain and result in the perception of fullness and satiety. Distention is one of the mechanisms that modulates food intake. We measured regional brain activation during dynamic gastric balloon distention in 18 health subjects using functional magnetic resonance imaging and the blood oxygenation level-dependent (BOLD) responses. The BOLD signal was significantly changed by both inflow and outflow changes in the balloon's volume. For lower balloon volumes, water inflow was associated with activation of sensorimotor cortices and right insula. The larger volume condition additionally activated left posterior amygdala, left posterior insula and the left precuneus. The response in the left amygdala and insula was negatively associated with changes in self-reports of fullness and positively with changes in plasma ghrelin concentration, whereas those in the right amygdala and insula were negatively associated with the subject's body mass index. The widespread activation induced by gastric distention corroborates the influence of vagal afferents on cortical and subcortical brain activity. These findings provide evidence that the left amygdala and insula process interoceptive signals of fullness produced by gastric distention involved in the controls of food intake. Published by Elsevier Inc. C1 [Wang, Gene-Jack; Tomasi, Dardo; Wang, Ruiliang; Bauman, Angela; Fowler, Joanna S.; Thanos, Panayotis K.] Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. [Wang, Gene-Jack; Fowler, Joanna S.] Mt Sinai Sch Med, New York, NY USA. [Backus, Walter; Bauman, Angela] SUNY Stony Brook, Dept Anesthesiol, Stony Brook, NY 11794 USA. [Telang, Frank; Thanos, Panayotis K.; Volkow, Nora D.] NIAAA, NIDA, Rockville, MD 20852 USA. [Geliebter, Allan] St Lukes Roosevelt Hosp, New York, NY USA. [Geliebter, Allan; Korner, Judith] Columbia Univ, Coll Phys & Surg, New York, NY 10027 USA. RP Wang, GJ (reprint author), Brookhaven Natl Lab, Dept Med, 30 Bell Ave, Upton, NY 11973 USA. EM gjwang@bnl.gov RI Tomasi, Dardo/J-2127-2015 FU NCRR NIH HHS [M01 RR 10710]; NIAAA NIH HHS [AA 9481, Y1 AA 3009]; NIDA NIH HHS [DA 00280, DA 7092]; NIDDK NIH HHS [DK 072011, R01 DK054318-01A1, R01 DK054318-02, R01 DK054318-03, R01 DK080153-01A2, R01 DK080153-02, R01 DK080153-03, R01 DK080153-04, R03 DK068603-01A2, R03 DK068603-02] NR 49 TC 128 Z9 130 U1 4 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2008 VL 39 IS 4 BP 1824 EP 1831 DI 10.1016/j.neuroimage.2007.11.008 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 263UK UT WOS:000253241800031 PM 18155924 ER PT J AU Yoo, WK You, SH Ko, MH Kim, ST Park, CH Park, JW Ohn, SH Hallett, M Kimg, YH AF Yoo, Woo-Kyoung You, Sung H. Ko, Myoung-Hwan Kim, Sung Tae Park, Chang-hyun Park, Ji-Won Ohn, Suk Hoon Hallett, Mark Kimg, Yun-Hee TI High frequency rTMS modulation of the sensoirmotor networks: Behavioral changes and fMRI correlates SO NEUROIMAGE LA English DT Article DE repetitive transcranial magnetic stimulation; sensorimotor networks; functional magnetic resonance imaging ID TRANSCRANIAL MAGNETIC STIMULATION; PRIMARY MOTOR CORTEX; CEREBRAL-BLOOD-FLOW; CORTICAL EXCITABILITY; NEUROPATHIC PAIN; FUNCTIONAL MRI; REPETITIVE TMS; TACTILE DISCRIMINATION; PARKINSONS-DISEASE; CHRONIC STROKE AB Repetitive transcranial magnetic stimulation (rTMS) to the primary motor cortex (M1) may induce functional modulation of motor performance and sensory perception. To address the underlying neurophysiological modulation following 10 Hz rTMS applied over M1, we examined cortical activation using 3T functional magnetic resonance imaging (fMRI), as well as the associated motor and sensory behavioral changes. The motor performance measure involved a sequential finger motor task that was also used as an activation task during fMRI. For sensory assessment, current perception threshold was measured before and after rTMS outside the MR scanner, and noxious mechanical stimulation was used as an activation task during fMRI. We found that significant activation in the bilateral basal ganglia, left superior frontal gyros, bilateral pre-SMA, right medial temporal lobe, right inferior parietal lobe, and right cerebellar hemisphere correlated with enhanced motor performance in subjects that received real rTMS compared with sham-stimulated controls. Conversely, significant deactivation in the right superior and middle frontal gyri, bilateral postcentral and bilateral cingulate gyri, left SMA, right insula, right basal ganglia, and right cerebellar hemisphere were associated with an increase in the sensory threshold. Our findings reveal that rTMS induced rapid changes in the sensorimotor networks associated with sensory perception and motor performance and demonstrate the complexity of such intervention. (c) 2007 Elsevier Inc. All rights reserved. C1 [Ohn, Suk Hoon; Kimg, Yun-Hee] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr,Stroke & Cerebrovasc Ctr, Dept Phys Med & Rehabil,Div Neurorehabil, Seoul 135710, South Korea. [Hallett, Mark] NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. [Park, Ji-Won] Catholic Univ Daegu, Dept Phys Therapy, Taegu, South Korea. [Yoo, Woo-Kyoung] Hallym Univ, Sacred Heart Hosp, Dept Phys & Rehabil Med, Anyang 431070, South Korea. [You, Sung H.] Yonsei Univ, Grad Sch Rehabil Sci, Director Virtual Real Educ & Res Ctr, Dept Phys Therapy, Seoul 120749, South Korea. [Ko, Myoung-Hwan] Chonbuk Natl Univ, Sch Med, Dept Phys Med & Rehabil, Jeonju 561712, Jeonbuk, South Korea. [Kim, Sung Tae] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Dept Diagnost Radiol & Imaging Sci, Seoul 135710, South Korea. [Park, Chang-hyun] Korea Adv Inst Sci & Technol, Dept Phys, Taejon 305701, South Korea. RP Kimg, YH (reprint author), Sungkyunkwan Univ, Sch Med, Samsung Med Ctr,Stroke & Cerebrovasc Ctr, Dept Phys Med & Rehabil,Div Neurorehabil, 50 Irwon Dong, Seoul 135710, South Korea. EM yunkim@skku.edu RI Kim, Yun Hee/F-4600-2014; Park, Chang-hyun/I-2217-2016; OI Yoo, Woo-Kyoung/0000-0002-1273-0647 NR 54 TC 33 Z9 33 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2008 VL 39 IS 4 BP 1886 EP 1895 DI 10.1016/j.neuroimage.2007.10.035 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 263UK UT WOS:000253241800038 PM 18086536 ER PT J AU Buydens-Branchey, L Branchey, M Hibbeln, JR AF Buydens-Branchey, Laure Branchey, Marc Hibbeln, Joseph R. TI Associations between increases in plasma n-3 polyunsaturated fatty acids following supplementation and decreases in anger and anxiety in substance abusers SO PROGRESS IN NEURO-PSYCHOPHARMACOLOGY & BIOLOGICAL PSYCHIATRY LA English DT Review DE anger; anxiety; docosahexaenoic acid (DHA); eicosapentaenoic acid (EPA); supplementation ID PLACEBO-CONTROLLED TRIAL; ETHYL-EICOSAPENTAENOIC ACID; PRELIMINARY DOUBLE-BLIND; DOCOSAHEXAENOIC ACID; SEAFOOD CONSUMPTION; DEPRESSIVE DISORDER; ECOLOGICAL ANALYSIS; BIPOLAR DEPRESSION; YOUNG-ADULTS; OMEGA-3-FATTY-ACIDS AB Objective: Mounting evidence indicates that low levels of n-3 polyunsaturated fatty acids (PUFAs) play a role in the pathophysiology of a large number of psychiatric disorders. In light of the suboptimal n-3 PUFAs intake due to poor dietary habits among substance abusers and the strong associations between aggression, anxiety and substance use disorders we examined if insurance of adequate intakes of n-3 PUFAs with supplementation would decrease their anger and anxiety scores. Method: Substance abusers (n=22) were assigned to either 3 g of n-3 PUFAs, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) or soybean oil in identically looking capsules. The trial was double-blind, randomized and lasted 3 months. Anger and anxiety scales were administered at baseline and once a month thereafter. Blood samples were collected at baseline and at the end of the trial. Results: Patients' dietary intakes of n-3 PUFAs fell below recommended levels. Assignment to n-3 PUFA treatment was accompanied by significant decreases in anger and anxiety scores compared to placebo assignment. These changes were associated with increases in plasma levels of both EPA and DHA but an increase in EPA was more robustly correlated with low end-of-trial anxiety scores and an increase in DHA was more robustly correlated with low end-of-trial anger scores. Conclusion: These pilot data indicate that ensuring adequate n-3 PUFA intake via supplementation benefits substance abusers by reducing their anger and anxiety levels. The strong correlations between an increase in plasma EPA and lower anxiety scores and between an increase in plasma DHA and lower anger scores suggests a need for the further exploration of the differential responses to these two n-3 PUFAs in different psychiatric conditions. Published by Elsevier Inc. C1 [Buydens-Branchey, Laure; Branchey, Marc] DVA New York Harbor Hlthcare Syst, Psychiat Serv, Brooklyn, NY 11209 USA. [Hibbeln, Joseph R.] NIAAA, Bethesda, MD USA. RP Buydens-Branchey, L (reprint author), DVA New York Harbor Hlthcare Syst, Psychiat Serv, Brooklyn Campus 151 BK,800 Poly Pl, Brooklyn, NY 11209 USA. EM lbuydens@worldnet.att.net FU NIDA NIH HHS [R01-DA15360, R01 DA015360-03, R01 DA015360] NR 41 TC 43 Z9 44 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0278-5846 J9 PROG NEURO-PSYCHOPH JI Prog. Neuro-Psychopharmacol. Biol. Psychiatry PD FEB 15 PY 2008 VL 32 IS 2 BP 568 EP 575 DI 10.1016/j.pnpbp.2007.10.020 PG 8 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 272GD UT WOS:000253847000036 PM 18060675 ER PT J AU Song, Y Tangen, C Goodman, P Parnes, HL Lucia, MS Thompson, IM Kristal, AR AF Song, Yoonju Tangen, Catherine Goodman, Phyllis Parnes, Howard L. Lucia, M. Scott Thompson, Ian M. Kristal, Alan R. TI Finasteride, prostate cancer, and weight gain: Evidence for genetic or environmental factors that affect cancer outcomes during finasteride treatment SO PROSTATE LA English DT Article DE prostate cancer; weight gain; finasteride ID PREVENTION TRIAL; MEN; TESTOSTERONE; SENSITIVITY; RISK AB OBJECTIVE. Finasteride affects both prostate cancer risk and body weight. We examined whether, during 7 years of finasteride treatment, the magnitude of weight change was associated with the diagnosis of no, low-, or high-grade cancer. METHODS. Data are from 10,057 participants in Prostate Cancer Prevention Trial (PCPT), a randomized trial of finasteride for primary prevention of prostate cancer. Mixed linear models were used to calculate percentage change in weight per year, controlling for demographic and health-related covariates. RESULTS. Weight gain was modestly lower in the finasteride compared to placebo arms (0.14 vs. 0.16% per year, P < 0.025). On the placebo arm, there was no association of weight gain with cancer outcomes. In the finasteride arm, annual weight gain among men without cancer was 0.14%, and among men with cancer ranged from 0.01% for those diagnosed with high-grade cancer following a clinical indication for biopsy (P = 0.03 vs. no cancer) to 0.25% among men diagnosed with low-grade cancer at the end of the trial with no indication for biopsy (P = 0.002 vs. no cancer). CONCLUSIONS. In finasteride-treated men, there are significant associations between prostate cancer outcomes and weight gain, which suggest that there are common or closely related individual-level factors that affect both treatment responses. This supports the hypothesis that there are genetic characteristics and/or environmental exposures that affect finasteride outcomes which, when identified, could be used to target men most likely to benefit from finasteride treatment. C1 [Song, Yoonju; Tangen, Catherine; Goodman, Phyllis; Kristal, Alan R.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA USA. [Parnes, Howard L.] Natl Canc Inst, Div Canc Prevent, Bethesda, MD USA. [Lucia, M. Scott] Univ Colorado, Hlth Sci Ctr, Dept Pathol, Denver, CO USA. [Thompson, Ian M.] Univ Texas Hlth Sci Ctr San Antonio, Dept Urol, San Antonio, TX USA. [Kristal, Alan R.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA USA. RP Kristal, AR (reprint author), Fred Hutchinson Canc Res Ctr, Canc Prevent Program, 1100 Fairview Ave N,M4-B402,PO Box 19024, Seattle, WA 98109 USA. EM akristal@fhcrc.org RI Kristal, Alan/A-8779-2008; OI Kristal, Alan/0000-0002-7329-1617 FU NCI NIH HHS [CA37429, CA108964] NR 13 TC 5 Z9 5 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD FEB 15 PY 2008 VL 68 IS 3 BP 281 EP 286 DI 10.1002/pros.20637 PG 6 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 263US UT WOS:000253242600006 PM 18163420 ER PT J AU Berg, JM AF Berg, Jeremy M. TI A Nobel lesson: The grant behind the prize SO SCIENCE LA English DT Letter C1 Natl Inst Gen Med Sci, NIH, Bethesda, MD 20892 USA. RP Berg, JM (reprint author), Natl Inst Gen Med Sci, NIH, Bethesda, MD 20892 USA. EM bergj@mail.nih.gov NR 0 TC 3 Z9 3 U1 1 U2 3 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 15 PY 2008 VL 319 IS 5865 BP 900 EP 900 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 262RM UT WOS:000253165700018 PM 18276870 ER PT J AU Collins, FS Gray, GM Bucher, JR AF Collins, Francis S. Gray, George M. Bucher, John R. TI Toxicology - Transforming environmental health protection SO SCIENCE LA English DT Editorial Material ID CHEMICALS; PROGRAM C1 [Collins, Francis S.] NHGRI, NIH, Bethesda, MD 20892 USA. [Gray, George M.] US EPA, Off Res & Dev, Washington, DC 20460 USA. [Bucher, John R.] NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Collins, FS (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM francisc@mail.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 11 TC 314 Z9 327 U1 2 U2 66 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 15 PY 2008 VL 319 IS 5865 BP 906 EP 907 DI 10.1126/science.1154619 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 262RM UT WOS:000253165700028 PM 18276874 ER PT J AU Zhanga, H Chen, HF Li, ZH AF Zhanga, Hong Chen, Hanfeng Li, Zhaohai TI An explicit representation of the limit of the LRT for interval mapping of quantitative trait loci SO STATISTICS & PROBABILITY LETTERS LA English DT Article DE backcross population; limiting threshold; marker interval; mixture model ID LINE CROSSES AB Consider the interval mapping method for quantitative trait loci (QTL) detection of an experimental organism in a backcross population. In a recent paper, Chen and Chen [2005. On some statistical aspects of the interval mapping for QTL detection. Statist. Sinica 15, 909-925] show that the limiting null distribution of the likelihood ratio test (LRT) statistic for testing existence of a QTL flanked by two markers is that of the supremum of a chi(2)-process. In this note, an explicit representation of the supremum in terms of the recombination fraction between two markers of the chi(2)-process is presented. Based on the explicit representation, a simulation algorithm for determining a limiting threshold of the LRT is given. (c) 2007 Elsevier B.V. All rights reserved. C1 [Chen, Hanfeng] Bowling Green State Univ, Dept Math & Stat, Bowling Green, OH 43403 USA. [Zhanga, Hong] Univ Sci & Technol China, Dept Stat & Finance, Hefei 230026, Peoples R China. [Li, Zhaohai] George Washington Univ, Dept Stat, Washington, DC 20052 USA. [Li, Zhaohai] Natl Canc Inst, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. RP Chen, HF (reprint author), Bowling Green State Univ, Dept Math & Stat, Bowling Green, OH 43403 USA. EM hchen@bgsu.edu NR 10 TC 0 Z9 0 U1 1 U2 1 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 FEB 15 PY 2008 VL 78 IS 3 BP 207 EP 213 DI 10.1016/j.spl.2007.05.020 PG 7 WC Statistics & Probability SC Mathematics GA 264YU UT WOS:000253327100001 ER PT J AU Wei, H Kim, SJ Zhang, Z Tsai, PC Wisniewski, KE Mukherjee, AB AF Wei, Hui Kim, Sung-Jo Zhang, Zhongjian Tsai, Pei-Chih Wisniewski, Krystyna E. Mukherjee, Anil B. TI ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative lysosomal storage disorders and are alleviated by chemical chaperones SO HUMAN MOLECULAR GENETICS LA English DT Article ID UNFOLDED PROTEIN RESPONSE; ENDOPLASMIC-RETICULUM STRESS; NEURONAL CEROID-LIPOFUSCINOSES; ACTIVATION; INCL; DISEASE; THIOESTERASE; BRAIN; LEADS AB It is estimated that more than 40 different lysosomal storage disorders (LSDs) cumulatively affect one in 5000 live births, and in the majority of the LSDs, neurodegeneration is a prominent feature. Neuronal ceroid lipofuscinoses (NCLs), as a group, represent one of the most common (one in 12 500 births) neurodegenerative LSDs. The infantile NCL (INCL) is the most devastating neurodegenerative LSD, which is caused by inactivating mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. We previously reported that neuronal death by apoptosis in INCL, and in the PPT1-knockout (PPT1-KO) mice that mimic INCL, is at least in part caused by endoplasmic reticulum (ER) and oxidative stresses. In the present study, we sought to determine whether ER and oxidative stresses are unique manifestations of INCL or they are common to both neurodegenerative and non-neurodegenerative LSDs. Unexpectedly, we found that ER and oxidative stresses are common manifestations in cells from both neurodegenerative and non-neurodegenerative LSDs. Moreover, all LSD cells studied show extraordinary sensitivity to brefeldin-A-induced apoptosis, which suggests pre-existing ER stress conditions. Further, we uncovered that chemical disruption of lysosomal homeostasis in normal cells causes ER stress, suggesting a cross-talk between the lysosomes and the ER. Most importantly, we found that chemical chaperones that alleviate ER and oxidative stresses are also cytoprotective in all forms of LSDs studied. We propose that ER and oxidative stresses are common mediators of apoptosis in both neurodegenerative and non-neurodegenerative LSDs and suggest that the beneficial effects of chemical/pharmacological chaperones are exerted, at least in part, by alleviating these stress conditions. C1 [Wei, Hui; Kim, Sung-Jo; Zhang, Zhongjian; Tsai, Pei-Chih; Mukherjee, Anil B.] NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. [Wisniewski, Krystyna E.] New York State Inst Basic Res Dev Disabil, Dept Dev Neurobiol, Staten Isl, NY 10314 USA. RP Mukherjee, AB (reprint author), NICHHD, Sect Dev Genet, Heritable Disorders Branch, NIH, Bldg 10,Room 9D42,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukherja@exchange.nih.gov FU Intramural NIH HHS NR 33 TC 119 Z9 122 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD FEB 14 PY 2008 VL 17 IS 4 BP 469 EP 477 DI 10.1093/hmg/ddm324 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 258YL UT WOS:000252906200001 PM 17989065 ER PT J AU Tikhonova, IG Sum, CS Neumann, S Engel, S Raaka, BM Costanzi, S Gershengorn, MC AF Tikhonova, Irina G. Sum, Chi Shing Neumann, Susanne Engel, Stanislav Raaka, Bruce M. Costanzi, Stefano Gershengorn, Marvin C. TI Discovery of novel Agonists and antagonists of the free fatty acid receptor 1 (FFAR1) using virtual screening SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; INSULIN-SECRETION; GPR40; IDENTIFICATION; MODEL; ACID; 3D; RECOGNITION; MOLECULES; DATABASE AB The G-protein-coupled receptor free fatty acid receptor 1 (FFAR1), previously named GPR40, is a possible novel target for the treatment of type 2 diabetes. In an attempt to identify new ligands for this receptor, we performed virtual screening (VS) based on two-dimensional (2D) similarity, three-dimensional (3D) pharmacophore searches, and docking studies by using the structure of known agonists and our model of the ligand binding site, which was validated by mutagenesis. VS of a database of 2.6 million compounds followed by extraction of structural neighbors of functionally confirmed hits resulted in identification of 15 compounds active at FFAR1 either as full agonists, partial agonists, or pure antagonists. Site-directed mutagenesis and docking studies revealed different patterns of ligand-receptor interactions and provided important information on the role of specific amino acids in binding and activation of FFAR1. C1 [Tikhonova, Irina G.; Costanzi, Stefano] NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. [Sum, Chi Shing; Neumann, Susanne; Engel, Stanislav; Raaka, Bruce M.; Gershengorn, Marvin C.] NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Costanzi, S (reprint author), NIDDK, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. EM stefanoc@mail.nih.gov; marving@intra.niddk.nih.gov RI Engel, Stanislav/G-2799-2013; Costanzi, Stefano/G-8990-2013; OI Costanzi, Stefano/0000-0003-3183-7332 FU Intramural NIH HHS [Z01 DK013025-01, Z99 DK999999] NR 25 TC 102 Z9 103 U1 4 U2 23 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 FEB 14 PY 2008 VL 51 IS 3 BP 625 EP 633 DI 10.1021/jm7012425 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 259VJ UT WOS:000252968700031 PM 18193825 ER PT J AU McFarland, HF AF McFarland, Henry F. TI Focus on research: The B cell - Old player, new position on the team SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID MULTIPLE-SCLEROSIS C1 [McFarland, Henry F.] Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, Bethesda, MD 20892 USA. RP McFarland, HF (reprint author), Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, Bethesda, MD 20892 USA. NR 5 TC 40 Z9 41 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 FEB 14 PY 2008 VL 358 IS 7 BP 664 EP 665 DI 10.1056/NEJMp0708143 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 262CX UT WOS:000253127700002 PM 18272890 ER PT J AU Horvath, A Mericq, V Stratakis, CA AF Horvath, Anelia Mericq, Veronica Stratakis, Constantine A. TI Mutation in PDE8B, a cyclic AMP-specific phosphodiesterase in adrenal hyperplasia SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID PDE11A C1 [Horvath, Anelia; Stratakis, Constantine A.] NICHHD, Bethesda, MD 20892 USA. [Mericq, Veronica] Univ Chile, Santiago, Chile. RP Horvath, A (reprint author), NICHHD, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov RI Mericq, Veronica/F-3927-2010 NR 5 TC 84 Z9 89 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 FEB 14 PY 2008 VL 358 IS 7 BP 750 EP 752 DI 10.1056/NEJMc0706182 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 262CX UT WOS:000253127700031 PM 18272904 ER PT J AU Koizumi, H Smith, JC AF Koizumi, Hidehiko Smith, Jeffrey C. TI Persistent Na+ and K+-dominated leak currents contribute to respiratory rhythm generation in the pre-Botzinger complex in vitro SO JOURNAL OF NEUROSCIENCE LA English DT Article DE oscillations; brainstem; breathing; bursting neurons; membrane conductances; neuromodulation ID HYPERPOLARIZATION-ACTIVATED CURRENT; SODIUM CURRENT; PACEMAKER NEURONS; PREBOTZINGER COMPLEX; SUBSTANCE-P; POTASSIUM CHANNELS; NETWORK; RAT; MODULATION; MODELS AB A central problem in analyzing neural circuit function is establishing how intrinsic neuronal conductances contribute to the generation of network activity. We used real-time calcium activity imaging combined with whole-cell patch-clamp recording to analyze contributions of subthreshold conductances in the excitatory rhythm-generating network in the respiratory pre-Botzinger complex (pre-BotC) of neonatal rat in vitro brainstem slice preparations. Voltage-clamp ramp recordings from imaged pre-BotC neurons revealed that persistent sodium (NaP) and K+-dominated leak currents primarily contribute to subthreshold I-V relations. We quantified NaP and leak conductance densities (g/C-m) in intrinsic oscillatory bursters and intrinsically nonbursters, the two main electrophysiological phenotypes of inspiratory neurons within the pre-BotC. Densities of g(NaP) were significantly higher for intrinsic bursters, whereas leak conductance densities were not significantly different between intrinsic bursters and nonbursters. By pharmacologically manipulating gNaP and/or g(Leak) directly within the pre-BotC, we could modulate network oscillation frequency over a wide dynamic range and cause transitions between oscillatory and quiescent states. These results were consistent with models of the pre-BotC excitatory network consisting of heterogeneous mixtures of intrinsic bursters and nonintrinsic bursters incorporating g(NaP) and g(Leak) with parameter values found experimentally. We propose a paradigm whereby NaP and Leak represent a functional set of subthreshold conductances that endow the pre-BotC with rhythmogenic properties and represent targets for modulatory control of inspiratory rhythm generation. C1 [Koizumi, Hidehiko; Smith, Jeffrey C.] Natl Inst Neurol Disorders & Stroke, Porter Neurosci Res Ctr, Cellular & Syst Neurobiol Sect, NIH, Bethesda, MD 20892 USA. RP Smith, JC (reprint author), Natl Inst Neurol Disorders & Stroke, Porter Neurosci Res Ctr, Cellular & Syst Neurobiol Sect, NIH, 35 Convent Dr,Room 3C-917, Bethesda, MD 20892 USA. EM jsmith@helix.nih.gov FU Intramural NIH HHS NR 50 TC 81 Z9 82 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 13 PY 2008 VL 28 IS 7 BP 1773 EP 1785 DI 10.1523/JNEUROSCI.3916-07.2008 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 262LM UT WOS:000253150000024 PM 18272697 ER PT J AU Ichijo, T Chrousos, GP Kino, T AF Ichijo, Takamasa Chrousos, George P. Kino, Tomoshige TI Activated glucocorticoid receptor interacts with the INHAT component Set/TAF-I beta and releases it from a glucocorticoid-responsive gene promoter, relieving repression: Implications for the pathogenesis of glucocorticoid resistance in acute undifferentiated leukemia with Set-Can translocation SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE glucocorticoid receptor; Set/TAF-I beta; inhibitor of histone acetyltransferases complex; histone acetylation; Set-Can translocation; leukemia ID PROTEIN PHOSPHATASE 2A; DNA-BINDING DOMAIN; TRANSCRIPTIONAL ACTIVITY; HISTONE ACETYLATION; DEK-CAN; TEMPLATE; INHIBITOR; COMPLEX; VPR; REPLICATION AB Set/template-activating factor (TAF)-I beta, part of the Set-Can oncogene product found in acute undifferentiated leukemia, is a component of the inhibitor of acetyltransferases (INHAT) complex. Set/TAF-I beta interacted with the DNA-binding domain of the glucocorticoid receptor (GR) in yeast two-hybrid screening, and repressed GR-induced transcriptional activity of a chromatin-integrated glucocorticoid-responsive and a natural promoter. Set/TAF-I beta was co-precipitated with glucocorticoid response elements (GREs) of these promoters in the absence of dexamethasone, while addition of the hormone caused dissociation of Set/TAF-I beta from and attraction of the p160-type coactivator GRIP1 to the promoter GREs. Set-Can fusion protein, on the other hand, did not interact with GR, was constitutively co-precipitated with GREs and suppressed GRIP1-induced enhancement of GR transcriptional activity and histone acetylation. Thus, Set/TAF-I beta acts as a ligand-activated GR-responsive transcriptional repressor, while Set-Can does not retain physiologic responsiveness to ligand-bound GR, possibly contributing to the poor responsiveness of Set-Can-harboring leukemic cells to glucocorticoids. Published by Elsevier Ireland Ltd. C1 [Ichijo, Takamasa; Chrousos, George P.; Kino, Tomoshige] NICHHD, NIH, Sect pediat Endocrinol Reprod Biol, Clin Res Ctr, Bethesda, MD 20892 USA. [Ichijo, Takamasa; Chrousos, George P.; Kino, Tomoshige] NICHHD, NIH, Med Branch, Clin Res Ctr, Bethesda, MD 20892 USA. [Chrousos, George P.] Univ Athens, Sch Med, Dept Pediat 1, GR-11527 Athens, Greece. RP Kino, T (reprint author), NICHHD, NIH, Sect pediat Endocrinol Reprod Biol, Clin Res Ctr, Bldg 10,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM kinot@mail.nih.gov FU Intramural NIH HHS [Z01 HD008732-06] NR 37 TC 19 Z9 22 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB 13 PY 2008 VL 283 IS 1-2 BP 19 EP 31 DI 10.1016/j.mce.2007.10.014 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 277PW UT WOS:000254228200003 PM 18096310 ER PT J AU Szapary, D Song, LN He, YZ Simons, SS AF Szapary, Daniele Song, Liang-Nian He, Yuangzheng Simons, S. Stoney, Jr. TI Differential modulation of glucocorticoid and progesterone receptor transactivation SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE progesterone receptor; glucocorticoid receptor; transcription modulatory factor; GME; GMEB-2; Ubc9; STAMP ID TYROSINE AMINOTRANSFERASE GENE; UBIQUITIN-CONJUGATING ENZYME; PARTIAL AGONIST ACTIVITY; LIGAND-BINDING DOMAIN; INDUCTION PROPERTIES; TRANSCRIPTION FACTOR; ANDROGEN RECEPTOR; DEPENDENT TRANSCRIPTION; ANTAGONIST COMPLEXES; RESPONSIVE ELEMENTS AB The determinants of the different biological activities of progesterone receptors (PRs) vs. glucocorticoid receptors (GRs), which bind to the same DNA sequences, remain poorly understood. The mechanisms by which differential expression of a common target gene can be achieved by PR and GR include unequal agonist steroid concentrations for half maximal induction (EC50) and dissimilar amounts of residual partial agonist activity for antisteroids in addition to the more common changes in total gene induction, or V-max. Several factors are known to alter some or all of these three parameters for GR-regulated gene induction and some (i.e., the corepressors NCoR and SMRT) modulate the EC50 and partial agonist activity for GR and PR induction of the same gene in opposite directions. The current study demonstrates that other factors known to modulate GR properties (GME, GMEB-2, Ubc9, and STAMP) can also differentially interact with PRs or alter several of the above induction parameters under otherwise identical conditions. These results support the hypothesis that the modulation of EC50, partial agonist activity, and V-max by a given factor is not limited to one receptor in a specific cell line. Furthermore, the number of factors that unequally modulate PR and GR induction parameters is now greatly expanded, thereby increasing the possible mechanisms for differential gene regulation by PRs vs. GRs. Published by Elsevier Ireland Ltd. C1 [Szapary, Daniele; Song, Liang-Nian; He, Yuangzheng; Simons, S. Stoney, Jr.] NIDDK, CEB, NIH, Steroid Hormones Sect, Bethesda, MD 20892 USA. RP Simons, SS (reprint author), NIDDK, CEB, NIH, Steroid Hormones Sect, Bldg 10,Room 8N-307B, Bethesda, MD 20892 USA. EM steroids@helix.nih.gov FU Intramural NIH HHS [Z01 DK047041-01] NR 81 TC 16 Z9 18 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD FEB 13 PY 2008 VL 283 IS 1-2 BP 114 EP 126 DI 10.1016/j.mce.2007.11.031 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 277PW UT WOS:000254228200013 PM 18215457 ER PT J AU Dicko, A Sagara, I Ellis, RD Miura, K Guindo, O Kamate, B Sogoba, M Niambele, MB Sissoko, M Baby, M Dolo, A Mullen, GED Fay, MP Pierce, M Diallo, DA Saul, A Miller, LH Doumbo, OK AF Dicko, Alassane Sagara, Issaka Ellis, Ruth D. Miura, Kazutoyo Guindo, Ousmane Kamate, Beh Sogoba, Moussa Niambele, Mohamed Balla Sissoko, Mady Baby, Mounirou Dolo, Amagana Mullen, Gregory E. D. Fay, Michael P. Pierce, Mark Diallo, Dapa A. Saul, Allan Miller, Louis H. Doumbo, Ogobara K. TI Phase 1 Study of a Combination AMA1 Blood Stage Malaria Vaccine in Malian Children SO PLOS ONE LA English DT Article AB Background: Apical Membrane Antigen-1 (AMA1) is one of the leading blood stage malaria vaccine candidates. AMA1-C1/Alhydrogel (R) consists of an equal mixture of recombinant AMA1 from FVO and 3D7 clones of P. falciparum, adsorbed onto Alhydrogel (R). A Phase 1 study in semi-immune adults in Mali showed that the vaccine was safe and immunogenic, with higher antibody responses in those who received the 80 mu g dose. The aim of this study was to assess the safety and immunogenicity of this vaccine in young children in a malaria endemic area. Design: This was a Phase 1 dose escalating study in 36 healthy children aged 2-3 years started in March 2006 in Doneguebougou, Mali. Eighteen children in the first cohort were randomized 2:1 to receive either 20 mg AMA1-C1/Alhydrogel (R) or Haemophilus influenzae type b Hiberix (R) vaccine. Two weeks later 18 children in the second cohort were randomized 2: 1 to receive either 80 mg AMA1-C1/Alhydrogel (R) or Haemophilus influenzae type b Hiberix (R) vaccine. Vaccinations were administered on Days 0 and 28 and participants were examined on Days 1, 2, 3, 7, and 14 after vaccination and then about every two months. Results to Day 154 are reported in this manuscript. Results: Of 36 volunteers enrolled, 33 received both vaccinations. There were 9 adverse events related to the vaccination in subjects who received AMA1-C1 vaccine and 7 in those who received Hiberix (R). All were mild to moderate. No vaccine-related serious or grade 3 adverse events were observed. There was no increase in adverse events with increasing dose of vaccine or number of immunizations. In subjects who received the test vaccine, antibodies to AMA1 increased on Day 14 and peaked at Day 42, with changes from baseline significantly different from subjects who received control vaccine. Conclusion: AMA-C1 vaccine is well tolerated and immunogenic in children in this endemic area although the antibody response was short lived. C1 [Ellis, Ruth D.; Miura, Kazutoyo; Mullen, Gregory E. D.; Pierce, Mark; Saul, Allan; Miller, Louis H.] Natl Inst Hlth, NIAID, Malaria Vaccine Dev Branch, Bethesda, MD USA. [Dicko, Alassane; Sagara, Issaka; Guindo, Ousmane; Kamate, Beh; Sogoba, Moussa; Niambele, Mohamed Balla; Sissoko, Mady; Baby, Mounirou; Dolo, Amagana; Diallo, Dapa A.; Doumbo, Ogobara K.] Univ Bamako, Malaria Res & Training Ctr, Fac Med, Dept Epidemiol Parasitic Dis, Bamako, Mali. [Fay, Michael P.] Natl Inst Hlth, NIAID, Biostat Res Branch, Bethesda, MD USA. RP Dicko, A (reprint author), Natl Inst Hlth, NIAID, Malaria Vaccine Dev Branch, Bethesda, MD USA. EM lmiller@niaid.nih.gov; okd@mrtcbko.org RI Saul, Allan/I-6968-2013; OI Saul, Allan/0000-0003-0665-4091; Fay, Michael P./0000-0002-8643-9625 FU Intramural Program of the National Institute of Allergy and Infectious Diseases/National Institutes of Health FX This work was supported by the Intramural Program of the National Institute of Allergy and Infectious Diseases/National Institutes of Health. NR 19 TC 34 Z9 36 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 FEB 13 PY 2008 VL 3 IS 2 AR e1563 DI 10.1371/journal.pone.0001563 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 367ES UT WOS:000260535900005 PM 18270560 ER PT J AU Singer, DE Schneerson, R Bautista, CT Rubertone, MV Robbins, JB Taylor, DN AF Singer, Darrell E. Schneerson, Rachel Bautista, Christian T. Rubertone, Mark V. Robbins, John B. Taylor, David N. TI Serum IgG antibody response to the protective antigen (PA) of Bacillus anthracis induced by anthrax vaccine adsorbed (AVA) among US military personnel SO VACCINE LA English DT Article DE anthrax; vaccine; IgG; Bacillus anthracis; military ID INHALATION ANTHRAX; TOXIN; IMMUNOGENICITY; HUMANS; SAFETY; IMMUNIZATION; CHALLENGE; IMMUNITY; CHILDREN; CEREUS AB The seroconversion rates and geometric mean concentrations (GMC) of IgG anti-PA for stored sera from U.S. military personnel. immunized 3, 4, and 6 times with the U.S. licensed anthrax vaccine adsorbed were studied. Anti-PA IgG concentrations were measured by ELISA. All. 246 vaccines had low but detectable pre-immunization anti-PA IgG (GMC 1.83 mu g/ml). Three doses elicited a GMC of 59.92 mu g/mL and a seroconversion rate of 85.3%, four doses elicited a GMC of 157.44 mu g/mL and 67.9% and the sixth of 276.95 mu g/ml and 45.5%, respectively. The forth dose elicited 100% seroconversion compared to the pre-immunization level. These results should facilitate comparison between different immunization schedules and new vaccines. Published by Elsevier Ltd. C1 [Singer, Darrell E.; Bautista, Christian T.] Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD USA. [Singer, Darrell E.; Bautista, Christian T.] US Mil Acad, HIV Res Program, Rockville, MD USA. [Schneerson, Rachel; Robbins, John B.] NICHHD, NIH, Bethesda, MD 20892 USA. [Rubertone, Mark V.] USA, Ctr Hlth Promot & Prevent Med, Army Med Surveillance Activ, Washington, DC 20310 USA. [Taylor, David N.] Vaxlnnate Corp, Cranbury, NJ USA. RP Singer, DE (reprint author), Walter Reed Army Inst Res, Div Retrovirol, Rockville, MD USA. EM dsinger@hivresearch.org RI Bautista, Christian/B-2812-2011 FU Intramural NIH HHS [Z01 HD008779-03] NR 23 TC 13 Z9 15 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 13 PY 2008 VL 26 IS 7 BP 869 EP 873 DI 10.1016/j.vaccine.2007.11.085 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 268LG UT WOS:000253580700002 PM 18206278 ER PT J AU Wright, PF Ankrah, S Henderson, SE Durbin, AP Speicher, J Whitehead, SS Murphy, BR Pletnev, AG AF Wright, Peter F. Ankrah, Sharon Henderson, Susan E. Durbin, Anna P. Speicher, Jim Whitehead, Stephen S. Murphy, Brian R. Pletnev, Alexander G. TI Evaluation of the Langat/dengue 4 chimeric virus as a live attenuated tick-borne encephalitis vaccine for safety and immunogenicity in healthy adult volunteers SO VACCINE LA English DT Article DE tick borne encephalitis; live virus vaccine; human ID COMPLETE ACTIVE VACCINATION; DENGUE TYPE-4 VIRUSES; BIOLOGICAL-PROPERTIES; ANTIBODY-RESPONSE; LANGAT-E5 VIRUS; SA14-14-2 VIRUS; RHESUS-MONKEYS; POWASSAN VIRUS; SEQUENCE; DISEASE AB With the steady rise in tick-borne encephalitis virus (TBEV) infections in Europe, development of a Live attenuated vaccine that will generate long-lasting immunity would be of considerable benefit. A chimeric flavivirus, designated LGT/DEN4, was previously constructed to have a genome containing the prM and E protein genes of Langat virus (LGT), a naturally attenuated member of the TBEV complex, and the remaining genetic sequences derived from dengue 4 virus (DEN4). LGT/DEN4 was highly attenuated in rodents and non-human primates, and clinical trials in humans were initiated. Twenty-eight healthy seronegative adult volunteers were randomly assigned in a 4:1 ratio to receive 103 plaque-forming units (PFU) of LGT/DEN4 or placebo. Volunteers were closely monitored for clinical. responses and for blood chemistry and hematological changes, and the level of viremia and the magnitude and duration of the neutralizing antibody response were determined. The LGT/DEN4 vaccine was safe and viremia was seen in only one vaccinee. Infection induced a neutralizing antibody response to wildtype LGT in 80% of volunteers with a geometric mean titer (GMT) of 1:63 present on day 42 post-immunization; however the antibody response against TBEV was both much less frequent (35%) and Lower in magnitude (GMT=1:9). To assess the response to a booster dose, 21 of the original. 28 volunteers were re-randomized to receive a second dose of either 10(3) PFU of vaccine or placebo given 6-18 months after the first dose. The immunogenicity against either LGT or TBEV was not significantly enhanced after the second dose of vaccine. Thus, chimerization of LGT with DEN4 yielded a vaccine virus that was highly attenuated yet infectious in humans. The Level of replication was sufficiently restricted to induce only a weak cross-reactive antibody response to TBEV. To provide a sufficient level of immunity to widely prevalent, highly neurovirulent strains of TBEV in humans, vaccine candidates wilt likely need to be based on the TBEV structural protein genes. Published by Elsevier Ltd. C1 [Speicher, Jim; Whitehead, Stephen S.; Murphy, Brian R.; Pletnev, Alexander G.] NIAID, NIH, Infect Dis Lab, Bethesda, MD 20892 USA. [Durbin, Anna P.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Ctr Immunizat Res, Baltimore, MD USA. [Wright, Peter F.; Ankrah, Sharon; Henderson, Susan E.] Vanderbilt Univ, Ctr Med, Div Pediat Infect Dis, Dept Pediat, Nashville, TN 37232 USA. RP Pletnev, AG (reprint author), NIAID, NIH, Infect Dis Lab, 33 n Dr,Room 3W10A,MSC 3203, Bethesda, MD 20892 USA. EM apietnev@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000637-16]; NCRR NIH HHS [M01 RR000095] NR 36 TC 17 Z9 19 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 13 PY 2008 VL 26 IS 7 BP 882 EP 890 DI 10.1016/j.vaccine.2007.12.015 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 268LG UT WOS:000253580700004 PM 18207289 ER PT J AU Balla, A Tuymetova, G Toth, B Szentpetery, Z Zhao, X Knight, ZA Shokat, K Steinbach, PJ Balla, T AF Balla, Andras Tuymetova, Galina Toth, Balazs Szentpetery, Zsofia Zhao, Xiaohang Knight, Zachary A. Shokat, Kevan Steinbach, Peter J. Balla, Tamas TI Design of drug-resistant alleles of type-III phosphatidylinositol 4-kinases using mutagenesis and molecular modeling SO BIOCHEMISTRY LA English DT Article ID PHOSPHOINOSITIDE 3-KINASE; SACCHAROMYCES-CEREVISIAE; GOLGI-COMPLEX; WORTMANNIN; SECRETION; REVEALS; CLONING; YEAST; INHIBITION; MEMBRANE AB Molecular modeling and site directed mutagenesis were used to analyze the structural features determining the unique inhibitor sensitivities of type-III phosphatidylinositol 4-kinase enzymes (PI4Ks). Mutation of a highly conserved Tyr residue that provides the bottom of the hydrophobic pocket for ATP yielded a PI4KIII beta enzyme that showed greatly reduced wortmannin sensitivity and was catalytically still active. Similar substitutions were not tolerated in the type-III(x enzyme rendering it catalytically inactive. Two conserved Cys residues located in the active site of PI4KIII alpha were found responsible for the high sensitivity of this enzyme to the oxidizing agent, phenylarsine oxide. Mutation of one of these Cys residues reduced the phenylarsine oxide sensitivity of the enzyme to the same level observed with the PI4KIII beta protein. In search of inhibitors that would discriminate between the closely related PI4KIII alpha and -III beta enzymes, the PI3K gamma inhibitor, PIK93, was found to inhibit PI4KIII beta with significantly greater potency than PI4KIII alpha. These studies should aid development of subtype-specific inhibitors of type-III PI4Ks and help to better understand the significance of localized PtdIns4P production by the various PI4Ks isoforms in specific cellular compartments. C1 [Balla, Andras; Tuymetova, Galina; Toth, Balazs; Szentpetery, Zsofia; Balla, Tamas] NIH, NICHD, Sect Mol Signal Transduct, Ctr Dev Neurosci, Bethesda, MD 20892 USA. [Balla, Andras] Semmelweis Univ, Fac Med, Dept Physiol, H-1085 Budapest, Hungary. [Steinbach, Peter J.] NIH, CIT, Div Computat Biosci, Ctr Mol Modeling, Bethesda, MD 20892 USA. [Zhao, Xiaohang] Chinese Acad Med Sci, Canc Inst & Hosp, Mol Oncol Lab, Beijing, Peoples R China. [Zhao, Xiaohang] Peking Union Med Coll, Beijing, Peoples R China. [Knight, Zachary A.; Shokat, Kevan] Univ Calif San Francisco, Program Chem & Chem Biol, San Francisco, CA USA. [Knight, Zachary A.; Shokat, Kevan] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. [Knight, Zachary A.; Shokat, Kevan] Univ Calif San Francisco, Dept Cell & Mol Pharmacol, San Francisco, CA 94143 USA. RP Balla, T (reprint author), NIH, NICHD, Sect Mol Signal Transduct, Ctr Dev Neurosci, Bldg 49,Rm 6A35,49 Covenant Dr, Bethesda, MD 20892 USA. EM ballat@mail.nih.gov RI Toth, Balazs/B-4252-2012; OI Knight, Zachary/0000-0001-7621-1478; Balla, Tamas/0000-0002-9077-3335; Balla, Andras/0000-0002-6450-2793 FU Intramural NIH HHS NR 43 TC 22 Z9 22 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 FEB 12 PY 2008 VL 47 IS 6 BP 1599 EP 1607 DI 10.1021/bi7017927 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 259LK UT WOS:000252940600014 PM 18205404 ER PT J AU Obsilova, V Nedbalkova, E Silhan, J Boura, E Herman, P Vecer, J Sulc, M Teisinger, J Dyda, F Obsil, T AF Obsilova, Veronika Nedbalkova, Eliska Silhan, Jan Boura, Evzen Herman, Petr Vecer, Jaroslav Sulc, Miroslav Teisinger, Jan Dyda, Fred Obsil, Tomas TI The 14-3-3 protein affects the conformation of the regulatory domain of human tyrosine hydroxylase SO BIOCHEMISTRY LA English DT Article ID SITE-DIRECTED MUTAGENESIS; ACTIVATES TRYPTOPHAN 5-MONOOXYGENASE; DEPENDENT PROTEIN-KINASE; AMINO-ACID HYDROXYLASES; LIGAND-BINDING; CATECHOLAMINE BINDING; PHOSPHORYLATION; SERINE-40; 3-MONOOXYGENASE; STABILITY AB Tyrosine hydroxylase (TH) catalyzes the first step in the biosynthesis of catecholamines. Regulation of TH enzyme activity is controlled through the posttranslational modification of its regulatory domain. The regulatory domain of TH can be phosphorylated at four serines (8, 19, 31, and 40) by a variety of protein kinases. Phosphorylation of Ser(19) does not by itself increase TH activity but induces its binding to the 14-3-3 protein. That leads to the enhancement of TH activity with a still not fully understood mechanism. The main goal of this work was to investigate whether the 14-3-3 protein binding affects the conformation of the regulatory domain of human TH isoform 1 (THIR). Site-directed mutagenesis was used to generate five single-tryptophan mutants of THIR with the Trp residue located at five different positions within the domain (positions 14, 34, 73, 103, and 13 1). Time-resolved tryptophan fluorescence measurements revealed that phosphorylation of Ser(19) and Ser(40) does not itself induce any significant structural changes in regions surrounding inserted tryptophans. On the other hand, the interaction between the 14-3-3 protein and phosphorylated THIR decreases the solvent exposure of tryptophan residues at positions 14 and 34 and induces distinct structural change in the vicinity of Trp(73). The 14-3-3 protein binding also reduces the sensitivity of phosphorylated THIR to proteolysis by protecting its N-terminal part (first 33 residues). Circular dichroism measurements showed that THIR is an unstructured protein with a low content of secondary structure and that neither phosphorylation nor the 14-3-3 protein binding changes its secondary structure. C1 [Nedbalkova, Eliska; Silhan, Jan; Boura, Evzen; Obsil, Tomas] Charles Univ Prague, Fac Sci, Dept Phys & Macromol Sci, Prague 12843, Czech Republic. [Obsilova, Veronika; Nedbalkova, Eliska; Silhan, Jan; Boura, Evzen; Teisinger, Jan; Obsil, Tomas] Acad Sci Czech Republic, Inst Physiol, CR-14220 Prague, Czech Republic. [Herman, Petr; Vecer, Jaroslav] Charles Univ Prague, Fac Math & Phys, Inst Phys, Prague 12116, Czech Republic. [Sulc, Miroslav] Acad Sci Czech Republic, Inst Microbiol, Prague 14220, Czech Republic. [Sulc, Miroslav] Charles Univ Prague, Fac Sci, Dept Biochem, Prague 12843, Czech Republic. [Dyda, Fred] NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Obsil, T (reprint author), Charles Univ Prague, Fac Sci, Dept Phys & Macromol Sci, Prague 12843, Czech Republic. EM obsil@natur.cuni.cz RI Teisinger, Jan /B-7122-2012; Boura, Evzen/I-2626-2012; Obsilova, Veronika/B-7116-2012; Herman, Petr/A-2626-2008; Obsil, Tomas/B-7142-2012; Sulc, Miroslav/K-1029-2014; Boura, Evzen/G-5275-2014 OI Obsilova, Veronika/0000-0003-4887-0323; Herman, Petr/0000-0001-6918-2576; Obsil, Tomas/0000-0003-4602-1272; NR 54 TC 34 Z9 36 U1 1 U2 10 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 12 PY 2008 VL 47 IS 6 BP 1768 EP 1777 DI 10.1021/bi7019468 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 259LK UT WOS:000252940600031 PM 18181650 ER PT J AU D'Arcy, V Pore, N Docquier, F Abdullaev, ZK Chernukhin, I Kita, GX Rai, S Smart, M Farrar, D Pack, S Lobanenkov, V Klenova, E AF D'Arcy, V. Pore, N. Docquier, F. Abdullaev, Z. K. Chernukhin, I. Kita, G-X Rai, S. Smart, M. Farrar, D. Pack, S. Lobanenkov, V. Klenova, E. TI BORIS, a paralogue of the transcription factor, CTCF, is aberrantly expressed in breast tumours SO BRITISH JOURNAL OF CANCER LA English DT Article DE bORIS; CTCF; breast cancer; progesterone receptor; oestrogen receptor ID CANCER-TESTIS ANTIGEN; PROGESTERONE-RECEPTOR; ESTROGEN-RECEPTOR; MAMMARY-GLAND; GENE; PROTEIN; CELLS; CARCINOMAS; PROMOTER; LUNG AB BORIS (for brother of the regulator of imprinted sites), a paralogue of the transcription factor, CTCF, is a novel member of the cancer-testis antigen family. The aims of the present study were as follows: (1) to investigate BORIS expression in breast cells and tumours using immunohistochemical staining, western and real-time RT-PCR analyses and (2) assess potential correlation between BORIS levels in tumours with clinical/pathological parameters. BORIS was detected in all 18 inspected breast cell lines, but not in a primary normal breast cell culture. In 70.7% (41 of 58 cases) BORIS was observed in breast tumours. High levels of BORIS correlated with high levels of progesterone receptor (PR) and oestrogen receptor (ER). The link between BORIS and PR/ER was further confirmed by the ability of BORIS to activate the promoters of the PR and ER genes in the reporter assays. Detection of BORIS in a high proportion of breast cancer patients implies potential practical applications of BORIS as a molecular biomarker of breast cancer. This may be important for diagnosis of the condition and for the therapeutic use of BORIS. The ability of BORIS to activate promoters of the RP and ER genes points towards possible involvement of BORIS in the establishment, progression and maintenance of breast tumours. C1 [D'Arcy, V.; Pore, N.; Docquier, F.; Chernukhin, I.; Kita, G-X; Rai, S.; Smart, M.; Farrar, D.; Klenova, E.] Univ Essex, Dept Sci Biol, Colchester CO4 3SQ, Essex, England. [Abdullaev, Z. K.; Pack, S.; Lobanenkov, V.] Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Immunopathol Lab, Mol Pathol Sect, Rockville, MD 20852 USA. RP Klenova, E (reprint author), Univ Essex, Dept Sci Biol, Wivenhoe Pk, Colchester CO4 3SQ, Essex, England. EM klenovae@essex.ac.uk RI Pack, Svetlana/C-2020-2014; OI Lobanenkov, Victor/0000-0001-6665-3635; Smart, Melissa/0000-0002-2655-3880 FU Biotechnology and Biological Sciences Research Council; Intramural NIH HHS; Medical Research Council [, G0401088]; Worldwide Cancer Research [99-0514] NR 46 TC 47 Z9 47 U1 2 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 FEB 12 PY 2008 VL 98 IS 3 BP 571 EP 579 DI 10.1038/sj.bjc.6604181 PG 9 WC Oncology SC Oncology GA 259IR UT WOS:000252933500009 PM 18195709 ER PT J AU Grigoriev, I Gouveia, S Van der Vaart, B Demmers, J Smyth, JT Honnappa, S Splinter, D Steinmetz, MO Putney, JW Hoogenraad, CC Akhmanova, A AF Grigoriev, Ilya Gouveia, Susana Montenegro Van der Vaart, Babet Demmers, Jeroen Smyth, Jeremy T. Honnappa, Srinivas Splinter, Daniel Steinmetz, Michel O. Putney, James W., Jr. Hoogenraad, Casper C. Akhmanova, Anna TI STIM1 is a MT-plus-end-tracking protein involved in remodeling of the ER SO CURRENT BIOLOGY LA English DT Article ID CA2+ STORE DEPLETION; ENDOPLASMIC-RETICULUM; PLASMA-MEMBRANE; ENTRY; DYNAMICS; CLIP-170; CELLS AB Stromal interaction molecule 1 (STIM1) is a transmembrane protein that is essential for store-operated Ca(2+) entry, a process of extracellular Ca(2+) influx in response to the depletion of Ca(2+) stores in the endoplasmic reticulum (ER) (reviewed in [1-4]). STIM1 localizes predominantly to the ER; upon Ca(2+) release from the ER, STIM1 translocates to the ER-plasma membrane junctions and activates Ca2+ channels (reviewed in [1-4]). Here, we show that STIM1 directly binds to the microtubule-plus-end-tracking protein EB1 and forms EB1-dependent comet-like accumulations at the sites where polymerizing microtubule ends come in contact with the ER network. Therefore, the previously observed tubulovesicular motility of GFP-STIM1 [5] is not a motor-based movement but a traveling wave of diffusion-dependent STIM1 concentration in the ER membrane. STIM1 overexpression strongly stimulates ER extension occurring through the microtubule "tip attachment complex" (TAC) mechanism [6, 7], a process whereby an ER tubule attaches to and elongates together with the EB1-positive end of a growing microtubule. Depletion of STIM1 and EB1 decreases TAC-dependent ER protrusion, indicating that microtubule growth-dependent concentration of STIM1 in the ER membrane plays a role in ER remodeling. C1 [Grigoriev, Ilya; Gouveia, Susana Montenegro; Van der Vaart, Babet; Splinter, Daniel; Akhmanova, Anna] Erasmus MC, Dept Cell Biol, NL-3000 CA Rotterdam, Netherlands. [Demmers, Jeroen] Erasmus MC, Dept Biochem, NL-3000 CA Rotterdam, Netherlands. [Smyth, Jeremy T.; Putney, James W., Jr.] Natl Inst Environm Hlth Sci, Dept Hlth & Human Serv, Lab Signal Tranduct, Res Triangle Pk, NC 27709 USA. [Honnappa, Srinivas; Steinmetz, Michel O.] Paul Scherrer Inst, CH-5232 Villigen, Switzerland. [Hoogenraad, Casper C.] Erasmus MC, Dept Neurosci, NL-3000 CA Rotterdam, Netherlands. RP Akhmanova, A (reprint author), Erasmus MC, Dept Cell Biol, NL-3000 CA Rotterdam, Netherlands. EM a.akhmanova@erasmusmc.nl RI Hoogenraad, Casper/B-8866-2011; Akhmanova, Anna/B-8896-2011; OI Hoogenraad, Casper/0000-0002-2666-0758; Akhmanova, Anna/0000-0002-9048-8614; Demmers, Jeroen/0000-0002-8757-9611; gouveia, susana/0000-0003-1220-410X FU Intramural NIH HHS [Z01 ES090087-11, Z99 ES999999] NR 17 TC 204 Z9 207 U1 0 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD FEB 12 PY 2008 VL 18 IS 3 BP 177 EP 182 DI 10.1016/j.cub.2007.12.050 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 263RI UT WOS:000253233800024 PM 18249114 ER PT J AU Johnson-Taylor, WL Fisher, RA Hubbard, VS Starke-Reed, P Eggers, PS AF Johnson-Taylor, Wendy L. Fisher, Rachel A. Hubbard, Van S. Starke-Reed, Pamela Eggers, Paul S. TI The change in weight perception of weight status among the overweight: comparison of NHANES III (1988-1994) and 1999-2004 NHANES SO INTERNATIONAL JOURNAL OF BEHAVIORAL NUTRITION AND PHYSICAL ACTIVITY LA English DT Article ID BODY-MASS INDEX; UNITED-STATES; SELF-PERCEPTION; IMAGE; PREVALENCE; OBESITY; HEALTH; WOMEN; SIZE; SEX AB Objectives: This study seeks to determine whether perception of weight status among the overweight has changed with the increasing overweight/obesity prevalence. Methods: The perception of weight status was compared between overweight participants (BMI between 25.0-29.9 kg/m(2)) from NHANES III (1988-1994) and overweight participants from NHANES 1999-2004. Perception of weight status was assessed by asking participants to classify their weight as about the right weight, underweight or overweight. Comparisons were made across age groups, genders, race/ethnicities and various income levels. Results: Fewer overweight people during the NHANES 1999-2004 survey perceived themselves as overweight when compared to overweight people during the NHANES III survey. The change in distortion between the survey periods was greatest among persons with lower income, males and African-Americans. Conclusion: The increase in overweight/obesity between the survey years (NHANES III and NHANES 1999-2004 has been accompanied with fewer overweight people perceiving themselves as overweight. C1 [Johnson-Taylor, Wendy L.; Fisher, Rachel A.; Hubbard, Van S.; Starke-Reed, Pamela] US Dept HHS, Natl Inst Hlth, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. [Eggers, Paul S.] US Dept HHS, NIDDK, Natl Inst Hlth, Bethesda, MD USA. RP Johnson-Taylor, WL (reprint author), US Dept HHS, Natl Inst Hlth, Div Nutr Res Coordinat, Bethesda, MD 20892 USA. EM wj50v@nih.gov; fisherrachel@mail.nih.gov; hubbardv@mail.nih.gov; starkep@mail.nih.gov; eggersp@mail.nih.gov NR 22 TC 55 Z9 57 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1479-5868 J9 INT J BEHAV NUTR PHY JI Int. J. Behav. Nutr. Phys. Act. PD FEB 12 PY 2008 VL 5 AR 9 DI 10.1186/1479-5868-5-9 PG 6 WC Nutrition & Dietetics; Physiology SC Nutrition & Dietetics; Physiology GA 278VD UT WOS:000254313500001 PM 18269748 ER PT J AU Iwata, NK Aoki, S Okabe, S Arai, N Terao, Y Kwak, S Abe, O Kanazawa, I Tsuji, S Ugawa, Y AF Iwata, N. K. Aoki, S. Okabe, S. Arai, N. Terao, Y. Kwak, S. Abe, O. Kanazawa, I. Tsuji, S. Ugawa, Y. TI Evaluation of corticospinal tracts in ALS with diffusion tensor MRI and brainstem stimulation SO NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; UPPER MOTOR-NEURON; FORAMEN MAGNUM LEVEL; NERVOUS-SYSTEM; INVOLVEMENT AB Objective: To assess corticospinal tract involvement in patients with amyotrophic lateral sclerosis (ALS) by correlating diffusion tensor imaging (DTI) measures with intra- and extracranial central motor conduction time (CMCT) and clinical features of the patients. Methods: We investigated 31 patients with ALS and 31 normal volunteers by DTI and measured fractional anisotropy (FA) within the corticospinal tracts and in the extramotor white matter. We measured CMCT for the first dorsal interosseous muscle and segmented it into corticalbrainstem (CTX-BS CT) and brainstem-cervical root (BS-CV CT) conduction times by magnetic brainstem stimulation at the foramen magnum level. Clinical status of each patient was evaluated with the ALS Functional Rating Scale-Revised (ALSFRS-R) and upper motor neuron (UMN) score devised for this study. Results: We found a significant decrease of mean FA in all regions of the corticospinal tracts in patients with ALS as compared with controls. We found that FA along the corticospinal tract decreased significantly with higher UMN scores. There was no significant correlation between FA and ALSFRS-R, to which both upper and lower motoneuron involvements contribute. FA showed a significant correlation with the intracranial part of the central motor conduction (CTX-BS CT) but not with the extracranial conduction time. Conclusions: Fractional anisotropy reflects functional abnormality of intracranial corticospinal tracts and can be used for objective evaluation of upper motor neuron impairment in amyotrophic lateral sclerosis. C1 [Iwata, N. K.] Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Iwata, N. K.; Okabe, S.; Arai, N.; Terao, Y.; Kanazawa, I.; Tsuji, S.; Ugawa, Y.] Univ Tokyo, Grad Sch Med, Dept Neurol, Div Neurosci, Tokyo, Japan. [Aoki, S.; Abe, O.] Univ Tokyo, Grad Sch Med, Dept Radiol & Bioengn, Tokyo, Japan. [Kanazawa, I.] Natl Ctr Neurol & Psychiat, Natl Inst Neurosci, Tokyo, Japan. RP Iwata, NK (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, Med Neurol Branch, Natl Inst Hlth, Bldg 10,Room 5N226,10 Ctr Dr, Bethesda, MD 20892 USA. EM iwatan@ninds.nih.gov NR 11 TC 67 Z9 69 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2008 VL 70 IS 7 BP 528 EP 532 DI 10.1212/01.wnl.0000299186.72374.19 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 260XJ UT WOS:000253043400006 PM 18268244 ER PT J AU Chio, A Traynor, BJ Lombardo, F Fimognari, M Calvo, A Ghiglione, P Mutani, R Restagno, G AF Chio, A. Traynor, B. J. Lombardo, F. Fimognari, M. Calvo, A. Ghiglione, P. Mutani, R. Restagno, G. TI Prevalence of SOD1 mutations in the Italian ALS population SO NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; CU/ZN SUPEROXIDE-DISMUTASE; GENE-MUTATIONS; IDENTIFICATION; SUPEROXIDE-DISMUTASE-1 AB Background: Five to 10% of amyotrophic lateral sclerosis (ALS) cases are reported to be familial (FALS), and mutations of SOD1 account for 20% of these cases. However, estimates of SOD1 mutation prevalence have been exclusively based on case series and clinic referral cohorts. Objective: To assess the frequency and nature of SOD1 mutations in a large population-based cohort of Italian patients diagnosed with ALS over a 6-year period. Methods: All ALS cases incident in Piemonte and Valle d'Aosta, Italy, are collected through a prospective epidemiologic register. Almost all patients with ALS resident in the largest province of Piemonte ( Turin) have been evaluated for SOD1 mutations in the 6-year period 2000 through 2005. Results: During the study period, 386 residents of Turin province were diagnosed with ALS (mean crude incidence rate of 2.9/100,000/year). Twenty-two patients (5.7%) had a positive family history of ALS. SOD1 analysis was performed in 325 patients (84.2% of the whole cohort), including all FALS cases. Five patients carried a SOD1 coding mutation, three with a family history of ALS (13.6% of FALS) and two in sporadic cases (0.7% of sporadic ALS). Conclusions: In this population-based series, the frequency of familial amyotrophic lateral sclerosis (FALS) was lower than that reported in series from ALS referral centers. While the frequency of SOD1 mutations in FALS was similar to the data reported in the literature, only 0.7% of sporadic ALS cases had a SOD1 mutation. Our data indicate that studies from referral centers may overestimate the frequency of FALS and of SOD1 mutations in sporadic ALS. C1 [Chio, A.; Calvo, A.; Ghiglione, P.; Mutani, R.] Univ Turin, Dept Neurosci, ALS Ctr, I-10126 Turin, Italy. [Traynor, B. J.] NIMH, Sect Dev Genet Epidemiol, NIH, Bethesda, MD 20892 USA. [Lombardo, F.; Fimognari, M.; Restagno, G.] ASO OIRMS, Childrens Hosp, Mol Diagnosis & Genet Counseling Unit, Turin, Italy. RP Chio, A (reprint author), Univ Turin, Dept Neurosci, ALS Ctr, Via Cherasco 15, I-10126 Turin, Italy. EM achio@usa.net RI Traynor, Bryan/G-5690-2010; Calvo, Andrea/K-4141-2016; OI Calvo, Andrea/0000-0002-5122-7243; Chio, Adriano/0000-0001-9579-5341 NR 25 TC 65 Z9 65 U1 4 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2008 VL 70 IS 7 BP 533 EP 537 DI 10.1212/01.wnl.0000299187.90432.3f PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 260XJ UT WOS:000253043400007 PM 18268245 ER PT J AU Saunders, K Merikangas, K Low, NCP Von Korff, M Kessler, RC AF Saunders, K. Merikangas, K. Low, N. C. P. Von Korff, M. Kessler, R. C. TI Impact of comorbidity on headache-related disability SO NEUROLOGY LA English DT Article ID QUALITY-OF-LIFE; TENSION-TYPE HEADACHE; INTERNATIONAL DIAGNOSTIC INTERVIEW; WORLD-HEALTH-ORGANIZATION; REPLICATION NCS-R; UNITED-STATES; PSYCHIATRIC COMORBIDITY; AMERICAN MIGRAINE; PANIC DISORDER; MAJOR DEPRESSION AB Objective: To assess and compare the extent to which comorbid conditions explain the role disability associated with migraine and other severe headaches. Methods: A probability sample of US adults (n = 5,692) was interviewed. Presence of headaches, other chronic pain conditions, and chronic physical conditions was assessed in a structured interview administered by trained interviewers. Diagnostic criteria for migraine were based on the International Headache Society classification. Mental disorders were ascertained with the Composite International Diagnostic Interview that collected diagnostic criteria according to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition. Role disability was assessed with World Health Organization Disability Assessment Schedule questions about days out of role and days with impaired role functioning. Results: Eighty-three percent of migraineurs and 79% of persons with other severe types of headache had some form of comorbidity. Compared with headache-free subjects, migraineurs were at significantly increased risk for mental disorders (odds ratio [OR] 3.1), other pain conditions (OR 3.3), and physical diseases (OR 2.1). Compared with headache-free subjects, persons with nonmigraine headache were also at significantly increased risk for mental disorders (OR 2.0), other pain conditions (OR 3.5), and physical diseases (OR 1.7). Migraineurs experienced role disability on 25.2% of the last 30 days compared with 17.6% of the days for persons with nonmigraine headaches and 9.7% of the days for persons without headache. Comorbid conditions explained 65% of the role disability associated with migraine and all of the role disability associated with other severe headaches. Conclusions: Comorbidity is an important factor in understanding disability among persons with headache. C1 [Saunders, K.; Von Korff, M.] Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. [Merikangas, K.; Low, N. C. P.] NIMH, Intramural Res Program, Rockville, MD 20857 USA. [Kessler, R. C.] Harvard Univ, Dept Hlth Policy, Boston, MA 02115 USA. [Low, N. C. P.] McGill Univ, Dept Psychiat, Montreal, PQ, Canada. RP Saunders, K (reprint author), Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, 1730 Minor Ave,Suite 1600, Seattle, WA 98101 USA. EM saunders.k@ghc.org FU NIDA NIH HHS [R01 DA016558]; NIMH NIH HHS [R01-MH069864, R13-MH066849, U01-MH60220] NR 67 TC 55 Z9 57 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0028-3878 EI 1526-632X J9 NEUROLOGY JI Neurology PD FEB 12 PY 2008 VL 70 IS 7 BP 538 EP 547 DI 10.1212/01.wnl.0000297192.84581.21 PG 10 WC Clinical Neurology SC Neurosciences & Neurology GA 260XJ UT WOS:000253043400008 PM 18268246 ER PT J AU Blakeley, MP Ruiz, F Cachau, R Hazemann, I Meilleur, F Mitschler, A Ginell, S Afonine, P Ventura, ON Cousido-Siah, A Haertlein, M Joachimiak, A Myles, D Podjarny, A AF Blakeley, Matthew P. Ruiz, Federico Cachau, Raul Hazemann, Isabelle Meilleur, Flora Mitschler, Andre Ginell, Stephan Afonine, Pavel Ventura, Oscar N. Cousido-Siah, Alexandra Haertlein, Michael Joachimiak, Andrzej Myles, Dean Podjarny, Alberto TI Quantum model of catalysis based on a mobile proton revealed by subatomic x-ray and neutron diffraction studies of h-aldose reductase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE enzymatic mechanism; helium cooling; subatomic resolution crystallography; x-ray plus neutrons joint refinement ID PROTEIN CRYSTALLOGRAPHY; DIABETIC COMPLICATIONS; CRYSTAL-STRUCTURE; ACTIVE-SITE; MUTAGENESIS; MECHANISM; ANGSTROM; HYDROGEN AB We present results of combined studies of the enzyme human aldose reductase (h-AR, 36 kDa) using single-crystal x-ray data (0.66 angstrom, 100K; 0.80 angstrom, 15K; 1.75 angstrom, 293K), neutron Laue data (2.2 angstrom, 293K), and quantum mechanical modeling. These complementary techniques unveil the internal organization and mobility of the hydrogen bond network that defines the properties of the catalytic engine, explaining how this promiscuous enzyme overcomes the simultaneous requirements of efficiency and promiscuity offering a general mechanistic view for this class of enzymes. C1 [Ruiz, Federico; Hazemann, Isabelle; Mitschler, Andre; Cousido-Siah, Alexandra; Podjarny, Alberto] Inst Natl Sante & Rech Med, Ctr Natl Rech Sci, Inst Genet & Biol Mol & Cellulaire, ULP, F-67404 Illkirch Graffenstaden, France. [Blakeley, Matthew P.; Haertlein, Michael] Inst Laue Langevin, F-38042 Grenoble, France. [Cachau, Raul] SAIC Frederick Inc, Natl Canc Inst, Frederick, MD 21702 USA. [Meilleur, Flora; Myles, Dean] Oak Ridge Natl Lab, Oak Ridge, TN 37831 USA. [Ginell, Stephan; Joachimiak, Andrzej] Argonne Natl Lab, Struct Biol Ctr, Argonne, IL 60439 USA. [Afonine, Pavel] Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. [Ventura, Oscar N.] Univ Republica, Fac Quim, Computat Chem Phys Grp, Dept Expt & Teoria Estruct Mat & Aplicac, Montevideo 11800, Uruguay. RP Podjarny, A (reprint author), Inst Natl Sante & Rech Med, Ctr Natl Rech Sci, Inst Genet & Biol Mol & Cellulaire, ULP, 1 Rue Laurent Fries, F-67404 Illkirch Graffenstaden, France. EM podiarny@titus.u-strasbg.fr RI myles, dean/D-5860-2016; Blakeley, Matthew/G-7984-2015; OI myles, dean/0000-0002-7693-4964; Blakeley, Matthew/0000-0002-6412-4358; Podjarny, Alberto/0000-0002-7685-1077 FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NIGMS NIH HHS [R01 GM071939, R01GM071939] NR 24 TC 51 Z9 51 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 12 PY 2008 VL 105 IS 6 BP 1844 EP 1848 DI 10.1073/pnas.0711659105 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 264CC UT WOS:000253261900015 PM 18250329 ER PT J AU Landgren, O Gridley, G Caporaso, NE Turesson, I AF Landgren, Ola Gridley, Gloria Caporaso, Neil E. Turesson, Ingemar TI Prevalence of type 1 Gaucher disease in the United States - Reply SO ARCHIVES OF INTERNAL MEDICINE LA English DT Letter ID US VETERANS; CANCER; MALIGNANCIES; RISK C1 [Landgren, Ola] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Landgren, O (reprint author), NCI, Div Canc Epidemiol & Genet, 6125 Executive Blvd, Bethesda, MD 20892 USA. EM landgreo@mail.nih.aov NR 10 TC 0 Z9 0 U1 1 U2 1 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 FEB 11 PY 2008 VL 168 IS 3 BP 327 EP 328 DI 10.1001/archinternmed.2007.92 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 259SX UT WOS:000252962300015 ER PT J AU Mitchell, DGV Rhodes, RA Pine, DS Blair, RJR AF Mitchell, D. G. V. Rhodes, R. A. Pine, D. S. Blair, R. J. R. TI The contribution of ventrolateral and dorsolateral prefrontal cortex to response reversal SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE response reversal; affective shift; response competition; ventrolateral prefrontal cortex; decision-making ID ANTERIOR CINGULATE CORTEX; FRONTAL-LOBE DAMAGE; EVENT-RELATED FMRI; ORBITOFRONTAL CORTEX; DECISION-MAKING; CAUDATE NEURONS; REWARD; HUMANS; INHIBITION; MODULATION AB Studies investigating response reversal consistently implicate regions of medial and lateral prefrontal cortex when reinforcement contingencies change. However, it is unclear from these studies how these regions give rise to the individual components of response reversal, such as reinforcement value encoding, response inhibition, and response change. Here we report a novel instrumental learning task designed to determine whether regions implicated in processing reversal errors are uniquely involved in this process, or whether they play a more general role in representing response competition, reinforcement value, or punishment value in the absence of demands for response change. In line with previous findings, reversal errors activated orbitofrontal cortex, dorsomedial prefrontal cortex, ventrolateral prefrontal cortex, caudate, and dorsolateral prefrontal cortex. These regions also showed increased activity to errors in the absence of contingency changes. In addition, ventrolateral PFC, caudate, and dorsolateral PFC each exhibited increased activity following correct reversals. Activity in these regions was not significantly modulated by changes in reinforcement value that were not sufficient to make an alternative response advantageous. These data do not support punishment-processing or prepotent response inhibition accounts of ventrolateral prefrontal cortex function. Instead, they support recent conceptualizations of ventrolateral prefrontal cortex function that implicate this region in resolving response competition by manipulating the representation of either motor response options, or object features. These data also suggest that dorsolateral prefrontal cortex plays a role in reversal learning, probably through top down attentional control of object or reinforcement features when task demands increase. (C) 2007 Elsevier B.V. All rights reserved. C1 [Mitchell, D. G. V.] Univ Western Ontario, Dept Psychiat, Schulish Sch Med & Dent, London, ON N6A 3K7, Canada. [Mitchell, D. G. V.] Univ Western Ontario, Dept Anat & Cell Biol, London, ON, Canada. [Mitchell, D. G. V.; Pine, D. S.; Blair, R. J. R.] NIMH, Mood & Anxiety Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Rhodes, R. A.] Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, MRC Clin Sci Ctr, Psychiat Grp, London, England. RP Mitchell, DGV (reprint author), Univ Western Ontario, Dept Psychiat, Schulish Sch Med & Dent, 339 Windermere Rd, London, ON N6A 3K7, Canada. EM dmitchS@uwo.ca FU Intramural NIH HHS [Z99 MH999999] NR 38 TC 23 Z9 23 U1 0 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD FEB 11 PY 2008 VL 187 IS 1 BP 80 EP 87 DI 10.1016/j.bbr.2007.08.034 PG 8 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 255AU UT WOS:000252629900011 PM 17950474 ER PT J AU Giddens, AC Nielsen, L Boshoff, HI Tasdemir, D Perozzo, R Kaiser, M Wang, F Sacchettini, JC Copp, BR AF Giddens, Anna C. Nielsen, Lone Boshoff, Helena I. Tasdemir, Deniz Perozzo, Remo Kaiser, Marcel Wang, Feng Sacchettini, James C. Copp, Brent R. TI Natural product inhibitors of fatty acid biosynthesis: synthesis of the marine microbial metabolites pseudopyronines A and B and evaluation of their anti-infective activities SO TETRAHEDRON LA English DT Article DE fatty acid biosynthesis; marine natural product; Leishmania; Mycobacteriun ID CARRIER PROTEIN REDUCTASE; PSEUDOMONAS SP F92S91; MYCOBACTERIUM-TUBERCULOSIS; ESCHERICHIA-COLI; SUBSTITUTED 2-PYRONES; IN-VITRO; FABI; THIOLACTOMYCIN; DISCOVERY; SYNTHASE AB Total syntheses of the title natural products, pseudopyronines A (1) and B (2), have been achieved using methyl beta-oxo carboxylic ester starting materials. The natural products and a small set of structurally related compounds were evaluated for growth inhibitory activity against a range of pathogenic microorganisms and were found to exhibit good potency (IC50 >= 0.46 mu g/mL) and selectivity towards Leishmania donovani. Several of the compounds inhibited recombinant fatty acid biosynthesis enzymes from both Plasmodium falciparum and Mycobacterium tuberculosis, validating these targets in the search for new anti-infective agents. (c) 2007 Elsevier Ltd. All rights reserved. C1 [Giddens, Anna C.; Nielsen, Lone; Copp, Brent R.] Univ Auckland, Dept Chem, Auckland, New Zealand. [Boshoff, Helena I.] NIAID, NIH, LCID, Tuberculosis Res Sect, Bethesda, MD 20892 USA. [Tasdemir, Deniz] Univ London, Ctr Pharmacognosy & Phytotherapy, London WC1N 1AX, England. [Perozzo, Remo] Univ Geneva, Sch Pharmaceut Sci, CH-1211 Geneva, Switzerland. [Kaiser, Marcel] Swiss Trop Inst, CH-4002 Basel, Switzerland. [Wang, Feng; Sacchettini, James C.] Texas A&M Univ, Dept Biochem & Biophys, College Stn, TX 77843 USA. RP Copp, BR (reprint author), Univ Auckland, Dept Chem, Private Bag 92019, Auckland, New Zealand. EM b.copp@auckland.ac.nz RI Copp, Brent/D-3706-2009; OI Copp, Brent/0000-0001-5492-5269; Kaiser, Marcel/0000-0003-1785-7302; Wang, Feng/0000-0003-2980-4646 NR 35 TC 29 Z9 31 U1 3 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD FEB 11 PY 2008 VL 64 IS 7 BP 1242 EP 1249 DI 10.1016/j.tet.2007.11.075 PG 8 WC Chemistry, Organic SC Chemistry GA 264IE UT WOS:000253280200010 ER PT J AU Bennett, RS Cress, CM Ward, JM Firestone, CY Murphy, BR Whitehead, SS AF Bennett, Richard S. Cress, Christina M. Ward, Jerrold M. Firestone, Cai-Yen Murphy, Brian R. Whitehead, Stephen S. TI La Crosse virus infectivity, pathogenesis, and immunogenicity in mice and monkeys SO VIROLOGY JOURNAL LA English DT Article ID CALIFORNIA SEROGROUP BUNYAVIRUSES; OPOSSUM DIDELPHIS-VIRGINIANA; CENTRAL-NERVOUS-SYSTEM; RACCOON PROCYON-LOTOR; FOX VULPES-FULVA; INTRANASAL INOCULATION; VESICULAR STOMATITIS; NEUTRALIZING ANTIBODIES; ENCEPHALITIS GROUP; AEDES-ALBOPICTUS AB Background: La Crosse virus (LACV), family Bunyaviridae, was first identified as a human pathogen in 1960 after its isolation from a 4 year-old girl with fatal encephalitis in La Crosse, Wisconsin. LACV is a major cause of pediatric encephalitis in North America and infects up to 300,000 persons each year of which 70-130 result in severe disease of the central nervous system (CNS). As an initial step in the establishment of useful animal models to support vaccine development, we examined LACV infectivity, pathogenesis, and immunogenicity in both weanling mice and rhesus monkeys. Results: Following intraperitoneal inoculation of mice, LACV replicated in various organs before reaching the CNS where it replicates to high titer causing death from neurological disease. The peripheral site where LACV replicates to highest titer is the nasal turbinates, and, presumably, LACV can enter the CNS via the olfactory neurons from nasal olfactory epithelium. The mouse infectious dose50 and lethal dose50 was similar for LACV administered either intranasally or intraperitoneally. LACV was highly infectious for rhesus monkeys and infected 100% of the animals at 10 PFU. However, the infection was asymptomatic, and the monkeys developed a strong neutralizing antibody response. Conclusion: In mice, LACV likely gains access to the CNS via the blood stream or via olfactory neurons. The ability to efficiently infect mice intranasally raises the possibility that LACV might use this route to infect its natural hosts. Rhesus monkeys are susceptible to LACV infection and develop strong neutralizing antibody responses after inoculation with as little as 10 PFU. Mice and rhesus monkeys are useful animal models for LACV vaccine immunologic testing although the rhesus monkey model is not optimal. C1 [Bennett, Richard S.; Cress, Christina M.; Firestone, Cai-Yen; Murphy, Brian R.; Whitehead, Stephen S.] NIAID, Infect Dis Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Ward, Jerrold M.] NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, Div Intramural Res,NIH, Bethesda, MD 20892 USA. RP Bennett, RS (reprint author), NIAID, Infect Dis Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. EM bennettri@niaid.nih.gov; cressc@mail.nih.gov; jeward@niaid.nih.gov; cfirestone@niaid.nih.gov; bmurphy@niaid.nih.gov; swhitehead@niaid.nih.gov OI Bennett, Richard/0000-0002-7227-4831 NR 40 TC 21 Z9 21 U1 1 U2 8 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 FEB 11 PY 2008 VL 5 AR 25 DI 10.1186/1743-422X-5-25 PG 15 WC Virology SC Virology GA 280PO UT WOS:000254438900001 PM 18267012 ER PT J AU Gralow, JR Zujewski, JA Winer, E AF Gralow, Julie R. Zujewski, Jo Anne Winer, Eric TI Preoperative therapy in invasive breast cancer: Reviewing the state of the science and exploring new research directions SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID SURGICAL ADJUVANT BREAST; CHEMOTHERAPY; WOMEN C1 [Gralow, Julie R.] Univ Washington, Dept Med Oncol, Seattle, WA 98195 USA. [Gralow, Julie R.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Zujewski, Jo Anne] NCI, Clin Invest Branch, Canc Therapy Evaluat Program, Div Canc Diag & Treatment, Bethesda, MD 20892 USA. [Winer, Eric] Dana Farber Canc Inst, Dept Med, Boston, MA 02115 USA. RP Gralow, JR (reprint author), Univ Washington, Dept Med Oncol, Seattle, WA 98195 USA. NR 9 TC 16 Z9 18 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2008 VL 26 IS 5 BP 696 EP 697 DI 10.1200/JCO.2007.15.9459 PG 2 WC Oncology SC Oncology GA 276XR UT WOS:000254177500002 PM 18258975 ER PT J AU Sparano, JA Paik, S AF Sparano, Joseph A. Paik, Soonmyung TI Development of the 21-gene assay and its application in clinical practice and clinical trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID POSITIVE BREAST-CANCER; GENE-EXPRESSION SIGNATURE; DNA MICROARRAY DATA; PROGNOSTIC CLASSIFICATION; VALIDATION; RECEPTOR; TAMOXIFEN; CHEMOTHERAPY; RECURRENCE; WOMEN AB Several multigene markers that predict relapse more accurately than classical clinicopathologic features have been developed. The 21-gene assay was developed specifically for patients with estrogen receptor (ER)-positive breast cancer, and has been shown to predict distant recurrence more accurately that classical clinicopathologic features in patients with ER-positive breast cancer and negative axillary nodes treated with adjuvant tamoxifen; validation studies in this population led to its approval as a diagnostic test. In a similar population, it also may be used to assess the benefit of adding chemotherapy to hormonal therapy. Other validation studies indicate that it also predicts the risk of distant and local recurrence in other populations with ER-positive disease, including node-negative patients receiving no adjuvant therapy and patients with positive axillary nodes treated with doxorubicin-containing chemotherapy. The Trial Assigning Individualized Options for Treatment (TAILORx) is multicenter trial that integrates the 21-gene assay into the clinical decision-making process and is designed to refine the utility of the assay in clinical practice and to provide a resource for evaluating additional molecular markers as they are developed in the future. C1 Montefiore Med Ctr, Albert Einstein Coll Med, Dept Oncol, Bronx, NY 10461 USA. Natl Surg Adjuvant Breast & Browel Project, Div Pathol, Pittsburgh, PA USA. RP Sparano, JA (reprint author), Montefiore Med Ctr, Albert Einstein Coll Med, Dept Oncol, 1825 Eastchester Rd, Bronx, NY 10461 USA. EM jsparano@montefiore.org NR 49 TC 271 Z9 279 U1 0 U2 8 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2008 VL 26 IS 5 BP 721 EP 728 DI 10.1200/JCO.2007.15.1068 PG 8 WC Oncology SC Oncology GA 276XR UT WOS:000254177500006 PM 18258979 ER PT J AU Wolff, AC Berry, D Carey, LA Colleoni, M Dowsett, M Ellis, M Garber, JE Mankoff, D Paik, S Pusztai, L Smith, ML Zujewski, J AF Wolff, Antonio C. Berry, Donald Carey, Lisa A. Colleoni, Marco Dowsett, Mitchell Ellis, Matthew Garber, Judy E. Mankoff, David Paik, Soonmyung Pusztai, Lajos Smith, Mary Lou Zujewski, JoAnne TI Research issues affecting preoperative systemic therapy for operable breast cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; PATHOLOGICAL COMPLETE RESPONSE; FACTOR RECEPTOR EXPRESSION; SURGICAL ADJUVANT BREAST; RECURRENCE-FREE SURVIVAL; PROJECT PROTOCOL B-27; BASAL-LIKE SUBTYPE; NEOADJUVANT CHEMOTHERAPY; GENE-EXPRESSION; CLINICAL-TRIAL AB Preoperative systemic therapy (PST) in operable breast cancer allows a small increase in breast conservation rates and has significant potential as a research platform. PST offers the ability to discern treatment effect in vivo, and may allow smaller trials targeting specific breast cancer subtypes and making more efficient use of resources. Early observations of a specific outcome of interest in individual patient subgroups may improve the design of larger definitive randomized adjuvant trials using survival as a main outcome. PST offers the potential for therapeutic adjustments midcourse, which assumes the existence of validated intermediate end points and effective alternative therapies. This article reviews critical research issues affecting the design of PST trials, including the appropriate selection of trial end points and markers for long-term outcome, baseline marker expression as a predictor of response, and statistical considerations using novel trial designs. Key issues regarding optimal tumor subtype selection for individual trials, novel approaches using nontherapeutic window trial designs, and ethical and advocacy considerations are also discussed. PST requires an experienced and cohesive multidisciplinary team for it to fulfill its potential in both research and clinical care. C1 Johns Hopkins Sydney Kimmel Canc Ctr, Baltimore, MD 21231 USA. NCI, Bethesda, MD 20892 USA. Univ Texas MD Anderson Canc Ctr, Houston, TX USA. Univ N Carolina, Chapel Hill, NC USA. European Inst Oncol, Milan, Italy. Royal Marsden Hosp, London SW3 6JJ, England. Washington Univ, Sch Med, St Louis, MO USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Washington, Sch Med, Seattle, WA 98195 USA. Natl Surg Adjuvant Breast & Bowel Project, Div Pathol, Pittsburgh, PA USA. Res Advocacy Network, Chicago, IL USA. RP Wolff, AC (reprint author), Johns Hopkins Sydney Kimmel Canc Ctr, 1650 Orleans St,Room 189, Baltimore, MD 21231 USA. EM awolff@jhmi.edu RI Mankoff, David/F-9576-2010; OI Wolff, Antonio/0000-0003-3734-1063 NR 83 TC 44 Z9 46 U1 0 U2 2 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 10 PY 2008 VL 26 IS 5 BP 806 EP 813 DI 10.1200/JCO.2007.15.2983 PG 8 WC Oncology SC Oncology GA 276XR UT WOS:000254177500017 PM 18258990 ER PT J AU Powers, JH AF Powers, John H. TI Noninferiority and equivalence trials: deciphering 'similarity' of medical interventions SO STATISTICS IN MEDICINE LA English DT Editorial Material ID OBSTRUCTIVE PULMONARY-DISEASE; RANDOMIZED-TRIALS; CLINICAL-TRIALS; EXACERBATIONS; METAANALYSIS; THERAPY C1 [Powers, John H.] NIAID, SAIC Support Collaborat Clin Res Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. [Powers, John H.] George Washington Univ, Sch Med, Washington, DC USA. [Powers, John H.] Univ Maryland, Sch Med, Bethesda, MD 20892 USA. RP Powers, JH (reprint author), NIAID, SAIC Support Collaborat Clin Res Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. EM powersjohn@mail.nih.gov FU NCI NIH HHS [N01-CO-12400] NR 23 TC 20 Z9 20 U1 1 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 FEB 10 PY 2008 VL 27 IS 3 BP 343 EP 352 DI 10.1002/sim.3138 PG 10 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 265IB UT WOS:000253351200003 PM 18186148 ER PT J AU Zhang, J Hawari, FI Shamburek, RD Adamik, B Kaler, M Islam, A Liao, DW Rouhani, FN Ingham, M Levine, SJ AF Zhang, Jing Hawari, Feras I. Shamburek, Robert D. Adamik, Barbara Kaler, Maryann Islam, Aminul Liao, Da-Wei Rouhani, Farshid N. Ingham, Matthew Levine, Stewart J. TI Circulating TNFR1 exosome-like vesicles partition with the LDL fraction of human plasma SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE cytokine receptors; cell surface receptors; human; cytokines; inflammation; TNF receptors; exosomes; exosome-like vesicles; human plasma ID CELL-DERIVED EXOSOMES; MULTIVESICULAR BODY; ASSOCIATION; MECHANISM; RELEASE; PATHWAY AB Extracellular type I tumor necrosis factor receptors (TNFR1) are generated by two mechanisms, proteolytic cleavage of TNFR1 ecto-domains and release of full-length TNFR1 in the membranes of exosome-like vesicles. Here, we assessed whether TNFR1 exosome-like vesicles circulate in human blood. Immunoelectron microscopy of human serum demonstrated TNFR1 exosome-like vesicles, with a diameter of 27 - 36 nm, while Western blots of human plasma showed a 48-kDa TNFR1, consistent with a membrane-associated receptor. Gel filtration chromatography revealed that the 48-kDa TNFR1 in human plasma co-segregated with LDL particles by size, but segregated independently by density, demonstrating that they are distinct from LDL particles. Furthermore, the 48-kDa exosome-associated TNFR1 in human plasma contained a reduced content of N-linked carbohydrates as compared to the 55-kDa membrane-associated TNFR1 from human vascular endothelial cells. Thus, a distinct population of TNFR1 exosome-like vesicles circulate in human plasma and may modulate TNF-mediated inflammation. Published by Elsevier Inc. C1 [Zhang, Jing; Hawari, Feras I.; Adamik, Barbara; Kaler, Maryann; Islam, Aminul; Liao, Da-Wei; Rouhani, Farshid N.; Ingham, Matthew; Levine, Stewart J.] NHLBI, Pulm Crit Care Branch, NIH, Bethesda, MD 20892 USA. [Shamburek, Robert D.] NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Pulm Crit Care Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU Intramural NIH HHS [Z01 HL002544-09] NR 21 TC 26 Z9 27 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 8 PY 2008 VL 366 IS 2 BP 579 EP 584 DI 10.1016/j.bbrc.2007.12.011 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 252GZ UT WOS:000252436300050 PM 18078813 ER PT J AU Waddington, SN Mcvey, JH Bhella, D Parker, AL Barker, K Atoda, H Pink, R Buckley, SMK Greig, JA Denby, L Custers, J Morita, T Francischetti, IMB Monteiro, RQ Barouch, DH van Rooijen, N Napoli, C Hlavenga, MJE Nicklin, SA Baker, AH AF Waddington, Simon N. McVey, John H. Bhella, David Parker, Alan L. Barker, Kristeen Atoda, Hideko Pink, Rebecca Buckley, Suzanne M. K. Greig, Jenny A. Denby, Laura Custers, Jerome Morita, Takashi Francischetti, Ivo M. B. Monteiro, Robson Q. Barouch, Dan H. van Rooijen, Nico Napoli, Claudio Hlavenga, Menzo J. E. Nicklin, Stuart A. Baker, Andrew H. TI Adenovirus serotype 5 hexon mediates liver gene transfer SO CELL LA English DT Article ID HEPARIN-BINDING EXOSITE; COAGULATION-FACTOR-X; IN-VIVO; SUBGROUP-D; ELECTRON-MICROSCOPY; ALPHA(V) INTEGRIN; CELLULAR RECEPTOR; VACCINE VECTORS; TUMOR-CELLS; CAR-BINDING AB Adenoviruses are used extensively as gene transfer agents, both experimentally and clinically. However, targeting of liver cells by adenoviruses compromises their potential efficacy. In cell culture, the adenovirus serotype 5 fiber protein engages the coxsackievirus and adenovirus receptor (CAR) to bind cells. Paradoxically, following intravascular delivery, CAR is not used for liver transduction, implicating alternate pathways. Recently, we demonstrated that coagulation factor (F)X directly binds adenovirus leading to liver infection. Here, we show that FX binds to the Ad5 hexon, not fiber, via an interaction between the FX Gla domain and hypervariable regions of the hexon surface. Binding occurs in multiple human adenovirus serotypes. Liver infection by the FX-Ad5 complex is mediated through a heparin-binding exosite in the FX serine protease domain. This study reveals an unanticipated function for hexon in mediating liver gene transfer in vivo. C1 [Parker, Alan L.; Barker, Kristeen; Greig, Jenny A.; Denby, Laura; Nicklin, Stuart A.; Baker, Andrew H.] Univ Glasgow, British Heart Fdn, Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. [Waddington, Simon N.] UCL Royal Free & Univ Coll Med Sch, Dept Haematol, Haemophilia Ctr, London NW3 2PF, England. [McVey, John H.] UCL Royal Free & Univ Coll Med Sch, Haemostasis Unit, London NW3 2PF, England. [Bhella, David; Pink, Rebecca] Univ Glasgow, MRC, Virol Unit, Glasgow G11 5JR, Lanark, Scotland. [Atoda, Hideko; Morita, Takashi] Meiji Pharmaceut Univ, Dept Biochem, Tokyo, Japan. [Custers, Jerome; Hlavenga, Menzo J. E.] Crucell, NL-2301 CA Leiden, Netherlands. [Francischetti, Ivo M. B.] NIAID NIH, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. [Monteiro, Robson Q.] Univ Fed Rio de Janeiro, Inst Bioquim Med, BR-21941 Rio De Janeiro, Brazil. [Barouch, Dan H.] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02215 USA. [van Rooijen, Nico] Vrije Univ Amsterdam, VUMC, Dept Mol Cell Biol, NL-1081 BT Amsterdam, Netherlands. [Napoli, Claudio] Univ Naples 2, Dept Gen Pathol, I-80138 Naples, Italy. [Napoli, Claudio] Temple Univ, Coll Sci & Technol, Sbarro Inst Canc Res & Mol Med, Philadelphia, PA 19122 USA. RP Baker, AH (reprint author), Univ Glasgow, British Heart Fdn, Glasgow Cardiovasc Res Ctr, 126 Univ Pl, Glasgow G12 8TA, Lanark, Scotland. EM ab11f@clinmed.gla.ac.uk RI Monteiro, Robson/B-8007-2014; Waddington, Simon/G-3778-2011; Parker, Alan/B-8187-2009; Bhella, David/J-8514-2012; Inbeb, Inct/K-2317-2013 OI Napoli, Claudio/0000-0002-5455-555X; McVey, John/0000-0002-7416-533X; bhella, david/0000-0003-2096-8310; Waddington, Simon/0000-0003-4970-4730; Parker, Alan/0000-0002-9302-1761; FU Biotechnology and Biological Sciences Research Council [BB/E02145X/1, BB/E021301/1]; Medical Research Council [, MC_U120074259] NR 55 TC 358 Z9 359 U1 4 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 8 PY 2008 VL 132 IS 3 BP 397 EP 409 DI 10.1016/j.cell.2008.01.016 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 262XD UT WOS:000253180700015 PM 18267072 ER PT J AU Piao, W Song, C Chen, H Wahl, LM Fitzgerald, KA O'Neill, LA Medvedev, AE AF Piao, Wenji Song, Chang Chen, Haiyan Wahl, Larry M. Fitzgerald, Katherine A. O'Neill, Luke A. Medvedev, Andrei E. TI Tyrosine phosphorylation of MyD88 adapter-like (Mal) is critical for signal transduction and blocked in endotoxin tolerance SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TOLL-LIKE RECEPTORS; NF-KAPPA-B; DOMAIN-CONTAINING ADAPTER; DOUBLE-STRANDED-RNA; INNATE IMMUNITY; CUTTING EDGE; TIR-DOMAIN; INTERLEUKIN-1 RECEPTOR; GENE-EXPRESSION; DOWN-REGULATION AB Toll-like receptor 4 (TLR4) recognition of lipopolysaccharide triggers signalosome assembly among TLR4, sorting ( e. g. MyD88 adapter-like (Mal)) and signaling (e.g. MyD88) adapters, initiating recruitment and activation of kinases, activation of transcription factors, and production of inflammatory mediators. In this study we examined whether tyrosine phosphorylation of Mal regulates its interactions with TLR4, MyD88, interleukin-1 (IL-1) receptor-associated kinase (IRAK)-2, and tumor necrosis factor receptor-associated factor (TRAF)-6 and is important for signaling. Overexpression of wild-type Mal in human embryonic kidney 293T cells induced its constitutive tyrosine phosphorylation and led to activation of p38, NF-kappa B, and IL-8 gene expression. Mutagenesis of Tyr-86, Tyr-106, and Tyr-159 residues within the Toll-IL-1 receptor domain impaired Mal tyrosine phosphorylation, interactions with Bruton tyrosine kinase, phosphorylation of p38, and NF-kappa B activation. Lipopolysaccharide triggered tyrosine phosphorylation of endogenous Mal and initiated Mal-Bruton-tyrosine kinase interactions in 293/TLR4/MD-2 cells and human monocytes that were suppressed in endotoxin-tolerant cells. Compared with wild-type Mal, Y86A-,Y06A-, and Y159A-Mal variants exhibited higher interactions with TLR4 and MyD88, whereas associations with IRAK-2 and TRAF-6 were not affected. Overexpression of Y86A- and Y106A-Mal in 293/TLR4/MD-2 cells exerted dominant-negative effects on TLR4-inducible p38 phosphorylation and NF-kappa B reporter activation to the extent comparable with P125H-Mal-mediated suppression. In contrast, tyrosine-deficient Mal species did not affect NF-kappa B activation when signaling was initiated at the post-receptor level by overexpression of MyD88, IRAK-2, or TRAF-6. Thus, tyrosine phosphorylation of Mal is required for adapter signaling, regulates Mal interactions with TLR4 and receptor signaling, and is inhibited in endotoxin tolerance. C1 [Piao, Wenji; Song, Chang; Chen, Haiyan; Medvedev, Andrei E.] Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. [Wahl, Larry M.] NIDCR, NIH, Bethesda, MD 20892 USA. [Fitzgerald, Katherine A.] Univ Massachusetts, Sch Med, Div Infect Dis & Immunol, Worcester, MA 01605 USA. [O'Neill, Luke A.] Trinity Coll Dublin, Sch Biochem & Immunol, Dublin 2, Ireland. RP Medvedev, AE (reprint author), Univ Maryland, Sch Med, Dept Microbiol & Immunol, 660 W Red Wood St,Howard Hall Bldg,Rm HH 324, Baltimore, MD 21201 USA. EM amedvedev@som.umaryland.edu FU NIAID NIH HHS [R01 AI-059524, R01 AI059524, R01 AI059524-05, R01 AI059524-04] NR 63 TC 50 Z9 50 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 FEB 8 PY 2008 VL 283 IS 6 BP 3109 EP 3119 DI 10.1074/jbc.M707400200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 261MJ UT WOS:000253083000014 PM 18070880 ER PT J AU Molina-Cruz, A Dejong, RJ Charles, B Gupta, L Kumar, S Jaramillo-Gutierrez, G Barillas-Mury, C AF Molina-Cruz, Alvaro Dejong, Randall J. Charles, Bradley Gupta, Lalita Kumar, Sanjeev Jaramillo-Gutierrez, Giovanna Barillas-Mury, Carolina TI Reactive oxygen species modulate anopheles gambiae immunity against bacteria and plasmodium SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MALARIA PARASITE INFECTION; GENE-EXPRESSION; INNATE IMMUNITY; NITRIC-OXIDE; MIDGUT CELLS; BLOOD MEAL; IN-VITRO; MOSQUITO; VECTOR; INVASION AB The involvement of reactive oxygen species (ROS) in mosquito immunity against bacteria and Plasmodium was investigated in the malaria vector Anopheles gambiae. Strains of An. gambiae with higher systemic levels of ROS survive a bacterial challenge better, whereas reduction of ROS by dietary administration of antioxidants significantly decreases survival, indicating that ROS are required to mount effective antibacterial responses. Expression of several ROS detoxification enzymes increases in the midgut and fat body after a blood meal. Furthermore, expression of several of these enzymes increases to even higher levels when mosquitoes are fed a Plasmodium berghei-infected meal, indicating that the oxidative stress after a blood meal is exacerbated by Plasmodium infection. Paradoxically, a complete lack of induction of catalase mRNA and lower catalase activity were observed in P. berghei-infected midguts. This suppression of midgut catalase expression is a specific response to ookinete midgut invasion and is expected to lead to higher local levels of hydrogen peroxide. Further reduction of catalase expression by double-stranded RNA-mediated gene silencing promoted parasite clearance by a lytic mechanism and reduced infection significantly. High mosquito mortality is often observed after P. berghei infection. Death appears to result in part from excess production of ROS, as mortality can be decreased by oral administration of uric acid, a strong antioxidant. We conclude that ROS modulate An. gambiae immunity and that the mosquito response to P. berghei involves a local reduction of detoxification of hydrogen peroxide in the midgut that contributes to limit Plasmodium infection through a lytic mechanism. C1 [Molina-Cruz, Alvaro; Dejong, Randall J.; Gupta, Lalita; Kumar, Sanjeev; Jaramillo-Gutierrez, Giovanna; Barillas-Mury, Carolina] NIAID, NIH, LMVR, Bethesda, MD 20892 USA. [Charles, Bradley] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. RP Molina-Cruz, A (reprint author), NIAID, NIH, LMVR, Twinbrook 3,MSC 8130,12735 Twinbrook Pkwy,Rm 2E-2, Bethesda, MD 20892 USA. EM amolina-cruz@niaid.nih.gov FU Intramural NIH HHS NR 34 TC 122 Z9 125 U1 2 U2 23 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 8 PY 2008 VL 283 IS 6 BP 3217 EP 3223 DI 10.1074/jbc.M705873200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 261MJ UT WOS:000253083000025 PM 18065421 ER PT J AU Yoshizaki, K Yamamoto, S Yamada, A Yuasa, K Iwamoto, T Fukumoto, E Harada, H Saito, M Nakasima, A Nonaka, K Yamada, Y Fukumoto, S AF Yoshizaki, Keigo Yamamoto, Shinya Yamada, Aya Yuasa, Kenji Iwamoto, Tsutomu Fukumoto, Emiko Harada, Hidemitsu Saito, Masahiro Nakasima, Akihiko Nonaka, Kazuaki Yamada, Yoshihiko Fukumoto, Satoshi TI Neurotrophic factor neurotrophin-4 regulates ameloblastin expression via full-length TrkB SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR SP3; GROWTH-FACTOR RECEPTOR; MICE LACKING; TOOTH DEVELOPMENT; EXTRACELLULAR-MATRIX; RAT TRKC; DIFFERENTIATION; CELLS; MORPHOGENESIS; DEFICITS AB Neurotrophic factors play an important role in the development and maintenance of not only neural but also nonneural tissues. Several neurotrophic factors are expressed in dental tissues, but their role in tooth development is not clear. Here, we report that neurotrophic factor neurotrophin (NT)-4 promotes differentiation of dental epithelial cells and enhances the expression of enamel matrix genes. Dental epithelial cells from 3-day-old mice expressed NT-4 and three variants of TrkB receptors for neurotrophins (full-length TrkB-FL and truncated TrkB-T1 and -T2). Dental epithelial cell line HAT-7 expressed these genes, similar to those in dental epithelial cells. We found that NT-4 reduced HAT-7 cell proliferation and induced the expression of enamel matrix genes, such as ameloblastin (Ambn). Transfection of HAT-7 cells with the TrkB-FL expression construct enhanced the NT-4-mediated induction of Ambn expression. This enhancement was blocked by K252a, an inhibitor for Trk tyrosine kinases. Phosphorylation of ERK1/2, a downstream molecule of TrkB, was induced in HAT-7 cells upon NT-4 treatment. TrkB-FL but not TrkB-T1 transfection increased the phosphorylation level of ERK1/2 in NT-4-treated HAT-7 cells. These results suggest that NT-4 induced Ambn expression via the TrkB-MAPK pathway. The p75 inhibitor TAT-pep5 decreased NT-4-mediated induction of the expression of Ambn, TrkB-FL, and TrkB-T1, suggesting that both high affinity and low affinity neurotrophin receptors were required for NT-4 activity. We found that NT-4-null mice developed a thin enamel layer and had a decrease in Ambn expression. Our results suggest that NT-4 regulates proliferation and differentiation of the dental epithelium and promotes production of the enamel matrix. C1 [Yoshizaki, Keigo; Yamamoto, Shinya; Yamada, Aya; Yuasa, Kenji; Iwamoto, Tsutomu; Nonaka, Kazuaki; Fukumoto, Satoshi] Kyushu Univ, Fac Dent Sci, Div Oral Hlth Growth & Dev, Sect Pediat Dent, Fukuoka 8128582, Japan. [Fukumoto, Emiko] Nagasaki Univ, Grad Sch Biomed Sci, Nagasaki 8528521, Japan. [Harada, Hidemitsu] Iwate Med Coll, Sch Dent, Dept Oral Anat 2, Morioka, Iwate 0208505, Japan. [Saito, Masahiro] Osaka Univ, Grad Sch Dent, Dept Mol & Cellular Biochem, Suita, Osaka 5650871, Japan. [Yamada, Yoshihiko] NIH, NIDCR, Craniofacial Dev Biol & Regenerat Biol Branch, Bethesda, MD 20892 USA. [Fukumoto, Satoshi] Tohoku Univ, Grad Sch Dent, Dept Oral Hlth & Dev Sci, Div Pediat, Sendai, Miyagi 9808575, Japan. RP Fukumoto, S (reprint author), Tohoku Univ, Dept Oral Hlth & Dev, Div Pediat Detn, Sendai, Miyagi 9808575, Japan. EM fukumoto@mail.tains.tohoku.ac.jp NR 40 TC 22 Z9 24 U1 2 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 FEB 8 PY 2008 VL 283 IS 6 BP 3385 EP 3391 DI 10.1074/jbc.M704913200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 261MJ UT WOS:000253083000043 PM 18045880 ER PT J AU Grubina, R Basu, S Tiso, M Kim-Shapiro, DB Gladwin, MT AF Grubina, Rozalina Basu, Swati Tiso, Mauro Kim-Shapiro, Daniel B. Gladwin, Mark T. TI Nitrite reductase activity of hemoglobin S (sickle) provides insight into contributions of heme redox potential versus ligand affinity SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CELL HEMOGLOBIN; ISCHEMIA-REPERFUSION; OXIDE BIOAVAILABILITY; OXYGEN-BINDING; BLOOD-CELLS; IN-VIVO; DEOXYHEMOGLOBIN; NO; OXIDATION; POLYMERIZATION AB Hemoglobin A (HbA) is an allosterically regulated nitrite reductase that reduces nitrite to NO under physiological hypoxia. The efficiency of this reaction is modulated by two intrinsic and opposing properties: availability of unliganded ferrous hemes and R-state character of the hemoglobin tetramer. Nitrite is reduced by deoxygenated ferrous hemes, such that heme deoxygenation increases the rate of NO generation. However, heme reactivity with nitrite, represented by its bimolecular rate constant, is greatest when the tetramer is in the R quaternary state. The mechanism underlying the higher reactivity of R-state hemes remains elusive. It can be due to the lower heme redox potential of R-state ferrous hemes or could reflect the high ligand affinity geometry of R-state tetramers that facilitates nitrite binding. We evaluated the nitrite reductase activity of unpolymerized sickle hemoglobin (HbS), whose oxygen affinity and cooperativity profile are equal to those of HbA, but whose heme iron has a lower redox potential. We now report that HbS exhibits allosteric nitrite reductase activity with competing proton and redox Bohr effects. In addition, we found that solution phase HbS reduces nitrite to NO significantly faster than HbA, supporting the thesis that heme electronics (i.e. redox potential) contributes to the high reactivity of R-state deoxy-hemes with nitrite. From a pathophysiological standpoint, under conditions where HbS polymers form, the rate of nitrite reduction is reduced compared with HbA and solution-phase HbS, indicating that HbS polymers reduce nitrite more slowly. C1 [Grubina, Rozalina; Tiso, Mauro; Gladwin, Mark T.] NHLBI, Vasc Med Branch, Bethesda, MD 20892 USA. [Gladwin, Mark T.] Natl Inst Hlth, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. [Grubina, Rozalina] Howard Hughes Med Inst, Natl Inst Res Scholars Program, Bethesda, MD 20814 USA. [Basu, Swati; Kim-Shapiro, Daniel B.] Wake Forest Univ, Dept Phys, Winston Salem, NC 27109 USA. RP Gladwin, MT (reprint author), CRC, Bldg 10,Rm 5-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM mgladwin@nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [HL078706, R37 HL058091, HL58091] NR 60 TC 31 Z9 31 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 FEB 8 PY 2008 VL 283 IS 6 BP 3628 EP 3638 DI 10.1074/jbc.M705222200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 261MJ UT WOS:000253083000068 PM 18056715 ER PT J AU Cox-Foster, D Conlan, S Holmes, EC Palacios, G Kalkstein, A Evans, JD Moran, NA Quan, PL Geiser, D Briese, T Hornig, M Hui, J Vanengelsdorp, D Pettis, JS Lipkin, WI AF Cox-Foster, Diana Conlan, Sean Holmes, Edward C. Palacios, Gustavo Kalkstein, Abby Evans, Jay D. Moran, Nancy A. Quan, Phenix-Lan Geiser, David Briese, Thomas Hornig, Mady Hui, Jeffrey Vanengelsdorp, Dennis Pettis, Jeffery S. Lipkin, W. Ian TI The latest buzz about colony collapse disorder - Response SO SCIENCE LA English DT Letter ID ACUTE PARALYSIS VIRUS C1 [Cox-Foster, Diana; Kalkstein, Abby; Vanengelsdorp, Dennis] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Conlan, Sean; Palacios, Gustavo; Quan, Phenix-Lan; Briese, Thomas; Hornig, Mady; Hui, Jeffrey; Lipkin, W. Ian] Columbia Univ, Ctr Infect & Immun, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Holmes, Edward C.] Columbia Univ, Ctr Infect & Immun, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Evans, Jay D.; Pettis, Jeffery S.] USDA ARS, Bee Res Lab, Beltsville, MD 20705 USA. [Moran, Nancy A.] Univ Arizona, Dept Ecol & Evolut Biol, Tucson, AZ 85721 USA. [Geiser, David] Penn State Univ, Dept Plant Pathol, University Pk, PA 16802 USA. [Moran, Nancy A.] Univ Arizona, Ctr Insect Sci, Tucson, AZ 85721 USA. [Vanengelsdorp, Dennis] Penn Dept Agr, Bur Plant Ind Apiculture, Harrisburg, PA 17110 USA. RP Cox-Foster, D (reprint author), Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. RI Moran, Nancy/G-1591-2010; vanEngelsdorp, Dennis/E-7934-2010 NR 5 TC 6 Z9 6 U1 1 U2 27 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 8 PY 2008 VL 319 IS 5864 BP 725 EP 725 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 259TE UT WOS:000252963000016 ER PT J AU Huff, J AF Huff, James TI More toxin tests needed SO SCIENCE LA English DT Letter C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Huff, J (reprint author), NIEHS, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. NR 2 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 8 PY 2008 VL 319 IS 5864 BP 725 EP 726 DI 10.1126/science.319.5864.725 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 259TE UT WOS:000252963000017 PM 18258879 ER PT J AU Salzer, U Neumann, C Thiel, J Woellner, C Pan-Hammarstrom, Q Lougaris, V Hagena, T Jung, J Birmelin, J Du, L Metin, A Webster, DA Plebani, A Moschese, V Hammarstroo, L Schaffer, AA Grimbacher, B AF Salzer, Ulrich Neumann, Carla Thiel, Jens Woellner, Cristina Pan-Hammarstrom, Qiang Lougaris, Vassilis Hagena, Tina Jung, Johannes Birmelin, Jennifer Du, Likun Metin, Ayse Webster, David A. Plebani, Alessandro Moschese, Viviana Hammarstrom, Lennart Schaeffer, Alejandro A. Grimbacher, Bodo TI Screening of functional and positional candidate genes in families with common variable immunodeficiency SO BMC IMMUNOLOGY LA English DT Article ID SELECTIVE IGA DEFICIENCY; MAJOR HISTOCOMPATIBILITY COMPLEX; LINKAGE ANALYSIS; B-CELLS; ICOS DEFICIENCY; PLASMA-CELLS; BONE-MARROW; MUTATIONS; IL-21; TACI AB Background: Common variable immunodeficiency (CVID) comprises a heterogeneous group of primary antibody deficiencies with complex clinical and immunological phenotypes. The recent discovery that some CVID patients show monogenic defects in the genes encoding ICOS, TACI or CD19 prompted us to investigate several functional candidate genes in individuals with CVID. Results: The exonic, protein coding regions of the genes encoding: APRIL, BCMA, IL10, IL10R alpha, IL10R beta, IL21, IL21R, and CCL18, were analyzed primarily in familial CVID cases, who showed evidence of genetic linkage to the respective candidate gene loci and CVID families with a recessive pattern of inheritance. Two novel SNPs were identified in exon 5 and exon 8 of the IL21R gene, which segregated with the disease phenotype in one CVID family. Eleven additional SNPs in the genes encoding BCMA, APRIL, IL10, IL10Ra, IL21 and IL21R were observed at similar frequencies as in healthy donors. Conclusion: We were unable to identify obvious disease causing mutations in the protein coding regions of the analyzed genes in the studied cohort. C1 [Salzer, Ulrich; Neumann, Carla; Thiel, Jens; Woellner, Cristina; Hagena, Tina; Jung, Johannes; Grimbacher, Bodo] Univ Hosp Freiburg, Sch Med, Div Clin Immunol & Rheumatol, D-79106 Freiburg, Germany. [Pan-Hammarstrom, Qiang; Du, Likun; Hammarstrom, Lennart] Karolinska Univ Hos Huddinge, Div Clin Immunol, SE-14186 Stockholm, Sweden. [Lougaris, Vassilis; Plebani, Alessandro] Univ Brescia, Dept Pediat, Brescia, Italy. [Lougaris, Vassilis; Plebani, Alessandro] Univ Brescia, Inst Med Angelo Nocivelli, Brescia, Italy. [Birmelin, Jennifer; Webster, David A.; Grimbacher, Bodo] UCL, Royal Free Hosp, Dept Immunol & Mol Pathol, London NW3 2QG, England. [Metin, Ayse] SB Ankara Diskapi Childrens Hosp, Div Pediat Immunol, Ankara, Turkey. [Moschese, Viviana] Univ Tor Vergata, Policlin Tor Vergata, Rome, Italy. [Schaeffer, Alejandro A.] NIH, Natl Ctr Biotechnol Informat, DHHS, Bethesda, MD 20892 USA. RP Grimbacher, B (reprint author), Univ Hosp Freiburg, Sch Med, Div Clin Immunol & Rheumatol, Hugstetterstr 55, D-79106 Freiburg, Germany. EM salzer@medizin.ukl.uni-freiburg.de; neumannc@Medizin.Ukl.Uni-Freiburg.De; jens.thiel@uniklinik-freiburg.de; c.woellner@medsch.ucl.ac.uk; lennart.hammarstrom@ki.se; vlougaris@yahoo.co.uk; tina.hagena@uniklinik-freiburg.de; JoeJung@gmx.de; j.birmelin@medsch.ucl.ac.uk; lennart.hammarstrom@ki.se; drmetin@anet.net.tr; David.Webster@royalfree.nhs.uk; plebani@med.unibs.it; moschese@med.uniroma2.it; lennart.hammarstrom@ki.se; schaffer@helix.nih.gov; bgrimbac@medsch.ucl.ac.uk RI Plebani, Alessandro/C-8593-2011; Schaffer, Alejandro/F-2902-2012; OI Jung, Johannes/0000-0003-0137-7929 NR 37 TC 22 Z9 22 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD FEB 7 PY 2008 VL 9 AR 3 DI 10.1186/1471-2172-9-3 PG 9 WC Immunology SC Immunology GA 278VJ UT WOS:000254314100001 PM 18254984 ER PT J AU Maragh, S Jakupciak, JP Wagner, PD Rom, WN Sidransky, D Srivastava, S O'Connell, CD AF Maragh, Samantha Jakupciak, John P. Wagner, Paul D. Rom, William N. Sidransky, David Srivastava, Sudhir O'Connell, Catherine D. TI Multiple strand displacement amplification of mitochondrial DNA from clinical samples SO BMC MEDICAL GENETICS LA English DT Article ID WHOLE-GENOME AMPLIFICATION; MUTATION DETECTION; CANCER BIOMARKERS; MICROARRAY; TUMORS AB Background: Whole genome amplification (WGA) methods allow diagnostic laboratories to overcome the common problem of insufficient DNA in patient specimens. Further, body fluid samples useful for cancer early detection are often difficult to amplify with traditional PCR methods. In this first application of WGA on the entire human mitochondrial genome, we compared the accuracy of mitochondrial DNA ( mtDNA) sequence analysis after WGA to that performed without genome amplification. We applied the method to a small group of cancer cases and controls and demonstrated that WGA is capable of increasing the yield of starting DNA material with identical genetic sequence. Methods: DNA was isolated from clinical samples and sent to NIST. Samples were amplified by PCR and those with no visible amplification were re-amplified using the Multiple Displacement Amplificaiton technique of whole genome amplification. All samples were analyzed by mitochip for mitochondrial DNA sequence to compare sequence concordance of the WGA samples with respect to native DNA. Real-Time PCR analysis was conducted to determine the level of WGA amplification for both nuclear and mtDNA. Results: In total, 19 samples were compared and the concordance rate between WGA and native mtDNA sequences was 99.995%. All of the cancer associated mutations in the native mtDNA were detected in the WGA amplified material and heteroplasmies in the native mtDNA were detected with high fidelity in the WGA material. In addition to the native mtDNA sequence present in the sample, 13 new heteroplasmies were detected in the WGA material. Conclusion: Genetic screening of mtDNA amplified by WGA is applicable for the detection of cancer associated mutations. Our results show the feasibility of this method for: 1) increasing the amount of DNA available for analysis, 2) recovering the identical mtDNA sequence, 3) accurately detecting mtDNA point mutations associated with cancer. C1 [Maragh, Samantha] NIST, Div Biochem Sci, Gaithersburg, MD 20899 USA. [Jakupciak, John P.] Cipher Syst, Crofton, MD USA. [Wagner, Paul D.] Natl Canc Inst, Canc Biomarkers Res Grp, Rockville, MD USA. [Rom, William N.] NYU, Sch Med, Div Pulm & Crit Care Med, New York, NY USA. [Sidransky, David] Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. [O'Connell, Catherine D.] Tetracore Inc, Rockville, MD USA. RP Maragh, S (reprint author), NIST, Div Biochem Sci, Gaithersburg, MD 20899 USA. EM samantha.maragh@nist.gov; johnjakupciak@verizon.net; wagnerp@mail.nih.gov; william.rom@med.nyu.edu; dsidrans@jhmi.edu; srivasts@mail.nih.gov; coconnell@tetracore.com FU NCI NIH HHS [Y1CN5001-01] NR 30 TC 7 Z9 8 U1 1 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD FEB 7 PY 2008 VL 9 AR 7 DI 10.1186/1471-2350-9-7 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 279QG UT WOS:000254369100001 PM 18257929 ER PT J AU Tycko, R AF Tycko, Robert TI Introduction to special topic: New developments in magnetic resonance SO JOURNAL OF CHEMICAL PHYSICS LA English DT Editorial Material ID MAGIC ANGLE; NUCLEAR; NMR; SPECTROSCOPY; SOLIDS C1 NIDDK, NIH, Phys Chem Lab, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, NIH, Phys Chem Lab, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov NR 22 TC 5 Z9 5 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 FEB 7 PY 2008 VL 128 IS 5 AR 052101 DI 10.1063/1.2833958 PG 2 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 262CD UT WOS:000253125700002 PM 18266405 ER PT J AU Ferrari, MJ Grais, RF Bharti, N Conlan, AJK Bjornstad, ON Wolfson, LJ Guerin, PJ Djibo, A Grenfell, BT AF Ferrari, Matthew J. Grais, Rebecca F. Bharti, Nita Conlan, Andrew J. K. Bjornstad, Ottar N. Wolfson, Lara J. Guerin, Philippe J. Djibo, Ali Grenfell, Bryan T. TI The dynamics of measles in sub-Saharan Africa SO NATURE LA English DT Article ID SIR EPIDEMIC MODEL; TIME-SERIES; DEVELOPING-COUNTRIES; CHILDHOOD DISEASES; MASS VACCINATION; COMMUNITY SIZE; PATTERNS; IMMUNIZATION; PERSISTENCE; OUTBREAK AB Although vaccination has almost eliminated measles in parts of the world, the disease remains a major killer in some high birth rate countries of the Sahel. On the basis of measles dynamics for industrialized countries, high birth rate regions should experience regular annual epidemics. Here, however, we show that measles epidemics in Niger are highly episodic, particularly in the capital Niamey. Models demonstrate that this variability arises from powerful seasonality in transmission - generating high amplitude epidemics - within the chaotic domain of deterministic dynamics. In practice, this leads to frequent stochastic fadeouts, interspersed with irregular, large epidemics. A metapopulation model illustrates how increased vaccine coverage, but still below the local elimination threshold, could lead to increasingly variable major outbreaks in highly seasonally forced contexts. Such erratic dynamics emphasize the importance both of control strategies that address build- up of susceptible individuals and efforts to mitigate the impact of large outbreaks when they occur. C1 [Ferrari, Matthew J.] Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Bharti, Nita; Bjornstad, Ottar N.; Grenfell, Bryan T.] Penn State Univ, Dept Biol, University Pk, PA 16802 USA. [Bjornstad, Ottar N.] Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. [Grais, Rebecca F.; Guerin, Philippe J.] Epictr, F-75011 Paris, France. [Conlan, Andrew J. K.] Ctr Math Sci, DAMTP, Cambridge CB3 0WA, England. [Bjornstad, Ottar N.; Grenfell, Bryan T.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. [Wolfson, Lara J.] WHO, CH-1211 Geneva 27, Switzerland. [Djibo, Ali] Minist Sante, Direct Gen Sante Publ, Niamey, Niger. RP Ferrari, MJ (reprint author), Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM mferrari@psu.edu RI Bjornstad, Ottar/I-4518-2012; OI Guerin, Philippe/0000-0002-6008-2963 NR 46 TC 138 Z9 140 U1 2 U2 42 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 7 PY 2008 VL 451 IS 7179 BP 679 EP 684 DI 10.1038/nature06509 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 259HD UT WOS:000252929500033 PM 18256664 ER PT J AU Chen, ES Zhang, K Nicolas, E Cam, HP Zofall, M Grewal, SIS AF Chen, Ee Sin Zhang, Ke Nicolas, Estelle Cam, Hugh P. Zofall, Martin Grewal, Shiv I. S. TI Cell cycle control of centromeric repeat transcription and heterochromatin assembly SO NATURE LA English DT Article ID RNA-POLYMERASE-II; FISSION YEAST; CHROMOSOME CONDENSATION; LYSINE-9 METHYLATION; EPIGENETIC CONTROL; UBIQUITIN LIGASE; PHOSPHORYLATION; CHROMATIN; COMPLEX; MITOSIS AB Heterochromatin in eukaryotic genomes regulates diverse chromosomal processes including transcriptional silencing(1). However, in Schizosaccharomyces pombe RNA polymerase II ( RNAPII) transcription of centromeric repeats is essential for RNA- interference- mediated heterochromatin assembly(2-5). Here we study heterochromatin dynamics during the cell cycle and its effect on RNAPII transcription. We describe a brief period during the S phase of the cell cycle in which RNAPII preferentially transcribes centromeric repeats. This period is enforced by heterochromatin, which restricts RNAPII accessibility at centromeric repeats for most of the cell cycle. RNAPII transcription during S phase is linked to loading of RNA interference and heterochromatin factors such as the Ago1 subunit of the RITS complex(6) and the Clr4 methyltransferase complex subunit Rik1 ( ref. 7). Moreover, Set2, an RNAPII- associated methyltransferase(8) that methylates histone H3 lysine 36 at repeat loci during S phase, acts in a pathway parallel to Clr4 to promote heterochromatin assembly. We also show that phosphorylation of histone H3 serine 10 alters heterochromatin during mitosis, correlating with recruitment of condensin that affects silencing of centromeric repeats. Our analyses suggest at least two distinct modes of heterochromatin targeting to centromeric repeats, whereby RNAPII transcription of repeats and chromodomain proteins bound to methylated histone H3 lysine 9 mediate recruitment of silencing factors. Together, these processes probably facilitate heterochromatin maintenance through successive cell divisions. C1 [Chen, Ee Sin; Zhang, Ke; Nicolas, Estelle; Cam, Hugh P.; Zofall, Martin; Grewal, Shiv I. S.] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Grewal, SIS (reprint author), NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov RI Nicolas, Estelle/C-4425-2008 OI Nicolas, Estelle/0000-0003-0412-8477 FU Intramural NIH HHS NR 30 TC 210 Z9 215 U1 6 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 7 PY 2008 VL 451 IS 7179 BP 734 EP 737 DI 10.1038/nature06561 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 259HD UT WOS:000252929500045 PM 18216783 ER PT J AU Merideth, MA Gordon, LB Clauss, S Sachdev, V Smith, ACM Perry, MB Brewer, CC Zalewski, C Kim, HJ Solomon, B Brooks, BP Gerber, LH Turner, ML Domingo, DL Hart, TC Graf, J Reynolds, JC Gropman, A Yanovski, JA Gerhard-Herman, M Collins, FS Nabel, EG Cannon, RO Gahl, WA Introne, WJ AF Merideth, Melissa A. Gordon, Leslie B. Clauss, Sarah Sachdev, Vandana Smith, Ann C. M. Perry, Monique B. Brewer, Carmen C. Zalewski, Christopher Kim, H. Jeffrey Solomon, Beth Brooks, Brian P. Gerber, Lynn H. Turner, Maria L. Domingo, Demetrio L. Hart, Thomas C. Graf, Jennifer Reynolds, James C. Gropman, Andrea Yanovski, Jack A. Gerhard-Herman, Marie Collins, Francis S. Nabel, Elizabeth G. Cannon, Richard O., III Gahl, William A. Introne, Wendy J. TI Phenotype and course of Hutchinson-Gilford progeria syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID 6-MINUTE WALK TEST; MUTANT LAMIN-A; CARDIOVASCULAR RISK; INHIBITING FARNESYLATION; AMERICAN-SOCIETY; CHILDREN; DISEASE; PROTEIN; ECHOCARDIOGRAPHY; ATHEROSCLEROSIS AB Background: Hutchinson-Gilford progeria syndrome is a rare, sporadic, autosomal dominant syndrome that involves premature aging, generally leading to death at approximately 13 years of age due to myocardial infarction or stroke. The genetic basis of most cases of this syndrome is a change from glycine GGC to glycine GGT in codon 608 of the lamin A (LMNA) gene, which activates a cryptic splice donor site to produce abnormal lamin A; this disrupts the nuclear membrane and alters transcription. Methods: We enrolled 15 children between 1 and 17 years of age, representing nearly half of the world's known patients with Hutchinson-Gilford progeria syndrome, in a comprehensive clinical protocol between February 2005 and May 2006. Results: Clinical investigations confirmed sclerotic skin, joint contractures, bone abnormalities, alopecia, and growth impairment in all 15 patients; cardiovascular and central nervous system sequelae were also documented. Previously unrecognized findings included prolonged prothrombin times, elevated platelet counts and serum phosphorus levels, measured reductions in joint range of motion, low-frequency conductive hearing loss, and functional oral deficits. Growth impairment was not related to inadequate nutrition, insulin unresponsiveness, or growth hormone deficiency. Growth hormone treatment in a few patients increased height growth by 10% and weight growth by 50%. Cardiovascular studies revealed diminishing vascular function with age, including elevated blood pressure, reduced vascular compliance, decreased ankle-brachial indexes, and adventitial thickening. Conclusions: Establishing the detailed phenotype of Hutchinson-Gilford progeria syndrome is important because advances in understanding this syndrome may offer insight into normal aging. Abnormal lamin A (progerin) appears to accumulate with aging in normal cells. (ClinicalTrials.gov number, NCT00365092.). C1 [Merideth, Melissa A.; Smith, Ann C. M.; Gropman, Andrea; Collins, Francis S.; Gahl, William A.; Introne, Wendy J.] NHGRI, NIH, Bethesda, MD 20892 USA. [Merideth, Melissa A.] NIH, Intramural Off Rare Dis, Bethesda, MD 20892 USA. [Sachdev, Vandana; Nabel, Elizabeth G.; Cannon, Richard O., III] NHLBI, Bethesda, MD 20892 USA. [Perry, Monique B.; Solomon, Beth] NIH, Dept Rehabil Med, Bethesda, MD 20892 USA. [Reynolds, James C.] NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. [Brewer, Carmen C.; Zalewski, Christopher; Kim, H. Jeffrey] Natl Inst Deafness & Other Communicat Disorders, Bethesda, MD USA. [Brooks, Brian P.] NEI, Bethesda, MD 20892 USA. NCI, Bethesda, MD 20892 USA. [Domingo, Demetrio L.; Hart, Thomas C.] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. [Yanovski, Jack A.] NICHHD, Bethesda, MD 20892 USA. [Gordon, Leslie B.] Brown Univ, Warren Alpert Med Sch, Providence, RI 02912 USA. [Clauss, Sarah; Gropman, Andrea] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Smith, Ann C. M.] Georgetown Univ, Med Ctr, Washington, DC 20007 USA. [Gerber, Lynn H.] George Mason Univ, Ctr Chron Illness & Disabil, Fairfax, VA 22030 USA. [Gerhard-Herman, Marie] Brigham & Womens Hosp, Boston, MA 02115 USA. RP Gahl, WA (reprint author), NHGRI, NIH, Bldg 10,Rm 10C-103, Bethesda, MD 20892 USA. EM bgahl@helix.nih.gov RI SMITH, ANN C.M./C-1122-2008 FU Intramural NIH HHS [Z01 HD000641-12, Z99 HD999999] NR 42 TC 223 Z9 232 U1 4 U2 32 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 7 PY 2008 VL 358 IS 6 BP 592 EP 604 DI 10.1056/NEJMoa0706898 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 259CJ UT WOS:000252916400006 PM 18256394 ER PT J AU Kaler, SG Holmes, CS Goldstein, DS Tang, JR Godwin, SC Donsante, A Liew, CJ Sato, S Patronas, N AF Kaler, Stephen G. Holmes, Courtney S. Goldstein, David S. Tang, Jingrong Godwin, Sarah C. Donsante, Anthony Liew, Clarissa J. Sato, Susumu Patronas, Nicholas TI Neonatal diagnosis and treatment of Menkes disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID COPPER-TRANSPORTING ATPASE; TANDEM MASS-SPECTROMETRY; OCCIPITAL-HORN-SYNDROME; KINKY HAIR SYNDROME; CANDIDATE GENE; HISTIDINE TREATMENT; THERAPY; ENCODES; MUTATIONS; PHENOTYPE AB Background: Menkes disease is a fatal neurodegenerative disorder of infancy caused by diverse mutations in a copper-transport gene, ATP7A. Early treatment with copper injections may prevent death and illness, but presymptomatic detection is hindered by the inadequate sensitivity and specificity of diagnostic tests. Exploiting the deficiency of a copper enzyme, dopamine-(beta)-hydroxylase, we prospectively evaluated the diagnostic usefulness of plasma neurochemical levels, assessed the clinical effect of early detection, and investigated the molecular bases for treatment outcomes. Methods: Between May 1997 and July 2005, we measured plasma dopamine, norepinephrine, dihydroxyphenylacetic acid, and dihydroxyphenylglycol in 81 infants at risk. In 12 newborns who met the eligibility criteria and began copper-replacement therapy within 22 days after birth, we tracked survival and neurodevelopment longitudinally for 1.5 to 8 years. We characterized ATP7A mutations using yeast complementation, reverse-transcriptase-polymerase-chain-reaction analysis, and immunohistochemical analysis. Results: Of 81 infants at risk, 46 had abnormal neurochemical findings indicating low dopamine-(beta)-hydroxylase activity. On the basis of longitudinal follow-up, patients were classified as affected or unaffected by Menkes disease, and the neurochemical profiles were shown to have high sensitivity and specificity for detecting disease. Among 12 newborns with positive screening tests who were treated early with copper, survival at a median follow-up of 4.6 years was 92%, as compared with 13% at a median follow-up of 1.8 years for a historical control group of 15 late-diagnosis and late-treatment patients. Two of the 12 patients had normal neurodevelopment and brain myelination; 1 of these patients had a mutation that complemented a Saccharomyces cerevisiae copper-transport mutation, indicating partial ATPase activity, and the other had a mutation that allowed some correct ATP7A splicing. Conclusions: Neonatal diagnosis of Menkes disease by plasma neurochemical measurements and early treatment with copper may improve clinical outcomes. Affected newborns who have mutations that do not completely abrogate ATP7A function may be especially responsive to early copper treatment. (ClinicalTrials.gov number, NCT00001262.). C1 [Kaler, Stephen G.; Godwin, Sarah C.; Donsante, Anthony] NICHHD, NIH, Unit Pediat Genet, Bethesda, MD 20892 USA. [Holmes, Courtney S.; Goldstein, David S.] Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, NIH, Bethesda, MD USA. [Liew, Clarissa J.; Sato, Susumu] Natl Inst Neurol Disorders & Stroke, Electroencephalog Sect, NIH, Bethesda, MD USA. [Patronas, Nicholas] NIH, Imaging Sci Program, Mark O Hatfield Clin Ctr, Bethesda, MD 20892 USA. RP Kaler, SG (reprint author), NICHHD, NIH, Unit Pediat Genet, Bldg 10,Rm 5-2571,10 Ctr Dr,MSC 1832, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov FU Intramural NIH HHS [Z01 HD008768-04, Z01 HD008768-05] NR 31 TC 104 Z9 111 U1 0 U2 7 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 7 PY 2008 VL 358 IS 6 BP 605 EP 614 DI 10.1056/NEJMoa070613 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 259CJ UT WOS:000252916400007 PM 18256395 ER PT J AU Binzoni, T Vogel, A Gandjbakhche, AH Marchesini, R AF Binzoni, T. Vogel, A. Gandjbakhche, A. H. Marchesini, R. TI Detection limits of multi-spectral optical imaging under the skin surface SO PHYSICS IN MEDICINE AND BIOLOGY LA English DT Article ID MONTE-CARLO SIMULATIONS; REFLECTANCE SPECTRA; TISSUES; BLOOD; COLOR; MELANOSOME; ABSORPTION; SCATTERING; SPECKLE; RANGE AB The present work shows that the optical/biological information contained in a typical spectral image mainly reflects the properties of a small (conic like) volume of tissue situated vertically under each individual pixel. The objects appearing on a spectral image reasonably reproduce the correct geometrical shape and size (like a non-deformed shadow) of underlying inclusions of pathological tissue. The information contained in a spectral image comes from a depth that does not exceed similar to 2-3 mm. The number of photons that visit a given tissue voxel situated at a depth larger than similar to 2 mm represents less than the 1% of the total number of photons reaching the corresponding detection pixel (forming the image). A pathological inclusion (e. g. a pool of blood or vascular tumor) situated at a depth of similar to 0.5 mm with a thickness of 0.5 mm produces an image intensity contrast of similar to 5% (for images taken at wavelengths in the 600-1000 nm range) when compared to the normal skin background. The same inclusion at a depth of 20 mu m provides a contrast decreasing from 55 to 20% with respect to an increase in wavelength. The dermis/hypodermis interface behaves as a partial barrier for the photons, limiting their access to deeper skin regions. The image contrast depends on the depth and the type of chromophore contained in the inclusion. An increase in the concentration of a given molecule may produce different contrast, independently of the depth, depending on the characteristics of the skin layer where this change occurs. C1 [Binzoni, T.] Univ Geneva, Dept Neurosci Fondamentales, CH-1211 Geneva 4, Switzerland. [Binzoni, T.] Univ Hosp Geneva, Dept Imagerie & Sci Informat Med, Geneva, Switzerland. [Vogel, A.; Gandjbakhche, A. H.] NIH, NICHHD, Lab Integrat & Med Biophys, Bethesda, MD USA. [Marchesini, R.] Fdn IRCCS, Ist Nazl Tumori, Milan, Italy. RP Binzoni, T (reprint author), Univ Geneva, Dept Neurosci Fondamentales, CH-1211 Geneva 4, Switzerland. EM Tiziano.Binzoni@medecine.unige.ch FU Intramural NIH HHS NR 39 TC 24 Z9 24 U1 0 U2 3 PU IOP PUBLISHING LTD PI BRISTOL PA TEMPLE CIRCUS, TEMPLE WAY, BRISTOL BS1 6BE, ENGLAND SN 0031-9155 J9 PHYS MED BIOL JI Phys. Med. Biol. PD FEB 7 PY 2008 VL 53 IS 3 BP 617 EP 636 DI 10.1088/0031-9155/53/3/008 PG 20 WC Engineering, Biomedical; Radiology, Nuclear Medicine & Medical Imaging SC Engineering; Radiology, Nuclear Medicine & Medical Imaging GA 257IP UT WOS:000252792700008 PM 18199906 ER PT J AU Hughes, I Binkley, J Hurle, B Green, ED Sidow, A Ornitz, DM AF Hughes, Inna Binkley, Jonathan Hurle, Belen Green, Eric D. Sidow, Arend Ornitz, David M. CA Nisc Comparative Sequencing TI Identification of the Otopetrin Domain, a conserved domain in vertebrate otopetrins and invertebrate otopetrin-like family members SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID PAROXYSMAL POSITIONAL VERTIGO; MULTIPLE SEQUENCE ALIGNMENT; ZEBRAFISH; PREDICTION; INFERENCE; PROTEIN; CALCIUM; REGIONS; MOUSE AB Background: Otopetrin 1 (Otop1) encodes a multi-transmembrane domain protein with no homology to known transporters, channels, exchangers, or receptors. Otop1 is necessary for the formation of otoconia and otoliths, calcium carbonate biominerals within the inner ear of mammals and teleost fish that are required for the detection of linear acceleration and gravity. Vertebrate Otop1 and its paralogues Otop2 and Otop3 define a new gene family with homology to the invertebrate Domain of Unknown Function 270 genes (DUF270; pfam03189). Results: Multi-species comparison of the predicted primary sequences and predicted secondary structures of 62 vertebrate otopetrin, and arthropod and nematode DUF270 proteins, has established that the genes encoding these proteins constitute a single family that we renamed the Otopetrin Domain Protein (ODP) gene family. Signature features of ODP proteins are three "Otopetrin Domains" that are highly conserved between vertebrates, arthropods and nematodes, and a highly constrained predicted loop structure. Conclusion: Our studies suggest a refined topologic model for ODP insertion into the lipid bilayer of 12 transmembrane domains, and highlight conserved amino-acid residues that will aid in the biochemical examination of ODP family function. The high degree of sequence and structural similarity of the ODP proteins may suggest a conserved role in the intracellular trafficking of calcium and the formation of biominerals. C1 [Hughes, Inna; Ornitz, David M.] Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA. [Binkley, Jonathan; Sidow, Arend] Stanford Univ, Med Ctr, Dept Genet, Stanford, CA 94305 USA. [Binkley, Jonathan; Sidow, Arend] Stanford Univ, Med Ctr, Dept Pathol, Stanford, CA 94305 USA. [Hurle, Belen; Green, Eric D.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. [Green, Eric D.; Nisc Comparative Sequencing] NHGRI, NISC, NIH, Bethesda, MD 20892 USA. RP Ornitz, DM (reprint author), Washington Univ, Sch Med, Dept Dev Biol, St Louis, MO 63110 USA. EM Inna_Hughes@urmc.rochester.edu; binkley@genome.stanford.edu; bhurle@nhgri.nih.gov; egreen@nhgri.nih.gov; arend@stanford.edu; dornitz@wustl.edu OI Ornitz, David/0000-0003-1592-7629 FU Intramural NIH HHS; NIDCD NIH HHS [DC02236, DC06974] NR 31 TC 7 Z9 8 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD FEB 6 PY 2008 VL 8 AR 41 DI 10.1186/1471-2148-8-41 PG 10 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 275EC UT WOS:000254053700001 PM 18254951 ER PT J AU Wakazono, Y Kiyatkin, EA AF Wakazono, Y. Kiyatkin, E. A. TI Electrophysiological evaluation of the time-course of dopamine uptake inhibition induced by intravenous cocaine at a reinforcing dose SO NEUROSCIENCE LA English DT Article DE striatum; dopamine transporter; iontophoresis; rats ID NUCLEUS-ACCUMBENS DOPAMINE; FREELY MOVING RATS; STRIATAL NEURONAL-ACTIVITY; IN-VIVO; INVIVO MICRODIALYSIS; UNRESTRAINED RATS; MONOAMINE UPTAKE; UPTAKE BLOCKERS; CONSCIOUS RATS; SAPHENOUS-VEIN AB Cocaine effectively inhibits dopamine (DA) uptake and this action appears to be the primary cause for increased DA transmission following systemic cocaine administration. Although this action had been reliably demonstrated in vivo with cocaine at high doses, data on the extent and the time-course of DA uptake inhibition induced by i.v. cocaine at low, reinforcing doses remain controversial. To clarify this issue, we examined how cocaine affects striatal neuronal responses to repeated iontophoretic DA applications in urethane-anesthetized rats. Because most striatal neurons during anesthesia have low, sporadic activity, DA tests were performed on cells tonically activated by continuous glutamate application. DA phasically decreased the activity of most dorsal and ventral striatal neurons; these responses in control conditions (i.v. saline) were current (dose)-dependent and remained highly stable following repeated DA applications at the same currents. DA also consistently decreased the activity of striatal neurons after i.v. cocaine (1 mg/kg); the magnitude of DA-induced inhibition slowly increased from similar to 5 min, became significantly larger from similar to 9 min, and peaked at 13-15 min after a single i.v. injection. Then, the difference in the DA response slowly decreased toward the pre-cocaine baseline. A similar enhancement of DA induced-inhibition was also seen after i.p. cocaine administration at a high dose (15 mg/ kg). In this case, the DA response became significantly stronger at 7-9 min and remained enhanced vs. a pre-drug control up to 24-26 min after the injection. Both regimens of cocaine treatment did not result in evident changes in either onset or offset of the DA-induced inhibitions. Our data confirm that cocaine at low, reinforcing doses inhibits DA uptake, resulting in potentiation of DA-induced neuronal inhibitions, but they suggest that this effect is relatively weak and delayed from the time of i.v. injection. These slow and prolonged effects of i.v. cocaine on DA-induced neuronal responses are consistent with previous binding and our electrochemical evaluations of DA uptake, presumably reflecting the total time necessary for i.v.-delivered cocaine to reach brain microvessels, cross the blood-brain barrier, passively diffuse within brain tissue, interact with the DA transporters, and finally inhibit DA uptake. Published by Elsevier Ltd on behalf of IBRO. C1 [Wakazono, Y.; Kiyatkin, E. A.] Natl Inst Drug Abuse Intramural Res Program, Natl Inst Hlth, Behav Neurosci Branch, DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), Natl Inst Drug Abuse Intramural Res Program, Natl Inst Hlth, Behav Neurosci Branch, DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 60 TC 6 Z9 6 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 FEB 6 PY 2008 VL 151 IS 3 BP 824 EP 835 DI 10.1016/j.neuroscience.2007.11.034 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 262ZS UT WOS:000253188000020 PM 18191902 ER PT J AU Blaney, JE Sathe, NS Goddard, L Hanson, CT Romero, TA Hanley, KA Murphy, BR Whitehead, SS AF Blaney, Joseph E., Jr. Sathe, Neeraj S. Goddard, Laura Hanson, Christopher T. Romero, Tammy A. Hanley, Kathryn A. Murphy, Brian R. Whitehead, Stephen S. TI Dengue virus type 3 vaccine candidates generated by introduction of deletions in the 3 ' untranslated region (3 '-UTR) or by exchange of the DENV-3 3 '-UTR with that of DENV-4 SO VACCINE LA English DT Article DE dengue; flavivirus; vaccine ID SECONDARY STRUCTURE; RHESUS-MONKEYS; 3'-UNTRANSLATED REGION; 3'-NONCODING REGION; HEMORRHAGIC-FEVER; ADULT VOLUNTEERS; LIVE; IMMUNOGENICITY; REPLICATION; RNA AB The dengue virus type 3 (DENV-3) vaccine candidate, rDEN3 Delta 30, was previously found to be under-attenuated in both SCID-HuH-7 mice and rhesus monkeys. Herein, two strategies have been employed to generate attenuated rDEN3 vaccine candidates which retain the full complement of structural and nonstructural proteins of DENV-3 and thus are able to induce humoral or cellular immunity to each of the DENV-3 proteins. First, using the predicted secondary structure of the 3' untranslated region (3'-UTR) of DENV-3 to design novel deletions, nine deletion mutant viruses were engineered and found to be viable. Four of nine deletion mutants replicated efficiently in Vero cells and were genetically stable. Second, chimeric rDENV-3 viruses were generated by replacement of the 3'-UTR of the rDENV-3 cDNA clone with that of rDENV-4 or rDEN4 Delta 30 yielding the rDEN3-3'D4 and rDEN3-3'D4 Delta 30 viruses, respectively. Immunization of rhesus monkeys with either of two deletion mutant viruses, rDEN3 Delta 30/31 and rDEN3 Delta 86, or with rDEN3-3'D4 Delta 30 resulted in infection without detectable viremia, with each virus inducing a strong neutralizing antibody response capable of conferring protection from DENV-3 challenge. The rDEN3 Delta 30/31 virus showed a strong host range restriction phenotype with complete loss of replication in C6/36 mosquito cells despite robust replication in Vero cells. In addition, rDEN3 Delta 30/31 had reduced replication in Toxorynchites mosquitoes following intrathoracic inoculation. The results are discussed in the context of vaccine development and the physical structure of the DENV 3'-UTR. (c) 2007 Elsevier Ltd. All rights reserved. C1 [Blaney, Joseph E., Jr.; Sathe, Neeraj S.; Goddard, Laura; Hanson, Christopher T.; Murphy, Brian R.; Whitehead, Stephen S.] NIH, NIAID, LID, Bethesda, MD 20892 USA. [Romero, Tammy A.; Hanley, Kathryn A.] New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. RP Blaney, JE (reprint author), NIH, NIAID, LID, 33 N Dr,Room 3W-10A, Bethesda, MD 20892 USA. EM jblaney@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000891-07]; NCRR NIH HHS [P20 RR016480, P20 RR016480-05]; NIGMS NIH HHS [R25 GM061222, GM61222] NR 43 TC 57 Z9 59 U1 0 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 6 PY 2008 VL 26 IS 6 BP 817 EP 828 DI 10.1016/j.vaccine.2007.11.082 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 264SI UT WOS:000253309700010 PM 18191005 ER PT J AU Olshen, AB Gold, B Lohmueller, KE Struewing, JP Satagopan, J Stefanov, SA Eskin, E Kirchhoff, T Lautenberger, JA Klein, RJ Friedman, E Norton, L Ellis, NA Viale, A Lee, CS Borgen, PI Clark, AG Offit, K Boyd, J AF Olshen, Adam B. Gold, Bert Lohmueller, Kirk E. Struewing, Jeffery P. Satagopan, Jaya Stefanov, Stefan A. Eskin, Eleazar Kirchhoff, Tomas Lautenberger, James A. Klein, Robert J. Friedman, Eitan Norton, Larry Ellis, Nathan A. Viale, Agnes Lee, Catherine S. Borgen, Patrick I. Clark, Andrew G. Offit, Kenneth Boyd, Jeff TI Analysis of genetic variation in Ashkenazi Jews by high density SNP genotyping SO BMC GENETICS LA English DT Article ID GENOME-WIDE ASSOCIATION; LINKAGE-DISEQUILIBRIUM; JEWISH POPULATION; POSITIVE SELECTION; UTAH MORMONS; SUSCEPTIBILITY; LOCALIZATION; MUTATIONS; FAMILIES; DISEASES AB Background: Genetic isolates such as the Ashkenazi Jews ( AJ) potentially offer advantages in mapping novel loci in whole genome disease association studies. To analyze patterns of genetic variation in AJ, genotypes of 101 healthy individuals were determined using the Affymetrix EAv3 500 K SNP array and compared to 60 CEPH-derived HapMap ( CEU) individuals. 435,632 SNPs overlapped and met annotation criteria in the two groups. Results: A small but significant global difference in allele frequencies between AJ and CEU was demonstrated by a mean F(ST) of 0.009 ( P < 0.001); large regions that differed were found on chromosomes 2 and 6. Haplotype blocks inferred from pairwise linkage disequilibrium ( LD) statistics ( Haploview) as well as by expectation-maximization haplotype phase inference ( HAP) showed a greater number of haplotype blocks in AJ compared to CEU by Haploview ( 50,397 vs. 44,169) or by HAP ( 59,269 vs. 54,457). Average haplotype blocks were smaller in AJ compared to CEU ( e. g., 36.8 kb vs. 40.5 kb HAP). Analysis of global patterns of local LD decay for closely-spaced SNPs in CEU demonstrated more LD, while for SNPs further apart, LD was slightly greater in the AJ. A likelihood ratio approach showed that runs of homozygous SNPs were approximately 20% longer in AJ. A principal components analysis was sufficient to completely resolve the CEU from the AJ. Conclusion: LD in the AJ versus was lower than expected by some measures and higher by others. Any putative advantage in whole genome association mapping using the AJ population will be highly dependent on regional LD structure. C1 [Olshen, Adam B.; Satagopan, Jaya; Lee, Catherine S.; Borgen, Patrick I.; Boyd, Jeff] Mem Sloan Kettering Canc Ctr, Dept Epidemiol, New York, NY 10021 USA. [Olshen, Adam B.; Satagopan, Jaya; Kirchhoff, Tomas; Norton, Larry; Offit, Kenneth; Boyd, Jeff] Mem Sloan Kettering Canc Ctr, Dept Biostat, New York, NY 10021 USA. [Klein, Robert J.] Mem Sloan Kettering Canc Ctr, Program Canc Biol, New York, NY 10021 USA. [Klein, Robert J.; Viale, Agnes] Mem Sloan Kettering Canc Ctr, Genet Program, New York, NY 10021 USA. [Gold, Bert; Struewing, Jeffery P.; Stefanov, Stefan A.; Lautenberger, James A.] NCI, Lab Genome Divers, Bethesda, MD 20892 USA. [Lohmueller, Kirk E.; Clark, Andrew G.] Cornell Univ, Dept Mol Biol & Genet, Ithaca, NY USA. [Eskin, Eleazar] Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA. [Friedman, Eitan] Chaim Sheba Med Ctr, IL-52621 Tel Hashomer, Israel. [Friedman, Eitan] Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. [Ellis, Nathan A.] Univ Chicago, Dept Med, Chicago, IL 60637 USA. RP Boyd, J (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol, 1275 York Ave, New York, NY 10021 USA. EM olshena@mskcc.org; goldb@ncifcrf.gov; kel38@cornell.edu; struewij@exchange.nih.gov; satagopj@mskcc.org; stefanovs@ncifcrf.gov; eeskin@cs.ucsd.edu; kirchhot@mskcc.org; lauten@ncifcrf.gov; kleinr@mskcc.org; eitan.friedman@sheba.health.gov.il; nortonl@mskcc.org; nellis@medicine.bsd.uchicago.edu; vialea@mskcc.org; lee1@mskcc.org; Pborgen@maimonidesmed.org; ac347@cornell.edu; offitk@mskcc.org; boydje1@memorialhealth.com RI Eskin, Eleazar/J-9187-2012; Klein, Robert/K-1888-2013; Struewing, Jeffery/I-7502-2013; OI Eskin, Eleazar/0000-0003-1149-4758; Klein, Robert/0000-0003-3539-5391; Struewing, Jeffery/0000-0002-4848-3334; Satagopan, Jaya/0000-0001-7102-5633; Norton, Larry/0000-0003-3701-9250; Kirchhoff, Tomas/0000-0002-9055-2364 FU NHLBI NIH HHS [K25 HL080079] NR 53 TC 23 Z9 24 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD FEB 5 PY 2008 VL 9 AR 14 DI 10.1186/1471-2156-9-14 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 275CS UT WOS:000254050100001 PM 18251999 ER PT J AU Pecon-Slattery, J McCracken, CL Troyer, JL VandeWoude, S Roelke, M Sondgeroth, K Winterbach, C Winterbach, H O'Brien, SJ AF Pecon-Slattery, Jill McCracken, Carrie L. Troyer, Jennifer L. VandeWoude, Sue Roelke, Melody Sondgeroth, Kerry Winterbach, Christiaan Winterbach, Hanlie O'Brien, Stephen J. TI Genomic organization, sequence divergence, and recombination of feline immunodeficiency virus from lions in the wild SO BMC GENOMICS LA English DT Article ID CROSS-SPECIES INFECTION; ENVELOPE GLYCOPROTEIN; NUCLEOTIDE-SEQUENCE; VIRAL-INFECTIONS; AFRICAN LIONS; PANTHERA-LEO; PHYLOGENETIC ASPECTS; GENETIC DIVERSITY; DOMESTIC CAT; AIDS VIRUSES AB Background: Feline immunodeficiency virus (FIV) naturally infects multiple species of cat and is related to human immunodeficiency virus in humans. FIV infection causes AIDS-like disease and mortality in the domestic cat ( Felis catus) and serves as a natural model for HIV infection in humans. In African lions ( Panthera leo) and other exotic felid species, disease etiology introduced by FIV infection are less clear, but recent studies indicate that FIV causes moderate to severe CD4 depletion. Results: In this study, comparative genomic methods are used to evaluate the full proviral genome of two geographically distinct FIV subtypes isolated from free-ranging lions. Genome organization of FIV(Ple) subtype B ( 9891 bp) from lions in the Serengeti National Park in Tanzania and FIVPle subtype E ( 9899 bp) isolated from lions in the Okavango Delta in Botswana, both resemble FIV genome sequence from puma, Pallas cat and domestic cat across 5' LTR, gag, pol, vif, orfA, env, rev and 3' LTR regions. Comparative analyses of available full-length FIV consisting of subtypes A, B and C from FIV(Fca), Pallas cat FIV(Oma) and two puma FIV(Pco) subtypes A and B recapitulate the species- specific monophyly of FIV marked by high levels of genetic diversity both within and between species. Across all FIVPle gene regions except env, lion subtypes B and E are monophyletic, and marginally more similar to Pallas cat FIVOma than to other FIV. Sequence analyses indicate the SU and TM regions of env vary substantially between subtypes, with FIVPle subtype E more related to domestic cat FIVFca than to FIVPle subtype B and FIVOma likely reflecting recombination between strains in the wild. Conclusion: This study demonstrates the necessity of whole-genome analysis to complement population/ gene-based studies, which are of limited utility in uncovering complex events such as recombination that may lead to functional differences in virulence and pathogenicity. These full-length lion lentiviruses are integral to the advancement of comparative genomics of human pathogens, as well as emerging disease in wild populations of endangered species. C1 [Pecon-Slattery, Jill; McCracken, Carrie L.; Troyer, Jennifer L.; Roelke, Melody] NCI, Lab Genom Divers, Basic Res Program SAIC Frederick, Frederick, MD 21702 USA. [Sondgeroth, Kerry] Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80532 USA. [Sondgeroth, Kerry] Washington State Univ, Dept Vet Microbiol & Pathol, Pullman, WA 99164 USA. [Winterbach, Christiaan; Winterbach, Hanlie] Tau Consultants, Maun, Botswana. RP Pecon-Slattery, J (reprint author), NCI, Lab Genom Divers, Basic Res Program SAIC Frederick, Frederick, MD 21702 USA. EM slattery@ncifcrf.gov; cmccracken@ncifcrf.gov; jtroyer@ncifcrf.gov; suev@lamar.colostate.edu; roelke@ncifcrf.gov; kss@vetmed.wsu.edu; tau@dynabyte.bw; tau@dynabyte.bw; obrien@ncifcrf.gov RI Troyer, Jennifer/B-8415-2012; OI McCracken, Carrie/0000-0002-8038-9727 FU Intramural NIH HHS; NCI NIH HHS [N01CO12400, N01-CO-12400] NR 61 TC 22 Z9 22 U1 1 U2 6 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 FEB 5 PY 2008 VL 9 AR 66 DI 10.1186/1471-2164-9-66 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 278KT UT WOS:000254285100001 PM 18251995 ER PT J AU Rozenberg, JM Shlyakhtenko, A Glass, K Rishi, V Myakishev, MV FitzGerald, PC Vinson, C AF Rozenberg, Julian M. Shlyakhtenko, Andrey Glass, Kimberly Rishi, Vikas Myakishev, Maxim V. FitzGerald, Peter C. Vinson, Charles TI All and only CpG containing sequences are enriched in promoters abundantly bound by RNA polymerase II in multiple tissues SO BMC GENOMICS LA English DT Article ID DNA METHYLATION PATTERNS; GENOME-WIDE ANALYSIS; TRANSCRIPTION FACTORS; BINDING-SITE; GENE-EXPRESSION; CHROMATIN; PROTEINS; ISLANDS; CREB; IDENTIFICATION AB Background: The promoters of housekeeping genes are well-bound by RNA polymerase II ( RNAP) in different tissues. Although the promoters of these genes are known to contain CpG islands, the specific DNA sequences that are associated with high RNAP binding to housekeeping promoters has not been described. Results: ChIP-chip experiments from three mouse tissues, liver, heart ventricles, and primary keratinocytes, indicate that 94% of promoters have similar RNAP binding, ranging from well-bound to poorly-bound in all tissues. Using all 8-base pair long sequences as a test set, we have identified the DNA sequences that are enriched in promoters of housekeeping genes, focusing on those DNA sequences which are preferentially localized in the proximal promoter. We observe a bimodal distribution. Virtually all sequences enriched in promoters with high RNAP binding values contain a CpG dinucleotide. These results suggest that only transcription factor binding sites ( TFBS) that contain the CpG dinucleotide are involved in RNAP binding to housekeeping promoters while TFBS that do not contain a CpG are involved in regulated promoter activity. Abundant 8-mers that are preferentially localized in the proximal promoters and exhibit the best enrichment in RNAP bound promoters are all variants of six known CpG-containing TFBS: ETS, NRF-1, BoxA, SP1, CRE, and E-Box. The frequency of these six DNA motifs can predict housekeeping promoters as accurately as the presence of a CpG island, suggesting that they are the structural elements critical for CpG island function. Experimental EMSA results demonstrate that methylation of the CpG in the ETS, NRF-1, and SP1 motifs prevent DNA binding in nuclear extracts in both keratinocytes and liver. Conclusion: In general, TFBS that do not contain a CpG are involved in regulated gene expression while TFBS that contain a CpG are involved in constitutive gene expression with some CpG containing sequences also involved in inducible and tissue specific gene regulation. These TFBS are not bound when the CpG is methylated. Unmethylated CpG dinucleotides in the TFBS in CpG islands allow the transcription factors to find their binding sites which occur only in promoters, in turn localizing RNAP to promoters. C1 [Rozenberg, Julian M.; Shlyakhtenko, Andrey; Rishi, Vikas; Myakishev, Maxim V.; Vinson, Charles] NCI, Lab Metab, Bethesda, MD 20892 USA. [Glass, Kimberly] Univ Maryland, Dept Phys, College Pk, MD 20742 USA. [Myakishev, Maxim V.] Univ Rochester, Sch Med, Dept Dermatol, Rochester, NY 14642 USA. [FitzGerald, Peter C.] NCI, Genome Anal Unit, Bethesda, MD 20892 USA. RP Vinson, C (reprint author), NCI, Lab Metab, Bethesda, MD 20892 USA. EM rozenbej@mail.nih.gov; shlyakha@mail.nih.gov; kg234f@nih.gov; rishiv@mail.nih.gov; Max_Myakishev@urmc.rochester.edu; FitzgePe@mail.nih.gov; Vinsonc@mail.nih.gov NR 49 TC 36 Z9 38 U1 0 U2 3 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 FEB 5 PY 2008 VL 9 AR 67 DI 10.1186/1471-2164-9-67 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 274FX UT WOS:000253988300001 PM 18252004 ER PT J AU Gladwin, MT AF Gladwin, Mark T. TI Evidence mounts that nitrite contributes to hypoxic vasodilation in the human circulation SO CIRCULATION LA English DT Editorial Material DE editorials; hemoglobin; nitric oxide; vasodilation ID REGIONAL BLOOD-FLOW; GUANYLATE-CYCLASE; S-NITROSOTHIOLS; SODIUM-NITRITE; OXIDE; DEOXYHEMOGLOBIN; OXYGEN; HEMOGLOBIN; REDUCTASE; NO C1 NIH, Crit Care Med Dept, Ctr Clin, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), NIH, Crit Care Med Dept, Ctr Clin, Bldg 10-CRC,Room 5-5140,10 Ctr Dr,MSC 1454, Bethesda, MD 20892 USA. EM mgladwin@nih.gov NR 29 TC 26 Z9 26 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 FEB 5 PY 2008 VL 117 IS 5 BP 594 EP 597 DI 10.1161/CIRCULATIONAHA.107.753897 PG 4 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 258UF UT WOS:000252894300002 PM 18250278 ER PT J AU Rosito, GA Massaro, JM Hoffmann, U Ruberg, FL Mahabadi, AA Vasan, RS O'Donnell, CJ Fox, CS AF Rosito, Guido A. Massaro, Joseph M. Hoffmann, Udo Ruberg, Frederick L. Mahabadi, Amir A. Vasan, Ramachandran S. O'Donnell, Christopher J. Fox, Caroline S. TI Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample - The framingham heart study SO CIRCULATION LA English DT Article DE pericardium; epidemiology; risk factors; obesity ID EPICARDIAL ADIPOSE-TISSUE; CORONARY-ARTERY-DISEASE; INSULIN-RESISTANCE; COMPUTED-TOMOGRAPHY; JAPANESE-AMERICANS; MEN; ASSOCIATION; HYPERTENSION; WOMEN; ECHOCARDIOGRAPHY AB Background - Pericardial fat may be an important mediator of metabolic risk. Correlations with cardiovascular disease risk factors and vascular calcification in a community-based sample are lacking. We sought to examine associations between pericardial fat, metabolic risk factors, and vascular calcification. Methods and Results - Participants free of cardiovascular disease from the Framingham Heart Study (n = 1155, mean age 63 years, 54.8% women) who were part of a multidetector computed tomography study underwent quantification of intrathoracic fat, pericardial fat, visceral abdominal fat (VAT), coronary artery calcification, and aortic artery calcification. Intrathoracic and pericardial fat volumes were examined in relation to body mass index, waist circumference, VAT, metabolic risk factors, coronary artery calcification, and abdominal aortic calcification. Intrathoracic and pericardial fat were directly correlated with body mass index (r = 0.41 to 0.51, P = 0.001), waist circumference (r = 0.43 to 0.53, P < 0.001), and VAT (r = 0.62 to 0.76, P < 0.001). Both intrathoracic and pericardial fat were associated with higher triglycerides (P < 0.0001), lower high-density lipoprotein (P < 0.0001), hypertension (P < 0.0001 to 0.01), impaired fasting glucose (P < 0.0001 to 0.001), diabetes mellitus (P = 0.0005 to 0.009), and metabolic syndrome (P < 0.0001) after multivariable adjustment. Associations generally persisted after additional adjustment for body mass index and waist circumference but not after adjustment for VAT (all P > 0.05). Pericardial fat, but not intrathoracic fat, was associated with coronary artery calcification after multivariable and VAT adjustment (odds ratio 1.21, 95% confidence interval 1.005 to 1.46, P = 0.04), whereas intrathoracic fat, but not pericardial fat, was associated with abdominal aortic calcification (odds ratio 1.32, 95% confidence interval 1.03 to 1.67, P = 0.03). Conclusions - Pericardial fat is correlated with multiple measures of adiposity and cardiovascular disease risk factors, but VAT is a stronger correlate of most metabolic risk factors. However, intrathoracic and pericardial fat are associated with vascular calcification, which suggests that these fat depots may exert local toxic effects on the vasculature. C1 [O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI Framingham Heart Study, Framingham, MA 01702 USA. [Rosito, Guido A.; Hoffmann, Udo; Mahabadi, Amir A.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Cardiac MR CT PET Program, Boston, MA USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Massachusetts Gen Hosp, Div Cardiol, Boston, MA USA. [Rosito, Guido A.] Fed Fdn Sch Med Sci Porto Alegre, Rio Grande Do Sul, Brazil. [Massaro, Joseph M.] Boston Univ, Dept Math, Boston, MA USA. [Ruberg, Frederick L.; Vasan, Ramachandran S.] Boston Med Ctr, Dept Cardiol, Boston, MA USA. [Fox, Caroline S.] Brigham & Womens Hosp, Div Endocrinol Metab & Diabet, Dept Med, Boston, MA 02115 USA. RP Fox, CS (reprint author), NHLBI Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Ruberg, Frederick/0000-0002-6424-4413; Massaro, Joseph/0000-0002-2682-4812; Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [N01-HC-25195] NR 38 TC 442 Z9 462 U1 4 U2 22 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD FEB 5 PY 2008 VL 117 IS 5 BP 605 EP 613 DI 10.1161/CIRCULATIONAHA.107.743062 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 258UF UT WOS:000252894300004 PM 18212276 ER PT J AU Das, K Bauman, JD Clark, AD Frenkel, YV Lewi, PJ Shatkin, AJ Hughes, SH Arnold, E AF Das, Kalyan Bauman, Joseph D. Clark, Arthur D., Jr. Frenkel, Yulia V. Lewi, Paul J. Shatkin, Aaron J. Hughes, Stephen H. Arnold, Eddy TI High-resolution structures of HIV-1 reverse transcriptase/TMC278 complexes: Strategic flexibility explains potency against resistance mutations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE drug design; drug resistance; nonnucleoside reverse transcriptase inhibitor; polymerase; x-ray crystallography ID IMMUNODEFICIENCY-VIRUS TYPE-1; CRYSTAL-STRUCTURES; NONNUCLEOSIDE INHIBITORS; MACROMOLECULAR STRUCTURES; POSITIONAL ADAPTABILITY; ANGSTROM RESOLUTION; ANTIVIRAL ACTIVITY; WILD-TYPE; DRUG; MUTANT AB TMC278 is a diarylpyrimidine (DAPY) nonnucleoside reverse transcriptase inhibitor (NNRTI) that is highly effective in treating wild-type and drug-resistant HIV-1 infections in clinical trials at relatively low doses (similar to 25-75 mg/day). We have determined the structure of wild-type HIV-1 RT complexed with TMC278 at 1.8 angstrom resolution, using an RT crystal form engineered by systematic RT mutagenesis. This high-resolution structure reveals that the cyanovinyl group of TMC278 is positioned in a hydrophobic tunnel connecting the NNRTI-binding pocket to the nucleic acid-binding cleft. The crystal structures of TMC278 in complexes with the double mutant K103N/Y181C (2.1 angstrom) and L1001/K103N HIV-1 RTs (2.9 angstrom) demonstrated that TMC278 adapts to bind mutant RTs. In the K103N/Y181C RT/TMC278 structure, loss of the aromatic ring interaction caused by the Y181C mutation is counterbalanced by interactions between the cyanovinyl group of TMC278 and the aromatic side chain of Y183, which is facilitated by an similar to 1.5 angstrom shift of the conserved Y183MDD motif. In the L1001/K103N RT/TMC278 structure, the binding mode of TMC278 is significantly altered so that the drug conforms to changes in the binding pocket primarily caused by the L1001 mutation. The flexible binding pocket acts as a molecular "shrink wrap" that makes a shape complementary to the optimized TMC278 in wild-type and drug-resistant forms of HIV-1 RT. The crystal structures provide a better understanding of how the flexibility of an inhibitor can compensate for drug-resistance mutations. C1 [Das, Kalyan; Bauman, Joseph D.; Clark, Arthur D., Jr.; Frenkel, Yulia V.; Shatkin, Aaron J.; Arnold, Eddy] Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. [Das, Kalyan; Bauman, Joseph D.; Clark, Arthur D., Jr.; Frenkel, Yulia V.; Arnold, Eddy] Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. [Lewi, Paul J.] Katholieke Univ Leuven, B-3000 Louvain, Belgium. [Hughes, Stephen H.] Natl Canc Inst, Frederick, MD 21702 USA. RP Arnold, E (reprint author), Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. EM shatkin@cabm.rutgers.edu FU Intramural NIH HHS; NIAID NIH HHS [R37 AI027690, AI 27690, R37 AI027690-20]; NIGMS NIH HHS [P01 GM 066671, P01 GM066671, P01 GM066671-05] NR 28 TC 188 Z9 198 U1 0 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 5 PY 2008 VL 105 IS 5 BP 1466 EP 1471 DI 10.1073/pnas.0711209105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 261KQ UT WOS:000253077900017 PM 18230722 ER PT J AU Deng, JP Lewis, PA Greggio, E Sluch, E Beilina, A Cookson, MR AF Deng, Junpeng Lewis, Patrick A. Greggio, Elisa Sluch, Eli Beilina, Alexandra Cookson, Mark R. TI Structure of the ROC domain from the Parkinson's disease-associated leucine-rich repeat kinase 2 reveals a dimeric GTPase SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID TRYPANOSOMA-BRUCEI; NEURONAL TOXICITY; CRYSTAL-STRUCTURE; LRRK2 MUTATION; PROTEIN; INSIGHTS; BINDING; MODEL; HYDROLYSIS; REFINEMENT AB Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of Parkinson's disease (PD). LRRK2 contains a Ras of complex proteins (ROC) domain that may act as a GTPase to regulate its protein kinase activity. The structure of ROC and the mechanism(s) by which it regulates kinase activity are not known. Here, we report the crystal structure of the LRRK2 ROC domain in complex with GDP-Mg2+ at 2.0-angstrom resolution. The structure displays a dimeric fold generated by extensive domain-swapping, resulting in a pair of active sites constructed with essential functional groups contributed from both monomers. Two PD-associated pathogenic residues, 81441 and 11371, are located at the interface of two monomers and provide exquisite interactions to stabilize the ROC dimer. The structure demonstrates that loss of stabilizing forces in the ROC dimer is likely related to decreased GTPase activity resulting from mutations at these sites. Our data suggest that the. ROC domain may regulate LRRK2 kinase activity as a dimer, possibly via the C-terminal of ROC (COR) domain as a molecular hinge. The structure of the LRRK2 ROC domain also represents a signature from a previously undescribed class of GTPases from complex proteins and results may provide a unique molecular target for therapeutics in PD. C1 [Deng, Junpeng; Sluch, Eli] Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74048 USA. [Lewis, Patrick A.; Greggio, Elisa; Beilina, Alexandra; Cookson, Mark R.] NIH, Cell Biol & Gene Express Unit, Neurogenet Lab, Bethesda, MD 20892 USA. RP Deng, JP (reprint author), Oklahoma State Univ, Dept Biochem & Mol Biol, 248 Noble Res Ctr, Stillwater, OK 74048 USA. EM junpeng.deng@okstate.edu RI Lewis , Patrick/C-3674-2009; Greggio, Elisa/H-6119-2013; OI Greggio, Elisa/0000-0002-8172-3598; Lewis, Patrick/0000-0003-4537-0489 FU Intramural NIH HHS NR 34 TC 134 Z9 135 U1 0 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 FEB 5 PY 2008 VL 105 IS 5 BP 1499 EP 1504 DI 10.1073/pnas.0709098105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 261KQ UT WOS:000253077900023 PM 18230735 ER PT J AU Uda, M Galanello, R Sanna, S Lettre, G Sankaran, VG Chen, WM Usala, G Busonero, F Maschio, A Albai, G Piras, MG Sestu, N Lai, S Dei, M Mulas, A Crisponi, L Naitza, S Asunis, I Deiana, M Nagaraja, R Perseu, L Satta, S Cipollina, MD Sollaino, C Moi, P Hirschhorn, JN Orkin, SH Abecasis, GR Schlessinger, D Cao, A AF Uda, Manuela Galanello, Renzo Sanna, Serena Lettre, Guillaume Sankaran, Vijay G. Chen, Weimin Usala, Gianluca Busonero, Fabio Maschio, Andrea Albai, Giuseppe Piras, Maria Grazia Sestu, Natascia Lai, Sandra Dei, Mariano Mulas, Antonella Crisponi, Laura Naitza, Silvia Asunis, Isadora Deiana, Manila Nagaraja, Ramaiah Perseu, Lucia Satta, Stefania Cipollina, Maria Dolores Sollaino, Carla Moi, Paolo Hirschhorn, Joel N. Orkin, Stuart H. Abecasis, Goncalo R. Schlessinger, David Cao, Antonio TI Genome-wide association study shows BCL11A associated with persistent fetal hemoglobin and Amelioration of the phenotype of beta-thalassemia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE globin gene regulation; polymorphism; sickle cell anemia ID SICKLE-CELL-DISEASE; LINKAGE ANALYSIS; RISK-FACTORS; HEREDITARY PERSISTENCE; F-CELLS; GENE; CHROMOSOME; PEDIGREES; VARIANCE; TRAITS AB beta-Thalassemia and sickle cell disease both display a great deal of phenotypic heterogeneity, despite being generally thought of as simple Mendelian diseases. The reasons for this are not well understood, although the level of fetal hemoglobin (HbF) is one well characterized ameliorating factor in both of these conditions. To better understand the genetic basis of this heterogeneity, we carried out genome-wide scans with 362,129 common SNPs on 4,305 Sardinians to look for genetic linkage and association with HbF levels, as well as other red blood cell-related traits. Among major variants affecting HbF levels, SNP rs11886868 in the BCL11A gene was strongly associated with this trait (P < 10(-35)). The C allele frequency was significantly higher in Sardinian individuals with elevated HbF levels, detected by screening for beta-thalassemia, and patients with attenuated forms of beta-thalassemia vs. those with thalassemia major. We also show that the same BCL11A variant is strongly associated with HbF levels in a large cohort of sickle cell patients. These results indicate that BCL11A variants, by modulating HbF levels, act as an important ameliorating factor of the beta-thalassemia phenotype, and it is likely they could help ameliorate other hemoglobin disorders. We expect our findings will help to characterize the molecular mechanisms of fetal globin regulation and could eventually contribute to the development of new therapeutic approaches for beta-thalassemia and sickle cell anemia. C1 [Lettre, Guillaume; Sankaran, Vijay G.; Hirschhorn, Joel N.; Orkin, Stuart H.] Childrens Hosp, Boston, MA 02115 USA. [Uda, Manuela; Sanna, Serena; Usala, Gianluca; Busonero, Fabio; Maschio, Andrea; Albai, Giuseppe; Piras, Maria Grazia; Sestu, Natascia; Lai, Sandra; Dei, Mariano; Mulas, Antonella; Crisponi, Laura; Naitza, Silvia; Asunis, Isadora; Deiana, Manila; Perseu, Lucia; Cao, Antonio] Cittadella Univ Monserrato, Consiglio Natl Ric, Ist Neurogenet & Neurofarmacol, I-09042 Cagliari, Italy. [Galanello, Renzo; Satta, Stefania; Cipollina, Maria Dolores; Sollaino, Carla; Moi, Paolo] Univ Cagliar, Dipartimento Sci Biomed & Biotechnol, Osped Microcitem, Pediat Clin, I-09121 Cagliari, Italy. [Lettre, Guillaume; Hirschhorn, Joel N.] Broad Inst Harvard, Cambridge, MA 02142 USA. [Lettre, Guillaume; Hirschhorn, Joel N.] MIT, Cambridge, MA 02142 USA. [Sankaran, Vijay G.; Orkin, Stuart H.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Chen, Weimin; Abecasis, Goncalo R.] Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. [Nagaraja, Ramaiah; Schlessinger, David] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Orkin, SH (reprint author), Childrens Hosp, 300 Longwood Ave, Boston, MA 02115 USA. EM stuart_orkin@dfci.harvard.edu; acao@mcweb.unica.it RI Chen, Wei-Min/A-8469-2009; Abecasis, Goncalo/B-7840-2010; Naitza, Silvia/D-5620-2017; OI sanna, serena/0000-0002-3768-1749; MOI, Paolo/0000-0001-7879-8057; Mulas, Antonella/0000-0002-6856-1483; Abecasis, Goncalo/0000-0003-1509-1825 FU Intramural NIH HHS; NIA NIH HHS [N01-AG-1-2109]; PHS HHS [263-MA-410953] NR 40 TC 252 Z9 259 U1 2 U2 17 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 5 PY 2008 VL 105 IS 5 BP 1620 EP 1625 DI 10.1073/pnas.0711566105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 261KQ UT WOS:000253077900043 PM 18245381 ER PT J AU Datta, S Costantino, N Zhou, XM Court, DL AF Datta, Simanti Costantino, Nina Zhou, Xiaomei Court, Donald L. TI Identification and analysis of recombineering functions from Gram-negative and Gram-positive bacteria and their phages SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bacteriophage lambda; beta; oligonucleotide recombination; RecT; ssDNA annealing proteins ID ESCHERICHIA-COLI; ANNEALING PROTEINS; GENE REPLACEMENT; STRAND EXCHANGE; MISMATCH REPAIR; BETA-PROTEIN; LAMBDA; RECOMBINATION; DNA; OLIGONUCLEOTIDES AB We report the identification and functional analysis of nine genes from Gram-positive and Gram-negative bacteria and their phages that are similar to lambda (lambda) bet or Escherichia coli recT. Beta and RecT are single-strand DNA annealing proteins, referred to here as recombinases. Each of the nine other genes when expressed in E. coli carries out oligonucleotide-mediated recombination. To our knowledge, this is the first study showing single-strand recombinase activity from diverse bacteria. Similar to bet and recT, most of these other recombinases were found to be associated with putative exonuclease genes. Beta and RecT in conjunction with their cognate exonucleases carry out recombination of linear double-strand DNA. Among four of these foreign recombinase/exonuclease pairs tested for recombination with double-strand DNA, three had activity, albeit barely detectable. Thus, although these recombinases can function in E. coli to catalyze oligonucleotide recombination, the double-strand DNA recombination activities with their exonuclease partners were inefficient. This study also demonstrated that Gam, by inhibiting host RecBCD nuclease activity, helps to improve the efficiency of x Red-mediated recombination with linear double-strand DNA, but Gam is not absolutely essential. Thus, in other bacterial species where Gam analogs have not been identified, double-strand DNA recombination may still work in the absence of a Gam-like function. We anticipate that at least some of the recombineering systems studied here will potentiate oligonucleotide and double-strand DNA-mediated recombineering in their native or related bacteria. C1 [Datta, Simanti; Costantino, Nina; Zhou, Xiaomei; Court, Donald L.] NCI, Ctr Canc Res, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. RP Court, DL (reprint author), NCI, Ctr Canc Res, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. EM court@ncifcrf.gov FU Intramural NIH HHS NR 34 TC 79 Z9 81 U1 1 U2 23 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 FEB 5 PY 2008 VL 105 IS 5 BP 1626 EP 1631 DI 10.1073/pnas.0709089105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 261KQ UT WOS:000253077900044 PM 18230724 ER PT J AU Bhoumik, A Fichtman, B DeRossi, C Breitwieser, W Kluger, HM Davis, S Subtil, A Meltzer, P Krajewski, S Jones, N Ronai, Z AF Bhoumik, Anindita Fichtman, Boris DeRossi, Charles Breitwieser, Wolfgang Kluger, Harriet M. Davis, Sean Subtil, Antonio Meltzer, Paul Krajewski, Stan Jones, Nic Ronai, Ze'ev TI Suppressor role of activating transcription factor 2 (ATF2) in skin cancer SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE beta-catenin; keratinocyte; presenilin; cyclin D1; papilloma ID MOUSE SKIN; C-JUN; TUMOR PROMOTION; INDUCED TRANSFORMATION; RETINOIC ACID; IN-VIVO; PATHWAY; CELLS; MICE; GENE AB Activating transcription factor 2 (ATF2) regulates transcription in response to stress and growth factor stimuli. Here, we use a mouse model in which ATF2 was selectively deleted in keratinocytes. Crossing the conditionally expressed ATF2 mutant with K14-Cre mice (K14.ATF2(f/f)) resulted in selective expression of mutant ATF2 within the basal layer of the epidermis. When subjected to a two-stage skin carcinogenesis protocol [7,12-dimethylbenz[a]anthracene/phorbol 12-tetradecanoate 13-acetate (DMBA/TPA)], K14.ATF2(f/f) mice showed significant increases in both the incidence and prevalence of papilloma development compared with the WT ATF2 mice. Consistent with these findings, keratinocytes of K14.ATF2(f/f) mice exhibit greater anchorage-independent growth compared with ATF2 WT keratinocytes. Papillomas of K14.ATF2(f/f) mice exhibit reduced expression of presenilin1, which is associated with enhanced beta-catenin and cyclin D1, and reduced Notch1 expression. Significantly, a reduction of nuclear ATF2 and increased beta-catenin expression were seen in samples of squamous and basal cell carcinoma, as opposed to normal skin. Our data reveal that loss of ATF2 transcriptional activity serves to promote skin tumor formation, thereby indicating a suppressor activity of ATF2 in skin tumor formation. C1 [Bhoumik, Anindita; Fichtman, Boris; DeRossi, Charles; Krajewski, Stan; Ronai, Ze'ev] Burnham Inst Med Res, La Jolla, CA 92037 USA. [Breitwieser, Wolfgang; Jones, Nic] Univ Manchester, Paterson Inst Canc Res, Manchester M20 4BX, Lancs, England. [Kluger, Harriet M.] Yale Univ, Sch Med, Dept Med, New Haven, CT 06520 USA. [Kluger, Harriet M.] Yale Univ, Sch Med, Dept Dermatol, New Haven, CT 06520 USA. [Davis, Sean; Meltzer, Paul] NCI, Genet Branch, Ctr Canc Res, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Ronai, Z (reprint author), Burnham Inst Med Res, La Jolla, CA 92037 USA. EM ronai@burnham.org OI RONAI, ZEEV/0000-0002-3859-0400; Davis, Sean/0000-0002-8991-6458 FU NCI NIH HHS [R01 CA099961, CA099961] NR 43 TC 40 Z9 44 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 FEB 5 PY 2008 VL 105 IS 5 BP 1674 EP 1679 DI 10.1073/pnas.0706057105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 261KQ UT WOS:000253077900052 PM 18227516 ER PT J AU Haque, ME Thomas, KJ D'Souza, C Callaghan, S Kitada, T Slack, RS Fraser, P Cookson, MR Tandon, A Park, DS AF Haque, M. Emdadul Thomas, Kelly J. D'Souza, Cheryl Callaghan, Steve Kitada, Tohru Slack, Ruth S. Fraser, Paul Cookson, Mark R. Tandon, Anurag Park, David S. TI Cytoplasmic Pink1 activity protects neurons from dopaminergic neurotoxin MPTP SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Parkinson's disease; neurodegeneration; neuroprotection ID DROSOPHILA-PARKIN MUTANTS; MITOCHONDRIAL DYSFUNCTION; OXIDATIVE STRESS; DISEASE; MUTATIONS; APOPTOSIS; DEATH; PATHOGENESIS; PATHWAY; DAMAGE AB PTEN-induced putative kinase 1 (Pink1) is a recently identified gene linked to a recessive form of familial Parkinson's disease (PD). The kinase contains a mitochondrial localization sequence and is reported to reside, at least in part, in mitochondria. However, neither the manner by which the loss of Pink1 contributes to dopamine neuron loss nor its impact on mitochondrial function and relevance to death is clear. Here, we report that depletion of Pink1 by RNAi increased neuronal toxicity induced by MPP+. Moreover, wild-type Pink1, but not the G309D mutant linked to familial PD or an engineered kinase-dead mutant K219M, protects neurons against MPTP both in vitro and in vivo. Intriguingly, a mutant that contains a deletion of the putative mitochondrial-targeting motif was targeted to the cytoplasm but still provided protection against 1-methyl-4-phenylpyridine (MPP+)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity. In addition, we also show that endogenous Pink1 is localized to cytosolic as well as mitochondrial fractions. Thus, our findings indicate that Pink1 plays a functional role in the survival of neurons and that cytoplasmic targets, in addition to its other actions in the mitochondria, may be important for this protective effect. C1 [Haque, M. Emdadul; Callaghan, Steve; Slack, Ruth S.; Park, David S.] Univ Ottawa, Neurosci Grp, Ottawa Hlth Res Inst, Ottawa, ON K1H 8M5, Canada. [Thomas, Kelly J.; Cookson, Mark R.] NIA, Neurogenet Lab, Bethesda, MD 20892 USA. [Kitada, Tohru] Harvard Univ, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. [D'Souza, Cheryl; Fraser, Paul; Tandon, Anurag] Univ Toronto, Ctr Res Neurodegenerat Dis, Toronto, ON M5S 3H2, Canada. RP Park, DS (reprint author), Univ Ottawa, Neurosci Grp, Ottawa Hlth Res Inst, Ottawa, ON K1H 8M5, Canada. EM dpark@uottawa.ca RI Fraser, Paul/D-1755-2012 NR 38 TC 147 Z9 151 U1 0 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 5 PY 2008 VL 105 IS 5 BP 1716 EP 1721 DI 10.1073/pnas.0705363105 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 261KQ UT WOS:000253077900059 PM 18218782 ER PT J AU Hajduch, J Nam, G Kim, EJ Frohlich, R Hanover, JA Kirk, KL AF Hajduch, Jan Nam, Ghilsoo Kim, Eun Ju Froehlich, Roland Hanover, John A. Kirk, Kenneth L. TI A convenient synthesis of the C-1-phosphonate analogue of UDP-GlcNAc and its evaluation as an inhibitor of O-linked GlcNAc transferase (OGT) SO CARBOHYDRATE RESEARCH LA English DT Article DE O-GlcNAc transferase; N-acetylglucosamine; UDP-GlcNAc; phosphate isostere; OGT inhibition ID PHOSPHONATES; GLUCOSAMINE AB The C-1-phosphonate analogue of UDP-GlcNAc has been synthesized using an alpha-configured C-1-aldehyde as a key intermediate. Addition of the anion of diethyl phosphate to the aldehyde produced the hydroxyphosphonate. The configuration of this key intermediate was determined by X-ray crystallography. Deoxygenation, coupling of the resulting phosphonic acid with UMP and deprotection gave the target molecule as a di-sodium salt. This analogue had no detectable activity as an inhibitor of (OGT). (c) 2007 Elsevier Ltd. All rights reserved. C1 [Hajduch, Jan; Nam, Ghilsoo; Kirk, Kenneth L.] NIDDK, Bioorgan Chem Lab, DHHS, Natl Inst Hlth, Bethesda, MD 20892 USA. [Kim, Eun Ju; Hanover, John A.] NIDDK, Lab Cell Biochem & Biol, DHHS, Natl Inst Hlth, Bethesda, MD 20892 USA. [Froehlich, Roland] Univ Munster, Inst Organ Chem, D-4400 Munster, Germany. RP Kirk, KL (reprint author), NIDDK, Bioorgan Chem Lab, DHHS, Natl Inst Hlth, Bethesda, MD 20892 USA. EM kennethk@bdg8.niddk.nih.gov FU Intramural NIH HHS [Z01 DK031113-31] NR 32 TC 27 Z9 27 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD FEB 4 PY 2008 VL 343 IS 2 BP 189 EP 195 DI 10.1016/j.carres.2007.10.027 PG 7 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 260QZ UT WOS:000253026500003 PM 18039537 ER PT J AU Hou, SJ Saksena, R Kovac, P AF Hou, Shu-jie Saksena, Rina Kovac, Pavol TI Preparation of glycoconjugates by dialkyl squarate chemistry revisited SO CARBOHYDRATE RESEARCH LA English DT Article; Proceedings Paper CT 7th International Meeting of the Portuguese-Carbohydrate-Group (GLUPOR 7) CY SEP 12-15, 2007 CL Oieras, PORTUGAL SP Portuguese Carbohydrate Grp DE conjugate; neoglycoconjugate; squaric acid diester; 5-methoxycarbonyl-beta-lactoside; SELDI TOF-MS ID VIBRIO-CHOLERAE O-1; SEROTYPE OGAWA; SILVER TRIFLUOROMETHANESULFONATE; SYNTHETIC TETRASACCHARIDE; COUPLING REAGENT; DIETHYL SQUARATE; CARRIER PROTEIN; SERUM-ALBUMIN; ACID DIESTER; O-PS AB The methyl 6-hydroxyhexanoyl glycoside of lactose was treated with each of 1,2-diaminoethane or hydrazine hydrate, and the corresponding amino amide 4 and acyl hydrazide 13, were treated with each of squaric acid dimethyl, diethyl, dibutyl, and didecyl esters. The monoesters were conjugated to bovine serum albumin (BSA) at different concentrations of hapten using 0.05 and 0:5 M pH 9 borate buffer. Maximum loading was achieved faster, and the conjugation efficiency was higher, when the conjugation was conducted at higher concentrations of both hapten and buffer. Conjugations involving haptens 14-17 prepared from hydrazide 13 were generally slower and less efficient than those with compounds 5-8, which were made from amino amide 4. Maintaining pH 9 during conjugation was found to be the most important factor in ensuring that the conjugation was a fast, highly efficient, and reproducible process. When the pH of the conjugation mixture fell during the reaction, resulting in decreased reaction rate or even termination of the conjugation process, the normal course of the conjugation process could be restored by addition of buffer salts. Hydrolysis studies with monoesters formed from amino amide 4 under conjugation conditions showed that decyl ester 8 was the most stable and that the methyl compound 5 was the one most readily hydrolyzed. The stability of monoesters prepared from hydrazide 13 was similar and comparable to the decyl ester prepared from 4. No definite advantage was found for the use of any of the four dialkyl squarate reagents (methyl-, ethyl-, butyl-, and decyl-) for conversion of carbohydrate derivatives to species amenable for conjugation. Nevertheless, dimethyl squarate seemed to be the most convenient reagent because it is a crystalline, easy to handle, and commercially available material with very good reactivity. Published by Elsevier Ltd. C1 [Hou, Shu-jie; Saksena, Rina; Kovac, Pavol] NIDDK, LBC, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Kovac, P (reprint author), NIDDK, LBC, Natl Inst Hlth, Bethesda, MD 20892 USA. EM kpn@helix.nih.gov FU Intramural NIH HHS [Z01 DK059701-34] NR 38 TC 54 Z9 56 U1 4 U2 19 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0008-6215 J9 CARBOHYD RES JI Carbohydr. Res. PD FEB 4 PY 2008 VL 343 IS 2 BP 196 EP 210 DI 10.1016/j.carres.2007.10.015 PG 15 WC Biochemistry & Molecular Biology; Chemistry, Applied; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 260QZ UT WOS:000253026500004 PM 18048016 ER PT J AU Weecharangsan, W Opanasopit, P Ngawhirunpat, T Apirakaramwong, A Rojanarata, T Ruktanonchai, U Lee, RJ AF Weecharangsan, Wanlop Opanasopit, Praneet Ngawhirunpat, Tanasait Apirakaramwong, Auayporn Rojanarata, Theerasak Ruktanonchai, Uracha Lee, Robert J. TI Evaluation of chitosan salts as non-viral gene vectors in CHO-K1 cells SO INTERNATIONAL JOURNAL OF PHARMACEUTICS LA English DT Article DE chitosan salt; transfection efficiency; gene delivery; CHO-K1 cells ID MOLECULAR-WEIGHT; IN-VITRO; TRANSFECTION EFFICIENCY; DELIVERY-SYSTEM; DEACETYLATION; NANOPARTICLES; VIVO; DNA; ABSORPTION; OLIGOMERS AB The aim of this study was to investigate chitosan/DNA complexes formulated with various chitosan salts (CS) including chitosan hydrochloride (CHy), chitosan lactate (CLa), chitosan acetate (CAc), chitosan aspartate (CAs) and chitosan glutamate (CGI). They were assesed for their DNA complexing ability, transfection efficiency in CHO-K1 (Chinese hamster ovary) cells and their effect on cell viability. CHy, CLa, CAc, CAs and CGI, MW 45 kDa formed a complex with pcDNA3-CMV-Luc at various N/P ratios. CGI/DNA complexes were formulated with various chitosan molecular weights (20, 45, 200 and 460 kDa). The CS/DNA complexes were characterized by agarose gel electrophoresis and investigated for their transfection efficiency in CHO-K1 cells. The cytotoxicity of the complexes was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay in CHO-K1 cells. Gel electrophoresis illustrated that complete complexes formed at Nip ratios above 2 in all CS of MW 45 kDa. The transfection efficiency of CS/DNA complexes was dependent on the salt form and MW of chitosan, and the N/P ratio of CS/DNA complexes. Of different CS, the maximum transfection efficiency was found in different N/P ratios. CHy/DNA, CLa/DNA, CAc/DNA, CAs/DNA and CGI/DNA complexes showed maximum transfection efficiencies at N/P ratios of 12, 12, 8, 6 and 6, respectively. Cytotoxicity results showed that all CS/DNA complexes had low cytotoxicity. This study suggests CS have the potential to be used as safe gene delivery vectors. (c) 2007 Elsevier B.V. All rights reserved. C1 [Weecharangsan, Wanlop; Opanasopit, Praneet; Ngawhirunpat, Tanasait; Apirakaramwong, Auayporn; Rojanarata, Theerasak] Silpakorn Univ, Fac Pharm, Nanotechnol Drug Gene Delivery Syst Grp, Nakhon Pathom 73000, Thailand. [Ruktanonchai, Uracha] Natl Nanotechnol Ctr, Pathum Thani 12120, Thailand. [Lee, Robert J.] Ohio State Univ, Coll Pharm, NCI, OSU Comprehens Canc Ctr,NSF Nanoscales Sci & Engn, Columbus, OH 43210 USA. RP Opanasopit, P (reprint author), Silpakorn Univ, Fac Pharm, Dept Pharmaceut Technol, Nakhon Pathom 73000, Thailand. EM praneet@email.pharm.su.ac.th RI Ruktanonchai, Uracha/E-8893-2010 NR 25 TC 66 Z9 69 U1 0 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5173 J9 INT J PHARM JI Int. J. Pharm. PD FEB 4 PY 2008 VL 348 IS 1-2 BP 161 EP 168 DI 10.1016/j.ijpharm.2007.07.011 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 260UT UT WOS:000253036600020 PM 17714894 ER PT J AU Bikbulatov, RV Stewart, J Jin, WT Yan, F Roth, BL Ferreira, D Zjawiony, JK AF Bikbulatov, Ruslan V. Stewart, Jeremy Jin, Wentao Yan, Feng Roth, Bryan L. Ferreira, Daneel Zjawiony, Jordan K. TI Short synthesis of a novel class of salvinorin A analogs with hemiacetalic structure SO TETRAHEDRON LETTERS LA English DT Article DE salvinorin A; KOR ligands; hemiacetal; dual affinity ID MINT SALVIA-DIVINORUM; KAPPA-OPIOID RECEPTOR; NEOCLERODANE DITERPENES; SALVINICIN-A; AGONIST; POTENT AB Novel semisynthetic analogs of salvinorin A, a full agonist having extraordinary affinity as well as selectivity for the K-Opioid receptor (KOR), were obtained in good yields. The derivatives are remarkable for their unusual and unique hemiacetal structure in the salvinorin series of compounds. The formation of the hemiacetal occurs with epimerization at C-12, thus preserving the original configuration of salvinorin A. The dimethyl ester derivative of the hemiacetal was found to have an affinity for both KOR and MOR (mu-opioid receptor). (c) 2007 Elsevier Ltd. All rights reserved. C1 [Bikbulatov, Ruslan V.; Stewart, Jeremy; Jin, Wentao; Ferreira, Daneel; Zjawiony, Jordan K.] Univ Mississippi, Sch Pharm, Dept Pharmacognosy, University, MS 38677 USA. [Yan, Feng] Univ N Carolina, NIMH Psychoact Drug Screening Program, Dept Pharmacol, Sch Med, Chapel Hill, NC 27599 USA. [Yan, Feng; Roth, Bryan L.] Univ N Carolina, NIMH Psychoact Drug Screening Program, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. [Ferreira, Daneel; Zjawiony, Jordan K.] Univ Mississippi, Sch Pharm, Res Inst Pharmaceut Sci, Natl Ctr Nat Prod Res, University, MS 38677 USA. RP Zjawiony, JK (reprint author), Univ Mississippi, Sch Pharm, Dept Pharmacognosy, University, MS 38677 USA. EM jordan@olemiss.edu RI Roth, Bryan/F-3928-2010 FU NCRR NIH HHS [C06 RR014503]; NIDA NIH HHS [R01 DA017204, R01 DA017204-05] NR 23 TC 7 Z9 7 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4039 J9 TETRAHEDRON LETT JI Tetrahedron Lett. PD FEB 4 PY 2008 VL 49 IS 6 BP 937 EP 940 DI 10.1016/j.tetlet.2007.12.041 PG 4 WC Chemistry, Organic SC Chemistry GA 264IH UT WOS:000253280500001 PM 19197341 ER PT J AU Sedelnikova, OA Horikawa, I Redon, C Nakamura, A Zimonjic, DB Popescu, NC Bonner, WM AF Sedelnikova, Olga A. Horikawa, Izumi Redon, Christophe Nakamura, Asako Zimonjic, Drazen B. Popescu, Nicholas C. Bonner, William M. TI Delayed kinetics of DNA double-strand break processing in normal and pathological aging SO AGING CELL LA English DT Article DE aging; cellular senescence; DNA damage; DSB repair; gamma-H2AX; Werner syndrome ID WERNER-SYNDROME PROTEIN; ONCOGENE-INDUCED SENESCENCE; HEMATOPOIETIC STEM-CELLS; CELLULAR SENESCENCE; HISTONE H2AX; IN-VIVO; TELOMERE DYSFUNCTION; GENOMIC INSTABILITY; PROGEROID SYNDROMES; CHROMATIN-STRUCTURE AB Accumulation of DNA damage may play an essential role in both cellular senescence and organismal aging. The ability of cells to sense and repair DNA damage declines with age. However, the underlying molecular mechanism for this age-dependent decline is still elusive. To understand quantitative and qualitative changes in the DNA damage response during human aging, DNA damage-induced foci of phosphorylated histone H2AX (gamma-H2AX), which occurs specifically at sites of DNA double-strand breaks (DSBs) and eroded telomeres, were examined in human young and senescing fibroblasts, and in lymphocytes of peripheral blood. Here, we show that the incidence of endogenous gamma-H2AX foci increases with age. Fibroblasts taken from patients with Werner syndrome, a disorder associated with premature aging, genomic instability and increased incidence of cancer, exhibited considerably higher incidence of gamma-H2AX foci than those taken from normal donors of comparable age. Further increases in gamma-H2AX focal incidence occurred in culture as both normal and Werner syndrome fibroblasts progressed toward senescence. The rates of recruitment of DSB repair proteins to gamma-H2AX foci correlated inversely with age for both normal and Werner syndrome donors, perhaps due in part to the slower growth of gamma-H2AX foci in older donors. Because genomic stability may depend on the efficient processing of DSBs, and hence the rapid formation of gamma-H2AX foci and the rapid accumulation of DSB repair proteins on these foci at sites of nascent DSBs, our findings suggest that decreasing efficiency in these processes may contribute to genome instability associated with normal and pathological aging. C1 [Sedelnikova, Olga A.; Redon, Christophe; Nakamura, Asako; Bonner, William M.] NCI, NIH, Ctr Canc Res, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Horikawa, Izumi] NCI, NIH, Ctr Canc Res, Lab Biosyst & Canc, Bethesda, MD 20892 USA. [Zimonjic, Drazen B.; Popescu, Nicholas C.] NCI, NIH, Ctr Canc Res, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. RP Sedelnikova, OA (reprint author), NCI, NIH, Ctr Canc Res, Mol Pharmacol Lab, Bldg 37,Room 5050,9000 Rockville Pike, Bethesda, MD 20892 USA. EM sedelnio@mail.nih.gov FU Intramural NIH HHS NR 65 TC 108 Z9 110 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1474-9718 J9 AGING CELL JI Aging Cell PD FEB PY 2008 VL 7 IS 1 BP 89 EP 100 DI 10.1111/j.1474-9726.2007.00354.x PG 12 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 252IN UT WOS:000252440300010 PM 18005250 ER PT J AU Di Bari, M Pecchioli, A Mazzaglia, G Marini, M Maciocco, G Ferrucci, L Marchionni, N AF Di Bari, Mauro Pecchioli, Alessandro Mazzaglia, Giampiero Marini, Monica Maciocco, Gavino Ferrucci, Luigi Marchionni, Niccolo TI Care available to severely disabled older persons living at home in Florence, Italy SO AGING CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE disability; healthcare; home-bound elderly; ASSI survey ID RANDOMIZED CONTROLLED-TRIAL; CAREGIVER; HEALTH; INSTRUMENTS; PROJECT; ADULTS AB Aims: To characterize the epidemiology of disability in, and the level of care available to, older community-dwellers in an Italian urban sample. Methods: In a 2-phase survey, persons aged 65+ years, randomly selected from the patients lists of 98 primary care physicians (PCP), were screened (phase I) by their PCP with a structured questionnaire to detect the presence of: 1) need of help in performing Basic and 2) Instrumental Activities of Daily Living (BADL, IADL); 3) poor vision or 4) hearing; 5)weight loss; 6) use of homecare services; 7) self-perceived inadequacy of income. Subjects reporting 2+ problems were further evaluated in face-to-face structured interviews (phase II), Results: Of 5445 participants, 597 (11%) screened positive in phase I and 416 were interviewed in phase II. Of these, 4, 29, 19 and 49% were disabled in 1-2 IADL, 3+ IADL, 1-2 BADL, and 3+ BADL. The extent of the support network increased with disability severity (p<0.01). The 274 participants with BADL disability received most of their help from close relatives (58.3 +/- 2.5%), followed by salaried assistants (20.5 +/- 2.1%), other relatives (19.5 +/- 1.9%), and public healthcare services (0.6 +/- 0.36%). Of the 397 care-givers interviewed, one-third were willing to institutionalize the older participants in case of further functional deterioration. This propensity was predicted only by a self-reported poor attitude towards caring. Conclusion: Many severely disabled older Italians receive care in their home by highly supportive family members. The level of assistance provided to them by public healthcare services is minimal. C1 [Di Bari, Mauro; Marini, Monica; Marchionni, Niccolo] Univ Florence, Dept Crit Care Med & Surg, Unit Gerontol & Geriatr, I-50141 Florence, Italy. [Di Bari, Mauro; Marini, Monica; Marchionni, Niccolo] Azienda Osped Univ Careggi, Florence, Italy. [Pecchioli, Alessandro; Maciocco, Gavino] Univ Florence, Dept Publ Hlth, I-50121 Florence, Italy. [Mazzaglia, Giampiero] Reg Agcy Healthcare Serv Tuscany, Florence, Italy. [Ferrucci, Luigi] NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD USA. RP Di Bari, M (reprint author), Univ Florence, Dept Crit Care Med & Surg, Unit Gerontol & Geriatr, Via Oblate 4, I-50141 Florence, Italy. EM dibari@unifi.it RI DI BARI, MAURO/J-1524-2012 FU Intramural NIH HHS [Z99 AG999999] NR 20 TC 5 Z9 5 U1 0 U2 1 PU EDITRICE KURTIS S R L PI MILAN PA VIA LUIGI ZOJA 30, 20153 MILAN, ITALY SN 1594-0667 J9 AGING CLIN EXP RES JI Aging Clin. Exp. Res. PD FEB PY 2008 VL 20 IS 1 BP 31 EP 39 PG 9 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 270NE UT WOS:000253726700006 PM 18283226 ER PT J AU Mannheimer, S Thackeray, L Hullsiek, KH Chesney, M Gardner, EM Wu, AW Telzak, EE Lawrence, J Baxter, J Friedland, G AF Mannheimer, S. Thackeray, L. Hullsiek, K. Huppler Chesney, M. Gardner, E. M. Wu, A. W. Telzak, E. E. Lawrence, J. Baxter, J. Friedland, G. CA Terry Beirn Community Program Clin TI A randomized comparison of two instruments for measuring self-reported antiretroviral adherence SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article ID STRUCTURED TREATMENT INTERRUPTION; HUMAN-IMMUNODEFICIENCY-VIRUS; CLINICAL-TRIALS; VIROLOGICAL RESPONSE; PROTEASE INHIBITORS; THERAPY ADHERENCE; MEDICATION; HIV-1; NONADHERENCE; POPULATION AB A randomised trial compared two instruments for assessing self-reported adherence to antiretroviral medications: (1) a day-by-day recall instrument that elicited the number of missed doses in each of the prior three days (3-day instrument; n=64) and (2) a general recall instrument that elicited an estimate of proportion of pills taken during the prior seven days (7-day instrument; n=70). Adherence was measured at study visits over 12 months among participants in a clinical trial assessing treatment strategies for individuals with virologic failure and multidrug-resistant HIV. Participants had a median (interquartile range) of 133 (41-264) CD4 cells/ml(3) and a median of 10 major HIV resistance mutations at baseline. Mean adherence levels were 90-98% throughout the study. There was a greater trend in the likelihood of 100% adherence when measured by the 3-day versus the 7-day instrument (odds ratio (OR)=1.45; p=0.06). The likelihood of consistent 100% adherence measured by either instrument decreased over time (p<0.001). Participants reporting 100% adherence at more than half of study visits had better virologic and immunologic outcomes at month-12 compared to those reporting 100% adherence at half or fewer visits (HIV RNA decline of 0.96 versus 0.51 log, respectively, p=0.02; and CD4 cell increase of 51.0 versus 17.8 cells, p=0.04). This study demonstrated the utility of the general 7-day recall adherence self-report instrument as well as the 3-day day-by-day recall adherence self-report instrument for measuring antiretroviral adherence. Self-reported adherence was significantly associated with virologic and immunologic outcomes in this population with advanced drug-resistant HIV disease. C1 [Mannheimer, S.] Columbia Univ Coll Phys & Surg, Harlem Hosp Ctr, Div Infect Dis, New York, NY 10032 USA. [Thackeray, L.; Hullsiek, K. Huppler] Univ Minnesota, Div Biostat, Minneapolis, MN USA. [Chesney, M.] NIH, Div Extramural Res & Training, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. [Gardner, E. M.] Univ Colorado, Div Infect Dis, Denver, CO 80202 USA. [Gardner, E. M.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Wu, A. W.] Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. [Wu, A. W.] Johns Hopkins Univ, Dept Med, Baltimore, MD USA. [Telzak, E. E.] Dept Med, New York, NY USA. [Telzak, E. E.] Dept Epidemiol & Populat Hlth, New York, NY USA. [Telzak, E. E.] Albert Einstein Coll Med, New York, NY USA. [Telzak, E. E.] Bronx Lebanon Hosp Ctr, New York, NY USA. [Lawrence, J.] Univ Calif San Francisco, San Francisco Gen Hosp, Posit Hlth Program, Dept Med, San Francisco, CA 94143 USA. [Baxter, J.] Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Cooper Univ Hosp, Div Infect Dis, Camden, NJ 08103 USA. [Friedland, G.] Yale Univ, Yale New Haven Hosp, Yale Sch Med, New Haven, CT USA. RP Mannheimer, S (reprint author), Columbia Univ, Harlem Hosp, Div Infect Dis, New York, NY 10027 USA. EM sbm20@columbia.edu NR 29 TC 32 Z9 33 U1 0 U2 4 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD FEB PY 2008 VL 20 IS 2 BP 161 EP 169 DI 10.1080/09540120701534699 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 267JH UT WOS:000253504800004 PM 18293124 ER PT J AU Selvarajah, S Puffer, BA Lee, FH Zhu, P Li, YX Wyatt, R Roux, KH Doms, RW Burton, DR AF Selvarajah, Suganya Puffer, Bridget A. Lee, Fang-Hua Zhu, Ping Li, Yuxing Wyatt, Richard Roux, Kenneth H. Doms, Robert W. Burton, Dennis R. TI Focused dampening of antibody response to the immunodominant variable loops by engineered soluble gp140 SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODY; ENVELOPE GLYCOPROTEIN TRIMERS; ELICIT NEUTRALIZING ANTIBODIES; 2ND HYPERVARIABLE REGION; CD4 BINDING-SITE; TYPE-1 HIV-1; PARTIAL DELETION; MONOMERIC GP120; IMMUNE-RESPONSES AB Immunization studies with modified gp120 monomers using a hyperglycosylation strategy, in which undesired epitopes are masked by the selective incorporation of N-linked glycans, were described in a previous paper (Selvarajah S, et al., J Virol 2000; 79: 12148-12163). In this report, we applied the hyperglycosylation strategy to soluble uncleaved gp140 trimers to improve the antigenic and immunogenic profile in the context of a trimeric conformation of the immunogen. The JR-FL gp140 gene was added upstream of a soluble trimerization domain of chicken cartilage matrix (CART) protein and expressed predominantly as a trimer and called gp140-CART wild-type. In the hyperglycosylated gp140-CART mCHO(V) mutant, four extra sugar attachment motifs on the variable loops helped mask epitope recognition by monoclonal antibodies specific to the variable loops. The gp140-CART mCHO(V) mutant and gp140-CART wild-type soluble trimer protein were used to immunize rabbits. The gp140-CART mCHO(V) immune sera had reduced antibody response to the variable loops compared to gp140-CART wild-type immune sera as shown by peptide reactivity, competition assays, and the reduced ability of sera to neutralize SF162 virus (a variable loop neutralization-sensitive virus). The antibody response to the CD4 binding site was retained in the gp140-CART mCHO(V) mutant immune sera similar to gp140-CART wild-type immune sera. The results demonstrate that the strategy of hyperglycosylation is clearly useful in the context of a compact form of Env immunogen such as the soluble gp140 trimer in dampening responses to variable loops while maintaining responses to an important epitope, the CD4 binding site. However, the results also show that in order to elicit broadly neutralizing antibodies that target conserved epitopes, the soluble gp140 trimer immunogen template will require further modifications. C1 [Selvarajah, Suganya; Burton, Dennis R.] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. [Selvarajah, Suganya; Burton, Dennis R.] Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. [Puffer, Bridget A.; Lee, Fang-Hua; Doms, Robert W.] Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. [Zhu, Ping; Roux, Kenneth H.] Florida State Univ, Dept Biol Sci, Tallahassee, FL 32306 USA. [Zhu, Ping; Roux, Kenneth H.] Florida State Univ, Inst Mol Biophys, Tallahassee, FL 32306 USA. [Li, Yuxing; Wyatt, Richard] NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Burton, DR (reprint author), Scripps Res Inst, Dept Immunol IMM 2, 10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM burton@scripps.edu FU NIAID NIH HHS [AI055461, AI060425, AI33292] NR 68 TC 23 Z9 23 U1 1 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD FEB PY 2008 VL 24 IS 2 BP 301 EP 314 DI 10.1089/aid.2007.0158 PG 14 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 268PI UT WOS:000253591300022 PM 18284327 ER PT J AU Rodd, ZA Oster, SM Ding, ZM Toalston, JE Deehan, G Bell, RL Li, TK McBride, WJ AF Rodd, Zachary A. Oster, Scott M. Ding, Zheng-Ming Toalston, Jamie E. Deehan, Gerald Bell, Richard L. Li, Ting-Kai McBride, William J. TI The reinforcing properties of salsolinol in the ventral tegmental area: Evidence for regional heterogeneity and the involvement of serotonin and dopamine SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE salsolinol; intracranial self-administration; ventral tegmental area; serotonin-3 receptors; reinforcement ID ALCOHOL-PREFERRING RATS; WISTAR RATS; NUCLEUS-ACCUMBENS; CHRONIC ETHANOL; INVIVO MICRODIALYSIS; P RATS; ACETALDEHYDE; ALKALOIDS; NEURONS; BRAIN AB Background: Salsolinol (SAL), the condensation product of acetaldehyde and dopamine, may be a factor contributing to alcohol abuse. Previous research indicated that both ethanol and acetaldehyde are self-administered into the posterior ventral tegmental area (VTA). The current study examined SAL self-infusions into the VTA, and determined the involvement of dopamine neurons and 5-HT3 receptors in this process. Methods: The intracranial self-administration technique was used to determine the self-infusion of SAL into the VTA of adult, male Wistar rats. The rats were placed in 2-lever (active and inactive) experimental chambers, and allowed to respond for the self-infusion of 0, 0.03, 0.1, 0.3, 1.0 or 3.0 mu M SAL into the posterior or anterior VTA. In a second experiment, rats self-administered 0.3 mu M SAL for the initial 4 sessions, co-administered SAL with ICS-205,930 (a 5-HT3 receptor antagonist) or quinpirole (a D-2,D-3 receptor agonist) for sessions 5 and 6, and then only 0.3 mu M SAL for session 7. Results: Wistar rats, given 0.03 to 0.3 mu M SAL, received more infusions per session than did the group given artificial cerebrospinal fluid (aCSF) alone (e.g., 41 infusions for 0.1 mu M SAL versus 9 infusions for the aCSF group), and responded more on the active than inactive lever. These effects were observed in the posterior but not in anterior VTA. Co-infusion of 100 mu M ICS-205,930, or quinpirole significantly reduced self-infusions and active lever responding. Conclusions: SAL produces reinforcing effects in the posterior VTA of Wistar rats, and these effects are mediated by activation of DA neurons and local 5-HT3 receptors. C1 [Rodd, Zachary A.; Oster, Scott M.; Ding, Zheng-Ming; Toalston, Jamie E.; Deehan, Gerald; Bell, Richard L.; McBride, William J.] Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, Indianapolis, IN 46202 USA. [Oster, Scott M.; Toalston, Jamie E.] Indiana Univ Purdue Univ, Dept Psychol, Purdue Sch Sci, Indianapolis, IN 46202 USA. [Deehan, Gerald] Kansas State Univ, Dept Psychol, Manhattan, KS 66506 USA. [Li, Ting-Kai] NIAAA, Bethesda, MD USA. RP Rodd, ZA (reprint author), Indiana Univ, Sch Med, Inst Psychiat Res, Dept Psychiat, 791 Union Dr, Indianapolis, IN 46202 USA. EM zrodd@iupui.edu RI Rodd, Zachary/L-1580-2015; OI Rodd, Zachary/0000-0002-8105-1920; Toalston, Jamie/0000-0001-5115-6644 FU NIAAA NIH HHS [AA14437] NR 44 TC 39 Z9 40 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2008 VL 32 IS 2 BP 230 EP 239 DI 10.1111/j.1530-0277.2007.00572.x PG 10 WC Substance Abuse SC Substance Abuse GA 254KY UT WOS:000252586700008 PM 18162075 ER PT J AU Farkouh, ME Dangas, G Leon, MB Smith, C Nesto, R Buse, JB Cohen, DJ Mahoney, E Sleeper, L King, S Domanski, M McKinlay, S Fuster, V AF Farkouh, Michael E. Dangas, George Leon, Martin B. Smith, Craig Nesto, Richard Buse, John B. Cohen, David J. Mahoney, Elizabeth Sleeper, Lynn King, Spencer, III Domanski, Michael McKinlay, Sonja Fuster, Valentin TI Design of the Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease (FREEDOM) trial SO AMERICAN HEART JOURNAL LA English DT Article ID QUALITY-OF-LIFE; TRANSLUMINAL CORONARY ANGIOPLASTY; DRUG ELUTING STENTS; CLINICAL-TRIALS; BYPASS-SURGERY; ARTERY DISEASE; HEALTH; RANDOMIZATION AB Background Prior randomized trials suggested that revascularization of diabetic patients by coronary artery bypass grafting (CABG) produced results superior to balloon angioplasty. The introduction of drug-eluting stents (DESs) calls into question the relevance of past studies to the current era. The FREEDOM Trial is designed to determine whether CABG or percutoneous coronary intervention (PCI) is the superior approach for revascularization of diabetic patients. Study Design The FREEDOM Trial is a multicenter, open-label prospective randomized superiority trial of PCI versus CABG in at least 2000 diabetic patients in whom revascularization is indicated. Consenting diabetic patients with multivessel disease will be randomized on a 1: 1 basis to either CABG or multivessel stenting using DESs and observed at 30 days, 1 year, and annually for up to 5 years. At the discretion of the primary physician or interventionalists, patients randomized to the PCI/DES arm will receive any approved DESs. The primary outcome measure is the composite of all-cause mortality, nonfatal myocardial infarction, or stroke. Patients will be observed for a mean of 4 years. Implications At present, coronary revascularization with CABG surgery is the treatment of choice in diabetic patients with multivessel coronary artery disease. Drug-eluting stents have shown promising preliminary results in the diabetic population. The FREEDOM Trial is an international study designed to define the optimal revascularization strategy for the diabetic patient with multivessel coronary disease. C1 [Farkouh, Michael E.; Fuster, Valentin] Mt Sinai Sch Med, New York, NY 10029 USA. [Dangas, George; Leon, Martin B.; Smith, Craig] Columbia Univ, Med Ctr, New York, NY USA. [Nesto, Richard] Lahey Clin Med Ctr, Burlington, MA 01803 USA. [Buse, John B.] Univ N Carolina, Chapel Hill, NC USA. [Cohen, David J.; Mahoney, Elizabeth] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [King, Spencer, III] Piedmont Hosp, Fuqua Heart Ctr, Atlanta, GA USA. [Domanski, Michael] NHLBI, Bethesda, MD 20892 USA. [Fuster, Valentin] New England Res Inst, Watertown, MA 02172 USA. RP Farkouh, ME (reprint author), Mt Sinai Sch Med, 1 Gustave L Levy Pl,Box 1074, New York, NY 10029 USA. EM michael.forkouh@mssm.edu RI Fuster, Valentin/H-4319-2015 OI Fuster, Valentin/0000-0002-9043-9986 FU NHLBI NIH HHS [5U01HL071988] NR 21 TC 114 Z9 114 U1 0 U2 7 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD FEB PY 2008 VL 155 IS 2 BP 215 EP 223 DI 10.1016/j.ahj.2007.10.012 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 257QE UT WOS:000252812800005 PM 18215589 ER PT J AU Levitzky, YS Cupples, LA Murabito, JM Kannel, WB Kiel, DP Wilson, PWF Wolf, PA O'Donnell, CJ AF Levitzky, Yammi S. Cupples, L. Adrienne Murabito, Joanne M. Kannel, William B. Kiel, Douglas P. Wilson, Peter W. F. Wolf, Philip A. O'Donnell, Christopher J. TI Prediction of intermittent claudication, ischemic stroke, and other cardiovascular disease by detection of abdominal aortic calcific deposits by plain lumbar radiographs SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; SURVIVAL ANALYSIS; NATURAL-HISTORY; RISK-FACTORS; FRAMINGHAM; ATHEROSCLEROSIS; ROTTERDAM; MORTALITY; DISCRIMINATION; CLASSIFICATION AB There has been little attention to vascular calcium testing for generalized assessment of cardiovascular disease (CVD) outcomes, such as intermittent claudication (IC) and ischemic stroke (IS). We hypothesize that aortic calcium is an important predictor of CVD outcomes. Lumbar x-rays were obtained in 848 men and 1,301 women (mean ages 59.7 and 60.1 years, respectively) from the original cohort of the Framingham Heart Study. Abdominal aortic calcium (AAC) deposits were graded using a previously validated scale. Participants were categorized according to a 10-year Framingham coronary heart disease (CHD) risk score. Multivariable Cox proportional hazards analyses were performed to relate AAC to CVD outcomes. There were 199 IC events, 201 IS events, 702 CHD events, and 1,121 CVD events' during 32 years of follow-up. Multivariable adjusted hazard ratios for the third versus first AAC tertile in the combined cohort were 1.68 (95 % confidence interval [CI] 1.12 to 2.50) for IC, 1.73 (95% CI 1.12 to 2.65) for IS, 1.59 (95% CI 1.26 to 2.00) for CHD, and 1.64 (95% CI 1.37 to 1.97) for CVD. Hazard ratios for IC and IS were similar in magnitude to those for CHD and CVD. A high AAC score was associated with significantly higher incidence of events in subjects at intermediate Framingham CHD risk for all end points. Risk prediction based on cardiovascular risk factors improved for most outcomes when AAC was added. In conclusion, there was a graded, increasing, and independent association of AAC with incident IC and IS, similar in magnitude to risks predicted for CHD and CVD. AAC appears to be useful for risk stratification in patients at intermediate CHD risk. (c) 2008 Elsevier Inc. All rights reserved. C1 [Levitzky, Yammi S.; Murabito, Joanne M.; Kannel, William B.; Wolf, Philip A.; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Cupples, L. Adrienne] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Wolf, Philip A.] Boston Univ, Sch Med, Dept Neurol, Boston, MA 02215 USA. [Wolf, Philip A.] Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02215 USA. [Wolf, Philip A.] Boston Univ, Sch Med, Dept Epidemiol, Boston, MA 02215 USA. [Murabito, Joanne M.] Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02215 USA. [Kiel, Douglas P.] Harvard Univ, Sch Med, Inst Aging Res Hebrew SeniorLife, Massachusetts Gen Hosp, Boston, MA 02115 USA. [O'Donnell, Christopher J.] Harvard Univ, Sch Med, Div Cardiol, Massachusetts Gen Hosp, Boston, MA 02115 USA. [Wilson, Peter W. F.] Emory Univ, Sch Med, Div Cardiol, Atlanta, GA 30322 USA. RP O'Donnell, CJ (reprint author), NHLBI, Framingham Heart Study, Framingham, MA USA. EM odonnellc@nhlbi.nih.gov OI Cupples, L. Adrienne/0000-0003-0273-7965; Murabito, Joanne/0000-0002-0192-7516; Kiel, Douglas/0000-0001-8474-0310 FU NHLBI NIH HHS [N01-HC-38038]; NIA NIH HHS [R01 AR/AG 41398]; NINDS NIH HHS [2R01 NS017950] NR 28 TC 27 Z9 27 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206 STE 3, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 1 PY 2008 VL 101 IS 3 BP 326 EP 331 DI 10.1016/j.amjcard.2007.08.032 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 259EY UT WOS:000252923100010 PM 18237594 ER PT J AU Koska, J Stefan, N Permana, PA Weyer, C Sonoda, M Bogardus, C Smith, SR Joanisse, DR Funahashi, T Krakoff, J Bunt, JC AF Koska, Juraj Stefan, Norbert Permana, Paska A. Weyer, Christian Sonoda, Mina Bogardus, Clifton Smith, Steven R. Joanisse, Denis R. Funahashi, Tohru Krakoff, Jonathan Bunt, Joy C. TI Increased fat accumulation in liver may link insulin resistance with subcutaneous abdominal adipocyte enlargement, visceral adiposity, and hypoadiponectinemia in obese individuals SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE obesity; adipocyte size; adiponectin; intrahepatic fat; intramyocellular fat; insulin action ID ACTIVATED PROTEIN-KINASE; CELL SIZE; SKELETAL-MUSCLE; PIMA-INDIANS; PLASMA ADIPONECTIN; METABOLIC SYNDROME; HEPATIC STEATOSIS; GLUCOSE-UPTAKE; SENSITIVITY; TISSUE AB Background: Enlargement of adipocytes from subcutaneous abdominal adipose tissue (SAT), increased intrahepatic lipid content (IHL), intramyocellular lipid content (IMCL), and low circulating adiponectin concentrations are associated with insulin resistance. Objective: Because adiponectin increases fat oxidation in skeletal muscle and liver, and the expression of the adiponectin gene in SAT is inversely associated with adipocyte size, we hypothesized that hypoadiponectinemia links hypertrophic obesity with insulin resistance via increased IMCL and IHL. Design: Fifty-three obese Pima Indians with a mean ( +/- SD) age of 27 +/- 8 y, body fat of 35 +/- 5%, and normal glucose regulation (normal fasting and 2-h glucose concentration per WHO 1999 criteria) underwent euglycemic-hyperinsulinemic clamp, biopsies of SAT and vastus lateral is muscle, and magnetic resonance imaging of the abdomen. Results: Adipocyte diameter (AD) correlated positively with body fat (P < 0.0001) and IHL (estimated from magnetic resonance imaging intensity of liver; P = 0.047). No association was found between AD and plasma adiponectin or IMCL. Plasma adiponectin negatively correlated with type 11 IMCL (IIA, P = 0.004; IIX, P = 0.009) or IHL (P = 0.02). In a multivariate analysis, plasma adiponectin, AD, and visceral adipose tissue (VAT) independently predicted IHL. Low insulin-mediated glucose disposal was associated with low plasma adiponectin (P = 0.02) and high IHL (P = 0.0003), SAT (P = 0.02), and VAT (P = 0.04). High IHL was the only predictor of reduced insulin-mediated suppression of hepatic glucose production (P = 0.02) and the only independent predictor of insulin-mediated glucose disposal in a multivariate analysis. Conclusions: Increased lipid content in the liver may independently link hypoadiponectinemia, hypertrophic obesity, and increased visceral adiposity with peripheral and hepatic insulin resistance. C1 [Koska, Juraj; Stefan, Norbert; Weyer, Christian; Bogardus, Clifton; Krakoff, Jonathan; Bunt, Joy C.] NIDDKD, NIH, DHHS, ODCRS, Phoenix, AZ 85016 USA. [Permana, Paska A.] Carl T Hayden Vet Affaris Med Ctr, Phoenix, AZ USA. [Sonoda, Mina; Funahashi, Tohru] Osaka Univ, Dept Internal Med & Mol Sci, Grad Sch Med, Osaka, Japan. [Smith, Steven R.] Pennington Biomed Res Ctr, Baton Rouge, LA USA. [Joanisse, Denis R.] Univ Laval, Dept Kinesiol, Quebec City, PQ, Canada. RP Krakoff, J (reprint author), NIDDKD, NIH, DHHS, ODCRS, 4212 N 16Th St, Phoenix, AZ 85016 USA. EM jkrakoff@mail.nih.gov OI Joanisse, Denis R./0000-0001-9699-0616 FU Intramural NIH HHS NR 46 TC 63 Z9 64 U1 0 U2 2 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB PY 2008 VL 87 IS 2 BP 295 EP 302 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 260KR UT WOS:000253009700005 PM 18258617 ER PT J AU Swanson, CA Liu, QY AF Swanson, Christine A. Liu, Qi-Ying TI Introduction to the national institutes of health botanical research centers program SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material C1 [Swanson, Christine A.] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Liu, Qi-Ying] NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Swanson, CA (reprint author), NIH, Off Dietary Supplements, Room 3B01,MSC 7517,6100 Execut Blvd, Bethesda, MD 20892 USA. EM swansonc@od.nih.gov NR 4 TC 4 Z9 5 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 FEB PY 2008 VL 87 IS 2 BP 471S EP 471S PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 260KR UT WOS:000253009700029 PM 18258640 ER PT J AU Farnsworth, NR Krause, EC Bolton, JL Pauli, GF van Breemen, RB Graham, JG AF Farnsworth, Norman R. Krause, Elizabeth C. Bolton, Judy L. Pauli, Guido F. van Breemen, Richard B. Graham, James G. TI The university of Illinois at Chicago/National institutes of health center for botanical dietary supplements research for women's health: from plant to clinical use SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT 63rd Annual Meeting of the Japan-Neurosurgical-Society CY OCT 07, 2004 CL Nagoya, JAPAN SP Japan Neurosurg Soc DE black cohosh; botanical dietary supplements; menopause; multidisciplinary research ID HOPS HUMULUS-LUPULUS; CLOVER TRIFOLIUM-PRATENSE; TANDEM MASS-SPECTROMETRY; MIXED COMPETITIVE LIGAND; VITEX-AGNUS-CASTUS; MU-OPIATE RECEPTOR; INDUCED DNA-DAMAGE; CIMICIFUGA-RACEMOSA; BLACK COHOSH; ANGELICA-SINENSIS AB The University of Illinois at Chicago/National Institutes of Health Center for Botanical Dietary Supplements Research began in 1999 with an emphasis on botanical dietary supplements for women's health. We have concentrated on plants that may improve women's health, especially to reduce hot flashes in menopausal women, alleviate the symptoms of premenstrual syndrome, and reduce persistent urinary tract infections. The primary focus of this article is to describe the operation of our center, from acquiring and identifying botanicals to isolating and identifying active constituents, to elucidating their mechanisms of action, and to conducting phase I and phase II clinical studies. Black cohosh (Actaea racemosa; syn Cimicifuga racemosa) has been used as a model to illustrate the steps involved in taking this plant from the field to clinical trials. Bioassays are described that were necessary to elucidate the pertinent biological studies of plant extracts and their mechanisms of action. We conclude that this type of research can only be successful with the use of a multidisciplinary approach. C1 [Farnsworth, Norman R.; Krause, Elizabeth C.; Bolton, Judy L.; Pauli, Guido F.; van Breemen, Richard B.; Graham, James G.] Univ Illinois, Coll Pharm, Program Collaborat Res Pharmaceut Sci MC 877, NIH,Ctr Bot Dietary Supplements Res,Dept Med Chem, Chicago, IL 60612 USA. RP Farnsworth, NR (reprint author), Univ Illinois, Coll Pharm, Program Collaborat Res Pharmaceut Sci MC 877, NIH,Ctr Bot Dietary Supplements Res,Dept Med Chem, 833 S Wood St, Chicago, IL 60612 USA. EM norman@uic.edu FU NCCIH NIH HHS [R21 AT001868, P50 AT000155, K01 AT002321] NR 36 TC 12 Z9 12 U1 0 U2 7 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 FEB PY 2008 VL 87 IS 2 BP 504S EP 508S PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 260KR UT WOS:000253009700036 PM 18258647 ER PT J AU van Breemen, RB Fong, HHS Farnsworth, NR AF van Breemen, Richard B. Fong, Harry H. S. Farnsworth, Norman R. TI Ensuring the safety of botanical dietary supplements SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article; Proceedings Paper CT 63rd Annual Meeting of the Japan-Neurosurgical-Society CY OCT 07, 2004 CL Nagoya, JAPAN SP Japan Neurosurg Soc DE safety; toxicity; botanical dietary supplements; complementary and alternative medicine; hepatoxicity; metabolic activation ID FOOD SUPPLEMENTS; PC-SPES; IDENTIFICATION; NOMENCLATURE; METABOLITES; LIVER; RAPD AB Botanical dietary supplements with a history of safe human use may not require the same level of toxicity testing as synthetic pharmaceutical drugs. Most of the documented examples of acute toxicity caused by botanical dietary supplements have been caused by the substitution of toxic plants for the desired species, probably through misidentification or production errors, or by contamination with pharmaceutical agents, either as a result of poor manufacturing practices or adulteration. Although more difficult to document, chronic toxicities attributed to botanical dietary supplements may be caused by contamination by heavy metals, pesticides, or microbes or by inherent properties of constituents of the botanicals themselves. Like drug-drug interactions, botanical-drug interactions can also be a source of toxicity. Most of these toxicity problems may be prevented by implementing good agricultural practices and good manufacturing practices and applying existing toxicity testing similar to those used in drug development or new toxicity assays under development based on proteomics, genomics, or metabolomics. C1 [van Breemen, Richard B.; Fong, Harry H. S.; Farnsworth, Norman R.] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, NIH,Ctr Bot Dietary Supplements Res, Chicago, IL 60612 USA. RP van Breemen, RB (reprint author), Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, NIH,Ctr Bot Dietary Supplements Res, 833 S Wood St,MC 781, Chicago, IL 60612 USA. EM breemen@uic.edu FU NCCIH NIH HHS [P50 AT00155] NR 23 TC 33 Z9 33 U1 0 U2 13 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 FEB PY 2008 VL 87 IS 2 BP 509S EP 513S PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 260KR UT WOS:000253009700037 PM 18258648 ER PT J AU Sun, Y Vestergaard, M Pedersen, CB Christensen, J Basso, O Olsen, J AF Sun, Yuelian Vestergaard, Mogens Pedersen, Carsten B. Christensen, Jakob Basso, Olga Olsen, Jorn TI Gestational age, birth weight, intrauterine growth, and the risk of epilepsy SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE birth weight; Denmark; epilepsy; follow-up studies; infant; small for gestational age; premature birth; siblings ID NATIONAL-HOSPITAL-REGISTER; CEREBRAL-PALSY; POSTTERM DELIVERY; POPULATION; SEIZURES; CHILDREN; PRETERM; COHORT; CHILDHOOD; 1ST AB The authors evaluated the association between gestational age, birth weight, intrauterine growth, and epilepsy in a population-based cohort of 1.4 million singletons born in Denmark (1979-2002). A total of 14,334 inpatients (1979-2002) and outpatients (1995-2002) with epilepsy were registered in the Danish National Hospital Register. Children who were potentially growth restricted were identified through two methods: 1) sex-, birth-order-, and gestational-age-specific z score of birth weight; and 2) deviation from the expected birth weight estimated based on the birth weight of an older sibling. The incidence rates of epilepsy increased consistently with decreasing gestational age and birth weight. The incidence rate ratios of epilepsy in the first year of life were more than fivefold among children born at 22-32 weeks compared with 39-41 weeks and among children whose birth weight was < 2,000 g compared with 3,000-3,999 g. The association was modified by age but remained into early adulthood. Incidence rate ratios of epilepsy were increased among children identified as growth restricted according to either of the two methods. In conclusion, short gestational age, low birth weight, and intrauterine growth restriction are associated with an increased risk of epilepsy. C1 [Sun, Yuelian; Vestergaard, Mogens] Univ Aarhus, Dept Epidemiol, Inst Publ Hlth, DK-8000 Aarhus C, Denmark. [Sun, Yuelian] Shanghai Inst Planned Parenthood Res, Shanghai, Peoples R China. [Vestergaard, Mogens] Univ Aarhus, Dept Gen Practice, Inst Publ Hlth, Aarhus, Denmark. [Pedersen, Carsten B.] Univ Aarhus, Natl Ctr Register Based Res, Aarhus, Denmark. [Christensen, Jakob] Aarhus Univ Hosp, Dept Neurol, DK-8000 Aarhus, Denmark. [Christensen, Jakob] Aarhus Univ Hosp, Dept Clin Pharmacol, DK-8000 Aarhus, Denmark. [Olsen, Jorn] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Basso, Olga] NIEHS, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Sun, Y (reprint author), Univ Aarhus, Dept Epidemiol, Inst Publ Hlth, Vennelyst Blvd 6, DK-8000 Aarhus C, Denmark. EM ys@soci.au.dk RI Basso, Olga/E-5384-2010; Vestergaard, Mogens/M-9333-2014; Olsen, Jorn/F-8801-2015; Pedersen, Carsten Bocker/B-8441-2013 OI Basso, Olga/0000-0001-9298-4921; Vestergaard, Mogens/0000-0001-8830-2174; Olsen, Jorn/0000-0001-7462-5140; Pedersen, Carsten Bocker/0000-0003-2077-8533 FU Intramural NIH HHS [Z99 ES999999] NR 49 TC 31 Z9 31 U1 2 U2 7 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 FEB 1 PY 2008 VL 167 IS 3 BP 262 EP 270 DI 10.1093/aje/kwm316 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 258XH UT WOS:000252903200003 PM 18042672 ER PT J AU Koutros, S Zhang, Y Zhu, Y Mayne, ST Zahm, SH Holford, TR Leaderer, BP Boyle, P Zheng, T AF Koutros, Stella Zhang, Yawei Zhu, Yong Mayne, Susan T. Zahm, Sheila Hoar Holford, Theodore R. Leaderer, Brian P. Boyle, Peter Zheng, Tongzhang TI Nutrients contributing to one-carbon metabolism and risk of non-Hodgkin lymphoma subtypes SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; diet; folic acid; lymphoma; non-Hodgkin; metabolism; methionine; vitamins ID DIETARY FACTORS; MALIGNANT-LYMPHOMA; HISTOLOGIC SUBTYPE; UNITED-STATES; CANCER RISK; FOLATE; POLYMORPHISMS; CARCINOGENESIS; WOMEN; SUSCEPTIBILITY AB Because little is known about the etiology of non-Hodgkin lymphoma (NHL), a heterogeneous disease, and because dietary factors are modifiable, the authors examined the associations between nutrients related to one-carbon metabolism and risk of NHL in a population-based case-control study of Connecticut women diagnosed between 1996 and 2000. A total of 594 cases and 710 controls completed a food frequency questionnaire for determination of intakes of folate, vitamins B-2, B-6, and B-12, and methionine. Through unconditional logistic regression, the authors estimated the risk of NHL associated with intake of each nutrient. Comparing the highest quartile of intake with the lowest, the authors found lower risks of all NHL associated with increasing intakes of folate and methionine. Analysis by NHL subtype indicated lower risks of diffuse large B-cell lymphoma (highest quartile vs. lowest: odds ratio (OR) = 0.54, 95% confidence interval (CI): 0.30, 0.98; p-trend = 0.02) and marginal zone lymphoma (highest quartile vs. lowest: OR = 0.08, 95% CI: 0.02, 0.26; p-trend < 0.0001) associated with folate. Vitamin B-6 intake was also associated with lower risk of NHL overall and of marginal zone lymphoma (highest quartile vs. lowest: OR = 0.23, 95% CI: 0.08, 0.65; p-trend = 0.002). These findings suggest that these nutrients may be important for susceptibility to NHL. C1 [Koutros, Stella; Zahm, Sheila Hoar] Natl Canc Inst, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. [Koutros, Stella; Zhang, Yawei; Zhu, Yong; Mayne, Susan T.; Holford, Theodore R.; Leaderer, Brian P.; Zheng, Tongzhang] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Boyle, Peter] Int Agcy Res Canc, F-69372 Lyon, France. RP Koutros, S (reprint author), Natl Canc Inst, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Execut Plaza S 8111,MSC 7240, Rockville, MD 20852 USA. EM koutross@mail.nih.gov RI Boyle, Peter/A-4380-2014; Zahm, Shelia/B-5025-2015 OI Boyle, Peter/0000-0001-6251-0610; FU NCI NIH HHS [TU2 CA105666, CA62006] NR 43 TC 14 Z9 17 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 FEB 1 PY 2008 VL 167 IS 3 BP 287 EP 294 DI 10.1093/aje/kwm307 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 258XH UT WOS:000252903200006 PM 17989056 ER PT J AU Zablotska, LB Bogdanova, TI Ron, E Epstein, OV Robbins, J Likhtarev, IA Hatch, M Markov, VV Bouville, AC Olijnyk, VA McConnell, RJ Shpak, VM Brenner, A Terekhova, GN Greenebaum, E Tereshchenko, VP Fink, DJ Brill, AB Zamotayeva, GA Masnyk, IJ Howe, GR Tronko, MD AF Zablotska, Lydia B. Bogdanova, Tetyana I. Ron, Elaine Epstein, Ovsiy V. Robbins, Jacob Likhtarev, Illya A. Hatch, Maureen Markov, Valentyn V. Bouville, Andre C. Olijnyk, Valery A. McConnell, Robert J. Shpak, Victor M. Brenner, Alina Terekhova, Galina N. Greenebaum, Ellen Tereshchenko, Valery P. Fink, Daniel J. Brill, Aaron B. Zamotayeva, Galina A. Masnyk, Ihor J. Howe, Geoffrey R. Tronko, Mykola D. TI A cohort study of thyroid cancer and other thyroid diseases after the chornobyl accident: Dose-response analysis of thyroid follicular adenomas detected during first screening in Ukraine (1998-2000) SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adenoma; Chernobyl nuclear accident; dose-response relationship; radiation; iodine; thyroid neoplasms ID POPULATION-BASED COHORT; ATOMIC-BOMB SURVIVORS; EXTERNAL RADIATION; CHILDHOOD IRRADIATION; BRYANSK-OBLAST; EXPOSURE; I-131; RISK; NEOPLASIA; BYELARUS AB The Chornobyl (Chernobyl) accident in 1986 exposed many individuals to radioactive iodines, chiefly I-131, the effects of which on benign thyroid diseases are largely unknown. To investigate the risk of follicular adenoma in relation to radiation dose after Chornobyl, the authors analyzed the baseline data from a prospective screening cohort study of those exposed as children or adolescents. A stratified random sample was selected from all individuals who were younger than 18 years, had thyroid radioactivity measurements taken within 2 months after the accident, and resided in the three heavily contaminated areas in Ukraine. This analysis is based on the 23 cases diagnosed in 12,504 subjects for whom personal history of thyroid diseases was known. The dose-response relation was linear with an excess relative risk of 2.07 per gray (95% confidence interval: 0.28, 10.31). The risk was significantly higher in women compared with men, with no clear modifying effects of age at exposure. In conclusion, persons exposed to radioactive iodines as children and adolescents have an increased risk of follicular adenoma, though it is smaller than the risk of thyroid cancer in the same cohort. Compared with results from other studies, this estimate is somewhat smaller, but confidence intervals overlap, suggesting compatibility. C1 [Zablotska, Lydia B.] Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. [Bogdanova, Tetyana I.; Markov, Valentyn V.; Olijnyk, Valery A.; Shpak, Victor M.; Terekhova, Galina N.; Tereshchenko, Valery P.; Zamotayeva, Galina A.; Tronko, Mykola D.] Inst Endocrinol & Metab, Kiev, Ukraine. [Ron, Elaine; Hatch, Maureen; Bouville, Andre C.; Brenner, Alina; Masnyk, Ihor J.] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. [Robbins, Jacob] NIDDK, Genet & Biochem Branch, Bethesda, MD USA. [Likhtarev, Illya A.] Acad Med Sci, Sci Ctr Radiat Med, Kiev, Ukraine. [McConnell, Robert J.] Columbia Univ, Coll Phys & Surg, Thyroid Clin, Dept Med, New York, NY USA. [Greenebaum, Ellen; Fink, Daniel J.] Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY USA. [Brill, Aaron B.] Vanderbilt Univ, Sch Med, Dept Radiat & Radiol Sci, Nashville, TN 37212 USA. RP Zablotska, LB (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, 722 W 168th St,Suite 1103, New York, NY 10032 USA. EM lbz7@columbia.edu RI Brill, Aaron/H-3732-2014 OI Brill, Aaron/0000-0001-7538-086X NR 43 TC 17 Z9 20 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 1 PY 2008 VL 167 IS 3 BP 305 EP 312 DI 10.1093/aje/kwm301 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 258XH UT WOS:000252903200008 PM 17989057 ER PT J AU Shea, MK Booth, SL Massaro, JM Jacques, PF D'Agostino, RB Dawson-Hughes, B Ordovas, JM O'Donnell, CJ Kathiresan, S Keaney, JF Vasan, RS Benjamin, EJ AF Shea, M. Kyla Booth, Sarah L. Massaro, Joseph M. Jacques, Paul F. D'Agostino, Ralph B., Sr. Dawson-Hughes, Bess Ordovas, Jose M. O'Donnell, Christopher J. Kathiresan, Sekar Keaney, John F., Jr. Vasan, Ramachandran S. Benjamin, Emelia J. TI Vitamin K and vitamin D status: Associations with inflammatory markers in the framingham offspring study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE inflammation; vitamin D; vitamin K ID BONE-MINERAL DENSITY; CARDIOVASCULAR-DISEASE; POSTMENOPAUSAL WOMEN; PHYLLOQUINONE INTAKE; BIOCHEMICAL MEASURES; CYTOKINE PRODUCTION; D SUPPLEMENTATION; INHIBITORY FACTOR; OXIDATIVE STRESS; SERUM-LEVELS AB In vitro data suggest protective roles for vitamins K and D in inflammation. To examine associations between vitamins K and D and inflammation in vivo, the authors used multiple linear regression analyses, adjusted for age, sex, body mass index, triglyceride concentrations, use of aspirin, use of lipid-lowering medication, season, menopausal status, and hormone replacement therapy. Participants were from the Framingham Offspring Study (1997-2001; n = 1,381; mean age = 59 years; 52% women). Vitamin K status, measured by plasma phylloquinone concentration and phylloquinone intake, was inversely associated with circulating inflammatory markers as a group and with several individual inflammatory biomarkers (p < 0.01). Percentage of undercarboxylated osteocalcin, a functional measure of vitamin K status, was not associated with overall inflammation but was associated with C-reactive protein (p < 0.01). Although plasma 25-hydroxyvitamin D was inversely associated with urinary isoprostane concentration, an indicator of oxidative stress (p < 0.01), overall associations between vitamin D status and inflammation were inconsistent. The observation that high vitamin K status was associated with lower concentrations of inflammatory markers suggests that a possible protective role for vitamin K in inflammation merits further investigation. C1 [Shea, M. Kyla; Booth, Sarah L.; Jacques, Paul F.; Dawson-Hughes, Bess; Ordovas, Jose M.] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. [Massaro, Joseph M.] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. [Benjamin, Emelia J.] Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02215 USA. [Massaro, Joseph M.; D'Agostino, Ralph B., Sr.] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Sch Med, Dept Med, Cardiol & Prevent Med Sect, Boston, MA 02215 USA. [Keaney, John F., Jr.; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ, Med Ctr, Whitaker Cardiovasc Inst, Boston, MA 02215 USA. [O'Donnell, Christopher J.; Kathiresan, Sekar] Harvard Univ, Massachusetts Gen Hosp, Dept Med, Boston, MA 02115 USA. [Massaro, Joseph M.; D'Agostino, Ralph B., Sr.; O'Donnell, Christopher J.; Vasan, Ramachandran S.; Benjamin, Emelia J.] NHLBI, Framingham Heart Study, Framingham, MA USA. RP Booth, SL (reprint author), Tufts Univ, USDA, Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM sarah.booth@tufts.edu OI Massaro, Joseph/0000-0002-2682-4812; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Ordovas, Jose/0000-0002-7581-5680 FU NCRR NIH HHS [M01 RR001066, M01-RR-01066]; NHLBI NIH HHS [HL076784, 2K24HL04334, HC-25195, HL064753, HL58090, K24 HL004334, N01 HC025195, N01-HC-38038, N01HC25195, R01 HL058090, R01 HL058090-02, R01 HL058090-07, R01 HL064753, R01 HL064753-04, R01 HL076784, R01 HL076784-01, R01 HL076784-05, T32HL69772-0141]; NIA NIH HHS [AG028321, AG14759, R01 AG014759, R01 AG014759-04, R01 AG028321, R01 AG028321-03] NR 49 TC 126 Z9 130 U1 0 U2 11 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 FEB 1 PY 2008 VL 167 IS 3 BP 313 EP 320 DI 10.1093/aje/kwm306 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 258XH UT WOS:000252903200009 PM 18006902 ER PT J AU Shen, M Cozen, W Huang, L Colt, J De Roos, AJ Severson, RK Cerhan, JR Bernstein, L Morton, LM Pickle, L Ward, MH AF Shen, Min Cozen, Wendy Huang, Lan Colt, Joanne De Roos, Anneclaire J. Severson, Richard K. Cerhan, James R. Bernstein, Leslie Morton, Lindsay M. Pickle, Linda Ward, Mary H. TI Census and geographic differences between respondents and nonrespondents in a case-control study of non-Hodgkin lymphoma SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bias (epidemiology); case-control studies; censuses; epidemiologic methods; geographic information systems; lymphoma; non-Hodgkin ID RESPONSE BIAS; CANCER AB To quantify nonresponse bias and estimate its potential impact, the authors compared census-based socioeconomic and demographic factors and geographic locations among respondents and nonrespondents in a multicenter case-control study of non-Hodgkin lymphoma (1998-2000). Using a geographic information system, the authors mapped current addresses and linked them to the 2000 US Census database to determine group-level demographic and socioeconomic information. They used logistic regression analysis to compute the risk of being a nonrespondent, separately for cases and controls. They used spatial scan methods to evaluate spatial clustering at each study center. Among cases at one or more centers, nonresponse was significantly associated with non-White race, lower household income, a greater proportion of multiple-unit housing, fewer years of education, and living in a more urbanized area. For most factors, the authors observed similar patterns among controls, although findings were mostly nonsignificant. They found two nonrandom elliptical clusters in Los Angeles, California, and Detroit, Michigan, that disappeared after adjustment for the demographic factors. The authors determined the bias in non-Hodgkin lymphoma risk associated with census-tract educational level by comparing risks among respondents and all subjects. The bias was 8%, indicating that the socioeconomic and demographic differences between respondents and nonrespondents did not result in a large bias in the risk estimate for education. C1 [Shen, Min; Colt, Joanne; Morton, Lindsay M.; Ward, Mary H.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Huang, Lan; Pickle, Linda] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. [Cozen, Wendy; Bernstein, Leslie] Univ So Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA. [De Roos, Anneclaire J.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [De Roos, Anneclaire J.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. [Severson, Richard K.] Wayne State Univ, Sch Med, Dept Family Med & Publ Hlth Sci, Detroit, MI USA. [Severson, Richard K.] Karmanos Canc Inst, Detroit, MI USA. [Cerhan, James R.] Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. RP Ward, MH (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Execut Plaza S 8006,MSC 7240, Rockville, MD 20892 USA. EM wardm@mail.nih.gov RI Morton, Lindsay/B-5234-2015; OI Morton, Lindsay/0000-0001-9767-2310; Cerhan, James/0000-0002-7482-178X FU Intramural NIH HHS; NCI NIH HHS [N01-PC-67010, N01-PC-65064, N01-PC-67008, N01-PC-67009, N02-CP-31003, N02-PC-71105] NR 21 TC 20 Z9 20 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 1 PY 2008 VL 167 IS 3 BP 350 EP 361 DI 10.1093/aje/kwm292 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 258XH UT WOS:000252903200013 PM 17989060 ER PT J AU Tsai, CJ Leitzmann, ME Willett, WC Giovannucci, EL AF Tsai, Chung-Jyi Leitzmann, Michael E. Willett, Walter C. Giovannucci, Edward L. TI Long-term effect of magnesium consumption on the risk of symptomatic gallstone disease among men SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID MALE HEALTH-PROFESSIONALS; SERUM HDL-CHOLESTEROL; DIETARY MAGNESIUM; DEFICIENCY; INSULIN; RATS; REPRODUCIBILITY; QUESTIONNAIRE; ASSOCIATION; LIPOPROTEIN AB BACKGROUND: Magnesium deficiency can cause dyslipidemia and insulin hypersecretion, which may facilitate gallstone formation. However, the effect of long-term consumption of magnesium on the risk of gallstone disease is unknown. METHODS: We prospectively studied magnesium consumption and risk of gallstone disease in a cohort of 42,705 U.S. men from 1986 to 2002. Magnesium consumption was assessed using a validated semiquantitative food frequency questionnaire. Newly diagnosed gallstone disease was ascertained biennially. RESULTS: We documented 2,195 incident cases of symptomatic gallstones during 560,810 person-years of follow-up. The age-adjusted relative risks (RRs) for men with total magnesium intake and dietary magnesium, when the highest and lowest quintiles were compared, were 0.67 (95% confidence interval [CI] 0.59-0.77, P for trend < 0.0001) and 0.67 (CI 0.59-0.76, P for trend < 0.0001), respectively. After adjusting for multiple potential confounding variables, when extreme quintiles were compared, the multivariate RR of total magnesium intake (RR 0.72, CI 0.61-0.86, P for trend = 0.006) and dietary magnesium (RR 0.68, CI 0.57-0.82, P for trend = 0.0006) remained significant with a dose-response relationship. CONCLUSIONS: Our findings suggest a protective role of magnesium consumption in the prevention of symptomatic gallstone disease among men. C1 [Tsai, Chung-Jyi] Univ Kentucky, Med Ctr, Div Digest Dis & Nutr, Lexington, KY 40536 USA. [Tsai, Chung-Jyi; Willett, Walter C.; Giovannucci, Edward L.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA USA. [Tsai, Chung-Jyi; Willett, Walter C.; Giovannucci, Edward L.] Harvard Univ, Sch Med, Boston, MA USA. [Willett, Walter C.; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. [Willett, Walter C.; Giovannucci, Edward L.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. [Leitzmann, Michael E.] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. RP Tsai, CJ (reprint author), Univ Kentucky, Med Ctr, Div Digest Dis & Nutr, 800 Rose St, Lexington, KY 40536 USA. OI Corkey, Barbara/0000-0002-5467-1630 FU NCI NIH HHS [CA55075]; NIDDK NIH HHS [DK46200] NR 45 TC 7 Z9 9 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD FEB PY 2008 VL 103 IS 2 BP 375 EP 382 DI 10.1111/j.1572-0241.2007.01696.x PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 260ZU UT WOS:000253049700018 PM 18076730 ER PT J AU Rodig, SJ Payne, EG Degar, BA Rollins, B Feldman, AL Jaffe, ES Androkites, A Silverman, LB Longtine, JA Kutok, JL Fleming, MD Aster, JC AF Rodig, Scott J. Payne, Ethan G. Degar, Barbara A. Rollins, Barrett Feldman, Andrew L. Jaffe, Elaine S. Androkites, Arlene Silverman, Lewis B. Longtine, Janina A. Kutok, Jeffery L. Fleming, Mark D. Aster, Jon C. TI Aggressive Langerhans cell histiocytosis following T-ALL: Clonally related neoplasms with persistent expression of constitutively active NOTCH1 SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; C-MYC; PRECURSOR; DIFFERENTIATION; PATHWAY; LINEAGE AB Langerhans cell histiocytosis (LCH) and related entities are neoplasms of unknown pathogenesis. Here, we describe studies assessing the role of NOTCH1 mutations in LCH, which were based on a case of fatal Langerhans cell tumor after T-cell acute lymphoblastic leukemia (T-ALL). Although the two types of neoplasm in this patient were temporally and pathologically distinct, molecular analyses showed that they harbored the same T-cell receptor gene rearrangements and two activating NOTCH1 mutations involving exons 27 and 34. The exon 27 mutation altered a conserved cysteine residue in the N-terminal portion of the NOTCH1 heterodimerization domain, while the mutation in exon 34 introduced a premature stop codon that results in the deletion of C-terminal negative regulatory PEST domain. Analysis of cDNA prepared from the aggressive Langerhans cell tumor showed that the NOTCH1 mutations were aligned in cis, a configuration that caused synergistic increases in NOTCH1 signal strength in reporter gene assays. Immunohistochemistry confirmed that the Langerhans cell tumor also expressed NOTCH1 protein. Although these data suggested that NOTCH1 mutations might contribute to the pathogenesis of typical sporadic LCH and related neoplasms occurring in the absence of T-ALL, an analysis of 24 cases of LCH and Rosai-Dorfman Disease occurring in patients without an antecedent history of T-ALL revealed no mutations. Thus, activating NOTCH1 mutations appear to be unique to aggressive Langerhans cell tumors occurring after T-ALL. Persistent expression of NOTCH1 in such tumors suggests that Notch pathway inhibitors could have a role in the treatment of these unusual neoplasms. C1 [Fleming, Mark D.] Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. [Rodig, Scott J.; Payne, Ethan G.; Longtine, Janina A.; Kutok, Jeffery L.; Aster, Jon C.] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. [Degar, Barbara A.; Androkites, Arlene; Silverman, Lewis B.] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA. [Degar, Barbara A.; Rollins, Barrett] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Feldman, Andrew L.] Mayo Clin, Dept Lab Med & Pathol, Rochester, MI USA. [Jaffe, Elaine S.] Natl Canc Inst, Pathol Lab, Bethesda, MD USA. RP Fleming, MD (reprint author), Childrens Hosp, Dept Pathol, Boston, MA 02115 USA. EM mark.fleming@childrens.harvard.edu; jaster@rics.bwh.harvard.edu RI Feldman, Andrew/D-5028-2012 FU NCI NIH HHS [CA082308, P01 CA119070, P01 CA119070-02]; NIAID NIH HHS [AI050225] NR 21 TC 26 Z9 26 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD FEB PY 2008 VL 83 IS 2 BP 116 EP 121 DI 10.1002/ajh.21044 PG 6 WC Hematology SC Hematology GA 253JG UT WOS:000252513900007 PM 17874453 ER PT J AU Savage, SA Giri, N Baerlocher, GM Orr, N Lansdorp, PM Alter, BP AF Savage, Sharon A. Giri, Neelarn Baerlocher, Gabriela M. Orr, Nick Lansdorp, Peter M. Alter, Blanche P. TI TINF2, a component of the shelterin telomere protection complex, is mutated in dyskeratosis congenita SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID BONE-MARROW FAILURE; REVERSE-TRANSCRIPTASE COMPONENT; STEM-CELL TRANSPLANTATION; EXONIC SPLICING ENHANCERS; APLASTIC-ANEMIA; GENETIC-VARIATION; LINKAGE DISEQUILIBRIUM; MUTATIONS; CANCER; LENGTH AB Patients with dyskeratosis congenita (DC), a heterogeneous inherited bone marrow failure syndrome, have abnormalities in telomere biology, including very short telomeres and germline mutations in DKC1, TERC, TERT, or NOP10, but similar to 60% of DC patients lack an identifiable mutation. With the very short telomere phenotype and a highly penetrant, rare disease model, a linkage scan was performed on a family with autosomal-dominant DC and no mutations in DKC1, TERC, or TERT Evidence favoring linkage was found at 2p24 and 14q11.2, and this led to the identification of TINF2 (14q11.2) mutations, K280E, in the proband and her five affected relatives and TINF2R282H in three additional unrelated DC probands, including one with Revesz syndrome; a fifth DC proband had a R282S mutation. TINF2 mutations were not present in unaffected relatives, DC probands with mutations in DKC1, TERC, or TERT or 298 control subjects. We demonstrate that a fifth gene, TINF2, is mutated in classical DC and, for the first time, in Revesz syndrome. This represents the first shelterin complex mutation linked to human disease and confirms the role of very short telomeres as a diagnostic test for DC. C1 [Savage, Sharon A.; Giri, Neelarn; Alter, Blanche P.] NCI, Dept Hlth & Human Serv, NIH, Div Canc Epidemiol & Genet,Clin Genet Branch, Bethesda, MD 20892 USA. [Baerlocher, Gabriela M.] Univ Hosp Bern, Dept Hematol, CH-3010 Bern, Switzerland. [Orr, Nick] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Baerlocher, Gabriela M.; Lansdorp, Peter M.] British Columbia Canc Res Ctr, Terry Fox Lab, Vancouver, BC V5Z 1L3, Canada. RP Savage, SA (reprint author), NCI, Dept Hlth & Human Serv, NIH, Div Canc Epidemiol & Genet,Clin Genet Branch, Bethesda, MD 20892 USA. EM savagesh@mail.nili.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 FU Intramural NIH HHS; NCI NIH HHS [N02CP11019]; NIAID NIH HHS [R01 AI029524, AI29524, R21 AI029524] NR 45 TC 202 Z9 212 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB PY 2008 VL 82 IS 2 BP 501 EP 509 DI 10.1016/j.ajhg.2007.10.004 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 263NN UT WOS:000253223900022 PM 18252230 ER PT J AU Franceschini, N MacCluer, JW Rose, KM Rutherford, S Cole, SA Laston, S Goring, HHH Diego, VP Roman, MJ Lee, ET Best, LG Howard, BV Fabsitz, RR North, KE AF Franceschini, Nora MacCluer, Jean W. Rose, Kathreen M. Rutherford, Sue Cole, Shelley A. Laston, Sandy Goering, Harald H. H. Diego, Vincent P. Roman, Mary J. Lee, Elisa T. Best, Lyle G. Howard, Barbara V. Fabsitz, Richard R. North, Kari E. TI Genome-wide linkage analysis of pulse pressure in American Indians: The strong heart study SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article; Proceedings Paper CT 15th Annual Meeting of the International-Genetic-Epidemiology-Society CY NOV 16-17, 2006 CL St Petersburg, FL SP Int Genet Epidemiol Soc ID SYSTOLIC BLOOD-PRESSURE; APPARENTLY HEALTHY-MEN; CARDIOVASCULAR-DISEASE; ARTERIAL COMPLIANCE; NEUROPEPTIDE-Y; POLYMORPHISM; GENE; FAMILY; RISK; SCAN AB BACKGROUND Pulse pressure, a measure of central arterial stiffness and a predictor of cardiovascular mortality, has known genetic components. METHODS To localize the genetic effects of pulse pressure, we conducted a genome-wide linkage analysis of 1,892 American-Indian participants of the Strong Heart Family Study (SHFS). Blood pressure was measured three times and the average of the last two measures was used for analyses. Pulse pressure, the difference between systolic blood pressure (SBP) and diastolic blood pressure (DBP), was log-transformed and adjusted for the effects of age and sex within each study center. Variance component linkage analyses were performed using marker allele frequencies derived from all individuals and multipoint identity-by-descent matrices calculated in Loki. RESULTS We identified a quantitative-trait locus influencing pulse pressure on chromosome 7 at 37cM (marker D7S493, LOD = 3.3) and suggestive evidence of linkage on chromosome 19 at 92 cM (marker D19S888, LOD = 1.8). CONCLUSIONS The signal on 7p15.3 overlaps positive findings for pulse pressure among Utah population samples, suggesting that this region may harbor gene variants for blood pressure related traits. C1 [Franceschini, Nora; Rose, Kathreen M.; North, Kari E.] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. [MacCluer, Jean W.; Rutherford, Sue; Cole, Shelley A.; Laston, Sandy; Goering, Harald H. H.; Diego, Vincent P.] SW Fdn Biomed Res, Dept Genet, San Antonio, TX 78284 USA. [Roman, Mary J.] Weill Med Coll Cornell Univ, New York, NY USA. [Lee, Elisa T.] Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK USA. [Best, Lyle G.] Missouri Breaks Ind Res, Timber Lake, SD USA. [Howard, Barbara V.] MedStar Res Inst, Washington, DC USA. [Fabsitz, Richard R.] NHLBI, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. RP Franceschini, N (reprint author), Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. EM noraf@unc.edu OI Diego, Vincent/0000-0002-0007-2085 FU NHLBI NIH HHS [U01 HL041642, U01 HL041642-18A1, U01 HL041652, U01 HL041652-19, U01 HL041654, U01 HL041654-19, U01 HL065520, U01 HL065520-07, U01 HL065521, U01 HL065521-07, U01 HL41642, U01 HL41652, U01 HL41654, U01 HL65520, U01 HL65521]; NIMH NIH HHS [MH059490, R01 MH059490, R37 MH059490, R37 MH059490-10] NR 31 TC 10 Z9 10 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD FEB PY 2008 VL 21 IS 2 BP 194 EP 199 DI 10.1038/ajh.2007.34 PG 6 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 254XR UT WOS:000252621800019 PM 18188160 ER PT J AU Wilson, RT Donahue, M Gridley, G Adami, J El Ghormli, L Dosemeci, M AF Wilson, Robin Taylor Donahue, Mark Gridley, Gloria Adami, Johanna El Ghormli, Laure Dosemeci, Mustafa TI Shared occupational risks for transitional cell cancer of the bladder and renal pelvis among men and women in Sweden SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Review DE epidemiology; bladder neoplasms; kidney neoplasms; occupational exposure; industry ID LOWER URINARY-TRACT; PHYSICAL-ACTIVITY; AGRICULTURAL HEALTH; SOCIOECONOMIC-STATUS; IONIZING-RADIATION; PRINTING WORKERS; AROMATIC-AMINES; UTILITY WORKERS; UNITED-STATES; VITAMIN-D AB Background Unlike cancer of the bladder, cancer of the renal pelvis is not considered an occupational cancer and little is known about risks among women. Methods Using the Swedish national census and cancer registry-linked data (1971-1989), we identified transitional cell cancers of the renal pelvis (N = 1, 374) and bladder (N = 21,591). Correlation between cancer sites for the standardized incidence ratios (SIR) were determined using Pearson's coefficient of the log SIR. Relative risks of job exposure matrix variables were calculated using Poisson regression. Results Both cancer sites were significantly elevated among women and men employed in the machine/electronics industry, sedentary work, and indoor work, and men in the metal industry. The highest proportion of the bladder (12%) and renal pelvis (14%) cancers occurred among men employed in shop and construction metal work. Risks by industry were more correlated among women (r = 0.49, P = 0.002) than men (r = 0.24, P = 0.04). Cancers of the renal pelvis were elevated in several occupational and industry groups for which there was no elevated bladder cancer risk. Conclusion Cancers of the renal pelvis and bladder share common occupational risk factors that may be more frequent among women. In addition, there may be some jobs that pose an increased risk specifically for cancer of the renal pelvis but not bladder. C1 [Wilson, Robin Taylor] Penn State Coll Med, Div Epidemiol, Dept Publ Hlth Sci, Penn State Canc Inst, Hershey, PA 17033 USA. [Donahue, Mark; Gridley, Gloria; Dosemeci, Mustafa] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Adami, Johanna] Karolinska Inst, Dept Med, Clin Epidemiol Unit, Stockholm, Sweden. [El Ghormli, Laure] George Washington Univ, Dept Biostat, Washington, DC USA. RP Wilson, RT (reprint author), Penn State Coll Med, Div Epidemiol, Dept Publ Hlth Sci, Penn State Canc Inst, 600 Ctrview Dr,Suite 2200,Mail Code A210, Hershey, PA 17033 USA. EM rwilson@psu.edu FU Intramural NIH HHS [Z01 CP010120-13] NR 135 TC 10 Z9 10 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD FEB PY 2008 VL 51 IS 2 BP 83 EP 99 DI 10.1002/ajim.20522 PG 17 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 254BU UT WOS:000252562200001 PM 18067176 ER PT J AU Ji, BT Blair, A Shu, XO Chow, WH Hauptmann, M Dosemeci, M Yang, G Lubin, J Gao, YT Rothman, N Zheng, W AF Ji, Bu-Tian Blair, Aaron Shu, Xiao-Ou Chow, Wong-Ho Hauptmann, Michael Dosemeci, Mutafa Yang, Gong Lubin, Jay Gao, Yu-Tang Rothman, Nathaniel Zheng, Wei TI Occupation and breast cancer risk among Shanghai women in a population-based cohort study SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE occupations; breast cancer; Shanghai women health study (SWHS); Shanghai China ID DRY-CLEANING WORKERS; UNITED-STATES; ELECTROMAGNETIC-FIELDS; MAGNETIC-FIELDS; URBAN SHANGHAI; INCIDENCE TRENDS; MORTALITY; FEMALE; EXPOSURES; HEALTH AB Introduction A total of 74,942 female subjects were recruited in a population-based cohort study in Shanghai, China between 1997 and 2000. We examined the relationship between occupation and breast cancer risk. Methods Cases were 586 women previously diagnosed with breast cancer at baseline and 438 women newly diagnosed with breast cancer during follow-up through December 2004. Eight controls were randomly selected for each case from cancer free cohort members and frequency-matched to the cases by year of birth and age at diagnosis. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) ofbreast cancer risk associated with occupations, adjusting for established breast cancer risk factors. Results In the prevalent breast cancer data analysis, increased risks ofbreast cancer were associated with technicians in engineering/agriculture/forestry (OR = 1.6, CI: 1.0-2.4), teaching personnel (OR = 1.5, CI: 1.1-2.0), tailoring/sewing workers (OR = 1.6, CI:1.0-2.7), and examiners/measurers/testers (OR = 1.5, CI:1.1-2.1) among those who started the jobs at least 20 years ago. Among incident breast cancer cases, significantly increased risks were associated with medical/health care workers (OR=1.4, CI:1.0-2.0), administrative clerical workers (OR = 1.5, CI:1.0-2.4), postal/telecommunication workers (OR = 2.2, CI:1.0-5.5), and odd-job workers (OR = 1.7, CI:1.1-2.8) among those who started the jobs at least 20 years ago. The excess risks were found in both prevalent and incident cases for postal/telecommunication workers and purchasing/marketing personnel, although ORs reached only marginal significance. Conclusions: This study suggests that white-collar professionals and several production occupations may be associated with an increased risk of breast cancer. C1 [Ji, Bu-Tian; Blair, Aaron; Chow, Wong-Ho; Hauptmann, Michael; Dosemeci, Mutafa; Lubin, Jay; Rothman, Nathaniel] Natl Canc Inst, DHHS, Rockville, MD 20852 USA. [Shu, Xiao-Ou; Yang, Gong; Zheng, Wei] Vanderbilt Univ, Nashville, TN USA. [Gao, Yu-Tang] Shanghai Canc Inst, Shanghai, Peoples R China. RP Ji, BT (reprint author), Natl Canc Inst, DHHS, 6120 Execut Blvd,EPS 8104, Rockville, MD 20852 USA. EM jib@exchange.nih.gov FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [R01 CA70867, R01 CA070867] NR 56 TC 7 Z9 7 U1 1 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD FEB PY 2008 VL 51 IS 2 BP 100 EP 110 DI 10.1002/ajim.20507 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 254BU UT WOS:000252562200002 PM 18067183 ER PT J AU Wang, D Strandgaard, S Borresen, ML Luo, ZM Connors, SG Yan, Q Wilcox, CS AF Wang, Dan Strandgaard, Svend Borresen, Malene L. Luo, Zaiming Connors, Stephanie G. Yan, Qing Wilcox, Christopher S. TI Asymmetric dimethylarginine and lipid peroxidation products in early autosomal dominant polycystic kidney disease SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE nitric oxide synthase (NOS); reactive oxygen species (ROS); dimethylarginine; dimethylaminohydrolases (DDAH); 13-hydroxyoctadecadienoic acid (HODE); hypertension ID NITRIC-OXIDE SYNTHASE; ENDOTHELIUM-DEPENDENT RELAXATION; STAGE RENAL-DISEASE; OXIDATIVE STRESS; SALT INTAKE; RESISTANCE VESSELS; S-NITROSYLATION; HYPERTENSION; RAT; DYSFUNCTION AB Background: Patients with autosomal dominant polycystic kidney disease (ADPKD) with normal renal function have endothelial dysfunction and decreased nitric oxide synthase activity in subcutaneous resistance vessels. We investigated asymmetric dimethylarginine (ADMA) as a marker of an inhibitor of nitric oxide synthase and the lipid peroxidation product 13-hydroxyoctadecadienoic acid (HODE) as a marker of oxidative stress in patients with early ADPKD. Study Design: Cross-sectional study. Setting & Participants: Patients with early ADPKD (n = 27) and age-matched volunteers (n = 30) from a single academic medical center. Factor: Patients with ADPKD versus controls. Outcomes & Measurement: Plasma (P) levels, urinary (U) excretion, and urinary clearance (C) of ADMA and HODE. Because of multiple comparisons, P for significance is considered less than 0.0167. Results: Patients with ADPKD had significantly increased P-ADMA levels (604 +/- 131 versus 391 +/- 67 nmol/L; P < 0.01) and U-ADMA excretion (22 +/- 4 versus 15.2 +/- 3 nmol/Amol creatinine; P = 0.01), decreased C-ADMA (25 +/- 3 versus 33 +/- 4 mL/min; P = 0.01), increased P-HODE levels (316 +/- 64 versus 230 +/- 38 nmol/L; P < 0.01) and U-HODE excretion (467 +/- 67 versus 316 +/- 40 nmol/mu mol creatinine; P < 0.01), and decreased plasma nitrite plus nitrate (P-NOx) levels (21 +/- 5 versus 32 +/- 6 mu mol/L; P < 0.01) and U-NOx excretion (59 +/- 7 versus 138 +/- 27 mu mol/mu mol creatinine; P < 0.01). Limitations: Small sample size, cross-sectional nature of study, and limited number of markers of oxidative stress. Conclusions: P-ADMA and P-HODE levels are increased in patients with early ADPKD. Increased P-ADMA level is related to decreased CADMA and is accompanied by oxidative stress. Am J Kidney Dis 51:184-191. (c) 2008 by the National Kidney Foundation, Inc. C1 [Wang, Dan; Luo, Zaiming; Connors, Stephanie G.; Wilcox, Christopher S.] Georgetown Univ, Div Nephrol & Hypertens, Cardiovasc Kidney Hypertens Inst, Washington, DC 20007 USA. [Wang, Dan; Luo, Zaiming; Connors, Stephanie G.; Wilcox, Christopher S.] Georgetown Univ, Lombardi Canc Inst, Angiogenesis Sect, Washington, DC 20007 USA. [Wang, Dan; Strandgaard, Svend; Borresen, Malene L.] Univ Copenhagen, Herlev Hosp, Dept Nephrol, DK-2730 Herlev, Denmark. [Yan, Qing] NEI, Div Epidemiol & Clin Res, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Wang, D (reprint author), Georgetown Univ, Div Nephrol & Hypertens, Cardiovasc Kidney Hypertens Inst, 4000 Reservoir Rd NW, Washington, DC 20007 USA. EM dw32@georgetowiz.edu FU NHLBI NIH HHS [HL68686-01]; NIDDK NIH HHS [DK-36079, DK-49870] NR 62 TC 36 Z9 36 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD FEB PY 2008 VL 51 IS 2 BP 184 EP 191 DI 10.1053/j.ajkd.2007.09.020 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 285TR UT WOS:000254799600004 PM 18215696 ER PT J AU Duru, OK Li, S Jurkovitz, C Bakris, G Brown, W Chen, SC Collins, A Klag, M McCullough, PA McGill, J Narva, A Pergola, P Singh, A Norris, K AF Duru, Obidiugwu Kenrik Li, Suying Jurkovitz, Claudine Bakris, George Brown, Wendy Chen, Shu-Cheng Collins, Allan Klag, Michael McCullough, Peter A. McGill, Janet Narva, Andrew Pergola, Pablo Singh, Ajay Norris, Keith TI Race and sex differences in hypertension control in CKD: Results from the kidney early evaluation program (KEEP) SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE hypertension; chronic kidney disease; ethnic groups; sex ID STAGE RENAL-DISEASE; GLOMERULAR-FILTRATION-RATE; UNITED-STATES; BLOOD-PRESSURE; PROGRESSION; PREVALENCE; MEN; AMERICANS; GENDER; HEALTH AB Background: African American men with chronic kidney disease (CKD) progress to end-stage renal disease more rapidly than African American women or whites. Uncontrolled hypertension worsens CKD, and disparities in hypertension control may contribute to disparities in CKD progression. Study Design: Cross-sectional. Setting & Participants: 10,827 individuals with CKD and self-reported hypertension screened in the Kidney Early Evaluation Program. Predictors: African American race, sex. Outcomes: Hypertension control (blood pressure < 130 mm Hg systolic and/or < 80 mm Hg diastolic). Measurements: Self-report, physical examination (blood pressure), laboratory data (serum creatinine, microalbuminuria by urine dipstick). We calculated estimated glomerular filtration rates by using the 4-variable isotope dilution mass spectrometry Modification of Diet in Renal Disease Study equation. We classified CKD as early (stages 1 to 2) or late (stages 3 to 5) based on estimated glomerular filtration rate and microalbuminuria. Results: In individuals with early CKD, African American women (odds ratio [OR], 1.47; 95% confidence interval [CI], 1.14 to 1.88), white men (OR, 1.85; 95% CI,1.39 to 2.46), and white women (OR, 1.69; 95% CI, 1.28 to 2.22) had greater odds of hypertension control (blood pressure < 130/80 mm Hg) than African American men. In individuals with late CKD, white men (OR, 1.66; 95% Cl, 1.10 to 2.52) and white women (OR, 1.67; 95% CI, 1.13 to 2.46) had greater odds of hypertension control than African American men. No differences were seen between African American men and women with late CKD. Limitations: No information for medication regimens. Conclusions: African American men with CKD have poorly controlled hypertension compared with African American women and whites, particularly in the early stages of disease. Efforts to aggressively treat hypertension in this population may help narrow the race and sex disparities in progression to end-stage renal disease. Am J Kidney Dis 51:192-198. (c) 2008 by the National Kidney Foundation, Inc. C1 [Duru, Obidiugwu Kenrik] Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med Hlth Serv Res, Los Angeles, CA 90095 USA. [Li, Suying; Chen, Shu-Cheng; Collins, Allan] USRDS Coordinating Ctr, Dept Med, Div Nephrol, Minneapolis, MN USA. [Jurkovitz, Claudine] Christiana Care Hlth Syst, Ctr Outcomes Res, Newark, DE USA. [Bakris, George] Univ Chicago, Pritzker Sch Med, Dept Med, Div Prevent Med, Chicago, IL 60637 USA. [Bakris, George] Univ Chicago, Pritzker Sch Med, Dept Med, Div Hypertens, Chicago, IL 60637 USA. [Bakris, George] Univ Chicago, Pritzker Sch Med, Dept Med, Div Nephrol, Chicago, IL 60637 USA. [Brown, Wendy] Jesse Brown Vet Affairs Med Ctr, Dept Med, Chicago, IL USA. [Klag, Michael] Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. [McCullough, Peter A.] William Beaumont Hosp, Dept Med, Div Cardiol, Royal Oak, MI 48072 USA. [McCullough, Peter A.] William Beaumont Hosp, Dept Med, Div Nutr, Royal Oak, MI 48072 USA. [McCullough, Peter A.] William Beaumont Hosp, Dept Med, Div Prevent Med, Royal Oak, MI 48072 USA. [McGill, Janet] Washington Univ, Sch Med, Dept Med, Div Endocrinol, St Louis, MO 63110 USA. [Narva, Andrew] NIDDK, Natl Kidney Dis Educ Program, Natl Inst Hlth, Bethesda, MD USA. [Pergola, Pablo] Univ Texas Hlth Sci Ctr San Antonio, Dept Med, Div Nephrol, San Antonio, TX 78229 USA. [Singh, Ajay] Brigham & Womens Hosp, Dept Med, Div Nephrol, Boston, MA 02115 USA. [Norris, Keith] Charles R Drew Univ Med & Sci, Dept Med, Lynwood, CA USA. RP Duru, OK (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Gen Internal Med Hlth Serv Res, Los Angeles, CA 90095 USA. EM kduru@mednet.ucla.edu FU NCRR NIH HHS [U54RR019234, U54 RR019234]; NIMHD NIH HHS [P20 MD000148, P20 MD000182, P20MD000182, P20MD000148, P20 MD000182-01] NR 32 TC 24 Z9 26 U1 0 U2 3 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD FEB PY 2008 VL 51 IS 2 BP 192 EP 198 DI 10.1053/j.ajkd.2007.09.023 PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 285TR UT WOS:000254799600005 PM 18215697 ER PT J AU Unutzer, J Katon, WJ Fan, MY Schoenbaum, MC Lin, EHB Della Penna, RD Powers, D AF Unutzer, Jurgen Katon, Wayne J. Fan, Ming-Yu Schoenbaum, Michael C. Lin, Elizabeth H. B. Della Penna, Richard D. Powers, Diane TI Long-term cost effects of collaborative care for late-life depression SO AMERICAN JOURNAL OF MANAGED CARE LA English DT Article ID RANDOMIZED CONTROLLED TRIAL; IMPROVING PRIMARY-CARE; ELDERLY-PATIENTS; OLDER; INTERVENTION; MANAGEMENT; OUTCOMES AB Objective: To determine the long-term effects on total healthcare costs of the Improving Mood: Promoting Access to Collaborative Treatment (IMPACT) program for late-life depression compared with usual care. Study Design: Randomized controlled trial with enrollment from July 1999 through August 2001. The IMPACT trial, conducted in primary care practices in 8 delivery organizations across the United States, enrolled 1801 depressed primary care patients 60 years or older. Data are from the 2 IMPACT sites for which 4-year cost data were available. Trial enrollment across these 2 health maintenance organizations was 551 patients. Methods: Participants were randomly assigned to the IMPACT intervention (n = 279) or to usual primary care (n = 272). Intervention patients had access to a depression care manager who provided education, behavioral activation, support of antidepressant medication management prescribed by their regular primary care provider, and problem-solving treatment in primary care for up to 12 months. Care managers were supervised by a psychiatrist and a primary care provider. The main outcome measures were healthcare costs during 4 years. Results: IMPACT participants had lower mean total healthcare costs ($29 422; 95% confidence interval, $26 479-$32 365) than usual care patients ($32 785; 95% confidence interval, $27 648-$37 921) during 4 years. Results of a bootstrap analysis suggested an 87% probability that the IMPACT program was associated with lower healthcare costs than usual care. Conclusion: Compared with usual primary care, the IMPACT program is associated with a high probability of lower total healthcare costs during a 4-year period. C1 [Unutzer, Jurgen; Katon, Wayne J.; Fan, Ming-Yu; Powers, Diane] Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA. [Lin, Elizabeth H. B.] Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. [Schoenbaum, Michael C.] NIMH, Bethesda, MD 20892 USA. [Della Penna, Richard D.] Kaiser Permanente, Oakland, CA USA. RP Unutzer, J (reprint author), Univ Washington, Sch Med, Dept Psychiat & Behav Sci, Box 356560,1959 NE Pacific St, Seattle, WA 98195 USA. EM unutzer@u.washington.edu OI Penna, Maria Pietronilla/0000-0002-0982-3893 FU NIMH NIH HHS [1 K24 MH 069471-01, K24 MH069471] NR 19 TC 158 Z9 159 U1 3 U2 10 PU AMER MED PUBLISHING, M W C COMPANY PI JAMESBURG PA 241 FORSGATE DR, STE 102, JAMESBURG, NJ 08831 USA SN 1088-0224 J9 AM J MANAG CARE JI Am. J. Manag. Care PD FEB PY 2008 VL 14 IS 2 BP 95 EP 100 PG 6 WC Health Care Sciences & Services; Health Policy & Services; Medicine, General & Internal SC Health Care Sciences & Services; General & Internal Medicine GA 266TC UT WOS:000253458900005 PM 18269305 ER PT J AU Weiss, JS Kruth, HS Kuivaniemi, H Tromp, G Karkera, J Mahurkar, S Lisch, W Dupps, WJ White, PS Winters, RS Kim, C Rapuano, CJ Sutphin, J Reidy, J Hu, FR Lu, DW Ebenezer, N Nickerson, ML AF Weiss, Jayne S. Kruth, Howard S. Kuivaniemi, Helena Tromp, Gerard Karkera, Jayaprakash Mahurkar, Sunil Lisch, Walter Dupps, William J., Jr. White, Peter S. Winters, R. Scott Kim, Chaesik Rapuano, Christopher J. Sutphin, John Reidy, Jim Hu, Fung-Rong Lu, Da Wen Ebenezer, Neil Nickerson, Michael L. TI Genetic analysis of 14 families with Schnyder crystalline corneal dystrophy reveals clues to UBIAD1 protein function SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE Schnyder crystalline corneal dystrophy; Schnyder corneal dystrophy; UBIAD1; hypercholesterolemia; HDL; prenyltransferase; corneal dystrophy; phospholipids; LDL; cholesterol; genetic disease; ocular; eye; cornea ID CHROMOSOME 1P34.1-P36; ESCHERICHIA-COLI; APOLIPOPROTEIN-E; HYPERLIPOPROTEINEMIA; LOCALIZATION; PREDICTION; MUTATIONS; SEQUENCE; LOCUS AB Schnyder crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease characterized by progressive corneal opacification resulting from abnormal deposition of cholesterol and phospholipids. Recently, six different mutations on the UBIAD1 gene on chromosome 1p36 were found to result in SCCD. The purpose of this article is to further characterize the mutation spectrum of SCCD and identify structural and functional consequences for UBIAD1 protein activity. DNA sequencing was performed on samples from 36 individuals front 14 SCCD families. One affected individual was African American and SCCD has not been previously reported in this ethnic group. We identified UBIAD1 mutations in all 14 families which had 30 affected and 6 unaffected individuals. Eight different UBIAD1. mutations, novel (L121F, D118G, and S171P in exon 1, G186R and D236E in exon 2) were identified. in four families with DNA samples from both affected and unaffected individuals, the D118G, G186R, T175I, and G177R mutations cosegregated with SCCD. In combination with our previous report, we have identified the genetic mutation in UBIAD1 in 20 unrelated families with 10 (including 5 reported here), having the N102S imitation. The results suggest that N102S may be a mutation hot spot because the affected families were unrelated including Caucasian and Asian individuals. There was no genotype phenotype correlation except for the T175I Mutation which demonstrated prominent diffuse corneal haze, typically without corneal crystals. Protein analysis revealed structural and functional implications of SCCD mutations which may affect UBIAD1 function, ligand binding and interaction with binding partners, like apo E. (C) 2008 Wiley-Liss, Inc. C1 [Weiss, Jayne S.; Kim, Chaesik] Wayne State Univ, Kresge Eye Inst, Sch Med, Detroit, MI 48201 USA. [Weiss, Jayne S.; Kim, Chaesik] Wayne State Univ, Sch Med, Dept Ophthalmol, Detroit, MI USA. [Weiss, Jayne S.; Kim, Chaesik] Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI USA. [Kruth, Howard S.] Sect Expt Atherosclerosis, NIH, Bethesda, MD USA. [Kuivaniemi, Helena; Tromp, Gerard] Wayne State Univ, Ctr Mol Med & Genet, Sch Med, Detroit, MI 48201 USA. [Kuivaniemi, Helena] Wayne State Univ, Dept Surg, Sch Med, Detroit, MI 48201 USA. [Mahurkar, Sunil] Transgenom, Gaithersburg, MD USA. [Lisch, Walter] Klinikum Hanau, Dept Ophthalmol, Hanau, Germany. [Dupps, William J., Jr.] Cleveland Clin, Cole Eye Inst, Cleveland, OH 44106 USA. [Dupps, William J., Jr.] Cleveland Clin, Lerner Res Inst, Cleveland, OH 44106 USA. [White, Peter S.; Winters, R. Scott] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Rapuano, Christopher J.] Wills Eye Inst, Philadelphia, PA USA. [Sutphin, John] Kansas Univ Med Ctr, Prarie Village, KS USA. [Reidy, Jim] SUNY Coll Buffalo, Buffalo, NY 14222 USA. [Hu, Fung-Rong] Natl Taiwan Univ, Coll Med, Natl Taiwan Univ Hosp, Dept Ophthalmol, Taipei 10764, Taiwan. [Lu, Da Wen] TriServ Memorial Hosp, Taipei, Taiwan. [Ebenezer, Neil] UCL, Inst Ophthalmol, Dept Mol Genet, London, England. RP Weiss, JS (reprint author), Wayne State Univ, Kresge Eye Inst, Sch Med, 4717 St Antoine, Detroit, MI 48201 USA. EM jweiss@med.wayne.edu RI Tromp, Gerard/B-2677-2017; OI Tromp, Gerard/0000-0002-7761-0806; HU, FUNG-RONG/0000-0002-2102-5317; Kuivaniemi, Helena/0000-0001-5753-8766; Dupps, William/0000-0003-0761-8658 FU NCRR NIH HHS [KL2 RR024990]; NEI NIH HHS [EY12972] NR 43 TC 28 Z9 33 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD FEB 1 PY 2008 VL 146A IS 3 BP 271 EP 283 DI 10.1002/ajmg.a.32201 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 260KD UT WOS:000253008300001 PM 18176953 ER PT J AU Hourani, R Brant, LJ Rizk, T Weingart, JD Barker, PB Horska, A AF Hourani, R. Brant, L. J. Rizk, T. Weingart, J. D. Barker, P. B. Horska, A. TI Can proton MR spectroscopic and perfusion imaging differentiate between neoplastic and nonneoplastic brain lesions in adults? SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID MAGNETIC-RESONANCE-SPECTROSCOPY; INTRACRANIAL MASS LESIONS; CONTRAST-ENHANCED MR; TUMEFACTIVE DEMYELINATING LESIONS; INITIAL-EXPERIENCE; TUMORS; ACCURACY; CHOLINE; MYOINOSITOL; DIAGNOSIS AB BACKGROUND AND PURPOSE: Noninvasive diagnosis of brain lesions is important for the correct choice of treatment. Our aims were to investigate whether 1) proton MR spectroscopic imaging (H-1-MRSI) can aid in differentiating between tumors and nonneoplastic brain lesions, and 2) perfusion MR imaging can improve the classification. MATERIALS AND METHODS: We retrospectively examined 69 adults with untreated primary brain lesions (brain tumors, n = 36; benign lesions, n = 10; stroke, n = 4; demyelination, n = 10; and stable lesions not confirmed on pathologic examination, n = 9). MR imaging and 1H-MRSI were performed at 1.5T before biopsy or treatment. Concentrations of N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) in the lesion were expressed as metabolite ratios and were normalized to the contralateral hemisphere. Dynamic susceptibility contrast-enhanced perfusion MR imaging was performed in a subset of patients (n = 32); relative cerebral blood volume (rCBV) was evaluated. Discriminant function analysis was used to identify variables that can predict inclusion in the neoplastic or nonneoplastic lesion groups. Receiver operator characteristic (ROC) analysis was used to compare the discriminatory capability of H-1-MRSI and perfusion MR imaging. RESULTS: The discriminant function analysis correctly classified 84.2% of original grouped cases (P <.0001), on the basis of NAA/Cho, Cho(norm.) NAA(norm,) and NAA/Cr ratios. MRSI and perfusion MR imaging had similar discriminatory capabilities in differentiating tumors from nonneoplastic lesions. With cutoff points of NAA/Cho <= 0.61 and rCBV >= 1.50 (corresponding to diagnosis of the tumors), a sensitivity of 72.2% and specificity of 91.7% in differentiating tumors from nonneoplastic lesions were achieved. CONCLUSION: These results suggest a promising role for H-1-MRSI and perfusion MR imaging in the distinction between brain tumors and nonneoplastic lesions in adults. C1 [Hourani, R.; Barker, P. B.; Horska, A.] Johns Hopkins Univ Hosp, Dept Radiol & Radiol Sci, Baltimore, MD USA. [Weingart, J. D.] Johns Hopkins Univ Hosp, Dept Neurol Surg, Baltimore, MD USA. [Brant, L. J.] Natl Inst Hlth, NIA, Gerontol Res Ctr, Baltimore, MD USA. [Hourani, R.] Amer Univ Beirut, Med Ctr, Dept Radiol, Beirut, Lebanon. [Rizk, T.] Hop Hotel Dieu, Dept Neurosurg, Beirut, Lebanon. [Barker, P. B.] Kennedy Krieger Inst, FM Kirby Res Ctr, Baltimore, MD USA. RP Horska, A (reprint author), Johns Hopkins Univ, Dept Radiol & Radiol Sci, 217 Traylor Bldg, 720 Rutland Ave, Baltimore, MD 21205 USA. EM ahorska@jhmi.edu FU NCRR NIH HHS [P41 RR015241-060002, P41 RR015241, P41 RR015241-040002]; NINDS NIH HHS [R01 NS042851, 1R01 NS042851] NR 35 TC 55 Z9 56 U1 0 U2 2 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD FEB PY 2008 VL 29 IS 2 BP 366 EP 372 DI 10.3174/ajnr.A0810 PG 7 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 265FT UT WOS:000253345200037 PM 18055564 ER PT J AU Bailit, JL Landon, MB Lai, YL Rouse, DJ Spong, CY Varner, MW Moawad, AH Simhan, HN Harper, M Wapner, RJ Sorokin, Y Miodovnik, M O'Sullivan, MJ Sibai, BM Langer, O AF Bailit, Jennifer L. Landon, Mark B. Lai, Yinglei Rouse, Dwight J. Spong, Catherine Y. Varner, Michael W. Moawad, Atef H. Simhan, Hyagriv N. Harper, Margaret Wapner, Ronald J. Sorokin, Yoram Miodovnik, Menachem O'Sullivan, Mary Jo Sibai, Baha M. Langer, Oded CA Natl Inst Child Hlth Human Dev Maternal-Fetal Med Units TI Maternal-fetal medicine units network cesarean registry: impact of shift change on cesarean complications SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE change of shift; obstetrics; quality of care; work hours ID QUALITY; CLAIMS; CARE AB OBJECTIVE: This study was undertaken to evaluate the effect of change of shift for physicians and nurses on complications associated with cesarean delivery. STUDY DESIGN: 17,996 term women undergoing an unscheduled cesarean delivery in 13 centers from 1999-2000 were included. Maternal and neonatal morbidities were evaluated by time of infant delivery vis-a-vis nursing change of shift (6 AM-8 AM, 2 PM- 4 PM, 10 PM-12 AM vs all other hours). The sample was then limited to weekdays only and physician shift changes were evaluated ( physician shift change 6 AM-8 AM, 5 PM-7 PM vs all others). A composite of 30 maternal morbidities was also evaluated by logistic regression, controlling for potentially confounding factors. RESULTS: Physician change of shift had no measurable effect on maternal and neonatal outcomes. Neonatal facial nerve palsies were increased at nursing change of shift ( 5 vs 0) as were hysterectomies (33 [0.24%] vs 23 [0.53%]; P < .007). Nursing change of shift had no impact on composite maternal morbidity after controlling for age, race, insurance, medical problems, prior incision type, weekend day, and prenatal care (odds ratio = 0.98; 95% confidence interval = 0.89-1.08). CONCLUSION: Physician change of shift does not appear to be associated with an increase in morbidities. However, cesarean delivery during nursing change of shift is associated with increased risk of neonatal facial nerve palsy and hysterectomy. Further investigation is needed to understand the cause of this association. C1 [Bailit, Jennifer L.] Case Western Reserve Univ, Dept Obstet, Cleveland, OH 44106 USA. [Bailit, Jennifer L.] Case Western Reserve Univ, Dept Gynecol, Cleveland, OH USA. [Landon, Mark B.] Ohio State Univ, Columbus, OH 43210 USA. [Rouse, Dwight J.] Univ Alabama, Birmingham, AL USA. [Varner, Michael W.] Univ Utah, Salt Lake City, UT USA. [Moawad, Atef H.] Univ Chicago, Chicago, IL 60637 USA. [Simhan, Hyagriv N.] Univ Pittsburgh, Pittsburgh, PA USA. [Harper, Margaret] Wake Forest Univ, Winston Salem, NC 27109 USA. [Wapner, Ronald J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Sorokin, Yoram] Wayne State Univ, Detroit, MI USA. [Miodovnik, Menachem] Univ Cincinnati, Cincinnati, OH USA. [O'Sullivan, Mary Jo] Univ Miami, Miami, FL 33152 USA. [Sibai, Baha M.] Univ Tennessee, Memphis, TN USA. [Langer, Oded] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Lai, Yinglei] George Washington Univ, Ctr Biostat, Washington, DC USA. [Spong, Catherine Y.] NICHHD, Bethesda, MD 20892 USA. RP Bailit, JL (reprint author), Case Western Reserve Univ, Dept Obstet, Cleveland, OH 44106 USA. RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU NICHD NIH HHS [HD27869, HD21410, HD21414, HD27860, HD27861, HD27905, HD27915, HD27917, HD34116, HD34122, HD34136, HD34208, HD34210, HD36801, K12 HD98004] NR 8 TC 0 Z9 0 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD FEB PY 2008 VL 198 IS 2 AR 173.e1 DI 10.1016/j.ajog.2007.11.003 PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 268NU UT WOS:000253587300008 PM 18226616 ER PT J AU Carter, TC Druschel, CM Romitti, PA Bell, EM Werler, MM Mitchell, AA AF Carter, Tonia C. Druschel, Charlotte M. Romitti, Paul A. Bell, Erin M. Werler, Martha M. Mitchell, Allen A. CA Natl Birth Defects Prevent Study TI Antifungal drugs and the risk of selected birth defects SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE antifungal agents; congenital abnormalities; pregnancy; teratogens ID PREGNANCY OUTCOMES; FLUCONAZOLE; CLOTRIMAZOLE; MALFORMATIONS; PREVENTION; MICONAZOLE; ABSORPTION; ECONAZOLE; THERAPY AB OBJECTIVE: This study examined whether first-trimester antifungal drug use was associated with the risk of selected birth defects. STUDY DESIGN: Subjects were participants in a case-control study, the National Birth Defects Prevention Study, with singleton deliveries from 1997 to 2003. Based on maternal interviews, first-trimester antifungal drug use was compared between 7047 cases with isolated defects and 4774 nonmalformed controls using unconditional logistic regression. RESULTS: Risk was elevated for hypoplastic left heart syndrome (odds ratio, 2.30; 95% confidence interval, 1.04, 5.06) but not for other cardiovascular defects. An increased risk of 1.88 was observed for diaphragmatic hernia but was not statistically significant. Estimates approximated unity for neural tube defects, oral clefts, anorectal atresia, hypospadias, and craniosynostosis. CONCLUSION: First-trimester antifungal drug exposure was not strongly associated with the risk of most birth defects, but further studies should examine the preliminary results of an association with hypoplastic left heart syndrome. C1 [Carter, Tonia C.; Druschel, Charlotte M.; Bell, Erin M.] SUNY Albany, Sch Publ Hlth, Dept Epidemiol, Albany, NY 12222 USA. [Druschel, Charlotte M.] Ctr Environm Hlth, New York State Dept Hlth, Congenital Malformat Registry, Troy, NY USA. [Romitti, Paul A.] Univ Iowa, Coll Med, Dept Epidemiol, Iowa City, IA USA. [Werler, Martha M.; Mitchell, Allen A.] Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. RP Carter, TC (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, Epidemiol Branch, 6100 Execut Blvd,Room 7B03C MSC 7510, Bethesda, MD 20892 USA. EM carterto@mail.nih.gov RI Publications, NBDPS/B-7692-2013; OI Mitchell, Allen/0000-0003-0950-6799; Werler, Martha/0000-0003-3392-6814 FU PHS HHS [U50/CCU223184] NR 27 TC 3 Z9 3 U1 1 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD FEB PY 2008 VL 198 IS 2 AR 191.e1 DI 10.1016/j.ajog.2007.08.044 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 268NU UT WOS:000253587300015 PM 18226621 ER PT J AU Bianco, C Strizzi, L Mancino, M Watanabe, K Gonzales, M Hamada, S Raafat, A Sahlah, L Chang, C Sotgia, F Normanno, N Lisanti, M Salomon, DS AF Bianco, Caterina Strizzi, Luigi Mancino, Mario Watanabe, Kazuhide Gonzales, Monica Hamada, Shin Raafat, Ahmed Sahlah, Lawson Chang, Cindy Sotgia, Federica Normanno, Nicola Lisanti, Michael Salomon, David S. TI Regulation of cripto-1 signaling and biological activity by caveolin-1 in mammary epithelial cells SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID HUMAN BREAST-CANCER; CERVICAL-CARCINOMA CELLS; FACTOR-RELATED PROTEINS; EMBRYONIC STEM-CELLS; EGF-CFC FAMILY; TRANSGENIC MICE; IN-VIVO; TUMOR PROGRESSION; GLAND DEVELOPMENT; TYROSINE KINASE AB Human and mouse Cripto-1 (CR-1/Cr-1) proteins play an important role in mammary gland development and tumorigenesis. in this study, we examined the relationship between Cripto-1 and caveolin-1 (Cav-1), a membrane protein that acts as a tumor suppressor in the mammary gland. Cripto-1 was found to interact with Cav-1 in COS7 cells and mammary epithelial cells. Using EpH4 mouse mammary epithelial cells expressing Cr-1 (EpH4 Cr-1) or Cr-1 and Cav-1 (EpH4 Cr-1/Cav-1), we demonstrate that Cav-1 expression markedly reduced the ability of Cr-1 to enhance migration, invasion, and formation of branching structures in EpH4 Cr-1/Cav-1 cells as compared to EpH4 Cr-1 cells. Furthermore, coexpression of Cav-1 together with Cr-1 in EpH4 Cr-1/Cav-1 cells inhibited Cr-1-mediated activation of c-src and mitogen-activated protein kinase signaling pathways. Conversely, primary mammary epithelial cells isolated from Cav-1 null(-/-)/mouse mammary tumor virus-CR-1 transgenic animals showed enhanced motility and activation of mitogen-activated protein kinase and c-src as compared to Cav-1(+/-)/CR-1 mammary cells. Finally, mammary tumors derived from mouse mammary tumor virus-CR-1 mice showed a dramatic reduction of Cav-1 expression as compared to mammary tissue from normal FVB/N mice, suggesting that in vivo Cav-1 is down-regulated during the process of CR-1-mediated mammary tumorigenesis. C1 [Bianco, Caterina; Strizzi, Luigi; Mancino, Mario; Watanabe, Kazuhide; Gonzales, Monica; Hamada, Shin; Salomon, David S.] NIH, Natl Canc Inst, Sect Tumor Growth Factor, Bethesda, MD 20892 USA. [Raafat, Ahmed; Sahlah, Lawson] NIH, Natl Canc Inst, Sect Oncogenet, Bethesda, MD 20892 USA. [Chang, Cindy] Univ Med & Dent New Jersey, New Jersey Dent Sch, Newark, NJ 07103 USA. [Sotgia, Federica; Lisanti, Michael] Thomas Jefferson Univ, Kimmel Canc Ctr, Dept Canc Biol, Philadelphia, PA 19107 USA. [Normanno, Nicola] ITN Fondaz, Cell Biol & Preclin Models Unit, Naples, Italy. RP Salomon, DS (reprint author), NCI, 97 Convent Dr,Bldg 37,Room 1118, Bethesda, MD 20892 USA. EM salomond@mail.nih.gov OI Normanno, Nicola/0000-0002-7158-2605 FU Intramural NIH HHS; Associazione Italiana per la Ricerca sul Cancro NR 73 TC 15 Z9 16 U1 0 U2 3 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD FEB PY 2008 VL 172 IS 2 BP 345 EP 357 DI 10.2353/ajpath.2008.070696 PG 13 WC Pathology SC Pathology GA 259EB UT WOS:000252920800008 PM 18202186 ER PT J AU Tongbai, R Idellmar, G Nordgard, SH Cui, WW Jacobs, JL Haggerty, CM Chanock, SJ Borresen-Dale, AL Livingston, G Shaunessy, P Chiang, CH Kristensen, VN Bilke, S Gardner, K AF Tongbai, Ron Idellmar, Gila Nordgard, Silje H. Cui, Wenwu Jacobs, Jonathan L. Haggerty, Cynthia M. Chanock, Stephen J. Borresen-Dale, Anne-Lise Livingston, Gary Shaunessy, Patrick Chiang, Chih-Hung Kristensen, Vessela N. Bilke, Sven Gardner, Kevin TI Transcriptional networks inferred from molecular signatures of breast cancer SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID NF-KAPPA-B; GROWTH-FACTOR RECEPTOR; GENOME-WIDE ANALYSIS; GENE-EXPRESSION; COMPLEX NETWORKS; CPG ISLANDS; IN-VIVO; PROMOTER; CELLS; ACTIVATION AB Global genomic approaches in cancer research have provided new and innovative strategies for the identification of signatures that differentiate various types of human cancers. Computational analysis of the promoter composition of the genes within these signatures may provide a powerful method for deducing the regulatory transcriptional networks that mediate their collective function. in this study we have systematically analyzed the promoter composition of gene classes derived from previously established genetic signatures that recently have been shown to reliably and reproducibly distinguish five molecular subtypes of breast cancer associated with distinct clinical outcomes. Inferences made from the trends of transcription factor binding site enrichment in the promoters of these gene groups led to the identification of regulatory pathways that implicate discrete transcriptional networks associated with specific molecular subtypes of breast cancer. One of these inferred pathways predicted a role for nuclear factor-kappa B in a novel feed-forward, self-amptifying, autoregulatory module regulated by the ERBB family of growth factor receptors. The existence of this pathway was verified in vivo by chromatin immunoprecipitation and shown to be deregulated in breast cancer cells overexpressing ERBB2. This analysis indicates that approaches of this type can provide unique insights into the differential regulatory molecular programs associated with breast cancer and will aid in identifying specific transcriptional networks and pathways as potential targets for tumor subtype-specific therapeutic intervention. C1 [Tongbai, Ron; Idellmar, Gila; Cui, Wenwu; Jacobs, Jonathan L.; Haggerty, Cynthia M.; Gardner, Kevin] NCI, Lab Receptor Biol & Gene Express, Bethesda, MD USA. [Chanock, Stephen J.] NCI, Sect Genome Variat, Bethesda, MD USA. [Bilke, Sven] NCI, Pediat Oncol Branch, Bethesda, MD USA. [Livingston, Gary; Shaunessy, Patrick; Chiang, Chih-Hung] Univ Massachusetts, Dept Comp Sci, Lowell, MA USA. [Nordgard, Silje H.; Kristensen, Vessela N.] Radiumhosp Med Ctr, Rikshosp, Inst Canc Res, Dept Genet, Oslo, Norway. [Nordgard, Silje H.; Borresen-Dale, Anne-Lise; Kristensen, Vessela N.] Univ Oslo, Fac Med, Oslo, Norway. RP Gardner, K (reprint author), 41 Library Dr,Bldg 41-D305, Bethesda, MD 20892 USA. EM gardnerk@mail.nih.gov RI Nord, Silje/R-5212-2016; OI Nord, Silje/0000-0002-3271-5356; Jacobs, Jonathan/0000-0001-5608-4256 FU Intramural NIH HHS NR 63 TC 10 Z9 10 U1 0 U2 1 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 FEB PY 2008 VL 172 IS 2 BP 495 EP 509 DI 10.2353/ajpath.2008.061079 PG 15 WC Pathology SC Pathology GA 259EB UT WOS:000252920800021 PM 18187569 ER PT J AU Buxbaum, LJ Haaland, KY Hallett, M Wheaton, L Heilman, KM Rodriguez, A Rothi, LJG AF Buxbaum, Laurel J. Haaland, Kathleen Y. Hallett, Mark Wheaton, Lewis Heilman, Kenneth M. Rodriguez, Amy Rothi, Leslie J. Gonzalez TI Treatment of limb apraxia - Moving forward to improved action SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Review DE apraxia; ideomotor apraxia; treatment; rehabilitation ID TRANSCRANIAL MAGNETIC STIMULATION; HAND-OBJECT INTERACTIONS; BRAIN-DAMAGED PATIENTS; IDEOMOTOR APRAXIA; STROKE PATIENTS; NATURALISTIC ACTION; IDEATIONAL APRAXIA; INTERNAL-MODELS; CORTICOBASAL DEGENERATION; NEURAL REPRESENTATIONS AB Limb apraxia is a common disorder of skilled, purposive movement that is frequently associated with stroke and degenerative diseases such as Alzheimer disease. Despite evidence that several types of limb apraxia significantly impact functional abilities, surprisingly few studies have focused on development of treatment paradigms. Additionally, although the most disabling types of apraxia reflect damage to gesture and/or object memory systems, existing treatments have not fully taken advantage of principles of experience known to affect learning and neural plasticity. We review the current state of the art in the rehabilitation of limb apraxia, indicate possible points of contact with the learning literature, and generate suggestions for how translational principles might be applied to the development of future research on treatment of this disabling disorder. C1 [Buxbaum, Laurel J.] Moss Rehabil Res Inst, Philadelphia, PA 19141 USA. [Buxbaum, Laurel J.] Thomas Jefferson Univ, Philadelphia, PA 19107 USA. [Haaland, Kathleen Y.] Albuquerque Vet Affairs Med Ctr, Albuquerque, NM USA. [Haaland, Kathleen Y.] Univ New Mexico, Albuquerque, NM 87131 USA. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. [Wheaton, Lewis] Dept Vet Affairs, Baltimore, MD USA. [Wheaton, Lewis] Baltimore Geriatr Res Educ & Clin Ctr, Baltimore, MD USA. [Heilman, Kenneth M.; Rodriguez, Amy; Rothi, Leslie J. Gonzalez] N Florida S Georgia Vet Hlth Syst, Gainesville, FL USA. [Heilman, Kenneth M.; Rodriguez, Amy; Rothi, Leslie J. Gonzalez] Univ Florida, Gainesville, FL USA. RP Buxbaum, LJ (reprint author), Moss Rehabil Res Inst, 1200 W Tabor Rd, Philadelphia, PA 19141 USA. RI Wheaton, Lewis /B-4482-2009; Rodriguez, Amy/F-8332-2011 OI Wheaton, Lewis /0000-0003-0771-0294; FU NINDS NIH HHS [R01-NS036387] NR 122 TC 33 Z9 33 U1 1 U2 14 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD FEB PY 2008 VL 87 IS 2 BP 149 EP 161 DI 10.1097/PHM.0b013e31815e6727 PG 13 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 330PN UT WOS:000257955400009 PM 18209511 ER PT J AU Lee, S Muniyappa, R Yan, X Chen, H Yue, LQ Hong, EG Kim, JK Quon, MJ AF Lee, Sihoon Muniyappa, Ranganath Yan, Xu Chen, Hui Yue, Lilly Q. Hong, Eun-Gyoung Kim, Jason K. Quon, Michael J. TI Comparison between surrogate indexes of insulin sensitivity and resistance and hyperinsulinemic euglycemic clamp estimates in mice SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE calibration model; quantitative insulin-sensitivity check index ID HOMEOSTASIS MODEL ASSESSMENT; TYPE-2 DIABETIC-PATIENTS; FASTING PLASMA-GLUCOSE; BETA-CELL FUNCTION; CHECK INDEX; CARDIOVASCULAR-DISEASE; RECIPROCAL INDEX; MOUSE; TOLERANCE; QUICKI AB Insulin resistance contributes to the pathophysiology of diabetes, obesity, and their cardiovascular complications. Mouse models of these human diseases are useful for gaining insight into pathophysiological mechanisms. The reference standard for measuring insulin sensitivity in both humans and animals is the euglycemic glucose clamp. Many studies have compared surrogate indexes of insulin sensitivity and resistance with glucose clamp estimates in humans. However, regulation of metabolic physiology in humans and rodents differs and comparisons between surrogate indexes and the glucose clamp have not been directly evaluated in rodents previously. Therefore, in the present study, we compared glucose clamp-derived measures of insulin sensitivity (GIR and SIClamp) with surrogate indexes, including quantitative insulin-sensitivity check index (QUICKI), homeostasis model assessment (HOMA), 1/HOMA, log(HOMA), and 1/fasting insulin, using data from 87 mice with a wide range of insulin sensitivities. We evaluated simple linear correlations and performed calibration model analyses to evaluate the predictive accuracy of each surrogate. All surrogate indexes tested were modestly correlated with both GIR and SIClamp. However, a stronger correlation between body weight per se and both GIR and SIClamp was noted. Calibration analyses of surrogate indexes adjusted for body weight demonstrated improved predictive accuracy for GIR [e.g., R = 0.68, for QUICKI and log(HOMA)]. We conclude that linear correlations of surrogate indexes with clamp data and predictive accuracy of surrogate indexes in mice are not as substantial as in humans. This may reflect intrinsic differences between human and rodent physiology as well as increased technical difficulties in performing glucose clamps in mice. C1 [Lee, Sihoon; Muniyappa, Ranganath; Chen, Hui; Quon, Michael J.] NIH, NCCAM, Diabet Unit, Bethesda, MD 20892 USA. [Yan, Xu; Yue, Lilly Q.] US FDA, Ctr Devices & Radiol Hlth, Div Biostat, Rockville, MD 20857 USA. [Hong, Eun-Gyoung; Kim, Jason K.] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA USA. RP Muniyappa, R (reprint author), NIH, NCCAM, Diabet Unit, 9 Mem Dr,Bldg 9,Room 1M-105 MSC 0920, Bethesda, MD 20892 USA. EM quonm@nih.gov RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 FU Intramural NIH HHS; NIDDK NIH HHS [U24 DK 59635] NR 36 TC 72 Z9 73 U1 2 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD FEB PY 2008 VL 294 IS 2 BP E261 EP E270 DI 10.1152/ajpendo.00676.2007 PG 10 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 261KN UT WOS:000253077600008 PM 18003716 ER PT J AU Mott, DM Stone, K Gessel, MC Bunt, JC Bogardus, C AF Mott, David M. Stone, Karen Gessel, Mary C. Bunt, Joy C. Bogardus, Clifton TI Palmitate action to inhibit glycogen synthase and stimulate protein phosphatase 2A increases with risk factors for type 2 diabetes SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE skeletal muscle; cell culture; obesity; insulin resistance ID SKELETAL-MUSCLE CELLS; INSULIN-RESISTANT SUBJECTS; PIMA-INDIANS; FATTY-ACIDS; CARBOHYDRATE-METABOLISM; GLUCOSE STORAGE; PHOSPHORYLATION; CERAMIDE; PATHWAY; KINASE AB Recent studies have suggested that abnormal regulation of protein phosphatase 2A (PP2A) is associated with Type 2 diabetes in rodent and human tissues. Results with cultured mouse myotubes support a mechanism for palmitate activation of PP2A, leading to activation of glycogen synthase kinase 3. Phosphorylation and inactivation of glycogen synthase by glycogen synthase kinase 3 could be the mechanism for long-chain fatty acid inhibition of insulin-mediated carbohydrate storage in insulin-resistant subjects. Here, we test the effects of palmitic acid on cultured muscle glycogen synthase and PP2A activities. Palmitate inhibition of glycogen synthase fractional activity is increased in subjects with high body mass index compared with subjects with lower body mass index (r = -0.43, P = 0.03). Palmitate action on PP2A varies from inhibition in subjects with decreased 2-h plasma glucose concentration to activation in subjects with increased 2-h plasma glucose concentration (r = 0.45, P < 0.03) during oral glucose tolerance tests. The results do not show an association between palmitate effects on PP2A and glycogen synthase fractional activity. We conclude that subjects at risk for Type 2 diabetes have intrinsic differences in palmitate regulation of at least two enzymes (PP2A and glycogen synthase), contributing to abnormal insulin regulation of glucose metabolism. C1 [Mott, David M.; Stone, Karen; Gessel, Mary C.; Bunt, Joy C.; Bogardus, Clifton] NIDDKD, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH,Dept Hlth & Human Serv, Phoenix, AZ USA. RP Mott, DM (reprint author), NIDDK, NIH, DHHS, 4212 N 16th St, Phoenix, AZ 85016 USA. EM dmott@mail.nih.gov FU Intramural NIH HHS [Z01 DK069015-25] NR 49 TC 8 Z9 8 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD FEB PY 2008 VL 294 IS 2 BP E444 EP E450 DI 10.1152/ajpendo.00386.2007 PG 7 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 261KN UT WOS:000253077600030 PM 18056794 ER PT J AU LaCroix, C Freeling, J Giles, A Wess, J Li, YF AF LaCroix, Carly Freeling, Jessica Giles, Alese Wess, Juergen Li, Yi-Fan TI Deficiency of M-2 muscarinic acetylcholine receptors increases susceptibility of ventricular function to chronic adrenergic stress SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE muscarinic; cardiac; contractility; matrix metalloproteinase; isoproterenol ID CONGESTIVE-HEART-FAILURE; CORONARY-ARTERY-DISEASE; DIASTOLIC DYSFUNCTION; MYOCARDIAL-INFARCTION; CARDIAC-HYPERTROPHY; RATE-VARIABILITY; PARASYMPATHETIC WITHDRAWAL; EXTRACELLULAR-MATRIX; VAGAL-STIMULATION; KNOCKOUT MICE AB Suppressed parasympathetic nervous system (PSNS)function has been found in a variety of cardiovascular diseases, such as hypertension, heart failure, and diabetes. However, whether impaired PSNS function plays a significant role in ventricular dysfunction remains to be investigated. Cardiac regulation by the PSNS is primarily mediated by the M-2 muscarinic acetylcholine receptor (M-2-AChR). In this study, we tested the hypothesis that lack of M-2-AChR-mediated PSNS function may adversely impact cardiac ventricular function. Using M-2-AChR knockout (KO) and wild-type (WT) mice, we found that the basal levels of heart rate and left ventricular function were similar in M-2-AChR KO and WT mice. A bolus injection of isoproterenol (Iso) induced a greater increase in heart rate in M-2-AChR KO mice than in WT mice. However, the responses of change in pressure over time (dP/dt) to Iso were similar in the two groups. After chronic infusion with Iso for 1 wk, the baseline values of left ventricular function were increased to similar extents in M-2-AChR KO and WT mice. However, the M-2-AChR KO mice exhibited impaired ventricular function, indicated as attenuated dP/dt and increased end-diastolic pressure, during an increase in cardiac afterload induced by a bolus injection of phenylephrine. Furthermore, chronic Iso infusion significantly increased matrix metalloproteinase (MMP) activity in the heart in M-2-AChR KO mice. In primary culture of mixed neonatal rat cardiac fibroblast and cardiomyocytes, cotreatment with muscarinic agonist bethanechol reversed phenylephrine-induced increase in MMP-9 activation. These data suggest that M-2-AChR may mediate an inhibitory regulation on MMP function. The overall results from this study suggest that M-2-AChR-mediated PSNS function may provide cardiac protection. Lack of this protective mechanism will increase the susceptibility of the heart to cardiac stresses. C1 [LaCroix, Carly; Freeling, Jessica; Giles, Alese; Li, Yi-Fan] Univ S Dakota, Stanford Sch Med, Div Basic Biomed Sci, Vermillion, SD 57069 USA. [Wess, Juergen] NIH, NIDDKD, Mol Signaling Sect, Lab Bioorgan Chem, Bethesda, MD USA. RP Li, YF (reprint author), Univ S Dakota, Stanford Sch Med, Div Basic Biomed Sci, 414 E Clark St, Vermillion, SD 57069 USA. EM yli01@usd.edu FU NCRR NIH HHS [2 P20 RR016479, 5 P20 RR017662] NR 61 TC 31 Z9 33 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD FEB PY 2008 VL 294 IS 2 BP H810 EP H820 DI 10.1152/ajpheart.00724.2007 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 261IN UT WOS:000253072400032 PM 18055517 ER PT J AU Kennedy, DJ Elkareh, J Shidyak, A Shapiro, AP Smaili, S Mutgi, K Gupta, S Tian, J Morgan, E Khouri, S Cooper, CJ Periyasamy, SM Xie, ZJ Malhotra, D Fedorova, OV Bagrov, AY Shapiro, JI AF Kennedy, David J. Elkareh, Jihad Shidyak, Amjad Shapiro, Anna P. Smaili, Sleiman Mutgi, Krishna Gupta, Shalini Tian, Jiang Morgan, Eric Khouri, Samer Cooper, Christopher J. Periyasamy, Sankaridrug M. Xie, Zijian Malhotra, Deepak Fedorova, Olga V. Bagrov, Alexei Y. Shapiro, Joseph I. TI Partial nephrectomy as a model for uremic cardiomyopathy in the mouse SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article; Proceedings Paper CT 39th Annual Meeting of the American-Society-of-Nephrology/Annual Renal Week CY NOV 14-19, 2006 CL San Diego, CA SP Amer Soc Nephrol DE renal failure; TGF-beta; cardiotonic steroids; reactive oxygen species; fibrosis ID PRESSURE-VOLUME RELATIONSHIP; CHRONIC-RENAL-FAILURE; HEART-FAILURE; MYOCARDIAL-INFARCTION; TISSUE DOPPLER; BLOOD-PRESSURE; MICE; RATS; MARINOBUFAGENIN AB Because of the plethora of genetic manipulations available in the mouse, we performed a partial nephrectomy in the mouse and examined whether the phenotypical features of uremic cardiomyopathy described in humans and rats were also present in the murine model. A 5/6 nephrectomy was performed using a combination of electrocautory to decrease renal mass on the left kidney and right surgical nephrectomy. This procedure produced substantial and persistent hypertension as well as increases in circulating concentrations of marinobufagenin. Invasive physiological measurements of cardiac function demonstrated that the 5/6 nephrectomy resulted in impairment of both active and passive left ventricular relaxation at 4 wk whereas tissue Doppler imaging detected changes in diastolic function after 6 wk. Morphologically, hearts demonstrated enlargement and progressive fibrosis, and biochemical measurements demonstrated downregulation of the sarcoplasmic reticulum calcium ATPase as well as increases in collagen-1, fibronectin, and vimentin expression. Our results suggest that partial nephrectomy in the mouse establishes a model of uremic cardiomyopathy which shares phenotypical features with the rat model as well as patients with chronic renal failure. C1 [Kennedy, David J.; Elkareh, Jihad; Shidyak, Amjad; Shapiro, Anna P.; Smaili, Sleiman; Mutgi, Krishna; Gupta, Shalini; Tian, Jiang; Morgan, Eric; Khouri, Samer; Cooper, Christopher J.; Periyasamy, Sankaridrug M.; Xie, Zijian; Malhotra, Deepak; Shapiro, Joseph I.] Univ Toledo, Dept Med, Coll Med, Toledo, OH 43614 USA. [Kennedy, David J.; Elkareh, Jihad; Shidyak, Amjad; Shapiro, Anna P.; Smaili, Sleiman; Mutgi, Krishna; Gupta, Shalini; Tian, Jiang; Morgan, Eric; Khouri, Samer; Cooper, Christopher J.; Periyasamy, Sankaridrug M.; Xie, Zijian; Malhotra, Deepak; Shapiro, Joseph I.] Univ Toledo, Dept Pharmacol, Coll Med, Toledo, OH 43614 USA. [Fedorova, Olga V.; Bagrov, Alexei Y.] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. RP Shapiro, JI (reprint author), Univ Toledo, Dept Med, Coll Med, 3120 Glendale Ave, Toledo, OH 43614 USA. EM joseph.shapiro@utoledo.edu FU Intramural NIH HHS [Z01 AG000609-15, Z99 AG999999]; NHLBI NIH HHS [HL-67963, R01 HL067963] NR 19 TC 51 Z9 52 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 2008 VL 294 IS 2 BP F450 EP F454 DI 10.1152/ajprenal.00472.2007 PG 5 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 256QI UT WOS:000252744300020 PM 18032546 ER PT J AU Hunter, CM Peterson, AL Alvarez, LM Poston, WC Brundige, AR Haddock, K Van Brunt, DL Foreyt, JP AF Hunter, Christine M. Peterson, Alan L. Alvarez, Lisa M. Poston, Walker C. Brundige, Antoinette R. Haddock, Keith Van Brunt, David L. Foreyt, John P. TI Weight management using the Internet - A randomized controlled trial SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID UNITED-STATES; AIR-FORCE; OBESITY; GAIN; METAANALYSIS; OVERWEIGHT; PROGRAM; MAINTENANCE; PREVENTION; ADULTS AB Background: Most weight-loss research targets obese individuals who desire large weight reductions. However, evaluation of weight-gain prevention in over-weight individuals is also critical as most Americans become obese as a result of a gradual gain of 1-2 pounds per year over many years. Method: This study evaluated the efficacy of an Internet-based program for weight-loss and weight-gain prevention with a two-group, prospective, randomized controlled trial. A military medical research center with a population of 17,000 active-duty military personnel supplied 446 overweight individuals (222 men; 224 women) with a mean age of 34 years and a mean BMI of 29. Recruitment and study participation occurred 2003-2005 and data were analyzed in 2006. Participants were randomly assigned to receive the 6-month behavioral Internet treatment (BIT, n=227) or usual care (n=224). Change in body weight, BMI, percent body fat, and waist circumference; presented as group by time interactions, were measured. Results: After 6 months, completers who received BIT lost 1.3 kg while those assigned to usual care gained 0.6 kg (F-(df=366)=24.17; I<0.001). Results were similar for the intention-to-treat model. BIT participants also had significant changes in BMI (-0.5 vs +0.2 kg/m(2); F-(df=366)=24.58); percent body fat (-0.4 vs +0.6%; F-(df=366)=10.45); and waist circumference (-2.1 vs -0.4 cm; F-(df=366)=17.09); p<0.001 for all. Conclusions: Internet-based weight-management interventions result in small amounts of weight loss, prevent weight gain, and have potential for widespread dissemination as a population health approach. C1 [Hunter, Christine M.] Natl Inst Diabet & Digest & Kidney Dis, Div Diabet Endocrinol & Metab Dis, Bethesda, MD 20892 USA. [Peterson, Alan L.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. [Peterson, Alan L.; Alvarez, Lisa M.; Brundige, Antoinette R.] Wilford Hall USAF Med Ctr, Dept Psychol, San Antonio, TX 78236 USA. [Poston, Walker C.; Haddock, Keith] Univ Missouri, Kansas City Sch Med, Kansas City, MO 64110 USA. [Van Brunt, David L.] Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. [Alvarez, Lisa M.; Brundige, Antoinette R.; Foreyt, John P.] Eli Lilly & Co, Indianapolis, IN 46285 USA. [Alvarez, Lisa M.; Brundige, Antoinette R.; Foreyt, John P.] Baylor Coll Med, Houston, TX 77030 USA. RP Hunter, CM (reprint author), Natl Inst Diabet & Digest & Kidney Dis, Div Diabet Endocrinol & Metab Dis, 6707 Democracy Blvd,Room 605 MCS 5460, Bethesda, MD 20892 USA. EM hunterchristine@niddk.nih.gov NR 48 TC 64 Z9 64 U1 0 U2 10 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 FEB PY 2008 VL 34 IS 2 BP 119 EP 126 DI 10.1016/j.amepre.2007.09.026 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 256VP UT WOS:000252758300005 PM 18201641 ER PT J AU King, AC Ahn, DK Oliveira, BM Atienza, AA Castro, CM Gardner, CD AF King, Abby C. Ahn, David K. Oliveira, Brian M. Atienza, Audie A. Castro, Cynthia M. Gardner, Christopher D. TI Promoting physical activity through hand-held computer technology SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; OLDER-ADULTS; MOMENTARY ASSESSMENT; BEHAVIOR-CHANGE; PRIMARY-CARE; WEIGHT-LOSS; INTERVENTIONS; OUTCOMES; PROGRAM AB Background: Efforts to achieve population-wide increases in walking and similar moderate-intensity physical activities potentially can be enhanced through relevant applications of state-of-the-art interactive communication technologies. Yet few systematic efforts to evaluate the efficacy of hand-held computers and similar devices for enhancing physical activity levels have occurred. The purpose of this first-generation study was to evaluate the efficacy of a hand-held computer (i.e., personal digital assistant [PDA]) for increasing moderate intensity or more vigorous (MOD+) physical activity levels over 8 weeks in mid-life and older adults relative to a standard information control arm. Design: Randomized, controlled 8-week experiment. Data were collected in 2005 and analyzed in 2006-2007. Setting/Participants: Community-based study of 37 healthy, initially underactive adults aged 50 years and older who were randomized and completed the 8-week study (intervention=19, control=18). Intervention: Participants received an instructional session and a PDA programmed to monitor their physical activity levels twice per day and provide daily and weekly individualized feedback, goal setting, and support. Controls received standard, age-appropriate written physical activity educational materials. Main Oucome Measure: Physical activity was assessed via the Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire at baseline and 8 weeks. Results: Relative to controls, intervention participants reported significantly greater 8-week mean estimated caloric expenditure levels and minutes per week in MOD+ activity (p<0.04). Satisfaction with the PDA was reasonably high in. this largely PDA-naive sample. Conclusions: Results from this first-generation study indicate that hand-held computers may be effective tools for increasing initial physical activity levels among underactive adults. C1 [King, Abby C.; Ahn, David K.; Oliveira, Brian M.; Castro, Cynthia M.; Gardner, Christopher D.] Stanford Univ, Sch Med, Stanford Prevent Res Ctr, Dept Med, Stanford, CA 94305 USA. [Atienza, Audie A.] Natl Canc Inst, Div Canc Control & Populat Sci, Behav Res Program, Hlth Promot Res Branch, Bethesda, MD USA. RP King, AC (reprint author), Stanford Univ, Sch Med, Stanford Prevent Res Ctr, Dept Med, Hoover Pavilion,Rm N229,211 Quarry Rd, Stanford, CA 94305 USA. EM king@stanford.edu FU NHLBI NIH HHS [T32 HL007034, T32 HL007034-33]; PHS HHS [5T32H107034] NR 27 TC 61 Z9 62 U1 2 U2 23 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 FEB PY 2008 VL 34 IS 2 BP 138 EP 142 DI 10.1016/j.amepre.2007.09.025 PG 5 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 256VP UT WOS:000252758300008 PM 18201644 ER PT J AU Miller, KE Laszlo, K Suomi, SJ AF Miller, Kimran E. Laszlo, Katalin Suomi, Stephen J. TI Why do captive tufted capuchins (Cebus apella) urine wash? SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE urine washing; aggression; thermoregalation; territoriality; sexual solicitations; cortisol ID BEHAVIOR; CORTISOL; MONKEYS; HYPOTHESES; CAPUCINUS; PRIMATES AB Urine washing (UW) has been observed in numerous species of prosimians and New World monkeys. 14 The functional significance of UW in Cebidae, specifically, Cebus apella, has not been determined. The objective of our study was to test two major hypotheses related to the function of UW: (1) UW functions as a thermoregulatory mechanism, and (2) UW functions as a means of social communication related to (a) territoriality, (b) sexual encounters, or (c) intragroup aggression/agitation. We collected focal data on a captive group of 28 tufted capuchins (C. apella; July-October 2004 and February-July 2005). We found no significant correlation between UW rates and temperature, at a constant, moderate humidity level. Rates of UW were significantly greater outdoors (no conspecific neighbors) vs. indoors (conspecific neighbors). Qualitative evidence suggests a relationship between UW by the alpha male and sexual solicitations from females. UW rates associated with aggression received were significantly higher than UW rates associated with aggression given and UW rates associated with potential fear/stress. There was also a significant negative correlation between cortisol measures and UW frequencies. Our results suggest that UW does not function in thermoregulation or in territorial communication. Alternatively, our results suggest that UW may be associated with sexual encounters and receiving aggression. Additionally, further investigation is warranted to determine whether UW is used as an appeasement mechanism or as a stress reliever or as both. C1 [Miller, Kimran E.; Laszlo, Katalin; Suomi, Stephen J.] NICHHD, Comparat Ethol Lab, NIH, Anim Ctr, Poolesville, MD USA. RP Miller, KE (reprint author), Univ No Iowa, Dept Biol, McCollum Sci Hall, Cedar Falls, IA 50614 USA. EM bocolobo00@yahoo.com FU Intramural NIH HHS NR 33 TC 4 Z9 5 U1 1 U2 9 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD FEB PY 2008 VL 70 IS 2 BP 119 EP 126 DI 10.1002/ajp.20462 PG 8 WC Zoology SC Zoology GA 254BP UT WOS:000252561700003 PM 17708538 ER PT J AU Stover, E Insel, TR AF Stover, Ellen Insel, Thomas R. TI Wayne Fenton, MD SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID SCHIZOPHRENIA SUBTYPES; NATURAL-HISTORY C1 [Insel, Thomas R.] NIMH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, 6001 Execut Blvd,Rm 8235,MSC 9669, Bethesda, MD 20892 USA. EM insel@moil.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 1 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 FEB PY 2008 VL 165 IS 2 BP 177 EP 178 PG 2 WC Psychiatry SC Psychiatry GA 260ZV UT WOS:000253049800006 PM 18245186 ER PT J AU Nuechterlein, KH Green, MF Kern, RS Baade, LE Barch, DM Cohen, JD Essock, S Fenton, WS Frese, FJ Gold, JM Goldberg, T Heaton, RK Keefe, RSE Kraemer, H Mesholam-Gately, R Seidman, LJ Stover, E Weinberger, DR Young, AS Zalcman, S Marder, SR AF Nuechterlein, Keith H. Green, Michael F. Kern, Robert S. Baade, Lyle E. Barch, Deanna M. Cohen, Jonathan D. Essock, Susan Fenton, Wayne S. Frese, Frederick J., III Gold, James M. Goldberg, Terry Heaton, Robert K. Keefe, Richard S. E. Kraemer, Helena Mesholam-Gately, Raquelle Seidman, Larry J. Stover, Ellen Weinberger, Daniel R. Young, Alexander S. Zalcman, Steven Marder, Stephen R. TI The MATRICS consensus cognitive battery, part 1: Test selection, reliability, and validity SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID SEVERE MENTAL-ILLNESS; IMPROVE COGNITION; SCHIZOPHRENIA; SUPPORT; REHABILITATION; PERFORMANCE; PROGRAMS; MEMORY; SCALE AB Objective: The lack of an accepted standard for measuring cognitive change in schizophrenia has been a major obstacle to regulatory approval of cognition-enhancing treatments. A primary mandate of the National institute of Mental Health's Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative was to develop a consensus cognitive battery for clinical trials of cognition-enhancing treatments for schizophrenia through a broadly based scientific evaluation of measures. Method: The MATRICS Neurocognition Committee evaluated more than 90 tests in seven cognitive domains to identify the 36 most promising measures. A separate expert panel evaluated the degree to which each test met specific selection criteria. Twenty tests were selected as a beta battery. The beta battery was administered to 176 individuals with schizophrenia and readministered to 167 of them 4 weeks later so that the 20 tests could be compared directly. Results: The expert panel ratings are presented for the initially selected 36 tests. For the beta battery tests, data on test-retest reliability, practice effects, relationships to functional status, practicality, and tolerability are presented. Based on these data, 10 tests were selected to represent seven cognitive domains in the MATRICS Consensus Cognitive Battery. Conclusions: The structured consensus method was a feasible and fair mechanism for choosing candidate tests, and direct comparison of beta battery tests in a common sample allowed selection of a final consensus battery. The MATRICS Consensus Cognitive Battery is expected to be the standard tool for assessing cognitive change in clinical trials of cognition-enhancing drugs for schizophrenia. it may also aid evaluation of cognitive remediation strategies. C1 [Nuechterlein, Keith H.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Geffen Sch Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Geffen Sch Med, Dept Psychol, Los Angeles, CA 90095 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Kansas, Sch Med, Wichita, KS 67214 USA. Washington Univ, Dept Psychol, St Louis, MO 63130 USA. Washington Univ, Dept Psychiat, St Louis, MO 63130 USA. Princeton Univ, Dept Psychol, Princeton, NJ 08544 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. James J Peters VA Med Ctr, Mental Illness Res Educ & Clin Ctr, Bronx, NY USA. NIMH, Bethesda, MD 20892 USA. Northeastern Ohio Univ Coll Med & Pharm, Dept Psychiat, Rootstown, OH 44272 USA. Univ Maryland, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. Zucker Hillside Hosp, Psychiat Res Div, Glen Oaks, NY USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. Stanford Univ, Dept Psychiat & Behav Sci, Stanford, CA 94305 USA. Beth Israel Deaconess Med Ctr, Div Publ Psychiat, Massachusetts Mental Hlth Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Nuechterlein, KH (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Geffen Sch Med, 300 Med Plaza,Rm 2251, Los Angeles, CA 90095 USA. EM keithn@ucla.edu RI Barch, Deanna/G-8638-2013; Young, Alexander/A-1523-2009 OI Young, Alexander/0000-0002-9367-9213 FU NIMH NIH HHS [N01MH22006] NR 37 TC 607 Z9 624 U1 5 U2 46 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 FEB PY 2008 VL 165 IS 2 BP 203 EP 213 DI 10.1176/appi.ajp.2007.07010042 PG 11 WC Psychiatry SC Psychiatry GA 260ZV UT WOS:000253049800012 PM 18172019 ER PT J AU Kern, RS Nuechterlein, KH Green, MF Laade, LE Fenton, WS Gold, JM Keefe, RSE Mesholam-Gately, R Mintz, J Seidman, LJ Stover, E Marder, SR AF Kern, Robert S. Nuechterlein, Keith H. Green, Michael F. Laade, Lyle E. Fenton, Wayne S. Gold, James M. Keefe, Richard S. E. Mesholam-Gately, Raquelle Mintz, Jim Seidman, Larry J. Stover, Ellen Marder, Stephen R. TI The MATRICS consensus cognitive battery, part 2: Co-norming and standardization SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID CLINICAL-TRIALS; SCHIZOPHRENIA; NEUROPSYCHOLOGISTS; PERFORMANCE AB Objective: The consensus cognitive battery developed by the National Institute of Mental Health's (NIMH's) Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative includes 10 independently developed tests that are recommended as the standard battery for clinical trials of cognition-enhancing interventions for schizophrenia. To facilitate interpretation of results from the MATRICS Consensus Cognitive Battery using a common scaling across tests, normative data were obtained from a single representative U.S. community sample with the battery administered as a unit. Method: The MATRICS Consensus Cognitive Battery was administered to 300 individuals from the general community at five sites in differing geographic regions. For each site, recruitment was stratified by age, gender, and education. A scientific survey sampling method was used to help avoid sampling bias. The battery was administered in a standard order to each participant in a single session lasting approximately 60 minutes. Descriptive data were generated, and age, gender, and education effects on performance were examined. Results: Prominent age and education effects were observed across tests. The results for gender differed by measure, suggesting the need for age and gender corrections in clinical trials. The MATRICS Consensus Cognitive Battery components were co-normed, with allowance for demographic corrections. Conclusions: Co-norming a battery such as the MATRICS Consensus Cognitive Battery, comprising tests from independent test developers each with their own set of norms, facilitates valid interpretation of test scores and communication of findings across studies. These normative data will aid in estimating the magnitude of change during clinical trials of cognition-enhancing agents and make it possible to derive more directly interpretable composite scores. C1 Univ Calif Los Angeles, Geffen Sch Med, Dept Psychol, Los Angeles, CA USA. Univ Calif Los Angeles, Geffen Sch Med, Semel Inst Neurosci & Human Behav, Los Angeles, CA USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Kansas, Sch Med, Wichita, KS 67214 USA. Univ Maryland, Dept Psychiat, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. NIMH, Bethesda, MD 20892 USA. Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. Beth Israel Deaconess Med Ctr, Div Publ Psychiat, Massachusetts Mental Hlth Ctr, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Kern, RS (reprint author), VA Greater Los Angeles Healthcare Ctr, MIRECC 210 A,Bldg 210,Rm 116,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM rkern@ucla.edu FU NIMH NIH HHS [N01MH22006] NR 28 TC 183 Z9 195 U1 3 U2 12 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 FEB PY 2008 VL 165 IS 2 BP 214 EP 220 DI 10.1176/appi.ajp.2007.07010043 PG 7 WC Psychiatry SC Psychiatry GA 260ZV UT WOS:000253049800013 PM 18172018 ER PT J AU Green, MF Nuechterlein, KH Kern, RS Baade, LE Fenton, WS Gold, JM Keefe, RSE Mesholam-Gately, R Seidman, L Stover, E Marder, SR AF Green, Michael F. Nuechterlein, Keith H. Kern, Robert S. Baade, Lyle E. Fenton, Wayne S. Gold, James M. Keefe, Richard S. E. Mesholam-Gately, Raquelle Seidman, LarryJ Stover, Ellen Marder, Stephen R. TI Functional co-primary measures for clinical trials in schizophrenia: Results from the MATRICS psychometric and standardization study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID COGNITION; PERFORMANCE; PROGRAMS; CAPACITY; WORKSHOP; SUPPORT; SCALE AB Objective: During the consensus meetings of the National Institute of Mental Health Measurement and Treatment Research to Improve Cognition in Schizophrenia (NIMH-MATRICS) Initiative, the U.S. Food and Drug Administration took the position that a drug for this purpose should show changes on 1) an accepted consensus cognitive performance measure and 2) an additional measure (i. e., a co-primary) that is considered functionally meaningful. The goal of the current study was to describe steps to evaluate four potential co-primary measures for psychometric properties and validity. Method: As part of the five-site MATRICS Psychometric and Standardization Study (PASS), two measures of functional capacity and two interview-based measures of cognition were evaluated in 176 patients with schizophrenia (167 of these patients were retested 4 weeks later). Results: Data are presented for each co-primary measure for test-retest reliability, utility as a repeated measure, relationship to cognitive performance, relationship to functioning, tolerability/practicality, and number of missing data. Conclusions: Psychometric properties of all of the measures were considered acceptable, and the measures were generally comparable across the various criteria, except that the functional capacity measures had stronger relationships to cognitive performance and fewer missing data. The development and evaluation of potential co-primary measures is still at an early stage, and it was decided not to endorse a single measure for clinical trials at this point. The current findings offer the initial steps to identify functionally meaningful co-primary measures in this area and will help to guide further evaluation of such measures. C1 [Green, Michael F.] Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Geffen Sch Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Geffen Sch Med, Dept Psychol, Los Angeles, CA 90095 USA. VA Greater Los Angeles Healthcare Syst, Los Angeles, CA USA. Univ Kansas, Sch Med, Wichita, KS 67214 USA. NIMH, Bethesda, MD 20892 USA. Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. Beth Israel Deaconess Med Ctr, Dept Psychiat, Massachusetts Mental Hlth Ctr, Publ Psychiat Div, Boston, MA 02215 USA. Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. RP Green, MF (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci & Human Behav, Geffen Sch Med, 300 Med Plaza,Rm 2263, Los Angeles, CA 90095 USA. EM mgreen@ucla.edu FU NIMH NIH HHS [N01MH22006] NR 21 TC 112 Z9 119 U1 5 U2 11 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 FEB PY 2008 VL 165 IS 2 BP 221 EP 228 DI 10.1176/appi.ajp.2007.07010089 PG 8 WC Psychiatry SC Psychiatry GA 260ZV UT WOS:000253049800014 PM 18172017 ER PT J AU Blum, N Fee, E AF Blum, Nava Fee, Elizabeth TI Howard A. Rusk (1901-1989) from military medicine to comprehensive rehabilitation SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Biographical-Item C1 [Blum, Nava] Univ Haifa, Sch Publ Hlth, IL-31905 Haifa, Israel. [Fee, Elizabeth] Natl Inst Hlth, Natl Lib Med, Bethesda, MD USA. RP Blum, N (reprint author), Univ Haifa, Sch Publ Hlth, Mt Carmel, IL-31905 Haifa, Israel. EM navablum@hot-mail.com NR 0 TC 3 Z9 3 U1 2 U2 4 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 FEB PY 2008 VL 98 IS 2 BP 256 EP 257 DI 10.2105/AJPH.2007.120220 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 257XU UT WOS:000252833400016 PM 18172131 ER PT J AU Panettieri, RA Kotlikoff, MI Gerthoffer, WT Hershenson, MB Woodruff, PG Hall, IP Banks-Schlegel, S AF Panettieri, Reynold A., Jr. Kotlikoff, Michael I. Gerthoffer, William T. Hershenson, Marc B. Woodruff, Prescott G. Hall, Ian P. Banks-Schlegel, Susan TI Airway smooth muscle in bronchial tone, inflammation, and remodeling - Basic knowledge to clinical relevance SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE myocyte; signal transduction; force generation; migration; remodeling ID EXTRACELLULAR-MATRIX; CELL-PROLIFERATION; ASTHMATIC SUBJECTS; GROWTH; LUNG; HYPERRESPONSIVENESS; FIBRONECTIN; MECHANISMS; EXPRESSION; SECRETION AB Airway smooth muscle (ASM) plays a pivotal role in modulating bronchomotor tone but also orchestrates and perpetuates airway inflammation and remodeling. Despite substantial research, there remain important unanswered questions. In 2006, the National Heart, Lung, and Blood Institute sponsored a workshop to define new directions in ASM biology. Important questions concerning the key functions of ASM include the following: Does developmental dysregulation of ASM function promote airway disease, what key signaling pathways in ASM evoke airway hyperresponsiveness in vivo, do alterations in ASM mass affect excitation-contraction coupling, and can ASM modulate airway inflammation and remodeling in a physiologically relevant manner? This workshop identified critical issues in ASM biology to delineate areas for scientific investigation in the identification of new therapeutic and diagnostic approaches in asthma, chronic obstructive pulmonary disease, and cystic fibrosis. C1 [Banks-Schlegel, Susan] NHLBI, Div Lung Dis, Rockledge Ctr, Bethesda, MD 20892 USA. [Panettieri, Reynold A., Jr.] Univ Penn, Dept Med, Philadelphia, PA 19104 USA. [Kotlikoff, Michael I.] Cornell Univ, Coll Vet Med, Dept Biomed Sci, Ithaca, NY 14853 USA. [Gerthoffer, William T.] Univ Nevada, Sch Med, Dept Pharmacol, Reno, NV 89557 USA. [Hershenson, Marc B.] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. [Woodruff, Prescott G.] Univ Calif San Francisco, Div Pulm & Crit Care Med, San Francisco, CA 94143 USA. [Hall, Ian P.] Univ Nottingham Hosp, Div Therapeut, Nottingham NG7 2UH, England. RP Banks-Schlegel, S (reprint author), NHLBI, Div Lung Dis, Rockledge Ctr, Suite 10042,6701 Rockledge Dr,MSC 7952, Bethesda, MD 20892 USA. EM schleges@nih.gov OI Hall, Ian/0000-0001-9933-3216; Gerthoffer, William/0000-0001-5154-4962 FU NHLBI NIH HHS [R01 HL077726] NR 44 TC 45 Z9 47 U1 0 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 FEB 1 PY 2008 VL 177 IS 3 BP 248 EP 252 DI 10.1164/rccm.200708-1217PP PG 5 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 255IC UT WOS:000252650600003 PM 18006883 ER PT J AU Gladwin, MT Patel, RP AF Gladwin, Mark T. Patel, Rakesh P. TI The role of red blood cells and hemoglobin-nitric oxide interactions on blood flow SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Editorial Material ID PLASMA HEMOGLOBIN; DISEASE; ERYTHROPOIETIN; ERYTHROCYTES; CIRCULATION; DIFFUSION; MORTALITY; HEMOLYSIS C1 [Gladwin, Mark T.] NIH, Bethesda, MD 20892 USA. [Patel, Rakesh P.] Univ Alabama, Birmingham, AL USA. RP Gladwin, MT (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. OI Patel, Rakesh/0000-0002-1526-4303 NR 22 TC 6 Z9 7 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD FEB PY 2008 VL 38 IS 2 BP 125 EP 126 DI 10.1165/rcmb.2007-0006ED PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 255VJ UT WOS:000252685600001 PM 18195245 ER PT J AU Lehman, CD Rutter, CM Eby, PR White, E Buist, DSM Taplin, SH AF Lehman, Constance D. Rutter, Carolyn M. Eby, Peter R. White, Emily Buist, Diana S. M. Taplin, Stephen H. TI Lesion and patient characteristics associated with malignancy after a probably benign finding on community practice mammography SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE BI-RADS; breast cancer; mammography; probably benign finding ID INTERVAL FOLLOW-UP; SCREENING MAMMOGRAPHY; BREAST-CANCER; RECOMMENDATIONS; CONCORDANCE AB OBJECTIVE. The purpose of this study was to identify patient and lesion characteristics associated with a diagnosis of breast malignancy within 3 years of having a probably benign finding (BI-RADS category 3) on a mammogram obtained in a community radiology practice. MATERIALS and METHODS. The subjects were women 30 years old and older without breast implants or previous breast cancer who received notice of a probably benign finding on a bilateral screening mammogram between January 1, 1996, and June 30, 1999, in a community-based practice. From 82,898 mammograms, we identified 129 breast lesions designated probably benign that progressed to malignancy within 3 years of an index examination (cases) and matched them to 129 lesions designated probably benign that did not progress to malignancy within 3 years (controls). A breast imaging specialist blinded to case-control status interpreted all examinations and recorded detailed lesion descriptors according to the BI-RADS lexicon. RESULTS. Case lesions were more likely in patients who were older, postmenopausal, or had a strong family history of breast cancer or previous biopsy. The lesions were more likely masses with obscured, indistinct, or spiculated margins compared with control lesions (84.6% vs 66%, p = 0.03). Case lesions were more likely calcifications (29.5% vs 17.8%, p = 0.03). No cases were encountered among calcifications considered typically benign in the BI-RADS lexicon (vascular or coarse), and no controls were encountered among calcifications considered suspicious or highly suggestive of malignancy in the BI-RADS lexicon (amorphous, pleomorphic, branching, and fine linear) (p < 0.0001). CONCLUSION. In community practice, patient and lesion mammographic characteristics can be predictive of the likelihood of a subsequent cancer diagnosis of mammographic lesions designated as probably benign. Careful evaluation of mass margins and of the morphologic features of calcifications can help distinguish a malignant lesion from a probably benign finding. C1 [Lehman, Constance D.; Eby, Peter R.] Univ Washington, Med Ctr, Seattle Canc Care Alliance, Dept Radiol, Seattle, WA 98109 USA. [Rutter, Carolyn M.; Buist, Diana S. M.] Grp Hlth Ctr hlth Studies, Seattle, WA USA. [White, Emily; Buist, Diana S. M.] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. [White, Emily; Buist, Diana S. M.] Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA USA. [Taplin, Stephen H.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. RP Lehman, CD (reprint author), Univ Washington, Med Ctr, Seattle Canc Care Alliance, Dept Radiol, 825 Eastlake Ave E,G2-600,POB 19023, Seattle, WA 98109 USA. EM lehman@u.washington.edu FU NCI NIH HHS [CA063731] NR 17 TC 14 Z9 14 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2008 VL 190 IS 2 BP 511 EP 515 DI 10.2214/AJR.07.2153 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 259ID UT WOS:000252932100033 PM 18212240 ER PT J AU Smith-Bindman, R Miglioretti, DL Rosenberg, R Reid, RJ Taplin, SH Geller, BM Kerlikowske, K AF Smith-Bindman, Rebecca Miglioretti, Diana L. Rosenberg, Robert Reid, Robert J. Taplin, Stephen H. Geller, Berta M. Kerlikowske, Karla CA Natl Inst Hlth Breast Canc Surveil TI Physician workload in mammography SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE mammography; physician workforce; volume ID SCREENING MAMMOGRAPHY; PERFORMANCE; ACCURACY; PROGRAM; VOLUME AB OBJECTIVE. United States Food and Drug Administration (FDA) guidelines for certification require that radiologists interpret >= 960 mammography examinations within each 2-year period (approximately 480 annually). The purpose of our study was to estimate per-physician annual volumes of mammography interpretation. SUBJECTS AND METHODS. Our study includes 4.2 million mammography examinations performed at 196 facilities between 1998 and 2004. We calculated the annual interpretive volumes per physician, the proportion of mammography examinations interpreted by radiologists in specified volume categories, and the impact on mammography capacity if annual interpretive volume requirements increased. RESULTS. The mean annual mammographic interpretive volume was 1,777. Approximately 31% of radiologists interpreted < 1,000 mammography examinations annually, yet these low-volume radiologists interpreted only 10% of all mammograms. The 10% of radiologists who interpreted >= 3,000 mammography examinations annually interpreted 32% of all examinations. Rural radiologists interpreted fewer examinations annually compared with urban radiologists. If the minimum annual volume requirement were increased to 1,000 mammograms per year, only 10% of the overall U. S. mammography capacity would be affected. If the requirement were increased to 2,000 mammograms annually, 47% of capacity would be eliminated, and a major rearrangement of workload would be required because most radiologists would no longer interpret enough examinations to meet the revised standards. CONCLUSION. Doubling physician annual volume requirements would result in a small impact on overall mammography capacity. Increasing volume requirements to 2,000 mammography examinations annually would require a dramatic increase in the number of mammography examinations interpreted by the higher volume radiologists. Unless previously low-volume radiologists increased their volumes, raising requirements to 2,000 examinations could curtail access to mammography, particularly in rural areas. C1 [Smith-Bindman, Rebecca] Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94107 USA. [Smith-Bindman, Rebecca; Kerlikowske, Karla] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA. [Miglioretti, Diana L.; Reid, Robert J.] Grp Hlth Ctr Hlth Studies, Seattle, WA USA. [Miglioretti, Diana L.] Univ Washington, Dept Biostat, Seattle, WA 98195 USA. [Rosenberg, Robert] Univ New Mexico, Dept Radiol, Albuquerque, NM 87131 USA. [Taplin, Stephen H.] NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. [Geller, Berta M.] Univ Vermont, Vermont Canc Ctr, Dept Family Med & Radiol, Burlington, VT USA. [Kerlikowske, Karla] Univ Calif San Francisco, Dept Vet Affairs, Gen Internal Med Sect, San Francisco, CA USA. RP Smith-Bindman, R (reprint author), Univ Calif San Francisco, Dept Radiol, 185 Berry St,Ste 350,Lobby 7,Campus Box 0946, San Francisco, CA 94107 USA. FU NCI NIH HHS [U01CA86076, U01CA70040, U01CA70013, U01CA69976, U01CA63736, U01 CA086076-07, U01 CA086076, U01 CA086076-06, U01CA63731, U01CA63740, U01CA86082] NR 16 TC 9 Z9 9 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2008 VL 190 IS 2 BP 526 EP 532 DI 10.2214/AJR.07.2500 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 259ID UT WOS:000252932100035 PM 18212242 ER PT J AU Proschan, MA AF Proschan, Michael A. TI The normal approximation to the binomial SO AMERICAN STATISTICIAN LA English DT Article DE Bernoulli random variables; binomial distribution; central limit theorem AB This note presents a heuristic derivation of the central limit theorem for Bernoulli random variables. While not a proof, it lends insight into why the normal distribution approximates the binomial. C1 NIAID, Bethesda, MD 20892 USA. RP Proschan, MA (reprint author), NIAID, 6700B Rockledge Dr,MSC 7609, Bethesda, MD 20892 USA. EM ProschaM@niaid.nih.gov NR 3 TC 1 Z9 1 U1 0 U2 0 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0003-1305 J9 AM STAT JI Am. Stat. PD FEB PY 2008 VL 62 IS 1 BP 62 EP 63 DI 10.1198/000313008X267848 PG 2 WC Statistics & Probability SC Mathematics GA 256VZ UT WOS:000252759300010 ER PT J AU Patterson, AD Li, H Eichler, GS Krausz, KW Weinstein, JN Formace, AJ Gonzalez, FJ Idle, JR AF Patterson, Andrew D. Li, Henghong Eichler, Gabriel S. Krausz, Kristopher W. Weinstein, John N. Formace, Albert J., Jr. Gonzalez, Frank J. Idle, Jeffrey R. TI UPLC-ESI-TOFMS-based metabolomics and gene expression dynamics inspector self-organizing metabolomic maps as tools for understanding the cellular response to ionizing radiation SO ANALYTICAL CHEMISTRY LA English DT Article ID EXTRACELLULAR ADENOSINE; TUMOR-CELLS; GAMMA-RAYS; SOLUBLE METABOLITES; PROTON-BEAMS; CANCER-CELLS; H-1 MRS; MICE; GLUTATHIONE; DAMAGE AB Global transcriptomic and proteomic profiling platforms have yielded important insights into the complex response to ionizing radiation (IR). Nonetheless, little is known about the ways in which small cellular metabolite concentrations change in response to IR. Here, a metabolomics approach using ultraperformance liquid chromatography coupled with electrospray time-of-flight mass spectrometry was used to profile, over time, the hydrophilic metabolome of TK6 cells exposed to IR doses ranging from 0.5 to 8.0 Gy. Multivaiiate data analysis of the positive ions revealed dose- and time-dependent clustering of the irradiated cells and identified certain constituents of the water-soluble metabolome as being significantly depleted as early as 1 h after IR. Tandem mass spectrometry was used to confirm metabolite identity. Many of the depleted metabolites are associated with oxidative stress and DNA repair pathways. Included are reduced glutathione, adenosine monophosphate, nicotinamide adenine dinucleotide, and spermine. Similar measurements were performed with a transformed fibroblast cell line, BJ, and it was found that a subset of the identified TK6 metabolites were effective in IR dose discrimination. The GEDI (Gene Expression Dynamics Inspector) algorithm, which is based on self-organizing maps, was used to visualize dynamic global changes in the TK6 metabolome that resulted from IR. It revealed dose-dependent clustering of ions sharing the same trends in concentration change across radiation doses. "Radiation metabolomics," the application of metabolomic analysis to the field of radiobiology, promises to increase our understanding of cellular responses to stressors such as radiation. C1 [Idle, Jeffrey R.] Univ Bern, Inst Clin Pharmacol, CH-3012 Bern, Switzerland. [Patterson, Andrew D.; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD USA. [Li, Henghong; Formace, Albert J., Jr.] Georgetown Univ, Lombardi Comprehens Canc Res, Washington, DC USA. [Eichler, Gabriel S.; Weinstein, John N.] NCI, Gen & Bioinformat Grp, Mol Pharmacol Lab, Ctr Canc Res,NIH, Bethesda, MD USA. RP Idle, JR (reprint author), Univ Bern, Inst Clin Pharmacol, CH-3012 Bern, Switzerland. EM jeff.idle@ikp.unibe.ch RI Patterson, Andrew/G-3852-2012; OI Patterson, Andrew/0000-0003-2073-0070; Idle, Jeff/0000-0002-6143-1520 FU Intramural NIH HHS [Z01 BC005562-19]; NIAID NIH HHS [U19 AI067773, U19AI067773-02] NR 45 TC 84 Z9 91 U1 0 U2 21 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 FEB 1 PY 2008 VL 80 IS 3 BP 665 EP 674 DI 10.1021/ac701807 PG 10 WC Chemistry, Analytical SC Chemistry GA 258LW UT WOS:000252870400020 PM 18173289 ER PT J AU Campbell, MK McLerran, D Turner-McGrievy, G Feng, Z Havas, S Sorensen, G Buller, D Beresford, SAA Nebeling, L AF Campbell, Marci Kramish McLerran, Dale Turner-McGrievy, Gabrielle Feng, Ziding Havas, Stephen Sorensen, Glorian Buller, David Beresford, Shirley A. A. Nebeling, Linda TI Mediation of adult fruit and vegetable consumption in the national 5 a day for better health community studies SO ANNALS OF BEHAVIORAL MEDICINE LA English DT Article DE cancer prevention; fruit and vegetable consumption; health promotion; mediation ID DIETARY CHANGE; NUTRITION INTERVENTION; PSYCHOSOCIAL FACTORS; PROMOTION PROGRAM; INCREASING FRUIT; PREVENTION; WORKSITE; PREDICTORS; MODERATORS; AWARENESS AB Background The 5 A Day for Better Health community studies demonstrated in randomized trials the efficacy of population-based strategies to increase fruit and vegetable consumption in diverse geographic areas and settings. Purpose Mediation analysis can help to elucidate the theoretical basis of changing dietary habits. This is important for informing more powerful cancer prevention and control interventions to achieve broad public health impact. Methods Five sites that focused on adults were included in mediation analyses to determine whether theoretically derived constructs assessed at baseline and follow-up contributed to explaining change in fruit and vegetable (F&V) consumption. These variables were knowledge, self-efficacy, and autonomy/responsibility. Stage of change also was considered as a potential moderating variable. Results Self-efficacy and knowledge of the 5 A Day recommendation increased in those who received the interventions and were positively associated with higher F&V. Mediation of intervention effect was demonstrated for these variables. Autonomy/responsibility did not meet the criteria for mediation. There was no evidence of differential effect of mediators according to baseline stage. Conclusions The present study findings provide strong support for mediation of F&V consumption by two variables: self-efficacy and knowledge. The authors discuss the findings in relation to study limitations and future research directions. C1 [Campbell, Marci Kramish; Turner-McGrievy, Gabrielle] Univ N Carolina, Dept Nutr, Chapel Hill, NC 27599 USA. [McLerran, Dale; Feng, Ziding] Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. [Havas, Stephen] Amer Med Assoc, Chicago, IL 60610 USA. [Sorensen, Glorian] Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. [Sorensen, Glorian] Dana Farber Canc Inst, Boston, MA 02115 USA. [Buller, David] Klein Buendel Inc, Golden, CO 80401 USA. [Beresford, Shirley A. A.] Univ Washington, Grp Hlth Cooperat, Dept Hlth Serv, Seattle, WA 98101 USA. [Beresford, Shirley A. A.] Univ Washington, Grp Hlth Cooperat, Ctr Hlth Studies, Seattle, WA 98101 USA. [Nebeling, Linda] NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Campbell, MK (reprint author), Univ N Carolina, Dept Nutr, Campus Box 7461, Chapel Hill, NC 27599 USA. EM marci_campbell@unc.edu OI Turner-McGrievy, Gabrielle/0000-0002-1683-5729 FU NCI NIH HHS [R01 CA 98014]; NIDDK NIH HHS [P30 DK056350, DK 56350] NR 37 TC 21 Z9 21 U1 0 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0883-6612 J9 ANN BEHAV MED JI Ann. Behav. Med. PD FEB PY 2008 VL 35 IS 1 BP 49 EP 60 DI 10.1007/s12160-007-9002-y PG 12 WC Psychology, Multidisciplinary SC Psychology GA 268IQ UT WOS:000253573900006 PM 18347904 ER PT J AU Ross, GW Petrovitch, H Abbott, RD Tanner, CM Popper, J Masaki, K Launer, L White, LR AF Ross, G. Webster Petrovitch, Helen Abbott, Robert D. Tanner, Caroline M. Popper, Jordan Masaki, Kamal Launer, Lenore White, Lon R. TI Association of olfactory dysfunction with risk for future Parkinson's disease SO ANNALS OF NEUROLOGY LA English DT Article ID SMELL IDENTIFICATION TEST; LOGISTIC-REGRESSION; DE-NOVO; MEN; PROGRESSION; NEUROGENESIS; MORTALITY; PATHOLOGY; RELATIVES; DEMENTIA AB Objective: Although olfactory dysfunction is commonly associated with Parkinson's disease (PD), it is not known whether such dysfunction can predate the onset of clinical PD in a community-based Population. This study examines the association of olfactory dysfunction with future development of PD in Honolulu-Asia Aging Study cohort members. Methods: Olfaction was assessed from 1991 to 1996 in 2,267 men in the Honolulu-Asia Aging Study aged 71 to 95 years who were free of clinical PD and dementia at the time of olfaction testing. Participants were followed for up to 8 years for incident PD. Results: In the course of follow-Lip, 35 men were diagnosed with PD (24.6/10,000 person-years). The average age at the time of diagnosis was 82.9 +/- 3.8 (range, 76-93) years, and the average time to a diagnosis was 4.0 +/- 1.9 (range, 1-8) years. During the first 4 years of follow-up, age-adjusted incidence of PD declined from 54.5/10,000 person-years in the lowest quartile of odor identification to 26.6, 8.2, and 8.4/10,000 person-years in the second, third, and fourth quartiles, respectively (p < 0.001 for trend). After adjustment for age and other potential confounders, the odds ratios for PD in the lowest quartile was 5.2 (95% confidence interval, 1.5-25.6) compared with the top two quartiles. This relation was not evident beyond 4 years of follow-up. Interpretation: Impaired olfaction can predate clinical PD in men by at least 4 years and may be a useful screening tool to detect those at high risk For development of PD in later life. C1 [Ross, G. Webster; Petrovitch, Helen; Popper, Jordan; White, Lon R.] VA Pacific Isl Hlth Care Syst, Honolulu, HI 96819 USA. [Ross, G. Webster; Petrovitch, Helen; Popper, Jordan; White, Lon R.] Univ Hawaii, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. [Ross, G. Webster; Petrovitch, Helen; Masaki, Kamal; White, Lon R.] Univ Hawaii, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. [Ross, G. Webster; Petrovitch, Helen; Abbott, Robert D.; Masaki, Kamal; White, Lon R.] Kuakini Med Ctr Honolulu Asia Aging Study, Pacific Hlth Res Inst, Honolulu, HI USA. [Abbott, Robert D.] Univ Virginia, Sch Med, Div Biostat & Epidemiol, Charlottesville, VA 22908 USA. [Abbott, Robert D.] Shiga Univ Med Sci, Dept Hlth Sci, Otsu, Shiga 52021, Japan. [Abbott, Robert D.] Japan Soc Promot Sci, Tokyo, Japan. [Tanner, Caroline M.] Parkinsons Inst, Sunnyvale, CA USA. [Launer, Lenore] NIA, NIH, Bethesda, MD 20892 USA. RP Ross, GW (reprint author), VA Pacific Isl Hlth Care Syst, 459 Patterson Rd, Honolulu, HI 96819 USA. EM wross@phrihawaii.org FU NIA NIH HHS [U01 AG19349, 5 R01 AG017155]; NINDS NIH HHS [R01 NS041265] NR 45 TC 254 Z9 269 U1 6 U2 31 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2008 VL 63 IS 2 BP 167 EP 173 DI 10.1002/ana.21291 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 270AG UT WOS:000253691500011 PM 18067173 ER PT J AU Mann, M Tendulkar, A Birger, N Howard, C Ratcliffe, MB AF Mann, Michael Tendulkar, Amod Birger, Noy Howard, Cheryl Ratcliffe, Mark B. TI National institutes of health funding for surgical research SO ANNALS OF SURGERY LA English DT Article ID TRANSLATIONAL RESEARCH; PHYSICIAN-SCIENTIST; SURGEON; TRENDS AB Objective: The objective was to compare National Institutes of Health (NIH) funding rates and application success rates among surgeon and nonsurgeon-scientists over the past 2 decades. Summary Background Data: Surgeons may be capable of accelerating the translation of basic research into new clinical therapies. Nevertheless, most surgeon-scientists believe they are at a disadvantage in competing for peer-reviewed funding, despite a recent emphasis on "translational science" by organizations such as the NIH. Methods: We accessed databases from the NIH and the American Association of Medical Colleges. Results: Although total competing NIH awards rose 79.2% from 5608 to 10,052, the much smaller number of surgical awards increased only by 41.4% from 157 to 222. There was a small but statistically significant difference between total NIH and surgical application success rates (29% vs. 25%, P < 0.01). However, the persistently low percent of NIH funding going to surgical investigators was due primarily to the very small number of surgical applications, and to a much smaller increase in the absolute number of applications over time (464 vs. 23,847). As a result, the number of grants per 100 faculty members, was more than 4 times higher among nonsurgical than surgical faculties at US medical schools. Conclusion: NIH funding to academic surgeons is declining relative to their nonsurgical colleagues. This trend will likely be reversed only by an increase in the number of grant applications submitted by surgeon-scientists. Structural changes in surgical training programs, and in the economics of academic surgery, may support a greater contribution of surgeon-scientists to the success of translational research. C1 [Mann, Michael; Birger, Noy; Ratcliffe, Mark B.] San Francisco VA Med Ctr, San Francisco, CA 94121 USA. [Mann, Michael; Tendulkar, Amod; Ratcliffe, Mark B.] Univ Calif San Francisco, Dept Surg, San Francisco, CA 94143 USA. [Howard, Cheryl] NHLBI, Div Sci Program Operat, Bethesda, MD 20892 USA. RP Ratcliffe, MB (reprint author), San Francisco VA Med Ctr, 4150 Clement St, San Francisco, CA 94121 USA. EM mark.ratcliffe@med.va.gov NR 15 TC 52 Z9 52 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD FEB PY 2008 VL 247 IS 2 BP 217 EP 221 DI 10.1097/SLA.0b013e3181568e26 PG 5 WC Surgery SC Surgery GA 256VR UT WOS:000252758500003 PM 18216525 ER PT J AU Niederhubey, JE AF Niederhubey, John E. TI An old problem that may be getting worse SO ANNALS OF SURGERY LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Niederhubey, JE (reprint author), NCI, Bldg 31,Room 11A48,31 Ctr Dr,MSC 2590, Bethesda, MD 20892 USA. EM niederj@mail.nih.gov NR 2 TC 5 Z9 5 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD FEB PY 2008 VL 247 IS 2 BP 222 EP 223 DI 10.1097/SLA.0b013e318163ff78 PG 2 WC Surgery SC Surgery GA 256VR UT WOS:000252758500004 PM 18216526 ER PT J AU Henry, LR Shaha, A Solomon, N Howard, R Gurevich-Uvena, J Horst, L Orlikoff, R Libutti, S Stojadinovic, A AF Henry, L. R. Shaha, A. Solomon, N. Howard, R. Gurevich-Uvena, J. Horst, L. Orlikoff, R. Libutti, S. Stojadinovic, A. TI Functional voice implications of sternothyroid muscle division during thyroidectomy SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 61st Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 13-16, 2008 CL Chicago, IL SP Soc Surg Oncol C1 [Henry, L. R.] Natl Naval Med Ctr, Dept Surg, Bethesda, MD USA. [Shaha, A.] Mem Sloan Kettering Canc Ctr, New York, NY USA. [Solomon, N.; Howard, R.; Gurevich-Uvena, J.; Horst, L.; Stojadinovic, A.] Walter Reed Army Med Ctr, Washington, DC USA. [Orlikoff, R.] Seton Hall Univ, S Orange, NJ 07079 USA. [Libutti, S.] Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2008 VL 15 SU 2 BP 48 EP 48 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 258RT UT WOS:000252887900146 ER PT J AU Gensler, LS Ward, MM Reveille, JD Learch, TJ Weisman, MH Davis, JC AF Gensler, L. S. Ward, M. M. Reveille, J. D. Learch, T. J. Weisman, M. H. Davis, J. C., Jr. TI Clinical, radiographic and functional differences between juvenile-onset and adult-onset ankylosing spondylitis: results from the PSOAS cohort SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID RHEUMATOID-ARTHRITIS; IDIOPATHIC ARTHRITIS; NATURAL-HISTORY; DISEASE COURSE; SPONDYLOARTHROPATHIES; INDEX; HEALTH; AGE; PROGRESSION; PREDICTORS AB Aims: Previous data suggests that patients with juvenile-onset ankylosing spondylitis (JoAS) have more severe disease and worse functional outcomes than adult-onset AS (AoAS). The purpose of this study was to evaluate clinical, functional and radiographic differences between patients with JoAS and AoAS in a large cohort of patients with long-standing disease. Methods: A total of 402 subjects who met the Modified New York Criteria for definitive AS and had had disease >= 20 years were enrolled in a multi-centre cross-sectional study (Prospective Study of Outcomes in Ankylosing Spondylitis; PSOAS). JoAS was defined as initial symptoms (16 years of age. A total of 79 subjects with JoAS and 323 subjects with AoAS were identified. An analysis of clinical and demographic comparisons between the two groups was performed including HLA B27 status. Functional outcomes were assessed by Bath AS Functional Index (BASFI) and the Health Assessment Questionnaire modified for the Spondyloarthropathies (HAQS). Radiographic disease severity was assessed by the Bath AS Radiology Index (BASRI). Results: With the exception of obvious differences in age at onset and disease duration, demographic and clinical characteristics were similar between the two groups. However, the JoAS group trended towards more women (32.9 vs 22.9%, p = 0.07). Controlling for multiple covariates including disease duration, both the BASRI hip score and the need for total hip arthroplasty (THA) was higher in the JoAS group. The BASRI spine score (including total, lumbar and cervical spine) was significantly lower in the patients with JoAS even after controlling for multiple covariates including disease duration and gender. No difference in function (BASFI or HAQS scores) between groups was identified. Conclusions: Compared to AoAS, subjects with JoAS have ( 1) less severe axial involvement radiographically, ( 2) similar functional outcomes, ( 3) more hip involvement with a greater need for THA, and ( 4) a slightly higher proportion of women. C1 [Gensler, L. S.; Davis, J. C., Jr.] Univ Calif San Francisco, Div Rheumatol, San Francisco, CA 94143 USA. [Ward, M. M.] NIH, Natl Inst Arthritis & Musculoskeletal & Skin Dis, Bethesda, MD USA. [Reveille, J. D.] Univ Texas Houston, Houston, TX USA. [Learch, T. J.] Univ So Calif, Los Angeles, CA USA. [Weisman, M. H.] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. RP Davis, JC (reprint author), Univ Calif San Francisco, Div Rheumatol, 533 Parnassus Ave Box 0633 Room U383, San Francisco, CA 94143 USA. EM jdavis@medicine.ucsf.edu FU Intramural NIH HHS; NCRR NIH HHS [M01-RR02558, MO1-RR00425] NR 37 TC 37 Z9 42 U1 0 U2 2 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 FEB PY 2008 VL 67 IS 2 BP 233 EP 237 DI 10.1136/ard.2007.072512 PG 5 WC Rheumatology SC Rheumatology GA 250LN UT WOS:000252301700016 PM 17604288 ER PT J AU Aletaha, D Strand, V Smolen, JS Ward, MM AF Aletaha, D. Strand, V. Smolen, J. S. Ward, M. M. TI Treatment-related improvement in physical function varies with duration of rheumatoid arthritis: a pooled analysis of clinical trial results SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID PLACEBO-CONTROLLED TRIAL; ANTITUMOR NECROSIS FACTOR; INTERLEUKIN-1 RECEPTOR ANTAGONIST; LOW-DOSE METHOTREXATE; DOUBLE-BLIND TRIAL; ALPHA MONOCLONAL-ANTIBODY; COMBINATION THERAPY; RANDOMIZED-TRIAL; DISEASE-ACTIVITY; JOINT DAMAGE AB Background: Physical function in rheumatoid arthritis ( RA) has reversible and irreversible components, and is typically assessed by the Health Assessment Questionnaire Disability Index (HAQ). Since irreversible components are expected to increase with longer duration of RA and reduce the ability for improvement in physical function, we analysed responsiveness of HAQ scores in patient populations with differing RA durations in randomised controlled trials (RCTs). Methods: Data from all RCTs published between 1980 and 2005 that reported changes from baseline in HAQ at 6 and/or 12 months were analysed. Treatments were grouped as "biologics'', or "traditional'' disease modifying antirheumatic drugs ( DMARDs), and "placebo''. We computed effect sizes of HAQ in each trial, and contrasted the association between these effects and duration of RA among treatment groups using regression models. Results: We identified 42 RCTs with complete data for the statistical models. The models indicate that discrimination of functional improvement between active drug groups and placebo is reduced in patients with a longer duration of RA (p = 0.02 for the change in discrimination over time). The placebo-adjusted HAQ responses decreased on average by 0.37 per year of RA duration. Conclusion: Responsiveness in HAQ scores is inversely associated with mean disease duration in RA. This impacts assessment of physical function, a key outcome measure in RCTs and practice, and impacts the ability to discriminate active treatment from placebo. C1 [Aletaha, D.] Med Univ Vienna, Dept Rheumatol, A-1090 Vienna, Austria. [Strand, V.] Stanford Univ, Potola Vally, CA USA. [Smolen, J. S.] Hietzing Hosp, Dept Med 3, Vienna, Austria. [Ward, M. M.] NIH, Natl Inst Arthritis & Musculoskeletal & Skin Dis, Bethesda, MD USA. RP Aletaha, D (reprint author), Med Univ Vienna, Dept Rheumatol, Waehringer Guertel 18-20, A-1090 Vienna, Austria. EM daniel.aletaha@meduniwien.ac.at FU Intramural NIH HHS NR 59 TC 45 Z9 48 U1 0 U2 4 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 FEB PY 2008 VL 67 IS 2 BP 238 EP 243 DI 10.1136/ard.2007.071415 PG 6 WC Rheumatology SC Rheumatology GA 250LN UT WOS:000252301700017 PM 17644550 ER PT J AU Kiser, JJ Fletcher, CV Flynn, PM Cunningham, CK Wilson, CM Kapogiannis, BG Major-Wilson, H Viani, RM Liu, NX Muenz, LR Harris, DR Havens, PL AF Kiser, Jennifer J. Fletcher, Courtney V. Flynn, Patricia M. Cunningham, Coleen K. Wilson, Craig M. Kapogiannis, Bill G. Major-Wilson, Hanna Viani, Rolando M. Liu, Nancy X. Muenz, Larry R. Harris, D. Robert Havens, Peter L. CA Adolescent Trials Network TI Pharmacokinetics of antiretroviral regimens containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and young adults with human immunodeficiency virus infection SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PLASMA-CONCENTRATIONS; SALVAGE THERAPY; HIV; CHILDREN; TRIAL; COMBINATION; LAMIVUDINE; DIPHOSPHATE; ZIDOVUDINE; EFAVIRENZ AB The primary objective of this study was to measure atazanavir-ritonavir and tenofovir pharmacokinetics when the drugs were used in combination in young adults with human immunodeficiency virus (HIV). HIV-infected subjects >= 18 to <25 years old receiving (>= 28 days) 300/100 mg atazanavir-ritonavir plus 300 mg tenofovir disoproxil fumarate (TDF) plus one or more other nucleoside analogs underwent intensive 24-h pharmacokinetic studies following a light meal. Peripheral blood mononuclear cells were obtained at 1, 4, and 24 h postdose for quantification of intracellular tenofovir diphosphate (TFV-DP) concentrations. Twenty-two subjects were eligible for analyses. The geometric mean (95% confidence interval [CI]) atazanavir area under the concentration-time curve from 0 to 24 h (AUC(0-24)), maximum concentration of drug in serum (C-max), concentration at 24 h postdose (C-24), and total apparent oral clearance (CL/F) values were 35,971 ng center dot hr/ml (30,853 to 41,898), 3,504 ng/ml (2,978 to 4,105), 578 ng/ml (474 to 704), and 8.3 liter/hr (7.2 to 9.7), respectively. The geometric mean (95% Cl) tenofovir AUC(0-24), C-max C-24, and CL/F values were 2,762 ng center dot hr/ml (2,392 to 3,041), 254 ng/ml (221 to 292), 60 ng/ml (52 to 68), and 49.2 liter/hr (43.8 to 55.3), respectively. Body weight was significantly predictive of CL/F for all three drugs. For every 10-kg increase in weight, there was a 10%, 14.8%, and 6.8% increase in the atazanavir, ritonavir, and tenofovir CL/F, respectively (P <= 0.01). Renal function was predictive of tenofovir CL/F. For every 10 ml/min increase in creatinine clearance, there was a 4.6% increase in tenofovir CL/F (P < 0.0001). The geometric mean (95% Cl) TFV-DP concentrations at 1, 4, and 24 h postdose were 96.4 (71.5 to 130), 93.3 (68 to 130), and 92.7 (70 to 123) fmol/million cells. There was an association between renal function, tenofovir AUC, and tenofovir C-max and intracellular TFV-DP concentrations, although none of these associations reached statistical significance. In these HIV-infected young adults treated with atazanavir-ritonavir plus TDF, the atazanavir AUC was similar to those of older adults treated with the combination. Based on data for healthy volunteers, a higher tenofovir AUC may have been expected, but was not seen in these subjects. This might be due to faster tenofovir CL/F because of higher creatinine clearance in this age group. Additional studies of the exposure-response relationships of this regimen in children, adolescents, and adults would advance our knowledge of its pharmacodynamic properties. C1 [Havens, Peter L.] Med Coll Wisconsin, Pediat Infect Dis, Milwaukee, WI 53201 USA. [Kiser, Jennifer J.; Fletcher, Courtney V.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Flynn, Patricia M.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Cunningham, Coleen K.] Duke Univ, Med Ctr, Durham, NC USA. [Wilson, Craig M.] Univ Alabama, Birmingham, AL USA. [Kapogiannis, Bill G.] NICHHD, Bethesda, MD 20892 USA. [Major-Wilson, Hanna] Univ Miami, Miller Sch Med, Miami, FL 33152 USA. [Viani, Rolando M.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Liu, Nancy X.; Muenz, Larry R.; Harris, D. Robert] Westat Corp, Rockville, MD USA. RP Havens, PL (reprint author), Med Coll Wisconsin, Pediat Infect Dis, Suite C450,POB 1997, Milwaukee, WI 53201 USA. EM phavens@mcw.edu RI Viani, Rolando/C-3501-2013 FU NCRR NIH HHS [M01 RR000071, M01 RR000043, M01 RR000240, M01 RR00043, M01 RR00071, M01 RR00240, M01 RR165001]; NICHD NIH HHS [U01 HD040474, U01 HD040533, U01-HD040533] NR 28 TC 40 Z9 42 U1 0 U2 0 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 FEB PY 2008 VL 52 IS 2 BP 631 EP 637 DI 10.1128/AAC.00761-07 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 256JN UT WOS:000252724800035 PM 18025112 ER PT J AU Bachrach, G Altman, H Kolenbrander, PE Chalmers, NI Gabai-Gutner, M Mor, A Friedman, M Steinberg, D AF Bachrach, Gilad Altman, Hamutal Kolenbrander, Paul E. Chalmers, Natalia I. Gabai-Gutner, Michal Mor, Amram Friedman, Michael Steinberg, Doron TI Resistance of Porphyromonas gingivalis ATCC 33277 to direct killing by antimicrobial peptides is protease independent SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID DERMASEPTIN S4 DERIVATIVES; HUMAN BETA-DEFENSINS; STAPHYLOCOCCUS-AUREUS; INNATE IMMUNITY; ANTIBACTERIAL PEPTIDES; TREPONEMA-DENTICOLA; ORAL BACTERIA; HOST-DEFENSE; LL-37; LIPOPOLYSACCHARIDES AB Antimicrobial peptides are short, positively charged, amphipathic peptides that possess a wide spectrum of antimicrobial activity and have an important role in the host's innate immunity. Lack of, or dysfunctions in, antimicrobial peptides have been correlated with infectious diseases, including periodontitis. Porphyromonas gingivalis, a gram-negative anaerobe and a major pathogen associated with periodontal diseases, is resistant to antimicrobial peptides of human and nonhuman origin, a feature that likely contributes to its virulence. Expressing a robust proteolytic activity, P. gingivalis hydrolyzes antimicrobial peptides. In this study, P. gingivalis inactivated three antimicrobial peptides, while a D-enantiomer was resistant to degradation. P. gingivalis was resistant to the protease-resistant D-enantiomer peptide, and importantly, a protease-deficient P. gingivalis mutant was also resistant to the antimicrobial peptide. Finally, the binding of a fluorescently labeled antimicrobial peptide to protease-deficient P. gingivalis was much weaker than the binding of susceptible Escherichia coli. Our results suggest that the resistance of P. gingivalis ATCC 33277 to direct killing by antimicrobial peptides is protease independent and results (at least partially) from the low affinity of antimicrobial peptides to P. gingivalis. C1 [Bachrach, Gilad; Altman, Hamutal; Gabai-Gutner, Michal; Steinberg, Doron] Hebrew Univ Jerusalem, Hadassah Sch Dent Med, Inst Dent Sci, Jerusalem, Israel. [Chalmers, Natalia I.] Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. [Mor, Amram] Technion Israel Inst Technol, Dept Food Engn & Biotechnol, Lab Antimicrobial Peptides Investgat, Haifa, Israel. [Friedman, Michael] Hebrew Univ Jerusalem, Fac Med, Sch Pharm, Dept Pharmaceut, Jerusalem, Israel. RP Bachrach, G (reprint author), Hebrew Univ Jerusalem, Hadassah Sch Dent Med, Inst Dent Sci, Jerusalem, Israel. EM giladba@ekmd.huji.ac.il NR 45 TC 25 Z9 26 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2008 VL 52 IS 2 BP 638 EP 642 DI 10.1128/AAC.01271-07 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 256JN UT WOS:000252724800036 PM 18086848 ER PT J AU Chamilos, G Lewis, RE Lamaris, G Walsh, TJ Kontoyiannis, DP AF Chamilos, G. Lewis, R. E. Lamaris, G. Walsh, T. J. Kontoyiannis, D. P. TI Zygomycetes hyphae trigger an early, robust proinflammatory response in human polymorphonuclear neutrophils through toll-like receptor 2 induction but display relative resistance to oxidative damage SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID NEISSERIA-GONORRHOEAE; BURST AB Human polymorphonuclear neutrophils (HPMNs) displayed attenuated hyphal damage associated with impaired O-2(-) release following exposure to Rhizopus oryzae versus that with Aspergillus fumigatus. Exposure of HPMNs to R. oryzae hyphae resulted in upregulation in Toll-like receptor 2 mRNA and a robust proinflammatory gene expression with rapid (1-h) induction of NF-kappa B pathway-related genes. C1 [Chamilos, G.; Lewis, R. E.; Lamaris, G.; Kontoyiannis, D. P.] Univ Texas Houston, MD Anderson Canc Ctr, Unit 402, Dept Infect Dis Infect Control & Employee Hlth, Houston, TX 77030 USA. [Lewis, R. E.; Kontoyiannis, D. P.] Univ Houston, Coll Pharm, Houston, TX 77030 USA. [Walsh, T. J.] NCI, Pediat Oncol Branch, Immunocompromised Host Sect, Bethesda, MD 20892 USA. RP Kontoyiannis, DP (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Unit 402, Dept Infect Dis Infect Control & Employee Hlth, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM dkontoyi@mdanderson.org OI Lewis, Russell/0000-0002-2002-4339 NR 14 TC 27 Z9 27 U1 0 U2 1 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 FEB PY 2008 VL 52 IS 2 BP 722 EP 724 DI 10.1128/AAC.01136-07 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 256JN UT WOS:000252724800047 PM 18025115 ER PT J AU Walters, DM Cho, HY Kleeberger, SR AF Walters, Dianne M. Cho, Hye-Youn Kleeberger, Steven R. TI Oxidative stress and antioxidants in the pathogenesis of pulmonary fibrosis: A potential role for Nrf2 SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID EXTRACELLULAR-SUPEROXIDE DISMUTASE; INTERSTITIAL LUNG-DISEASES; TRANSCRIPTION FACTOR NRF2; ORAL N-ACETYLCYSTEINE; GAMMA-GLUTAMYLCYSTEINE SYNTHETASE; LOWER RESPIRATORY-TRACT; GENE-EXPRESSION; EPITHELIAL-CELLS; NF-E2-RELATED FACTOR-2; GLUTATHIONE DEFICIENCY AB Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disorder in which excessive deposition of extracellular matrix leads to irreversible scarring of interstitial lung tissue. The etiology of IPF remains unknown, but growing evidence suggests that disequilibrium in oxidant/antioxidant balance contributes significantly. IPF is currently regarded as a fibroproliferative disorder triggered by repeated alveolar epithelial cell injury. Oxidative stress plays a role in many processes involved in alveolar epithelial cell injury and fibrogenesis. Here we review the role of oxidative stress in IPF, and other forms of pulmonary fibrosis, with particular attention to antioxidant defenses regulated by the redox-sensitive transcription factor nuclear factor, erythroid derived 2, like (Nrf2). Nrf2 binds specific antioxidant response elements (AREs) in the promoter of antioxidant enzyme and defense protein genes and regulates their expression in many tissue types. Nrf2 protects from several phenotypes in which enhanced oxidative burden contributes to disease pathogenesis, including cancer, acute lung injury, and pulmonary fibrosis. We suggest that promoter polymorphisms in human NRF2 may contribute to IPF susceptibility, although this hypothesis has not been tested. Pulmonary fibrosis is a highly complex disease and involves multiple genes and processes, and new therapies for cellular and molecular targets involved in pathogenic mechanisms are needed. C1 [Walters, Dianne M.; Cho, Hye-Youn; Kleeberger, Steven R.] NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Kleeberger, SR (reprint author), NIEHS, Lab Resp Biol, NIH, 111 TW Alexander Dr,Bldg 101,D240, Res Triangle Pk, NC 27709 USA. EM kleeber1@niehs.nih.gov OI Walters, Dianne/0000-0003-3888-2646 NR 112 TC 68 Z9 73 U1 2 U2 10 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD FEB PY 2008 VL 10 IS 2 BP 321 EP 332 DI 10.1089/ars.2007.1901 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 245PN UT WOS:000251947600010 PM 17999635 ER PT J AU Hines, HB Kim, AD Stafford, RG Badie, SS Brueggeman, EE Newman, DJ Schmidt, JJ AF Hines, Harry B. Kim, Alexander D. Stafford, Robert G. Badie, Shirin S. Brueggeman, Ernst E. Newman, David J. Schmidt, James J. TI Use of a recombinant fluorescent substrate with cleavage sites for all botulinum neurotoxins in high-throughput screening of natural product extracts for inhibitors of serotypes A, B, and E SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID LIGHT-CHAIN; ZINC-ENDOPEPTIDASE; PROTEASE ACTIVITY; TOXIN; IDENTIFICATION; DELIVERY; ASSAYS; REQUIREMENTS; PROTEINS; AFFINITY AB The seven serotypes of botulinum neurotoxin (BoNTs) are zinc metalloproteases that cleave and inactivate proteins critical for neurotransmission. The synaptosomal protein of 25 kDa (SNAP-25) is cleaved by BoNTs A, C, and E, while vesicle-associated membrane protein (VAMP) is the substrate for BoNTs B, D, F, and G. BoNTs not only are medically useful drugs but also are potential bioterrorist and biowarfare threat agents. Because BoNT protease activity is required for toxicity, inhibitors of that activity might be effective for antibotulinum therapy. To expedite inhibitor discovery, we constructed a hybrid gene encoding (from the N terminus to the C terminus, with respect to the expressed product) green fluorescent protein, then a SNAP-25 fragment encompassing residues Met-127 to Gly-206, and then VAMP residues Met-1 to Lys-94. Cysteine was added as the C terminus. The expressed product, which contained the protease cleavage sites for all seven botulinum serotypes, was purified and coupled covalently through the C-terminal sulfhydryl group to maleimide-activated 96-well plates. The substrate was readily cleaved by BoNTs A, B, D, E, and F. Using this assay and an automated 96-well pipettor, we screened 528 natural product extracts for inhibitors of BoNT A, B, and E protease activities. Serotype-specific inhibition was found in 30 extracts, while 5 others inhibited two serotypes. C1 [Hines, Harry B.; Kim, Alexander D.; Stafford, Robert G.; Badie, Shirin S.; Brueggeman, Ernst E.; Schmidt, James J.] USA, Med Res Inst Infect Dis, Dept Biochem & Cell Biol, Integrated Toxicol Div, Frederick, MD 21702 USA. [Newman, David J.] NCI, Nat Prod Branch, Dev Therapeut Program, Div Canc Treatment & Diag, Frederick, MD 21701 USA. RP Schmidt, JJ (reprint author), USA, Med Res Inst Infect Dis, Dept Biochem & Cell Biol, Integrated Toxicol Div, Frederick, MD 21702 USA. EM james.schmidt@amedd.army.mil NR 43 TC 26 Z9 27 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD FEB PY 2008 VL 74 IS 3 BP 653 EP 659 DI 10.1128/AEM.01690-07 PG 7 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 260OG UT WOS:000253019000012 PM 18083881 ER PT J AU Phillips, RS McPhie, P Miles, EW Marchal, S Lange, R AF Phillips, Robert S. McPhie, Peter Miles, Edith W. Marchal, Stephane Lange, Reinhard TI Quantitative effects of allosteric ligands and mutations on conformational equilibria in Salmonella typhimurium tryptophan synthase SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE allosteric; conformational change; hydrostatic pressure ID NUCLEAR-MAGNETIC-RESONANCE; BIENZYME COMPLEX; ALPHA(2)BETA(2) COMPLEX; MONOVALENT CATIONS; ESCHERICHIA-COLI; INTERSUBUNIT COMMUNICATION; SUBSTRATE-SPECIFICITY; BETA-SUBUNIT; 3-DIMENSIONAL STRUCTURE; PYRIDOXAL 5'-PHOSPHATE AB Allosteric communications are important in coordination of the reactions in the tryptophan (Trp) synthase alpha(2)beta(2) multienzyme complex. We have measured the conformational equilibria of L-Ser and L-Trp complexes, using absorption and fluorescence spectrophotometry with hydrostatic pressure equilibrium perturbation. The effects of monovalent cations, disodium a-glycerophosphate (Na(2)GP), indoleacetylglycine (IAG), and benzimidazole (BZI), as well as of beta E109D and beta D305A mutations, on K-eq for the conformational equilibria were determined. The L-Ser external aldimine-aminoacrylate equilibrium (K(e)q = [external aldimine]/[aminoacrylate]) has the largest value with Na+ (0.12), followed by K+ (0.04), Li+ (7.6 x 10(-4)), Rb+ (4.3 x 10(-4)), NH4+ (2.3 x 10(-4)), no cation (2.0 x 10(-4)) and Cs+ (1.6 x 10(-5)). alpha-Site ligands, Na(2)GP and IAG, have modest 3- to 40-fold effects on K-eq in the direction of aminoacrylate, but BZI in the presence of Na+ gives a low value of Keq comparable to that obtained with Cs+. There is no additivity of free energy for Na(2)GP and BZI, suggesting a common pathway for allosteric communications for both ligands. The values of Delta V-o range from -126 mL/mol for the Na+ complex to -204 mL/mol for the Na+ complex with BZI. The beta D305A mutation changes the K-eq by a factor of at least 10(5) (26.7 kJ/mol) and nearly abolishes allosteric communications. There are also dramatic decreases in the magnitude of both Delta Vo and Delta S for the L-Ser external aldimine-aminoacrylate equilibrium for beta D305A Trp synthase, consistent with a large decrease in solvation accompanying the conformational change in beta D305A Trp synthase relative to wild-type Trp synthase. The beta E109D mutation has more modest but significant effects on K-eq, which differ with the ligand, ranging from 40-fold for GP to 2200-fold for BZI, even though beta Glu-109 is not directly involved in allosteric communications. The effect of GP on the external aldimine-quinonoid intermediate equilibrium of the Trp synthase-L-Trp complex is similar to that of GP on the Trp synthase-L-Ser external aldimine-aminoacrylate equilibrium. These results have allowed a quantitative comparison of the allosteric effects of ligand and mutations in Trp synthase. These allosteric effects are finely tuned to control the synthesis of L-Trp without resulting in substrate or product inhibition. (C) 2007 Elsevier Inc. All rights reserved. C1 [Phillips, Robert S.] Univ Georgia, Dept Chem, Athens, GA 30602 USA. [Phillips, Robert S.] Univ Georgia, Dept Biochem & Mol Biol, Athens, GA 30602 USA. [McPhie, Peter; Miles, Edith W.] NIDDK, Natl Inst Hlth, Bethesda, MD 20892 USA. [Marchal, Stephane; Lange, Reinhard] INSERM, F-34095 Montpellier, France. [Marchal, Stephane; Lange, Reinhard] Univ Montpellier 2, F-34095 Montpellier, France. [Marchal, Stephane; Lange, Reinhard] EPHE, F-75007 Paris, France. RP Phillips, RS (reprint author), Univ Georgia, Dept Chem, 1001 Cedar St, Athens, GA 30602 USA. EM rsphillips@chem.uga.edu OI Phillips, Robert/0000-0001-8710-562X FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM042588] NR 43 TC 12 Z9 12 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD FEB 1 PY 2008 VL 470 IS 1 BP 8 EP 19 DI 10.1016/j.abb.2007.11:003 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 256VK UT WOS:000252757800002 PM 18047826 ER PT J AU Glanz, K Yaroch, AL Dancel, M Saraiya, M Crane, LA Buller, DB Manne, S O'Riordan, DL Heckman, CJ Hay, J Robinson, JK AF Glanz, Karen Yaroch, Amy L. Dancel, Monica Saraiya, Mona Crane, Lori A. Buller, David B. Manne, Sharon O'Riordan, David L. Heckman, Carolyn J. Hay, Jennifer Robinson, June K. TI Measures of sun exposure and sun protection practices for behavioral and epidemiologic research SO ARCHIVES OF DERMATOLOGY LA English DT Article ID UNITED-STATES; SUNBURN; CANCER; ADULTS; TRENDS AB Objective: To develop, in a collaborative project, core measures of sun exposure and sun protection habits, since the lack of standard outcome measures hampers comparison of population surveys and interventions used in skin cancer prevention research. Design: A work group of investigators evaluated available questionnaire measures of sun exposure and protection. Their deliberations led to a proposed set of core questionnaire items for adults, adolescents aged 11 to 17 years, and children 10 years or younger. These core items were used in cognitive testing by the investigators. Cross-site summaries of methods, response samples, and descriptive data were prepared. Setting: Nine locations across the United States. Participants: The study population comprised 81 individuals. Results: No unusual response patterns were detected in any of the respondent groups or for any specific question. Some revisions to the survey items resulted from the need for clarification or emphasis of frames of reference such as adding or underlining key phrases in a question. Conclusions: The combination of expert review followed by cognitive interviewing yielded standardized core survey items with good clarity and applicability for measuring sun exposure and sun protection behaviors across a broad range of populations. They are appropriate for studies tracking morbidity and/ or mortality and evaluating prevention program effects. C1 [Glanz, Karen; Dancel, Monica] Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. [Yaroch, Amy L.] NCI, Bethesda, MD 20892 USA. [Saraiya, Mona] Ctr Dis Control & Prevent, Atlanta, GA USA. [Crane, Lori A.] Univ Colorado, Hlth Sci Ctr, Denver, CO USA. [Buller, David B.] Klein Buendel Inc, Golden, CO USA. [Manne, Sharon; Heckman, Carolyn J.] Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. [Hay, Jennifer] Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. [Robinson, June K.] Northwestern Univ, Sch Med, Chicago, IL USA. Univ Queensland, Herston, Qld, Australia. RP Glanz, K (reprint author), Emory Univ, Rollins Sch Publ Hlth, 1518 Clifton Rd NE,Room 530, Atlanta, GA 30322 USA. EM kglanz@sph.emory.edu FU NCATS NIH HHS [UL1 TR000454]; NCI NIH HHS [P30 CA006927] NR 20 TC 110 Z9 110 U1 0 U2 6 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 FEB PY 2008 VL 144 IS 2 BP 217 EP 222 DI 10.1001/archdermatol.2007.46 PG 6 WC Dermatology SC Dermatology GA 262RE UT WOS:000253164900010 PM 18283179 ER PT J AU Anton, RF Oroszi, G O'Malley, S Couper, D Swift, R Pettinati, H Goldman, D AF Anton, Raymond F. Oroszi, Gabor O'Malley, Stephanie Couper, David Swift, Robert Pettinati, Helen Goldman, David TI An evaluation of mu-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID TESTING COMBINED PHARMACOTHERAPIES; COMPULSIVE DRINKING SCALE; PLACEBO-CONTROLLED TRIAL; GENE OPRM1; BEHAVIORAL INTERVENTIONS; FUNCTIONAL POLYMORPHISM; A118G POLYMORPHISM; NUCLEUS-ACCUMBENS; BETA-ENDORPHIN; ASSOCIATION AB Context: Naltrexone hydrochloride treatment for alcohol dependence works for some individuals but not for everyone. Asn40Asp, a functional polymorphism of the mu-opioid receptor gene (OPRM1), might predict naltrexone response. Objective: To evaluate whether individuals with alcoholism who are heterozygous (Asp40/Asn40) or homozygous (Asp40/Asp40) for the OPRM1 Asp40 allele respond better to naltrexone. Design: Pharmacogenetic analysis conducted between January 1, 2001, and January 31, 2004. Setting: Eleven academic sites in the COMBINE Study. Participants: Recently abstinent volunteers who met all 3 of the following conditions: (1) DSM-IV criteria for primary alcohol dependence; (2) participation in the COMBINE Study; and (3) availability of DNA. Interventions: Alcoholic subjects were treated for 16 weeks with 100 mg of naltrexone hydrochloride (234 Asn40 homozygotes and 67 with at least 1 copy of the Asp40 allele) or placebo (235 Asn40 homozygotes and 68 with at least 1 copy of the Asp40 allele). All participants received medical management (MM) alone or with combined behavioral intervention (CBI). Main Outcome Measures: Time trends in percentage of days abstinent, percentage of heavy drinking days, and rates of good clinical outcome. Results: Alcoholic subjects with an Asp40 allele receiving MM alone (no CBI) had an increased percentage of days abstinent (P=. 07) and a decreased percentage of heavy drinking days (P=. 04) if treated with naltrexone vs placebo, while those with the Asn40/Asn40 genotype showed no medication differences. If treated with MM alone and naltrexone, 87.1% of Asp40 carriers had a good clinical outcome, compared with only 54.8% of individuals with the Asn40/Asn40 genotype (odds ratio, 5.75; confidence interval, 1.88-17.54), while, if treated with placebo, 48.6% of Asp40 carriers and 54.0% of individuals with the Asn40/Asn40 genotype had a good clinical outcome (interaction between medication and genotype, P=. 005). No gene X medication interactions were observed in those treated with both MM and CBI. Conclusions: These results confirm and extend the observation that the functionally significant OPRM1 Asp40 allele predicts naltrexone treatment response in alcoholic individuals. This relationship might be obscured, however, by other efficacious treatments. OPRM1 geno-typing in alcoholic individuals might be useful to assist in selecting treatment options. Trial Registration: clinicaltrials. gov Identifier: NCT00006206. C1 [Anton, Raymond F.] Med Univ S Carolina, Ctr Drug & Alcohol Programs, Charleston, SC 29425 USA. [Oroszi, Gabor; Goldman, David] NIAAA, Natl Inst Hlth, Neurogenet Lab, Rockville, MD USA. [O'Malley, Stephanie] Yale Univ, Sch Med, Substance Abuse Treatment Unit, New Haven, CT USA. [Couper, David] Univ N Carolina, Collaborat Studies Coordinating Ctr, Chapel Hill, NC USA. [Swift, Robert] Brown Univ, Roger Williams Med Ctr, Providence, RI 02912 USA. [Swift, Robert] Brown Univ, Providence Vet Affairs Med Ctr, Providence, RI 02912 USA. [Pettinati, Helen] Univ Penn, Sch Med, Treatment Res Ctr, Philadelphia, PA 19104 USA. RP Anton, RF (reprint author), Med Univ S Carolina, Ctr Drug & Alcohol Programs, 67 President St,POB 250861, Charleston, SC 29425 USA. EM antonr@musc.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [Z01 AA000301-09]; NIAAA NIH HHS [U10AA11783, U10 AA011715, U10AA11715, U10AA11716, U10AA11721, U10AA11727, U10AA11756, U10AA11768, U10AA11773, U10AA11776, U10AA11777, U10AA11787, U10AA11799] NR 64 TC 251 Z9 256 U1 5 U2 18 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD FEB PY 2008 VL 65 IS 2 BP 135 EP 144 DI 10.1001/archpsyc.65.2.135 PG 10 WC Psychiatry SC Psychiatry GA 258HV UT WOS:000252859900003 PM 18250251 ER PT J AU Luo, S McNeill, M Myers, TG Hohman, RJ Levine, RL AF Luo, Shen McNeill, Megan Myers, Timothy G. Hohman, Robert J. Levine, Rodney L. TI Lon protease promotes survival of Escherichia coli during anaerobic glucose starvation SO ARCHIVES OF MICROBIOLOGY LA English DT Article DE Lon protease; Clp protease; anaerobiosis; carbon starvation; stationary phase survival ID DEPENDENT CLP PROTEASE; MUTATIONAL ANALYSIS; NUTRITIONAL STRESS; CELL-DIVISION; SULA PROTEIN; DEGRADATION; GENE; PROTEOLYSIS; EXPRESSION; INHIBITOR AB In Escherichia coli, Lon is an ATP-dependent protease which degrades misfolded proteins and certain rapidly-degraded regulatory proteins. Given that oxidatively damaged proteins are generally degraded rather than repaired, we anticipated that Lon deficient cells would exhibit decreased viability during aerobic, but not anaerobic, carbon starvation. We found that the opposite actually occurs. Wild-type and Lon deficient cells survived equally well under aerobic conditions, but Lon deficient cells died more rapidly than the wild-type under anaerobiosis. Aerobic induction of the Clp family of ATP-dependent proteases could explain these results, but direct quantitation of Clp protein established that its level was not affected by Lon deficiency and overexpression of Clp did not rescue the cells under anaerobic conditions. We conclude that the Lon protease supports survival during anaerobic carbon starvation by a mechanism which does not depend on Clp. C1 [Luo, Shen; Levine, Rodney L.] NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. [McNeill, Megan; Myers, Timothy G.; Hohman, Robert J.] NIAID, Res Technol Branch, NIH, Rockville, MD 20852 USA. RP Levine, RL (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Room 2351, Bethesda, MD 20892 USA. EM rhohman@niaid.nih.gov; rlevine@nih.gov RI Levine, Rodney/D-9885-2011 FU Intramural NIH HHS [Z01 HL000225-31] NR 32 TC 2 Z9 2 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0302-8933 J9 ARCH MICROBIOL JI Arch. Microbiol. PD FEB PY 2008 VL 189 IS 2 BP 181 EP 185 DI 10.1007/s00203-007-0304-z PG 5 WC Microbiology SC Microbiology GA 249TG UT WOS:000252252100011 PM 17891379 ER PT J AU Rasch, EK Hochberg, MC Magder, L Magaziner, J Altman, BM AF Rasch, Elizabeth K. Hochberg, Marc C. Magder, Larry Magaziner, Jay Altman, Barbara M. TI Health of community-dwelling adults with mobility limitations in the United States: Prevalent health conditions. Part I SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article; Proceedings Paper CT 133rd Annual Meeting of the American-Public-Health-Association CY DEC 10-14, 2005 CL Philadelphia, PA SP Amer Public Hlth Assoc DE comorbidity; persons with disabilities; public health; rehabilitation ID SPINAL-CORD-INJURY; SECONDARY CONDITIONS; PHYSICAL-DISABILITIES; MEDICAL CONDITIONS; MULTICENTER ANALYSIS; BRAIN-INJURY; POPULATION; COMPLICATIONS; COMORBIDITY; MORBIDITY AB Objective: To characterize the extent and types of prevalent health conditions among nationally representative groups of adults with mobility, nonmobility, and no limitations. Design: Data were collected during 5 rounds of household interviews from a probability subsample of households that represent the civilian, noninstitutionalized U.S. Population. With some exceptions, round 1 variables were used for this analysis. Setting: Community. Participants: Data were analyzed on the same respondents from the 1996 to 1997 Medical Expenditure Panel Survey (MEPS) and the 1995 National Health Interview Survey Disability Supplement. Respondents were categorized into 3 groups for analysis: those with mobility limitations, nonmobility limitations: and no limitations. The analytic sample 'included 13,897 MEPS adults (>= 18y). Interventions: Not applicable. Main Outcome Measures: Number, types, and prevalence of self-reported health conditions compared across groups. Results: On average. adults with mobility limitations had significantly more prevalent conditions (3.6) than those with nonmobility limitations (2.4), or no limitations (1.3). Greater comorbidity existed in the context of fewer personal resources and more than half of adults with mobility limitations were working age. Conclusions: Determining factors that influence the health of adults with mobility limitations is a critical public health issue. C1 [Rasch, Elizabeth K.] NIH, Dept Rehabil Med, Clin Res Ctr, Bethesda, MD 20892 USA. [Hochberg, Marc C.; Magder, Larry; Magaziner, Jay] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Altman, Barbara M.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Rasch, EK (reprint author), NIH, Dept Rehabil Med, Clin Res Ctr, Bldg 10,Room 1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM RaschE@cc.nih.gov NR 57 TC 26 Z9 27 U1 1 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD FEB PY 2008 VL 89 IS 2 BP 210 EP 218 DI 10.1016/j.apmr.2007.08.146 PG 9 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 260OD UT WOS:000253018700003 PM 18226643 ER PT J AU Rasch, EK Magder, L Hochberg, MC Magaziner, J Altman, BM AF Rasch, Elizabeth K. Magder, Larry Hochberg, Marc C. Magaziner, Jay Altman, Barbara M. TI Health of community-dwelling adults with mobility limitations in the United States: Incidence of secondary health conditions. Part II SO ARCHIVES OF PHYSICAL MEDICINE AND REHABILITATION LA English DT Article; Proceedings Paper CT 133rd Annual Meeting of the American-Public-Health-Association CY DEC 10-14, 2005 CL Philadelphia, PA SP Amer Public Hlth Assoc DE disabled persons; mobility limitations; incidence; public health; rehabilitation ID SPINAL-CORD-INJURY; PHYSICAL-DISABILITIES; DEVELOPMENTAL-DISABILITIES; MEDICAL COMPLICATIONS; MULTICENTER ANALYSIS; PUBLIC-HEALTH; BRAIN-INJURY; POPULATION; WOMEN; RISK AB Objective: To compare incident health conditions that occurred over a 2-year period in nationally representative groups of adults with mobility, nonmobility, and no limitations. Design: Data were collected prospectively from a probability subsample of households that represent the civilian, noninstitutionalized U.S. population. Setting: Five rounds of household interviews were conducted over 2 years. Participants: Data were analyzed on the same respondents from the 1996-1997 Medical Expenditure Panel Survey (MEPS) and the 1995 National Health Interview Survey Disability Supplement. Respondents were categorized into 3 groups for analysis; those with mobility limitations, nonmobility limitations, and no limitations. The analytic sample included 12,302 MEPS adults (>= 18y). Interventions: Not applicable. Main Outcome Measures: Number, types, and 2-year incidence of self-reported health conditions compared across groups. Results: The mean number of incident conditions (95% confidence intervals [CIs]) over the 2-year period was greatest in adults with mobility limitations (mean, 4.7; 95% CI, 4.4-4.9) compared with those with nonmobility limitations (mean, 3.9; 95% CI, 3.7-4.2) or no limitations (mean, 2.6; 95% CI, 2.5-2.7). Incident conditions affected most major body systems. Conclusions: Because secondary conditions are potentially preventable, determining factors that influence their occurrence is an important public health issue requiring specific action. C1 [Rasch, Elizabeth K.] NCI, Clin Res Ctr, Dept Rehabil Med, Bethesda, MD 20892 USA. [Magder, Larry; Hochberg, Marc C.; Magaziner, Jay] Univ Maryland, Sch Med, Baltimore, MD 21201 USA. [Altman, Barbara M.] Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. RP Rasch, EK (reprint author), NCI, Clin Res Ctr, Dept Rehabil Med, Bldg 10,Room 1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM RaschE@cc.nih.gov NR 66 TC 31 Z9 32 U1 1 U2 5 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0003-9993 J9 ARCH PHYS MED REHAB JI Arch. Phys. Med. Rehabil. PD FEB PY 2008 VL 89 IS 2 BP 219 EP 230 DI 10.1016/j.apmr.2007.08.159 PG 12 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 260OD UT WOS:000253018700004 PM 18226644 ER PT J AU Sumner, AE Cowie, CC AF Sumner, Anne E. Cowie, Catherine C. TI Ethnic differences in the ability of triglyceride levels to identify insulin resistance SO ATHEROSCLEROSIS LA English DT Article DE triglyceride; metabolic syndrome; insulin resistance ID HOMEOSTASIS MODEL ASSESSMENT; NUTRITION EXAMINATION SURVEY; TREATMENT PANEL-III; METABOLIC SYNDROME; LIPOPROTEIN-LIPASE; GLUCOSE-TOLERANCE; ADIPOSE-TISSUE; AFRICAN-AMERICANS; NATIONAL-HEALTH; US POPULATION AB The Metabolic Syndrome is used to predict the onset of coronary artery disease and Type 2 diabetes. As the predictive value of the Metabolic Syndrome has been challenged, alternative syndromes have been developed. All of these syndromes were developed in populations that were predominantly non-Hispanic white (NHW). They include the Enlarged Waist Elevated Triglyceride Syndrome, the Overweight-Lipid Syndrome and the Hypertriglyceridemic Waist Syndrome. The first applies to postmenopausal women, the second to overweight individuals (BMI >= 25 kg/m(2)), and the third to men. Each syndrome uses hypertriglyceridemia as a criterion. However, the definition of hypertriglyceridemia varies by syndrome i.e. TG >= 128 mg/dL for the Enlarged Waist Elevated Triglyceride Syndrome, TG >= 130 mg/dL for the Overweight-Lipid Syndrome, >= 150 mg/dL for the Metabolic Syndrome, and TG >= 176 mg/dL for the Hypertriglyceridemic Waist Syndrome. Insulin resistance and hypertriglyceridemia are highly correlated. But as insulin resistant non-Hispanic blacks (NHB) often have triglyceride (TG) levels below the thresholds set by these syndromes, the ability of either TG or these syndromes to identify high risk NHB is unknown. Using the National Health and Nutrition Examination Survey (NHANES) 1999 - 2002, our goals were to determine by ethnicity: (1) the prevalence of each of these syndromes; (2) the ability of fasting TG concentrations to identify insulin resistance at cut-off levels established by these syndromes, specifically 130, 150 and 176 mg/dL. Participants were 2804 adults from NHANES 1999 - 2002. The cohort was divided into tertiles of homeostasis model assessment. Insulin resistance was defined as the upper tertile (>= 2.73). The prevalence of each syndrome was lower in NHB than NHW or Mexican Americans (MA) (all P < 0.05). Mean TG levels in NHB, non-Hispanic Whites (NHW) and Mexican Americans (MA) were: 99, 140 and 144 mg/dL, respectively. The mean percents of insulin-resistant NHB, NHW and MA with TG < 130 mg/dL were: 64, 31 and 36. The percents of insulin-resistant NHB, NHW and MA with TG < 150 mg/dL were: 75, 46 and 47. The percents of insulin-resistant NHB, NHW and MA with TG < 176 mg/dL were: 81, 58 and 59. Significance was P < 0.001 for each comparison to NHB. In conclusion, the prevalence of syndromes that use TG as a diagnostic criterion is lower in NHB than NHW or MA. NHB are more likely than NHW or MA to be insulin-resistant and have TG levels below threshold values. As syndromes are formulated to identify individuals at high risk for conditions such as cardiovascular disease and Type 2 diabetes, ethnic differences in TG levels should be considered. Published by Elsevier Ireland Ltd. C1 [Sumner, Anne E.] NIDDK, NIH Rockville Pike 9000, Clin Endocrinol Branch, Bethesda, MD 20892 USA. [Cowie, Catherine C.] NIDDK, NIH, Diabet Epidemiol Program, Bethesda, MD 20892 USA. RP Sumner, AE (reprint author), NIDDK, NIH Rockville Pike 9000, Clin Endocrinol Branch, Bldg 10-CRC,Rm 6W-5940, Bethesda, MD 20892 USA. EM AnneS@intra.niddk.nih.gov FU Intramural NIH HHS; NIDDK NIH HHS [N01-DK-1-2478] NR 35 TC 103 Z9 103 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0021-9150 J9 ATHEROSCLEROSIS JI Atherosclerosis PD FEB PY 2008 VL 196 IS 2 BP 696 EP 703 DI 10.1016/j.atherosclerosis.2006.12.018 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 270TT UT WOS:000253743800026 PM 17254586 ER PT J AU Grandjean, P Bellinger, D Bergman, A Cordier, S Davey-Smith, G Eskenazi, B Gee, D Gray, K Hanson, M Van den Hazel, P Heindel, JJ Heinzow, B Hertz-Picciotto, I Hu, H Huang, TTK Jensen, TK Landrigan, PJ McMillen, IC Murata, K Ritz, B Schoeters, G Skakkebaek, NE Skerfving, S Weihe, P AF Grandjean, Philippe Bellinger, David Bergman, Ake Cordier, Sylvaine Davey-Smith, George Eskenazi, Brenda Gee, David Gray, Kimberly Hanson, Mark Van den Hazel, Peter Heindel, Jerrold J. Heinzow, Birger Hertz-Picciotto, Irva Hu, Howard Huang, Terry T-K Jensen, Tina Kold Landrigan, Philip J. McMillen, I. Caroline Murata, Katsuyuki Ritz, Beate Schoeters, Greet Skakkebaek, Niels Erik Skerfving, Staffan Weihe, Pal TI The faroes statement: Human health effects of developmental exposure to chemicals in our environment SO BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY LA English DT Editorial Material C1 [Grandjean, Philippe; Jensen, Tina Kold] Univ So Denmark, Inst Publ Hlth, Dept Environm Med, DK-5000 Odense, Denmark. [Grandjean, Philippe; Bellinger, David] Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. [Bergman, Ake] Stockholm Univ, Dept Environm Chem, S-10691 Stockholm, Sweden. [Cordier, Sylvaine] Univ Rennes 1, INSERM, U625, Rennes, France. [Davey-Smith, George] Univ Bristol, Dept Social Med, Bristol, Avon, England. [Eskenazi, Brenda] Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. [Gee, David] European Environm Agcy, Copenhagen, Denmark. [Gray, Kimberly; Heindel, Jerrold J.] Natl Inst Environm Hlth Sci, Natl Inst Hlth, Dept Hlth & Human Serv, Durham, NC USA. [Hanson, Mark] Univ Southampton, Princess Anne Hosp, Southampton, Hants, England. [Van den Hazel, Peter] Publ Hlth Serv Gelderland Midden, Arnhem, Netherlands. [Heinzow, Birger] State Agcy Hlth Occupat Safety Land Schleswig Hol, Kiel, Germany. [Hertz-Picciotto, Irva] Univ Calif Davis, Dept Publ Hlth Sci, Davis, CA 95616 USA. [Hu, Howard] Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. [Huang, Terry T-K] NICHHD, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Landrigan, Philip J.] Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY USA. [McMillen, I. Caroline] Univ S Australia, Sansom Res Inst, Adelaide, SA 5001, Australia. [Murata, Katsuyuki] Akita Univ, Sch Med, Div Environm Hlth Sci, Akita 010, Japan. [Ritz, Beate] Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90024 USA. [Schoeters, Greet] Flemish Inst Technol Res, Mol, Belgium. [Skakkebaek, Niels Erik] Natl Univ Hosp, Dept Growth & Reproduct, Copenhagen, Denmark. [Skerfving, Staffan] Univ Lund Hosp, Dept Occupat & Environm Med, S-22185 Lund, Sweden. RP Grandjean, P (reprint author), Univ So Denmark, Inst Publ Hlth, Dept Environm Med, Winsloewsparken 17, DK-5000 Odense, Denmark. EM pgrand@hsph.harvard.edu RI Ritz, Beate/E-3043-2015; Cordier, Sylvaine/F-7919-2013; OI Grandjean, Philippe/0000-0003-4046-9658 FU ATSDR CDC HHS [TS000065]; NIEHS NIH HHS [ES015442] NR 0 TC 90 Z9 91 U1 0 U2 26 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1742-7835 J9 BASIC CLIN PHARMACOL JI Basic Clin. Pharmacol. Toxicol. PD FEB PY 2008 VL 102 IS 2 BP 73 EP 75 DI 10.1111/j.1742-7843.2007.00114.x PG 3 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 254LU UT WOS:000252588900002 PM 18226057 ER PT J AU Heindel, JJ AF Heindel, Jerrold J. TI Animal models for probing the developmental basis of disease and dysfunction paradigm SO BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY LA English DT Article; Proceedings Paper CT International Conference on Foetal Programming and Development Toxicity CY MAY 20-24, 2007 CL Torshavn, DENMARK ID MAMMARY-GLAND DEVELOPMENT; BISPHENOL-A ALTERS; IN-UTERO EXPOSURE; ENDOCRINE DISRUPTORS; PRENATAL EXPOSURE; PERINATAL EXPOSURE; OBESITY EPIDEMIC; RAT; PROSTATE; DIETHYLSTILBESTROL AB There is a major paradigm shift taking place in science that while simple is profound. The new paradigm suggests that susceptibility to disease is set in utero or neonatally as a result of the influences of nutrition and exposures to environmental stressors/toxicants. In utero nutrition and/or in utero or neonatal exposures to environmental toxicants alter susceptibility to disease later in life as a result of their ability to affect the programming of tissue function that occurs during development. This concept, which is still a hypothesis undergoing scientific testing and scrutiny, is called the developmental basis of health and disease. If true, then it says that the focus on disease prevention and intervention must change from the time of disease onset to perhaps decades prior: during the in utero and neonatal period. Perhaps the reason it has been so difficult to link environmental exposure to disease susceptibility is that scientists have been looking at the wrong time! Certainly, not all exposures that result in increased disease or dysfunction occur during development. This paradigm shift just suggests that this is a sensitive window of exposure that should be examined more thoroughly. This overview focuses on animal models for the assessment of this new scientific paradigm and the animal data that now supports it. C1 NIEHS, Natl Inst Hlth, Dept Hlth & Human Serv, Div Extramural Res & Training, Res Triangle Pk, NC 27709 USA. RP Heindel, JJ (reprint author), NIEHS, Natl Inst Hlth, Dept Hlth & Human Serv, Div Extramural Res & Training, POB 12233, Res Triangle Pk, NC 27709 USA. EM heindelj@niehs.nih.gov NR 42 TC 19 Z9 20 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1742-7835 J9 BASIC CLIN PHARMACOL JI Basic Clin. Pharmacol. Toxicol. PD FEB PY 2008 VL 102 IS 2 BP 76 EP 81 DI 10.1111/j.1742-7843.2007.00184.x PG 6 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 254LU UT WOS:000252588900003 PM 18226058 ER PT J AU Le Foll, B Justinova, Z Wertheim, CE Barnes, C Goldberg, SR AF Le Foll, Bernard Justinova, Zuzana Wertheim, Carrie E. Barnes, Chanel Goldberg, Steven R. TI Topiramate does not alter nicotine or cocaine discrimination in rats SO BEHAVIOURAL PHARMACOLOGY LA English DT Article DE cocaine; drug discrimination; nicotine; rat; reward; subjective effects; topiramate ID DOPAMINE D-3 RECEPTOR; CONDITIONED PLACE PREFERENCES; RANDOMIZED CONTROLLED-TRIAL; ALCOHOL DEPENDENCE; STIMULUS PROPERTIES; SEEKING BEHAVIOR; DRUG-DEPENDENCE; ORAL TOPIRAMATE; ADDICTION; ANTAGONISTS AB The effects of topiramate, a potential treatment for drug dependence, were evaluated in two groups of rats trained to discriminate the administration of either 0.4 mg/kg nicotine or 10 mg/kg cocaine from that of saline, under a fixed-ratio 10 schedule of food delivery. Topiramate (1-60 mg/kg, intraperitoneal) did not produce any nicotine-like or cocaine-like discriminative effects by itself and did not produce any shift in the dose-response curves for nicotine or cocaine discrimination. Thus, the ability to discriminate the effects of nicotine or cocaine does not appear to be altered by topiramate administration. Furthermore, topiramate, given either alone or in combination with nicotine or cocaine, did not depress rates of responding. These experiments indicate that topiramate does not enhance or reduce the ability of rats to discriminate the effects of nicotine or cocaine. C1 [Le Foll, Bernard] Univ Toronto, Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON M5S 2S1, Canada. [Le Foll, Bernard; Justinova, Zuzana; Wertheim, Carrie E.; Barnes, Chanel; Goldberg, Steven R.] Univ Maryland, Sch Med, Natl Inst Drug Abuse, Intramural Res Program,Preclin Pharmacol Sect, Baltimore, MD 21201 USA. [Justinova, Zuzana] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. RP Le Foll, B (reprint author), Univ Toronto, Ctr Addict & Mental Hlth, Translat Addict Res Lab, 33 Russell St, Toronto, ON M5S 2S1, Canada. EM bernard_lefoll@camh.net RI Justinova, Zuzana/A-9109-2011; Le Foll, Bernard/K-2952-2014 OI Justinova, Zuzana/0000-0001-5793-7484; Le Foll, Bernard/0000-0002-6406-4973 FU Intramural NIH HHS [Z99 DA999999, Z01 DA000003-22]; NIDA NIH HHS [N01 DA059909] NR 52 TC 7 Z9 7 U1 1 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 FEB PY 2008 VL 19 IS 1 BP 13 EP 20 PG 8 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 259XN UT WOS:000252974300002 PM 18195590 ER PT J AU Burbelo, PD Groot, S Dalakas, MC Iadarola, MJ AF Burbelo, Peter D. Groot, Sandra Dalakas, Marinos C. Iadarola, Michael J. TI High definition profiling of autoantibodies to glutamic acid decarboxylases GAD65/GAD67 in stiff-person syndrome SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE autoantibodies; autoimmune; biomarkers; diagnostic; GAD65; neurological disease; stiff-person syndrome ID SYNDROME TYPE-I; TYPE-1 DIABETES-MELLITUS; ANTIBODIES; GAD; IDENTIFICATION; AUTOANTIGEN; QUANTIFICATION; RECOGNITION; PREVALENCE; EPITOPES AB Highly reliable biomarkers for the diagnosis of neurological diseases are not widely available. Here we evaluated a luciferase immunoprecipitation technology (LIPS) for the diagnosis of a CNS autoimmune disorder, stiff-person syndrome (SPS). Analysis by LIPS of 40 sera samples from SPS and control subjects for anti-GAD65 antibodies revealed dramatic titer differences allowing diagnosis of SPS with 100% sensitivity and 100% specificity. Anti-GAD65 antibody titers of SPS were segregated from controls with values greater than 23 standard deviations above the control subject mean. By analyzing patient antibody responses directly to GAD65 sub-fragments, the central region containing the decarboxylase catalytic domain was highly immunoreactive with all of the SPS sera, while the N- and C-terminal regions showed lower antibody titers and only reacted with subsets of SPS sera. Additional profiling revealed that some SPS patients showed autoantibodies against GAD67 and tyrosine hydroxylase, but no significant immunoreactivity was detected with cysteine sulfinic acid decarboxylase or GABA transaminase. This study validates LIPS as a robust method to interrogate autoantibodies for the diagnosis of SPS and potentially other neurological diseases. Published by Elsevier Inc. C1 [Burbelo, Peter D.; Groot, Sandra; Iadarola, Michael J.] Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, Bethesda, MD 20892 USA. [Dalakas, Marinos C.] NINDS, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Burbelo, PD (reprint author), Natl Inst Dent & Craniofacial Res, Neurobiol & Pain Therapeut Sect, Lab Sensory Biol, Bethesda, MD 20892 USA. EM burbelop@nidcr.nih.gov FU Intramural NIH HHS [Z99 DE999999] NR 25 TC 31 Z9 31 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 1 PY 2008 VL 366 IS 1 BP 1 EP 7 DI 10.1016/j.bbrc.2007.11.077 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 251RU UT WOS:000252392400001 PM 18047830 ER PT J AU Fang, QM Loktionova, NA Moschel, RC Javanmard, S Pauly, GT Pegg, AE AF Fang, Qingming Loktionova, Natalia A. Moschel, Robert C. Javanmard, Sahar Pauly, Gary T. Pegg, Anthony E. TI Differential inactivation of polymorphic variants of human O-6-alkylguanine-DNA alkyltransferase SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE alkyltransferase; O-6-benzylgunaine; polymorphisms; cancer chemotherapy; O-4-benzylfolate; DNA repair ID HUMAN O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; LUNG-CANCER RISK; DNA-REPAIR PROTEIN; PHASE-I; PLUS O-6-BENZYLGUANINE; GENETIC-POLYMORPHISM; SOLID TUMORS; CODON 160; MGMT; CHEMOTHERAPY AB The human DNA repair protein O-6-alkylguanine-DNA alkyltransferase (hAGT) is an important source of resistance to some therapeutic alkylating agents and attempts to circumvent this resistance by the use of hAGT inhibitors have reached clinical trials. Several human polymorphisms in the MGMT gene that encodes hAGT have been described including L84F and the linked double alteration I143V/K178R. We have investigated the inactivation of these variants and the much rarer variant W65C by O-6-benzylguanine, which is currently in clinical trials, and a number of other second generation hAGT inhibitors that contain folate derivatives (O-4-benzylfolic acid, the 3' and 5' folate esters of O-6-benzyl-2'-deoxyguanosine and the folic acid gamma ester of O-6-(p-hydroxymethyl)benzylguanine). The I143V/K178R variant was resistant to all of these compounds. The resistance was due solely to the I143V change. These results suggest that the frequency of the I143V/K178R variant among patients in the clinical trials with hAGT inhibitors and the correlation with response should be considered. (c) 2007 Elsevier Inc. All rights reserved. C1 [Fang, Qingming; Loktionova, Natalia A.; Pegg, Anthony E.] Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. [Moschel, Robert C.; Javanmard, Sahar; Pauly, Gary T.] NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. RP Pegg, AE (reprint author), Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, POB 850, Hershey, PA 17033 USA. EM aep1@psu.edu RI Fang, Qingming/B-6839-2008 OI Fang, Qingming/0000-0002-4006-0636 FU Intramural NIH HHS; NCI NIH HHS [R01 CA018137, R01 CA071976, R01 CA071976-12, CA 018137, CA 071976, R01 CA018137-31, R37 CA018137] NR 54 TC 11 Z9 11 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD FEB 1 PY 2008 VL 75 IS 3 BP 618 EP 626 DI 10.1016/j.bcp.2007.09.022 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 260MU UT WOS:000253015200003 PM 17996846 ER PT J AU Pliszka, B Martin, BM Karczewska, E AF Pliszka, Barbara Martin, Brian M. Karczewska, Emilia TI Ionic interaction of myosin loop 2 with residues located beyond the N-terminal part of actin probed by chemical cross-linking SO BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS LA English DT Article DE actin-myosin interaction; subfragment 1; chemical cross-linking ID I-BINDING LOOP; DICTYOSTELIUM ACTIN; MUSCLE-CONTRACTION; ENERGY-TRANSFER; F-ACTIN; COMPLEX; SUBFRAGMENT-1; INTERFACE; SEQUENCE; SITE AB To probe ionic contacts of skeletal muscle myosin with negatively charged residues located beyond the N-terminal part of actin, myosin subfragment 1 (S1) and actin split by ECP32 protease (ECP-actin) were cross-linked with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). We have found that unmodified S1 can be cross-linked not only to the N-terminal part, but also to the C-terminal 36 kDa fragment of ECP-actin. Subsequent experiments performed on S1 cleaved by elastase or trypsin indicate that the cross-linking site in S1 is located within loop 2. This site is composed of Lys-636 and Lys-637 and can interact with negatively charged residues of the 36 kDa actin fragment, most probably with Glu-99 and Glu-100. Cross-links are formed both in the absence and presence of MgATP.P-i analog, although the addition of nucleotide decreases the efficiency of the cross-linking reaction. (c) 2007 Elsevier B.V. All rights reserved. C1 [Pliszka, Barbara; Karczewska, Emilia] M Nencki Inst Expt Biol, Dept Biochem, PL-02093 Warsaw, Poland. [Martin, Brian M.] NIH, NIMH, Bethesda, MD 20892 USA. RP Pliszka, B (reprint author), M Nencki Inst Expt Biol, Dept Biochem, 3 Pasteur St, PL-02093 Warsaw, Poland. EM b.pliszka@nencki.gov.pl FU Intramural NIH HHS NR 40 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-9639 EI 0006-3002 J9 BBA-PROTEINS PROTEOM JI BBA-Proteins Proteomics PD FEB PY 2008 VL 1784 IS 2 BP 285 EP 291 DI 10.1016/j.bbapap.2007.11.004 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 265IZ UT WOS:000253353600004 PM 18054341 ER PT J AU Kim, Y Hechler, B Klutz, AM Gachet, C Jacobson, KA AF Kim, Yoonkyung Hechler, Beatrice Klutz, Athena M. Gachet, Christian Jacobson, Kenneth A. TI Toward multivalent signaling across G protein-coupled receptors from poly(amidoamine) dendrimers SO BIOCONJUGATE CHEMISTRY LA English DT Article ID DRUG-DELIVERY; POLYAMIDOAMINE DENDRIMERS; BIOMEDICAL APPLICATIONS; ADENOSINE RECEPTORS; PAMAM DENDRIMERS; FUNCTIONALIZED DENDRIMERS; DESIGNING DENDRIMERS; MOLECULAR-DYNAMICS; DENDRITIC POLYMERS; AGONIST AB Activation of the A(2A) receptor, a G protein-coupled receptor (GPCR), by extracellular adenosine, is antiaggregatory in platelets and anti-inflammatory. Multiple copies of an A(2A) agonist, the nucleoside CGS21680, were coupled covalently to PAMAM dendrimers and characterized spectroscopically. A fluorescent PAMAM-CGS21680 conjugate 5 inhibited aggregation of washed human platelets and was internalized. We envision that our multivalent dendrimer conjugates may improve overall pharmacological profiles compared to the monovalent GPCR ligands. C1 [Kim, Yoonkyung; Klutz, Athena M.; Jacobson, Kenneth A.] NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. [Hechler, Beatrice; Gachet, Christian] Univ Strasbourg 1, Strasbourg, France. [Hechler, Beatrice; Gachet, Christian] INSERM, U 311, EFS Alsace, Strasbourg, France. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009; Hechler, Beatrice/D-4227-2017; Gachet, Christian/H-9156-2016 OI Jacobson, Kenneth/0000-0001-8104-1493; FU Intramural NIH HHS NR 52 TC 31 Z9 34 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD FEB PY 2008 VL 19 IS 2 BP 406 EP 411 DI 10.1021/bc700327u PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 265AB UT WOS:000253330400003 PM 18176997 ER PT J AU Friedman, A AF Friedman, Alex TI Beyond accountability for reasonableness SO BIOETHICS LA English DT Article DE accountability for reasonableness; priority setting; limit setting; democratic deliberation; relevance condition; Daniels & Sabin ID HEALTH-CARE; FAIRNESS; RIGHTS AB This paper is a critique of Norman Daniels' and James Sabin's 'Accountability for Reasonableness' framework for making priority-setting decisions in health care in the face of widespread disagreement about values. Accountability for Reasonableness has been rapidly gaining worldwide acceptance, arguably to the point of becoming the dominant paradigm in the field of health policy. The framework attempts to set ground rules for a procedure that ensures that whatever decisions result will be fair, reasonable, and legitimate to the extent that even those who would be adversely affected will have reason to abide by them. I argue that the framework's four conditions are inadequate to this task. While we certainly require a fair and legitimate procedure for making priority setting decisions in health care despite a lack of consensus on relevant ethical and political issues, we must significantly revise the four conditions, and we cannot avoid facing our substantive disagreements head on if we hope to arrive at decisions that would (and should) be acceptable to everyone. I offer two suggestions. First, there is need for greater public involvement in all stages of deliberation. Second, we should give up on the idea that we can simplify the task of democratic deliberation by disallowing particular kinds or reasons and types of reasoning. Reasons of all kinds should be on the table, but then should be judged on their merits, such as consistency, plausibility and explanatory power, without any regard for their alleged sources of authority. C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Friedman, A (reprint author), NIH, Dept Clin Bioeth, 10 Ctr Dr,10-1C118, Bethesda, MD 20892 USA. EM friedmana@cc.nih.gov NR 21 TC 28 Z9 28 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0269-9702 J9 BIOETHICS JI Bioethics PD FEB PY 2008 VL 22 IS 2 BP 101 EP 112 DI 10.1111/j.1467-8519.2007.00605.x PG 12 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 257NL UT WOS:000252805700005 PM 18251770 ER PT J AU Cumberlidge, N Von Sternberg, RM Daniels, SR AF Cumberlidge, Neil Von Sternberg, Richard M. Daniels, Savel R. TI A revision of the higher taxonomy of the Afrotropical freshwater crabs (Decapoda : Brachyura) with a discussion of their biogeography SO BIOLOGICAL JOURNAL OF THE LINNEAN SOCIETY LA English DT Article DE Deckeniina; Deckeniinae; Deckeniini; Gecarcinucidae; Gecarcinucoidea; Globonautina; Hydrothelphusini; Potamoidea; Potamonautidae; Potamonautinae ID A.-MILNE-EDWARDS; LAKE TANGANYIKA; EAST-AFRICA; POTAMOIDEA; GENUS; PLATYTHELPHUSIDAE; CRUSTACEA; POTAMONAUTIDAE; POTAMIDAE; GECARCINUCOIDEA AB The higher taxonomy of the 20 known genera of Afrotropical freshwater crabs is revised to reflect the evolutionary relationships revealed by the consensus of a series of recent morphological and molecular phylogenetic studies of the group. The Afrotropical freshwater crab genera fall into two monophyletic groups, one from Socotra with two genera (Potamidae) and another that includes the remaining 18 genera. The latter group, which includes the bulk of the region's freshwater crab fauna, forms a well-supported monophyletic clade. We recognize two monophyletic sister groups (subfamilies) within the Potamonautidae, one for seven genera from Africa (the Potamonautinae) and one for 11 genera from Africa, the Seychelles, and Madagascar (the Deckeniinae). The Deckeniinae includes two monophyletic groups (tribes), one with seven genera from Madagascar (the Hydrothelphusini), and one with four genera from Africa and the Seychelles (the Deckeniini). The Deckeniini is further divided here into two subtribes, the Deckeniina and the Globonautina. The Platythelphusidae is not recognized, and the Deckeniidae and Globonautinae are lowered in rank. There is no phylogenetic support for the continued inclusion of any genus from the Afrotropical region in the Gecarcinucidae which is treated here as an exclusively Oriental family. The Afrotropical freshwater crabs (excluding those from Socotra) form a monophyletic assemblage that has no representatives outside of the region. The wider biogeographical implications of the taxonomic revision are discussed. (c) 2008 The Linnean Society of London. C1 [Cumberlidge, Neil] No Michigan Univ, Dept Biol, Marquette, MI 49855 USA. [Von Sternberg, Richard M.] Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. [Daniels, Savel R.] Univ Stellenbosch, Dept Bot & Zool, ZA-7602 Matieland, South Africa. RP Cumberlidge, N (reprint author), No Michigan Univ, Dept Biol, 1401 Presque Isle Ave, Marquette, MI 49855 USA. EM ncumberl@nmu.edu NR 62 TC 25 Z9 27 U1 1 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0024-4066 EI 1095-8312 J9 BIOL J LINN SOC JI Biol. J. Linnean Soc. PD FEB PY 2008 VL 93 IS 2 BP 399 EP 413 PG 15 WC Evolutionary Biology SC Evolutionary Biology GA 250SA UT WOS:000252319500013 ER PT J AU Schoenbaum, G Shaham, Y AF Schoenbaum, Geoffrey Shaham, Yavin TI The role of orbitofrontal cortex in drug addiction: A review of preclinical studies SO BIOLOGICAL PSYCHIATRY LA English DT Review DE drug cues; orbitofrontal cortex; reinstatement; relapse; reversal learning; stress ID OBSESSIVE-COMPULSIVE DISORDER; ORBITAL PREFRONTAL CORTEX; COCAINE-EXPERIENCED RATS; DECISION-MAKING; NUCLEUS-ACCUMBENS; BASOLATERAL AMYGDALA; REINSTATEMENT MODEL; DENDRITIC SPINES; SEEKING BEHAVIOR; RHESUS-MONKEYS AB Studies using brain imaging methods have shown that neuronal activity in the orbitofrontal cortex, a brain area thought to promote the ability to control behavior according to likely outcomes or consequences, is altered in drug addicts. These human imaging findings have led to the hypothesis that core features of addiction like compulsive drug use and drug relapse are mediated in part by drug-induced changes in orbitofrontal function. Here, we discuss results from laboratory studies using rats and monkeys on the effect of drug exposure on orbitofrontal-mediated learning tasks and on neuronal structure and activity in orbitofrontal cortex. We also discuss results from studies on the role of the orbitofrontal cortex in drug self-ad ministration and relapse. Our main conclusion is that although there is clear evidence that drug exposure impairs orbitofrontal-dependent learning tasks and alters neuronal activity in orbitofrontal cortex, the precise role these changes play in compulsive drug use and relapse has not yet been established. C1 [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. [Schoenbaum, Geoffrey] Univ Maryland, Dept Psychol, Baltimore, MD 21201 USA. [Shaham, Yavin] Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. RP Schoenbaum, G (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, 685 W Baltimore St,HSF-1 Room 280K, Baltimore, MD 21201 USA. EM schoenbg@schoenbaumlab.org RI shaham, yavin/G-1306-2014 FU Intramural NIH HHS; NIDA NIH HHS [R01 DA015718, R01 DA015718-01A1, R01 DA015718-02, R01 DA015718-02S1, R01 DA015718-03, R01 DA015718-03S1, R01 DA015718-04, R01 DA015718-05, R01-DA015718] NR 117 TC 118 Z9 122 U1 2 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 1 PY 2008 VL 63 IS 3 BP 256 EP 262 DI 10.1016/j.biopsych.2007.06.003 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 254WT UT WOS:000252619400002 PM 17719014 ER PT J AU Kraemer, GW Moore, CF Newman, TK Barr, CS Schneider, ML AF Kraemer, Gary W. Moore, Colleen F. Newman, Timothy K. Barr, Christina S. Schneider, Mary L. TI Moderate level fetal alcohol exposure and serotonin transporter gene promoter polymorphism affect neonatal temperament and limbic-hypothalamic-pituitary-adrenal axis regulation in monkeys SO BIOLOGICAL PSYCHIATRY LA English DT Article DE adrenocorticotropic hormone (ACTH); cortisol (CORT); fetal alcohol exposure; infant negativity; LHPA axis; rhesus monkey; serotonin transporter gene ID ETHANOL EXPOSURE; PRENATAL ALCOHOL; RHESUS-MONKEYS; FUNCTIONAL POLYMORPHISM; PERSONALITY-TRAITS; PLACE PREFERENCE; EARLY EXPERIENCE; COCAINE REWARD; 5-HTT GENE; ADULT-RATS AB Background: A length polymorphism in the serotonin (5-HT) transporter gene promoter region in humans and rhesus monkeys affects functional characteristics of the brain 5-HT system. Prenatal alcohol exposure (FA-exposure) can have an impact on brain and psychosocial development that could interact with genetic endowment. This study determined whether moderate FA-exposure interacts with polymorphism in the 5-HT transporter gene to increase the incidence or severity of fetal alcohol effects in rhesus monkeys. Methods: The offspring of monkeys who did or did not consume moderate amounts of alcohol during pregnancy were assessed for temperament as neonates and adrenocorticotropic hormone (ACTH) and cortisol (CORT) in response to mother-infant separation at 6 months of age. Serotonin promoter region genotypes (homozygous s/s or heterozygous s/l versus homozygous l/l were determined. Results: Prenatal alcohol exposed carriers of the s allele exhibited increased neonatal irritability and increased ACTH and CORT compared with FA-exposed monkeys homozygous for the / allele and monkeys that were not FA-exposed regardless of genotype. Conclusions: The s allele of the 5-HT transporter increases the probability of neonatal irritability and increased stress responsiveness in FA-exposed monkeys, and this gene-environment interaction may affect psychosocial development. It is probable that FA-exposure contributes to 5-HT transporter gene-environment interactions in humans. C1 [Kraemer, Gary W.; Schneider, Mary L.] Univ Wisconsin, Dept Kinesiol, Madison, WI 53715 USA. [Moore, Colleen F.; Schneider, Mary L.] Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. [Kraemer, Gary W.; Schneider, Mary L.] Univ Wisconsin, Harlow Ctr Biol Psychol, Madison, WI 53706 USA. [Newman, Timothy K.; Barr, Christina S.] NIAAA, NIH, Bethesda, MD USA. [Kraemer, Gary W.] Univ Toronto, Dept Psychol, Mississauga, ON L5L 1C6, Canada. [Newman, Timothy K.] Univ Cape Town, Dept Psychiat, ZA-7925 Cape Town, South Africa. RP Schneider, ML (reprint author), Univ Wisconsin, Dept Kinesiol, 22 N Charter St, Madison, WI 53715 USA. EM schneider@education.wisc.edu FU Intramural NIH HHS; NIAAA NIH HHS [AA10079, AA12277, R01 AA012277-08, R01 AA012277-07, R01 AA010079, R01 AA010079-12, R01 AA012277, R01 AA010079-11]; NIMH NIH HHS [MH60318] NR 66 TC 31 Z9 31 U1 4 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 1 PY 2008 VL 63 IS 3 BP 317 EP 324 DI 10.1016/j.biopsych.2007.07.017 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 254WT UT WOS:000252619400010 PM 17884019 ER PT J AU Imanguli, MM Swaim, WD League, SC Guadagnini, JP Pavletic, SZ Gress, RE Hakim, FT AF Imanguli, M. M. Swaim, W. D. League, S. C. Guadagnini, J.-P. Pavletic, S. Z. Gress, R. E. Hakim, F. T. TI EPITHELIAL APOPTOSIS IN ORAL CHRONIC GVHD IS MEDIATED BY EFFECTOR-MEMORY COB CELLS: POTENTIAL ROLE OF IL-15 SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Imanguli, M. M.; League, S. C.; Pavletic, S. Z.; Gress, R. E.; Hakim, F. T.] NCI, Bethesda, MD 20892 USA. [Swaim, W. D.; Guadagnini, J.-P.] Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 26 BP 12 EP 12 DI 10.1016/j.bbmt.2007.12.034 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100027 ER PT J AU Ringden, OTH Pavletic, S Anasetti, C Barrett, JA Wang, T Antin, JH Di Bartolomeo, P Bolwell, BJ Bredeson, C Cairo, MS Gale, RP Giralt, S Hahn, T Hale, GA Halter, J Jagasia, M Litzow, MR Locatelli, F McCarthy, PL Cowan, MJ Petersdorf, EW Russel, JA Schiller, GJ Schouten, H Tallman, MS Verdonck, LF Wiley, JM Wingard, JR Horowitz, MM Arora, M AF Ringden, O. T. H. Pavletic, S. Anasetti, C. Barrett, J. A. Wang, T. Antin, J. H. Di Bartolomeo, P. Bolwell, B. J. Bredeson, C. Cairo, M. S. Gale, R. P. Giralt, S. Hahn, T. Hale, G. A. Halter, J. Jagasia, M. Litzow, M. R. Locatelli, F. McCarthy, P. L. Cowan, M. J. Petersdorf, E. W. Russel, J. A. Schiller, G. J. Schouten, H. Tallman, M. S. Verdonck, L. F. Wiley, J. M. Wingard, J. R. Horowitz, M. M. Arora, M. TI SIMILAR GRAFT-VERSUS-LEUKEMIA EFFECT USING MATCHED UNRELATED DONORS, COMPARED TO HLA-IDENTICAL SIBLINGS FOR HEMATOPOIETIC STEM CELL TRANSPLANTATION SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Ringden, O. T. H.] Karolinska Univ Hosp Huddinge, Stockholm, Sweden. [Pavletic, S.; Barrett, J. A.] NIH, Bethesda, MD 20892 USA. [Anasetti, C.] Univ S Florida, Coll Med, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL 33612 USA. [Wang, T.; Horowitz, M. M.] Med Coll Wisconsin, Milwaukee, WI 53226 USA. [Antin, J. H.] Brigham & Womens Hosp, Boston, MA 02115 USA. [Di Bartolomeo, P.] Osped Civile, Pescara, Italy. [Bolwell, B. J.] Cleveland Clin Fdn, Cleveland, OH 44195 USA. [Bredeson, C.] Manitoba BMT Program, Winnipeg, MB, Canada. [Cairo, M. S.] Columbia Univ, Med Ctr, New York, NY USA. [Gale, R. P.] Ctr Adv Studies Leukemia, Los Angeles, CA USA. [Giralt, S.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. [Hahn, T.; McCarthy, P. L.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Hale, G. A.] St Jude Childrens Hosp, Memphis, TN 38105 USA. [Halter, J.] Univ Basel Hosp, CH-4031 Basel, Switzerland. [Jagasia, M.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. [Litzow, M. R.] Mayo Clin, Rochester, MN USA. [Locatelli, F.] IRCCS, Policlin San Matteo, Pavia, Italy. [Cowan, M. J.] USCF Childrens Hosp, San Francisco, CA USA. [Petersdorf, E. W.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Russel, J. A.] Tom Baker Canc Clin, Calgary, AB, Canada. [Schiller, G. J.] Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. [Schouten, H.] Univ Hosp Maastricht, Maastricht, Netherlands. [Tallman, M. S.] Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. [Verdonck, L. F.] Univ Utrecht Hosp, Utrecht, Netherlands. [Wiley, J. M.] Herman & Walter Samuelson Childrens Hosp Sinai, Baltimore, MD USA. [Wingard, J. R.] Univ Florida, HSC Coll Med, Gainesville, FL USA. [Arora, M.] Univ Minnesota, Minneapolis, MN USA. RI Halter, Joerg/C-9487-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 33 BP 14 EP 15 DI 10.1016/j.bbmt.2007.12.041 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100034 ER PT J AU Chu, YW Bodnar, D Singh, N Gress, R AF Chu, Y.-W. Bodnar, D. Singh, N. Gress, R. TI PRE-TRANSPLANT ADMINISTRATION OF KERATINOCYTE GROWTH FACTOR AFFECTS PERIPHERAL T-CELL HOMEOSTASIS THROUGH INCREASED RECENT THYMIC EMIGRANT EXPORT AND AFFECTS THE COURSE OF MURINE CHRONIC GRAFT-VS.-HOST DISEASE SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Chu, Y.-W.; Bodnar, D.; Singh, N.; Gress, R.] NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 41 BP 17 EP 18 DI 10.1016/j.bbmt.2007.12.049 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100042 ER PT J AU Pulsipher, MA Chitphakdithai, P Logan, B Leitman, S Anderlini, P Klein, J Horowitz, M Miller, J King, R Confer, D AF Pulsipher, M. A. Chitphakdithai, P. Logan, B. Leitman, S. Anderlini, P. Klein, J. Horowitz, M. Miller, J. King, R. Confer, D. TI OUTCOMES OF A PROSPECTIVE TRIAL OF NMDP-FACILITATED UNRELATED DONOR (UD) PBSC HEMATOPOIETIC CELL TRANSPLANTATION (HCT) FOR LEUKEMIA AND MYELODYSPLASIA: COMPARABLE SURVIVAL REGARDLESS OF REGIMEN INTENSITY AND IMPROVED SURVIVAL WITH HIGHER CELL DOSES SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Pulsipher, M. A.] Univ Utah, Salt Lake City, UT USA. [Chitphakdithai, P.; Miller, J.; King, R.; Confer, D.] Nat Marrow Donor Prog, Minneapolis, MN USA. [Logan, B.; Horowitz, M.] Ctr Int Blood & Marrow Transplant Res, Milwaukee, WI USA. [Leitman, S.] NIH, Bethesda, MD 20892 USA. [Anderlini, P.] Univ Texas Houston, MD Anderson Canc Ctr, Houston, TX 77030 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 40 BP 17 EP 17 DI 10.1016/j.bbmt.2007.12.048 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100041 ER PT J AU Hakim, FT Memon, SA Sportes, C Zhang, H Chua, K Fry, T Engel, J Buffet, R Morre, M Mackall, C Gress, RE AF Hakim, F. T. Memon, S. A. Sportes, C. Zhang, H. Chua, K. Fry, T. Engel, J. Buffet, R. Morre, M. Mackall, C. Gress, R. E. TI ADMINISTRATION OF rhIL-7 INCREASES TCR REPERTOIRE DIVERSITY THROUGH PREFERENTIAL EXPANSION OF NAIVE T CELLS SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Hakim, F. T.; Memon, S. A.; Sportes, C.; Zhang, H.; Chua, K.; Fry, T.; Mackall, C.; Gress, R. E.] NCI, NIH, Bethesda, MD 20892 USA. [Engel, J.; Buffet, R.; Morre, M.] Cytheris Inc, Rockville, MD USA. RI Memon, Sarfraz/E-1198-2013 NR 0 TC 0 Z9 0 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 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 43 BP 18 EP 18 DI 10.1016/j.bbmt.2007.12.051 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100044 ER PT J AU Pusic, I Saini, D Pavletic, SZ Hakim, F Shannon, WD Mohanakumar, T DiPersio, JF AF Pusic, I Saini, D. Pavletic, S. Z. Hakim, F. Shannon, W. D. Mohanakumar, T. DiPersio, J. F. TI DEVELOPMENT OF ANTIBODIES TO SELF ANTIGENS K-ALPHA-I TUBULIN AND COLLAGEN V IN PATIENTS WITH CHRONIC GRAFT VERSUS HOST DISEASE SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Pusic, I; Saini, D.; Shannon, W. D.; Mohanakumar, T.; DiPersio, J. F.] Washington Univ, Sch Med, St Louis, MO USA. [Pavletic, S. Z.; Hakim, F.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 45 BP 19 EP 19 DI 10.1016/j.bbmt.2007.12.053 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100046 ER PT J AU Williams, KM Lucas, PJ Bare, CV Wang, J Chu, YW Gress, RE AF Williams, K. M. Lucas, P. J. Bare, C., V Wang, J. Chu, Y.-W. Gress, R. E. TI ANDROGEN WITHDRAWAL MODULATES THYMOPOIESIS BY INDUCING THYMIC EPITHELIAL CELL PROLIFERATION AND INCREASING PRECURSOR NICHE SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Williams, K. M.; Lucas, P. J.; Bare, C., V; Wang, J.; Chu, Y.-W.; Gress, R. E.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 46 BP 19 EP 19 DI 10.1016/j.bbmt.2007.12.054 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100047 ER PT J AU Savani, BN Shenoy, A Stratton, P Filie, A Kozanas, E Chaurvet, D Donobute, T Le, Q Childs, RW Goodman, S Barrett, AJ AF Savani, B. N. Shenoy, A. Stratton, P. Filie, A. Kozanas, E. Chaurvet, D. Donobute, T. Le, Q. Childs, R. W. Goodman, S. Barrett, A. J. 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 Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Savani, B. N.; Shenoy, A.; Stratton, P.; Filie, A.; Kozanas, E.; Chaurvet, D.; Donobute, T.; Le, Q.; Childs, R. W.; Barrett, A. J.] NIH, Bethesda, MD 20892 USA. [Savani, B. N.; Goodman, S.] Vet Affairs Med Ctr, Nashville, TN 37212 USA. [Savani, B. N.; Goodman, S.] Vanderbilt Univ, Med Ctr, Nashville, TN USA. NR 0 TC 0 Z9 0 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 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 50 BP 21 EP 21 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100051 ER PT J AU Podsakoff, G Engel, BC Sokolic, R Carbonaro, DA Muul, L Garabedian, E Ireland, J Hershfield, M Wayne, A Dunbar, C Candotii, F Kohn, DB AF Podsakoff, G. Engel, B. C. Sokolic, R. Carbonaro, D. A. Muul, L. Garabedian, E. Ireland, J. Hershfield, M. Wayne, A. Dunbar, C. Candotii, F. Kohn, D. B. TI GENE THERAPY FOR ADENOSINE DEAMINASE (ADA)-DEFICIENT SEVERE COMBINED IMMUNE DEFICIENCY (SCID): COMPARATIVE RESULTS WITH OR WITHOUT PEG-ADA WITHDRAWAL AND MYELOSUPPRESSIVE CHEMOTHERAPY SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Podsakoff, G.; Engel, B. C.; Carbonaro, D. A.; Ireland, J.; Kohn, D. B.] Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. [Sokolic, R.; Muul, L.; Garabedian, E.; Wayne, A.; Dunbar, C.; Candotii, F.] NIH, Bethesda, MD 20892 USA. [Hershfield, M.] Duke Univ, Med Ctr, Durham, NC USA. RI Sokolic, Robert/I-6072-2012 NR 0 TC 0 Z9 0 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 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 68 BP 27 EP 28 DI 10.1016/j.bbmt.2007.12.076 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100069 ER PT J AU Lundquist, A Childs, R AF Lundquist, A. Childs, R. TI ADOPTIVE INFUSION OF DONOR NK CELLS REDUCES GVHD IN RECIPIENTS OF T-CELL DEPLETED AND T-CELL REPLETE ALLOGENEIC MHCMATCHED HEMATOPOIETIC STEM CELL TRANSPLANTATION SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Lundquist, A.; Childs, R.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 71 BP 29 EP 29 DI 10.1016/j.bbmt.2007.12.079 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100072 ER PT J AU Heugel, J Storek, J Young, JA Kukreja, M Gress, R Tomblyn, M Boeckh, M AF Heugel, J. Storek, J. Young, J. A. Kukreja, M. Gress, R. Tomblyn, M. Boeckh, M. TI AN INTERNATIONAL COMPARISON OF CURRENT STRATEGIES TO PREVENT HERPESVIRUS AND FUNGAL DISEASES IN HCT RECIPIENTS SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Heugel, J.; Boeckh, M.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Storek, J.] Univ Calgary, Calgary, AB T2N 1N4, Canada. [Storek, J.; Young, J. A.; Kukreja, M.; Gress, R.; Tomblyn, M.; Boeckh, M.] Ctr Int Bone & Marrow Transplantat Res, Minneapolis, MN USA. [Young, J. A.; Tomblyn, M.] Univ Minnesota, Minneapolis, MN USA. [Gress, R.] NIH, Bethesda, MD 20892 USA. RI Young, Jo-Anne/G-2617-2013 OI Young, Jo-Anne/0000-0003-4182-341X NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 76 BP 30 EP 31 DI 10.1016/j.bbmt.2007.12.084 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100077 ER PT J AU Srivastava, S Lundqvist, A Berg, M Yokoyama, H Smith, A Mccoy, JP Childs, R AF Srivastava, S. Lundqvist, A. Berg, M. Yokoyama, H. Smith, A. McCoy, J. P. Childs, R. TI LENALIDOMIDE DIRECTLY UPREGULATES NK (NATURAL KILLER) CELL TRAIL AND GRANZYME B EXPRESSION: IMPLICATIONS FOR ADOPTIVE NK CELL IMMUNOTHERAPY FOLLOWING ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (HCT) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Srivastava, S.] Indiana Univ, Indianapolis, IN 46204 USA. [Lundqvist, A.; Berg, M.; Yokoyama, H.; Smith, A.; McCoy, J. P.; Childs, R.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 111 BP 43 EP 43 DI 10.1016/j.bbmt.2007.12.120 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100112 ER PT J AU Weiss, BM Neff, RT Verma, P Agodoa, L Abbott, KC AF Weiss, B. M. Neff, R. T. Verma, P. Agodoa, L. Abbott, K. C. TI CHARACTERISTICS AND OUTCOMES OF MULTIPLE MYELOMA PATIENTS ON HEMODIALYSIS UNDERGOING AUTOLOGOUS STEM CELL TRANSPLANTATION: ANALYSIS OF THE US RENAL DATABASE SYSTEM SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Weiss, B. M.; Neff, R. T.; Abbott, K. C.] Walter Reed Army Med Ctr, Washington, DC 20307 USA. [Verma, P.] Womack Army Med Ctr, Ft Bragg, NC USA. [Agodoa, L.] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2008 VL 14 IS 2 MA 169 BP 63 EP 63 DI 10.1016/j.bbmt.2007.12.178 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100170 ER PT J AU Baird, K Love, C Steinberg, SM Mackall, CL Wayne, AS Fry, TJ AF Baird, K. Love, C. Steinberg, S. M. Mackall, C. L. Wayne, A. S. Fry, T. J. TI PROLONGED SURVIVAL FOR ULTRA HIGH-RISK PEDIATRIC SARCOMA PATIENTS FOLLOWING REDUCED-INTENSITY ALLOGENEIC STEM CELL TRANSPLANTATION (ALLOSCT) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Baird, K.; Love, C.; Steinberg, S. M.; Mackall, C. L.; Wayne, A. S.] NCI, NIH, Bethesda, MD 20892 USA. [Fry, T. J.] Childrens Natl Med Ctr, Washington, DC 20010 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 FEB PY 2008 VL 14 IS 2 MA 249 BP 92 EP 92 DI 10.1016/j.bbmt.2007.12.258 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100250 ER PT J AU Mariotti, J Foley, J Amarnath, S Buxhoeveden, N Ryan, K Costanzo, CM Fowler, DH AF Mariotti, J. Foley, J. Amarnath, S. Buxhoeveden, N. Ryan, K. Costanzo, C. M. Fowler, D. H. TI GRAFT REJECTION AS A TYPE I IMMUNE RESPONSE AMENABLE TO MODULATION BY TYPE II DONOR T CELLS VIA AN "INFECTIOUS" MECHANISM SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Mariotti, J.; Foley, J.; Amarnath, S.; Buxhoeveden, N.; Ryan, K.; Costanzo, C. M.; Fowler, D. H.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 284 BP 105 EP 105 DI 10.1016/j.bbmt.2007.12.294 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100285 ER PT J AU Amarnath, S Foley, J Mariotti, J Costanzo, CM Ryan, K Fong, T Warner, N Fowler, DH AF Amarnath, S. Foley, J. Mariotti, J. Costanzo, C. M. Ryan, K. Fong, T. Warner, N. Fowler, D. H. TI RELATIVE CONTRIBUTION OF CD 127 NEGATIVE SELECTION, RAPAMYCIN, AND TGF-beta TO THE GENERATION OF HUMAN REGULATORY T CELLS THAT INHIBIT ALLOREACTIVITY VIA DENDRITIC CELL MODULATION SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Amarnath, S.; Foley, J.; Mariotti, J.; Costanzo, C. M.; Ryan, K.; Fowler, D. H.] NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Fong, T.; Warner, N.] BD Biosci, San Jose, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 336 BP 123 EP 124 DI 10.1016/j.bbmt.2007.12.346 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100337 ER PT J AU Srinivasan, R Arrington, J Karpovich, J Donohue, T Goodwin, R Ramos, C Cook, L Barrett, J Childs, R AF Srinivasan, R. Arrington, J. Karpovich, J. Donohue, T. Goodwin, R. Ramos, C. Cook, L. Barrett, J. Childs, R. TI INFLIXIMAB COMBINED WITH DACLIZUMAB RESULTS IN A HIGH COMPLETE RESPONSE RATE WHEN USED TO TREAT ACUTE STEROID REFRACTORY GRAFT-VERSUS-HOST DISEASE (SR-GVHD) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Srinivasan, R.] NCI, Bethesda, MD 20892 USA. [Arrington, J.; Karpovich, J.; Donohue, T.; Goodwin, R.; Ramos, C.; Cook, L.; Barrett, J.; Childs, R.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 339 BP 124 EP 125 DI 10.1016/j.bbmt.2007.12.349 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100340 ER PT J AU Hakim, FT Rehman, N Dickinson, J Beal, M Baskar, S Rader, C Cowen, E Pavletic, S Gress, RE AF Hakim, F. T. Rehman, N. Dickinson, J. Beal, M. Baskar, S. Rader, C. Cowen, E. Pavletic, S. Gress, R. E. TI HOMEOSTATIC AND INFLAMMATORY PROCESSES CONTRIBUTE TO ELEVATED PLASMA LEVELS OF B CELL ACTIVATING FACTOR (BAFF) IN CHRONIC GRAFT VERSUS HOST DISEASE (CGVHD) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Hakim, F. T.; Rehman, N.; Dickinson, J.; Beal, M.; Baskar, S.; Rader, C.; Cowen, E.; Pavletic, S.; Gress, R. E.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 346 BP 127 EP 127 DI 10.1016/j.bbmt.2007.12.356 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100347 ER PT J AU Le, Q Melenhorst, JJ Hensel, N Eniafe, R Barrett, AJ AF Le, Q. Melenhorst, J. J. Hensel, N. Eniafe, R. Barrett, A. J. TI HUMAN NEUTROPHIL ELASTASE STIMULATING CD4+AND CD8+T CELLS IS A POTENTIAL PROTEIN VACCINE FOR LEUKEMIA PATIENTS WITH DIVERSE HLA TYPES SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Le, Q.; Melenhorst, J. J.; Hensel, N.; Eniafe, R.; Barrett, A. J.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 348 BP 127 EP 128 DI 10.1016/j.bbmt.2007.12.358 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100349 ER PT J AU Rebman, NK Dickinson, J Baskar, S Rader, C Pavkth, SZ Gress, RE Hakim, FT AF Rebman, N. K. Dickinson, J. Baskar, S. Rader, C. Pavkth, S. Z. Gress, R. E. Hakim, F. T. TI ELEVATED LEVELS OF CD19+CD21-TRANSITIONAL B CELLS IN CHRONIC GRAFT VERSUS HOST DISEASE (CGVHD) ASSOCIATED WITH ELEVATED PLASMA BAFF LEVELS AND BAFF RECEPTOR EXPRESSION SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Rebman, N. K.; Dickinson, J.; Baskar, S.; Rader, C.; Pavkth, S. Z.; Gress, R. E.; Hakim, F. T.] NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 354 BP 130 EP 130 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100355 ER PT J AU Yokoyama, H Berg, M Lundqvist, A Mccoy, JP Srivastava, S Smith, A Childs, R AF Yokoyama, H. Berg, M. Lundqvist, A. McCoy, J. P. Srivastava, S. Smith, A. Childs, R. TI CYCLOSPORINE A (CSA) SIGNIFICANTLY REDUCES THE CYTOTOXIC EFFECTS OF IN VITRO EXPANDED NK CELLS: IMPLICATIONS FOR ADON TIVE NK CELL THERAPY IN THE SETTING OF ALLOGENEIC HEMATOPOIETIC STEM CELL (HCT) TRANSPLANTATION SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Yokoyama, H.; Berg, M.; Lundqvist, A.; McCoy, J. P.; Srivastava, S.; Smith, A.; Childs, R.] NHLBI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 390 BP 142 EP 142 DI 10.1016/j.bbmt.2007.12.400 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100391 ER PT J AU Shenoy, A Solomon, S Pichon, S Cadoz, M Barrett, AJ AF Shenoy, A. Solomon, S. Pichon, S. Cadoz, M. Barrett, A. J. TI VACCINATION WITH CARNARYPOX PP65 CMV VACCINE INDUCES RELIABLE CD4+AND CD8+T CELL RESPONSES ONLY IN INDIVIDUALS WHO LACK BASELINE RESPONSES. IMPLICATIONS FOR DONOR VACCINATION TO BOOST CMV IMMUNITY IN STEM CELL TRANSPLANT RECIPIENTS SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Shenoy, A.; Barrett, A. J.] NIH, Bethesda, MD 20892 USA. [Solomon, S.] Blood & Marrow Transplant Program, Atlanta, GA USA. [Pichon, S.; Cadoz, M.] Sanofi Pasteur, Marcy Letoile, France. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 394 BP 143 EP 143 DI 10.1016/j.bbmt.2007.12.404 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100395 ER PT J AU Memon, SA Gress, RE Hakim, FT AF Memon, S. A. Gress, R. E. Hakim, F. T. TI EXAMINING HUMAN TCR CDR3 DIVERSITY DURING LYMPHOPENIA SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Annual Meeting of the American-Society-for-Blood-and-Marrow-Transplantation CY FEB 13-17, 2008 CL San Diego, CA SP Amer Soc Blood & Marrow Transplantat C1 [Memon, S. A.; Gress, R. E.; Hakim, F. T.] NCI, NIH, Bethesda, MD 20892 USA. RI Memon, Sarfraz/E-1198-2013 NR 0 TC 0 Z9 0 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 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 MA 399 BP 145 EP 145 DI 10.1016/j.bbmt.2007.12.409 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 364IT UT WOS:000260330100400 ER PT J AU Hsieh, MM Link, MB Tisdale, JF AF Hsieh, Matthew M. Link, M. Beth Tisdale, John F. TI Sirolimus associated pneumonitis after nonmyeloablative peripheral blood stem cell transplant for sickle cell disease SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Letter ID CHILDREN; ASTHMA; SYMPTOMS; LUNG C1 [Hsieh, Matthew M.; Link, M. Beth; Tisdale, John F.] NIDDK, NIH, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. RP Hsieh, MM (reprint author), NIDDK, NIH, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z01 DK027010-04] NR 10 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2008 VL 14 IS 2 BP 256 EP 257 DI 10.1016/j.bbmt.2007.11.001 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 264FH UT WOS:000253271100010 PM 18215786 ER PT J AU DeRouchey, J Schmidt, C Walker, GF Koch, C Plank, C Wagner, E Radler, JO AF DeRouchey, Jason Schmidt, Claudia Walker, Greg F. Koch, Christian Plank, Christian Wagner, Ernst Radler, Joachim O. TI Monomolecular assembly of siRNA and poly(ethylene glycol)-peptide copolymers SO BIOMACROMOLECULES LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; SEMIDILUTE POLYMER-SOLUTIONS; POLYSTYRENE LATEX SPHERES; GENE DELIVERY; RNA INTERFERENCE; PROBE DIFFUSION; LIGHT-SCATTERING; POTENTIAL USE; IN-VITRO; DNA AB In this work, we design and investigate the complex formation of highly uniform monomolecular siRNA complexes utilizing block copolymers consisting of a cationic peptide moiety covalently bound to a poly(ethylene glycol) (PEG) moiety. The aim of the study was to design a shielded siRNA construct containing a single siRNA molecule to achieve a sterically stabilized complex with enhanced diffusive properties in macromolecular networks. Using a 14 lysine-PEG (K-14-PEG) linear diblock copolymer, formation of monomolecular siRNA complexes with a stoichiometric 1:3 grafting density of siRNA to PEG is realized. Alternatively, similar PEGylated monomolecular siRNA particles are achieved through complexation with a graft copolymer consisting of six cationic peptide side chains bound to a PEG backbone. The hydrodynamic radii of the resulting complexes as measured by fluorescence correlation spectroscopy (FCS) were found to be in good agreement with theoretical predictions using polymer brush scaling theory of a PEG decorated rodlike molecule. It is furthermore demonstrated that the PEG coating of the siRNA-PEG complexes can be rendered biodegradable through the use of a OH-sensitive hydrazone or a reducible disulfide bond linker between the K, and the PEG blocks. To model transport under in vivo conditions, diffusion of these PEGylated siRNA complexes is studied in various charged and uncharged matrix materials. In PEG solutions, the diffusion coefficient of the siRNA complex is observed to decrease with increasing polymer concentration, in agreement with theory of probe diffusion in semidilute solutions. In charged networks, the behavior is considerably more,complex. FCS measurements in fibrin gels indicate complete dissociation of the diblock copolymer from the complex, while transport in collagen solutions results in particle aggregation. C1 [DeRouchey, Jason; Schmidt, Claudia; Radler, Joachim O.] Univ Munich, Dept Phys, D-80539 Munich, Germany. [Walker, Greg F.; Wagner, Ernst] Univ Munich, Dept Chem & Pharm, D-80539 Munich, Germany. [Wagner, Ernst; Radler, Joachim O.] Univ Munich, Ctr NanoSci, D-80539 Munich, Germany. [Koch, Christian; Plank, Christian] Tech Univ Munich, Inst Expt Oncol, D-81675 Munich, Germany. [DeRouchey, Jason] NIH, NICHHD, Bethesda, MD 20692 USA. RP DeRouchey, J (reprint author), Univ Munich, Dept Phys, Marchioninistr 15, D-80539 Munich, Germany. EM deroucja@mail.nih.gov RI DeRouchey, Jason/B-3437-2009; DeRouchey, Jason/C-5907-2011; Plank, Christian/F-9628-2011; Wagner, Ernst/A-7435-2012 OI DeRouchey, Jason/0000-0002-3624-4432; Wagner, Ernst/0000-0001-8413-0934 NR 56 TC 54 Z9 54 U1 2 U2 17 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1525-7797 J9 BIOMACROMOLECULES JI Biomacromolecules PD FEB PY 2008 VL 9 IS 2 BP 724 EP 732 DI 10.1021/bm7011482 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Organic; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 261TE UT WOS:000253102100043 PM 18220349 ER PT J AU Chakrapani, H Goodblatt, MM Udupi, V Malaviya, S Shami, PJ Keefer, LK Saavedra, JE AF Chakrapani, Harinath Goodblatt, Michael M. Udupi, Vidya Malaviya, Swati Shami, Paul J. Keefer, Larry K. Saavedra, Joseph E. TI Synthesis and in vitro anti-leukemic activity analogues of JS-K, an anti-cancer lead of structural compound SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE nitric oxide; prodrugs; glutathione; glutathione S-transferase; JS-K; diazeniumdiolate; anti-leukemic; anti-cancer; GST; nitric oxide donors; NSAID; nucleophilic aromatic substitution ID NITRIC-OXIDE DONOR; BIOLOGICAL EVALUATION; LEUKEMIA-CELLS; S-TRANSFERASE; RELEASE; PRODRUG; CARCINOGENICITY; NITROSOPROLINE; APOPTOSIS; PROLI/NO AB Structural analogues of JS-K, an anti-cancer lead compound, were prepared and their in vitro anti-leukemic activity was determined. The rate of nitric oxide release from the corresponding diazeniumdiolate anions did not appear to affect the anti-leukemic activity of the prodrug forms. Two compounds with potent inhibitory activity and a potentially favorable toxicological profile were identified. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Chakrapani, Harinath; Goodblatt, Michael M.; Keefer, Larry K.] Natl Canc Inst, Chem Sect, Lab Comparat Carconogenesis, Ft Detrick, MD 21702 USA. [Udupi, Vidya; Malaviya, Swati; Shami, Paul J.] Univ Utah, Dept Internal Med, Div Oncol, Salt Lake City, UT 84112 USA. [Saavedra, Joseph E.] NCI, SAIC Frederick Inc, Basic Res Program, Ft Detrick, MD 21702 USA. RP Saavedra, JE (reprint author), Natl Canc Inst, Chem Sect, Lab Comparat Carconogenesis, POB B, Ft Detrick, MD 21702 USA. EM chakrah@ncifcrf.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU Intramural NIH HHS [NIH0012791200]; NCI NIH HHS [N01CO12400, N01-CO-12400]; PHS HHS [NIH0012791200] NR 29 TC 12 Z9 14 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 1 PY 2008 VL 18 IS 3 BP 950 EP 953 DI 10.1016/j.bmcl.2007.12.044 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 270KT UT WOS:000253720400015 PM 18178089 ER PT J AU Liu, F Stephen, AG Fisher, RJ Burke, TR AF Liu, Fa Stephen, Andrew G. Fisher, Robert J. Burke, Terrence R., Jr. TI Protected aminooxyprolines for expedited library synthesis: Application to Tsg101-directed proline-oxime containing peptides SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE proline analog aminooxy; oxime; peptide library; Tsg101 ID CONFORMATION; AFFINITY; MOTIFS AB The stereoselective synthesis of aminooxy-containing proline analogues bearing Fmoc/Boc or Fmoc/Mtt protection that renders them suitable for incorporation into peptides using Fmoc protocols is reported. Acid-catalyzed unmasking at the completion of peptide synthesis yields free aminooxy-functionalities for oxime formation through reaction with libraries of aldehydes. This allows post solid-phase diversification strategies that may facilitate structure-activity relationship studies. Published by Elsevier Ltd. C1 [Liu, Fa; Burke, Terrence R., Jr.] NCI Frederick, NIH, CCR, Med Chem Lab, Frederick, MD 21702 USA. [Stephen, Andrew G.; Fisher, Robert J.] SAIC Frederick Inc, Prot Chem Lab, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI Frederick, NIH, CCR, Med Chem Lab, Bldg 376 Boyles St, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Fisher, Robert/B-1431-2009; Burke, Terrence/N-2601-2014 FU Intramural NIH HHS [Z01 BC007363-12]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 19 TC 16 Z9 18 U1 1 U2 5 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 FEB 1 PY 2008 VL 18 IS 3 BP 1096 EP 1101 DI 10.1016/j.bmcl.2007.12.003 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 270KT UT WOS:000253720400044 PM 18083557 ER PT J AU Evilevitch, A Fang, LT Yoffe, AM Castelnovo, M Rau, DC Parsegian, VA Gelbart, WM Knobler, CM AF Evilevitch, Alex Fang, Li Tai Yoffe, Aron M. Castelnovo, Martin Rau, Donald C. Parsegian, V. Adrian Gelbart, William M. Knobler, Charles M. TI Effects of salt concentrations and bending energy on the extent of ejection of phage genomes SO BIOPHYSICAL JOURNAL LA English DT Article ID BACTERIOPHAGE-LAMBDA; VIRAL CAPSIDS; DNA; FORCES; RECEPTOR; CONDENSATION; SPERMIDINE; STABILITY; DYNAMICS; RELEASE AB Recent work has shown that pressures inside dsDNA phage capsids can be as high as many tens of atmospheres; it is this pressure that is responsible for initiation of the delivery of phage genomes to host cells. The forces driving ejection of the genome have been shown to decrease monotonically as ejection proceeds, and hence to be strongly dependent on the genome length. Here we investigate the effects of ambient salts on the pressures inside phage-lambda, for the cases of mono-, di-, and tetravalent cations, and measure how the extent of ejection against a fixed osmotic pressure (mimicking the bacterial cytoplasm) varies with cation concentration. We find, for example, that the ejection fraction is halved in 30 mM Mg2+ and is decreased by a factor of 10 upon addition of 1 mM spermine. These effects are calculated from a simple model of genome packaging, using DNA-DNA repulsion energies as determined independently from x-ray diffraction measurements on bulk DNA solutions. By comparing the measured ejection fractions with values implied from the bulk DNA solution data, we predict that the bending energy makes the d-spacings inside the capsid larger than those for bulk DNA at the same osmotic pressure. C1 [Fang, Li Tai; Yoffe, Aron M.; Gelbart, William M.; Knobler, Charles M.] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90024 USA. [Evilevitch, Alex] Lund Univ, Dept Biochem, Ctr Chem & Chem Engn, Lund, Sweden. [Castelnovo, Martin] Ecole Normale Super Lyon, Phys Lab, Lab Joliot Curie, F-69364 Lyon, France. [Rau, Donald C.; Parsegian, V. Adrian] NICHHD, Natl Inst Hlth, Lab Phys & Struct Biol, Bethesda, MD 20892 USA. RP Knobler, CM (reprint author), Univ Calif Los Angeles, Dept Chem & Biochem, 405 Hilgard Ave, Los Angeles, CA 90024 USA. EM knobler@chem.ucla.edu RI M & C, Matter & Complexity/B-9044-2011; Fang, Li Tai/D-4760-2011; Evilevitch, Alex/P-3103-2014 OI Evilevitch, Alex/0000-0002-0245-9574 NR 35 TC 47 Z9 48 U1 2 U2 8 PU BIOPHYSICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB 1 PY 2008 VL 94 IS 3 BP 1110 EP 1120 DI 10.1529/biophysj.107.115345 PG 11 WC Biophysics SC Biophysics GA 249QF UT WOS:000252243200036 PM 17890396 ER PT J AU Payne, JL MacKinnon, DF Mondimore, FM McInnis, MG Schweizer, B Zamoiski, RB McMahon, FJ Nurnberger, JI Rice, JP Scheftner, W Coryell, W Berrettini, WH Kelsoe, JR Byerley, W Gershon, ES DePaulo, JR Potash, JB AF Payne, Jennifer L. MacKinnon, Dean F. Mondimore, Francis M. McInnis, Melvin G. Schweizer, Barbara Zamoiski, Rachel B. McMahon, Francis J. Nurnberger, John I., Jr. Rice, John P. Scheftner, William Coryell, William Berrettini, Wade H. Kelsoe, John R. Byerley, William Gershon, Elliot S. DePaulo, J. Raymond, Jr. Potash, James B. TI Familial aggregation of postpartum mood symptoms in bipolar disorder pedigrees SO BIPOLAR DISORDERS LA English DT Article DE bipolar; genetics; postpartum ID POSTNATAL DEPRESSION; PUERPERAL PSYCHOSIS; NATIONAL-INSTITUTE; WOMEN; SYMPTOMATOLOGY; PREVALENCE; PREGNANCY; SLEEP; HORMONE; EVENTS AB Objectives: We sought to determine if postpartum mood symptoms and depressive episodes exhibit familial aggregation in bipolar I pedigrees. Methods: A total of 1,130 women were interviewed with the Diagnostic Interview for Genetic Studies as part of the National Institute of Mental Health (NIMH) Genetics Initiative Bipolar Disorder Collaborative Study and were asked whether they had ever experienced mood symptoms within four weeks postpartum. Women were also asked whether either of two major depressive episodes described in detail occurred postpartum. We examined the odds of postpartum mood symptoms in female siblings, who had previously been pregnant and had a diagnosis of bipolar I, bipolar II, or schizoaffective (bipolar type) disorders (n = 303), given one or more relatives with postpartum mood symptoms. Results: The odds ratio for familial aggregation of postpartum mood symptoms was 2.31 (p = 0.011) in an Any Mood Symptoms analysis (n = 304) and increased to 2.71 (p = 0.005) when manic symptoms were excluded, though this was not significantly different from the Any Mood Symptoms analysis. We also examined familial aggregation of postpartum major depressive episodes; however, the number of subjects was small. Conclusions: Limitations of the study include the retrospective interview, the fact that the data were collected for other purposes and the inability to control for such factors as medication use. Taken together with previous studies, these data provide support for the hypothesis that there may be a genetic basis for the trait of postpartum mood symptoms generally and postpartum depressive symptoms in particular in women with bipolar disorder. Genetic linkage and association studies incorporating this trait are warranted. C1 [Payne, Jennifer L.; MacKinnon, Dean F.; Mondimore, Francis M.; Schweizer, Barbara; Zamoiski, Rachel B.; DePaulo, J. Raymond, Jr.; Potash, James B.] Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. [McInnis, Melvin G.] Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI 48109 USA. [McMahon, Francis J.] Natl Inst Hlth, NIMH, Genet Basis Mood & Anxiety Disorders Unit, Mood & Anxiety Program, Bethesda, MD USA. [McMahon, Francis J.] Natl Inst Hlth, NIMH, Clin Sci Lab, Bethesda, MD USA. [Nurnberger, John I., Jr.] Indiana Univ, Sch Med, Inst Psychiat Res, Indianapolis, IN 46204 USA. [Rice, John P.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. [Scheftner, William] Rush Univ, Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. [Coryell, William] Univ Iowa, Sch Med, Dept Psychiat, Iowa City, IA 52242 USA. [Berrettini, Wade H.] Univ Penn, Sch Med, Dept Psychiat, Ctr Neurobiol & Behav, Philadelphia, PA 19104 USA. [Kelsoe, John R.] Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. [Byerley, William] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. [Gershon, Elliot S.] Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. RP Payne, JL (reprint author), Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. RI McMahon, Francis/A-7290-2009; McInnis, Melvin/F-6963-2012; OI McInnis, Melvin/0000-0002-0375-6247; Nurnberger, John/0000-0002-7674-1767; McMahon, Francis/0000-0002-9469-305X NR 39 TC 23 Z9 24 U1 3 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-5647 J9 BIPOLAR DISORD JI Bipolar Disord. PD FEB PY 2008 VL 10 IS 1 BP 38 EP 44 PG 7 WC Clinical Neurology; Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 250RY UT WOS:000252319300002 PM 18199240 ER PT J AU Sharifi, N Dahut, WL Figg, WD AF Sharifi, Nima Dahut, William L. Figg, William D. TI Secondary hormonal therapy for prostate cancer: what lies on the horizon? SO BJU INTERNATIONAL LA English DT Review ID ANDROGEN RECEPTOR; ANTIGEN DECLINE; BINDING DOMAIN; BICALUTAMIDE; DISRUPTION; RESISTANCE; FLUTAMIDE; TRIALS AB Androgen deprivation therapy with medical or surgical castration is generally the first-line treatment against advanced prostate cancer. Almost invariably, metastatic prostate cancer overcomes testosterone depletion and grows, despite castrate levels of testosterone. Despite advances in cytotoxic chemotherapy, secondary hormonal therapies are often used after the development of castrate-resistant prostate cancer. Secondary hormonal therapies either lower the androgen levels further or directly antagonize the androgen receptor in prostate cancer cells. We discuss novel secondary hormonal agents that are under development, which work by either inhibiting androgen synthesis or directly targeting the androgen receptor. C1 [Sharifi, Nima; Dahut, William L.; Figg, William D.] NCI, Med Oncol Branch, Bethesda, MD 20892 USA. RP Sharifi, N (reprint author), NCI, Med Oncol Branch, Bld 10,Room 5A01, Bethesda, MD 20892 USA. EM nima.sharifi@nih.gov RI Figg Sr, William/M-2411-2016 FU Intramural NIH HHS NR 20 TC 12 Z9 12 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1464-4096 J9 BJU INT JI BJU Int. PD FEB PY 2008 VL 101 IS 3 BP 271 EP 274 DI 10.1111/j.1464-410X.2007.07236.x PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 247YZ UT WOS:000252119800005 PM 17922868 ER PT J AU Elias, KM Laurence, A Davidson, TS Stephens, G Kanno, Y Shevach, EM O'Shea, JJ AF Elias, Kevin M. Laurence, Arian Davidson, Todd S. Stephens, Geoffrey Kanno, Yuka Shevach, Ethan M. O'Shea, John J. TI Retinoic acid inhibits Th17 polarization and enhances FoxP3 expression through a Stat-3/Stat-5 independent signaling pathway SO BLOOD LA English DT Article ID REGULATORY T-CELLS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; CUTTING EDGE; INTERFERON-PRODUCTION; DENDRITIC CELLS; TH2 RESPONSES; X-RECEPTOR; INFLAMMATION; INTERLEUKIN-17; AUTOIMMUNE AB CD4(+) helper T (Th) cells play a crucial role in the delicate balance between host defense and autoimmune disease. Two important populations of helper T cells are the proinflammatory, interleukin-17 (IL-17)-producing (Th17) cells and the anti-inflammatory forkhead box P3-positive (FoxP3(+)) T regulatory (Treg) cells. Here we show that all-trans retinoic acid (ATRA) and other agonists of the retinoic acid receptor alpha (RAR alpha) inhibit the formation of Th17 cells and promote FoxP3 expression. Conversely, inhibition of retinoic acid signaling constrains transforming growth factor beta (TGF-beta 1) induction of FoxP3. The effect of ATRA is mediated independently of IL-2, signal transducer and activator of transcription 5 (Stat5) and Stat3, representing a novel mechanism for the induction of FoxP3 in CD4 T cells. As previous studies have shown that vitamin A derivatives are protective in animal models of autoimmune disease, the current data suggest a previously unrecognized role for RAR alpha in the regulation of CD4(+) T-cell differentiation and provide a mechanism for the anti-inflammatory effects of retinoic acid. C1 [Elias, Kevin M.] Howard Hughes Med Inst, NIH, Res Scholars Program, Bethesda, MD 20817 USA. [Elias, Kevin M.; Laurence, Arian; Kanno, Yuka; O'Shea, John J.] NIAMSD, Mol Immunol & Inflammat Branch, Lymphocyte Cell Biol Sect, Bethesda, MD 20892 USA. [Davidson, Todd S.; Stephens, Geoffrey; Shevach, Ethan M.] NIAID, Cellular Immunol Sect, Immunol Lab, Bethesda, MD 20892 USA. RP Elias, KM (reprint author), Howard Hughes Med Inst, NIH, Res Scholars Program, Bethesda, MD 20817 USA. RI Laurence, Arian/A-8770-2009; Kanno, Yuka/B-5802-2013; OI Laurence, Arian/0000-0003-0942-8292; Kanno, Yuka/0000-0001-5668-9319; Elias, Kevin/0000-0003-1502-5553 NR 44 TC 254 Z9 270 U1 1 U2 16 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 FEB 1 PY 2008 VL 111 IS 3 BP 1013 EP 1020 DI 10.1182/blood-2007-06-096438 PG 8 WC Hematology SC Hematology GA 257IR UT WOS:000252792900018 PM 17951529 ER PT J AU Cokic, VP Andric, SA Stojilkovic, SS Noguchi, CT Schechter, AN AF Cokic, Vladan P. Andric, Silvana A. Stojilkovic, Stanko S. Noguchi, Constance T. Schechter, Alan N. TI Hydroxyurea nitrosylates and activates soluble guanylyl cyclase in human erythroid cells SO BLOOD LA English DT Article ID RED-BLOOD-CELLS; GLOBIN GENE-EXPRESSION; NITRIC-OXIDE PRODUCTION; RIBONUCLEOTIDE REDUCTASE; FETAL-HEMOGLOBIN; CYCLIC-AMP; L-ARGININE; ENDOTHELIAL-CELLS; SIGNALING PATHWAY; IN-VITRO AB Hydroxyurea, a drug widely used for treating myeloproliferative diseases, has also been approved for the treatment of sickle cell disease by raising fetal hemoglobin (HbF). We have shown that nitric oxide (NO) and the soluble guanylyl cyclase (sGC) pathways are involved in hydroxyurea induction of HbF levels in erythroid progenitor cells (EPCs). We demonstrate now that during erythroid differentiation, endothelial NO synthase mRNA and protein levels decline steadily, as does the production of NO derivatives and cyclic adenosine monophosphate (cAMP) levels, but guanosine 3',5'-cyclic monophosphate (cGMP) levels are stable. Hydroxyurea increased intracellular cGMP levels and cAMP levels in EPCs. The NO donor, DEANONOate, induced much higher cGMP levels, but reduced cAMP levels. Hydroxyurea (1 mM) induced production of approximately 45 pM cGMP/minute/ng of purified sGC, similar to induction by 1 mu M DEANONOate. We found that hydroxyurea and ProliNONOate produced iron-nitrosyl derivatives of sGC. Thus, we confirm that hydroxyurea can directly interact with the deoxy-heme of sGC, presumably by a free-radical nitroxide pathway, and activate cGMP production. These data add to an expanding appreciation of the role of hydroxyurea as an inducer of the NO/cGMP pathway in EPCs. These mechanisms may also be involved in the cytostatic effects of hydroxyurea, as well as the induction of HbF. C1 [Noguchi, Constance T.; Schechter, Alan N.] NIH, NIDDK, Mol Med Branch, Bethesda, MD 20892 USA. [Cokic, Vladan P.] Inst Med Res, Lab Expt Hematol, Belgrade, Serbia. [Andric, Silvana A.; Stojilkovic, Stanko S.] NIH, NICHHD, Sect Cellular Signaling, Bethesda, MD 20892 USA. RP Schechter, AN (reprint author), NIH, NIDDK, Mol Med Branch, 10 Ctr Dr,Bldg 10,Rm 9N307, Bethesda, MD 20892 USA. EM aschecht@helix.nih.gov OI Schechter, Alan N/0000-0002-5235-9408 FU Intramural NIH HHS NR 42 TC 46 Z9 49 U1 3 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 FEB 1 PY 2008 VL 111 IS 3 BP 1117 EP 1123 DI 10.1182/blood-2007-05-088732 PG 7 WC Hematology SC Hematology GA 257IR UT WOS:000252792900031 PM 17993617 ER PT J AU Ertl, RP Chen, J Astle, CM Duffy, TM Harrison, DE AF Ertl, Robin P. Chen, Jichun Astle, Clinton M. Duffy, Theodore M. Harrison, David E. TI Effects of dietary restriction on hematopoietic stem-cell aging are genetically regulated SO BLOOD LA English DT Article ID SELF-RENEWAL; PROGENITOR CELLS; SIDE POPULATION; IN-VIVO; MICE; SENESCENCE; GROWTH; AGE; CANCER; PURIFICATION AB Diminished stem-cell functions with age may be a major cause of anemias and other defects. Unfortunately, treatments that increase stem-cell function can also increase the incidence of cancers. Lifelong dietary restriction (DR) is known to decrease spontaneous cancers and lengthen lifespan. This study examines the effect of DR on the ability of bone marrow cells to repopulate irradiated recipients and produce erythrocytes and lymphocytes. In BALB/cByJ (BALB) mice, repopulating abilities decline with age; DR ameliorates this trend. In C57BL/6J (136) and (BALB x B6) F1 hybrid (F1) mice, repopulating abilities increase with age; DR maintains this increase. Hematopoietic stem cell (HSC) numbers are highly variable in aged BALB mice; however, the observed loss of marrow function results from a major loss in repopulating ability per HSC. DR greatly ameliorates this loss of function with age. In contrast, function per HSC in B6 mice is affected neither by age nor by DR. Thus, DR increases or maintains increased marrow repopulating ability with age in the 3 different genotypes tested, but effects on function per HSC depend on genotype. That DR increases or maintains stem-cell function with age, while decreasing cancer, has far-reaching health implications. (Blood. 2008;111:1709-1716). (C) 2008 by The American Society of Hematology. C1 [Ertl, Robin P.; Astle, Clinton M.; Duffy, Theodore M.; Harrison, David E.] Jackson Lab, Bar Harbor, ME 04609 USA. [Chen, Jichun] Natl Inst Hlth, NHLBI, Hematol Branch, Bethesda, MD USA. RP Harrison, DE (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM david.harrison@jax.org FU NHLBI NIH HHS [HL63620]; NIA NIH HHS [AG025007, U01 AG022308, R01 AG025007, AG026074, AG025707, AG022308, P30 AG025707, R01 AG026074]; NIDDK NIH HHS [T32 DK007449, DK07449] NR 51 TC 35 Z9 35 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 FEB 1 PY 2008 VL 111 IS 3 BP 1709 EP 1716 DI 10.1182/blood-2007-01-069807 PG 8 WC Hematology SC Hematology GA 257IR UT WOS:000252792900104 PM 17947508 ER PT J AU Scheinberg, P Young, NS Barrett, J AF Scheinberg, Phillip Young, Neal S. Barrett, John TI EBV reactivation in the immunosuppressed: to treat or not to treat? SO BLOOD LA English DT Letter RP Scheinberg, P (reprint author), NHLBI, Dept Hematol, 10 Ctr Dr, Bldg 10 CRC, Rm 3-5140, Bethesda, MD 20892 USA. EM scheinbp@mail.nih.gov NR 0 TC 0 Z9 2 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 FEB 1 PY 2008 VL 111 IS 3 BP 1739 EP 1740 PG 2 WC Hematology SC Hematology GA 257IR UT WOS:000252792900109 ER PT J AU Fitzhugh, CD Perl, S Hsieh, MM AF Fitzhugh, Courtney D. Perl, Shira Hsieh, Matthew M. TI Late effects of myeloablative bone marrow transplantation (BMT) in sickle cell disease (SCD) SO BLOOD LA English DT Letter ID GONADAL-FUNCTION; ANEMIA; CHILDHOOD; CHILDREN; GROWTH RP Hsieh, MM (reprint author), NHLBI, 9000 Rockville Pike, Bldg 10, Bethesda, MD 20892 USA. EM matthewhs@mail.nih.gov NR 10 TC 4 Z9 4 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 1 PY 2008 VL 111 IS 3 BP 1742 EP 1743 PG 2 WC Hematology SC Hematology GA 257IR UT WOS:000252792900113 PM 18223176 ER PT J AU Tsutsui, TW Riminucci, M Holmbeck, K Bianco, P Robey, PG AF Tsutsui, T. W. Riminucci, M. Holmbeck, Kenn Bianco, P. Robey, P. G. TI Development of craniofacial structures in transgenic mice with constitutively active PTH/IPTHrP receptor SO BONE LA English DT Article DE teeth; dentin; pulp; alveolar bone; mandibular condyle ID HORMONE-RELATED PROTEIN; MESSENGER RIBONUCLEIC-ACIDS; PARATHYROID-HORMONE; PTH/PTHRP RECEPTOR; TOOTH DEVELOPMENT; INDIAN HEDGEHOG; PEPTIDE RECEPTOR; BONE-FORMATION; FETAL-DEVELOPMENT; EXPRESSION AB Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) regulate calcium homeostasis, and PTHrP further regulates growth and development. A transgenic mouse carrying the constitutively active PTH/PTHrP receptor (HKrk-H223R) under the control of the mouse bone and odontoblast-specific alpha 1(I) collagen promoter (Col1-caPPR) has been developed to demonstrate the complex actions of this mutant receptor in hard tissue formation. We have further characterized Col1-caPPR mice abnormalities in the craniofacial region as a function of development. Col1-caPPR mice exhibited a delay in embryonic bone formation, followed by expansion of a number of craniofacial bones including the maxilla and mandible, delay in tooth eruption and teratosis, and a disrupted temporomandibular joint (TMJ). These findings suggest that the Col1-caPPR mouse is a useful model for characterization of the downstream effects of the constitutively active receptor during development and growth, and as a model for development of treatments of human diseases with similar characteristics. Published by Elsevier Inc. C1 [Tsutsui, T. W.; Holmbeck, Kenn; Bianco, P.; Robey, P. G.] NIH, Craniofacial & Skeletal Dis Branch, Natl Inst Dent & Caniofacial Res, Bethesda, MD 20892 USA. [Riminucci, M.] Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. [Riminucci, M.; Bianco, P.] Fondaz Parco Sci Biomed San Raffaele, Rome, Italy. [Bianco, P.] Univ Roma La Sapienza, Dipartimento Med Sperimentale, Rome, Italy. RP Robey, PG (reprint author), 30 Convent Dr,MSC 4320,Bldg 30,Room 229, Bethesda, MD 20892 USA. EM ryuryu@tokyo.ndu.ac.jp; probey@dir.nider.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Intramural NIH HHS [Z01 DE000380-24]; Telethon [GGP04263] NR 52 TC 13 Z9 13 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD FEB PY 2008 VL 42 IS 2 BP 321 EP 331 DI 10.1016/j.bone.2007.09.057 PG 11 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 259BR UT WOS:000252914600011 PM 18063434 ER PT J AU Zanna, C Ghelli, A Porcelli, AM Karbowski, M Youle, RJ Schimpf, S Wissinger, B Pinti, M Cossarizza, A Vidoni, S Valentino, ML Rugolo, M Carelli, V AF Zanna, Claudia Ghelli, Anna Porcelli, Anna Maria Karbowski, Mariusz Youle, Richard J. Schimpf, Simone Wissinger, Bernd Pinti, Marcello Cossarizza, Andrea Vidoni, Sara Valentino, Maria Lucia Rugolo, Michela Carelli, Valerio TI OPA1 mutations associated with dominant optic atrophy impair oxidative phosphorylation and mitochondrial fusion SO BRAIN LA English DT Article DE OPA1; DOA; oxidative phosphorylation; mitochondrial fusion; AIF ID DYNAMIN-RELATED PROTEIN; COMPLEX-I; GALACTOSE MEDIUM; APOPTOSIS; CELLS; NEUROPATHY; MEMBRANE; GENE; QUANTITATION; DYSFUNCTION AB Dominant optic atrophy ( DOA) is characterized by retinal ganglion cell degeneration leading to optic neuropathy. A subset of DOA is caused by mutations in the OPA1 gene, encoding for a dynamin-related GTPase required for mitochondrial fusion. The functional consequences of OPA1 mutations in DOA patients are still poorly understood. This study investigated the effect of five different OPA1 pathogenic mutations on the energetic efficiency and mitochondrial network dynamics of skin fibroblasts from patients. Although DOA fibroblasts maintained their ATP levels and grew in galactose medium, i.e. under forced oxidative metabolism, a significant impairment in mitochondrial ATP synthesis driven by complex I substrates was found. Furthermore, balloon-like structures in the mitochondrial reticulum were observed in galactose medium and mitochondrial fusion was completely inhibited in about 50% of DOA fibroblasts, but not in control cells. Respiratory complex assembly and the expression level of complex I subunits were similar in control and DOA fibroblasts. Co-immunoprecipitation experiments revealed that OPA1 directly interacts with subunits of complexes I, II and III, but not IV and with apoptosis inducing factor. The results disclose a novel link between OPA1, apoptosis inducing factor and the respiratory complexes that may shed some light on the pathogenic mechanism of DOA. C1 [Zanna, Claudia; Ghelli, Anna; Porcelli, Anna Maria; Vidoni, Sara; Rugolo, Michela] Univ Bologna, Dipartimento Biol Evoluz Sperimentale, I-40126 Bologna, Italy. [Karbowski, Mariusz; Youle, Richard J.] NINDS, Biochem Sect, NIH, Bethesda, MD 20892 USA. [Schimpf, Simone; Wissinger, Bernd] Univ Eye Hosp, Mol Genet Lab, Tubingen, Germany. [Pinti, Marcello; Cossarizza, Andrea] Univ Modena, Sezione Patol Gen, Dipartimento Sci Biomed, I-41100 Modena, Italy. [Pinti, Marcello; Cossarizza, Andrea] Univ Reggio Emilia, Dipartimento Biol Evoluz Sperimentale, Reggio Emilia, Italy. [Valentino, Maria Lucia; Carelli, Valerio] Univ Bologna, Dipartimento Sci Neurol, I-40126 Bologna, Italy. RP Zanna, C (reprint author), Univ Bologna, Dipartimento Biol Evoluz Sperimentale, Via Irnerio 42, I-40126 Bologna, Italy. EM zanna@alma.unibo.it RI Pinti, Marcello/C-9351-2015; OI Pinti, Marcello/0000-0001-9118-1262; CARELLI, VALERIO/0000-0003-4923-6404; VALENTINO, MARIA LUCIA/0000-0001-5323-0115; Rugolo, Michela/0000-0002-4597-0452; Cossarizza, Andrea/0000-0002-5381-1558 FU Telethon [GGP06233] NR 46 TC 151 Z9 154 U1 1 U2 25 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD FEB PY 2008 VL 131 BP 352 EP 367 DI 10.1093/brain/awm335 PN 2 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 258XO UT WOS:000252903900008 PM 18222991 ER PT J AU Simonyan, K Tovar-Moll, F Ostuni, J Hallett, M Kalasinsky, VF Lewin-Smith, MR Rushing, EJ Vortmeyer, AO Ludlow, CL AF Simonyan, Kristina Tovar-Moll, Fernanda Ostuni, John Hallett, Mark Kalasinsky, Victor F. Lewin-Smith, Michael R. Rushing, Elisabeth J. Vortmeyer, Alexander O. Ludlow, Christy L. TI Focal white matter changes in spasmodic dysphonia: a combined diffusion tensor imaging and neuropathological study SO BRAIN LA English DT Article DE laryngeal dystonia; corticobulbar tract; basal ganglia; neuroimaging; neuropathology ID BOTULINUM TOXIN TREATMENT; BASAL GANGLIA; INTERNAL CAPSULE; WRITERS CRAMP; HUMAN BRAIN; LANGUAGE LATERALIZATION; COMPUTED-TOMOGRAPHY; WATER DIFFUSION; PYRAMIDAL TRACT; RHESUS-MONKEY AB Spasmodic dysphonia is a neurological disorder characterized by involuntary spasms in the laryngeal muscles during speech production. Although the clinical symptoms are well characterized, the pathophysiology of this voice disorder is unknown. We describe here, for the first time to our knowledge, disorder-specific brain abnormalities in these patients as determined by a combined approach of diffusion tensor imaging ( DTI) and postmortem histopathology. We used DTI to identify brain changes and to target those brain regions for neuropathological examination. DTI showed right-sided decrease of fractional anisotropy in the genu of the internal capsule and bilateral increase of overall water diffusivity in the white matter along the corticobulbar/ corticospinal tract in 20 spasmodic dysphonia patients compared to 20 healthy subjects. In addition, water diffusivity was bilaterally increased in the lentiform nucleus, ventral thalamus and cerebellar white and grey matter in the patients. These brain changes were substantiated with focal histopathological abnormalities presented as a loss of axonal density and myelin content in the right genu of the internal capsule and clusters of mineral depositions, containing calcium, phosphorus and iron, in the parenchyma and vessel walls of the posterior limb of the internal capsule, putamen, globus pallidus and cerebellum in the postmortem brain tissue from one patient compared to three controls. The specificity of these brain abnormalities is confirmed by their localization, limited only to the corticobulbar/ corticospinal tract and its main input/ output structures. We also found positive correlation between the diffusivity changes and clinical symptoms of spasmodic dysphonia ( r= 0.509, P= 0.037). These brain abnormalities may alter the central control of voluntary voice production and, therefore, may underlie the pathophysiology of this disorder. C1 [Simonyan, Kristina; Ludlow, Christy L.] NINDS, Med Neurol Branch, Laryngeal & Speech Sect, NIH, Bethesda, MD 20892 USA. [Tovar-Moll, Fernanda] NINDS, Neuroimmunol Branch, NIH, Bethesda, MD USA. [Ostuni, John] NINDS, Clin Neurosci Program, NIH, Bethesda, MD USA. [Hallett, Mark] NINDS, Human Motor Control Sect, NIH, Bethesda, MD USA. [Kalasinsky, Victor F.; Lewin-Smith, Michael R.] NINDS, Dept Environm & Infect Dis Sci, NIH, Bethesda, MD USA. [Rushing, Elisabeth J.] NINDS, Dept Neuropathol & Ophthalm Pathol, Armed Forces Inst Pathol, NIH, Bethesda, MD USA. [Vortmeyer, Alexander O.] NINDS, Surg Neurol Branch, NIH, Bethesda, MD USA. RP Simonyan, K (reprint author), NINDS, Med Neurol Branch, Laryngeal & Speech Sect, NIH, 10 Canc Dr,Bldg 10,Room 5D38, Bethesda, MD 20892 USA. EM simonyak@ninds.nih.gov RI Neurociencia, Inct/I-1011-2013; OI Simonyan, Kristina/0000-0001-7444-0437; Ludlow, Christy/0000-0002-2015-6171 FU Intramural NIH HHS [Z01 NS002980-08, Z99 NS999999] NR 86 TC 46 Z9 47 U1 1 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD FEB PY 2008 VL 131 BP 447 EP 459 DI 10.1093/brain/awm303 PN 2 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 258XO UT WOS:000252903900016 PM 18083751 ER PT J AU Raymont, V Greathouse, A Reding, K Lipsky, R Salazar, A Grafman, J AF Raymont, Vanessa Greathouse, Amanda Reding, Katherine Lipsky, Robert Salazar, Andres Grafman, Jordan TI Demographic, structural and genetic predictors of late cognitive decline after penetrating head injury SO BRAIN LA English DT Article DE cognitive decline; brain injury; penetrating brain injury; genetics; predictors ID TRAUMATIC BRAIN-INJURY; APOLIPOPROTEIN-E EPSILON-4; AMYLOID BETA-PROTEIN; MINI-MENTAL-STATE; ALZHEIMERS-DISEASE; APOE GENOTYPE; RISK-FACTOR; VAL(158)MET POLYMORPHISM; FUNCTIONAL POLYMORPHISM; COMT GENOTYPE AB We examined the relationship of pre-injury intelligence, demographic variables, lesion location, brain tissue volume loss and a number of genetic markers to long-term cognitive decline in a group of Vietnam veterans with predominantly penetrating head injury (PHI) suffered more than 30 years ago. Using linear and stepwise regression procedures, we found that those with PHI demonstrated a greater degree of cognitive decline overall during the years following recovery from injury compared with a control group of uninjured Vietnam veterans. This became increasingly significant later in life. We also found that pre-injury intelligence was the most consistent predictor of cognitive outcome across all phases of potential recovery and decline after such injuries. While laterality of lesion was not a factor, we did find some associations between atrophy and specific regions of tissue loss and long-term cognitive functioning. Finally, we found evidence for an association between level of cognitive decline following PHI and the possession of certain genetic markers that have been linked with brain injury and neurodegeneration. Thus exacerbated decline does occur in Vietnam veterans with PHI and it is apparently unrelated to dementia and is determined by multiple factors (most notably pre-injury intelligence). C1 [Raymont, Vanessa; Greathouse, Amanda; Reding, Katherine; Salazar, Andres; Grafman, Jordan] Natl Naval Med Ctr, Vietnam Head Injury Study, Henry M Jackson Fdn, Bethesda, MD 20889 USA. [Lipsky, Robert] NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 7D43,MSC 1440, Bethesda, MD 20892 USA. EM grafmanj@ninds.nih.gov OI Grafman, Jordan H./0000-0001-8645-4457; Lipsky, Robert/0000-0001-7753-1473 FU Intramural NIH HHS NR 88 TC 45 Z9 45 U1 1 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD FEB PY 2008 VL 131 BP 543 EP 558 DI 10.1093/brain/awm300 PN 2 PG 16 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 258XO UT WOS:000252903900024 PM 18094019 ER PT J AU Nash, RA Stuve, O Bowen, JD Frohman, EM Griffith, LM Hutton, GJ Kraft, GH Popat, U Racke, MK Muraro, PA AF Nash, Richard A. Stuve, Olaf Bowen, James D. Frohman, Elliot M. Griffith, Linda M. Hutton, George J. Kraft, George H. Popat, Uday Racke, Michael K. Muraro, Paolo A. TI Autologous HSCT for advanced MS: Is the glass half-empty or really half-full SO BRAIN LA English DT Letter ID STEM-CELL TRANSPLANTATION; MULTIPLE-SCLEROSIS C1 [Nash, Richard A.] Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. [Stuve, Olaf; Frohman, Elliot M.] Univ Texas SW, Dallas, TX USA. [Bowen, James D.] Evergreen Hosp Med Ctr, MS Ctr Evergreen, Kirkland, WA 98034 USA. [Griffith, Linda M.] NIAID, NIH, Bethesda, MD USA. [Hutton, George J.] Baylor Coll Med, Houston, TX 77030 USA. [Nash, Richard A.; Kraft, George H.] Univ Washington, Seattle, WA 98195 USA. [Popat, Uday] MD Anderson Canc Ctr, Houston, TX USA. [Racke, Michael K.] Ohio State Univ, Columbus, OH 43210 USA. [Muraro, Paolo A.] Univ London Imperial Coll Sci Technol & Med, London, England. RP Nash, RA (reprint author), Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA. EM rnash@fhcrc.org OI Muraro, Paolo/0000-0002-3822-1218 NR 5 TC 6 Z9 6 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD FEB PY 2008 VL 131 AR e89 DI 10.1093/brain/awm180 PN 2 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 258XO UT WOS:000252903900001 PM 17908695 ER PT J AU Goloshevsky, AG Silva, AC Dodd, SJ Koretsky, AP AF Goloshevsky, Artem G. Silva, Afonso C. Dodd, Stephen J. Koretsky, Alan P. TI BOLD fMRI and somatosensory evoked potentials are well correlated over a broad range of frequency content of somatosensory stimulation of the rat forepaw SO BRAIN RESEARCH LA English DT Article DE fMRI; BOLD; somatosensory evoked potential; forepaw ID CEREBRAL-BLOOD-FLOW; ACTIVITY-DEPENDENT INCREASES; NITRIC-OXIDE SYNTHASE; NEURONAL-ACTIVITY; FUNCTIONAL MRI; HEMODYNAMIC-RESPONSE; CORTEX; BRAIN; SIGNAL; ACTIVATION AB Electrical stimulation of the rat paw is commonly used to study the hemodynamic, metabolic and neuronal mechanisms of functional MRI (fMRI) responses in somatosensory cortex. Several groups have reported good correlation between the blood oxygenation level-dependent (BOLD) fMRI signal and somatosensory evoked potentials (SEPs) using short, typically 300 mu s, square stimulation pulses. The spectral power of these short pulses is evenly distributed over a wide range of frequencies and thus the effects of the frequency content of the stimulation pulse on fMRI responses have not been previously described. Here, the effects that different stimulation pulse waveforms with a range of frequency content have on neuronal activity, as measured by SEPs, and on the amplitude of the BOLD fMRI signal in rat somatosensory cortex are investigated. The peak-to-peak SEP amplitudes increased as the power in the high frequency harmonics of the different pulse waveforms increased, using either triangular or sinusoidal stimuli waveforms from 9 Hz to 180 Hz. Similarly, BOLD fMRI response increased with increased high frequency content of the stimulation pulse. There was a linear correlation between SEPs and BOLD fMRI over the full range of frequency content in the stimulations. Published by Elsevier B.V. C1 [Goloshevsky, Artem G.; Dodd, Stephen J.; Koretsky, Alan P.] NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. [Silva, Afonso C.] NINDS, Cerebral Microcirculat Unit, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Goloshevsky, AG (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,B1D728,MSC 1065, Bethesda, MD 20892 USA. EM artgol@ninds.nih.gov RI Silva, Afonso/A-7129-2009; Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS002989-08, Z99 NS999999] NR 51 TC 19 Z9 21 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB PY 2008 VL 1195 BP 67 EP 76 DI 10.1016/j.brainres.2007.11.036 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 277KG UT WOS:000254210500008 PM 18206862 ER PT J AU Post, RM Luckenbaugh, DA Leverich, GS Altshuler, LL Frye, MA Suppes, T Keck, PE McElroy, SL Nolen, WA Kupka, R Grunze, H Walden, J AF Post, Robert M. Luckenbaugh, David A. Leverich, Gabriele S. Altshuler, Lori L. Frye, Mark A. Suppes, Trisha Keck, Paul E. McElroy, Susan L. Nolen, Willem A. Kupka, Ralph Grunze, Helnz Walden, Joerg TI Incidence of childhood-onset bipolar illness in the USA and Europe SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Article ID DISORDER; PHENOMENOLOGY; CHILDREN AB The relative incidence of childhood-onset bipolar illness in the USA compared with that in Europe is controversial. We examined this issue in more than 500 out-patients (average age 42 years) with bipolar illness who reported age at onset of first episode, family history, and childhood physical or sexual abuse. Childhood or adolescent onset of bipolar illness was reported by 61% of those in the US cohort but by only 30% of those in The Netherlands or Germany. In the USA there was also twice the incidence of childhood adversity and genetic/familial risk for affective disorder. The findings deserve replication and further exploration. Declaration of interest None. C1 [Post, Robert M.] George Washington Univ, Dept Psychiat, Washington, DC USA. [Post, Robert M.] Penn State Coll Med, Hershey, PA USA. [Luckenbaugh, David A.; Leverich, Gabriele S.] NIMH, Anxiety Disorder Program, Bethesda, MD 20892 USA. [Altshuler, Lori L.] Univ Calif Los Angeles, Los Angeles, CA USA. [Altshuler, Lori L.] Mood Disorders Res Program, Los Angeles, CA USA. [Altshuler, Lori L.] VA Med Ctr, Los Angeles, CA USA. [Frye, Mark A.] Mayo Clin, Dept Psychiat, Rochester, MN USA. [Suppes, Trisha] Univ Texas Dallas, SW Med Ctr, Dept Psychiat, Dallas, TX 75230 USA. [Keck, Paul E.; McElroy, Susan L.] Univ Cincinnati, Coll Med, Biol Psychiat Program, Cincinnati, OH USA. [Nolen, Willem A.] Univ Groningen, Univ Med Ctr Groningen, NL-9713 AV Groningen, Netherlands. [Kupka, Ralph] Willem Arntsz Huis, Rumke Groep, Utrecht, Netherlands. [Grunze, Helnz] Univ Freiburg, Dept Psychiat, D-7800 Freiburg, Germany. [Walden, Joerg] Univ Munich, Psychiat Clin, Munich, Germany. RP Post, RM (reprint author), Bipolar Collaborat Network, 5415 W Cedar Lane,Suite 201-B, Bethesda, MD 20814 USA. EM Robert.post@speakeasy.net RI Nolen, Willem/E-9006-2014; OI Grunze, Heinz/0000-0003-4712-8979 NR 16 TC 56 Z9 56 U1 1 U2 1 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD FEB PY 2008 VL 192 IS 2 BP 150 EP 151 DI 10.1192/bjp.bp.107.037820 PG 2 WC Psychiatry SC Psychiatry GA 266DD UT WOS:000253410700013 PM 18245035 ER PT J AU MacDonald, IM AF MacDonald, Ian M. TI Personalized medicine: the translation of genetic knowledge to eye care SO CANADIAN JOURNAL OF OPHTHALMOLOGY-JOURNAL CANADIEN D OPHTALMOLOGIE LA English DT Editorial Material ID COMPLEMENT FACTOR-H; MACULAR DEGENERATION; ASSOCIATION; LOC387715; RISK C1 NEI, NIH, Bethesda, MD 20892 USA. RP MacDonald, IM (reprint author), NEI, NIH, Bethesda, MD 20892 USA. EM macdonaldi@nei.nih.gov OI MacDonald, Ian/0000-0001-7472-8385 NR 8 TC 0 Z9 0 U1 0 U2 0 PU CANADIAN OPHTHAL SOC PI OTTAWA PA 1525 CARLING AVE SUITE 610, OTTAWA, ONTARIO K1Z 8R9, CANADA SN 0008-4182 J9 CAN J OPHTHALMOL JI Can. J. Opthalmol.-J. Can. Opthalmol. PD FEB PY 2008 VL 43 IS 1 BP 15 EP 16 DI 10.3129/i07-210 PG 2 WC Ophthalmology SC Ophthalmology GA 270GM UT WOS:000253709000003 PM 18204502 ER PT J AU Come, SE Buzdar, AU Ingle, JN Johnston, SRD Brodie, AM Coombes, RC Miller, WR Pritchard, KI Winer, EP Zujewski, JA Goss, PE AF Come, Steven E. Buzdar, Aman U. Ingle, James N. Johnston, Stephen R. D. Brodie, Angela M. Coombes, R. Charles Miller, William R. Pritchard, Kathleen I. Winer, Eric P. Zujewski, Jo Anne Goss, Paul E. TI Endocrine and Targeted Manipulation of Breast Cancer: Summary statement for the Sixth Cambridge Conference SO CANCER LA English DT Article; Proceedings Paper CT 6th Cambridge Conference on Endocrine and Targeted Manipulation of Breast Cancer CY APR 30-MAY 01, 2007 CL Cambridge, MA DE endocrine therapy; breast cancer; estrogen; aromatase inhibitors; tamoxifen ID THERAPY AB The Sixth Cambridge Conference on Endocrine and Targeted Manipulation of Breast Cancer was convened in Cambridge, Massachusetts on April 30 and May 1, 2007. The purpose of this multidisciplinary meeting of leaders in clinical and basic research and patient treatment was to assess the most recent data in the field, articulate current best practices, and identify the next steps to advance both patient care and research. Topics included a review of data from major recent and ongoing trials of endocrine treatment in patients with early breast cancer and from studies combining endocrine therapy with other treatment. The current status of breast cancer prevention efforts was examined. Preclinical models of response and resistance, initial efforts to profile tumor response and resistance during endocrine therapy in patients, and new developments in pharmacogenomics were also highlighted. In this article, a synopsis of the key issues discussed, conclusions, and recommendations are summarized; these are presented at greater length in the individual articles and accompanying Open Discussions that comprise the full conference proceedings. In the 2 years since the Fifth Conference, we have gained valuable follow-up data from key trials in early breast cancer, which have helped to clarify both the efficacy and safety and tolerability of the available strategies for endocrine therapy. Observations using endocrine agents in combination with other treatment have been similarly extended. More detailed analysis of preclinical models has improved our understanding of resistance to endocrine therapy, and efforts to explore these and other mechanisms in the clinic are now underway. All of this has and continues to contribute to a growing understanding of how to optimize the use of endocrine agents in both treating and preventing breast cancer. C1 [Come, Steven E.] Beth Israel Deaconess Med Ctr, Breast Cancer Program, Boston, MA 02215 USA. [Buzdar, Aman U.] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX USA. [Ingle, James N.] Mayo Clin, Div Med Oncol, Rochester, MN USA. [Johnston, Stephen R. D.] Royal Marsden Hosp, Dept Med, London, England. [Brodie, Angela M.] Univ Maryland, Sch Med, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. [Coombes, R. Charles] Imperial Coll Sch Med, Dept Med, Breast Unit, London, England. [Miller, William R.] Univ Edinburgh, Breast Res Grp, Edinburgh, Midlothian, Scotland. [Pritchard, Kathleen I.] Univ Toronto, Toronto Sunnybrool Reg Canc Ctr, Clin Trial & Epidemiol, Toronto, ON, Canada. [Winer, Eric P.] Dana Farber Canc Inst, Breast Oncol Ctr, Boston, MA USA. [Zujewski, Jo Anne] Natl Canc Inst, Canc Therapy Evaluat Program, Bethesda, MD USA. [Goss, Paul E.] Massachusetts Gen Canc Ctr, Breast Canc Res, Boston, MA USA. RP Come, SE (reprint author), Beth Israel Deaconess Med Ctr, Breast Cancer Program, 330 Brookline Ave,Room CC-913, Boston, MA 02215 USA. EM scome@caregroup.harvard.edu NR 2 TC 7 Z9 7 U1 1 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 1 PY 2008 VL 112 IS 3 SU S BP 673 EP 678 DI 10.1002/cncr.23194 PG 6 WC Oncology SC Oncology GA 258QN UT WOS:000252882800001 PM 18072254 ER PT J AU Eng-Wong, J Zujewski, JA AF Eng-Wong, Jennifer Zujewski, Jo Anne TI Current NCI-sponsored cooperative group trials of endocrine therapies in breast cancer SO CANCER LA English DT Article; Proceedings Paper CT 6th Cambridge Conference on Endocrine and Targeted Manipulation of Breast Cancer CY APR 30-MAY 01, 2007 CL Cambridge, MA DE breast cancer; endocrine therapy; clinical trial; hormone therapy; aromatase inhibitor; tamoxifen ID SURGICAL ADJUVANT BREAST; RECEPTOR-POSITIVE TUMORS; AROMATASE INHIBITORS; GENE-EXPRESSION; RANDOMIZED-TRIAL; POSTMENOPAUSAL WOMEN; TAMOXIFEN THERAPY; UPDATED FINDINGS; ESTROGEN; CHEMOTHERAPY AB Over several decades, investigators working through National Cancer Institute-sponsored Cooperative Groups have contributed to major advances in the endocrine treatment of breast cancer. Accomplishments include the benefit of tamoxifen therapy for early stage invasive and noninvasive breast cancer, the benefit of raloxifene and tamoxifen for prevention of breast cancer, the improved efficacy of tamoxifen after chemotherapy as opposed to concurrent administration, and the ability of letrozole administered after 5 years of tamoxifen to improve disease-free survival. Most recently, Cooperative Group studies have contributed to the development of a molecular profiling test, Oncotype Dx, which identifies women who have an excellent prognosis with hormonal therapy alone. Ongoing phase 3 clinical trials address the following questions: Is prolonged duration of aromatase inhibitor (AI) therapy beneficial? What is the efficacy and toxicity of steroidal versus nonsteroidal AIs in adjuvant treatment? Is combination hormonal therapy with an estrogen receptor down-regulator (fulvestrant) and an AI superior to an AI alone in the treatment of metastatic breast cancer? Does ovarian suppression offer superior benefit to standard therapy in the treatment of premenopausal breast cancer? What is the role of chemotherapy for early stage breast cancer selected via molecular profiling analysis? How can targeted therapies be used effectively in combination? Studies in subsets of patients defined by molecular profiling will be necessary to fully define breast cancer subtypes and realize the promise of personalized medicine. Close research partnerships that promote large-scale translational research are essential to the continuation of rapid achievements in this field. C1 [Eng-Wong, Jennifer] Natl Canc Inst, Med Oncol Branch, Bethesda, MD USA. [Zujewski, Jo Anne] Natl Canc Inst, Canc Therapy Evaluat Program, Bethesda, MD USA. RP Eng-Wong, J (reprint author), Georgetown Univ, Lombardi Canc Ctr, Washington, DC 20057 USA. EM je95@georgetown.edu NR 39 TC 3 Z9 3 U1 2 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 FEB 1 PY 2008 VL 112 IS 3 SU S BP 723 EP 729 DI 10.1002/cncr.23188 PG 7 WC Oncology SC Oncology GA 258QN UT WOS:000252882800008 PM 18072276 ER PT J AU Morin, PJ AF Morin, Patrice J. TI Learning about ovarian tumorigenesis by watching Cables SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE ovarian cancer; tumor suppressor; cell cycle; gene inactivation ID SURFACE EPITHELIAL-CELLS; CYCLIN D1; CANCER; EXPRESSION; GENE; AMPLIFICATION; PROTEIN; P53 C1 NIA, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. RP Morin, PJ (reprint author), NIA, Cellular & Mol Biol Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM morinp@mail.nih.gov NR 17 TC 0 Z9 0 U1 0 U2 1 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD FEB PY 2008 VL 7 IS 2 BP 189 EP 190 DI 10.4161/cbt.7.2.5743 PG 2 WC Oncology SC Oncology GA 312GZ UT WOS:000256658500005 PM 18347430 ER PT J AU Koutros, S Mahajan, R Zheng, TZ Hoppin, JA Ma, XM Lynch, CF Blair, A Alavanja, MCR AF Koutros, Stella Mahajan, Rajeev Zheng, Tongzhang Hoppin, Jane A. Ma, Xiaomei Lynch, Charles F. Blair, Aaron Alavanja, Michael C. R. TI Dichlorvos exposure and human cancer risk: results from the Agricultural Health Study SO CANCER CAUSES & CONTROL LA English DT Article DE pesticides; organophosphate insecticides; dichlorvos (DDVP); prospective cohort; cancer etiology ID PESTICIDE USE; IOWA; PARTICIPANTS; MINNESOTA; LEUKEMIA; CHILDREN; MEN AB Objectives We evaluated cancer risk from DDVP (2,2-Dichloroethenyl dimethylphosphate) exposure among pesticide applicators enrolled in the Agricultural Health Study (AHS) cohort. Methods The AHS is a cohort of 57,311 pesticide applicators in North Carolina and Iowa, enrolled from 1993 to 1997 and followed for cancer through 2004. A comprehensive questionnaire collected information on exposure to DDVP and potential confounders. Among the 49,762 licensed pesticide applicators eligible for analysis, 4,613 reported use of DDVP. DDVP exposure was classified as intensity-weighted cumulative exposure days (IWED), calculated as [years of use x days per year x intensity level]. Poisson regression analysis was used to calculate rate ratios (RR) and 95% confidence intervals (CI) to evaluate the association of DDVP exposure among 2,943 incident cases of cancer. Results DDVP exposure was not associated with any cancer studied here. We observed no elevation in risk among lymphohematopoietic cancers, RR = 1.00 (95% CI 0.51, 1.96) and a small excess risk associated with exposure among those with a family history of prostate cancer (RR = 1.18 (95% CI 0.73, 1.82). Conclusion We find little evidence of an association between cumulative lifetime use of DDVP and risk of any cancer at this stage of follow up of the AHS. C1 [Koutros, Stella; Mahajan, Rajeev; Blair, Aaron; Alavanja, Michael C. R.] NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Rockville, MD 20852 USA. [Koutros, Stella; Zheng, Tongzhang; Ma, Xiaomei] Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06510 USA. [Hoppin, Jane A.] NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Lynch, Charles F.] Univ Iowa, Coll Publ Hlth, Iowa City, IA USA. RP Koutros, S (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, 6120 Execut Blvd, Rockville, MD 20852 USA. EM koutross@mail.nih.gov FU Intramural NIH HHS [Z01 ES049030-11]; NCI NIH HHS [TU2 CA105666, TU2 CA 105666] NR 25 TC 18 Z9 20 U1 1 U2 5 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD FEB PY 2008 VL 19 IS 1 BP 59 EP 65 DI 10.1007/s10552-007-9070-0 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 251PT UT WOS:000252386400007 PM 17943454 ER PT J AU Kuehl, WM AF Kuehl, W. Michael TI Modeling multiple myeloma by AID-dependent conditional activation of MYC SO CANCER CELL LA English DT Editorial Material ID PATHOGENESIS; LESSONS; CELLS AB Efforts to create a mouse model that provides even a phenocopy of human multiple myeloma (MM) have been unsuccessful. In this issue of Cancer Cell, Bergsagel and colleagues describe an apparent solution to this problem by creating a model in which a MYC transgene containing a stop codon and flanking Ig kappa regulatory sequences is activated sporadically in germinal center B cells by AID-dependent somatic hypermutation that reverts the stop codon. Although much remains to be done to fully characterize this model, this approach is likely to impact the creation of sporadic models for other kinds of germinal center B cell tumors. C1 NCI, Genet Branch, Bethesda, MD 20889 USA. RP Kuehl, WM (reprint author), NCI, Genet Branch, Bethesda, MD 20889 USA. EM wmk@helix.nih.gov NR 10 TC 7 Z9 7 U1 0 U2 1 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 FEB PY 2008 VL 13 IS 2 BP 85 EP 87 DI 10.1016/j.ccr.2008.01.022 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 260QW UT WOS:000253026200003 PM 18242508 ER PT J AU Holman, DH Turner, LS El-Zawahry, A Elojeimy, S Liu, X Bielawski, J Szulc, ZM Norris, K Zeidan, YH Hannun, YA Bielawska, A Norris, JS AF Holman, David H. Turner, Lorianne S. El-Zawahry, Ahmed Elojeimy, Saeed Liu, Xiang Bielawski, Jacek Szulc, Zdzislaw M. Norris, Kristi Zeidan, Youssef H. Hannun, Yusuf A. Bielawska, Alicja Norris, James S. TI Lysosomotropic acid ceramidase inhibitor induces apoptosis in prostate cancer cells SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE ceramide; lysosomes; apoptosis; LCL204; B13; acid ceramidase inhibitors ID ENDOPLASMIC-RETICULUM CA2+; FAS-MEDIATED APOPTOSIS; CYTOCHROME-C; TUMOR-GROWTH; BAK; DEATH; ANALOGS; BCL-2; SPHINGOLIPIDS; RESISTANCE AB Purpose Alterations in ceramide metabolism have been reported in prostate cancer (PCa), resulting in escape of cancer cells from ceramide-induced apoptosis. Specifically, increased expression of lysosomal acid ceramidase (AC) has been shown in some primary PCa tissues and in several PCa cell lines. To determine if this represents a novel therapeutic target, we designed and synthesized LCL204, a lysosomotropic analog of B13, a previously reported inhibitor of AC Methods Prostate cancer cell lines were treated with LCL204 for varying times and concentrations. Effects of treatment on cytotoxicity, sphingolipid content, and apoptotic markers were assessed. Results Treatment of DU145 PCa cells resulted in increased ceramide and decreased sphingosine levels. Interestingly, LCL204 caused degradation of AC in a cathepsin-dependent manner. We also observed rapid destabilization of lysosomes and the release of lysosomal proteases into the cytosol following treatment with LCL204. Combined, these events resulted in mitochondria depolarization and executioner caspase activation, ultimately ending in apoptosis Conclusions These results provide evidence that treatment with molecules such as LCL204, which restore ceramide levels in PCa cells may serve as a new viable treatment option for PCa. C1 Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29403 USA. Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29403 USA. NIH, Natl Inst Neurol Disorders & Stroke, Surg Neurol Branch, Biochem Sect, Bethesda, MD 20892 USA. RP Norris, JS (reprint author), Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29403 USA. EM norrisjs@musc.edu OI Szulc, Zdzislaw M./0000-0003-1756-9028 FU NCI NIH HHS [P01 CA97132] NR 43 TC 45 Z9 49 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD FEB PY 2008 VL 61 IS 2 BP 231 EP 242 DI 10.1007/s00280-007-0465-0 PG 12 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 232HM UT WOS:000251009400006 PM 17429631 ER PT J AU Hazra, A Chanock, S Giovannucci, E Cox, DG Niu, T Fuchs, C Willett, WC Hunter, DJ AF Hazra, Aditi Chanock, Stephen Giovannucci, Edward Cox, David G. Niu, Tianhua Fuchs, Charles Willett, Walter C. Hunter, David J. TI Large-scale evaluation of genetic variants in candidate genes for colorectal cancer risk in the Nurses' Health Study and the Health Professionals' Follow-up Study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CATECHOL-O-METHYLTRANSFERASE; SINGLE-NUCLEOTIDE POLYMORPHISMS; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE; SEQUENCE VALIDATION; ASSAY DEVELOPMENT; PUBLIC RESOURCE; COLON-CANCER; SNP500CANCER; ASSOCIATION; ILLUMINA AB Advances in genomics offer new strategies for assessing the association of common genetic variations at multiple loci and risk of many diseases, including colorectal cancer. Low-penetrance alleles of genes in many biological pathways, such as DNA repair, metabolism, inflammation, cell cycle, apoptosis, and Wnt signaling, may influence the risk of nonfamilial colorectal cancer. To identify susceptibility genes for colorectal cancer, we designed a large-scale case-control association study nested within the Nurses' Health Study (190 cases and 190 controls) and the Health Professionals' Follow-up Study (168 cases and 168 controls). We used a custom Golden Gate (Illumina) oligonucleotide pool assay including 1,536 single nucleotide polymorphisms (SNP) selected in candidate genes from cancer-related pathways, which have been sequenced and genotyped in the SNP500Cancer project; 1,412 of the 1,536 (92%) of the SNPs were genotyped successfully within 388 genes. SNPs in high linkage disequilibrium (r(2) >= 0.90) with another assayed SNP were excluded from further analyses. As expected by chance (and not significant compared with a corrected Bonferroni P = 0.00004), in the additive model, 11 of 1,253 (0.9%) SNPs had a P-trend < 0.01 and 38 of 1,253 (3.0%) SNPs had a P-trend >= 0.01 and P-trend < 0.05. Of note, the MGMT Lys(178) Arg (rs2308237) SNP, in linkage disequilibrium with the previously reported MGMT Ile(143) Val SNP, had an inverse association with colorectal cancer risk (MGMT Lys(178) Arg: odds ratio, 0.52; 95% confidence interval, 0.35-0.78; unadjusted P-trend = 0.0003 for the additive model; gene-based test global P = 0.00003). The SNP500Cancer database and the Illumina Golden Gate Assay allowed us to test a larger number of SNPs than previously possible. We identified several SNPs worthy of investigation in larger studies. C1 [Giovannucci, Edward; Cox, David G.; Fuchs, Charles; Willett, Walter C.; Hunter, David J.] Brigham & Womens Hosp, Dept Med, Channing Lab, Boston, MA 02115 USA. [Giovannucci, Edward; Cox, David G.; Fuchs, Charles; Willett, Walter C.; Hunter, David J.] Harvard Univ, Sch Med, Boston, MA 02115 USA. [Hazra, Aditi; Giovannucci, Edward; Cox, David G.; Niu, Tianhua; Willett, Walter C.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Program Mol & Genet Epidemiol, Cambridge, MA 02138 USA. [Giovannucci, Edward; Willett, Walter C.; Hunter, David J.] Harvard Univ, Sch Publ Hlth, Dept Nutr, Cambridge, MA 02138 USA. [Fuchs, Charles] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. [Chanock, Stephen] NCI, Core Genotype Facil, Adv Technol Ctr, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Chanock, Stephen] NCI, Div Canc Epidemiol & Genet, Adv Technol Ctr, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hazra, A (reprint author), Brigham & Womens Hosp, Dept Med, Channing Lab, 181 Longwood Ave, Boston, MA 02115 USA. EM ahazra@hsph.harvard.edu RI Cox, David/A-2023-2009 OI Cox, David/0000-0002-2152-9259 FU NCI NIH HHS [CA55075, CA70817, CA87969, T32- CA 09001-30] NR 32 TC 9 Z9 11 U1 0 U2 0 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 FEB PY 2008 VL 17 IS 2 BP 311 EP 319 DI 10.1158/1055-9965.EPI-07-0195 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 263ZR UT WOS:000253255500009 PM 18268114 ER PT J AU Shin, A Shrubsole, MJ Rice, JM Cai, Q Doll, MA Long, JR Smalley, WE Shyr, Y Sinha, R Ness, RM Hein, DW Zheng, W AF Shin, Aesun Shrubsole, Martha J. Rice, Jeffrey M. Cai, Qiuyin Doll, Mark A. Long, Jirong Smalley, Walter E. Shyr, Yu Sinha, Rashmi Ness, Reid M. Hein, David W. Zheng, Wei TI Meat intake, heterocyclic amine exposure, and metabolizing enzyme polymorphisms in relation to colorectal polyp risk SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SINGLE NUCLEOTIDE POLYMORPHISMS; FOOD FREQUENCY QUESTIONNAIRE; N-ACETYLTRANSFERASE GENOTYPE; CANCER-RISK; MICROSATELLITE INSTABILITY; HYPERPLASTIC POLYPS; GENETIC POLYMORPHISMS; HUMAN N-ACETYLTRANSFERASE-2; DIETARY FACTORS; COLON-CANCER AB Most colorectal cancers arise from adenomatous polyps or certain hyperplastic polyps. Only a few studies have investigated potential genetic modifiers of the associations between meat intake and polyp risk, and results are inconsistent. Using data from the Tennessee Colorectal Polyp Study, a large colonoscopy-based study, including 1,002 polyp cases (557 adenoma only, 250 hyperplastic polyp only, 195 both polyps) and 1,493 polyp-free patients, we evaluated the association of colorectal polyp risk with carcinogen exposure from meat and genetic polymorphisms in enzymes involved in heterocyclic amine (HCA) metabolism, including N-acetyltransferase 1 (NAT1) and N-acetyltransferase 2 (NAT2), cytochrome P450 1A2 (CYP1A2), and aryl hydrocarbon receptor (AhR). Data on intake levels of meats by preparation methods, doneness preferences, and other lifestyle factors were obtained. Fourteen single nucleotide polymorphisms in the AhR, CYP1A2, NAT1, and NAT2 genes were evaluated. No clear association was found for any polymorphisms with polyp risk. However, apparent interactions were found for intake of meat and HCAs with AhR, NAT1, and NAT2 genotypes, and the interactions were statistically significant for the group with both adenomatous and hyperplastic polyps. Dose-response relationships with meat or HCA intake were found only among those with the AhR GA/AA (rs2066853) genotype, NAT1 rapid, or NAT2 rapid/intermediate acetylators but not among those with other genotypes of these genes. This dose-response relationship was more evident among those with both AhR GA/AA and the NAT1 rapid acetylator than those without this genotype combination. These results provide strong evidence for a modifying effect of metabolizing genes on the association of meat intake and HCA exposure with colorectal polyp risk. C1 [Shin, Aesun; Shrubsole, Martha J.; Cai, Qiuyin; Long, Jirong; Smalley, Walter E.; Ness, Reid M.; Zheng, Wei] Vanderbilt Univ, Sch Med, Dept Med, Vanderbilt Epidemiol Ctr, Nashville, TN 37203 USA. [Shrubsole, Martha J.; Cai, Qiuyin; Long, Jirong; Smalley, Walter E.; Shyr, Yu; Ness, Reid M.; Zheng, Wei] Vanderbilt Ingram Canc Ctr, Nashville, TN USA. [Rice, Jeffrey M.; Doll, Mark A.; Hein, David W.] Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. [Sinha, Rashmi] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Zheng, W (reprint author), Vanderbilt Univ, Sch Med, Dept Med, Vanderbilt Epidemiol Ctr, 8th Floor,2525 W End Ave, Nashville, TN 37203 USA. EM wei.zheng@vanderbilt.edu RI Hein, David/A-9707-2008; Shin, Aesun/E-9145-2014; Sinha, Rashmi/G-7446-2015; Shrubsole, Martha/K-5052-2015 OI Shin, Aesun/0000-0002-6426-1969; Sinha, Rashmi/0000-0002-2466-7462; Shrubsole, Martha/0000-0002-5591-7575 FU NCI NIH HHS [R01 CA097386-01, P50 CA095103, P50 CA095103-010005, P50 CA950103, R01 CA034627, R01 CA034627-15, R01 CA097386, R01 CA34627] NR 52 TC 41 Z9 41 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 FEB PY 2008 VL 17 IS 2 BP 320 EP 329 DI 10.1158/1055-9965.EPI-07-0615 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 263ZR UT WOS:000253255500010 PM 18268115 ER PT J AU Wang, S Chanock, S Tang, DL Li, ZG Jedrychowski, W Perera, FP AF Wang, Shuang Chanock, Stephen Tang, Deliang Li, Zhigang Jedrychowski, Wieslaw Perera, Frederica P. TI Assessment of interactions between PAH exposure and genetic polymorphisms on PAH-DNA adducts in African American, Dominican, and Caucasian mothers and newborns SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; ENVIRONMENTAL TOBACCO-SMOKE; LUNG-CANCER; INDIVIDUAL SUSCEPTIBILITY; PRENATAL EXPOSURE; PROSTATE-CANCER; GESTATION STAGE; BIRTH OUTCOMES; GENOTYPE DATA; RISK AB Polycyclic aromatic hydrocarbons (PAH) are widespread pollutants commonly found in air, food, and drinking water. Benzo[a]pyrene is a well-studied representative PAH found in air from fossil fuel combustion and a transplacental carcinogen experimentally. PAHs bind covalently to DNA to form DNA adducts, an indicator of DNA damage, and an informative biomarker of potential cancer risk. Asso-Leoneciations between PAH-DNA adduct levels and both cancer risk and developmental deficits have been seen in previous experimental and epidemiologic studies. Several genes have been shown to play an important role in the metabolic activation or detoxification of PAHs, including,the cytochrome P450 genes CYP1A1 and CYP1B1 and the glutathione S-transferase (GST) genes GSTM1, and GSTT2. Genetic variation in these genes could influence susceptibility to adverse effects of PAHs in polluted air. Here, we have explored interactions between prenatal PAH exposure and 17 polymorphisms in these genes (rs2198843, rs1456432, rs4646903, rs4646421, rs2606345, rs7495708, rs2472299, rs162549, rs1056837, rs1056836, rs162560, rs10012, rs2617266, rs2719, rs1622002, rs140194, and gene deletion GSTM1-02) and haplotypes on PAH-DNA adducts in cord blood of 547 newborns and in maternal blood of 806 mothers from three different self-described ethnic groups: African Americans, Dominicans, and Caucasians. PAHs were measured by personal air monitoring of mothers during pregnancy. Significant interactions (p < 0.05) were observed between certain genetic polymorphisms and CYP1A1 haplotype and PAHs in mothers and their newborns in the three ethnic groups. However, with our limited sample size, the current findings are suggestive only, warranting further study. C1 [Tang, Deliang; Jedrychowski, Wieslaw; Perera, Frederica P.] Columbia Univ, Columbia Ctr Children Environm Hlth, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Wang, Shuang; Li, Zhigang] Columbia Univ, Dept Biostat, Mailman Sch Publ Hlth, New York, NY 10032 USA. [Chanock, Stephen] NCI, Bethesda, MD 20892 USA. RP Perera, FP (reprint author), Columbia Univ, Columbia Ctr Children Environm Hlth, Mailman Sch Publ Hlth, 25F,Tower 3,100 Haven Ave, New York, NY 10032 USA. EM fpp1@columbia.edu FU NCI NIH HHS [5P30 CA 13696-23, P30 CA013696]; NIEHS NIH HHS [ES09089, P01 ES009600, P01 ES009600-01, P30 ES009089, R01 ES008977, R01 ES008977-10, R01 ES011158, R01 ES012468, R01 ES08977, R01 ES111158]; PHS HHS [P01 009600] NR 49 TC 41 Z9 55 U1 1 U2 7 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 FEB PY 2008 VL 17 IS 2 BP 405 EP 413 DI 10.1158/1055-9965.EPI-07-0695 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 263ZR UT WOS:000253255500022 PM 18268125 ER PT J AU Chalikonda, S Kivlen, MH O'Malley, ME Dong, XD McCart, JA Gorry, MC Yin, XY Brown, CK Zeh, HJ Guo, Z Bartlett, DL AF Chalikonda, S. Kivlen, M. H. O'Malley, M. E. Dong, X. D. (Eric) McCart, J. A. Gorry, M. C. Yin, X-Y Brown, C. K. Zeh, H. J., III Guo, Z. S. Bartlett, D. L. TI Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene SO CANCER GENE THERAPY LA English DT Article; Proceedings Paper CT 9th Annual Meeting of the American-Society-of-Gene-Therapy CY MAY 31-JUN 04, 2006 CL Baltimore, MD SP Amer Soc Gene Therapy DE poxvirus; ovarian cancer; peritoneal carcinomatosis; suicide gene; cytosine deaminase ID QUALITY-OF-LIFE; THYMIDINE KINASE; INTRAPERITONEAL THERAPY; GEMCITABINE POTENTIATE; RECOMBINANT VACCINIA; PANCREATIC-CANCER; TUMOR-REGRESSION; COLON-CANCER; ADENOVIRUS; DELIVERY AB In this study, we assessed the ability of a highly tumor-selective oncolytic vaccinia virus armed with a yeast cytosine deaminase gene to infect and lyse human and murine ovarian tumors both in vitro and in vivo. The virus vvDD-CD could infect, replicate in and effectively lyse both human and mouse ovarian cancer cells in vitro. In two different treatment schedules involving either murine MOSEC or human A2780 ovarian carcinomatosis models, regional delivery of vvDD-CD selectively targeted tumor cells and ovarian tissue, effectively delaying the development of either tumor or ascites and leading to significant survival advantages. Oncolytic virotherapy using vvDD-CD in combination with the prodrug 5-fluorocytosine conferred an additional long-term survival advantage upon tumor-bearing immunocompetent mice. These findings demonstrate that a tumor-selective oncolytic vaccinia combined with gene-directed enzyme prodrug therapy is a highly effective strategy for treating advanced ovarian cancers in both syngeneic mouse and human xenograft models. Given the biological safety, tumor selectivity and oncolytic potency of this armed oncolytic virus, this dual therapy merits further investigation as a promising new treatment for metastatic ovarian cancer. C1 [Chalikonda, S.; O'Malley, M. E.; Dong, X. D. (Eric); Gorry, M. C.; Yin, X-Y; Brown, C. K.; Zeh, H. J., III; Guo, Z. S.; Bartlett, D. L.] Univ Pittsburgh, Sch Med, Univ Pittsburgh Canc Inst, Dept Surg, Pittsburgh, PA 15213 USA. [Kivlen, M. H.; McCart, J. A.; Bartlett, D. L.] NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. [Yin, X-Y] Sun Yat Sen Univ, Affiliated Hosp 1, Dept Hepatobiliary Surg, Guangzhou, Guangdong, Peoples R China. RP Guo, Z (reprint author), Univ Pittsburgh, Sch Med, Univ Pittsburgh Canc Inst, Dept Surg, UPCI Res Pavil,Suite 1-46,5117 Ctr Ave, Pittsburgh, PA 15213 USA. EM guozs@upmc.edu FU Intramural NIH HHS; NCI NIH HHS [CA100415, R01 CA100415, R01 CA100415-04] NR 46 TC 45 Z9 46 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD FEB PY 2008 VL 15 IS 2 BP 115 EP 125 DI 10.1038/sj.cgt.7701110 PG 11 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 251QR UT WOS:000252389000007 PM 18084242 ER PT J AU Lee, JH Horak, CE Khanna, C Meng, ZJ Yu, LR Veenstra, TD Steeg, PS AF Lee, Jong Heun Horak, Christine E. Khanna, Chand Meng, Zhaojing Yu, Li Rong Veenstra, Timothy D. Steeg, Patricia S. TI Alterations in Gemin5 expression contribute to alternative mRNA splicing patterns and tumor cell motility SO CANCER RESEARCH LA English DT Article ID SMN COMPLEX; PROTEIN; ACTIVATION; NM23-H1; RHO AB The role of Gemin5 in alternative mRNA splicing, tumor cell motility, and proteomic instability was investigated. Isotope Capture Affinity Tag proteomic analysis was conducted on MDA-MB-435 tumor cells transfected with either a control vector (C-100) or the Nm23-H1 metastasis suppressor (H1-177). Ingenuity pathway analysis revealed that RNA posttranscriptional processing was the most prominent class of differentially expressed proteins. Within this category, overexpression of Acinus1, Poly(a) binding protein, HNRPA2B1, Bop1, and Gemin5 was confirmed in less metastatic H1-177 cells. Overexpression of the latter four proteins was also observed in the lower metastatic antisense Ezrin transfectant of a murine osteosarcoma model system, confirming the general relevance of the trends. Gemin5, a component of the spliceosomal complex, was chosen for further study. Analysis of global mRNA splicing by SpliceArray chips revealed that 16 genes were differentially spliced in C-100 compared with H1-177 cells; transient transfection of gemin5 into C-100 cells restored the splice pattern to that of H1-177 cells. Alternative splicing patterns for the engulfment and cell motility 1 and thrombospondin 4 genes were confirmed by semiquantitative reverse transcription-PCR. Gemin5 overexpression coordinately reduced C-100 cell motility by 50%, and siRNA-mediated reduction of Gemin5 expression increased the motility of H1-177 cells by 2-fold (P < 0.004). The data provide the first demonstration that alterations in the expression of a spliceosome protein can effect both specific splicing events and tumor cell motility. The data also show that changes in mRNA splicing patterns accompany metastatic progression, which may contribute to proteome instability. C1 [Lee, Jong Heun; Horak, Christine E.; Steeg, Patricia S.] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Khanna, Chand] NCI, Pediat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Meng, Zhaojing; Yu, Li Rong; Veenstra, Timothy D.] NCI, Sci Applicat Int Corp Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD 21701 USA. RP Steeg, PS (reprint author), Bldg 37,Room 1122, Bethesda, MD 20892 USA. EM steegp@mail.nih.gov FU Intramural NIH HHS [Z01 SC000892-24] NR 20 TC 17 Z9 19 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 FEB 1 PY 2008 VL 68 IS 3 BP 639 EP 644 DI 10.1158/0008-5472.CAN-07-2632 PG 6 WC Oncology SC Oncology GA 259QD UT WOS:000252952900004 PM 18245461 ER PT J AU Laguinge, LM Samara, RN Wang, W El-Deiry, WS Corner, G Augenlicht, L Mishra, L Jessup, JM AF Laguinge, Luciana M. Samara, Raed N. Wang, Wenge El-Deiry, Wafik S. Corner, Georgia Augenlicht, Leonard Mishra, Lopa Jessup, J. Miburn TI DR5 receptor mediates anoikis in human colorectal carcinoma cell lines SO CANCER RESEARCH LA English DT Article ID APOPTOSIS-INDUCING LIGAND; DETACHMENT-INDUCED APOPTOSIS; INTESTINAL EPITHELIAL-CELLS; TRAIL-INDUCED APOPTOSIS; MATRIX ADHESION; GENE-EXPRESSION; CYTOCHROME-C; DEATH; ACTIVATION; SURVIVAL AB As human colorectal cancer (CRC) cells metastasize to distant sites, they are susceptible to detachment-induced cell death or anoikis - a form of apoptosis that occurs when anchorage-dependent CRC cells go into suspension. Our goal was to identify whether tumor necrosis factor receptor apoptosis-inducing ligand (TRAIL) receptors mediate anoikis in human CRC cells. First, we assessed whether caspases of the extrinsic (caspase-8) or intrinsic (caspase-9) death pathways were involved. Caspase-8 was cleaved during exposure to suspension culture in four CRC lines, and cell death was inhibited by caspase-3 and caspase-8 inhibitors but not by a caspase-9 inhibitor. Gene transcripts in macrophage inflammatory protein-101 (MIP-110), a weakly metastatic human CRC, were increased at least 2-fold for TRAIL-R2 (DR5) and TRAIL after 24 h of suspension culture compared with cells in monolayer culture. The increased expression of DR5 was confirmed at the protein level at 24 h, and exposure of MIP-101 cells to an antagonistic antibody to DR5 decreased caspase-8 activation. The antagonistic antibody to DR5 inhibited anoikis in four human CRC lines. Treatment with an antagonistic DR4 antibody or a neutralizing antibody to TRAIL ligand did not reduce anoikis consistently. Knockdown of DR5 or TRAIL also inhibited anoikis, whereas exogenous TRAIL or FasL did not consistently increase anoikis. In summary, DR5 receptor mediates death signals for anoikis in human CRC cells through the extrinsic apoptotic pathway. C1 [Laguinge, Luciana M.; Samara, Raed N.; Jessup, J. Miburn] Georgetown Univ, Med Ctr, Dept Oncol, Washington, DC 20007 USA. [Mishra, Lopa] Georgetown Univ, Med Ctr, Dept Surg, Washington, DC 20007 USA. [Wang, Wenge; El-Deiry, Wafik S.] Univ Penn, Sch Med, Abramson Canc Ctr, Dept Med, Philadelphia, PA 19104 USA. [Corner, Georgia; Augenlicht, Leonard] Montefiore Med Ctr, Albert Einstein Canc Ctr, Dept Oncol, Bronx, NY 10467 USA. RP Jessup, JM (reprint author), NCI, Canc Diag Program, 6040 EPN,6130 Execut Blvd, Bethesda, MD 20892 USA. EM jessupj@mail.nih.gov FU NCI NIH HHS [1P30-CA-51008, R01 CA 42587] NR 48 TC 27 Z9 29 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 FEB 1 PY 2008 VL 68 IS 3 BP 909 EP 917 DI 10.1158/0008-5472.CAN-06-1806 PG 9 WC Oncology SC Oncology GA 259QD UT WOS:000252952900037 PM 18245494 ER PT J AU Wallace, TA Prueitt, RL Yi, M Howe, TM Gillespie, JW Yfantis, HG Stephens, RM Caporaso, NE Loffredo, CA Ambs, S AF Wallace, Tiffany A. Prueitt, Robyn L. Yi, Ming Howe, Tiffany M. Gillespie, John W. Yfantis, Harris G. Stephens, Robert M. Caporaso, Neil E. Loffredo, Christopher A. Ambs, Stefan TI Tumor immunobiological differences in prostate cancer between African-American and European-American men SO CANCER RESEARCH LA English DT Article ID GENE-EXPRESSION; GERMLINE MUTATIONS; ETHNIC-DIFFERENCES; CXCL12 SDF-1; METASTASIS; BONE; ASSOCIATION; PATHWAY; RISK; CARCINOGENESIS AB The incidence and mortality rates of prostate cancer are significantly higher in African-American men when compared with European-American men. We tested the hypothesis that differences in tumor biology contribute to this survival health disparity. Using microarray technology, we obtained gene expression profiles of primary prostate tumors resected from 33 African-American and 36 European-American patients. These tumors were matched on clinical variables. We also evaluated 18 nontumor prostate tissues from seven African-American and 11 European-American patients. The resulting datasets were analyzed for expression differences on the gene and pathway level comparing African-American with European-American patients. Our analysis revealed a significant number of genes, e.g., 162 transcripts at a false-discovery rate of <= 5% to be differently expressed between African-American and European-American patients. Using a disease association analysis, we identified a common relationship of these transcripts with autoimmunity and inflammation. These findings were corroborated on the pathway level with numerous differently expressed genes clustering in immune response, stress response, cytokine signaling, and chemotaxis pathways. Several known metastasis-promoting genes, including autocrine mobility factor receptor, chemokine (C-X-C motif) receptor 4, and matrix metalloproteinase 9, were more highly expressed in tumors from African-Americans than European-Americans. Furthermore, a two-gene tumor signature that accurately differentiated between African-American and European-American patients was identified. This finding was confirmed in a blinded analysis of a second sample set. In conclusion, the gene expression profiles of prostate tumors indicate prominent differences in tumor immunobiology between African-American and European-American men. The profiles portray the existence of a distinct tumor microenvironment in these two patient groups. C1 [Wallace, Tiffany A.; Prueitt, Robyn L.; Howe, Tiffany M.; Ambs, Stefan] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. [Gillespie, John W.] NCI, NIH, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. [Yi, Ming; Stephens, Robert M.] Sci Applicat Int Corp Frederick Inc, Natl Canc Inst, Adv Biomed Comp Ctr, Frederick, MD USA. [Yfantis, Harris G.] Baltimore Vet Affairs Met Ctr, Pathol & Lab Med, Baltimore, MD USA. [Caporaso, Neil E.] NCI, NIH, Genet Epidemiol Branch, Div Canc Epidemol & Genet, Rockville, MD USA. [Loffredo, Christopher A.] Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Canc Genet & Epidemiol Program, Washington, DC 20007 USA. RP Ambs, S (reprint author), NCI, Human Carcinogenesis Lab, NIH, Bldg 37-Room 3050B, Bethesda, MD 20892 USA. EM ambss@mail.nih.gov FU Intramural NIH HHS NR 50 TC 183 Z9 185 U1 1 U2 13 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 FEB 1 PY 2008 VL 68 IS 3 BP 927 EP 936 DI 10.1158/0008-5472.CAN-07-2608 PG 10 WC Oncology SC Oncology GA 259QD UT WOS:000252952900039 PM 18245496 ER PT J AU Schetter, AJ You, WC Lennette, ET Gail, MT Rabkin, CS AF Schetter, Aaron J. You, Wei-cheng Lennette, Evelyne T. Gail, Mitchell T. Rabkin, Charles S. TI Association of Epstein-Barr virus antibody levels with precancerous gastric lesions in a high-risk cohort SO CANCER SCIENCE LA English DT Article ID HELICOBACTER-PYLORI INFECTION; CANCER; CARCINOMA; ADENOCARCINOMA; POPULATION; PATTERNS AB We evaluated associations between Epstein-Barr virus (EBV) antibody levels and precancerous gastric lesions (chronic atrophic gastritis, intestinal metaplasia, and dysplasia) in 183 subjects from Linqu, China. Immunoglobulin G antibody titers to EBV nuclear antigen (EBNA) and viral capsid antigen (VCA) were determined by two-fold serial dilution using immunofluorescence assays. Histological progression and regression were assessed by gastroscopic examination at the time of phlebotomy and at follow up 2 years later. Antibody titers did not differ significantly among histological diagnoses determined at the time of phlebotomy. However, subjects with dysplasia at follow up had significantly higher geometric mean antibody titers for both anti-VCA and anti-EBNA. Subjects with greater than median antibody levels were more likely to progress between examinations, especially in the subgroup with intestinal metaplasia at the time of phlebotomy (odds ratios [95% confidence intervals]: 5.7 [1.6-20] for anti-EBNA >= 1:320; 3.8 [1.0-15] for anti-VCA >= 1:640). Our findings suggest a possible role for EBV reactivation at an early phase of gastric carcinogenesis. C1 [Gail, Mitchell T.; Rabkin, Charles S.] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Schetter, Aaron J.] NCI, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. [You, Wei-cheng] Peking Univ, Beijing Canc Hosp & Inst, Sch Oncol, Beijing 100036, Peoples R China. [Lennette, Evelyne T.] Nectandra Inst, San Ramon, Costa Rica. RP Rabkin, CS (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM rabkinc@mail.nih.gov FU Intramural NIH HHS NR 30 TC 13 Z9 14 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1347-9032 J9 CANCER SCI JI Cancer Sci. PD FEB PY 2008 VL 99 IS 2 BP 350 EP 354 DI 10.1111/j.1349-7006.2007.00668.x PG 5 WC Oncology SC Oncology GA 259UQ UT WOS:000252966800025 PM 18201267 ER PT J AU Luo, DL Yang, DM Lan, XM Li, KT Li, XD Chen, J Zhang, YY Xiao, RP Han, QD Cheng, HP AF Luo, Dali Yang, Dongmei Lan, Xiaomei Li, Kaitao Li, Xiaodong Chen, Ju Zhang, Youyi Xiao, Rui-Ping Han, Qide Cheng, Heping TI Nuclear Ca2+ sparks and waves mediated by inositol 1,4,5-trisphosphate receptors in neonatal rat cardiomyocytes SO CELL CALCIUM LA English DT Article DE cardiomyocytes; nuclear Ca2+ signaling; inositol 1,4,5-trisphosphate receptors; Ca2+ sparks; alpha(1) adrenergic stimulation ID CYTOSOLIC CALCIUM; CARDIAC MYOCYTES; TRISPHOSPHATE RECEPTOR; CYTOPLASMIC CALCIUM; LIVER NUCLEI; RELEASE; EXPRESSION; CELLS; RETICULUM; SIGNAL AB Dynamic nuclear Ca2+ signals play pivotal roles in diverse cellular functions including gene transcription, cell growth, differentiation, and apoptosis. Here we report a novel nuclear Ca2+ regulatory mechanism mediated by mositol 1,4,5-trispliosphate receptors (IP(3)Rs) around the nucleus in developing cardiac myocytes. Activation Of IP(3)Rs by alpha(1)-adrenergic receptor (alpha(1)AR) stimulation or by IP3 application (in saponinpermeabilized cells) increases Ca2+ spark frequency preferentially in the region around the nucleus in neonatal rat ventricular myocytes. A nuclear enrichment Of IP3R distribution supports the higher responsiveness of Ca2+ release in this particular region. Strikingly, we observed "nuclear Ca2+ waves" that engulf the entire nucleus without spreading into the bulk cytosol. alpha(1)AR stimulation enhances the occurrence of nuclear Ca2+ waves and confers them the ability to trigger cytosolic Ca2+ waves via IP3R-dependent pathways. This finding accounts, at least partly, for a profound frequency-dependent modulation of global Ca2+ oscillations during alpha(1) AR stimulation. Thus, IP3R-mediated Ca2+ waves traveling in the nuclear region provide active, autonomous regulation of nuclear Ca2+ signaling, which provides for not only the local signal transduction, but also a pacemaker to drive global Ca2+ transient in the context of alpha(1)AR stimulation in developing cardiac myocytes. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Luo, Dali; Han, Qide] Capital Med Univ, Sch Chem Biol & Pharmaceut Sci, Dept Pharmacol, Beijing 100069, Peoples R China. [Luo, Dali; Lan, Xiaomei; Zhang, Youyi; Han, Qide] Peking Univ, Inst Cardiovasc Sci, Hlth Sci Ctr, Beijing 100083, Peoples R China. [Yang, Dongmei; Xiao, Rui-Ping] NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. [Li, Kaitao; Xiao, Rui-Ping; Cheng, Heping] Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. [Li, Kaitao; Xiao, Rui-Ping; Cheng, Heping] Peking Univ, Natl Lab Biomembrane & Membrane Biotechnol, Beijing 100871, Peoples R China. [Li, Xiaodong; Chen, Ju] Univ Calif San Diego, Inst Mol Med, La Jolla, CA 92093 USA. RP Luo, DL (reprint author), Capital Med Univ, Sch Chem Biol & Pharmaceut Sci, Dept Pharmacol, Beijing 100069, Peoples R China. EM luodl@bjniu.edu.cn RI Chen, Ju/E-5579-2011 FU Intramural NIH HHS [Z99 AG999999] NR 41 TC 51 Z9 53 U1 0 U2 17 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD FEB PY 2008 VL 43 IS 2 BP 165 EP 174 DI 10.1016/j.ceca.2007.04.017 PG 10 WC Cell Biology SC Cell Biology GA 276RA UT WOS:000254158600006 PM 17583790 ER PT J AU Wu, YT Zhang, S Kim, YS Tan, HL Whiteman, M Ong, CN Liu, ZG Ichijo, H Shen, HM AF Wu, Y-T Zhang, S. Kim, Y-S Tan, H-L Whiteman, M. Ong, C-N Liu, Z-G Ichijo, H. Shen, H-M TI Signaling pathways from membrane lipid rafts to JNK1 activation in reactive nitrogen species-induced non-apoptotic cell death SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE RNS; lipid rafts; TRAF2; ASK1; JNK1; non-apoptotic cell death ID NF-KAPPA-B; NITRIC-OXIDE; C-JUN; PROTEIN-KINASE; REGULATING KINASE-1; TERMINAL KINASE; MAP KINASES; RECEPTOR; NECROSIS; STRESS AB At present, the signaling pathways controlling reactive nitrogen species (RNS)-induced non-apoptotic cell death are relatively less understood. In this work, various RNS donors are found to induce caspase-independent non-apoptotic cell death in mouse embryonic fibroblasts (MEF). In search of the molecular mechanisms, we first established the role of c-Jun N-terminal kinase (JNK) in RNS-induced non-apoptotic cell death. RNS readily activate JNK, and the jnk1(-/-) MEF are resistant to RNS-induced cell death. Moreover, the reconstitution of JNK1 effectively restores the sensitivity to RNS. Next, we identified tumor necrosis factor receptor-associated factor 2 (TRAF2) and apoptosis signal-regulating kinase 1 (ASK1) as the essential upstream molecules for RNS-induced JNK activation and cell death. RNS fail to activate JNK and induce cell death in traf2(-/-) MEF; and reconstitution of TRAF2 effectively restores the responsiveness of traf2(-/-) MEF to RNS. Moreover, RNS-induced ASK1 activation is impaired in traf2(-/-) cells and overexpression of a mutant ASK1 protein suppresses RNS-induced cell death in wild-type MEF cells. Last, we explored the signaling events upstream of TRAF2 and found that translocation of TRAF2 and JNK1 onto membrane lipid rafts is required for RNS-mediated JNK1 activation and cell death. Taken together, data from our study reveal a novel signaling pathway regulating RNS-induced JNK1 activation and non-apoptotic cell death. C1 [Wu, Y-T; Zhang, S.; Tan, H-L; Ong, C-N; Shen, H-M] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Community Occupat & Family Med, Singapore 117597, Singapore. [Kim, Y-S; Liu, Z-G] NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Ichijo, H.] Univ Tokyo, Grad Sch Pharmaceut Sci, Lab Cell Signaling, Tokyo, Japan. RP Shen, HM (reprint author), Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Community Occupat & Family Med, MD3,16 Med Dr, Singapore 117597, Singapore. EM cofshm@nus.edu.sg RI Whiteman, Matthew/C-6079-2009; SHEN, Han-Ming/B-5942-2011; Ong, Choon Nam/E-8638-2010; Zhang, Siyuan/A-1276-2014 OI Whiteman, Matthew/0000-0002-6583-6779; SHEN, Han-Ming/0000-0001-7369-5227; Zhang, Siyuan/0000-0003-0910-3666 NR 42 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 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD FEB PY 2008 VL 15 IS 2 BP 386 EP 397 DI 10.1038/sj.cdd.4402273 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 251QG UT WOS:000252387900018 PM 18007661 ER PT J AU Plattner, F Yarovinsky, F Romero, S Didry, D Carlier, MF Sher, A Soldati-Favre, D AF Plattner, Fabienne Yarovinsky, Felix Romero, Stephane Didry, Dominique Carlier, Marie-France Sher, Alan Soldati-Favre, Dominique TI Toxoplasma profilin is essential for host cell invasion and TLR11-dependent induction of an interleukin-12 response SO CELL HOST & MICROBE LA English DT Article ID GONDII MYOSIN-A; ACTIN-FILAMENTS; APICOMPLEXAN PARASITES; MICROFILAMENT DYNAMICS; PROTOZOAN PARASITE; DENDRITIC CELLS; MOTILITY; EGRESS; HYDROLYSIS; PROTEINS AB Apicomplexan parasites exhibit actin-dependent gliding motility that is essential for migration across biological barriers and host cell invasion. Profilins are key contributors to actin polymerization, and the parasite Toxoplasma gondii possesses a profilin-like protein that is recognized by Toll-like receptor TLR11 in the host innate immune system. Here, we show by conditional disruption of the corresponding gene that T.gondii profilin, while not required for intracellular growth, is indispensable for gliding motility, host cell invasion, active egress from host cells, and virulence in mice. Furthermore, parasites lacking profilin are unable to induce TLR11-dependent production in vitro and in vivo of the defensive host cytokine interleukin-12. Thus, profilin is an essential element of two aspects of T. gondii infection. Like bacterial flagellin, profilin plays a role in motility while serving as a microbial ligand recognized by the host innate immune system. C1 [Plattner, Fabienne; Soldati-Favre, Dominique] Univ Geneva, CMU, Dept Microbiol & Mol Med, CH-1211 Geneva 4, Switzerland. [Yarovinsky, Felix; Sher, Alan] NIAID, Parasit Dis Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. [Romero, Stephane; Didry, Dominique; Carlier, Marie-France] CNRS, Lab Enzymol & Biochim Struct UPR A 9063, F-91198 Gif Sur Yvette, France. RP Soldati-Favre, D (reprint author), Univ Geneva, CMU, Dept Microbiol & Mol Med, 1 Rue Michel Servet, CH-1211 Geneva 4, Switzerland. EM dominique.soldati-favre@medecine.unige.ch RI Soldati-Favre, Dominique/A-2999-2009; OI Soldati-Favre, Dominique/0000-0003-4156-2109 FU Intramural NIH HHS NR 36 TC 145 Z9 153 U1 1 U2 15 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 FEB PY 2008 VL 3 IS 2 BP 77 EP 87 DI 10.1016/j.chom.2008.01.001 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 264PX UT WOS:000253302100005 PM 18312842 ER PT J AU Chen, C Shah, YM Morimura, K Krausz, KW Miyazaki, M Richardson, TA Morgan, ET Ntambi, JM Idle, JR Gonzalez, FJ AF Chen, Chi Shah, Yatrik M. Morimura, Keiichirou Krausz, Kristopher W. Miyazaki, Makoto Richardson, Terrilyn A. Morgan, Edward T. Ntambi, James M. Idle, Jeffrey R. Gonzalez, Frank J. TI Metabolomics reveals that hepatic stearoyl-CoA desaturase 1 downregulation exacerbates inflammation and acute colitis SO CELL METABOLISM LA English DT Article ID DEXTRAN SULFATE SODIUM; CITROBACTER-RODENTIUM INFECTION; POLYUNSATURATED FATTY-ACIDS; DSS-INDUCED COLITIS; BOWEL-DISEASE; GENE-EXPRESSION; ULCERATIVE-COLITIS; ENDOTHELIAL-CELLS; NITRIC-OXIDE; ACUTE-PHASE AB To investigate the pathogenic mechanism of ulcerative colitis, a dextran sulfate sodium (DSS)-induced acute colitis model was examined by serum metabolomic analysis. Higher levels of stearoyl lysophosphatidylcholine and lower levels of oleoyl lysophosphatidylcholine in DSS-treated mice compared to controls led to the identification of DSS-elicited inhibition of stearoyl-CoA desaturase 1 (SCD1) expression in liver. This decrease occurred prior to the symptoms of acute colitis and was well correlated with elevated expression of proinflammatory cytokines. Furthermore, Citrobacter rodentium-induced colitis and lipopolysaccharide treatment also suppressed SCD1 expression in liver. Scd1 null mice were more susceptible to DSS treatment than wild-type mice, while oleic acid feeding and in vivo SCD1 rescue with SCD1 adenovirus alleviated the DSS-induced phenotype. This study reveals that inhibition of SCD1-mediated oleic acid biogenesis exacerbates proinflammatory responses to exogenous challenges, suggesting that SCD1 and its related lipid species may serve as potential targets for intervention or treatment of inflammatory diseases. C1 [Chen, Chi; Shah, Yatrik M.; Morimura, Keiichirou; Krausz, Kristopher W.; Gonzalez, Frank J.] NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Miyazaki, Makoto; Ntambi, James M.] Univ Wisconsin, Dept Biochem & Nutr Sci, Madison, WI 53706 USA. [Richardson, Terrilyn A.; Morgan, Edward T.] Emory Univ, Dept Pharmacol, Atlanta, GA 30322 USA. [Idle, Jeffrey R.] Charles Univ Prague, Fac Med 1, Inst Pharmacol, Prague 12800 2, Czech Republic. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov RI Chen, Chi/B-4618-2008; OI Morgan, Edward/0000-0003-4273-2261; Idle, Jeff/0000-0002-6143-1520 FU Intramural NIH HHS [Z01 BC005562-19]; NIDDK NIH HHS [R01 DK072372, R01 DK072372-04] NR 58 TC 83 Z9 89 U1 3 U2 24 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD FEB PY 2008 VL 7 IS 2 BP 135 EP 147 DI 10.1016/j.cmet.2007.12.003 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 259WG UT WOS:000252971000008 PM 18249173 ER PT J AU Wickliffe, KE Leppla, SH Moayeri, M AF Wickliffe, Katherine E. Leppla, Stephen H. Moayeri, Mahtab TI Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasome SO CELLULAR MICROBIOLOGY LA English DT Article ID INTERLEUKIN-1-BETA CONVERTING-ENZYME; PROGRAMMED CELL-DEATH; BACILLUS-ANTHRACIS; CYSTEINE PROTEASE; MACROPHAGE APOPTOSIS; IL-1-BETA-CONVERTING ENZYME; MURINE MACROPHAGES; PROTECTIVE ANTIGEN; NALP3 INFLAMMASOME; EUKARYOTIC CELLS AB Anthrax lethal toxin (LT) is cytotoxic to macrophages from certain inbred mouse strains. The gene controlling macrophage susceptibility to LT is Nalp1b. Nalp1b forms part of the inflammasome, a multiprotein complex involved in caspase-1 activation and release of interleukin (IL)-1 beta and IL-18. We confirm the role of caspase-1 in LT-mediated death by showing that caspase inhibitors differentially protected cells against LT, with the degree of protection corresponding to each compound's ability to inhibit caspase-1. Caspase-1 activation and cytokine processing and release were late events inhibited by elevated levels of KCl and sucrose, by potassium channel blockers, and by proteasome inhibitors, suggesting that inflammasome formation requires a protein-degradation event and occurs downstream of LT-mediated potassium efflux. In addition, IL-18 and IL-1 beta release was dependent on cell death, indicating that caspase-1-mediated cytotoxicity is independent of these cytokines. Finally, inducing NALP3-inflammasome formation in LT-resistant macrophages did not sensitize cells to LT, suggesting that general caspase-1 activation cannot account for sensitivity to LT and that a Nalp1b-mediated event is specifically required for death. Our data indicate that inflammasome formation is a contributing, but not initiating, event in LT-mediated cytotoxicity and that earlier LT-mediated events leading to ion fluxes are required for death. C1 [Wickliffe, Katherine E.; Leppla, Stephen H.; Moayeri, Mahtab] NIH, Natl Inst Allergy & Infect Dis, Bacterial Toxins & Therapeut Sect, Bethesda, MD 20892 USA. RP Moayeri, M (reprint author), NIH, Natl Inst Allergy & Infect Dis, Bacterial Toxins & Therapeut Sect, Bldg 10, Bethesda, MD 20892 USA. EM mmoayeri@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000929-05] NR 67 TC 74 Z9 76 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-5814 EI 1462-5822 J9 CELL MICROBIOL JI Cell Microbiol. PD FEB PY 2008 VL 10 IS 2 BP 332 EP 343 DI 10.1111/j.1462-5822.2007.01044.x PG 12 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 249CZ UT WOS:000252205900007 PM 17850338 ER PT J AU Brett, PJ Burtnick, MN Su, H Nair, V Gherardini, FC AF Brett, Paul J. Burtnick, Mary N. Su, Hua Nair, Vinod Gherardini, Frank C. TI iNOS activity is critical for the clearance of Burkholderia mallei from infected RAW 264.7 murine macrophages SO CELLULAR MICROBIOLOGY LA English DT Article ID NITRIC-OXIDE-SYNTHASE; ACTIN-BASED MOTILITY; TOLL-LIKE-RECEPTORS; INTRACELLULAR SURVIVAL; LIPID-A; ANTIMICROBIAL ACTIVITY; VIRULENCE DETERMINANT; SIGNALING PATHWAYS; POSSIBLE MECHANISM; EUKARYOTIC CELLS AB Burkholderia mallei is a facultative intracellular pathogen that can cause fatal disease in animals and humans. To better understand the role of phagocytic cells in the control of infections caused by this organism, studies were initiated to examine the interactions of B. mallei with RAW 264.7 murine macrophages. Utilizing modified kanamycin-protection assays, B. mallei was shown to survive and replicate in RAW 264.7 cells infected at multiplicities of infection (moi) of <= 1. In contrast, the organism was efficiently cleared by the macrophages when infected at an moi of 10. Interestingly, studies demonstrated that the monolayers only produced high levels of TNF-alpha, IL-6, IL-10, GM-CSF, RANTES and IFN-beta when infected at an moi of 10. In addition, nitric oxide assays and inducible nitric oxide synthase (iNOS) immunoblot analyses revealed a strong correlation between iNOS activity and clearance of B. mallei from RAW 264.7 cells. Furthermore, treatment of activated macrophages with the iNOS inhibitor, aminoguanidine, inhibited clearance of B. mallei from infected monolayers. Based upon these results, it appears that moi significantly influence the outcome of interactions between B. mallei and murine macrophages and that iNOS activity is critical for the clearance of B. mallei from activated RAW 264.7 cells. C1 [Brett, Paul J.; Burtnick, Mary N.; Su, Hua; Gherardini, Frank C.] NIAID, Lab Zoonot Pathogens, RTB, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. [Nair, Vinod] NIAID, Res Technol Sect, RTB, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. RP Gherardini, FC (reprint author), NIAID, Lab Zoonot Pathogens, RTB, Rocky Mt Labs,NIH, Hamilton, MT 59840 USA. EM fgherardini@niaid.nih.gov FU Intramural NIH HHS NR 54 TC 31 Z9 32 U1 1 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-5814 EI 1462-5822 J9 CELL MICROBIOL JI Cell Microbiol. PD FEB PY 2008 VL 10 IS 2 BP 487 EP 498 DI 10.1111/j.1462-5822.2007.01063.x PG 12 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 249CZ UT WOS:000252205900020 PM 17970762 ER PT J AU Bang, J Yamaguchi, H Durell, SR Appella, E Appella, DH AF Bang, Jeong Yamaguchi, Hiroshi Durell, Stewart R. Appella, Ettore Appella, Daniel H. TI A small molecular scaffold for selective inhibition of Wip1 phosphatase SO CHEMMEDCHEM LA English DT Article DE enzyme inhibition; organic synthesis; pyrrole; small molecules; Wip1 ID UV-RADIATION; PPM1D; AMPLIFICATION; KINASE; TUMORIGENESIS; NITROALKENES; SUPPRESSION; DYNAMICS; PYRROLES; CHK2 C1 [Bang, Jeong; Yamaguchi, Hiroshi; Durell, Stewart R.; Appella, Ettore] NCI, Cell Biol Lab, Bethesda, MD 20892 USA. [Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA. RP Bang, J (reprint author), NCI, Cell Biol Lab, Bldg 37, Bethesda, MD 20892 USA. EM appellad@niddk.nih.gov FU Intramural NIH HHS [ZIA DK031123-06, ZIA DK031123-08, ZIA DK031123-07] NR 22 TC 9 Z9 11 U1 0 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1860-7179 J9 CHEMMEDCHEM JI ChemMedChem PD FEB PY 2008 VL 3 IS 2 BP 230 EP 232 DI 10.1002/cmdc.200700281 PG 3 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 274SY UT WOS:000254022600004 PM 18022979 ER PT J AU Harari, S Cassandro, R Chiodini, A Taveira-DaSilva, AM Moss, J AF Harari, Sergio Cassandro, Roberto Chiodini, Acopo Taveira-DaSilva, Angelo M. Moss, Joel TI Effect of a gonadotrophin-releasing hormone analogue on lung function in lymphangioleiomyomatosis SO CHEST LA English DT Article DE gonadotrophin-releasing hormone analogues; lung function; lymphangioleiomyomatosis; osteoporosis; triptorelin ID PULMONARY LYMPHANGIOLEIOMYOMATOSIS; PROGESTERONE; OOPHORECTOMY; LAM; ESTROGEN; DECLINE; UK AB Background: Lymphangioleiomyomatosis (LAM), a multisystem disease occurring primarily in women, is characterized by cystic lung destruction, and kidney:and lymphatic tumors, caused by the proliferation of abnormal-appearing cells (ie, LAM cells) with a smooth muscle cell phenotype that express melanoma antigens and are capable of metastasizing. Estrogen receptors are present in LAM cells, and this finding, along with reports of disease progression during pregnancy or following exogenous estrogen administration, suggest the involvement of estrogens in the pathogenesis of LAM. Consequently, antiestrogen therapies have been employed in treatment. The goal of this prospective study was to evaluate the efficacy of triptorelin, a gonadotrophin-releasing hormone analogue, in 11 premenopausal women with LAM. Methods: Patients were evaluated at baseline and every 3 to 6 months thereafter, for a total of 36 months. Hormonal assays, pulmonary function tests, 6-min walk tests, high-resolution CT scans of the chest, and bone mineral density studies were performed. Results: Gonadal suppression was achieved in all patients. Overall, a significant decline in lung function was observed; two patients underwent lung transplantation 1 year after study enrollment, and another patient was lost to follow-up. Treatment with triptorelin was associated with a decline in bone mineral density. Conclusions: Triptorelin appears not to prevent a decline in lung function in patients with LAM. Its use, however, may be associated with the loss of bone mineral density. C1 [Taveira-DaSilva, Angelo M.; Moss, Joel] NIH, NHLBI, Translat Med Branch, Bethesda, MD 20892 USA. [Harari, Sergio; Cassandro, Roberto] Osped San Giovanni AFAR, Unit Pneumol & Terapia Semi Intens Resp, Milan, Italy. [Chiodini, Acopo] Osped San Giovanni AFAR, Serv Fisiopathol Resp Emodinam Polmonare, Unidade Operat Endorcinol, Milan, Italy. RP Taveira-DaSilva, AM (reprint author), NIH, NHLBI, Translat Med Branch, Bldg 10, Bethesda, MD 20892 USA. EM dasilvan@nhlbi.nih.gov OI Harari, Sergio/0000-0001-8629-7391 FU Intramural NIH HHS [Z01 HL002541-12] NR 34 TC 35 Z9 37 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD FEB PY 2008 VL 133 IS 2 BP 448 EP 454 DI 10.1378/chest.07-2277 PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 262WJ UT WOS:000253178400020 PM 18071009 ER PT J AU Ngo, TD Laeyendecker, O La, H Hogrefe, W Morrow, RA Quinn, TC AF Ngo, Thoai D. Laeyendecker, Oliver La, Hanh Hogrefe, Wayne Morrow, Rhoda Ashley Quinn, Thomas C. TI Use of commercial enzyme immunoassays to detect antibodies to the herpes simplex virus type 2 glycoprotein G in a low-risk population in Hanoi, Vietnam SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID SIMPLEX-VIRUS TYPE-2; GENITAL HERPES; PERFORMANCE; HSV-2; ELISA; INFECTION; TESTS; ASSAY AB Sera from 1,238 Vietnamese women in Hanoi were tested for herpes simplex virus type 2 (HSV-2). HSV-2 prevalence was 2.0%. The Kalon and Biokit assays showed significantly higher concordance to Western blotting data than did the Focus assay (P < 0.01). Screening by Focus and then retesting with Kalon/Biokit of positive samples can reduce falsely positive results significantly (P < 0.01). C1 [Laeyendecker, Oliver; Quinn, Thomas C.] Johns Hopkins Univ, Sch Med, Dept Infect Dis, Dept Med, Baltimore, MD 21205 USA. [Ngo, Thoai D.; Laeyendecker, Oliver; Quinn, Thomas C.] NIAID, NIH, Bethesda, MD 20892 USA. [La, Hanh] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. [Hogrefe, Wayne] Focus Technol, Cypress, CA USA. [Morrow, Rhoda Ashley] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. RP Quinn, TC (reprint author), Johns Hopkins Univ, Sch Med, Dept Infect Dis, Dept Med, 1721 E Madison St,Ross Bldg,Room 1159, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu RI Laeyendecker, Oliver/B-9331-2009; OI Laeyendecker, Oliver/0000-0002-6429-4760 FU Intramural NIH HHS [Z99 AI999999]; NIAID NIH HHS [U01 AI068613, U01 AI068613-02] NR 13 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD FEB PY 2008 VL 15 IS 2 BP 382 EP 384 DI 10.1128/CVI.00437-06 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 340SZ UT WOS:000258666600029 PM 18077617 ER PT J AU Demark-Wahnefried, W Case, LD Blackwell, K Marcom, PK Kraus, W Aziz, N Snyder, DC Giguere, JK Shaw, E AF Demark-Wahnefried, Wendy Case, L. Douglas Blackwell, Kimberly Marcom, P. Kelly Kraus, William Aziz, Noreen Snyder, Denise Clutter Giguere, Jeffrey K. Shaw, Edward TI Results of a diet/exercise feasibility trial to prevent adverse body composition change in breast cancer patients on adjuvant chemotherapy SO CLINICAL BREAST CANCER LA English DT Article DE dual-energy X-ray absorptiometry; epirubicin; metabolic equivalent task; sarcopenia ID QUALITY-OF-LIFE; FOOD FREQUENCY QUESTIONNAIRES; RANDOMIZED CONTROLLED-TRIAL; RESTING ENERGY-EXPENDITURE; PHYSICAL-ACTIVITY; WEIGHT-GAIN; WOMEN; SURVIVORS; EXERCISE; VALIDATION AB Purpose: Patients with breast cancer on adjuvant chemotherapy can experience weight gain and concurrent losses in muscle mass. Exercise interventions can prevent these changes, but time and travel pose barriers to participation. The Survivor Training for Enhancing Total Health (STRENGTH) trial assessed the feasibility and impact of 2 home-based interventions. Patients and Methods: Ninety premenopausal patients with breast cancer on adjuvant chemotherapy were,randomized to a calcium-rich diet (CA) intervention (attention control) or to 2 experimental arms: a CA + exercise (EX) arm or a CA + EX and high fruit and vegetable, low-fat diet (FVLF) arm. Exercise arms included aerobic and strength-training exercises. Body composition, weight status, waist circumference, dietary intake, physical activity quality of life, anxiety, depression, serum lipids, sex-hormone binding globulin, insulin, proinsulin, C-reactive protein, interleukin-1B, and tumor-necrosis factor receptor-II were measured at baseline and at 6-month follow-up. Results: Accrual targets were achieved and modest attrition was observed (8.8%). Self-reports suggest increased calcium Intakes In all arms, and higher fruit and vegtable and lower fat intake in the CA + EX + FVLF arm; no differences in physical activity were observed. While measures of adiposity were generally lower in the CA + EX + FVLF arm, the only significant difference was in percentage of body fat (arms and legs); change in scores (mean standard deviation) were +0.7% +/- 2.3% (CA); +1.2% +/- 2.7% (CA + EX); and +0.1% +/- 2% (CA + EX + FVLF; P = .047). Lean body mass was largely preserved, even in the control arm (net gain of 452 g 2395 g). No differences were observed in other endpoints. Conclusion: Diet and exercise interventions can prevent weight gain and adverse body composition changes, but more research is needed to determine optimally effective interventions that can be implemented during active treatment and that promote adherence. C1 [Demark-Wahnefried, Wendy] Univ Texas Houston, MD Anderson Canc Ctr, Dept Behav Sci, Houston, TX 77030 USA. [Case, L. Douglas] Wake Forest Univ, Dept Biostat Sci, Winston Salem, NC 27109 USA. [Blackwell, Kimberly; Marcom, P. Kelly; Kraus, William] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. [Aziz, Noreen] NCI, Off Canc Survivorship, Bethesda, MD 20892 USA. [Snyder, Denise Clutter] Duke Univ, Med Ctr, Sch Nursing, Durham, NC USA. [Giguere, Jeffrey K.] Canc Ctr Carolinas, Greenville, SC USA. [Shaw, Edward] Wake Forest Univ, Dept Radiat Oncol, Winston Salem, NC 27109 USA. RP Demark-Wahnefried, W (reprint author), Univ Texas Houston, MD Anderson Canc Ctr, Dept Behav Sci, 1155 Pressler St,CPB3-3245, Houston, TX 77030 USA. EM wdemarkw@mdanderson.org OI Kraus, William E/0000-0003-1930-9684 FU NCI NIH HHS [1 U10 CA81851, R21 CA092468, R21-CA92468]; NCRR NIH HHS [M01-RR-30] NR 48 TC 63 Z9 64 U1 1 U2 23 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1526-8209 J9 CLIN BREAST CANCER JI Clin. Breast Cancer PD FEB PY 2008 VL 8 IS 1 BP 70 EP 79 DI 10.3816/CBC.2008.n.005 PG 10 WC Oncology SC Oncology GA 267IP UT WOS:000253503000007 PM 18501061 ER PT J AU Klimek, VM Fircanis, S Maslak, P Guernah, I Baum, M Wu, N Panageas, K Wright, JJ Pandolfi, PP Nimer, SD AF Klimek, Virginia M. Fircanis, Sophia Maslak, Peter Guernah, Ilhem Baum, Michael Wu, Nian Panageas, Katherine Wright, John J. Pandolfi, Pier Paolo Nimer, Stephen D. TI Tolerability, pharmacodynamics, and pharmacokinetics studies of depsipeptide (Romidepsin) in patients with acute myelogenous leukemia or advanced myelodysplastic syndromes SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE MYELOID-LEUKEMIA; HISTONE DEACETYLASE INHIBITOR; CHRONIC LYMPHOCYTIC-LEUKEMIA; DNA METHYLTRANSFERASE; FUSION PARTNER; FR901228; CELLS; APOPTOSIS; COMPLEX; TRANSCRIPTION AB Purpose: Epigenetic modulation of gene expression plays an important role in cancer, including leukemia. Furthermore, histone deacetylase inhibitors may induce the reexpression or repression of genes critical for normal hematopoiesis. The purpose of this study was to evaluate the toxicity, pharmacokinetic profile, and selected pharmacodynamic properties of the histone deacetylase inhibitor depsipeptide in patients with myelodysplastic syndromes (MDS) or acute myelogenous leukemia (AML). Experimental Design: Depsipeptide was administered to MDS or AML patients at a (solid tumor) phase I dose of 18 mg/m(2) i.v. on days 1 and 5 every 3 weeks. Toxicities and clinical activity were monitored and pharmacokinetic and pharmacodynamic studies were done. Results: Twelve patients (nine with AML, three with MDS) received one to five cycles of depsipeptide. The most common grade 3/4 toxicities were febrile neutropenia/infection (five patients), neutropenia/thrombocytopenia (nine patients), nausea (nine patients), and asymptomatic hypo-phosphatemia (three patients). No clinically significant cardiac toxicity was observed. The best response of 11 assessed patients was one complete remission in a patient with AML, stable disease in six patients, and progression of disease in four patients. Exploratory laboratory studies showed modest but rapid increases in apoptosis and changes in myeloid maturation marker expression. Histone H3 and H4 acetylation levels were evaluated in five patients; no consistent changes were observed. Conclusion: Depsipeptide therapy can be administered with acceptable short-term toxicity. However, gastrointestinal symptoms and fatigue seem to be treatment-limiting after multiple cycles. Depsipeptide monotherapy has limited clinical activity in unselected AML/MDS patients. C1 [Klimek, Virginia M.; Fircanis, Sophia; Baum, Michael; Nimer, Stephen D.] Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. [Panageas, Katherine] Mem Sloan Kettering Canc Ctr, Dept Biostat & Epidemiol, New York, NY 10021 USA. [Maslak, Peter] Mem Sloan Kettering Canc Ctr, Dept Clin Labs, New York, NY 10021 USA. [Guernah, Ilhem; Wu, Nian; Pandolfi, Pier Paolo; Nimer, Stephen D.] Sloan Kettering Inst, New York, NY USA. [Wright, John J.] NCI, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. RP Klimek, VM (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. EM klimekv@mskcc.org OI Maslak, Peter/0000-0003-1949-5819 FU NCI NIH HHS [P01 CA 05826] NR 21 TC 90 Z9 91 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 FEB 1 PY 2008 VL 14 IS 3 BP 826 EP 832 DI 10.1158/1078-0432.CCR-07-0318 PG 7 WC Oncology SC Oncology GA 258QK UT WOS:000252882400029 PM 18245545 ER PT J AU Robinson, MK Shaller, C Garmestani, K Plascjak, PS Hodge, KM Yuan, QA Marks, JD Waldmann, TA Brechbiel, MW Adams, GP AF Robinson, Matthew K. Shaller, Calvin Garmestani, Kayhan Plascjak, Paul S. Hodge, Kathryn M. Yuan, Qing-An Marks, James D. Waldmann, Thomas A. Brechbiel, Martin W. Adams, Gregory P. TI Effective treatment of established human breast tumor xenografts in immunodeficient mice with a single dose of the alpha-emitting radioisotope astatine-211 conjugated to anti-HER2/neu diabodies SO CLINICAL CANCER RESEARCH LA English DT Article ID IN-VIVO EVALUATION; CHAIN FV; ENGINEERED ANTIBODIES; OVARIAN-CANCER; NUDE-MICE; RADIOIMMUNOTHERAPY; THERAPY; AT-211; EXPRESSION; LINKERS AB Purpose: Successful radioimmunotherapy strategies depend on selecting radioisotopes with physical properties complementary to the biological properties of the targeting vehicle. Small, engineered antitumor antibody fragments are capable of rapid, highly specific tumor targeting in immunodeficient mouse models. We hypothesized that the C6.5 diabody, a noncovalent anti-HER2 single-chain Fv dimer, would be an ideal radioisotope carrier for the radioimmunotherapy of established tumors using the short-lived a-emitting radioisotope At-211. Experimental Design: Immunodeficient nude mice bearing established HER2/neu-positive MDA-MB-361/DYT2 tumors treated with N-succinimidyl N-(4-[At-211]astatophenethyl)succinamate (At-211-SAPS)-C6.5 diabody. Additional cohorts of mice were treated with At-211-SAPS T84.66 diabody targeting the carcinoembryonic antigen or At-211-SAPS on a diabody specific for the Mullerian inhibiting substance type II receptor, which is minimally expressed on this tumor cell line. Results: A single i.v. injection of At-211-SAPS C6.5 diabody led to a 30-day delay in tumor growth when a 20 mu Ci dose was administered and a 57-day delay in tumor growth (60% tumor-free after 1 year) when a 45 mu Ci dose was used. Treatment of mice bearing the same tumors with At-211-SAPS T84.66 diabody at the same doses led to a delay in tumor growth, but no complete responses, likely due to substantially lower expression of this antigen on the MDA-MB-361/DYT2 tumors. In contrast, a dose of 20 mu Ci of At-211-SAPS on the anti-Mullerian-inhibiting substance type II receptor diabody did not affect tumor growth rate, demonstrating specificity of the therapeutic effect. Conclusions: These findings indicate that diabody molecules can be effective agents for targeted radioimmunotherapy of solid tumors using powerful, short-lived alpha-emitting radioisotopes. C1 [Robinson, Matthew K.; Shaller, Calvin; Hodge, Kathryn M.; Yuan, Qing-An; Adams, Gregory P.] Fox Chase Canc Ctr, Dept Med Oncol, Philadelphia, PA 19111 USA. [Garmestani, Kayhan; Plascjak, Paul S.; Waldmann, Thomas A.; Brechbiel, Martin W.] NCI, NIH, Bethesda, MD 20892 USA. [Marks, James D.] Univ Calif San Francisco, Dept Anesthesiol & Pharmaceut Chem, San Francisco, CA 94143 USA. RP Adams, GP (reprint author), Fox Chase Canc Ctr, Dept Med Oncol, 333 Cottman Ave, Philadelphia, PA 19111 USA. EM gp.adams@fccc.edu FU Intramural NIH HHS [Z01 SC006353-24] NR 31 TC 24 Z9 27 U1 1 U2 7 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 FEB 1 PY 2008 VL 14 IS 3 BP 875 EP 882 DI 10.1158/1078-0432.CCR-07-1250 PG 8 WC Oncology SC Oncology GA 258QK UT WOS:000252882400035 PM 18245551 ER PT J AU Kil, WJ Cerna, D Burgan, WE Beam, K Carter, D Steeg, PS Tofilon, PJ Camphausen, K AF Kil, Whoon Jong Cerna, David Burgan, William E. Beam, Katie Carter, Donna Steeg, Patricia S. Tofilon, Philip J. Camphausen, Kevin TI In vitro and in vivo radiosensitization induced by the DNA methylating agent temozolomide SO CLINICAL CANCER RESEARCH LA English DT Article ID STRAND BREAK REPAIR; MALIGNANT GLIOMA; HISTONE H2AX; CELL CYCLE; GLIOBLASTOMA; ALKYLTRANSFERASE; IRRADIATION; EXPRESSION AB Purpose: Temozolomide, a DNA methylating agent, is currently undergoing clinical evaluation for cancer therapy. Because temozolomide has been shown to increase survival rates of patients with malignant gliomas when given combined with radiation, and there is conflicting preclinical data concerning the radiosensitizing effects of temozolomide, we further investigated the possible temozolomide-induced enhancement of radiosensitivity. Experimental Design: The effects of temozolomide on the in vitro radiosensitivity of U251 (a human glioma) and MDA-MB231BR (a brain-seeking variant of a human breast tumor) cell lines was evaluated using clonogenic assay. DNA damage and repair were evaluated using phosphorylated histone H2AX (gamma H2AX), and mitotic catastrophe was measured using nuclear fragmentation. Growth delay was used to evaluate the effects of temozolomide on in vivo (U251) tumor radiosensitivity. Results: Exposure of each cell line to temozolomide for 1 h before irradiation resulted in an increase in radiosensitivity with dose enhancement factors at a surviving fraction of 0.1 ranging from 1.30 to 1.32. Temozolomide had no effect on radiation-induced apoptosis or on the activation of the G(2) cell cycle checkpoint. As a measure of DNA double strand breaks, gamma H2AX foci were determined as a function of time after the temozolomide + irradiation combination. The number of gamma H2AX foci per cell was significantly greater at 24 h after the combined modality compared with the individual treatments. Mitotic catastrophe, measured at 72 h, was also significantly increased in cells receiving the temozolomide + irradiation combination compared with the single treatments. In vivo studies revealed that temozolomide administration to mice bearing U251 tumor xenografts resulted in a greater than additive increase in radiation-induced tumor growth delay with a dose enhancement factor of 2.8. Conclusions: These results indicate that temozolomide can enhance tumor cell radiosensitivity in vitro and in vivo and suggest that this effect involves an inhibition of DNA repair leading to an increase in mitotic catastrophe. C1 [Kil, Whoon Jong; Camphausen, Kevin] NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Cerna, David; Burgan, William E.; Beam, Katie; Carter, Donna] NCI, Mol Radiat Therapeut Branch, Bethesda, MD 20892 USA. [Steeg, Patricia S.] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. [Burgan, William E.; Beam, Katie; Carter, Donna] Sci Applicat Int Corp Frederick, Natl Canc Inst Frederick, Frederick, MD USA. [Tofilon, Philip J.] Univ S Florida, H Lee Moffitt Canc Ctr, Drug Discovery Program, Tampa, FL 33682 USA. RP Camphausen, K (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr 3B42, Bethesda, MD 20892 USA. EM camphauk@mail.nih.gov FU Intramural NIH HHS NR 23 TC 64 Z9 66 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2008 VL 14 IS 3 BP 931 EP 938 DI 10.1158/1078-0432.CCR-07-1856 PG 8 WC Oncology SC Oncology GA 258QK UT WOS:000252882400041 PM 18245557 ER PT J AU Strasak, A Ruttmann, E Brant, L Kelleher, C Klenk, J Concin, H Diem, G Pfeiffer, K Ulmer, H AF Strasak, Alexander Ruttmann, Elfriede Brant, Larry Kelleher, Cecily Klenk, Jochen Concin, Hans Diem, Guenter Pfeiffer, Karl Ulmer, Hanno CA VHM TI Serum uric acid and risk of cardiovascular mortality: A prospective long-term study of 83 683 Austrian men SO CLINICAL CHEMISTRY LA English DT Article ID CORONARY-HEART-DISEASE; ALL-CAUSE MORTALITY; MYOCARDIAL-INFARCTION; FOLLOW-UP; BLOOD-PRESSURE; STROKE; COHORT; WOMEN; HYPERURICEMIA; HYPERTENSION AB BACKGROUND: The role of serum uric acid (SUA) as an independent risk factor for cardiovascular disease (CVD) remains controversial, and little is known about its prognostic importance for mortality from congestive heart failure (CHF) and stroke. Few large-scale epidemiologic studies with sufficient follow-up have addressed the association of SUA and CVD mortality in apparently healthy men across a wide age range. METHODS: A cohort of 83 683 Austrian men (mean age, 41.6 years) was prospectively followed for a median of 13.6 years. We used Cox proportional hazards models adjusted for established risk factors to evaluate SUA as an independent predictor for CVD mortality. RESULTS: The highest quintile of SUA concentration (>398.81 mu mol/L) was significantly related to mortality from CHF (P = 0.03) and stroke (P <0.0001); adjusted hazard ratios (95% confidence interval) for the highest vs lowest quintiles of SUA were 1.51 (1.03-2.22) and 1.59 (1.23-2.04), respectively. SUA was not associated, however, with mortality from acute, subacute, or chronic forms of coronary heart disease (CHD) after adjustment for potential confounding factors (P = 0.12). Age was a significant effect modifier for the relation of SUA to fatal CHF (P = 0.05), with markedly stronger associations found in younger individuals. CONCLUSIONS: Our study demonstrates for the first time in a large prospective male cohort that SUA is independently related to mortality from CHF and stroke. Although increased SUA is not necessarily a causal risk factor, our results suggest the clinical importance of monitoring and intervention based on the presence of an increased SUA concentration, especially because SUA is routinely measured. (C) 2007 American Association for Clinical Chemistry. C1 [Strasak, Alexander; Pfeiffer, Karl; Ulmer, Hanno] Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, A-6020 Innsbruck, Austria. [Ruttmann, Elfriede] Innsbruck Med Univ, Dept Cardiac Surg, A-6020 Innsbruck, Austria. [Brant, Larry] NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. [Kelleher, Cecily] Univ Coll Dublin, Sch Publ Hlth & Polpulat Sci, Dublin 2, Ireland. [Klenk, Jochen] Univ Ulm, Dept Epidemiol, Ulm, Germany. [Concin, Hans; Diem, Guenter; Ulmer, Hanno] Agcy Prevent & Social Med, Bregenz, Austria. RP Strasak, A (reprint author), Innsbruck Med Univ, Dept Med Stat Informat & Hlth Econ, Schoepfstr 41, A-6020 Innsbruck, Austria. EM alexander.strasak@i-med.ac.at RI Ruttmann, Elfriede/D-6501-2011; vhmpp, aks/F-9756-2012; Klenk, Jochen/C-2164-2012; Ulmer, Hanno/C-3488-2011; OI Ulmer, Hanno/0000-0001-5911-1002; Klenk, Jochen/0000-0002-5987-447X NR 39 TC 107 Z9 121 U1 0 U2 3 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD FEB PY 2008 VL 54 IS 2 BP 273 EP 284 DI 10.1373/clinchem.2007.094425 PG 12 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 257ZI UT WOS:000252837800008 PM 18039719 ER PT J AU Kolbrich, EA Lowe, RH Huestis, MA AF Kolbrich, Erin A. Lowe, Ross H. Huestis, Marilyn A. TI Two-dimensional gas chromatography/electron-impact mass spectrometry with cryofocusing for simultaneous quantification of MDMA, MDA, HMMA, HMA, and MDEA in human plasma SO CLINICAL CHEMISTRY LA English DT Article ID ORAL FLUID; 11-NOR-DELTA(9)-TETRAHYDROCANNABINOL-9-CARBOXYLIC ACID; 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; DESIGNER DRUGS; ECSTASY; METABOLITES; BLOOD; USERS; THC AB BACKGROUND: 3,4-Methylenedioxymethamphetamine (MDMA, or Ecstasy) is a popular recreational drug. Analysis of MDMA and metabolites in human plasma, particularly in pharmacokinetic studies, requires low limits of quantification. Two-dimensional GC/MS with cryofocusing is a chromatographic technique recognized for its increased selectivity and resolution. METHODS: This method simultaneously quantifies 3,4-methylenedioxyethylamphetamine (MDEA), MDMA, and its metabolites, 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 4-hydroxy-3-methoxyamphetamine (HMA) in human plasma. With hydrochloric acid, we hydrolyzed 1 mL plasma, fortified with internal standard. Analytes were subjected to solid-phase extraction, derivatized with heptafluorobutyric acid anhydride, and quantified using cryofocused 2-dimensional GC/MS operated in electron-impact selected ion-monitoring mode. RESULTS: Limits of quantification were 1.0/mu g/L for MDA and 2.5 mu g/L for MDEA, MDMA, HMMA, and HMA. Calibration curves were linear to 100/mu g/L for MDA and HMA and to 400 mu g/L for MDEA, MDMA, and HMMA, with r(2) > 0.997. At 3 concentrations spanning the linear dynamic range of the assay, mean overall extraction efficiencies from plasma were >= 85% for all compounds of interest. Recoveries were 85.6% to 107.2% of target, and intra- and interassay imprecision (CV) was <8.5% for all drugs at 3 concentrations within the range of the assay. None of the 66 exogenous compounds tested interfered with analyte quantification. CONCLUSIONS: This GC/MS assay provides low limits of quantification for simultaneous determination of MDEA, MDMA, and metabolites MDA, HMMA, and HMA in human plasma. The 2D chromatographic system should be suitable for application to other analytes and to other complex matrices. (C) 2007 American Association for Clinical Chemistry. C1 [Kolbrich, Erin A.; Lowe, Ross H.; Huestis, Marilyn A.] Natl Inst Drug Abuse, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS NR 29 TC 18 Z9 18 U1 1 U2 6 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD FEB PY 2008 VL 54 IS 2 BP 379 EP 387 DI 10.1373/clinchem.2007.096800 PG 9 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 257ZI UT WOS:000252837800021 PM 18089653 ER PT J AU Lindsay, KL Morishima, C Wright, EC Dienstag, JL Shiffman, ML Everson, GT Lok, ASF Bonkovsky, HLR Lee, WM Morgan, TR Ghany, MG AF Lindsay, Karen L. Morishima, Chihiro Wright, Elizabeth C. Dienstag, Jules L. Shiffman, Mitchell L. Everson, Gregory T. Lok, Anna S. F. Bonkovsky, Herbert L. R. Lee, William M. Morgan, Timothy R. Ghany, Marc G. TI Blunted cytopenias and weight loss: New correlates of virologic null response to re-treatment of chronic hepatitis C SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article ID PEGINTERFERON ALPHA-2A; PEGYLATED INTERFERON; PLUS RIBAVIRIN; HCV-RNA; COMBINATION THERAPY; TREATMENT DURATION; ANTIVIRAL THERAPY; AMERICAN PATIENTS; AFRICAN-AMERICAN; VIRAL DYNAMICS AB Background & Aims: Peginterferon with ribavirin therapy for chronic hepatitis C leads to sustained loss of serum hepatitis C virus (HCV) RNA in half of treated patients. Although viral kinetic profiles in treatment responders shed light on the mechanism of action of interferon and ribavirin, minimal information is available to explain why some patients experience little or no virologic suppression. Methods: We evaluated factors that might be associated with the lack of a week-20 virologic response in previous nonresponder patients undergoing peginterferon and ribavirin retreatment. Among 1145 patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis Trial's lead-in treatment phase, 588 who received more than 80% of prescribed therapy for 20 weeks were analyzed. Results: By week 20, 245 patients (41.7%) had undetectable HCV RNA (full response), 186 (31.6%) had a 1 log(10) or greater decrease in HCV RNA (partial response), and 157 (26.7%) had less than a 1 log(10) decrease (null response) in HCV RNA. Null response was associated independently with African American race, genotype-1 infection, and less reduction in body weight, platelets, and white blood cells during treatment. Conclusions: On-treatment variables associated with null response suggest a blunted systemic response to interferon. These observations have important implications for the design and analysis of trial results in which novel agents are evaluated. Further studies are needed to discern whether host interferon resistance, viral drug resistance, or both are playing a role in patients who have no virologic response to interferon treatment. C1 [Lindsay, Karen L.] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA 90033 USA. [Morishima, Chihiro] Univ Washington, Dept Lab Med, Div Virol, Seattle, WA 98195 USA. [Wright, Elizabeth C.] New England Res Inst, Watertown, MA 02172 USA. [Dienstag, Jules L.] Massachusetts Gen Hosp, Gastrointestinal Unit, Med Serv, Boston, MA 02114 USA. [Dienstag, Jules L.] Harvard Univ, Sch Med, Dept Med, Boston, MA USA. [Shiffman, Mitchell L.] Virginia Commonwealth Univ Hlth Syst, Div Gastroenterol, Richmond, VA USA. [Everson, Gregory T.] Univ Colorado, Sch Med, Div Gastroenterol & Hepatol, Sect Hepatol, Denver, CO USA. [Lok, Anna S. F.] Univ Michigan, Med Ctr, Div Gastroenterol, Ann Arbor, MI USA. [Bonkovsky, Herbert L. R.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Bonkovsky, Herbert L. R.] Univ Connecticut, Ctr Hlth, Dept Biol Mol & Struct, Farmington, CT USA. [Bonkovsky, Herbert L. R.] Univ Connecticut, Ctr Hlth, Liver Biliary Pancreat Ctr, Farmington, CT USA. [Lee, William M.] Univ Texas SW Med Ctr Dallas, Div Digest & Liver Dis, Dallas, TX 75390 USA. [Morgan, Timothy R.] Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. [Morgan, Timothy R.] VA Long Beach Healthcare Syst, Gastroenterol Serv, Long Beach, CA USA. [Ghany, Marc G.] NIDDK, Liver Dis Branch, Div Digest Dis & Nutr, NIH,Dept Hlth & Human Serv, Bethesda, MD USA. RP Lindsay, KL (reprint author), Univ So Calif, Div GI Liver Dis, Dept Med, 1640 Marengo St,Suite 103, Los Angeles, CA 90033 USA. EM klindsay@usc.edu RI Lok, Anna /B-8292-2009; OI Yang, Shuman/0000-0002-9638-0890 FU NCRR NIH HHS [M01RR-00042, M01RR-00043, M01RR-00051, M01RR-00065, M01RR-00633, M01RR-00827, M01RR-01066, M01RR-06192]; NIDDK NIH HHS [N01-DK-9-2322, N01 DK092323, N01-DK-9-2318, N01-DK-9-2319, N01-DK-9-2320, N01-DK-9-2321, N01-DK-9-2323, N01-DK-9-2324, N01-DK-9-2325, N01-DK-9-2326, N01-DK-9-2327, N01-DK-9-2328] NR 37 TC 18 Z9 18 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD FEB PY 2008 VL 6 IS 2 BP 234 EP 241 DI 10.1016/j.cgh.2007.11.020 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 261YF UT WOS:000253115200018 PM 18237873 ER PT J AU Fragouli, E Eliopoulos, E Petraki, E Sidiropoulos, P Aksentijevich, I Galanakis, E Kritikos, H Repa, A Fragiadakis, G Boumpas, DT Goulielmos, GN AF Fragouli, E. Eliopoulos, E. Petraki, E. Sidiropoulos, P. Aksentijevich, I. Galanakis, E. Kritikos, H. Repa, A. Fragiadakis, G. Boumpas, D. T. Goulielmos, G. N. TI Familial Mediterranean Fever in Crete: a genetic and structural biological approach in a population of 'intermediate risk' SO CLINICAL GENETICS LA English DT Article DE familial Mediterranean fever (FMF); MEFV; mutational analysis; phylogenetic tree; pyrin; three-dimensional model (3D model) ID JEWISH ETHNIC-GROUPS; MEFV MUTATIONS; PRYSPRY-DOMAIN; GREEK PATIENTS; FMF MUTATIONS; PYRIN DOMAIN; DISEASE; PROTEIN; TUBERCULOSIS; INFLAMMATION AB Familial Mediterranean Fever (FMF) is an autosomal, recessively inherited disease, characterized by recurrent and short attacks of fever with serosal inflammation that are caused by mutations in MEFV gene that encodes pyrin protein. To date, more than 70 disease-associated mutations have been identified, almost all of them representing missense nucleotide changes. FMF is very common among patients with Mediterranean ancestry, although the exact prevalence is not yet known, Greeks are considered to be at 'intermediate risk'. In the present study, we studied FMF patients in natives of Crete, a population sharing a common genetic and cultural background. The spectrum of MEFV gene mutations in 71 patients as well as 158 healthy controls was studied by performing a molecular analysis focused on the 12 most frequent FMF-associated mutations. We found that 59 of 71 (83.1%) FMF patients had at least one MEFV mutation, five patients were homozygotes and 54 heterozygotes for FMF-associated mutations. No mutations were detected in 12 patients (16.9%). As in high-risk populations, common MEFV mutations were found in Cretan FMF patients, with the M694V being the most penetrant. M694V and M694I mutations were associated with severe phenotypes, with many patients presenting with uncommon clinical manifestations such as erysipelas-like erythema or renal disturbances. Of interest, 20 (37%) of our heterozygous FMF patients presented with a severe phenotype. Population genetics analysis showed an FMF carrier frequency in healthy Cretan population of approximately 6% (1:17) and places Cretans closer to the Western rather than Eastern populations of the Mediterranean basin. Finally, we constructed a three-dimensional model showing the interaction of the PRYSPRY domain of pyrin with caspase-1 onto which we mapped MEFV mutations, classified according to disease severity. In this model, the 'flexible loops' of caspase-1 appear to have no access to some positions that have been previously associated with mild disease, suggesting that alternative pathogenic pathways leading to FMF need to be explored. C1 [Fragouli, E.; Petraki, E.; Boumpas, D. T.; Goulielmos, G. N.] Univ Crete, Sch Med, Dept Internal Med, Iraklion 71409, Crete, Greece. [Eliopoulos, E.] Agr Univ Athens, Dept Agr Biotechnol, Athens, Greece. [Sidiropoulos, P.; Kritikos, H.; Repa, A.; Boumpas, D. T.] Univ Hosp Heraklion, Dept Rheumatol Clin Immunol & Allergy, Iraklion, Crete, Greece. [Aksentijevich, I.] NIAMSD, Arthrit & Rheumatol Branch, Genet Sect, Bethesda, MD 20892 USA. [Galanakis, E.] Univ Hosp Heraklion, Dept Pediat, Iraklion, Crete, Greece. [Fragiadakis, G.] Asklepieion Hosp Heraklion, Dept Gastroenterol, Iraklion, Crete, Greece. RP Goulielmos, GN (reprint author), Univ Crete, Sch Med, Dept Internal Med, Iraklion 71409, Crete, Greece. EM goulielmos@med.uoc.gr NR 54 TC 13 Z9 14 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD FEB PY 2008 VL 73 IS 2 BP 152 EP 159 DI 10.1111/j.1399-0004.2007.00948.x PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 250SE UT WOS:000252319900007 PM 18177465 ER PT J AU Walsh, TJ Anaissie, EJ Denning, DW Herbrecht, R Kontoyiannis, DP Marr, KA Morrison, VA Segal, BH Steinbach, WJ Stevens, DA van Burik, JA Wingard, JR Patterson, TF AF Walsh, Thomas J. Anaissie, Elias J. Denning, David W. Herbrecht, Raoul Kontoyiannis, Dimitrios P. Marr, Kieren A. Morrison, Vicki A. Segal, Brahm H. Steinbach, William J. Stevens, David A. van Burik, Jo-Anne Wingard, John R. Patterson, Thomas F. TI Treatment of aspergillosis: Clinical practice guidelines of the infectious diseases society of America SO CLINICAL INFECTIOUS DISEASES LA English DT Review ID LIPOSOMAL-AMPHOTERICIN-B; INVASIVE PULMONARY ASPERGILLOSIS; ALLERGIC BRONCHOPULMONARY ASPERGILLOSIS; CELL TRANSPLANT RECIPIENTS; CENTRAL-NERVOUS-SYSTEM; CHRONIC GRANULOMATOUS-DISEASE; BONE-MARROW-TRANSPLANTATION; LINKED-IMMUNOSORBENT-ASSAY; POLYMERASE-CHAIN-REACTION; PRIMARY CUTANEOUS ASPERGILLOSIS C1 [Patterson, Thomas F.] Univ Texas Hlth Sci Ctr San Antonio, Dept Med Infect Dis, San Antonio, TX 78229 USA. [Walsh, Thomas J.] NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. [Anaissie, Elias J.] Univ Arkansas Med Sci, Little Rock, AR 72205 USA. [Kontoyiannis, Dimitrios P.] Univ Texas MD Anderson Canc Ctr, Houston, TX USA. [Marr, Kieren A.] Oregon Hlth & Sci Univ, Portland, OR 97201 USA. [Morrison, Vicki A.] Vet Affairs Med Ctr, Minneapolis, MN USA. [van Burik, Jo-Anne] Univ Minnesota, Minneapolis, MN USA. [Segal, Brahm H.] Roswell Pk Canc Inst, Buffalo, NY 14263 USA. [Steinbach, William J.] Duke Univ, Med Ctr, Durham, NC USA. [Stevens, David A.] Santa Clara Valley Med Ctr, San Jose, CA 95128 USA. [Stevens, David A.] Stanford Univ, Palo Alto, CA 94304 USA. [Wingard, John R.] Univ Florida, Coll Med, Gainesville, FL USA. [Denning, David W.] Univ Manchester, Manchester, Lancs, England. [Herbrecht, Raoul] Univ Hosp Strasbourg, Strasbourg, France. RP Patterson, TF (reprint author), Univ Texas Hlth Sci Ctr San Antonio, Dept Med Infect Dis, 7703 Floyd Curl Dr,MSC 7881, San Antonio, TX 78229 USA. EM patterson@uthscsa.edu RI Herbrecht, Raoul/D-3471-2013; Young, Jo-Anne/G-2617-2013; OI Young, Jo-Anne/0000-0003-4182-341X; Herbrecht, Raoul/0000-0002-9381-4876; Denning, David/0000-0001-5626-2251 NR 316 TC 1316 Z9 1486 U1 5 U2 49 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 1 PY 2008 VL 46 IS 3 BP 327 EP 360 DI 10.1086/525258 PG 34 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 249IJ UT WOS:000252221200001 PM 18177225 ER PT J AU Klein, M Dwyer, J AF Klein, Marguerite Dwyer, Johanna TI Role of probiotics stakeholders in future research and policy on probiotics use in the United States SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material C1 [Dwyer, Johanna] NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. [Klein, Marguerite] Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Dwyer, J (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,Msc 7517, Bethesda, MD 20892 USA. EM DwyerJ1@od.nih.gov OI Dwyer, Johanna/0000-0002-0783-1769 NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1058-4838 EI 1537-6591 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 1 PY 2008 VL 46 SU 2 BP S144 EP S151 DI 10.1086/523322 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 249YV UT WOS:000252268100022 ER PT J AU Herning, RI Better, W Cadet, JL AF Herning, Ronald I. Better, Warren Cadet, Jean L. TI EEG of chronic marijuana users during abstinence: Relationship to years of marijuana use, cerebral blood flow and thyroid function SO CLINICAL NEUROPHYSIOLOGY LA English DT Article DE marijuana; cardiovascular function; cerebral blood flow velocity; resting EEG; thyroid function; prolonged marijuana abuse; psychological tests; ASPD ID ANTISOCIAL PERSONALITY-DISORDER; LOW-VOLTAGE-ALPHA; CANNABIS USE; STROKE; SMOKERS; REPLICATION; ADOLESCENTS; DYSFUNCTION; ASSOCIATION; PARAMETERS AB Objective: Marijuana abuse is associated with neurological changes including increases in frontal EEG alpha during abstinence. Research is needed to assess to what extent these EEG patterns are indicative of cerebral perfusion deficits. Methods: We recorded the resting eyes closed EEG of 75 abstinent marijuana users and 33 control subjects. Fifty-six marijuana users used marijuana for less than eight years and 19 used for eight years or more. The EEG evaluation occurred within 72 h of admission to an inpatient unit. Fifty-nine marijuana users remained abstinent for a month and were tested twice. Supplemental psychological and physiological data were also collected. Results: Log alpha2 and beta2 power at posterior sites were significantly lower for the marijuana abusers that used eight years or more than the other marijuana abusers and the control subjects. These EEG changes continued for the month of abstinence. The marijuana users who used marijuana for more than eight years, also, had lower heart rates and thyroid function (T4) compared to the other marijuana users and the control subjects. Conclusions: Chronic marijuana use was also associated with reduced EEG power in alpha and beta bands at posterior sites. These reductions in EEG power appear to be related to cerebral perfusion deficits and/or thyroid function in marijuana abusers. Significance: Our results suggest EEG, cerebral blood flow velocity, cardiovascular and thyroid function alterations in marijuana abuser with an extended period of use. These alterations reflect under arousal in these systems. Published by Elsevier Ireland Ltd on behalf of International Federation of Clinical Neurophysiology. C1 [Herning, Ronald I.; Better, Warren; Cadet, Jean L.] Natl Inst Drug Abuse, Mol Neuropsychiat Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Herning, RI (reprint author), Natl Inst Drug Abuse, Mol Neuropsychiat Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rherninig@intra.nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 60 TC 8 Z9 8 U1 4 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 1388-2457 J9 CLIN NEUROPHYSIOL JI Clin. Neurophysiol. PD FEB PY 2008 VL 119 IS 2 BP 321 EP 331 DI 10.1016/j.clinph.2007.09.140 PG 11 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 260SB UT WOS:000253029600010 PM 18065267 ER PT J AU Sheehan, FT Seisler, AR Alter, KE AF Sheehan, Frances T. Seisler, Andrea R. Alter, Katharine E. TI Three-dimensional in vivo quantification of knee kinematics in cerebral palsy SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID PATELLA ALTA; AMBULATORY CHILDREN; GAIT ABNORMALITIES; DISTAL POLE; SURGERY; AVULSION; MUSCLE; JOINT AB Cerebral palsy is the most common disabling condition in childhood, involving a diverse group of movement and posture disorders of varying etiologies. Yet, much is unknown about how cerebral palsy affects individual joints because currently applied techniques cannot quantify the three-dimensional kinematic parameters at the joint level. We quantified the effects of cerebral palsy at the knee using fast phase contrast MRI, with the ultimate intent of improving the assessment of joint impairments associated with cerebral palsy, improving clinical outcomes, and reducing the impact of cerebral palsy on function. We addressed three questions: (1) Can patients with cerebral palsy perform the required repetitive extension task? (2) Which of the 12 degrees of freedom defining complete knee kinematics are abnormal in individual patients with cerebral palsy and is the patellar tendon moment arm abnormal in these patients? (3) Are the individual kinematic differences consistent with clinical observations? All patients were able to perform the required task. We found kinematic differences for each patient with cerebral palsy consistent with clinical findings, in comparison to an able-bodied population. Fast phase contrast MRI may allow differentiation of patellofemoral and tibiofemoral function in various functional subtypes of cerebral palsy, providing insights into its management. C1 [Sheehan, Frances T.; Seisler, Andrea R.; Alter, Katharine E.] NICHHD, Phys Disabil Branch, NIH, Bethesda, MD 20892 USA. [Sheehan, Frances T.; Seisler, Andrea R.; Alter, Katharine E.] NIH, Ctr Clin, Bethesda, MD 20892 USA. [Alter, Katharine E.] Johns Hopkins Hlth Syst Corp, Mt Washington Pediat Hosp, Baltimore, MD USA. [Alter, Katharine E.] Maryland Med Syst Corp, Baltimore, MD USA. RP Sheehan, FT (reprint author), NICHHD, Phys Disabil Branch, NIH, 10 CRC RM 1-1469,10 Ctr Dr MSC 1604, Bethesda, MD 20892 USA. EM sheehan@cc.nih.gov RI sheehan, frances/B-6962-2009 NR 34 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD FEB PY 2008 VL 466 IS 2 BP 450 EP 458 DI 10.1007/s11999-007-0004-7 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 262QW UT WOS:000253164100029 PM 18196431 ER PT J AU Fletcher, CV Brundage, RC Fenton, T Alvero, CG Powell, C Mofenson, LM Spector, SA AF Fletcher, C. V. Brundage, R. C. Fenton, T. Alvero, C. G. Powell, C. Mofenson, L. M. Spector, S. A. TI Pharmacokinetics and pharmacodynamics of efavirenz and nelfinavir in HIV-infected children participating in an area-under-the-curve controlled trial SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; TREATMENT FAILURE AB Fifty human immunodeficiency virus (HIV)-infected children participated in an area-under-the plasma concentration-time curve (AUC)-controlled trial of efavirenz and nelfinavir. Pharmacokinetic evaluations were performed at weeks 2, 6, and 56. Efavirenz and nelfinavir doses were adjusted to achieve AUC values of 60-120 and >= 10 mg h/l, respectively. Thirty-seven (74%) children met the efavirenz target and 41 (82%) the nelfinavir by week 10. Children with AUC values for both drugs above the first quartile were more likely to reach <400 copies/ml of HIV RNA at week 8. Efavirenz and nelfinavir oral clearance increased 37 and 62% from weeks 2 to 56, respectively, in 34 children who continued on therapy at week 56. AUC values at week 56 were not different between children who did or did not have HIV RNA <400 copies/ml. Dose adjustment to achieve specific AUC values in these children reduced the risk of suboptimal exposure and achieved high rates of virologic suppression. C1 [Fletcher, C. V.] Univ Colorado, Hlth Sci Ctr, Dept Pharmaceut Sci, Div Infect Dis, Denver, CO 80202 USA. [Brundage, R. C.] Univ Minnesota, Dept Expt & Clin Pharmacol, Minneapolis, MN USA. [Fenton, T.; Alvero, C. G.; Powell, C.] Harvard Univ, Harvard Sch Publ Hlth, Boston, MA USA. [Mofenson, L. M.] Natl Inst Child Hlth & Human Dev, Rockville, MD USA. [Spector, S. A.] Univ Calif San Diego, Dept Pediat, San Diego, CA 92103 USA. RP Fletcher, CV (reprint author), Univ Colorado, Hlth Sci Ctr, Dept Pharmaceut Sci, Div Infect Dis, Denver, CO 80202 USA. EM courtney.fletcher@uchsc.edu OI Mofenson, Lynne/0000-0002-2818-9808 FU NIAID NIH HHS [U01 AI068632-03, U01 AI069536, U01 AI069536-03] NR 15 TC 18 Z9 18 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2008 VL 83 IS 2 BP 300 EP 306 DI 10.1038/sj.clpt.6100282 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 254KH UT WOS:000252585000024 PM 17609682 ER PT J AU Altar, CA AF Altar, C. A. TI The biomarkers consortium: On the critical path of drug discovery SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article ID ALZHEIMERS-DISEASE; ADIPONECTIN AB Recent advances in science have provided a variety of genetic, genomic, and protein-based methods to treat human diseases.(1,2) These advances, and equally great strides in in vivo imaging(3-7) and methods of tissue collection, have created an unprecedented opportunity to discover and develop biological markers of human disease. A biomarker is defined(8,9) as a molecular, biological, or physical characteristic that indicates a specific physiologic state (see Table 1 for definitions). It is used in clinical practice to identify risk for disease, diagnose disease and its severity, guide intervention strategies, and monitor patient responses to therapy. When used in a clinical research setting, biomarkers may predict whether a drug or other intervention is safe and effective(10) in a shorter time and at lower cost than clinical outcomes studies. For these and other reasons, including the ability to stratify patient groups based on objective criteria, biomarkers help promote regulatory approval of new therapeutic entities by pharmaceutical, biological, and device development teams. C1 Biomarkers Consortium, Fdn Natl Inst Hlth, Bethesda, MD 20892 USA. RP Altar, CA (reprint author), Biomarkers Consortium, Fdn Natl Inst Hlth, Rockville Pike 9650, Bethesda, MD 20892 USA. EM taltar@fnih.org NR 20 TC 39 Z9 40 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2008 VL 83 IS 2 BP 361 EP 364 DI 10.1038/sj.clpt.6100471 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 254KH UT WOS:000252585000034 PM 18183037 ER PT J AU Watts, DH Park, JG Cohn, SE Yu, S Hitti, J Stek, A Clax, PA Mudersnach, L Lertora, JJL AF Watts, D. Heather Park, Jeong-Gun Cohn, Susan E. Yu, Song Hitti, Jane Stek, Alice Clax, Pamela A. Mudersnach, Laila Lertora, Juan J. L. TI Safety and tolerability of depot medroxyprogesterone acetate among HIV-infected women on antiretroviral therapy: ACTG A5093 SO CONTRACEPTION LA English DT Article DE HIV; women; depotmedroxyprogesterone; antiretrovirals; contraception ID INJECTABLE CONTRACEPTIVE USERS; BONE-DENSITY; PLASMA; AIDS; PREGNANCY; INCREASE AB Background: Concomitant use of antiretroviral (ARV) and hormonal contraceptives may change the metabolism of each and the resulting safety profiles. We evaluated the safety and tolerability of depot medroxyprogesterone acetate (DMPA) among women on ARV. Study Design: HIV-infected women on selected ARV regimens or no ARV were administered DMPA 150 mg intramuscularly and evaluated for 12 weeks for adverse events, changes in CD4+ count and HIV RNA levels, and ovulation. Results: Seventy evaluable subjects were included, 16 on nucleoside only or no ARV, 21 on nelfinavir-containing regimens, 17 on efavirenz-containing regimens and 16 on nevirapine-containing regimens. Nine Grade 3 or 4 adverse events occurred in seven subjects; none were judged related to DMPA. The most common findings possibly related to DMPA were abnormal vaginal bleeding (nine, 12.7%), headache (three, 4.2%), abdominal pain, mood changes, insomnia, anorexia and fatigue, each occurring in two (2.9%) subjects. No significant changes in CD4+ count or HIV RNA levels occurred with DMPA. No evidence of ovulation was detected, and no pregnancies occurred. Conclusions: The clinical profile associated with DMPA administration in HIV-infected women, most on ARV, appears similar to that seen in HIV-uninfected women. DMPA prevented ovulation and did not affect CD4+ counts or HIV RNA levels. In concert with previously published DMPA/ARV interaction data, these data suggest that DMPA can be used safely by HIV-infected women on the ARV studied. (C) 2008 Elsevier Inc. All rights reserved. C1 [Watts, D. Heather] NICHHD, Bethesda, MD 20892 USA. [Park, Jeong-Gun; Yu, Song] Harvard Univ, Sch Publ Hlth & Frontier Sci, Boston, MA 02115 USA. [Park, Jeong-Gun; Yu, Song] Harvard Univ, Tech Res Fdn, Boston, MA 02115 USA. [Cohn, Susan E.] Univ Rochester, Med Ctr, Dept Med, Rochester, NY 14642 USA. [Hitti, Jane] Univ Washington, Dept Obstet & Gynecol, Seattle, WA 98195 USA. [Stek, Alice; Mudersnach, Laila] Univ So Calif, Sch Med, Los Angeles, CA 90033 USA. [Clax, Pamela A.] Pfizer Inc, Med Affairs, New York, NY 10017 USA. [Lertora, Juan J. L.] Tulane Univ, Hlth Sci Ctr, Tulane LSU Char Hosp GCRC, New Orleans, LA 70112 USA. RP Watts, DH (reprint author), CRMC NICHD NIh, AIDS Branch, 6100 Execut Blvd,Room 4B11,MSC 7510, Bethesda, MD 20892 USA. EM wattsh@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999]; NCRR NIH HHS [M01 RR 000750, M01 RR000044, M01 RR000044-430733, M01 RR000046, 5 M01 RR 00044, M01 RR005096, RR 00046, M01 RR 00044, M01 RR 05096, M01 RR000750]; NIAID NIH HHS [U01 AI 38855, U01 AI 32783, P30 AI050410, UM1 AI069501, UM1 AI069423, U01 AI069501, AI 32913, AI 69423, AI 69501, P30 AI045008, U01 AI027658, U01 AI027664, U01 AI027664-130006, U01 AI027673, U01 AI032782, U01 AI038855-04, U01 AI038858-020006, U01 AI038858-04, U01 AI069451, UM1 AI069451, P30 AI 45008, AI 68363, AI 69470, U01 AI069423, U01 AI038844-020005, U01 AI032913, AI 069434, AI 27658, AI 32782, AI 50410, AI 69451, IU01 AI 3844, U01 AI 27658, U01 AI025859, U01 AI027658-120006, U01 AI027664-170006, U01 AI032783, U01 AI038844-030006, U01 AI038855, U01 AI038858, U01 AI038858-030006, U01 AI046370, U01 AI069434, U01 AI069470, UM1 AI069434, UM1 AI069470, AI 25859, AI 27644, AI 32783, AI 38858, AI 46370, AI 27673]; NICHD NIH HHS [HD 33612, N01HD33345, N01 HD 33345] NR 26 TC 30 Z9 31 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0010-7824 J9 CONTRACEPTION JI Contraception PD FEB PY 2008 VL 77 IS 2 BP 84 EP 90 DI 10.1016/j.contraception.2007.10.002 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 258PZ UT WOS:000252881200003 PM 18226670 ER PT J AU Bassi, GL Zanella, A Cressoni, M Stylianou, M Kolobow, T AF Bassi, Gianluigi Li Zanella, Alberto Cressoni, Massimo Stylianou, Mario Kolobow, Theodor TI Following tracheal intubation, mucus flow is reversed in the semirecumbent position: Possible role in the pathogenesis of ventilator-associated pneumonia SO CRITICAL CARE MEDICINE LA English DT Article DE aspiration pneumonia; bacterial pneumonia; mucus transport; endotracheal tube; intensive care unit ID MUCOCILIARY TRANSPORT; NOSOCOMIAL PNEUMONIA; MUCOUS VELOCITY; TUBE CUFF; ASPIRATION; LEAKAGE; FLUID AB Objectives: Critically ill intubated patients are positioned in the semirecumbent position to prevent pneumonia. In tracheally intubated sheep, we investigated the effects of gravitational force on tracheal mucus transport and on bacterial colonization of the respiratory system. Design: Prospective randomized animal study. Setting: Animal research facility at the National Institutes of Health. Subjects: Sixteen healthy sheep. Interventions: Spontaneously breathing or mechanically ventilated sheep were randomized to be positioned with the orientation of the trachea above (40 degrees, trachea-up) or below (5 degrees, trachea-down) horizontal. Measurements and Main Results: Tracheal mucus velocity was measured through radiographic tracking of radiopaque tantalum disks, insufflated into the trachea. After 24 hrs, sheep were euthanized, and samples from the airways and lungs were taken for microbiological analysis. The proximal trachea was colonized in all sheep. In trachea-down sheep, all mucus moved toward the glottis at a mean velocity of 2.1 +/- 1.1 mm/min. When mucus reached the endotracheal tube, it either entered the endotracheal tube or was lodged at the inflated endotracheal tube cuff. In all trachea-up sheep, abnormal tracheal mucus clearance was found. Mucus, mostly on the nondependent part of the trachea, moved toward the glottis at an average velocity of 2.2 +/- 2.0 mm/min and constantly accumulated at the inflated endotracheal tube cuff. From the proximal trachea, mucus eventually moved toward the lungs on the dependent part of the trachea, leading to an "intratracheal route" of colonization of the lungs. Pneumonia was found in 6/8 of trachea-up sheep and the same microorganisms were isolated from the lungs and the proximal trachea. No pneumonia was found in trachea-down sheep (p = .007). Conclusions: The study indicates that following tracheal intubation gravitational force influences tracheal mucus clearance. When the trachea is oriented above horizontal, a flow of mucus from the proximal trachea toward the lungs is highly associated with bacterial colonization of the airways and pneumonia. C1 [Bassi, Gianluigi Li; Zanella, Alberto; Cressoni, Massimo; Kolobow, Theodor] NHLBI, NIH, Pulm & Crit Care Med Branch, Sect Pulm & Cardiac Assist Devices, Bethesda, MD 20892 USA. [Stylianou, Mario] NHLBI, NIH, Off Biostat Res, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Bassi, GL (reprint author), NHLBI, NIH, Pulm & Crit Care Med Branch, Sect Pulm & Cardiac Assist Devices, Bldg 10, Bethesda, MD 20892 USA. EM libassig@aim.com RI Cressoni, Massimo/B-7315-2017; OI Cressoni, Massimo/0000-0002-0089-2905; zanella, Alberto/0000-0002-2967-2527 NR 18 TC 36 Z9 39 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2008 VL 36 IS 2 BP 518 EP 525 DI 10.1097/01.CCM.0000299741.32078.E9 PG 8 WC Critical Care Medicine SC General & Internal Medicine GA 257JB UT WOS:000252794000021 ER PT J AU Harper, NC Al-Greene, NT Basrai, MA Belanger, KD AF Harper, Nicola C. Al-Greene, Nicole T. Basrai, Munira A. Belanger, Kenneth D. TI Mutations affecting spindle pole body and mitotic exit network function are synthetically lethal with a deletion of the nucleoporin NUP1 in S-cerevisiae SO CURRENT GENETICS LA English DT Article DE nucleoporin; nuclear pore complex; nuclear transport; spindle pole body; mitotic exit network; cell cycle ID NUCLEAR-PORE COMPLEX; MESSENGER-RNA EXPORT; CELL-CYCLE; BUDDING YEAST; NUCLEOCYTOPLASMIC TRANSPORT; LOCALIZATION SIGNALS; TRANSCRIPTION FACTOR; BINDING-PROTEIN; IN-VIVO; IMPORT AB Nuclear pore complexes (NPCs) are embedded in the nuclear envelope of eukaryotic cells and function to regulate passage of macromolecules in and out of the nucleus. Nup1 is one of 30 nucleoporins comprising the NPC of the yeast Saccharomyces cerevisiae and is located on the nucleoplasmic face of the NPC where it plays a role in mRNA export and protein transport. In order to further characterize the function of Nup1 we used a genetic approach to identify mutations that are synthetically lethal in combination with a deletion of NUP1 (nup1 Delta). We have identified one such nup1 lethal mutant (nle6) as a temperature sensitive allele of nud1. NUD1 encodes a component of the yeast spindle pole body (SPB) and acts as scaffolding for the mitotic exit network (MEN). We observe that nle6/nud1 mutant cells have a normal distribution of NPCs within the nuclear envelope and exhibit normal rates of nuclear protein import at both the permissive and restrictive temperatures. nup1 Delta also exhibits synthetic lethality with bub2 Delta and bfa1 Delta, both of which encode proteins that colocalize with Nud1 at spindle pole bodies and function in the mitotic exit network. However, we do not observe genetic interactions among nle6/nud1, bub2 Delta, or bfa1 Delta and mutations in the nucleoporin encoding genes NUP60 or NUP170, nor is nup1 Delta synthetically lethal with the absence of components downstream in the mitotic exit network, including Lte1, Swi5, and Dbf2. Our results suggest a novel functional connection between Nup1 and proteins comprising both the spindle pole body and early mitotic exit network. C1 [Harper, Nicola C.; Al-Greene, Nicole T.; Belanger, Kenneth D.] Colgate Univ, Dept Biol, Hamilton, NY 13346 USA. [Basrai, Munira A.] Natl Canc Inst, Natl Inst Hlth, Ctr Canc Res, Genet Branch, Bethesda, MD 20889 USA. RP Belanger, KD (reprint author), Colgate Univ, Dept Biol, 13 Oak Dr, Hamilton, NY 13346 USA. EM kbelanger@mail.colgate.edu FU Howard Hughes Medical Institute; Intramural NIH HHS; NIGMS NIH HHS [R15 GM065107-02, GM-65107, R15 GM065107, R15 GM065107-01] NR 63 TC 1 Z9 1 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0172-8083 J9 CURR GENET JI Curr. Genet. PD FEB PY 2008 VL 53 IS 2 BP 95 EP 105 DI 10.1007/s00294-007-0168-4 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 252SS UT WOS:000252467500003 PM 18058101 ER PT J AU Robertson, SM Davey, RT Voell, J Formentini, E Alfaro, RM Penzak, SR AF Robertson, Sarah M. Davey, Richard T. Voell, Jocelyn Formentini, Elizabeth Alfaro, Raul M. Penzak, Scott R. TI Effect of Ginkgo biloba extract on lopinavir, midazolarn and fexofenadine pharmacokinetics in healthy subjects SO CURRENT MEDICAL RESEARCH AND OPINION LA English DT Article DE CYP3A4; Ginkgo biloba; lopinavir; P-glycoprotein; ritonavir ID HIV-INFECTED PATIENTS; CYP3A ACTIVITY; LOPINAVIR/RITONAVIR; CYTOCHROME-P-450; PHARMACODYNAMICS; COMPLEMENTARY; NICARDIPINE; SUPPLEMENTS; VOLUNTEERS; ENZYMES AB Objective: Animal and in vitro data suggest that Ginkgo biloba extract (GBE) may modulate CYP3A4 activity. As such, GBE may alter the exposure of HIV protease inhibitors metabolized by CYP3A4. It is also possible that GBE could alter protease inhibitor pharmacokinetics (PK) secondary to modulation of P-glycoprotein (P-gp). The primary objective of the study was to evaluate the effect of GBE on the exposure of lopinavir in healthy volunteers administered lopinavir/ritonavir. Secondary objectives were to compare ritonavir exposure pre- and post-GBE, and assess the effect of GBE on single doses of probe drugs midazolam and fexofenadine. Methods: This open-label study evaluated the effect of 2 weeks of standardized GBE administration on the steady-state exposure of lopinavir and ritonavir in 14 healthy volunteers administered lopinavir/ritonavir to steady-state. In addition, single oral doses of probe drugs midazolam and fexofenadine were administered prior to and after 4 weeks of GBE (following washout of lopinavir/ritonavir) to assess the influence of GBE on CYP3A and P-gp activity, respectively. Results: Lopinavir, ritonavir and fexofenadine exposures were not significantly affected by GBE administration. However, GBE decreased midazolam AUC(0-infinity) and C-max by 34% (p = 0.03) and 31% (p = 0.03), respectively, relative to baseline. In general, lopinavir/ritonavir and GBE were well tolerated. Abnormal laboratory results included mild elevations in hepatic enzymes, cholesterol and triglycerides, and mild-to-moderate increases in total bilirubin. Conclusions: Our results suggest that GBE induces CYP3A metabolism, as assessed by a decrease in midazolam concentrations. However, there was no change in the exposure of lopinavir, likely due to ritonavir's potent inhibition of CYP3A4. Thus, GBE appears unlikely to reduce the exposure of ritonavir-boosted protease inhibitors, while concentrations of unboosted protease inhibitors may be affected. Limitations to our study include the single sequence design and the evaluation of a ritonavir-boosted protease inhibitor exclusively. C1 [Robertson, Sarah M.] US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, DHHS, Silver Spring, MD 20901 USA. [Davey, Richard T.] NIH, NIAID, Bethesda, MD 20892 USA. [Voell, Jocelyn; Formentini, Elizabeth] NIH, Clin Res Ctr, Dept Crit Care Med, Bethesda, MD 20892 USA. [Alfaro, Raul M.; Penzak, Scott R.] NIH, Clin Res Ctr, Dept Pharm, Bethesda, MD 20892 USA. RP Robertson, SM (reprint author), US FDA, Off Clin Pharmacol, Ctr Drug Evaluat & Res, DHHS, Bldg 21,Rm 4653,10903 New Hampshire Ave, Silver Spring, MD 20901 USA. EM sarah.robertson@fda.hhs.gov NR 33 TC 60 Z9 66 U1 0 U2 7 PU LIBRAPHARM/INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4 LQ, ENGLAND SN 0300-7995 J9 CURR MED RES OPIN JI Curr. Med. Res. Opin. PD FEB PY 2008 VL 24 IS 2 BP 591 EP 599 DI 10.1185/030079908X260871 PG 9 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 273AN UT WOS:000253902900030 PM 18205997 ER PT J AU Simon, R AF Simon, Richard TI Microarray-based expression profiling and informatics SO CURRENT OPINION IN BIOTECHNOLOGY LA English DT Review ID DIFFERENTIAL GENE-EXPRESSION; PROGNOSTIC CLASSIFICATION; ERROR ESTIMATION; SET ENRICHMENT; SELECTION; EXTRACTION; KNOWLEDGE; MODEL; BIAS AB Microarray-based expression profiling is a powerful technology for studying biological mechanisms and for developing clinically valuable predictive classifiers. The high-dimensional read-out for each sample assayed makes it possible to do new kinds of studies but also increases the risks of misleading conclusions. We review here the current state-of-the-art for design and analysis of microarray-based investigations. C1 NCI, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, 9000 Rockville Pike,MSC 7434, Bethesda, MD 20892 USA. EM rsimon@nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 29 TC 24 Z9 25 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0958-1669 J9 CURR OPIN BIOTECH JI Curr. Opin. Biotechnol. PD FEB PY 2008 VL 19 IS 1 BP 26 EP 29 DI 10.1016/j.copbio.2007.10.008 PG 4 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 271CX UT WOS:000253767600005 PM 18053704 ER PT J AU Nishizuka, S Spurrier, B AF Nishizuka, Satoshi Spurrier, Brett TI Experimental validation for quantitative protein network models SO CURRENT OPINION IN BIOTECHNOLOGY LA English DT Review ID P53-MDM2 FEEDBACK LOOP; CANCER-CELL LINES; SYSTEMS-BIOLOGY; LYSATE MICROARRAYS; SIGNALING NETWORKS; OVARIAN-CANCER; STEM-CELLS; ARRAYS; EXPRESSION; PATHWAYS AB Cellular responses are the consequence of complex reactions of protein networks. The complexity should ultimately be described by a set of formulas in a quantitative fashion, in which each formula defines the reactions in response to given types of input. However, testing these formulas has not been a simple task because of the lack of appropriate means for experimental validation. 'Reverse-phase' lysate microarrays have been proved to be powerful for such requirements and thus can be a good resource for providing an experimental reference point for the theoretical biology of protein networks. C1 [Nishizuka, Satoshi; Spurrier, Brett] NCI, Natl Inst Hlth, Ctr Canc Res, Mol Translat Technol Mol Therapeut Program, Bethesda, MD 20892 USA. [Nishizuka, Satoshi] SAIC Frederic Inc Frederick, Natl Canc Inst, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. [Nishizuka, Satoshi] Iwate Med Univ, Sch Med, Dept Surg, Morioka, Iwate 0208505, Japan. RP Nishizuka, S (reprint author), NCI, Natl Inst Hlth, Ctr Canc Res, Mol Translat Technol Mol Therapeut Program, Bldg 37,Room 1126B,9000 Rockville Pike, Bethesda, MD 20892 USA. EM nishizus@mail.nih.gov; snishizu@iwate-med.ac.jp FU NCI NIH HHS [N01-CO-12400] NR 47 TC 8 Z9 8 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0958-1669 J9 CURR OPIN BIOTECH JI Curr. Opin. Biotechnol. PD FEB PY 2008 VL 19 IS 1 BP 41 EP 49 DI 10.1016/j.copbio.2007.11.007 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 271CX UT WOS:000253767600008 PM 18187317 ER PT J AU Hurley, JH AF Hurley, James H. TI ESCRT complexes and the biogenesis of multivesicular bodies SO CURRENT OPINION IN CELL BIOLOGY LA English DT Article ID FACTOR RECEPTOR DEGRADATION; BODY-SORTING MACHINERY; C-TERMINAL DOMAIN; AAA-ATPASE VPS4; STRUCTURAL BASIS; UBIQUITIN RECOGNITION; PROTEIN INTERACTIONS; EAP45-GLUE DOMAIN; GLUE DOMAIN; MIT DOMAIN AB Multivesicular bodies (MVBs) are crucial intermediates in the trafficking of ubiquitinated receptors and other cargo destined for lysosomes. The formation of MVBs by invagination of the enclosomal limiting membrane is catalyzed by the enclosomal sorting complex required for transport (ESCRT) complexes, a process that has recently been visualized in three-dimensional detail by electron tomography. Structural and biochemical analysis of the upstream components, Vps27-Hse1, ESCRT-I, and ESCRT-II, shows how these complexes assemble and cluster cargo. Rapid progress has been made in understanding the assembly and disassembly of the ESCRT-III complex and the interactions of its subunits with MIT domain and other proteins. A key role for deubiquitination in the regulation of the system has been demonstrated. One central question remains largely unanswered, which is how the ESCRTs actually promote the invagination of the endosomal membrane. C1 NIDDK, Mol Biol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDK, Mol Biol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov FU Intramural NIH HHS [Z01 DK036118-14] NR 64 TC 194 Z9 198 U1 2 U2 12 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0955-0674 J9 CURR OPIN CELL BIOL JI Curr. Opin. Cell Biol. PD FEB PY 2008 VL 20 IS 1 BP 4 EP 11 DI 10.1016/j.ceb.2007.12.002 PG 8 WC Cell Biology SC Cell Biology GA 267YN UT WOS:000253545200002 PM 18222686 ER PT J AU Gonzalez, N Moody, TW Igarashi, H Ito, T Jensen, RT AF Gonzalez, Nieves Moody, Terry W. Igarashi, Hisato Ito, Tetsuhide Jensen, Robert T. TI Bombesin-related peptides and their receptors: recent advances in their role in physiology and disease states SO CURRENT OPINION IN ENDOCRINOLOGY DIABETES AND OBESITY LA English DT Article DE bombesin; bombesin-receptor-subtype-3; gastrin-releasing peptide; neuromedin B; obesity; peptide receptor mediated cytotoxicity ID GASTRIN-RELEASING-PEPTIDE; SMALL-BOWEL TRANSPLANTATION; NEUROMEDIN-B RECEPTOR; BRONCHIAL EPITHELIAL-CELLS; TARGETED CYTOTOXIC ANALOGS; HUMAN ORPHAN RECEPTOR; C-TERMINAL FRAGMENTS; PROSTATE-CANCER; LUNG-CANCER; BRONCHOPULMONARY DYSPLASIA AB Purpose of review Mammalian bombesin-related peptides, gastrin-releasing peptide and neuromedin B actions are mediated by two receptors (BB1-receptor, BB2-receptor), which are closely related to the orphan receptor BRS-3 (BB3-receptor). The purpose of this review is to highlight advances in the understanding of these peptides in physiology/disease states. Recent findings Pharmacologic/receptor-knockout studies show involvement of these receptors in a number of new processes/diseases. Neuromedin B/BB1-receptor is an important physiological regulator of pituitary-thyroid function; in mediating behavior, especially feas/anxiety; in mediating satiety through different cascades than gastrin-releasing peptide/BB2 receptors and for its autocrine tumor-growth effects. Gastrin-releasing peptide/BB2-receptor plays important roles in mediating signals for pruritus, lung development/injury, small intestinal mucosal defense, and central nervous system processes such as learning/memory. The signaling mechanisms of its potent growth effects are being elucidated and their possible therapeutic targets identified. BB3-receptor knockout mice provided insights for their obesity/glucose intolerance and demonstrated that this receptor may be important in the lung response to injury, tumor growth and gastrointestinal motility. Each receptor is frequently overexpressed in human tumors and has potent growth effects. This effect is being explored to develop new antitumor treatments, such as bombesin-receptor ligands conjugated to cytotoxic agents. Summary This receptor family is involved in an increasing number of central nervous system/peripheral processes physiologically and in disease states, and increased understanding of its role may lead to novel treatments. C1 [Gonzalez, Nieves; Jensen, Robert T.] NIH, Digest Dis Branch, Bethesda, MD 20892 USA. [Moody, Terry W.] NCI, NIH, Bethesda, MD 20892 USA. [Igarashi, Hisato; Ito, Tetsuhide] Kyushu Univ, Grad Sch Med Sci, Dept Med & Bioregulatory Sci, Fukuoka 812, Japan. RP Jensen, RT (reprint author), NIH, Digest Dis Branch, Bldg 10,Room 9C-103, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov FU National Institute of Diabetes, Digestive and Kidney Diseases; National Cancer Institute, National Institutes of Health FX This work was supported by intramural funds of the National Institute of Diabetes, Digestive and Kidney Diseases and from the National Cancer Institute, National Institutes of Health. NR 88 TC 101 Z9 105 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1752-296X J9 CURR OPIN ENDOCRINOL JI Curr. Opin. Endocrinol. Diabetes Obes. PD FEB PY 2008 VL 15 IS 1 BP 58 EP 64 DI 10.1097/MED.0b013e3282f3709b PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA V14SR UT WOS:000207754600008 PM 18185064 ER PT J AU Steele-Mortimer, O AF Steele-Mortimer, Olivia TI The Salmonella-containing vacuole - Moving with the times SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID ENTERICA SEROVAR TYPHIMURIUM; LATE ENDOCYTIC COMPARTMENTS; III SECRETED EFFECTOR; HOST-CELL MEMBRANES; PATHOGENICITY ISLAND; PHAGOSOME MATURATION; MURINE MACROPHAGES; VIRULENCE PROTEIN; EPITHELIAL-CELLS; INTRACELLULAR REPLICATION AB Salmonella pathogenesis is dependent on its ability to invade and replicate within host cells. Following invasion the bacteria remain within a modified phagosome known as the Salmonella-containing vacuole (SCV), within which they will survive and replicate. Invasion and SCV biogenesis are dependent on two Type III secretion systems, T3SS1 and T3SS2, which are used to translocate distinct cohorts of bacterial effector proteins into the host cell. Elucidating the roles of individual effector proteins in SCV biogenesis has proven difficult but several distinct themes are now emerging and it is apparent that SCV biogenesis is an extremely dynamic process involving; extensive membrane remodeling, interactions with the endolysosomal pathway, actin rearrangements and microtubule-based movement and tubule extension. C1 NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, Hamilton, MT 59840 USA. RP Steele-Mortimer, O (reprint author), NIAID, Rocky Mt Labs, Intracellular Parasites Lab, NIH, 903 S 4th St, Hamilton, MT 59840 USA. EM omortimer@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000909-06] NR 81 TC 104 Z9 106 U1 3 U2 18 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD FEB PY 2008 VL 11 IS 1 BP 38 EP 45 DI 10.1016/j.mib.2008.01.002 PG 8 WC Microbiology SC Microbiology GA 291YM UT WOS:000255233400007 PM 18304858 ER PT J AU Bukreyev, A Collins, PL AF Bukreyev, Alexander Collins, Peter L. TI Newcastle disease virus as a vaccine vector for humans SO CURRENT OPINION IN MOLECULAR THERAPEUTICS LA English DT Review DE intranasal immunization; vaccine; vector; virus ID RESPIRATORY SYNCYTIAL VIRUS; AVIAN INFLUENZA-VIRUSES; FOREIGN GENE; EBOLA-VIRUS; V-PROTEIN; NEUTRALIZING ANTIBODIES; INTERFERON-ANTAGONIST; FUSION PROTEIN; CLONED CDNA; IN-VITRO AB Emerging and re-emerging infectious diseases pose a threat to individuals worldwide and necessitate the development of new vaccines and vaccine platforms. Newcastle disease virus (NDV) is an enveloped cytoplasmic RNA virus of avian origin that is highly attenuated in humans and other primates because of a strong host-range restriction. NDV infects the respiratory tract of non-human primates and appears to remain restricted to that site. As a vaccine vector, NDV induced substantial local and systemic responses against a protein expressed by a foreign gene insert and was protective against pathogen challenge. NDV is antigenically distinct from common human viruses, accommodates foreign sequences with a good degree of stability, can be readily produced in a cell line acceptable for human product development, and exhibits a low incidence of recombination. Because of its natural tropism for the respiratory tract, NDV may be particularly effective for the development of vectored vaccines against respiratory infections as well as infections that can be transmitted through the respiratory tract. C1 [Bukreyev, Alexander; Collins, Peter L.] NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bukreyev, A (reprint author), NIAID, Infect Dis Lab, NIH, 50 S Dr, Bethesda, MD 20892 USA. EM ab176v@nih.gov FU Intramural NIH HHS NR 66 TC 43 Z9 45 U1 0 U2 4 PU THOMSON SCIENTIFIC PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND STREET, LONDON, W1T 4JE, ENGLAND SN 1464-8431 J9 CURR OPIN MOL THER JI Curr. Opin. Mol. Ther. PD FEB PY 2008 VL 10 IS 1 BP 46 EP 55 PG 10 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 255ZN UT WOS:000252697400006 PM 18228181 ER PT J AU Schuler, B Eaton, WA AF Schuler, Benjamin Eaton, William A. TI Protein folding studied by single-molecule FRET SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Review ID RESONANCE ENERGY-TRANSFER; ALTERNATING-LASER EXCITATION; TRANSFER CONFOCAL MICROSCOPY; UNFOLDED PROTEINS; FLUORESCENCE SPECTROSCOPY; CONFORMATIONAL DYNAMICS; STRUCTURAL HETEROGENEITIES; DIFFUSING BIOMOLECULES; DENATURED STATE; COLLAPSE AB A complete understanding of a protein-folding mechanism requires description of the distribution of microscopic pathways that connect the folded and unfolded states. This distribution can, in principle, be described by computer simulations and theoretical models of protein folding, but is hidden in conventional experiments on large ensembles of molecules because only average properties are measured. A long-term goal of single-molecule fluorescence studies is to time-resolve the structural events as individual molecules make transitions between folded and unfolded states. Although such studies are still in their infancy, the work till now shows great promise and has already produced novel and important information on current issues in protein folding that has been impossible or difficult to obtain from ensemble measurements. C1 [Schuler, Benjamin] Univ Zurich, Inst Biochem, CH-8057 Zurich, Switzerland. [Eaton, William A.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Schuler, B (reprint author), Univ Zurich, Inst Biochem, Winterthurerstr 190, CH-8057 Zurich, Switzerland. EM schuler@bioc.uzh.ch; eaton@helix.nih.gov RI Schuler, Benjamin/E-7342-2011 OI Schuler, Benjamin/0000-0002-5970-4251 FU Intramural NIH HHS [Z01 DK029010-35] NR 84 TC 360 Z9 362 U1 24 U2 166 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD FEB PY 2008 VL 18 IS 1 BP 16 EP 26 DI 10.1016/j.sbi.2007.12.003 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 273NH UT WOS:000253937100004 PM 18221865 ER PT J AU Van Duyne, GD Yang, W AF Van Duyne, Gregory D. Yang, Wei TI Protein-nucleic acid complexes: large, small, old, and new SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Editorial Material C1 [Van Duyne, Gregory D.] Univ Penn, Sch Med, Philadelphia, PA 19104 USA. [Van Duyne, Gregory D.] Howard Hughes Med Inst, Philadelphia, PA 19104 USA. [Yang, Wei] NIDDK, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Van Duyne, GD (reprint author), Univ Penn, Sch Med, 242 Anat Chem Bldg, Philadelphia, PA 19104 USA. NR 0 TC 1 Z9 1 U1 1 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD FEB PY 2008 VL 18 IS 1 BP 67 EP 69 DI 10.1016/j.sbi.2008.01.002 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 273NH UT WOS:000253937100010 PM 18262782 ER PT J AU Izevbigie, EB Howard, CB Lee, KS AF Izevbigie, Ernest B. Howard, C. B. Lee, K. S. TI V-Amygdalina: Folk medicine, analysis, and potential application for cancer treatment SO CURRENT PHARMACEUTICAL ANALYSIS LA English DT Review DE anti-cancer activity; apoptosis; sesquiterpene lactones; Vernonia amygdalina extracts ID SIGNAL-REGULATED KINASES; SESQUITERPENE LACTONES; VERNONIA-AMYGDALINA; BREAST-CANCER; ANTICANCER AGENTS; CONSUMPTION; INHIBITION; CELLS; CHEMOPROTECTION; VEGETABLES AB Folk medicine (FM) is practiced by people without access to conventional medical services; it usually involves the use of natural remedies such as herbs or vegetable substances. Before the use of pharmaceutical drugs, and surgical procedures, these healing methods were used, and are still in use today. It is estimated that twenty five percent of all therapeutic drugs trace their origins to plants, and almost two-thirds of the people of the world rely on their healing powers. One hundred years ago, health care in the U. S. was provided by a highly competitive medical sect, and quite infrequently, folk medicine practitioners were patronized. However, FM usage in the U. S. has increased drastically during the past decade. National surveys of adults (18 years of age or older) show that one in three adults use unconventional therapies or Complementary and Alternative Medicine (CAM) in the U. S. The rate of CAM usage is more than eighty percent among cancer patients. Vernonia amygdalina (VA) is well known for its medicinal importance. Fractionation of the VA extracts with solvents of varying polarities, by silica gels analyses, UV Spectrophotometer, HPLC, TLC and NMR techniques have yielded some biologically-active fractions. C1 [Izevbigie, Ernest B.] Jackson State Univ, Dept Biol, Lab Cellular Signaling Phytoceut Canc Prevent & T, Jackson, MS 39217 USA. [Izevbigie, Ernest B.; Howard, C. B.; Lee, K. S.] Jackson State Univ, Coll Sci, Ctr Environm Hlth, NIH, Jackson, MS 39217 USA. [Lee, K. S.] Jackson State Univ, Dept Chem, Jackson, MS 39217 USA. RP Izevbigie, EB (reprint author), Jackson State Univ, Dept Biol, Lab Cellular Signaling Phytoceut Canc Prevent & T, Jackson, MS 39217 USA. EM ernest.b.izevbigie@jsums.edu FU NCRR NIH HHS [G12 RR013459]; NIMHD NIH HHS [P20 MD000534] NR 45 TC 2 Z9 3 U1 1 U2 6 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1573-4129 J9 CURR PHARM ANAL JI Curr. Pharm. Anal. PD FEB PY 2008 VL 4 IS 1 BP 20 EP 24 DI 10.2174/157341208783497579 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 274RZ UT WOS:000254020000002 PM 27134615 ER PT J AU Chen, Z O'Shea, JJ AF Chen, Zhi O'Shea, John J. TI Regulation of IL-17 production in human lymphocytes SO CYTOKINE LA English DT Review DE T cell differentiation; human T lymphocytes; Th17; cytokines ID IL-17-PRODUCING T-CELLS; TGF-BETA; AUTOIMMUNE ENCEPHALOMYELITIS; RETINOIC-ACID; CUTTING EDGE; TH17 CELLS; HUMAN KERATINOCYTES; CYTOKINE PRODUCTION; MULTIPLE-SCLEROSIS; INTERFERON-GAMMA AB The discovery of a new lineage of helper T cells that selectively produces interleukin (IL)-17 has provided exciting new insights into immunoregulation, host defense and the pathogenesis of autoimmune diseases. Although the factors that promote murine Th17 differentiation have been intensively examined, there has been much less information on the regulation of this cytokine in human T cells. IL-17 is readily produced by human memory T cells, which we now know exhibit distinct patterns of chemokine receptor expression and may differentiate in response to selective pathogens. Recently it has been shown that IL-1, IL-6 and IL-23 are important in driving human Th17 differentiation. However, TGFP-1 which is important for the differentiation of murine Th17 cells and inducible regulatory T cells (iTregs), is reportedly not required and even inhibits for human Th17 differentiation. In addition, human Th17 cells also produce other proinflammatory cytokines. Further characterization of the transcription regulation of human IL-17 expression, and the epigenetic regulation of human Il17 locus should improve our understanding the lineage commitment of human Th17 cells. Targeting the production and action of this cytokine is also likely to be beneficial therapeutically for autoinflammatory and autoimmune diseases. Published by Elsevier Ltd. C1 [Chen, Zhi; O'Shea, John J.] NIAMSD, NIH, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. RP Chen, Z (reprint author), Univ Turku, Fac Med, Inst Biomed, Kiinamyllynkatu 10, FI-20520 Turku, Finland. EM zchen@utu.fi NR 68 TC 67 Z9 79 U1 1 U2 7 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD FEB PY 2008 VL 41 IS 2 BP 71 EP 78 DI 10.1016/j.cyto.2007.09.009 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 269AX UT WOS:000253623000001 PM 17981475 ER PT J AU Cassidy-Stone, A Chipuk, JE Ingerman', E Song, C Yoo, C Kuwana, T Kurth, MJ Shaw, JT Hinshaw, JE Green, DR Nunnari, J AF Cassidy-Stone, Ann Chipuk, Jerry E. Ingerman', Elena Song, Cheng Yoo, Choong Kuwana, Tomomi Kurth, Mark J. Shaw, Jared T. Hinshaw, Jenny E. Green, Douglas R. Nunnari, Jodi TI Chemical inhibition of the mitochondrial division dynamin reveals its role in Bax/Bak-dependent mitochondrial outer membrane permeabilization SO DEVELOPMENTAL CELL LA English DT Article ID CYTOCHROME-C RELEASE; CELL-DEATH; SACCHAROMYCES-CEREVISIAE; GTPASE ACTIVITY; BAX ACTIVATION; APOPTOSIS; FUSION; FISSION; DRP1; OPA1 AB Mitochondrial fusion and division play important roles in the regulation of apoptosis. Mitochondrial fusion proteins attenuate apoptosis by inhibiting release of cytochrome c from mitochondria, in part by controlling cristae structures. Mitochondrial division promotes apoptosis by an unknown mechanism. We addressed how division proteins regulate apoptosis using inhibitors of mitochondrial division identified in a chemical screen. The most efficacious inhibitor, mdivi-1 (for mitochondrial division inhibitor) attenuates mitochondrial division in yeast and mammalian cells by selectively inhibiting the mitochondrial division dynamin. In cells, mdivi-1 retards apoptosis by inhibiting mitochondrial outer membrane permeabilization. In vitro, mdivi-1 potently blocks Bid-activated Bax/Bak-dependent cytochrome c release from mitochondria. These data indicate the mitochondrial division dynamin directly regulates mitochondrial outer membrane permeabilization independent of Drp1-mediated division. Our findings raise the interesting possibility that mdivi-1 represents a class of therapeutics for stroke, myocardial infarction, and neurodegenerative diseases. C1 [Cassidy-Stone, Ann; Ingerman', Elena; Song, Cheng; Nunnari, Jodi] Univ Calif Davis, Sect Mol & Cellular Biol, Davis, CA 95616 USA. [Chipuk, Jerry E.; Green, Douglas R.] St Jude Childrens Res Hosp, Dept Immunol, Memphis, TN 38105 USA. [Yoo, Choong; Kurth, Mark J.] Univ Calif Davis, Dept Chem, Davis, CA 95616 USA. [Kuwana, Tomomi] Univ Iowa, Dept Pathol, Iowa City, IA 52242 USA. [Shaw, Jared T.] MIT, Broad Inst, Cambridge, MA 02142 USA. [Hinshaw, Jenny E.] NIDDK, Natl Inst Hlth, Lab Cell Biochem & Biol, Bethesda, MD 20892 USA. RP Nunnari, J (reprint author), Univ Calif Davis, Sect Mol & Cellular Biol, Davis, CA 95616 USA. EM jmnunnari@ucdavis.edu OI Shaw, Jared/0000-0001-5190-493X; Chipuk, Jerry Edward/0000-0002-1337-842X FU NCI NIH HHS [CA69301]; NEI NIH HHS [R01 EY015924-02, 1 R01 EY015924, R01 EY015924, R01 EY015924-01, R01 EY015924-03]; NIAID NIH HHS [AI40646, R01 AI040646]; NIGMS NIH HHS [GM52735, R01 GM052735, R01 GM062942, R01 GM062942-07, R37 GM052735] NR 60 TC 391 Z9 403 U1 3 U2 22 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 FEB PY 2008 VL 14 IS 2 BP 193 EP 204 DI 10.1016/j.devce1.2007.11.019 PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 263UG UT WOS:000253241400009 PM 18267088 ER PT J AU Ayala, JE Bracy, DP Hansotia, T Flock, G Seino, Y Wasserman, DH Drucker, DJ AF Ayala, Julio E. Bracy, Deanna P. Hansotia, Tanya Flock, Grace Seino, Yutaka Wasserman, David H. Drucker, Daniel J. TI Insulin action in the double incretin receptor knockout mouse SO DIABETES LA English DT Article ID GLUCAGON-LIKE PEPTIDE-1; GLUCOSE-HOMEOSTASIS; ENERGY-EXPENDITURE; ENTEROINSULAR AXIS; PROTEIN-KINASE; BODY-WEIGHT; MICE; RESISTANCE; HORMONES; GLP-1 AB OBJECTIVE-The incretins glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide have been postulated to play a role in regulating insulin action, although the mechanisms behind this relationship remain obscure. We used the hyperinsulinemic-euglycemic clamp to determine sites where insulin action may be modulated in double incretin receptor knockout (DIRKO) mice, which lack endogenous incretin action. RESEARCH DESIGN AND METHODS-DIRKO and wild-type mice were fed regular chow or high-fat diet for 4 months. Clamps were performed on 5-h-fasted, conscious, unrestrained mice using an arterial catheter for sampling. RESULTS-Compared with wild-type mice, chow and high fat-fed DIRKO mice exhibited decreased fat and muscle mass associated with increased energy expenditure and ambulatory activity. Clamp rates of glucose infusion (GIR), endogenous glucose production (endoR(a)), and disappearance (R-d) were not different in chow-fed wild-type and DIRKO mice, although insulin levels were lower in DIRKO mice. Liver Akt expression was decreased but Akt activation was increased in chow-fed DIRKO compared with wild-type mice. High-fat feeding resulted in fasting hyperinsulinemia and hyperglycemia in wild-type but not in DIRKO mice. GIR, suppression of endoRa, and stimulation of R-d were inhibited in high fat-fed wild-type mice but not in DIRKO mice. High-fat feeding resulted in impaired tissue glucose uptake (R-g) in skeletal muscle of wild-type mice but not of DIRKO mice. Liver and muscle Akt activation was enhanced in high fat-fed DIRKO compared with wild-type mice. CONCLUSIONS-ln summary, DIRKO mice exhibit enhanced insulin action compared with wild-type mice when fed a regular chow diet and are protected from high-fat diet-induced obesity and insulin resistance. C1 [Ayala, Julio E.; Bracy, Deanna P.; Wasserman, David H.] Vanderbilt Univ, Med Ctr, Sch Med, Mouse Metab Phenotyping Ctr,Dept Mol Physiol & Bi, Nashville, TN 37232 USA. [Ayala, Julio E.; Bracy, Deanna P.; Wasserman, David H.] Vanderbilt Univ, Med Ctr, Sch Med, Mouse Metab Phenotyping Ctr,Natl Inst Hlth, Nashville, TN 37232 USA. [Hansotia, Tanya; Flock, Grace; Drucker, Daniel J.] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Banting & Best Diabet Ctr,Dept Med & Lab Med, Toronto, ON M5G 1X5, Canada. [Hansotia, Tanya; Flock, Grace; Drucker, Daniel J.] Univ Toronto, Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Banting & Best Diabet Ctr,Dept Pathobiol, Toronto, ON M5G 1X5, Canada. [Seino, Yutaka] Kansai Elect Power Hosp, Osaka, Japan. RP Ayala, JE (reprint author), Vanderbilt Univ, Med Ctr, Sch Med, Mouse Metab Phenotyping Ctr,Dept Mol Physiol & Bi, 2200 Pierce Ave,702 Light Hall, Nashville, TN 37232 USA. EM julio.ayala@vanderbilt.edu RI Drucker, Daniel/A-4092-2010 FU NIDDK NIH HHS [R01 DK054902, R01-DK-50277, R01-DK-54902, U24 DK059637, U24-DK-59637] NR 37 TC 21 Z9 21 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2008 VL 57 IS 2 BP 288 EP 297 DI 10.2337/db07-0704 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 259BP UT WOS:000252914400002 PM 17977951 ER PT J AU Le Stunff, C Dechartres, A Mariot, V Lotton, C Trainor, C Del Giudice, EM Meyre, D Bieche, I Laurendeau, I Froguel, P Zelenika, D Fallin, D Lathrop, M Romeo, PH Bougneres, P AF Le Stunff, Catherine Dechartres, Agnes Mariot, Virginie Lotton, Chantal Trainor, Cecelia Del Giudice, Emanuele Miraglia Meyre, David Bieche, Ivan Laurendeau, Ingrid Froguel, Philippe Zelenika, Diana Fallin, Dani Lathrop, Mark Romeo, Paul-Henri Bougneres, Pierre TI Association analysis indicates that a variant GATA-binding site in the PIK3CB promoter is a cis-acting expression quantitative trait locus for this gene and attenuates insulin resistance in obese children SO DIABETES LA English DT Article ID PHOSPHATIDYLINOSITOL 3-KINASE ACTIVITY; RECEPTOR SUBSTRATE-1 PHOSPHORYLATION; HOMEOSTASIS MODEL ASSESSMENT; CATALYTIC SUBUNIT P110-BETA; IMPAIRED GLUCOSE-TOLERANCE; HUMAN SKELETAL-MUSCLE; AKT/PROTEIN KINASE-B; PHOSPHOINOSITIDE 3-KINASE; METABOLIC SYNDROME; P85-ALPHA SUBUNIT AB OBJECTTVE-In search of functional polymorphisms associated with the genetics of insulin resistance, we studied a variant in the promoter of PIK3CB, the gene coding for the catalytic P110 beta subunit of phosphatidylinositol (PI) 3-kinase, a major effector of insulin action. RESEARCH DESIGN AND METHODS-The rs361072 C/T variant was selected among single nucleotide polymorphisms of the PIK.3CB region because we suspected that its common C allele (allelic frequency similar to 50% in Europeans) could create a GATA-binding motif and was genotyped in five cohorts of obese (n = 1,876) and two cohorts of nonobese (n = 1,490) European children. To estimate insulin resistance in these children, the homeostasis model assessment for insulin resistance (HOMA-IR) index was measured in strict nutritional conditions. GATA-binding and functional effects of rs361072 were explored in transfected cell lines and in lymphocytes from obese children. RESULTS-The rs361072 C/T variant was associated with HOMA-IR in the obese children cohorts (1.7 x 10(-12) < P < 2 x 10(-4) for C/C vs. T/T using regression analysis). HOMA-IR averaged 3.3 +/- 0.1 in C/C and 4.5 +/- 0.2 in T/T obese children (P = 4.5 X 10(-6) by ANOVA). C/T patients had intermediate values. As shown by the interaction between BMI and genotype (P = 2.1 X 10(-9)), the association of rs361072 with HOMA-IR depended on BMI and was only marginal in nonobese children (P = 0.04). At the molecular level, the C allele of rs361072 was found to create a GATA-binding site able to increase transcription of PIK3CB. CONCLUSIONS-We postulate that the C allele of rs361072 is a causal variant capable of attenuating insulin resistance in obese children through increased expression of p110 beta. C1 [Le Stunff, Catherine; Mariot, Virginie; Lotton, Chantal; Bougneres, Pierre] Hop St Vincent de Paul, INSERM, Inst Natl Sante Rech Med, U561, F-75014 Paris, France. [Le Stunff, Catherine; Bougneres, Pierre] Univ Paris 05, Hop St Vincent de Paul, AP HP, Paris, France. [Dechartres, Agnes] Hop Necker Enfants Malad, Serv Biostat, Paris, France. [Trainor, Cecelia] NIDDK, NIH, Mol Biol Lab, Bethesda, MD USA. [Del Giudice, Emanuele Miraglia] Univ Naples 2, Dept Pediat, Naples, Italy. [Meyre, David; Froguel, Philippe] Inst Pasteur, CNRS, UMR8090, F-59019 Lille, France. [Bieche, Ivan; Laurendeau, Ingrid] INSERM, Fac Pharm, U745, Paris, France. [Zelenika, Diana; Lathrop, Mark] Genom Ctr Commissarate Energie Atom, Ctr Natl Genotypage, Evry, France. [Fallin, Dani] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. [Romeo, Paul-Henri] Inst Radiobiol Cellulaire & Mol, Dept Sci Vivant Commissariat Energie Atom, Fontenay Aux Roses, France. RP Bougneres, P (reprint author), Hop St Vincent de Paul, INSERM, Inst Natl Sante Rech Med, U561, 82 Ave Denfert Rochereau, F-75014 Paris, France. EM bougneres@paris5.inserm.fr RI Meyre, David/D-7315-2011 FU Intramural NIH HHS NR 52 TC 11 Z9 11 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2008 VL 57 IS 2 BP 494 EP 502 DI 10.2337/db07-1273 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 259BP UT WOS:000252914400027 PM 17977952 ER PT J AU Black, HR Davis, B Barzilay, J Nwachuku, C Baimbridge, C Marginean, H Wright, JT Basile, J Wong, ND Whelton, P Dart, RA Thadani, U AF Black, Henry R. Davis, Barry Barzilay, Joshua Nwachuku, Chuke Baimbridge, Charles Marginean, Horia Wright, Jackson T., Jr. Basile, Jan Wong, Nathan D. Whelton, Paul Dart, Richard A. Thadani, Udho TI Metabolic and Clinical Outcomes in Nondiabetic Individuals With the Metabolic Syndrome Assigned to Chlorthalidone, Amlodipine, or Lisinopril as Initial Treatment for Hypertension A report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) SO DIABETES CARE LA English DT Article; Proceedings Paper CT 15th Meeting of the European-Society-of-Hypertension CY JUN 17-21, 2005 CL Milan, ITALY SP European Soc Hypertens ID CONVERTING ENZYME-INHIBITORS; TYPE-2 DIABETES-MELLITUS; RENIN-ANGIOTENSIN SYSTEM; CARDIOVASCULAR EVENTS; BLOOD-PRESSURE; THERAPY; RISK; MORTALITY; RAMIPRIL; DISEASE AB OBJECTIVE - Optimal initial anti hypertensive drug therapy in people with the metabolic syndrome is unknown. RESEARCH DESIGN AND METHODS - We conducted a subgroup analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) to compare metabolic, cardiovascular, and renal outcomes in individuals assigned to initial hypertension treatment with a thiazide-like diuretic (chlorthalidone), a calcium channel blocker (CCB; amlodipine), or an ACE inhibitor (lisinopril) in nondiabetic individuals with or without metabolic syndrome. RESULTS - in participants with metabolic syndrome, at 4 years of follow-up, the incidence of newly diagnosed diabetes (fasting glucose >= 126 mg/dl) was 17.1% for chlorthalidone, 16.0% for amlodipine (P = 0.49, chlorthalidone vs. amlodipine) and 12.6% for lisinopril (P < 0.05, lisinopril vs. chlorthalidone). For those without metabolic syndrome, the rate of newly diagnosed diabetes was 7.7% for chlorthalidone, 4.2% for amlodipine, and 4.7% for lisinopril (P < 0.05 for both comparisons). There were no differences in relative risks (RRs) for outcomes With amlodipine compared with chlorthalidone in those with metabolic syndromes in those without metabolic syndrome, there was a higher risk for heart failure (RR 1.55 [95% CI 1.25-1.35]), In comparison With lisinopril, chlorthalidone was superior in those with Metabolic syndrome with respect to heart failure (1.31 [1.04-1.64]) and combined cardiovascular, disease (CVD) (1.19 - 1.07-1.32]). No significant treatment group-metabolic syndrome interaction was noted. CONCLUSIONS - Despite a less favor thiazide-like diuretic able Metabolic profile, initial therapy for hypertension offers similar, and in some instances possibly superior, CVD outcomes in older hypertensive adults with metabolic syndrome, as compared with treatment With CCBs and ACE inhibitors. C1 [Barzilay, Joshua] Kaiser Permanente Georgia, Tucker, GA 30084 USA. [Black, Henry R.] NYU, Sch Med, New York, NY USA. [Davis, Barry; Baimbridge, Charles] Univ Texas Hlth Sci Ctr Houston, Sch Publ Hlth, Houston, TX USA. [Nwachuku, Chuke] NHLBI, Bethesda, MD 20892 USA. [Marginean, Horia] Ottawa Hosp, Ottawa, ON, Canada. [Wright, Jackson T., Jr.] Univ Hosp Cleveland, Gen Clin Res Ctr, Cleveland, OH 44106 USA. [Basile, Jan] VA Med Ctr Charleston, Charleston, SC USA. [Wong, Nathan D.] Univ So Calif, Med Ctr, Los Angeles, CA USA. [Whelton, Paul] Loyola Univ, Sch Med, Maywood, IL 60153 USA. [Dart, Richard A.] Marshfield Clin Fdn Med Res & Educ, Marshfield, WI USA. [Thadani, Udho] Univ Oklahoma, Hlth Sci Ctr, VA Med Ctr, Oklahoma City, OK USA. RP Barzilay, J (reprint author), Kaiser Permanente Georgia, 200 Crescent Ctr Pkwy, Tucker, GA 30084 USA. EM joshua.barzilay@kp.org FU NHLBI NIH HHS [N01-HC-35130] NR 30 TC 52 Z9 55 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2008 VL 31 IS 2 BP 353 EP 360 DI 10.2337/dc07-1452 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 452TE UT WOS:000266563300034 PM 18000186 ER PT J AU Felmlee, MA Lon, HK Gonzalez, FJ Yu, AM AF Felmlee, Melanie A. Lon, Hoi-Kei Gonzalez, Frank J. Yu, Ai-Ming TI Cytochrome P450 expression and regulation in CYP3A4/CYP2D6 double transgenic humanized mice SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID DRUG-DRUG INTERACTIONS; HUMAN LIVER-MICROSOMES; IN-VITRO; GENDER-DIFFERENCES; HUMAN CYP2D6; HUMAN CYP3A4; METABOLISM; 3A4; PHARMACOKINETICS; MIDAZOLAM AB Analysis of the developmental and sexual expression of cytochrome P450 drug-metabolizing enzymes is impeded by multiple and varied external factors that influence its regulation. In the present study, a CYP2D6/CYP3A4-double transgenic (Tg-CYP2D6/CYP3A4) mouse model was employed to investigate hepatic CYP2D6 and CYP3A4 ontogeny and sexual dimorphism. Both age and sex have considerable effects on hepatic CYP3A4 protein expression in 3- to 8-week-old transgenic mice, whereas neither factor alters CYP2D6 content. Constitutive CYP2D6 expression resulted in 2- to 3-fold higher dextromethorphan O-demethylase activity in Tg-CYP2D6/CYP3A4 mouse liver microsomes compared with wild-type mice. In contrast, expression of CYP3A4 in transgenic mouse livers did not increase dextromethorphan N-demethylase and midazolam 1'-hydroxylase activities. Pretreatment with pregnenolone 16 alpha-carbonitrile (PCN) and 1,4-bis-2-(3, 5-dichloropyridyloxy)-benzene (TCPOBOP) elevated CYP3A4 expression in double transgenic mice. Interestingly, induction of hepatic CYP3A4 was greater in females than age- and treatment-matched males. Consequently, the increase in midazolam 1'-hydroxylase activity was markedly higher in 8-week-old female mice than in corresponding males (8-fold versus 6-fold for PCN treatment and 6-fold versus 5-fold for TCPOBOP). Furthermore, increases in testosterone 6 beta-hydroxylase activity after CYP3A induction were relatively lower compared with those in midazolam 1'-hydroxylation for age-, sex-, and treatment-matched mice. The difference in CYP3A4 expression and induction between male and female mice suggests that women may be more susceptible to CYP3A4-mediated drug-drug interactions, and the extent of drug-drug interactions could be substrate dependent. C1 [Felmlee, Melanie A.; Lon, Hoi-Kei; Yu, Ai-Ming] SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Buffalo, NY 14260 USA. [Gonzalez, Frank J.] NIH, NCI, Ctr Canc Res, Lab Metab, Bethesda, MD 20892 USA. RP Yu, AM (reprint author), SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Dept Pharmaceut Sci, Buffalo, NY 14260 USA. EM aimingyu@buffalo.edu RI Lon, Hoi-Kei/G-5848-2015 OI Lon, Hoi-Kei/0000-0001-9909-3144 NR 36 TC 34 Z9 36 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD FEB PY 2008 VL 36 IS 2 BP 435 EP 441 DI 10.1124/dmd.107.018838 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 255CR UT WOS:000252634900028 PM 18048490 ER PT J AU LoPiccolo, J Blumenthal, GM Bernstein, WB Dennis, PA AF LoPiccolo, Jaclyn Blumenthal, Gideon M. Bernstein, Wendy B. Dennis, Phillip A. TI Targeting the PI3K/Akt/mTOR pathway: Effective combinations and clinical considerations SO DRUG RESISTANCE UPDATES LA English DT Review DE PI3 kinase; Akt; combination; chemotherapy; cancer; wortmannin; PX-866; perfosine; mTOR inhibitors; rapamycin; RAD-001; PI-103; triciribine (API-2) ID GROWTH-FACTOR-RECEPTOR; CELL LUNG-CANCER; PROTEIN-KINASE-B; TRICYCLIC NUCLEOSIDE PHOSPHATE; HUMAN PANCREATIC-CANCER; PHASE-II TRIAL; MALIGNANT GLIOMA-CELLS; RECURRENT GLIOBLASTOMA-MULTIFORME; 3'-KINASE SIGNALING PATHWAY; ACTIVATED AKT EXPRESSION AB The PI3K/Akt/mTOR pathway is a prototypic survival pathway that is constitutively activated in many types of cancer. Mechanisms for pathway activation include loss of tumor suppressor PTEN function, amplification or mutation of PI3K, amplification or mutation of Akt, activation of growth factor receptors, and exposure to carcinogens. Once activated, signaling through Akt can be propagated to a diverse array of substrates, including mTOR, a key regulator of protein translation. This pathway is an attractive therapeutic target in cancer because it serves as a convergence point for many growth stimuli, and through its downstream substrates, controls cellular processes that contribute to the initiation and maintenance of cancer. Moreover, activation of the Akt/mTOR pathway confers resistance to many types of cancer therapy, and is a poor prognostic factor for many types of cancers. This review will provide an update on the clinical progress of various agents that target the pathway, such as the Akt inhibitors perifosine and PX-866 and mTOR inhibitors (rapamycin, CCI-779, RAD-001) and discuss strategies to combine these pathway inhibitors with conventional chemotherapy, radiotherapy, as well as newer targeted agents. We will also discuss how the complex regulation of the PI3K/Akt/mTOR pathway poses practical issues concerning the design of clinical trials, potential toxicities and criteria for patient selection. Published by Elsevier Ltd. C1 [LoPiccolo, Jaclyn; Blumenthal, Gideon M.; Bernstein, Wendy B.; Dennis, Phillip A.] NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20899 USA. RP Dennis, PA (reprint author), NCI, Med Oncol Branch, Ctr Canc Res, Bldg 8,Room 5101,8901 Wisconsin Ave, Bethesda, MD 20899 USA. EM pdennis@nih.gov RI leng, xianwei/F-9073-2011 FU Intramural NIH HHS [Z01 BC010450-06] NR 233 TC 400 Z9 427 U1 7 U2 77 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD FEB-APR PY 2008 VL 11 IS 1-2 BP 32 EP 50 DI 10.1016/j.drup.2007.11.003 PG 19 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 302QK UT WOS:000255983600004 PM 18166498 ER PT J AU Brown, MA Cunningham, MW Roca, AL Troyer, JL Johnson, WE O'Brien, SJ AF Brown, Meredith A. Cunningham, Mark W. Roca, Alfred L. Troyer, Jennifer L. Johnson, Warren E. O'Brien, Stephen J. TI Genetic characterization of feline leukemia virus from Florida panthers SO EMERGING INFECTIOUS DISEASES LA English DT Article ID LONG TERMINAL REPEAT; FELV-RELATED SEQUENCES; IMMUNODEFICIENCY VIRUS; SUBGROUP-B; INFECTION; CONCOLOR; CATS; SEROPREVALENCE; DETERMINANTS; TRANSMISSION AB From 2002 through 2005, an outbreak of feline leukemia virus (FeLV) occurred in Florida panthers (Puma concolor coryi). Clinical signs included lymphadenopathy, anemia, septicemia, and weight loss; 5 panthers died. Not associated with FeLV outcome were the genetic heritage of the panthers (pure Florida vs. Texas/Florida crosses) and co-infection with feline immunodeficiency virus. Genetic analysis of panther FeLV, designated FeLV-Pco, determined that the outbreak likely came from 1 cross-species transmission from a domestic cat. The FeLV-Pco virus was closely related to the domestic cat exogenous FeLV-A subgroup in lacking recombinant segments derived from endogenous FeLV. FeLV-Pco sequences were most similar to the well-characterized FeLV-945 strain, which is highly virulent and strongly pathogenic in domestic cats because of unique long terminal repeat and envelope sequences. These unique features may also account for the severity of the outbreak after cross-species transmission to the panther. C1 [Brown, Meredith A.; Roca, Alfred L.; Troyer, Jennifer L.; Johnson, Warren E.; O'Brien, Stephen J.] NCI, Frederick, MD 21702 USA. [Cunningham, Mark W.] Florida Fish & Wildlife Conservat Commiss, Gainesville, FL USA. [Troyer, Jennifer L.] Univ Illinois, Urbana, IL 61801 USA. [Roca, Alfred L.; Troyer, Jennifer L.] SAIC Frederick, Frederick, MD USA. RP O'Brien, SJ (reprint author), NCI, Bldg 560,Rm 11-82, Frederick, MD 21702 USA. EM obrien@nciferf.gov RI Troyer, Jennifer/B-8415-2012; Johnson, Warren/D-4149-2016 OI Johnson, Warren/0000-0002-5954-186X FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 37 TC 19 Z9 19 U1 2 U2 22 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2008 VL 14 IS 2 BP 252 EP 259 DI 10.3201/eid1402.070981 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 259VS UT WOS:000252969600009 PM 18258118 ER PT J AU Liu, D Deschamps, A Korach, KS Murphy, E AF Liu, Dianxin Deschamps, Anne Korach, Kenneth S. Murphy, Elizabeth TI Estrogen-enhanced gene expression of lipoprotein lipase in heart is antagonized by progesterone SO ENDOCRINOLOGY LA English DT Article ID RECEPTOR-BETA; UP-REGULATION; RAT; 17-BETA-ESTRADIOL; WOMEN; METABOLISM; FAILURE; BINDING; TISSUES; FEMALE AB Although estrogen has effects on the heart, little is known regarding which genes in the heart are directly responsive to estrogen. We have shown previously that lipoprotein lipase (LPL) expression was increased in female hearts compared with male hearts. To test whether LPL gene expression in heart is regulated by estrogen, we perfused mouse hearts from ovariectomized females with 100 nM 17 beta-estradiol or vehicle for 2 h, after which hearts were frozen, and RNA was isolated. The SYBR green real-time PCR method was used to detect LPL gene expression. We found that addition of 17 beta-estradiol to hearts from ovariectomized females resulted in a significant increase in LPL mRNA. This estrogen effect on LPL gene expression in mouse heart can be blocked by the estrogen receptor ER) antagonist ICI 182,780 or by progesterone. We also identified a potential estrogen receptor element (ERE) enhancer sequence located in the first intron of the mouse LPL gene. The potential ERE sequence was linked to a TATA-luciferase (LUC) reporter plasmid in HeLa cells. Both ER alpha and ER beta stimulated strong activity on the heterologous promoter reporter in Hela cells upon estrogen addition. Both E alpha and ER beta activities on the LPLERE reporter were abrogated by the ER antagonist ICI 182,780. Progesterone also dose dependently inhibited the estrogen-mediated increase in LPL ERE reporter activity. These results show that heart LPL is an estrogen-responsive gene exhibiting an intronic regulatory sequence. C1 [Liu, Dianxin; Deschamps, Anne; Murphy, Elizabeth] NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Korach, Kenneth S.] NIEHS, Reprod & Dev Toxicol Lab, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. [Deschamps, Anne; Murphy, Elizabeth] NHLBI, Vasc Med Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Murphy, E (reprint author), Natl Inst Hlth, Vasc Med Brnach, Room 7N112,10 Ctr Dr, Bethesda, MD 20892 USA. EM murphy1@niehs.nih.gov OI Deschamps, Anne/0000-0001-7415-1408; Korach, Kenneth/0000-0002-7765-418X FU Intramural NIH HHS NR 26 TC 10 Z9 11 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2008 VL 149 IS 2 BP 711 EP 716 DI 10.1210/en.2007-0620 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 253GN UT WOS:000252506800035 PM 17974624 ER PT J AU Benbrahim-Tallaa, L Waalkes, MP AF Benbrahim-Tallaa, Lamia Waalkes, Michael P. TI Inorganic arsenic and human prostate cancer SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE androgen-independent; AR; arsenic; carcinogenesis; DNA methylation; human malignant transformation; MAP kinase; prostate; Ras ID INDUCED MALIGNANT-TRANSFORMATION; EPITHELIAL-CELL LINES; DRINKING-WATER; WELL WATER; ANDROGEN INDEPENDENCE; ACTIVATION; GENE; TRANSPORT; MORTALITY; TOXICITY AB OBJECTIVE: We critically evaluated the etiologic role of inorganic arsenic in human prostate cancer. DATA SOURCES: We assessed data from relevant epidemiologic studies concerning environmental inorganic arsenic exposure. Whole animal studies were evaluated as were in vitro model systems of inorganic arsenic carcinogenesis in the prostate. DATA SYNTHESIS: Multiple studies in humans reveal an association between environmental inorganic arsenic exposure and prostate cancer mortality or incidence. Many of these human studies provide clear evidence of a dose-response relationship. Relevant whole animal models showing a relationship between inorganic arsenic and prostate cancer are not available. However, cellular model systems indicate arsenic can induce malignant transformation of human prostate epithelial cells in vitro. Arsenic also appears to impact prostate cancer cell progression by precipitating events leading to androgen independence in vitro. CONCLUSION: Available evidence in human populations and human cells in vitro indicates that the prostate is a target for inorganic arsenic carcinogenesis. A role for this common environmental contaminant in human prostate cancer initiation and/or progression would be very important. C1 [Benbrahim-Tallaa, Lamia; Waalkes, Michael P.] NIEHS, Inorgan Carcinogenesis Sect,Lab Comparat Carcinog, NCI, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Waalkes, MP (reprint author), NIEHS, Inorgan Carcinogenesis Sect,Lab Comparat Carcinog, NCI, NIH,Dept Hlth & Human Serv, MD F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov FU Intramural NIH HHS NR 78 TC 68 Z9 73 U1 0 U2 8 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2008 VL 116 IS 2 BP 158 EP 164 DI 10.1289/ehp.10423 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 257XH UT WOS:000252831800024 PM 18288312 ER PT J AU Cupul-Uicab, LA Gladen, BC Hernandez-Avila, M Weber, JP Longnecker, MP AF Cupul-Uicab, Lea A. Gladen, Beth C. Hernandez-Avila, Mauricio Weber, Jean-Philippe Longnecker, Matthew P. TI DDE, a degradation product of DDT, and duration of lactation in a highly exposed area of Mexico SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE breast-feeding; DDE; DDT; infant; lactation ID DICHLORODIPHENYL DICHLOROETHENE DDE; POLYCHLORINATED-BIPHENYLS PCBS; HUMAN-MILK; ANOGENITAL DISTANCE; MALE NEWBORNS; PREGNANCY; CHIAPAS; INFANT AB BACKGROUND: Higher levels of 1, 1 -dichloro-2,2-bis (p-chlorophenyl) ethylene (DDE), the major degradation product of 1,1, l-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT), have been related to shorter duration of breast-feeding in previous studies. If DDE truly shortens lactation, this has public health importance regarding infant mortality and the use of DDT for malaria control. OBJECTIVE: Our aim was to assess the relationship of maternal DDE concentrations with length of subsequent lactation. METHODS: We conducted a relatively large study in a highly exposed area of Mexico. We followed 784 mother-son pairs to dei ermine length of lactation. DDE and DDT were measured in maternal serum obtained within a day of delivery. We fit proportional hazard models with and without stratifying by previous breast-feeding, because an association of DDE with duration of lactation among those who breast-fed previously could be attributed to a noncausal mechanism. RESULTS: Compared with those with DDE concentrations :<= 3.00 mu g/g, the adjusted hazard ratios of weaning according to DDE category were, for concentrations 3.01-6.00 mu g/g, 1.27 [95% confidence interval (CI), 1.04-1.551; for concentrations 6.01-9.00 mu g/g, 1.23 (95% Cl, 0.92-1.63); and for concentrations > 9.00 mu g/g, 1.17 (95% CI, 0.92-1.49). The corresponding ratios for women who previously breast-fed were 1.40 (95% CI, 1.06-1.87); 1.91 (95% Cl, 1.24-2.93); and 1.76 (95% CI, 1.22-2.53). Those for women who had not breast-fed previously were 1.14 (95% CI, 0.86-1-52); 0.90 (95% CI, 0.61-1.31); and 0.91 (95% Cl, 0.66-1.26). CONCLUSIONS: Data from our relatively large study in a highly exposed area of Mexico did not support the hypothesis that exposure to DDE shortens length of lactation. The association seen in women who previously breast-fed was likely attributed to a noncausal mechanism. Nonetheless, whether DDT has other important adverse effects on humans is still an open question. C1 [Cupul-Uicab, Lea A.; Longnecker, Matthew P.] NIEHS, NIH, Dept Hlth & Human Serv, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. [Gladen, Beth C.] NIEHS, NIH, Dept Hlth & Human Serv, Biostat Branch, Res Triangle Pk, NC 27709 USA. [Cupul-Uicab, Lea A.; Hernandez-Avila, Mauricio] Inst Nacl Salud Publ, Ctr Populat Hlth Res, Cuernavaca, Morelos, Mexico. [Hernandez-Avila, Mauricio] Minist Hlth, Subsecretaria Promoc & Prevenc Salud, Mexico City, DF, Mexico. [Weber, Jean-Philippe] Inst Natl Sante Publ Quebec, Ctr Toxicol, Quebec City, PQ, Canada. RP Longnecker, MP (reprint author), NIEHS, NIH, Dept Hlth & Human Serv, Epidemiol Branch, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM longnecl@niehs.nih.gov RI CUPUL UICAB, LEA/C-8699-2014; OI CUPUL UICAB, LEA/0000-0001-6190-4474; Longnecker, Matthew/0000-0001-6073-5322 FU Intramural NIH HHS; NIEHS NIH HHS [N01 ES 15467] NR 27 TC 22 Z9 22 U1 0 U2 7 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2008 VL 116 IS 2 BP 179 EP 183 DI 10.1289/ehp.10550 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 257XH UT WOS:000252831800027 PM 18288315 ER PT J AU Galperin, MY AF Galperin, Michael Y. TI Social bacteria and asocial eukaryotes SO ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID MARINE ACTINOMYCETE SALINISPORA; LEGUME SESBANIA-ROSTRATA; AZORHIZOBIUM-CAULINODANS; GEN. NOV.; CHLOROPHYLL-D; ANAEROBIC OXIDATION; GENOME SEQUENCE; MAJOR PIGMENT; HERPETOSIPHON; ARENICOLA C1 Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 FU Intramural NIH HHS [Z99 LM999999] NR 59 TC 4 Z9 4 U1 0 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1462-2912 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD FEB PY 2008 VL 10 IS 2 BP 281 EP 288 DI 10.1111/j.1462-2920.2007.01552.x PG 8 WC Microbiology SC Microbiology GA 250SM UT WOS:000252320800001 PM 18199122 ER PT J AU Hartman, AL Lyle, M Rogawski, MA Gasior, M AF Hartman, Adam L. Lyle, Megan Rogawski, Michael A. Gasior, Maciej TI Efficacy of the ketogenic diet in the 6-Hz seizure test SO EPILEPSIA LA English DT Article DE ketogenic diet; 6-Hz seizure model; seizure; intractable epilepsy ID BETA-HYDROXYBUTYRATE; EPILEPSY; MICE; THRESHOLD; MODELS AB Purpose: Since the ketogenic diet is effective in drug-resistant epilepsies, we sought to determine whether it is active in the 6-Hz seizure test, which identifies agents with a broader spectrum of activity than conventional antiepileptic screening tests. Methods: Male (3-4 week old) NIH Swiss mice were fed a normal or ketogenic diet ad libitum for 2-21 days. The intensity of the corneal stimulation current required to elicit seizures in the 6-Hz test was measured. Blood glucose and beta-hydroxybutyrate were measured on the day of seizure testing. Results: CC50 (current intensity producing seizures in 50% of mice tested) was 50.6 mA and 15 mA in mice fed for 12 days with a ketogenic or normal diet, respectively (p < 0.001). CC50 was elevated in separate experiments after 16, but not 2, 5, and 21 days of ketogenic diet exposure. CC50 values of growing mice fed the normal diet does not differ, indicating CC50 does not vary with mouse weight during a rapid growth phase. beta-Hydroxybutyrate was significantly higher, and glucose was significantly lower in mice fed the ketogenic diet than those fed the normal diet. Blood glucose and beta-hydroxybutyrate levels did not correlate with CC50. Discussion: The ketogenic diet significantly elevates the seizure threshold in the 6-Hz test in a time-specific manner. Protection from seizures in this model was not related to level of ketosis. CC50 was insensitive to body weight in mice fed the normal diet, demonstrating that the 6-Hz model can assess anticonvulsant regimens where weight is a confounding factor. C1 [Hartman, Adam L.] Johns Hopkins Univ Hosp, Dept Neurol, John M Freeman Pediat Epilepsy Ctr, Baltimore, MD 21287 USA. [Hartman, Adam L.; Lyle, Megan; Rogawski, Michael A.; Gasior, Maciej] NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. [Rogawski, Michael A.] Univ Calif, Davis Sch Med, Dept Neurol, Sacramento, CA USA. [Gasior, Maciej] Cephalon Inc, W Chester, PA USA. RP Hartman, AL (reprint author), Johns Hopkins Univ Hosp, Dept Neurol, John M Freeman Pediat Epilepsy Ctr, 600 N Wolfe St,Meyer 2-147, Baltimore, MD 21287 USA. EM ahartma2@jhmi.edu RI Rogawski, Michael/B-6353-2009 OI Rogawski, Michael/0000-0002-3296-8193 FU Intramural NIH HHS [Z01 NS002877-15] NR 22 TC 31 Z9 31 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0013-9580 J9 EPILEPSIA JI Epilepsia PD FEB PY 2008 VL 49 IS 2 BP 334 EP 339 DI 10.1111/j.1528-1167.2007.01430.x PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 256FG UT WOS:000252712500016 PM 18070095 ER PT J AU Aroniadou-Anderjaska, V Fritsch, B Qashu, F Braga, MFM AF Aroniadou-Anderjaska, Vassiliki Fritsch, Brita Qashu, Felicia Braga, Maria F. M. TI Pathology and pathophysiology of the amygdala in epileptogenesis and epilepsy SO EPILEPSY RESEARCH LA English DT Review DE temporal lobe epilepsy; amygdala; basolateral amygdala; GABAergic synaptic transmission; glutamatergic synaptic transmission; epileptogenesis ID TEMPORAL-LOBE EPILEPSY; RAT BASOLATERAL AMYGDALA; LIMBIC STATUS EPILEPTICUS; TRAUMATIC BRAIN-INJURY; SOMAN-INDUCED SEIZURES; POSTTRAUMATIC-STRESS-DISORDER; LITHIUM-PILOCARPINE MODEL; GAMMA-AMINOBUTYRIC-ACID; GLUR5 KAINATE RECEPTORS; EXCITATORY AMINO-ACIDS AB Acute brain insults, such as traumatic brain injury, status epilepticus, or stroke are common etiologies for the development of epilepsy, including temporal lobe epilepsy (TLE), which is often refractory to drug therapy. The mechanisms by which a brain injury can lead to epilepsy are poorly understood. It is well recognized that excessive glutamatergic activity plays a major role in the initial pathological and pathophysiological damage. This initial damage is followed by a latent period, during which there is no seizure activity, yet a number of pathophysiological and structural alterations are taking place in key brain regions, that culminate in the expression of epilepsy. The process by which affected/injured neurons that have survived the acute insult, along with well-preserved neurons are progressively forming hyperexcitable, epileptic neuronal networks has been termed epileptogenesis. Understanding the mechanisms of epileptogenesis is crucial for the development of therapeutic interventions that will prevent the manifestation of epilepsy after a brain injury, or reduce its severity. The amygdala, a temporal lobe structure that is most welt known for its central role in emotional behavior, also plays a key role in epileptogenesis and epilepsy. In this article, we review the current knowledge on the pathology of the amygdala associated with epileptogenesis and/or epilepsy in TLE patients, and in animal models of TLE. In addition, because a derangement in the balance between glutamatergic and GABAergic synaptic transmission is a salient feature of hyperexcitable, epileptic neuronal circuits, we also review the information available on the role of the glutamatergic and GABAergic systems in epileptogenesis and epilepsy in the amygdala. Published by Elsevier B.V. C1 [Aroniadou-Anderjaska, Vassiliki; Fritsch, Brita; Braga, Maria F. M.] Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. [Qashu, Felicia; Braga, Maria F. M.] Uniformed Serv Univ Hlth Sci, Neurosci Program, Bethesda, MD 20814 USA. [Fritsch, Brita] NINDS, Epilepsy Res Sect, NIH, Bethesda, MD 20892 USA. RP Braga, MFM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM mbraga@usuhs.mil OI Fritsch, Brita/0000-0003-4884-9049 FU NINDS NIH HHS [U01 NS058162, U01 NS058162-01, U01 NS058162-02] NR 174 TC 76 Z9 81 U1 2 U2 12 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-1211 J9 EPILEPSY RES JI Epilepsy Res. PD FEB PY 2008 VL 78 IS 2-3 BP 102 EP 116 DI 10.1016/j.eplepsyres.2007.11.011 PG 15 WC Clinical Neurology SC Neurosciences & Neurology GA 274VT UT WOS:000254031600002 PM 18226499 ER PT J AU Sachs, B AF Sachs, Benjamin TI Reasons and Requirements SO ETHICAL THEORY AND MORAL PRACTICE LA English DT Article DE Reasons; Practical reason AB In this essay I defend the claim that all reasons can ground final requirements. I begin by establishing a prima facie case for the thesis by noting that on a common-sense understanding of what finality is, it must be the case that all reasons can ground such requirements. I spend the rest of the paper defending the thesis against two recent challenges. The first challenge is found in Joshua Gert's recent book, Brute Rationality. In it he argues that reasons play two logically distinct roles - requiring action and justifying action. He argues, further, that some reasons - 'purely justificatory' reasons - play only the latter role. Jonathan Dancy offers the second challenge in his Ethics Without Principles, where he distinguishes between the 'favoring' and 'ought-making' roles of reasons. While all reasons play the former role, some do not play the latter, and are therefore irrelevant to what one ought to do. My contention is that both Gert and Dancy are going to have trouble accounting for our intuitions in a number of cases. C1 NIH, Dept Bioeth, Bethesda, MD 20892 USA. RP Sachs, B (reprint author), NIH, Dept Bioeth, 10 Ctr Dr,Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM basachs@wisc.edu NR 6 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1386-2820 J9 ETHICAL THEORY MORAL JI Ethical Theory Moral Pract. PD FEB PY 2008 VL 11 IS 1 BP 73 EP 83 DI 10.1007/s10677-007-9086-2 PG 11 WC Philosophy SC Philosophy GA 506WS UT WOS:000270808600006 ER PT J AU Kutty, G Hernandez-Novoa, B Czapiga, M Kovacs, JA AF Kutty, Geetha Hernandez-Novoa, Beatriz Czapiga, Meggan Kovacs, Joseph A. TI Pneumocystis encodes a functional S-adenosylmethionine synthetase gene SO EUKARYOTIC CELL LA English DT Article ID METHIONINE ADENOSYLTRANSFERASE; SCHIZOSACCHAROMYCES-POMBE; SACCHAROMYCES-CEREVISIAE; LEISHMANIA-DONOVANI; ESCHERICHIA-COLI; STRUCTURAL GENE; SP-NOV.; CARINII; EXPRESSION; IDENTIFICATION AB S-Adenosylmethionine (AdoMet) synthetase (EC 2.5.1.6) is the enzyme that catalyzes the synthesis of AdoMet, a molecule important for all cellular organisms. We have cloned and characterized an AdoMet synthetase gene (sam1) from Pneumocystis spp. This gene was transcribed primarily as an similar to 1.3-kb mRNA which encodes a protein containing 381 amino acids in P. carinii or P. murina and 382 amino acids in P. jirovecii. sam1 was also transcribed as part of an apparent polycistronic transcript of similar to 5.6 kb, together with a putative chromatin remodeling protein homologous to Saccharomyces cerevisiae, CHD1. Recombinant Sam1, when expressed in Escherichia coli, showed functional enzyme activity. Immunoprecipitation and confocal immunofluorescence analysis using an antipeptide antibody showed that this enzyme is expressed in P. murina. Thus, Pneumocystis, like other organisms, can synthesize its own AdoMet and may not depend on its host for the supply of this important molecule. C1 [Kutty, Geetha; Hernandez-Novoa, Beatriz; Kovacs, Joseph A.] NIH Clin Ctr, Natl Inst Hlth, Dept Crit Care Med, Bethesda, MD USA. [Czapiga, Meggan] NIAID, Natl Inst Hlth, Res Technol Branch, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), Bldg 10,Room 2C145,MSC 1662, Bethesda, MD 20892 USA. EM jkovacs@nih.gov FU Intramural Research Program of the NIH Clinical Center; National Institute of Allergy and Infectious Diseases FX We thank Rene Costello and Howard Mostowski for their assistance with the animal studies.; This research was supported by the Intramural Research Program of the NIH Clinical Center and the National Institute of Allergy and Infectious Diseases. NR 37 TC 12 Z9 13 U1 0 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1535-9778 J9 EUKARYOT CELL JI Eukaryot. Cell PD FEB PY 2008 VL 7 IS 2 BP 258 EP 267 DI 10.1128/EC.00345-07 PG 10 WC Microbiology; Mycology SC Microbiology; Mycology GA 340SS UT WOS:000258665900008 PM 18065654 ER PT J AU Zannad, F Stough, WG Pitt, B Cleland, JGF Adams, KF Geller, NL Torp-Pedersen, C Kirwan, BA Follath, F AF Zannad, Faiez Stough, Wendy Gattis Pitt, Bertram Cleland, John G. F. Adams, Kirkwood F. Geller, Nancy L. Torp-Pedersen, Christian Kirwan, Bridget-Anne Follath, Ferenc TI Heart failure as an endpoint in heart failure and non-heart failure cardiovascular clinical trials: the need for a consensus definition SO EUROPEAN HEART JOURNAL LA English DT Article DE cardiovascular disease; heart failure; clinical trials; hypertension; hypercholesterolaemia ID CARDIAC TROPONIN-T; NATIONAL REGISTRY ADHERE; LIPID-LOWERING TREATMENT; CALCIUM-CHANNEL BLOCKER; MYOCARDIAL-INFARCTION; HYPERTENSIVE PATIENTS; ATTACK TRIAL; CORONARY-DISEASE; RANDOMIZED-TRIAL; TERM PROGNOSIS AB Specific criteria have been established to define the occurrence of myocardial infarction (MI) and stroke in cardiovascular clinical trials, but there is not a consistent definition for heart failure. Heart failure events appear to occur at a rate that is similar to stroke and MI in trials of hypertension, hyperlipidaemia, diabetes, and coronary heart disease, yet a consistent approach to defining heart failure events has not yet been realized. The wide range of definitions used in clinical trials makes it difficult to interpret new data in the context of existing literature. This inconsistency has led to challenges in determining the incidence of heart failure in cardiovascular studies and the effects of interventions on these endpoints. This paper examines issues related to defining heart failure events in cardiovascular clinical trials and presents a definition to formally address this issue. C1 [Zannad, Faiez] INSERM, U684, CHU,Hypertens & Prevent Cardiol Div, Ctr Invest Clinq,Dept Cardiovasc Dis, F-54200 Nancy, France. [Stough, Wendy Gattis] Campbell Univ, Sch Pharm, Dept Clin Res, Res Triangle Pk, NC USA. [Pitt, Bertram] Univ Michigan, Ann Arbor, MI 48109 USA. [Cleland, John G. F.] Univ Hull, Dept Cardiol, Kingston Upon Hull, Yorks, England. [Adams, Kirkwood F.] Univ N Carolina, Chapel Hill, NC USA. [Geller, Nancy L.] NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. [Torp-Pedersen, Christian] Univ Copenhagen, Copenhagen, Denmark. [Kirwan, Bridget-Anne] SOCAR Res, Nyon, Switzerland. [Follath, Ferenc] Univ Hosp, Zurich, Switzerland. RP Zannad, F (reprint author), INSERM, U684, CHU,Hypertens & Prevent Cardiol Div, Ctr Invest Clinq,Dept Cardiovasc Dis, F-54200 Nancy, France. EM zannad@chu-nancy.fr RI Torp-Pedersen, Christian/E-5931-2013; Stough, Wendy/R-4287-2016; OI Stough, Wendy/0000-0001-8290-1205; Kirwan, Bridget-Anne/0000-0002-3814-3598; Cleland, John/0000-0002-1471-7016 NR 63 TC 24 Z9 25 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0195-668X J9 EUR HEART J JI Eur. Heart J. PD FEB PY 2008 VL 29 IS 3 BP 413 EP 421 DI 10.1093/eurheartj/ehm603 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 258YI UT WOS:000252905900024 PM 18245122 ER PT J AU Abnet, CC Freedman, ND Hollenbeck, AR Fraumeni, JF Leitzmann, M Schatzkin, A AF Abnet, Christian C. Freedman, Neal D. Hollenbeck, Albert R. Fraumeni, Joseph F., Jr. Leitzmann, Michael Schatzkin, Arthur TI A prospective study of BMI and risk of oesophageal and gastric adenocarcinoma SO EUROPEAN JOURNAL OF CANCER LA English DT Article DE oesophageal adenocarcinoma; gastric adenocarcinorna; obesity; BMI; prospective; cohort ID BODY-MASS INDEX; RISING INCIDENCE; INCIDENCE RATES; CARDIA; CANCER; CLASSIFICATION; WOMEN; MEN; ASSOCIATION; CARCINOMAS AB The incidence of oesophageal. adenocarcinoma (EADC) is rapidly increasing in Western countries and obesity is thought to be a major risk factor. We examined the association between BMI and EADC, gastric cardia adenocarcinoma and gastric non-cardia adenocarcinoma in a cohort of approximately 500,000 people in the United States (US). We used Cox proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) with control for many potential confounders. We found that compared to people with a BMI of 18.5-25 kg/m(2), a BMI >= 35 was associated with significantly increased risk of EADC, HR (95% CI) = 2.27 (1.44-3.59) and gastric cardia adenocarcinoma 2.46 (1.60-3.80), but not gastric non-cardia adenocarcinoma 0.84 (0.50-1.42). Using non-linear models, we found that higher BMI was associated with increased risk of EADC even within the normal BMI. Increased adiposity was associated with higher risk of EADC even within the normal weight range. Published by Elsevier Ltd. C1 [Abnet, Christian C.; Fraumeni, Joseph F., Jr.; Leitzmann, Michael; Schatzkin, Arthur] NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Rockville, MD 20852 USA. [Freedman, Neal D.] NCI, Off Director, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. [Hollenbeck, Albert R.] AARP, Washington, DC USA. RP Abnet, CC (reprint author), NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, 6120 Execut Blvd,EPS-320,MSC 7232, Rockville, MD 20852 USA. EM abnetc@mail.nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098 FU Intramural NIH HHS [Z99 CA999999] NR 26 TC 76 Z9 78 U1 0 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0959-8049 J9 EUR J CANCER JI Eur. J. Cancer PD FEB PY 2008 VL 44 IS 3 BP 465 EP 471 DI 10.1016/j.ejca.2007.12.009 PG 7 WC Oncology SC Oncology GA 274UK UT WOS:000254027400023 PM 18221867 ER PT J AU Flood, A Mai, V Pfeiffer, R Kahle, L Remaley, AT Rosen, CJ Lanza, E Schatzkin, A AF Flood, A. Mai, V. Pfeiffer, R. Kahle, L. Remaley, A. T. Rosen, C. J. Lanza, E. Schatzkin, A. TI The effects of a high-fruit and -vegetable, high-fiber, low-fat dietary intervention on serum concentrations of insulin, glucose, IGF-1 and IGFBP-3 SO EUROPEAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE insulin; glucose; IGF-1; IGFBP-3; dietary intervention; fruits and vegetables; fiber ID GROWTH-FACTOR-I; LOW-GLYCEMIC-INDEX; FACTOR BINDING-PROTEIN-3 CONCENTRATIONS; LOW-CARBOHYDRATE DIET; WHOLE-GRAIN INTAKE; WEIGHT-LOSS; CARDIOVASCULAR-DISEASE; BINDING-PROTEINS; RANDOMIZED-TRIAL; RISK-FACTORS AB Objective: To determine the effects of dietary change on serum concentrations of insulin, glucose, IGF-1 and IGFBP-3. Subjects: From among participants in a randomized clinical trial of men and women without a history of diabetes who were 35 years old or older and who had at least one histologically confirmed colorectal adenoma removed during a qualifying colonoscopy within the 6 months before randomization, 750 subjects were selected for this analysis. Methods: The authors analyzed fasting serum from 375 subjects with and 375 subjects without a recurrent polyp among participants in a randomized trial of a low-fat (20% of energy), high-fiber (18 g per 1000 kcals of energy intake) and high-fruit and -vegetable (5-8 servings per day) dietary intervention. Results: After 4 years of follow-up, IGF-1 concentration in the intervention group (N = 248) declined by 8.86 ng/ml (initial mean of 133 ng/ml) and 7.74 ng/ml (initial mean value of 139 ng/ml) in the non-intervention group (N = 502). Based on an unpaired t-test, these declines were both statistically significant, but the difference between groups for the decline in IGF-1 (1.12 ng/ml ((95% confidence interval, - 3.24 to 5.48)) was not. After 4 years, concentrations of IGFBP-3, insulin and glucose were not statistically different from values at baseline, and there were no differences in these serum measures between the intervention and control groups. In analysis restricted to lean (body mass index < 25 kg/m(2)) subjects only, however, glucose concentrations in the intervention group decreased by 0.28 mmol/l, while they increased in the control group by 0.01 mmol/l (t-test for mean differences P = 0.0003) over 4 years. Conclusions: A low-fat, high-fiber, high-fruit and -vegetable dietary intervention had minimal impact on serum concentrations of insulin, glucose, IGF-1 and IGFBP-3 overall, but in lean subjects the intervention resulted in a significant reduction in serum glucose concentration. C1 [Flood, A.] Univ Minnesota, Div Epidemiol, Minneapolis, MN 55454 USA. [Mai, V.] Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. [Pfeiffer, R.; Schatzkin, A.] NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Kahle, L.] Informat Management Serv Inc, Silver Spring, MD USA. [Remaley, A. T.] NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. [Rosen, C. J.] Maine Ctr Osteoporosis Res & educ, Bangor, ME USA. [Lanza, E.] NCI, Canc Res Ctr, Bethesda, MD 20892 USA. RP Flood, A (reprint author), Univ Minnesota, Div Epidemiol, 1300 S Second St,Suite 300, Minneapolis, MN 55454 USA. EM flood@epi.umn.edu RI Pfeiffer, Ruth /F-4748-2011 FU NCI NIH HHS [K07 CA108910-01A1] NR 51 TC 9 Z9 9 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0954-3007 J9 EUR J CLIN NUTR JI Eur. J. Clin. Nutr. PD FEB PY 2008 VL 62 IS 2 BP 186 EP 196 DI 10.1038/sj.ejcn.1602726 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 259IL UT WOS:000252932900005 PM 17487212 ER PT J AU Winning, T Needleman, I Rohlin, M Carrassi, A Chadwick, B Eaton, K Hardwick, K Ivancakova, R Jallaludin, RL Johnsen, D Kim, JG Lekkas, D Li, D Onisei, D Pissiotis, A Reynolds, P Tonni, I Vanobbergen, J Vassileva, R Virtanen, J Wesselink, P Wilson, N AF Winning, T. Needleman, I. Rohlin, M. Carrassi, A. Chadwick, B. Eaton, K. Hardwick, K. Ivancakova, R. Jallaludin, R. L. Johnsen, D. Kim, J. -G. Lekkas, D. Li, D. Onisei, D. Pissiotis, A. Reynolds, P. Tonni, I. Vanobbergen, J. Vassileva, R. Virtanen, J. Wesselink, P. Wilson, N. TI The first five years. A framework for undergraduate dental education SO EUROPEAN JOURNAL OF DENTAL EDUCATION LA English DT Article CT Global Congress on Dental Education CY SEP 06-08, 2007 CL Dublin, IRELAND SP Int Federat Dent Educators & Assoc, European Union Themat Network Dent Educ, Amer Dent Educ Assoc, Assoc Dent Educ Europe DE curriculum; evidence-based oral healthcare; research ID EVIDENCE-BASED MEDICINE; CLINICAL-PRACTICE; QUALITY IMPROVEMENT; SYSTEMATIC REVIEWS; COST-EFFECTIVENESS; RANDOMIZED-TRIAL; PREVENTION; MANAGEMENT; IMPLEMENTATION; GUIDELINE AB An evidence-based (EB) approach has been a significant driver in reforming healthcare over the past two decades. This change has extended across a broad range of health professions, including oral healthcare. A key element in achieving an EB approach to oral healthcare is educating our practitioners, both current and future. This involves providing opportunities integrated within simulated and actual clinical settings for practitioners to learn and apply the principles and processes of evidence-based oral healthcare (EBOHC). Therefore, the focus of this discussion will be on ways in which EBOHC and associated research activities can be implemented into curricula, with the aim of improving patient care. This paper will initially define the scope of EBOHC and research, what these involve, why they are important, and issues that we need to manage when implementing EBOHC. This will be followed by a discussion of factors that enable successful implementation of EBOHC and research into curricula. The paper concludes with suggestions on the future of EBOHC and research in curricula. Key recommendations related to curricula include strengthening of the culture of a scientific approach to education and oral healthcare provision; complete integration of EBOHC into the curriculum at all levels; and faculty development to implement EBOHC based on their needs and evidence of effective approaches. Key recommendations to support implementation and maintenance of EBOHC include recognition and funding for high-quality systematic reviews and development of associated methodologies relevant for global environments; building global capacity of EBOHC researchers; research into improving translation of effective interventions into education and healthcare practice, including patient-reported outcomes, safety and harms, understanding and incorporation of patient values into EB decision-making, economic evaluation research specific to oral healthcare and effective methods for changing friendly' formats and languages tailored to meet users' needs. Realizing these recommendations may help to improve access to effective healthcare as a basic human right. C1 [Winning, T.; Lekkas, D.] Univ Adelaide, Adelaide, SA, Australia. [Needleman, I.] UCL Eastman Dent Inst, London, England. [Rohlin, M.] Malmo Univ Hosp, Malmo, Sweden. [Carrassi, A.] Univ Milan, Milan, Italy. [Chadwick, B.] Cardiff Univ, Cardiff, Wales. [Eaton, K.] Fac Gen Dent Practice, London, England. [Hardwick, K.] Natl Inst Dent & Craniofacial Res, Natl Inst Hlth, Bethesda, MD USA. [Ivancakova, R.] Charles Univ Prague, Prague, Czech Republic. [Jallaludin, R. L.] Univ Malaya, Kuala Lumpur, Malaysia. [Johnsen, D.] Univ Iowa, Iowa City, IA 52242 USA. [Kim, J. -G.] Chonbuk Natl Univ, Jeonju, South Korea. [Li, D.] First Mil Med Univ, Beijing, Peoples R China. [Onisei, D.] Victor Babes Fac Dent Med, Timisoara, Romania. [Pissiotis, A.] Aristotle Univ Thessaloniki, Thessaloniki, Greece. [Reynolds, P.; Wilson, N.] Kings Coll London, Inst Dent, London WC2R 2LS, England. [Tonni, I.] Univ Brescia, Brescia, Italy. [Vanobbergen, J.] Univ Ghent, Ghent, Belgium. [Vassileva, R.] Med Univ Sofia, Sofia, Bulgaria. [Virtanen, J.] Univ Helsinki, Helsinki, Finland. [Wesselink, P.] ACTA, Amsterdam, Netherlands. RP Winning, T (reprint author), Univ Adelaide, Adelaide, SA, Australia. EM tracey.winning@adelaide.edu.au RI Management Center, Dental Research/C-2478-2013; Koberova Ivancakova, Romana/O-8788-2015; Vanobbergen, Jacques/S-2284-2016 OI Koberova Ivancakova, Romana/0000-0002-8346-1835; NR 111 TC 10 Z9 10 U1 0 U2 18 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1396-5883 J9 EUR J DENT EDUC JI Eur. J. Dent. Educ. PD FEB PY 2008 VL 12 BP 48 EP 63 DI 10.1111/j.1600-0579.2007.00480.x PG 16 WC Dentistry, Oral Surgery & Medicine; Education, Scientific Disciplines SC Dentistry, Oral Surgery & Medicine; Education & Educational Research GA 269MO UT WOS:000253653300009 PM 18289268 ER PT J AU Ortega, E Koska, J Pannacciulli, N Bunt, JC Krakoff, J AF Ortega, Emilio Koska, Juraj Pannacciulli, Nicola Bunt, Joy C. Krakoff, Jonathan TI Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals SO EUROPEAN JOURNAL OF ENDOCRINOLOGY LA English DT Article ID BETA-CELL FAILURE; GROWTH-FACTOR-I; THYROID-HORMONE; HYPERTHYROID PATIENTS; DIABETES-MELLITUS; PIMA-INDIANS; C-PEPTIDE; GLUCOSE; SENSITIVITY; RESISTANCE AB Background: Thyroid hormones (TH) may influence glucose metabolism. Hyperthyroid subjects have higher insulin secretion rates when compared with euthyroid individuals. Objective: To evaluate the association between TH concentrations and insulin secretion in euthyroid, healthy Pima Indian adults (n=55, 29 +/- 7 years, females/males 36/19) with normal glucose tolerance (NGT) admitted to a Clinical Research Unit. Methods: TSH, free thyroxine (FT4), 3,5,3-L-tri-iodothyronine (FT3), and fasting plasma insulin (FPI) concentrations were measured in fasting plasma samples, percentage of body fat (%BF) by dual energy x-ray absorptiometry (DXA), acute insulin response (AIR), and incremental area under the curve (AUC) of insulin in response to a 25 g intravenous glucose tolerance test (IVGTT) and 75 g oral glucose tolerance test (OGTT) respectively and insulin action (M) during an euglycemic clamp. Results: FT3 concentrations were associated with FPI, AIR, and insulin AUC both before (r=0.33, P=0.01; r=0.29, P=0.03: and r=0.35, P=0.008 respectively) and after adjustment for age, sex, BF, glucose (fasting concentrations or glucose AUC), and M (beta=0.09, P=0.01; 0=0.16, P=0.03; and beta=0.24, P=0.0007 respectively). No associations were found for TSH or FT4. Conclusion: FT3 was associated with several measurements of insulin secretion in euthyroid individuals with NGT. T-3 concentrations may play a role in the regulation of insulin secretion. C1 [Ortega, Emilio; Koska, Juraj; Pannacciulli, Nicola; Bunt, Joy C.; Krakoff, Jonathan] NIDDKD, Natl Inst Hlth, Obes & Diabet Clin Res Div, Dept Hlth & Human Serv, Phoenix, AZ 85016 USA. RP Ortega, E (reprint author), NIDDKD, Natl Inst Hlth, Obes & Diabet Clin Res Div, Dept Hlth & Human Serv, 4212 N 16Th St,Room 5-35, Phoenix, AZ 85016 USA. EM eortega1@clinic.ub.es FU Intramural NIH HHS [Z01 DK069015-25] NR 42 TC 32 Z9 33 U1 0 U2 1 PU BIO SCIENTIFICA LTD PI BRISTOL PA EURO HOUSE, 22 APEX COURT WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 0804-4643 J9 EUR J ENDOCRINOL JI Eur. J. Endocrinol. PD FEB PY 2008 VL 158 IS 2 BP 217 EP 221 DI 10.1530/EJE-07-0592 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 265SI UT WOS:000253380800011 PM 18230829 ER PT J AU Hereld, D Jin, T AF Hereld, Dale Jin, Tian TI Slamming the DOR on chemokine receptor signaling: Heterodimerization silences ligand-occupied CXCR4 and delta-opioid receptors SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Editorial Material DE cell migration; chemokine receptors; signal transduction ID RESONANCE ENERGY-TRANSFER; HOMODIMERIZATION AB Dimerization has emerged as a common mechanism for regulating the function of G protein-coupled receptors (GPCR). Among these are chemokine receptors, which detect various chemokines and regulate a range of physiological process, including immune cell trafficking, cancer cell migration, and neuronal patterning. Homo- and heterodimerization in response to chemokine binding has been shown to be required for the initiation or alteration of signaling by a number of chemokine receptors. In this issue of the European Journal of Immunology, a new study indicates that the formation of heterodimers of chemokine receptor CXCR4 and the delta-opioid receptor (DOR) prevents each of them from actively signaling, suggesting a novel mechanism for silencing GPCR function. C1 [Hereld, Dale; Jin, Tian] NIAID, Immunogenet Lab, NIH, Twinbrook Facilit 2, Rockville, MD 20852 USA. RP Jin, T (reprint author), NIAID, Immunogenet Lab, NIH, Twinbrook Facilit 2, 12441 Parklawn Dr, Rockville, MD 20852 USA. EM TJIN@niaid.nih.gov NR 15 TC 9 Z9 9 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2008 VL 38 IS 2 BP 334 EP 337 DI 10.1002/eji.200738101 PG 4 WC Immunology SC Immunology GA 264YK UT WOS:000253326100002 PM 18203136 ER PT J AU Duvall, MG Precopio, ML Ambrozak, DA Jaye, A McMichael, AJ Whittle, HC Roederer, M Rowland-Jones, SL Koup, RA AF Duvall, Melody G. Precopio, Melissa L. Ambrozak, David A. Jaye, Assan McMichael, Andrew J. Whittle, Hilton C. Roederer, Mario Rowland-Jones, Sarah L. Koup, Richard A. TI Polyfunctional T cell responses are a hallmark of HIV-2 infection SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE chemokines; cytokines; HIV; T cells ID IMMUNODEFICIENCY-VIRUS TYPE-1; POLYMERASE CHAIN-REACTION; WEST-AFRICA; HIV-2-INFECTED PATIENTS; ANTIRETROVIRAL THERAPY; HUMAN CYTOMEGALOVIRUS; HEALTHY-INDIVIDUALS; EFFECTOR FUNCTIONS; PROVIRAL LOAD; CYTO-TOXICITY AB HIV-2 is distinguished clinically and immunologically from HIV-1 infection by delayed disease progression and maintenance of HIV-specific CD4(+) T cell help in most infected subjects. Thus, HIV-2 provides a unique natural human model in which to investigate correlates of immune protection against HIV disease progression. Here, we report a detailed assessment of the HIV-2-specific CD4(+) and CD8(+) T cell response compared to HIV-1, using polychromatic flow cytometry to assess the quality of the HIV-specific T cell response by measuring IFN-gamma, IL-2, TNF-alpha, MIP-1 beta, and CD107a mobilization (degranulation) simultaneously following Gag peptide stimulation. We find that HIV-2-specific CD4(+) and CD8(+) T cells are more polyfunctional that those specific for HIV-1 and that polyfunctional HIV-2-specific Tcells produce more IFN-gamma and TNF-alpha on a per-cell basis than monofunctional T cells. Polyfunctional HIV-2-specific CD4(+) T cells were generally more differentiated and expressed CD57, while there was no association between function and phenotype in the CD8(+) T cell fraction. Polyfunctional HIV-specific T cell responses are a hallmark of non-progressive HIV-2 infection and may be related to good clinical outcome in this setting. C1 [Duvall, Melody G.; Precopio, Melissa L.; Ambrozak, David A.; Koup, Richard A.] NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Duvall, Melody G.; McMichael, Andrew J.; Rowland-Jones, Sarah L.] Univ Oxford, Weatherall Inst Mol Med, MRC Human Immunol Unit, Oxford, England. [Roederer, Mario] NIAID, Immunol Technol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. [Jaye, Assan; Whittle, Hilton C.; Rowland-Jones, Sarah L.] MRC Labs Fajara, Banjul, Gambia. RP Koup, RA (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, 40 Convent Dr,MSC 3022,Bldg 40,Room 3502, Bethesda, MD 20892 USA. EM rkoup@mail.nih.gov RI Roederer, Mario/G-1887-2011 FU Intramural NIH HHS [Z99 AI999999]; Medical Research Council [, MC_U137884180, MC_U190081958] NR 51 TC 139 Z9 143 U1 0 U2 3 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2008 VL 38 IS 2 BP 350 EP 363 DI 10.1002/eji.200737768 PG 14 WC Immunology SC Immunology GA 264YK UT WOS:000253326100005 PM 18200635 ER PT J AU Stefan, K Classen, J Celnik, P Cohen, LG AF Stefan, K. Classen, J. Celnik, P. Cohen, L. G. TI Concurrent action observation modulates practice-induced motor memory formation SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE human; mirror neuron system; plasticity; transcranial magnetic stimulation ID USE-DEPENDENT PLASTICITY; VENTRAL PREMOTOR CORTEX; MIRROR-NEURON SYSTEM; MAGNETIC STIMULATION; FRONTAL-LOBE; HAND ACTIONS; IMITATION; FACILITATION; MECHANISMS; MOVEMENT AB Motor practice is associated with the formation of elementary motor memories. Here we tested in human subjects the hypothesis that observation of a motor training associated with physical practice will modulate the encoding process of a motor memory relative to physical practice alone. Voluntary thumb motions were practiced (i) alone in a direction opposite to the baseline direction of transcranial magnetic stimulation (TMS)-evoked movements (physical practice, PP) and in combination with observation of synchronous movements that were either (ii) directionally congruent (same direction, PP + AOc) or (iii) non-congruent (opposite direction, PP + AOnc) to the practiced ones. We evaluated the following measures of motor memory formation: percentage of TMS-evoked thumb movements falling in the direction of practiced motions, acceleration of TMS-evoked movements along the principal movement axis and corticomuscular excitability of training muscles as indexed by motor-evoked potential amplitudes. Both PP and PP + AOc, but not PP + AOnc, significantly increased the percentage of TMS-evoked movements falling in the practiced direction, changed the compound acceleration vector into the trained direction and enhanced the motor-evoked potential amplitudes in the training agonist muscle. The percentage of TMS-evoked movements falling in the practiced direction increased significantly more after PP + AOc than after PP. Across all measures of motor memory formation, PP + AOc was most efficacious, followed by PP and PP + AOnc. Action observation modulates practice effects on formation of a motor memory. Strengthening of the process of motor memory encoding depends on the directional congruency of the observed model. C1 [Stefan, K.; Classen, J.] Univ Wurzburg, Dept Neurol, Human Cort Physiol & Motor Control Lab, D-97080 Wurzburg, Germany. [Stefan, K.; Celnik, P.; Cohen, L. G.] NINDS, NIH, Human Cort Physiol Sect & Stroke Neurorehabil Cli, Bethesda, MD 20892 USA. [Celnik, P.] Johns Hopkins Univ, Dept Neurol, Dept Phys Med & Rehabil, Baltimore, MD 21218 USA. RP Classen, J (reprint author), Univ Wurzburg, Dept Neurol, Human Cort Physiol & Motor Control Lab, Schneider Str 11, D-97080 Wurzburg, Germany. EM Classen_j@klinik.uni-wuerzburg.de; cohenl@ninds.nih.gov FU Intramural NIH HHS NR 58 TC 74 Z9 77 U1 0 U2 9 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD FEB PY 2008 VL 27 IS 3 BP 730 EP 738 DI 10.1111/j.1460-9568.2008.06035.x PG 9 WC Neurosciences SC Neurosciences & Neurology GA 262AH UT WOS:000253120900020 PM 18279325 ER PT J AU Genovesio, A Tsujimoto, S Wise, SP AF Genovesio, Aldo Tsujimoto, Satoshi Wise, Steven P. TI Encoding problem-solving strategies in prefrontal cortex: activity during strategic errors SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE errors; frontal lobe; Macaca mulatta; rules; strategies ID ANTERIOR CINGULATE CORTEX; SUPPLEMENTARY EYE FIELD; VISUAL WORKING-MEMORY; NEURONAL-ACTIVITY; DECISION-MAKING; FRONTAL-CORTEX; NEURAL ACTIVITY; TEMPORAL-ORDER; TO-SAMPLE; TASK AB The primate prefrontal cortex (PF) plays a central role in choosing goals and strategies. To better understand its mechanisms, we recorded from PF neurons as monkeys used abstract response strategies to select a spatial goal. A visual cue, selected randomly from a set of three cues, appeared on each trial. All three cues were novel when neuronal recording commenced. From trial to trial, the cue could have either been repeated or changed from the previous trial; these were called repeat trials and change trials, respectively. On repeat trials, the monkeys used a Repeat-stay strategy to gain a reward by choosing the same spatial goal as on the previous trial; on change trials, they used a Change-shift strategy to reject the previous goal in favour of an alternative. We reported previously that when monkeys performed the task correctly, many PF neurons had activity encoding one of these two strategies. The monkeys sometimes chose the incorrect strategy, however. Strategy coding was weak or absent during the cue period of error trials which was, for correct trials, the time when the monkeys used a strategy to choose a future goal. By contrast, later in the trial, after the chosen goal had been attained and the monkeys awaited feedback, strategy coding was present and it reflected the strategy used, whether correct or incorrect. The weak cue-period strategy signal could, whatever its cause, have contributed to the errors made, whereas the activity prior to feedback suggests a role in monitoring task performance. C1 [Genovesio, Aldo; Tsujimoto, Satoshi; Wise, Steven P.] NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. RP Genovesio, A (reprint author), NIMH, Lab Syst Neurosci, Bldg 49,Room B1EE 17,49 Convent Dr,MSC 4401, Bethesda, MD 20892 USA. EM genovesa@mail.nih.gov RI Tsujimoto, Satoshi/B-8223-2011 FU Intramural NIH HHS [Z01 MH001092-29]; NIMH NIH HHS [Z01 MH001092] NR 58 TC 18 Z9 18 U1 1 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD FEB PY 2008 VL 27 IS 4 BP 984 EP 990 DI 10.1111/j.1460-9568.2008.06048.x PG 7 WC Neurosciences SC Neurosciences & Neurology GA 272UP UT WOS:000253886100019 PM 18279367 ER PT J AU Hilton, TF Chandler, RK Compton, WM AF Hilton, Thomas F. Chandler, Redonna K. Compton, Wilson M. TI Needed: Longitudinal research that can inform dynamic models for the treatment of addiction as a disease SO EVALUATION REVIEW LA English DT Editorial Material ID SUBSTANCE-ABUSE TREATMENT; TREATMENT CAREERS; DRUG-ABUSE; ORGANIZATION; MANAGEMENT; OUTCOMES; DATOS C1 [Hilton, Thomas F.] Natl Inst Drug Abuse, Bethesda, MD 20892 USA. [Hilton, Thomas F.; Chandler, Redonna K.; Compton, Wilson M.] US Dept HHS, Washington, DC 20201 USA. RP Hilton, TF (reprint author), Natl Inst Drug Abuse, 6001 Execut Blvd,Room 5197, Bethesda, MD 20892 USA. FU Intramural NIH HHS [Z99 DA999999] NR 10 TC 0 Z9 0 U1 1 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0193-841X J9 EVALUATION REV JI Eval. Rev. PD FEB PY 2008 VL 32 IS 1 BP 3 EP 6 DI 10.1177/0193841X07309581 PG 4 WC Social Sciences, Interdisciplinary SC Social Sciences - Other Topics GA 248VQ UT WOS:000252185600001 PM 22461723 ER PT J AU Epand, RF Zhang, YL Mirzabekov, T Kagan, B Silberstein, A Hubbell, WL Epand, RM Chakraborti, S Dimitrov, DS Anderson, WF Rozenberg-Adler, Y AF Epand, Raquel F. Zhang, Yan-Liang Mirzabekov, Tajib Kagan, Bruce Silberstein, Anatoly Hubbell, Wayne L. Epand, Richard M. Chakraborti, Samitabh Dimitrov, Dimiter S. Anderson, W. French Rozenberg-Adler, Yanina TI Membrane activity of an amphiphilic alpha-Helical membrane-proximal cytoplasmic domain of the MoMuLV envelope glycoprotein SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE MoMuLV; membrane proximal; cytoplasmic domain; fusion; amphiphilic helix; env; hexagonal phase transition ID INFLUENZA-VIRUS HEMAGGLUTININ; FUSION PEPTIDE; TRANSMEMBRANE PROTEIN; FUNCTIONAL-ANALYSIS; LIPID POLYMORPHISM; PORE FORMATION; ENV PROTEIN; LIPOSOMES; DESTABILIZATION; CONFORMATION AB In the Moloney murine leukemia virus (MoMuLV) envelope glycoprotein (Env) we identified a membrane-proximal cytoplasmic domain (residues 598-616) that facilitates the Env incorporation into virions and Env-mediated fusion [Rozenberg, Y., Conner, J., Aguilar-Carreno, H., Chakraborti, S., Dimiter, D.S., Anderson, W.F., 2008. Viral entry: membrane-proximal cytoplasmic domain of MoMuLV envelope tail facilitates fusion. In the same issue. (accompanying paper)]. By biophysical methods (CD, EPR) a corresponding peptide (membrane-proximal peptide, 598-616) was demonstrated to form a membrane-parallel amphiphilic alpha-helix in the presence of membranes. Electrophysiological studies with planar bilayers and liposomes indicate that the membrane-proximal peptide is membrane destabilizing. This peptide and the fusion peptide from the MoMuLV transmembrane (TM) ectodomain were tested for their effect on the bilayer for hexagonal phase transition temperature of dipalmitoleoylphosphatidylethanolamine (T-H). Importantly, the external fusion peptide and the internal membrane-proximal peptides of MoMuLV env exert opposite effects on membrane curvature. The fusion peptide lowers T, I while the membrane proximal peptide raises it. These effects on T-H correlate with the ability of these peptides to induce lipid mixing in large unilamellar vesicles composed of dioleoylphosphatidylethanolamine: dioleoylphosphatidylcholine: cholesterol (1: 1: 1 mol). When added externally to preformed liposomes, the N-terminal fusion peptide promotes lipid mixing while the cytoplasmic membrane-proximal peptide inhibits this effect. These finding indicate a possible mechanism by which the membrane-proximal domain in MoMuLV Env may affect the formation of membrane fusion intermediates. (c) 2007 Elsevier Inc. All rights reserved. C1 [Rozenberg-Adler, Yanina] San Diego Canc Res Inst, Encinitas, CA 92024 USA. [Zhang, Yan-Liang; Mirzabekov, Tajib; Silberstein, Anatoly; Anderson, W. French; Rozenberg-Adler, Yanina] Univ So Calif, Sch Med, Norris Cotton Canc Ctr, Gene Therapy Labs, Los Angeles, CA USA. [Epand, Raquel F.; Epand, Richard M.] McMaster Univ, Hlth Sci Ctr, Dept Biochem, Hamilton, ON L8N 3Z5, Canada. [Zhang, Yan-Liang; Hubbell, Wayne L.] La Jolla Bioengn Inst, La Jolla, CA 92037 USA. [Mirzabekov, Tajib] MSM Prot Technol Inc, Medford, MA USA. [Kagan, Bruce] Univ Calif Los Angeles, Brain Res Inst, Los Angeles, CA 90024 USA. [Silberstein, Anatoly] Russian Acad Sci, Inst Theoret & Expt Biophys, Moscow, Russia. [Chakraborti, Samitabh; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, CCRNP, NIH, Frederick, MD 21702 USA. RP Rozenberg-Adler, Y (reprint author), San Diego Canc Res Inst, 1200 Garden View,Suite 200, Encinitas, CA 92024 USA. EM YaninaAdler@cox.net FU NCI NIH HHS [P01 CA059318, CA59318] NR 46 TC 4 Z9 4 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 0014-4800 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD FEB PY 2008 VL 84 IS 1 BP 9 EP 17 DI 10.1016/j.yexmp.2007.11.003 PG 9 WC Pathology SC Pathology GA 276AQ UT WOS:000254113900002 PM 18206141 ER PT J AU Rozenberg-Adler, Y Conner, J Aguilar-Carreno, H Chakraborti, S Dimitrov, DS Anderson, WF AF Rozenberg-Adler, Yanina Conner, John Aguilar-Carreno, Hector Chakraborti, Samitabh Dimitrov, Dimiter S. Anderson, W. French TI Membrane-proximal cytoplasmic domain of Moloney murine leukemia Virus envelope tail facilitates fusion SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE MoMuLV; membrane-proximal; cytoplasmic domain; fusion; amphiphilic helix; env; viral entry ID VESICULAR STOMATITIS-VIRUS; RETROVIRAL TRANSMEMBRANE PROTEIN; R-PEPTIDE; CELL-FUSION; VIRAL ENTRY; INFLUENZA HEMAGGLUTININ; FUNCTIONAL-ANALYSIS; ECOTROPIC ENVELOPE; CRYSTAL-STRUCTURE; ENV PROTEIN AB Removal of the R peptide (residues 617-632) from the Moloney murine leukemia virus (MoMuLV) envelope protein (Env) cytoplasmic tail potentiates fusion. We examined the role of the membrane-proximal cytoplasmic domain (598-616) of the MoMuLV Env in the Env-mediated membrane fusion and incorporation. The Env truncated at 616 exhibits maximum fusogenicity in cell-to-cell fusion assay. By comparison, full tail Env (632) and the Env truncated to residue 601 mediated fusion at 40%. The Envs truncated to residues 598 or 595 are not fusogenic. Progressive cytoplasmic tail truncation correlated with decreased Env incorporation into virions. Substitution of the domain 598-616 with an amphiphilic alpha-helix from melittin results in maximally fusogenic Envs that efficiently incorporated into transduction competent virions. However, substitution of the domain 598-616 with random or hydrophilic sequences caused loss of the Env fusogenicity and titer while retaining incorporation. Further, a secondary structure prediction analysis of 27 unrelated Env cytoplasmic tails indicates a common (23/27) propensity for an amphiphilic alpha-helical domain at immediate proximity to the viral membrane. These results support the suggestion that viral fusion is enhanced by a membrane-proximal cytoplasmic amphiphilic a-helix in Env tail. The model of its action is proposed. (c) 2007 Elsevier Inc. All rights reserved. C1 [Rozenberg-Adler, Yanina] San Diego Canc Res Inst, Encinitas, CA 92024 USA. [Aguilar-Carreno, Hector] Univ Calif Los Angeles, Dept Microbiol Mol Genet & Immunol, Los Angeles, CA 90095 USA. [Chakraborti, Samitabh; Dimitrov, Dimiter S.] NCI, Prot Interact Grp, CCRNP, NIH, Frederick, MD 21702 USA. [Rozenberg-Adler, Yanina; Conner, John; Aguilar-Carreno, Hector; Anderson, W. French] Univ So Calif, Sch Med, Norris Cotton Canc Ctr, Gene Therapy Labs, Los Angeles, CA 90033 USA. RP Rozenberg-Adler, Y (reprint author), San Diego Canc Res Inst, 1200 Garden View,Suite 200, Encinitas, CA 92024 USA. EM YaninaAdler@cox.net FU NCI NIH HHS [CA59318, P01 CA059318] NR 74 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 0014-4800 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD FEB PY 2008 VL 84 IS 1 BP 18 EP 30 DI 10.1016/j.yexmp.2007.11.001 PG 13 WC Pathology SC Pathology GA 276AQ UT WOS:000254113900003 PM 18222422 ER PT J AU Wiechmann, AF Chignell, CF Roberts, JE AF Wiechmann, Allan F. Chignell, Colin F. Roberts, Joan E. TI Influence of dietary melatonin on photoreceptor survival in the rat retina: An ocular toxicity study SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE melatonin; photoreceptor; retina; toxicity; circadian ID HYDROXYINDOLE-O-METHYLTRANSFERASE; LOW-DOSE INTERLEUKIN-2; XENOPUS-LAEVIS RETINA; CHICKEN RETINA; MESSENGER-RNA; DOPAMINE RELEASE; PINEAL-GLAND; LIGHT DAMAGE; JET-LAG; LOCALIZATION AB Previous studies have shown that melatonin treatment increases the susceptibility of retinal photoreceptors to light-induced cell death. The purpose of this study was to evaluate under various conditions the potential toxicity of dietary melatonin on retinal photoreceptors. Male and female Fischer 344 (non-pigmented) and Long-Evans (pigmented) rats were treated with daily single doses of melatonin by gavage for a period of 14 days early in the light period or early in the dark period. In another group, rats were treated 3 times per week with melatonin early in the light period, and then exposed to high intensity illumination (1000-1500 lx; HII) for 2 h, and then returned to the normal cyclic lighting regime. At the end of the treatment periods, morphometric measurements of outer nuclear layer thickness (ONL; the layer containing the photoreceptor cell nuclei) were made at specific loci throughout the retinas. In male and female non-pigmented Fischer rats, melatonin administration increased the degree of photoreceptor cell death when administered during the nighttime and during the day when followed by exposure to HII. There were some modest effects of melatonin on photoreceptor cell death when administered to Fischer rats during the day or night without exposure to HII. Melatonin treatment caused increases in the degree of photoreceptor cell death when administered in the night to male pigmented Long-Evans rats, but melatonin administration during the day, either with or without exposure to HII, had little if any effect on photoreceptor cell survival. In pigmented female Long-Evans rats, melatonin administration did not appear to have significant effects on photoreceptor cell death in any treatment group. The results of this study confirm and extend previous reports that melatonin increases the susceptibility of photoreceptors to light-induced cell death in non-pigmented rats. It further suggests that during the dark period, melatonin administration alone (i.e., no HII exposure) to pigmented male rats may have a toxic effect on retinal cells. These results suggest that dietary melatonin, in combination with a brief exposure to high intensity illumination, induces cellular disruption in a small number of photoreceptors. Chronic exposure to natural or artificial light and simultaneous intake of melatonin may potentially contribute to a significant loss of photoreceptor cells in the aging retina. (c) 2007 Elsevier Ltd. All rights reserved. C1 [Wiechmann, Allan F.] Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, Oklahoma City, OK 73190 USA. [Wiechmann, Allan F.] Univ Oklahoma, Hlth Sci Ctr, Dept Ophthalmol, Oklahoma City, OK 73190 USA. [Chignell, Colin F.] Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. [Roberts, Joan E.] Fordham Univ, Dept Nat Sci, New York, NY 10023 USA. RP Wiechmann, AF (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Cell Biol, Oklahoma City, OK 73190 USA. EM allan-wiechmann@ouhsc.edu FU Intramural NIH HHS [NIH0010085416, Z01 ES050046-29]; NCRR NIH HHS [RR 017713]; NEI NIH HHS [R03 EY013686-03, EY 13686, R03 EY013686, EY 12191]; NIEHS NIH HHS [N01 ES 65406] NR 39 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 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD FEB PY 2008 VL 86 IS 2 BP 241 EP 250 DI 10.1016/j.exer.2007.10.015 PG 10 WC Ophthalmology SC Ophthalmology GA 278FY UT WOS:000254271600011 PM 18078931 ER PT J AU Yaung, J Kannan, R Wawrousek, EF Spee, C Sreckumar, PG Hinton, DR AF Yaung, Jennifer Kannan, Ram Wawrousek, Eric F. Spee, Christine Sreckumar, Parameswaran G. Hinton, David R. TI Exacerbation of retinal degeneration in the absence of alpha crystallins in an in vivo model of chemically induced hypoxia SO EXPERIMENTAL EYE RESEARCH LA English DT Article; Proceedings Paper CT Annual Meeting of the Association-for-Research-in-Vision-and-Ophthalmology CY MAY 06-10, 2007 CL Ft Lauderdale, FL SP Assoc Res Vis & Ophthalmol DE oxidative stress; crystallins; retinal pigment epithelium; retinal degeneration; hypoxia; apoptosis ID B-CRYSTALLIN; COBALT CHLORIDE; PIGMENT EPITHELIUM; INDUCED APOPTOSIS; MACULAR DEGENERATION; RETINITIS-PIGMENTOSA; MOLECULAR CHAPERONE; GENE-EXPRESSION; ISCHEMIC-INJURY; A-CRYSTALLIN AB This study evaluated the role of crystallins in retinal degeneration induced by chemical hypoxia. Wild-type, alpha A-crystallin (-/-), and alpha B-crystallin (-/-) mice received intravitreal injection of 12 nmol (low dose), 33 nmol (intermediate dose) or 60 nmol (high dose) cobalt chloride (CoCl2). Hematoxylin and eosin and TdT-mediated dUTP nick-end labeling (TUNEL) stains were performed after 24 h, 96 h, and 1 week post-injection, while immunofluorescent stains for alpha A- and aB-crystallin were performed 1 week post-injection. The in vitro effects of CoCl2 on alpha B-crystallin expression in ARPE-19 cells were determined by real time RT-PCR, Western blot, and confocal microscopy and studies evaluating subcellular distribution of alpha B-crystallin in the mitochondria and cytosol were also performed. Histologic studies revealed progressive retinal degeneration with CoCl2 injection in wild-type mice. Retinas Of CoCl2 injected mice showed transient increased expression of HIF-1 alpha which was maximal 24 h after injection. Intermediate-dose CoCl2 injection was associated with increased retinal immunofluorescence for both alpha A- and alpha B-crystallin; however, after high-dose injection, increased retinal degeneration was associated with decreased levels of crystallin expression. Injection of CoCl2 at either intermediate or high dose in alpha A-crystallin (-/-) and aB-crystallin (-/-) mice resulted in much more severe retinal degeneration compared to wild-type eyes. A decrease in ARPE-19 total and cytosolic alpha B-crystallin expression with increasing CoCl2 treatment and an increase in mitochondrial alpha B-crystallin were found. We conclude that lack of alpha-crystallins accentuates retinal degeneration in chemically induced hypoxia in vivo. (c) 2007 Elsevier Ltd. All rights reserved. C1 [Yaung, Jennifer; Hinton, David R.] Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. [Kannan, Ram; Hinton, David R.] Univ So Calif, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA 90033 USA. [Yaung, Jennifer; Kannan, Ram; Spee, Christine; Sreckumar, Parameswaran G.; Hinton, David R.] Arnold & Mabel Beckman Macular Res Ctr, Los Angeles, CA 90033 USA. [Kannan, Ram; Spee, Christine; Sreckumar, Parameswaran G.; Hinton, David R.] Doheny Eye Inst, Los Angeles, CA 90033 USA. [Wawrousek, Eric F.] NEI, NIH, Bethesda, MD 20892 USA. RP Hinton, DR (reprint author), Univ So Calif, Keck Sch Med, Dept Pathol, 2011 Zonal Ave,HMR 209, Los Angeles, CA 90033 USA. EM dhinton@use.edu OI Kannan, Ram/0000-0002-1583-3414 FU NEI NIH HHS [EY 02061, EY 03040, P30 EY003040, P30 EY003040-26A1, P30 EY003040-27, P30 EY003040-28, R01 EY001545, R01 EY002061, R01 EY002061-27, R01 EY002061-28, R01 EY002061-29] NR 53 TC 38 Z9 39 U1 0 U2 4 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD FEB PY 2008 VL 86 IS 2 BP 355 EP 365 DI 10.1016/j.exer.2007.11.007 PG 11 WC Ophthalmology SC Ophthalmology GA 278FY UT WOS:000254271600023 PM 18191123 ER PT J AU Moreira, EF Kantorow, M Rodriguez, IR AF Moreira, Ernesto F. Kantorow, Marc Rodriguez, Ignacio R. TI Peroxiredoxin 3 (PDRX3) is highly expressed in the primate retina especially in blue cones SO EXPERIMENTAL EYE RESEARCH LA English DT Article DE blue cones; photoreceptors; mitochondria; PrxIII ID OXIDATIVE STRESS; MITOCHONDRIA; SP-22; LOCALIZATION; PATHOGENESIS; REDUCTASE; MONKEY; EYE AB Oxidative stress and loss of mitochondrial function have been implicated in age-related ocular diseases and thus studying enzymes involved in these processes may be of particular importance in these diseases. Peroxiredoxin III (PRDX3) is one of a family of six known peroxiredoxins which are known to protect cells against oxidative damage. PRDX3 is localized to the mitochondria and has been reported to be induced by hydrogen peroxide in aortic endothelial and lens epithelial cells. Using a highly specific commercially available antibody, PRDX3 was readily detected by immunoblot in monkey neural retina. Immunohistochemical analysis of human and monkey retina localized PRDX3 mainly to the photoreceptor inner segments, the outer and inner plexiform layers, and the ganglion cells. These are areas of known high mitochondrial content. In the monkey retina some of the cone inner segments were much more strongly labeled than others. Dual labeling experiments using specific anti-cone opsin antibodies determined that the high expressing cones were of the blue subtype. By contrast, in the human retina all of the cone inner segments were immunoreactive. This difference may be due to a postmortem induction of PRDX3 in the human sample. These results suggest that PRDX3 may be important in protecting photoreceptor mitochondria especially in blue cones. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Moreira, Ernesto F.; Rodriguez, Ignacio R.] NEI, Mech Retinal Dis Sect, LRCMB, NIH, Bethesda, MD 20892 USA. [Kantorow, Marc] Florida Atlantic Univ, Coll Biomed Sci, Boca Raton, FL 33431 USA. RP Rodriguez, IR (reprint author), NEI, Mech Retinal Dis Sect, LRCMB, NIH, 7 Mem Dr,MSC0706 Bldg 7 Room 302, Bethesda, MD 20892 USA. EM rodriguezi@nei.nih.gov FU Intramural NIH HHS [Z01 EY000307-13]; NEI NIH HHS [R01 EY013022, R01 EY013022-09, EY 13022] NR 18 TC 6 Z9 6 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0014-4835 J9 EXP EYE RES JI Exp. Eye Res. PD FEB PY 2008 VL 86 IS 2 BP 452 EP 455 DI 10.1016/j.exer.2007.10.020 PG 4 WC Ophthalmology SC Ophthalmology GA 278FY UT WOS:000254271600033 PM 18078932 ER PT J AU Ramakrishnan, B Boeggeman, E Qasba, PK AF Ramakrishnan, Boopathy Boeggeman, Elizabeth Qasba, Pradman K. TI Applications of glycosyltransferases in the site-specific conjugation of biomolecules and the development of a targeted drug delivery system and contrast agents for MRI SO EXPERT OPINION ON DRUG DELIVERY LA English DT Editorial Material DE bioconjugation through glycan residues; cytotoxic agents; drug delivery systems; glycotargeting; lipids; MRI agents ID RECEPTOR-MEDIATED ENDOCYTOSIS; CANCER THERAPEUTICS; PROTEINS; GLYCOSYLATION; ANTIBODIES; PEPTIDE AB Background: The delivery of drugs to the proposed site of action is a challenging task. Tissue and cell-specific guiding molecules are being used to carry a cargo of therapeutic molecules. The cargo molecules need to be conjugated in a site-specific manner to the therapeutic molecules such that the bioefficacy of these molecules is not compromised. Methods: Using wild-type and mutant glycosyltransferases, the sugar moiety with a unique chemical handle is incorporated at a specific site in the cargo or therapeutic molecules, making it possible to conjugate these molecules through the chemical handle present on the modified glycan. Results/conclusions: The modified glycan residues introduced at specific sites on the cargo molecule make it possible to conjugate fluorophores for ELISA-based assays, radionuclides for imaging and immunotherapy applications, lipids for the assembly of immunoliposomes, cytotoxic drugs, cytokines, or toxins for antibody-based cancer therapy and the development of a targeted drug delivery system. C1 [Ramakrishnan, Boopathy; Boeggeman, Elizabeth; Qasba, Pradman K.] NCI, Ctr Canc Res, Nanobiol Program, Struct Glycobiol Sect, Frederick, MD 21702 USA. [Ramakrishnan, Boopathy; Boeggeman, Elizabeth] NCI, Ctr Canc Res, Nanobiol Program, SAIC Frederick Inc,Basic Res Program, Frederick, MD 21702 USA. RP Qasba, PK (reprint author), NCI, Ctr Canc Res, Nanobiol Program, Struct Glycobiol Sect, Bldg 469,Room 221, Frederick, MD 21702 USA. EM qasba@helix.nih.gov FU Intramural NIH HHS [Z01 BC009304-12, Z01 BC010742-01, Z99 CA999999]; NCI NIH HHS [N01CO12400] NR 28 TC 8 Z9 9 U1 2 U2 12 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1742-5247 J9 EXPERT OPIN DRUG DEL JI Expert Opin. Drug Deliv. PD FEB PY 2008 VL 5 IS 2 BP 149 EP 153 DI 10.1517/17425247.5.2.149 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 357WL UT WOS:000259877800001 PM 18248315 ER PT J AU Shukla, S Wu, CP Ambudkar, SV AF Shukla, Suneet Wu, Chung-Pu Ambudkar, Suresh V. TI Development of inhibitors of ATP-binding cassette drug transporters - present status and challenges SO EXPERT OPINION ON DRUG METABOLISM & TOXICOLOGY LA English DT Review DE ATP-binding cassette transporter; ATP hydrolysis; cancer chemotherapy; chemosensitizers; clinical trials; MRP1; multi-drug resistance; natural product modulators; P-glycoprotein ID CANCER RESISTANCE PROTEIN; MEDIATED MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN INHIBITOR; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; KAEMPFERIA-PARVIFLORA EXTRACTS; TYROSINE KINASE INHIBITORS; HIGH-AFFINITY INTERACTION; CALCIUM-CHANNEL BLOCKERS; CARCINOMA CELL-LINES; MOUSE LYMPHOMA-CELLS AB Background: Multi-drug resistance (MDR) of cancer cells is an obstacle to effective chemotherapy of cancer. The ATP-binding cassette (ABC) transporters, including P-glycoprotein (ABCB1), MRP1 (ABCC1) and ABCG2, play an important role in the development of this resistance. An attractive approach to overcoming MDR is the inhibition of the pumping action of these transporters. Several inhibitors/modulators of ABC transporters have been developed, but cytotoxic effects and adverse pharmacokinetics have prohibited their use. The ongoing search for such inhibitors/modulators that can be applied in the clinic has led to three generations of compounds. The most recent inhibitors are more potent and less toxic than first-generation compounds, yet some are still prone to adverse effects, poor solubility and unfavorable changes in the pharmacokinetics of the anticancer drugs. Objective: This review provides an update of the published work on the development of potent modulators to overcome MDR in cancer cells, their present status in clinical studies and suggestions for further improvement to obtain better inhibitors. Methods: This review summarizes recent advances in the development of less toxic modulators, including small molecules and natural products. In addition, a brief overview of other novel approaches that can be used to inhibit ABC drug transporters mediating MDR has also been provided. Conclusion: The multifactorial nature of MDR indicates that it may be important to develop modulators that can simultaneously inhibit both the function of the drug transporters and key signaling pathways, which are responsible for development of this phenomenon. C1 [Shukla, Suneet; Wu, Chung-Pu; Ambudkar, Suresh V.] NIH, NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Shukla, S (reprint author), NIH, NCI, Cell Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RI Ambudkar, Suresh/B-5964-2008; shukla, suneet/B-4626-2012 FU Intramural NIH HHS NR 229 TC 131 Z9 137 U1 1 U2 18 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1742-5255 EI 1744-7607 J9 EXPERT OPIN DRUG MET JI Expert Opin. Drug Metab. Toxicol. PD FEB PY 2008 VL 4 IS 2 BP 205 EP 223 DI 10.1517/17425255.4.2.205 PG 19 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 264GL UT WOS:000253275600007 PM 18248313 ER PT J AU Gogtay, N Rapoport, J AF Gogtay, Nitin Rapoport, Judith TI Clozapine use in children and adolescents SO EXPERT OPINION ON PHARMACOTHERAPY LA English DT Review DE childhood onset schizophrenia; clozapine; management; side effects; treatment refractory ID CHILDHOOD-ONSET SCHIZOPHRENIA; ATYPICAL ANTIPSYCHOTIC-DRUGS; RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; CLINICAL-RESPONSE; PLASMA CLOZAPINE; DOUBLE-BLIND; REFRACTORY SCHIZOPHRENIA; PEDIATRIC-PATIENTS; FOLLOW-UP AB Background: Although the role of clozapine is well established for treatment-resistant schizophrenia, it is rarely used in pediatric populations, mainly due to its potentially serious adverse effects. Objective: To summarize practical aspects of use of clozapine in treating children with schizophrenia and management of associated adverse effects. Methods: Available studies in the literature using clozapine in the pediatric population are summarized and the NIMH experience in treating refractory childhood-onset schizophrenia cases with clozapine is discussed. Conclusion: Despite a higher incidence of adverse effects in children, clozapine appears to be a uniquely beneficial second-line agent for treating children with refractory schizophrenia. C1 [Gogtay, Nitin; Rapoport, Judith] NIMH, NIH, Montreal Neurol Inst, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Gogtay, N (reprint author), NIMH, NIH, Montreal Neurol Inst, Child Psychiat Branch, Bldg 10,Rm 3N202,10 Ctr Dr, Bethesda, MD 20892 USA. EM gogtayn@mail.nih.gov RI Gogtay, Nitin/A-3035-2008 NR 57 TC 25 Z9 27 U1 5 U2 8 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1465-6566 J9 EXPERT OPIN PHARMACO JI Expert Opin. Pharmacother. PD FEB PY 2008 VL 9 IS 3 BP 459 EP 465 DI 10.1517/14656566.9.3.459 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 266BK UT WOS:000253406000010 PM 18220495 ER PT J AU Paugh, BS Paugh, SW Bryan, L Kapitonov, D Wilczynska, KM Gopalan, SM Rokita, H Milstien, S Spiegel, S Kordula, T AF Paugh, Barbara S. Paugh, Steven W. Bryan, Lauren Kapitonov, Dmitri Wilczynska, Katarzyna M. Gopalan, Sunita M. Rokita, Hanna Milstien, Sheldon Spiegel, Sarah Kordula, Tomasz TI EGF regulates plasminogen activator inhibitor-1 (PAI-1) by a pathway involving c-Src, PKC delta, and sphingosine kinase 1 in glioblastoma cells SO FASEB JOURNAL LA English DT Article DE glioma; invasiveness ID EPIDERMAL-GROWTH-FACTOR; HUMAN-BRAIN-TUMORS; FACTOR RECEPTOR GENE; HUMAN GLIOMA-CELLS; UROKINASE-TYPE; TRANSCRIPTION FACTOR; NECROSIS-FACTOR; BREAST-CANCER; ONCOSTATIN-M; KAPPA-B AB Patients with gliomas expressing high levels of epidermal growth factor receptor ( EGFR) and plasminogen activator inhibitor-1 (PAI-1) have a shorter overall survival prognosis. Moreover, EGF enhances PAI-1 expression in glioma cells. Although multiple known signaling cascades are activated by EGF in glioma cells, we show for the first time that EGF enhances expression of PAI-1 via sequential activation of c-Src, protein kinase C delta (PKC delta), and sphingosine kinase 1 (SphK1), the enzyme that produces sphingosine-1-phosphate. EGF induced rapid phosphorylation of c-Src and PKC delta and concomitant translocation of PKC delta as well as SphK1 to the plasma membrane. Down-regulation of PKC delta abolished EGF-induced SphK1 translocation and up-regulation of PAI-1 by EGF; whereas, down-regulation of PKC alpha had no effect on the EGF-induced PAI-1 activation but enhanced its basal expression. Similarly, inhibition of c-Src activity by PP2 blocked both EGF-induced translocation of SphK1 and PKC delta to the plasma membrane and up-regulation of PAI-1 expression. Furthermore, SphK1 was indispensable for both EGF-induced c-Jun phosphorylation and PAI-1 expression. Collectively, our results provide a functional link between three critical downstream targets of EGF, c-Src, PKC delta, and SphK1 that have all been implicated in regulating motility and invasion of glioma cells. C1 [Paugh, Barbara S.; Paugh, Steven W.; Bryan, Lauren; Kapitonov, Dmitri; Wilczynska, Katarzyna M.; Gopalan, Sunita M.; Spiegel, Sarah; Kordula, Tomasz] Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Dept Biochem & Mol Biol, Richmond, VA 23298 USA. [Rokita, Hanna] Jagiellonian Univ, Fac Biotechnol, Krakow, Poland. [Milstien, Sheldon] NIMH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. RP Kordula, T (reprint author), Virginia Commonwealth Univ, Sch Med, Massey Canc Ctr, Dept Biochem & Mol Biol, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM tkordula@vcu.edu RI Paugh, Steven/A-7739-2008; Paugh, Barbara/B-3625-2009 OI Paugh, Steven/0000-0001-5697-9228; FU Intramural NIH HHS; NCI NIH HHS [R01 CA061774, P30 CA016059, P30 CA16059, R01 CA061774-14, R01 CA061774-15, R01 CA61774]; NINDS NIH HHS [R01 NS044118, R01 NS044118-02, R01 NS044118-03, R01 NS044118-04]; PHS HHS [NSO44118, NSO46280] NR 50 TC 37 Z9 39 U1 0 U2 2 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD FEB PY 2008 VL 22 IS 2 BP 455 EP 465 DI 10.1096/fj.07-8276com PG 11 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 257TY UT WOS:000252822600016 PM 17855624 ER PT J AU Popat, VB Vanderhoof, VH Calis, KA Troendle, JF Nelson, LM AF Popat, Vaishali B. Vanderhoof, Vien H. Calis, Karim A. Troendle, James F. Nelson, Lawrence M. TI Normalization of serum luteinizing hormone levels in women with 46,XX spontaneous primary ovarian insufficiency SO FERTILITY AND STERILITY LA English DT Article DE transdermal estradiol therapy; premature ovarian failure; premature menopause; primary ovarian insufficiency; primary hypogonadism; hypergonadotropic hypogonadism; LH; FSH; hormone therapy ID UNRUPTURED FOLLICLE SYNDROME; NATURAL MENOPAUSE; MENSTRUAL-CYCLE; FAILURE; INFERTILITY; LIFE; AGE AB Objective: To determine the proportion of women with primary ovarian insufficiency who achieve normal serum LH levels on transdermal E-2 therapy. Design: Prospective. Setting: Clinical research center at a national US health research facility. Patient(s): Women with spontaneous primary ovarian insufficiency (n = 137) and 70 regularly menstruating control women (n = 70). Intervention(s): Blood sampled from controls in the midfollicular phase and from patients while they were off E-2 for 2 weeks, then again 3 months later during the E-2-only phase of hormone therapy (E-2 patch [100 mu g/d] and oral medroxyprogesterone acetate [10 mg for 12 d/mo]). Main Outcome Measure(s): Serum LH. Result(s): While on transdermal E-2 therapy, significantly more women (51.1%, 70/137; 95% confidence interval, 42%, 60%) had serum LH levels in the normal range (5/137, 3.9% at baseline). Mean (SD) serum E-2 level significantly increased on therapy to 95.4 (84.9) pg/mL. Conclusion(s): A regimen of 100 mu g/d of transdermal E-2 therapy achieves normal serum LH levels in approximately one half of women with spontaneous primary ovarian insufficiency. Theoretically, by avoiding inappropriate luteinization, physiologic E-2 therapy may improve follicle function in these women. Controlled studies to assess the effect of transdermal E-2 therapy on follicle function in these women are warranted. (Fertil Steril (R) 2008;89:429-33. (c) 2008 by American Society for Reproductive Medicine.) C1 [Popat, Vaishali B.; Vanderhoof, Vien H.; Nelson, Lawrence M.] Natl Inst Hlth, Warren O Hatfield Clin Res Ctr, Intramural Res Program, Reprod Biol & Med Branch,Integrat Reprod Med Uni, Bethesda, MD USA. [Calis, Karim A.] Natl Inst Hlth, Warren O Hatfield Clin Res Ctr, Dept Pharm, Bethesda, MD USA. [Troendle, James F.] Natl Inst Hlth, Warren O Hatfield Clin Res Ctr, NICHHD, Biometr & Math Stat Branch, Bethesda, MD USA. RP Nelson, LM (reprint author), NIH, NICHHD, Clin Res Ctr, Reprod Biol & Med Branch, Rm 1-3330, 10 Ctr Dr, Bethesda, MD 20892 USA. EM lawrence_nelson@nih.gov FU Intramural NIH HHS [Z01 HD000633-17] NR 23 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 0015-0282 J9 FERTIL STERIL JI Fertil. Steril. PD FEB PY 2008 VL 89 IS 2 BP 429 EP 433 DI 10.1016/j.fertnstert.2007.02.032 PG 5 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 263WB UT WOS:000253246100025 PM 17509587 ER PT J AU Moore, DF Brady, RO AF Moore, David F. Brady, Roscoe O. TI Systems-biology approach to sphingolipid-storage disorders SO FUTURE LIPIDOLOGY LA English DT Review DE hereditary metabolic storage disorders; improved therapeutic strategies; sphingolipidoses; systems biology ID FABRY-DISEASE MICE; ALPHA-GALACTOSIDASE; REPLACEMENT THERAPY; ENZYME REPLACEMENT; GLOBOTRIAOSYLCERAMIDE; ABNORMALITIES; EXPRESSION; MODEL AB The discovery of the enzymatic defects in sphingolipid-storage disorders led to important benefits for patients with these conditions. Diagnostic tests, genetic counseling procedures and prenatal diagnosis are available for these disorders. Enzyme-replacement therapy is especially effective for patients with Gaucher disease. It is also approved for patients with Fabry disease, but as yet unrecognized targets need to be addressed and treatment improved, probably because of the multiplicity of organs and tissues involved in patients with this condition. We propose that a significant increase of our understanding of the pathophysiology and etiopathogenesis underlying Fabry disease and other metabolic storage disorders is probably required to develop effective therapies for these patients. Significant advances in this aspect of Fabry disease and other disorders are anticipated from the application of a system- biology approach to understand the cellular and metabolic consequences of lipid accumulation. This strategy is discussed and its potential evaluated in this overview. C1 [Brady, Roscoe O.] NINDS, NIH, Dev & Metab Neurol Branch, Bethesda, MD 20892 USA. [Moore, David F.] Walter Reed Army Med Ctr, Def & Vet Brain Injury Ctr, Washington, DC 20307 USA. RP Brady, RO (reprint author), NINDS, NIH, Dev & Metab Neurol Branch, Bldg 10,Room 304, Bethesda, MD 20892 USA. EM david.f.moore@amedd.army.mil; rb57v@nih.gov NR 22 TC 0 Z9 0 U1 0 U2 2 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1746-0875 J9 FUTURE LIPIDOL JI Future Lipidol. PD FEB PY 2008 VL 3 IS 1 BP 105 EP 111 DI 10.2217/17460875.3.1.105 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 263XJ UT WOS:000253249500015 ER PT J AU Kim, YS Maruvada, P Milner, JA AF Kim, Young S. Maruvada, Padma Milner, John A. TI Metabolomics in biomarker discovery: future uses for cancer prevention SO FUTURE ONCOLOGY LA English DT Review DE biomarker; cancer; choline; glycolysis; lipids; metabolomics; polyamines ID M2 PYRUVATE-KINASE; MAGNETIC-RESONANCE-SPECTROSCOPY; IN-VIVO; COLORECTAL-CANCER; PROSTATE-CANCER; BREAST-CANCER; MASS-SPECTROMETRY; METABONOMIC TECHNIQUES; H-1-NMR SPECTROSCOPY; DIETARY ISOFLAVONES AB Metabolomics is the systematic study of small-molecular-weight substances in cells, tissues and/or whole organisms as influenced by multiple factors including genetics, diet, lifestyle and pharmaceutical interventions. These substances may directly or indirectly interact with molecular targets and thereby influence the risk and complications associated with various diseases, including cancer. Since the interaction between metabolites and specific targets is dynamic, knowledge regarding genetics, susceptibility factors, timing, and degree of exposure to an agent (drug or food component) is fundamental to understanding the metabolome and its potential use for predicting and preventing early phenotypic changes. The future of metabolomics rests with its ability to monitor subtle changes in the metabolome that occur prior to the detection of a gross phenotypic change reflecting disease. The integrated analysis of metabolomics and other 'omics' may provide more sensitive ways to detect changes related to disease and discover novel biomarkers. Knowledge regarding these multivariant characteristics is critical for establishing validated and predictive metabolomic models for cancer prevention. Understanding the metabolome will not only provide insights into the critical sites of regulation in health promotion, but will also assist in identifying intermediate or surrogate cancer biomarkers for establishing preemptive/ preventative or therapeutic approaches for health. While unraveling the metabolome will not be simple, the societal implications are enormous. C1 [Kim, Young S.; Milner, John A.] NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, Bethesda, MD 20892 USA. [Maruvada, Padma] NCI, Div Res Infrastruct, NIH, Bethesda, MD 20892 USA. RP Kim, YS (reprint author), NCI, Nutr Sci Res Grp, Canc Prevent Div, NIH, 6130 Execut Blvd,Execut Plaza N Suite 3156, Bethesda, MD 20892 USA. EM yk47s@nih.gov; maruvadap@mail.nih.gov; milnerj@mail.nih.gov NR 74 TC 45 Z9 49 U1 4 U2 31 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1479-6694 J9 FUTURE ONCOL JI Future Oncol. PD FEB PY 2008 VL 4 IS 1 BP 93 EP 102 DI 10.2217/14796694.4.1.93 PG 10 WC Oncology SC Oncology GA 384EM UT WOS:000261727100014 PM 18241004 ER PT J AU Pawlotsky, JM Dusheiko, G Hatzakis, A Lau, D Lau, G Liang, TJ Locarnini, S Martin, P Richman, DD Zoulim, F AF Pawlotsky, Jean-Michel Dusheiko, Geoffrey Hatzakis, Angelos Lau, Daryl Lau, George Liang, T. Jake Locarnini, Stephen Martin, Paul Richman, Douglas D. Zoulim, Fabien TI Virologic monitoring of hepatitis B virus therapy in clinical trials and practice: Recommendations for a standardized approach SO GASTROENTEROLOGY LA English DT Article ID LINE PROBE ASSAY; NUCLEOSIDE-NAIVE PATIENTS; CHRONIC HBV INFECTION; CLOSED CIRCULAR DNA; INNO-LIPA HBV; ADEFOVIR DIPIVOXIL; LAMIVUDINE THERAPY; DRUG-RESISTANCE; HEPATOCELLULAR-CARCINOMA; ENTECAVIR RESISTANCE AB Treatment of chronic hepatitis B virus (HBV) infection is aimed at suppressing viral replication to the lowest possible level, and thereby to halt the progression of liver disease and prevent the onset of complications. Two categories of drugs are used in HBV therapy: the interferons, including standard interferon alfa or pegylated interferon alfa, and specific nucleoside or nucleotide HBV inhibitors that target the reverse-transcriptase function of HBV-DNA polymerase. The reported results of clinical trials have used varying definitions of efficacy, failure, and resistance based on different measures of virologic responses. This article discusses HBV virologic markers and tests, and their optimal use both for planning and reporting clinical trials and in clinical practice. C1 [Pawlotsky, Jean-Michel] Univ Paris 07, Hop Henri Mondor, French Natl Ref Ctr Viral Hepatitis B C & Delta, Dept Virol, Creteil, France. [Pawlotsky, Jean-Michel] INSERM, U841, Creteil, France. [Dusheiko, Geoffrey] UCL Royal Free & Univ Coll, Sch Med, Ctr Hepatol, London, England. [Hatzakis, Angelos] Univ Athens, Sch Med, Dept Hyg Epidemiol & Med Stat, Athens, Greece. [Lau, Daryl] Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Liver Ctr,Dept Med, Boston, MA USA. [Lau, George] Univ Hong Kong, Queen Mary Hosp, Dept Med, Hong Kong, Peoples R China. [Liang, T. Jake] Natl Inst Hlth, NIDDK, Liver Dis Branch, Bethesda, MD USA. [Locarnini, Stephen] Victorian Infect Dis Ref Lab, Melbourne, Vic, Australia. [Martin, Paul] Mt Sinai Sch Med, Recanati Miller Transplant Inst, Div Liver Dis, New York, NY USA. [Richman, Douglas D.] Univ Calif San Diego, VA San Diego Hlthcare Syst, La Jolla, CA USA. [Zoulim, Fabien] Univ Lyon 1, Hosp Civils Lyon, INSERM, Dept Liver Dis,U871, Lyon, France. RP Pawlotsky, JM (reprint author), Hop Henri Mondor, Dept Virol, 51 Ave Marechal Lattre Tassigny, F-94010 Creteil, France. EM pawlotsky@hmn.aphp.fr FU Intramural NIH HHS [Z01 DK054500-11]; PHS HHS [R0-1 AIO60449] NR 91 TC 137 Z9 162 U1 1 U2 6 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 EI 1528-0012 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2008 VL 134 IS 2 BP 405 EP 415 DI 10.1053/j.gastro.2007.11.036 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 260TI UT WOS:000253032900010 PM 18242209 ER PT J AU Kunos, G Gao, B AF Kunos, George Gao, Bin TI Endocannabinoids, CB1 receptors, and liver disease: Hitting more than one bird with the same stone SO GASTROENTEROLOGY LA English DT Editorial Material ID DIET-INDUCED OBESITY; CHRONIC HEPATITIS-C; RISK-FACTORS; OVERWEIGHT PATIENTS; CANNABIS USE; RIMONABANT; STEATOSIS; RATS; MICE; MACROPHAGES C1 [Kunos, George] NIAAA, Sect Neuroendocrinol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. RP Kunos, G (reprint author), NIAAA, Sect Neuroendocrinol, Lab Physiol Studies, NIH, Bethesda, MD 20892 USA. NR 30 TC 4 Z9 4 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2008 VL 134 IS 2 BP 622 EP 625 DI 10.1053/j.gastro.2007.12.017 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 260TI UT WOS:000253032900031 PM 18242226 ER PT J AU Carter, MG Stagg, CA Falco, G Yoshikawa, T Bassey, UC Aiba, K Sharova, LV Shaik, N Ko, MSH AF Carter, Mark G. Stagg, Carole A. Falco, Geppino Yoshikawa, Toshiyuki Bassey, Uwem C. Aiba, Kazuhiro Sharova, Lioudmila V. Shaik, Nabeebi Ko, Minoru S. H. TI An in situ hybridzation-based screen for heterogeneously expressed genes in mouse ES cells SO GENE EXPRESSION PATTERNS LA English DT Article DE ES cells; EC cells; pluripotent stem cells; heterogeneous gene expression; homogeneous gene expression; Zscan4; Pou5f1; Oct4; Oct3/4; Krt8; EndoA; Whsc2; Nelfa; Rhox9; Zfp42; Rex1; Rest; Zfp42; Rex1; Rest; Atf4; Pa2g4; E2f2; Nanog; Dppa3; Pgc7; Stella; Esrrb; Fscn1 ID EMBRYONIC STEM-CELLS; HOMEOBOX GENE; ADHESION MOLECULE-1; FAMILY-MEMBERS; GERM-CELLS; PLURIPOTENCY; MICROARRAY; PROTEIN; NANOG; MICE AB We previously reported that Zscan4 showed heterogeneous expression patterns in mouse embryonic stem (ES) cells. To identify genes that show similar expression patterns, we carried out high-throughput in situ hybridization assays on ES cell cultures for 244 genes. Most of the genes are involved in transcriptional regulation, and were selected using microarray-based comparisons of gene expression profiles in ES and embryonal carcinoma (EC) cells versus differentiated cell types. Pou5f1 (Oct4, Oct3/4) and Krt8 (EndoA) were used as controls. Hybridization signals were detected on ES cell colonies for 147 genes (60%). The majority (136 genes) of them showed relatively homogeneous expression in ES cell colonies. However, we found that two genes unequivocally showed Zscan4-like spotted expression pattern (spot-in-colony pattern; Whsc2 and Rhox9). We also found that nine genes showed relatively heterogeneous expression pattern (mosaicin-colony pattern: Zfp42/Rex1, Rest, Atf4, Pa2g4, E2f2, Nanog, Dppa31Pgc71Ste11a, Esrrb, and Fscn1). Among these genes, Zfp42/Rex1 showed unequivocally heterogeneous expression in individual ES cells prepared by the CytoSpin. These results show the presence of different types or states of cells within ES cell cultures otherwise thought to be undifferentiated and homogeneous, suggesting a previously unappreciated complexity in ES cell cultures. Published by Elsevier B.V. C1 [Carter, Mark G.; Stagg, Carole A.; Falco, Geppino; Yoshikawa, Toshiyuki; Bassey, Uwem C.; Aiba, Kazuhiro; Sharova, Lioudmila V.; Shaik, Nabeebi; Ko, Minoru S. H.] NIA, NIH, Genet Lab, Dev Genom & Aging Sect, Baltimore, MD 21224 USA. RP Ko, MSH (reprint author), NIA, NIH, Genet Lab, Dev Genom & Aging Sect, Baltimore, MD 21224 USA. EM kom@mail.nih.gov RI Carter, Mark/B-5089-2010; Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 FU Intramural NIH HHS [Z01 AG000662-07] NR 44 TC 52 Z9 54 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1567-133X J9 GENE EXPR PATTERNS JI Gene Expr. Patterns PD FEB PY 2008 VL 8 IS 3 BP 181 EP 198 DI 10.1016/j.gep.2007.10.009 PG 18 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 263WY UT WOS:000253248400006 PM 18178135 ER PT J AU Feng, JQ Scott, G Guo, DY Jiang, BC Harris, M Ward, T Ray, M Bonewald, LF Harris, SE Mishina, Y AF Feng, Jian Q. Scott, Greg Guo, Dayong Jiang, Baichun Harris, Marie Ward, Toni Ray, Manas Bonewald, Lynda F. Harris, Stephen E. Mishina, Yuji TI Generation of a conditional null allele for Dmp1 in mouse SO GENESIS LA English DT Article DE DMP1; Cre-loxP; gene targeting; mouse; bone ID DENTIN MATRIX PROTEIN-1; IN-VIVO; DMP1-DEFICIENT MICE; SIBLING PROTEINS; EXPRESSION; GENE; BONE; PHOSPHOPROTEIN; OSTEOMALACIA; TISSUES AB Dentin matrix protein1 (DMP1), highly conserved in humans and mice, is highly expressed in teeth, the skeleton, and to a lesser extent in nonskeletal tissues such as brain, kidney, and salivary gland. Pathologically, DMP1 is associated with several forms of cancers and with tumor-induced osteomalacia. Conventional disruption of the murine Dmp1 gene results in defects in dentin in teeth and in the skeleton, including hypophosphatemic rickets, and abnormalities in phosphate homeostasis. Human DMPI mutations are responsible for the condition known as autosomal recessive hypophosphatemic rickets. For better understanding of the roles of DMP1 in different tissues at different stages of development and in pathological conditions, we generated Dmp1 floxed mice in which loxP sites flank exon 6 that encodes for over 80% of DMP1 protein. We demonstrate that Cre-mediated recombination using Sox2-Cre, a Cre line expressed in epiblast during early embryogenesis, results in early deletion of the gene and protein. These homozygous Cre-recombined null mice display an identical phenotype conventional null mice. This animal model will be useful reveal distinct roles of DMP1 in different tissues at different ages. C1 [Feng, Jian Q.; Jiang, Baichun] Texas A&M Univ, Hlth Sci Ctr, Baylor Coll Dent, Dept Biomed Sci, Dallas, TX USA. [Ward, Toni; Ray, Manas; Mishina, Yuji] NIH, Res Triangle Pk, NC USA. [Guo, Dayong; Bonewald, Lynda F.] Univ Missouri, Sch Dent, Kansas City, MO 64110 USA. [Harris, Marie; Harris, Stephen E.] Univ Texas Hlth Sci Ctr San Antonio, Dept Periodont & Cellular & Struct Biol, San Antonio, TX 78229 USA. [Mishina, Yuji] NIEHS, Natl Inst Hlth, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC USA. [Jiang, Baichun] Shandong Univ, Sch Med, Key Lab Expt Teratol, Minist Educ, Jinan 250100, Shandong, Peoples R China. [Jiang, Baichun] Shandong Univ, Sch Med, Inst Med Genet, Jinan 250100, Shandong, Peoples R China. RP Feng, JQ (reprint author), Baylor Coll Dent, Dept Biomed Sci, 3302 Gaston Ave, Dallas, TX 75246 USA. EM jfeng@bcd.tamhsc.edu; mishina@niehs.nih.gov FU Intramural NIH HHS [Z01 ES071003-10]; NIAMS NIH HHS [P01 AR046798, AR046798, AR051587, R01 AR051587]; NIEHS NIH HHS [ES071003-10, Z01 ES071003] NR 23 TC 8 Z9 8 U1 1 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1526-954X J9 GENESIS JI Genesis PD FEB PY 2008 VL 46 IS 2 BP 87 EP 91 DI 10.1002/dvg.20370 PG 5 WC Developmental Biology; Genetics & Heredity SC Developmental Biology; Genetics & Heredity GA 272CZ UT WOS:000253837900005 PM 18257058 ER PT J AU Gu, CC Yu, K Ketkar, S Templeton, AR Rao, DC AF Gu, C. Charles Yu, K. Ketkar, S. Templeton, Alan R. Rao, D. C. TI On transferability of genome-wide tagSNPs SO GENETIC EPIDEMIOLOGY LA English DT Review DE genome-wide association study; linkage disequilibrium mapping; SNP selection; tagSNPs; tagSNPs transferability ID LINKAGE-DISEQUILIBRIUM PATTERNS; SINGLE-NUCLEOTIDE POLYMORPHISMS; HAPLOTYPE-TAGGING SNPS; COMMON DISEASE GENES; TAG SNPS; ASSOCIATION ANALYSES; IMPROVING POWER; GENOTYPE DATA; POPULATIONS; SELECTION AB The question of tagging single nucleotide polymorphism (tagSNP) transferability is an important one because many ongoing and upcoming Genome-Wide Association studies rely critically upon the validity, and practical feasibility of using a universal core set of tagSNPs. A series of recent studies analyzed performance of tagSNPs selected based on the HapMap. While these studies showed largely satisfactory transferability of the tagSNPs, they also reported that the level of transferability varies, substantively sometimes, especially when tagSNPs selected in one population were used in another distant population. We present a review of the literature about where and why tagSNP transferability may become a problem and suggest research directions that may help the resolution. C1 [Gu, C. Charles; Ketkar, S.; Rao, D. C.] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. [Gu, C. Charles; Rao, D. C.] Washington Univ, Sch Med, Dept Genet, St Louis, MO USA. [Ketkar, S.] Washington Univ, Sch Med, Dept Biol, St Louis, MO USA. [Rao, D. C.] Washington Univ, Sch Med, Dept Psychiat, St Louis, MO USA. [Yu, K.] Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. RP Gu, CC (reprint author), Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA. RI Templeton, Alan/F-5963-2011; Gu, Charles/A-7934-2010 OI Gu, Charles/0000-0002-8527-8145 FU NHLBI NIH HHS [HL 054473, HL 071782, HL 072507]; NIGMS NIH HHS [GM 028719] NR 48 TC 10 Z9 10 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2008 VL 32 IS 2 BP 89 EP 97 DI 10.1002/gepi.20269 PG 9 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 264RK UT WOS:000253306500001 PM 17896344 ER PT J AU Schultz, GE Drake, JW AF Schultz, Gary E., Jr. Drake, John W. TI Templated mutagenesis in bacteriophage T4 involving imperfect direct or indirect sequence repeats SO GENETICS LA English DT Article ID MARKER-DEPENDENT RECOMBINATION; DNA-REPLICATION FORK; ESCHERICHIA-COLI; MUTATION-RATES; FRAMESHIFT MUTATION; MAMMALIAN-CELLS; BINDING PROTEIN; DDA HELICASE; BASE-PAIRS; REPAIR AB Some mutations arise in association with a potential sequence donor that consists of an imperfect direct or reverse repeat. Many such mutations are complex; that is, they consist of multiple close sequence changes. Current models posit that the primer terminus of a replicating DNA molecule dissociates, reanneals with an ectopic template, extends briefly, and then returns to the cognate template, bringing with it a locally different sequence; alternatively, a hairpin structure may form the mutational intermediate when processed by mismatch repair. This process resembles replication repair, in which primer extension is blocked by a lesion in the template; in this case, the ectopic template is the other daughter strand, and the result is error-free bypass of the lesion. We previously showed that mutations that impair replication repair can enhance templated mutagenesis. We show here that the intensity of templated mutation can be exquisitely sensitive to its local sequence, that the donor and recipient arms of an imperfect inverse repeat can exchange roles, and that double mutants carrying two alleles, each affecting both templated mutagenesis and replication repair, can have unexpected phenotypes. We also record an instance in which the mutation rates at two particular sites change concordantly with a distant sequence change, but in a manner that appears unrelated to templated mutagenesis. C1 [Schultz, Gary E., Jr.; Drake, John W.] NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Drake, JW (reprint author), NIEHS, Mol Genet Lab, 111 S Alexander Dr, Res Triangle Pk, NC 27709 USA. EM drike@niehs.nih.gov FU Intramural NIH HHS NR 39 TC 6 Z9 6 U1 0 U2 4 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD FEB PY 2008 VL 178 IS 2 BP 661 EP 673 DI 10.1534/genetics.107.083444 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 268JW UT WOS:000253577100005 PM 18245334 ER PT J AU Smith, S Banerjee, S Rilo, R Myung, KJ AF Smith, Stephanie Banerjee, Soma Rilo, Regina Myung, Kyungjae TI Dynamic regulation of single-stranded telomeres in Saccharomyces cerevisiae SO GENETICS LA English DT Article ID GROSS CHROMOSOMAL REARRANGEMENTS; SUBSTRATE-SPECIFIC INHIBITION; HUMAN AUTOANTIGEN KU; CELL-CYCLE ARREST; DNA-DAMAGE; GENOME INSTABILITY; YEAST KU; IN-VIVO; S-PHASE; V(D)J RECOMBINATION AB The temperature-sensitive phenotypes of yku70 Delta and yku80 Delta have provided a useful tool for understanding telomere homeostasis. Mutating the helicase domain of the telomerase inhibitor Pif1 resulted in the inactivation of cell cycle checkpoints and the subsequent rescue of temperature sensitivity of the yku70 Delta strain. The inactivation of Pif1 in yku70 Delta increased overall telomere length. However, the long G-rich, single-stranded overhangs at the telomeres, which are the major cause of temperature sensitivity were slightly increased. Interestingly, the rescue of temperature sensitivity in strains having both pif1-m2 and yku70 Delta mutations depended on the homologous recombination pathway. Furthermore, the BLM/ WRN helicase yeast homolog Sgs1 exacerbated the temperature sensitivity of the yku70 Delta strain. Therefore, the yKu70-80 heterodimer and telomerase maintain telomere size, and the helicase activity of Pif1 likely also helps to balance the overall size of telomeres and G-rich, single-stranded overhangs in wild-type cells by regulating telomere protein homeostasis. However, the absence of yKu70 may provide other proteins such as those involved in homologous recombination, Sgs1, or Pif1 additional access to G-rich, single-stranded DNA and may determine telomere size, cell cycle checkpoint activation, and, ultimately, temperature sensitivity. C1 [Smith, Stephanie; Banerjee, Soma; Rilo, Regina; Myung, Kyungjae] NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. RP Myung, KJ (reprint author), NHGRI, Genome Instabil Sect, Genet & Mol Biol Branch, NIH, Bldg 49,Room 4A22, Bethesda, MD 20892 USA. EM kmyung@nhgri.nih.gov FU Intramural NIH HHS NR 70 TC 5 Z9 5 U1 0 U2 3 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD FEB PY 2008 VL 178 IS 2 BP 693 EP 701 DI 10.1534/genetics.107.081091 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 268JW UT WOS:000253577100007 PM 18245359 ER PT J AU Feero, WG AF Feero, W. Gregory TI Genetics of common disease: a primary care priority aligned with a teachable moment? SO GENETICS IN MEDICINE LA English DT Editorial Material ID PROVIDERS C1 [Feero, W. Gregory] Natl Inst Hlth, NHGRI, Bethesda, MD USA. RP Feero, WG (reprint author), Bldg 31,Room 4B09,31 Ctr Dr,MSC 2152, Bethesda, MD 20892 USA. EM feerow@mail.nih.gov NR 13 TC 12 Z9 13 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD FEB PY 2008 VL 10 IS 2 BP 81 EP 82 DI 10.1097/GIM.0b013e3181639a6d PG 2 WC Genetics & Heredity SC Genetics & Heredity GA 264HC UT WOS:000253277400001 PM 18281913 ER PT J AU Riegert-Johnson, DL Macaya, D Hefferon, TW Boardman, LA AF Riegert-Johnson, Douglas L. Macaya, Daniela Hefferon, Timothy W. Boardman, Lisa A. TI The incidence of duplicate genetic testing SO GENETICS IN MEDICINE LA English DT Article DE genetic testing; molecular diagnostic techniques; duplicate genetic testing; laboratory techniques and procedures; inappropriate laboratory utilization AB Purpose: Duplicate genetic testing (DGT) should give the same results as the initial genetic test. Therefore, DGT is indicated only in the rare instances where the initial results require confirmation. The objective of this study was to determine the incidence of DGT by reviewing TPMT, HFE, and CYP450 2D6 polymorphism testing performed in our institution's laboratories in 2006. A secondary objective was to determine the savings in charges that resulted from a system in place to limit HFE DGT. Methods: A retrospective records review at an academic medical center. Results: The percentage of patients having the same genetic test more than once in 2006 was 3.3% (253/7710) for TPMT, 0.3% for HFE (24/7851), and 0.9% (4/433) for CYP450 2D6 testing. Retail laboratory charges for the DGT identified in 2006 were $76,728. To estimate the incidence of DGT over a longer period of time than 2006, an all-time records review was performed on a subset of internal patients and found the all-time incidence of DGT for TPMT, HFE, and CYP450 2D6 testing to be 6.9%, 1.9%, and 0.9%, respectively. No case of DGT with an appropriate indication for duplicate testing was found. A system in place to decrease HFE DGT is estimated to have saved $77,479 in charges for 2006 (95% CI, $35,512-184,015). Conclusions: Indicated DGT is rare and decreasing DGT could result in significant savings. Institutions should consider implementing a systems-based process to limit DGT. C1 [Riegert-Johnson, Douglas L.; Boardman, Lisa A.] Mayo Clin, Coll Med, Div Gastroenterol, Rochester, MN USA. [Macaya, Daniela] Univ Costa Rica, Dept Med Genet, San Jose, Costa Rica. [Hefferon, Timothy W.] NHGRI, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Riegert-Johnson, DL (reprint author), Mayo Clin, Coll Med, Div Gastroenterol & Hepatol, 200 Second St SW, Rochester, MN 55905 USA. EM riegertjohnson.douglas@mayo.edu NR 6 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD FEB PY 2008 VL 10 IS 2 BP 114 EP 116 DI 10.1097/GIM.0b013e31816166a7 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 264HC UT WOS:000253277400006 PM 18281918 ER PT J AU O'Neill, SC White, DB Sanderson, SC Lipkus, IM Bepler, G Bastian, LA McBride, CM AF O'Neill, Suzanne C. White, Della Brown Sanderson, Saskia C. Lipkus, Isaac M. Bepler, Gerold Bastian, Lori A. McBride, Colleen M. TI The feasibility of online genetic testing for lung cancer susceptibility: uptake of a web-based protocol and decision outcomes SO GENETICS IN MEDICINE LA English DT Article DE internet; genetic testing; test uptake; decision making; GSTM1; lung cancer ID SMOKING-CESSATION TREATMENT; AFRICAN-AMERICAN SMOKERS; HUNTINGTONS-DISEASE; MEDICAL GENETICS; QUIT SMOKING; BEHAVIOR; RISK; INFORMATION; KNOWLEDGE; ATTITUDES AB Purpose: To examine the feasibility of offering genetic susceptibility testing for lung cancer (GSTM1) via the Internet to smokers who were blood relatives of patients with lung cancer. Outcomes include proportion who logged on to the study website to consider testing, made informed decisions to log on and to be tested. Methods: Baseline measures were assessed via telephone survey. Participants could choose to log on to the study website; those who did were offered testing. Informed decisions to log on and to be tested were indicated by concordance between the decision outcome and test-related attitudes and knowledge. Results: Three hundred four relatives completed baseline interviews. One hundred sixteen eligible relatives expressed further interest in receiving information via the web. Fifty-eight logged on and 44 tested. Those logging on expressed greater quit motivation, awareness of cancer genetic testing, and were more likely to be daily Internet users than those who did not log on. Approximately half of the sample made informed decisions to log on and to be tested. Conclusion: Interest in a web-based protocol for genetic susceptibility testing was high. Internet-delivered decision support was as likely as other modalities to yield informed decisions. Some subgroups may need additional support to improve their decision outcomes. C1 [O'Neill, Suzanne C.; White, Della Brown; Sanderson, Saskia C.; McBride, Colleen M.] NIH, NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. [Lipkus, Isaac M.] Duke Comprehens Canc Ctr, Durham, NC USA. [Bepler, Gerold] H Lee Moffitt Comprehens Canc Ctr, Tampa, FL USA. [Bepler, Gerold] Ctr Hlth Serv Res Primary Care, Durham, NC USA. [Bastian, Lori A.] Duke Univ, Med Ctr, Durham, NC USA. RP O'Neill, SC (reprint author), NIH, NHGRI, Social & Behav Res Branch, Bldg ,B1B36B, Bethesda, MD 20892 USA. EM oneills@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [U01CA092622] NR 55 TC 23 Z9 23 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD FEB PY 2008 VL 10 IS 2 BP 121 EP 130 DI 10.1097/GIM.0b013e31875f8e06 PG 10 WC Genetics & Heredity SC Genetics & Heredity GA 264HC UT WOS:000253277400008 PM 18281920 ER PT J AU Leem, SH Yoon, YH Kim, SI Larionov, V AF Leem, S. -H. Yoon, Y. -H. Kim, S. I. Larionov, V. TI Purification of circular YACs from yeast cells for DNA sequencing SO GENOME LA English DT Article DE YAC purification; TAR cloning; unstable clone in E. coli; circular YAC; GAP sequence; YAC sequencing ID TRANSFORMATION-ASSOCIATED RECOMBINATION; ARTIFICIAL CHROMOSOMES; HUMAN GENOME; SELECTIVE ISOLATION; CLONING; SEGMENTS; GENES AB We describe a method for the purification of circular yeast artificial chromosome (YAC) DNA 120-150 kilobases (kb) in size that is of sufficient quantity and quality for restriction enzyme analysis and DNA sequencing. This method preferentially enriches for circular YAC DNA and avoids the time-consuming step of centrifugation in CsCl - ethidium bromide (EtBr) gradients. We applied this method to the purification of circular YACs carrying DNA segments that are extremely unstable in E. coli, including those that correspond to GAP2 and GAP3 on human chromosome 19. We showed that YAC DNA (GAP2 and GAP3) purified using this new method is clearly resolved in EtBr-stained gels. The sequence of YAC-GAP3 was obtained, representing the first GAP clone sequenced in YAC form. At present, it is estimated that there are more than 1000 gaps in the human genome that cannot be cloned using bacterial vectors. Thus, our new method may be very useful for completing the last stage of the human genome project. C1 [Leem, S. -H.; Yoon, Y. -H.] Dong A Univ, Dept Biol Sci, Pusan 604714, South Korea. [Kim, S. I.] Korea Basic Sci Inst, Prote Team, Taejon 305806, South Korea. [Larionov, V.] NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Leem, SH (reprint author), Dong A Univ, Dept Biol Sci, Pusan 604714, South Korea. EM shleem@dau.ac.kr NR 11 TC 2 Z9 2 U1 0 U2 2 PU NATL RESEARCH COUNCIL CANADA-N R C RESEARCH PRESS PI OTTAWA PA BUILDING M 55, OTTAWA, ON K1A 0R6, CANADA SN 0831-2796 J9 GENOME JI Genome PD FEB PY 2008 VL 51 IS 2 BP 155 EP 158 DI 10.1139/G07.109 PG 4 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 283OH UT WOS:000254645400008 PM 18356949 ER PT J AU Margulies, EH AF Margulies, Elliott H. TI Confidence in comparative genomics SO GENOME RESEARCH LA English DT Article ID CONSERVED NONCODING SEQUENCES; FUNCTIONAL ELEMENTS; REGULATORY ELEMENTS; EVOLUTION; IDENTIFICATION; ALIGNMENTS; CONSTRAINT; DISCOVERY; HUMANS C1 NHGRI, Natl Inst Hlth, Genome Informat Sect, Genome Technol Branch, Bethesda, MD 20892 USA. RP Margulies, EH (reprint author), NHGRI, Natl Inst Hlth, Genome Informat Sect, Genome Technol Branch, Bethesda, MD 20892 USA. EM Elliott@nhgri.nih.gov FU Intramural NIH HHS NR 21 TC 4 Z9 4 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1088-9051 J9 GENOME RES JI Genome Res. PD FEB PY 2008 VL 18 IS 2 BP 199 EP 200 DI 10.1101/gr.7228008 PG 2 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity GA 258ID UT WOS:000252860700001 PM 18245452 ER PT J AU Bergeron, SA Milla, LA Villegas, R Shen, MC Burgess, SM Allende, ML Karlstrom, RO Palma, V AF Bergeron, Sadie A. Milla, Luis A. Villegas, Rosario Shen, Meng-Chieh Burgess, Shawn M. Allende, Miguel L. Karlstrom, Rolf O. Palma, Veronica TI Expression profiling identifies novel Hh/Gli-regulated genes in developing zebrafish embryos SO GENOMICS LA English DT Article DE Hedgehog; detour (dtr); slow muscle omitted (smu); interrenal gland; pronephros; nervous system; microarray; transcriptional profiling ID HEDGEHOG SIGNAL-TRANSDUCTION; VENTRAL NEURAL-TUBE; SONIC-HEDGEHOG; VERTEBRATE DEVELOPMENT; NERVOUS-SYSTEM; IN-VITRO; GLI; PROTEIN; DIFFERENTIATION; DROSOPHILA AB The Hedgehog (Hh) signaling pathway plays critical instructional roles during embryonic development. Misregulation of Hh/Gli signaling is a major causative factor in human congenital disorders and in a variety of cancers. The zebrafish is a powerful genetic model for the study of Hh signaling during embryogenesis, as a large, number Of Mutants that affect different components of the Hh/Gli signaling system have been identified. By performing global profiling of gene expression in different Hh/Gli gain- and loss-of-function scenarios we identified known (e.g., ptc1 and nkx2.2a) and novel Hh-regulated genes that are differentially expressed in embryos with altered Hh/Gh signaling function. By uncovering changes in tissue-specific gene expression, we revealed new embryological processes that are influenced by Hh signaling. We thus provide a comprehensive survey of Hh/Gli-regulated genes during embryogenesis and we identify new Hh-regulated genes that may be targets of misregulation during tumorigenesis. (c) 2007 Elsevier Inc. All rights reserved. C1 [Bergeron, Sadie A.; Shen, Meng-Chieh; Karlstrom, Rolf O.] Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. [Milla, Luis A.; Villegas, Rosario; Allende, Miguel L.; Palma, Veronica] Univ Chile, Fac Ciencias, Ctr Genom Cell, Santiago, Chile. [Milla, Luis A.; Villegas, Rosario; Allende, Miguel L.; Palma, Veronica] Univ Chile, Fac Ciencias, Dept Biol, Santiago, Chile. [Burgess, Shawn M.] NHGRI, NIH, Bethesda, MD 20892 USA. RP Karlstrom, RO (reprint author), Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. EM karlstrom@bio.umass.edu; vpalma@uchile.cl RI Allende, Miguel/C-5167-2008; Milla, Luis/B-8293-2009; OI Allende, Miguel/0000-0002-2783-2152; Burgess, Shawn/0000-0003-1147-0596; Bergeron, Sadie/0000-0002-1238-8730 FU Intramural NIH HHS; NICHD NIH HHS [R01 HD044929, HD044929]; NINDS NIH HHS [R01 NS039994-04, R01 NS039994-04S1, NS03994, R01 NS039994-05A2, R01 NS039994-06, R01 NS039994] NR 67 TC 14 Z9 14 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD FEB PY 2008 VL 91 IS 2 BP 165 EP 177 DI 10.1016/j.ygeno.2007.09.001 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 259MX UT WOS:000252944500006 PM 18055165 ER PT J AU Alhamarneh, O Amarnath, SMP Stafford, ND Greenman, J AF Alhamarneh, Osama Amarnath, Shoba M. P. Stafford, Nicholas D. Greenman, John TI Regulatory T cells: What role do they play in antitumor immunity in patients with head and neck cancer? SO HEAD AND NECK-JOURNAL FOR THE SCIENCES AND SPECIALTIES OF THE HEAD AND NECK LA English DT Review DE regulatory T cells; antitumour immunity; HNSCC; immunotherapy; TGF-beta ID IMMUNOLOGICAL SELF-TOLERANCE; ZETA-CHAIN EXPRESSION; NATURAL-KILLER-CELL; TUMOR-IMMUNITY; PERIPHERAL-BLOOD; DENDRITIC CELLS; TGF-BETA; MEDIATED SUPPRESSION; METASTATIC MELANOMA; OVARIAN-CARCINOMA AB Advances in the treatment modalities for head and neck squamous cell carcinoma (HNSCC) over the last 20 years involving surgery, radiotherapy, chemotherapy, and immunotherapy are not fully reflected in increases in the 5-year survival rates, mainly due to locoregional recurrences and to a lesser extent, distant metastasis. This can, in part, be attributed to the fact that HNSCC induces severe depression of a patient's immune system. Recent advances in understanding the complex host-tumor interactions have led to the identification of a distinct suppressor cell population known as regulatory T cells that play a crucial role in maintaining T-cell tolerance to self-antigens. Here, we present a critical review of our understanding of the involvement of regulatory T cells in controlling the T-cell immune response in tumor occurrence and progression in HNSCC with an emphasis on current and future immunotherapeutic approaches involving regulatory T cells. (C) 2008 Wiley Periodicals, Inc. C1 [Alhamarneh, Osama; Stafford, Nicholas D.; Greenman, John] Univ Hull, Dept Otolaryngol Head & Neck Surg, Canc Div, Postgrad Med Inst, Kingston Upon Hull HU6 7RX, N Humberside, England. [Amarnath, Shoba M. P.] NCI, Expt Transplant & Immunol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Greenman, J (reprint author), Univ Hull, Dept Otolaryngol Head & Neck Surg, Canc Div, Postgrad Med Inst, Kingston Upon Hull HU6 7RX, N Humberside, England. EM j.greenman@hull.ac.uk NR 104 TC 23 Z9 23 U1 0 U2 6 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1043-3074 J9 HEAD NECK-J SCI SPEC JI Head Neck-J. Sci. Spec. Head Neck PD FEB PY 2008 VL 30 IS 2 BP 251 EP 261 DI 10.1002/hed.20739 PG 11 WC Otorhinolaryngology; Surgery SC Otorhinolaryngology; Surgery GA 259NK UT WOS:000252945800015 PM 18172882 ER PT J AU Shinkarev, SM Voilleque, PG Gavrilin, YI Khrouch, VT Bouville, A Hoshi, M Meckbach, R Minenko, VF Ulanovsky, AV Luckyanov, N AF Shinkarev, Sergey M. Voilleque, Paul G. Gavrilin, Yury I. Khrouch, Valery T. Bouville, Andre Hoshi, Masaharu Meckbach, Reinhard Minenko, Victor F. Ulanovsky, Alexander V. Luckyanov, Nicholas TI Credibility of Chernobyl thyroid doses exceeding 10 Gy based on in-vivo measurements of I-131 in Belarus SO HEALTH PHYSICS LA English DT Article DE Chernobyl; dose; internal; I-131; thyroid AB Many estimates of individual thyroid doses to children and adults in Belarus have been based on the results of direct thyroid measurements made using survey meters soon after the Chernobyl accident in 1986. Thyroid doses from internal exposure to I-131 that are estimated using such measurements are usually considered to be better than estimates obtained by environmental transport modeling of concentrations expected in milk. Nonetheless, some of the estimated doses, primarily those to children, were high enough to raise questions about their credibility. Questions about high thyroid doses, taken here to be those exceeding 10 Gy, identified the need for further analysis, which is reported in this article. The overall conclusion is that the initial dose estimates exceeding 10 Gy based on direct thyroid measurements in Belarus are credible estimates and not mistakes. While the possibility of copying and data entry errors cannot be completely ruled out, the consistency of multiple measurements for many individuals supports the high dose estimates. C1 [Voilleque, Paul G.] MJP Risk Assessment Inc, Denver, CO 80220 USA. [Shinkarev, Sergey M.; Gavrilin, Yury I.; Khrouch, Valery T.] Minist Hlth, Inst Biophys, State Res Ctr, Moscow 123182, Russia. [Bouville, Andre; Luckyanov, Nicholas] NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Rockville, MD 20852 USA. [Hoshi, Masaharu] Hiroshima Univ, Int Radiat Informat Ctr, Res Inst Radiat Biol & Med, Hiroshima, Japan. [Meckbach, Reinhard; Ulanovsky, Alexander V.] GSF, Natl Res Ctr Environm & Hlth, Inst Radiat Protect, D-85764 Neuherberg, Germany. [Minenko, Victor F.] Minist Hlth, Belarusian Med Acad Continuing Educ, Minsk, Byelarus. [Ulanovsky, Alexander V.] Joint Inst Power & Nucl Res SOSNY, Minsk 220109, Byelarus. RP Voilleque, PG (reprint author), MJP Risk Assessment Inc, POB 200937, Denver, CO 80220 USA. EM pgv@mindspring.com NR 8 TC 2 Z9 4 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0017-9078 EI 1538-5159 J9 HEALTH PHYS JI Health Phys. PD FEB PY 2008 VL 94 IS 2 BP 180 EP 187 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Nuclear Science & Technology; Radiology, Nuclear Medicine & Medical Imaging GA 251AK UT WOS:000252342400009 PM 18188052 ER PT J AU Schelbert, EB Rumsfeld, JS Krumholz, HM Canto, JG Magid, DJ Masoudi, FA Reid, KJ Spertus, JA AF Schelbert, E. B. Rumsfeld, J. S. Krumholz, H. M. Canto, J. G. Magid, D. J. Masoudi, F. A. Reid, K. J. Spertus, J. A. TI Ischaemic symptoms, quality of care and mortality during myocardial infarction SO HEART LA English DT Editorial Material CT 6th Scientific Forum on Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke CY MAY 14-16, 2005 CL Washington, DC SP Amer Heart Assoc, Qual Care & Outcomes Res Interdisciplinary Working Grp, Councils Cardiovasc Nursing, Councils Cardiovasc Surg & Anesthesia, Councils Clin Cardiol, Councils Epidemiol & Prevent & Stroke, Amer Coll Cardiol Fdn, Ctr Dis Control & Prevent, Dept Vet Affairs ID ACUTE CORONARY SYNDROMES; HEART-ASSOCIATION; CHEST-PAIN; GUIDELINES; TROPONIN; COMMITTEE; REGISTRY; COLLEGE; DISEASE; EVENTS AB Objective: To study in myocardial infarction (MI) whether documentation of ischaemic symptoms is associated with quality of care and outcomes, and to compare patient reports of ischaemic symptoms during interviews with chart documentation. Design: Observational acute MI study from 2003 to 2004 (Prospective Registry Evaluating Myocardial Infarction: Event and Recovery). Setting: 19 diverse US hospitals. Patients: 2094 consecutive patients with MI (10 911 patients screened; 3953 patients were eligible and enrolled) with both positive cardiac enzymes and other evidence of infarction (eg, symptoms, electrocardiographic changes). Transferred patients and those with confounding non-cardiac comorbidity were not included (n=1859). Main outcome measures: Quality of care indicators and adjusted in-hospital survival. Results: The records of 10% of all patients with MI (217/2094) contained no documented ischaemic symptoms at presentation. Patients without documented symptoms were less likely (p<0.05) to receive aspirin (89% vs 96%) or beta-blockers (77% vs 90%) within 24 hours, reperfusion therapy for ST-elevation MI (7% vs 58%) or to survive their hospitalisation (adjusted odds ratio= 3.2, 95% CI 1.8 to 5.8). Survivors without documented symptoms were also less likely (p< 0.05) to be discharged with aspirin (87% vs 93%), beta-blockers (81% vs 91%), ACE/ARB (67% vs 80%), or smoking cessation counselling (46% vs 66%). In the subset of 1356 (65%) interviewed patients, most of those without documented ischaemic symptoms (75%) reported presenting symptoms consistent with ischaemia. Conclusions: Failure to document patients' presenting MI symptoms is associated with poorer quality of care from admission to discharge, and higher in-hospital mortality. Symptom recognition may represent an important opportunity to improve the quality of MI care. C1 [Schelbert, E. B.] Univ Iowa, Iowa City, IA USA. [Rumsfeld, J. S.] Denver VA Med Ctr, Denver, CO USA. [Krumholz, H. M.] Yale Univ, New Haven, CT USA. [Canto, J. G.] Watson Clin, Ctr Cardiovasc Prevent Res & Educ, Lakeland, FL USA. [Canto, J. G.] Univ Alabama, Div Cardiovasc Dis, Birmingham, AL 35294 USA. [Magid, D. J.] Colorado Permanente Med Grp, Denver, CO USA. [Masoudi, F. A.] Denver Hlth Med Ctr, Denver, CO USA. [Reid, K. J.; Spertus, J. A.] St Lukes Hosp, Mid Amer Heart Inst, Kansas City, MO 64111 USA. [Reid, K. J.; Spertus, J. A.] Univ Missouri, Kansas City, MO 64110 USA. RP Schelbert, EB (reprint author), NHLBI, NIH, 10 Ctr Dr,Room B1D416,MSC 1061, Bethesda, MD 20892 USA. EM schelberteb@nhlbi.nih.gov FU NHLBI NIH HHS [K30 HL004117, HL 07121, K30HL04117-01A1, P50 HL077113, T32 HL007121] NR 24 TC 7 Z9 8 U1 0 U2 3 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 1355-6037 J9 HEART JI Heart PD FEB PY 2008 VL 94 IS 2 AR e2 DI 10.1136/hrt.2006.111674 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 256QX UT WOS:000252745800045 PM 17639097 ER PT J AU Shiina, M Rehermann, B AF Shiina, Masaaki Rehermann, Barbara TI Cell culture-produced hepatitis C virus impairs plasmacytoid dendritic cell function SO HEPATOLOGY LA English DT Article ID IMMUNE-RESPONSES; IN-VITRO; DC-SIGN; INFECTION; SYSTEM; CORE; QUANTIFICATION; INTERFERON; MATURATION; EFFECTOR AB Previous studies suggested a functional impairment of dendritic cells (DCs) in patients with chronic hepatitis C. To investigate whether this effect was mediated by a 4 irect interacti hepatitis C virus (HCV) with DCs, we studied the effects of infectious cell culture-produced hepatitis C virus (HCVcc) on peripheral blood mononuclear cells (PBMCs), ex vivo isolated plasmacytoid, and myeloid DCs and in vitro generated monocyte-derived DO of healthy blood donors. HCVcc inhibited toll-like receptor (TLR)-9 (CpG and herpes simples virus)mediated interferon alpha (IFN-alpha) production by peripheral blood mononuclear cells (PBMC) and plasmacytoid DO. This inhibitory effect was also observed in response to ultraviolet (UV)-inactivated, noninfectious HCVcc, and it was not abrogated by neutralizing antibodies, and thus did not appear to require DC infection. Influenza A virus restored maturation and TLR9-mediated IFN-alpha production. In contrast to its effect on plasmacytoid DO, HCVcc did not inhibit TLR3-mediated and TLR4-mediated maturation and interleukin (IL)-12, IL-6, IL-10, interferon gamma (IFN-gamma), and tumor necrosis factor alpha (TNF-alpha) production by myeloid DO and monocyte-derived DO. Likewise, HCVcc did neither alter the capacity of myeloid DO nor monocyte-derived DO to induce CD4 T cell proliferation. Whereas phagocytosis of apoptotic hepatoma cells resulted in DC maturation, this effect was independent of whether the phagocytosed Huh7.5.1 cells were infected with HCVcc. In contrast to HCVcc, vaccinia virus inhibited maturation and TNF-alpha expression of myeloid DC as well as maturation and IL-6 and IL-10 production of monocyte-derived DC. Conclusion: HCVcc inhibited plasmacytoid DO but not myeloid-derived and monocytoid-derived DO via a direct interaction that did not require infection. The response of plasmacytoid DO to influenza A virus infection was not impaired. C1 [Shiina, Masaaki; Rehermann, Barbara] NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, Bethesda, MD 20892 USA. RP Shiina, M (reprint author), NIDDK, Immunol Sect, Liver Dis Branch, NIH,DHHS, 10 Ctr Dr,Room 9B16, Bethesda, MD 20892 USA. RI Yang, Chen/G-1379-2010 NR 43 TC 74 Z9 79 U1 1 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD FEB PY 2008 VL 47 IS 2 BP 385 EP 395 DI 10.1002/hep.21996 PG 11 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 259KZ UT WOS:000252939500007 PM 18064579 ER PT J AU Chuang, YH Lian, ZX Yang, GX Shu, SA Moritoki, Y Ridgway, WM Ansari, AA Kronenberg, M Flavell, RA Gao, B Gershwin, ME AF Chuang, Ya-Hui Lian, Zhe-Xiong Yang, Guo-Xiang Shu, Shang-An Moritoki, Yuki Ridgway, William M. Ansari, Aftab A. Kronenberg, Mitchell Flavell, Richard A. Gao, Bin Gershwin, M. Eric TI Natural killer T cells exacerbate liver injury in a transforming growth factor beta receptor II dominant-negative mouse model of primary biliary cirrhosis SO HEPATOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; V(ALPHA)14 NKT CELLS; DENDRITIC CELLS; ALPHA-GALACTOSYLCERAMIDE; CYTOKINE PRODUCTION; IMMUNE-RESPONSE; HYPER-IGM; ACTIVATION; MICE; IDENTIFICATION AB Primary biliary cirrhosis (PBC) is an organ-specific autoinumme liver disease characterized by the presence of antimitochondrial antibodies and the destruction of small intrahepatic bile ducts with portal inflammation. In previous studies, we reported that both CD1d expression and the frequency of CD1d-restricted natural killer T (NKT) cells were increased in the livers of patients with PBC. To define a specific role of CD1d-restricted NKT cells in the pathogenesis of PBC, particularly early events, we investigated the function of hepatic CD1d-restricted NK-T cells in our transforming growth factor P (TGF-beta) receptor II dominant-negative (dnTGF beta RII) mouse model of PBC. We generated CD1d(-/-) and CD1d(-/-)dnTGF beta RII mice and performed a comparative study of liver immunopathology. We report herein that these dnTGF beta RII mice demonstrate a massive increase of hyperactive CD1d-restricted NKT cells within the hepatic tissues. CD1d(-/-)dnTGF beta RII mice, which lack CD1d-restricted CD1d-restricted NKT cells, exhibit significantly decreased hepatic lymphoid cell infiltrates and milder cholangitis compared with CD1d(-/-)dnTGF beta RII mice. Interestingly, there was a significant increase in the production of interferon-gamma in hepatic CD1d-restricted NKT cells activated by a-galactosylceramide in young but not older dnTGF beta RII mice, suggesting an age-dependent role of CD1d-restricted NKT cells. Conclusion: These data demonstrate that CD1d-restricted NKT cells in dnTGF beta RII mice are a critical factor in liver injury. C1 [Chuang, Ya-Hui; Lian, Zhe-Xiong; Yang, Guo-Xiang; Shu, Shang-An; Moritoki, Yuki; Gershwin, M. Eric] Univ Calif Davis, Davis Sch Med, Div Rheumatol Allergy & Clin Immunol, Davis, CA 95616 USA. [Ridgway, William M.] Univ Pittsburgh, Sch Med, Div Rheumatol & Immunol, Pittsburgh, PA USA. [Ansari, Aftab A.] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA. [Kronenberg, Mitchell] La Jolla Inst Allergy & Immunol, La Jolla, CA USA. [Flavell, Richard A.] Yale Univ, Sch Med, Howard Hughes Med Inst, Immunobiol Sect, New Haven, CT 06510 USA. [Gao, Bin] NIAAA, NIH, Lab Physiol Studies, Sect Liver Biol, Bethesda, MD USA. [Chuang, Ya-Hui] Natl Taiwan Univ, Coll Med, Dept Clin Lab Sci & Med Biotechnol, Taipei 10764, Taiwan. RP Lian, ZX (reprint author), Univ Calif Davis, Davis Sch Med, Div Rheumatol Allergy & Clin Immunol, 451 E Hlth Sci Dr,Suite 6510, Davis, CA 95616 USA. EM zxlian@ucdavis.edu OI CHUANG, YA-HUI/0000-0003-0857-0035 FU NIDDK NIH HHS [DK39588] NR 53 TC 61 Z9 64 U1 1 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD FEB PY 2008 VL 47 IS 2 BP 571 EP 580 DI 10.1002/hep.22052 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 259KZ UT WOS:000252939500026 PM 18098320 ER PT J AU Seeff, LB Curto, TM Szabo, G Everson, GT Bonkovsky, HL Dienstag, JL Shifftnan, ML Lindsay, KL Lok, ASF Bisceglie, AM Lee, WM Ghany, MG AF Seeff, Leonard B. Curto, Teresa M. Szabo, Gyongyi Everson, Gregory T. Bonkovsky, Herbert L. Dienstag, Jules L. Shifftnan, Mitchell L. Lindsay, Karen L. Lok, Anna S. F. Di Bisceglie, Adrian M. Lee, William M. Ghany, Marc G. CA HALT-C Trial Grp TI Herbal product use by persons enrolled in the hepatitis C antiviral long-term treatment against cirrhosis (HALT-C) trial SO HEPATOLOGY LA English DT Article ID ALTERNATIVE MEDICINE USE; CHRONIC LIVER-DISEASE; SILYMARIN TREATMENT; PLUS RIBAVIRIN; SUPPLEMENT USE; UNITED-STATES; MILK THISTLE; COMPLEMENTARY; ANTIOXIDANT; POPULATION AB Herbal products, used for centuries in Far Eastern countries, are gaining popularity in western countries. Surveys indicate that persons with chronic hepatitis C (CHC) often use herbals, especially silymarin (milk thistle extract), hoping to improve the modest response to antiviral therapy and reduce side effects. The Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) Trial, involving persons with advanced CHC, nonresponders to prior antiviral therapy but still willing to participate in long-term pegylated interferon treatment, offered the opportunity to examine the use and potential effects of silymarin. Among 1145 study participants, 56% had never taken herbals, 21% admitted past use, and 23% were using them at enrollment. Silymarin constituted 72% of 60 herbals used at enrollment. Among all participants, 67% had never used silymarin, 16% used it in the past, and 17% used it at baseline. Silymarin use varied widely among the 10 participating study centers; men were more frequent users than women, as were non-Hispanic whites than African Americans and Hispanics. Silymarin use correlated strongly with higher education. No beneficial effect of silymarin was found on serum alanine aminotransferase or hepatitis C virus (HCV) RNA levels. Univariate analysis showed significantly fewer liver-related symptoms and better quality-of-life parameters in users than nonusers, but after reanalysis adjusted for covariates of age, race, education, alcohol consumption, exercise, body mass index, and smoking, only fatigue, nausea, liver pain, anorexia, muscle and joint pain, and general health remained significantly better in silymarin users. Conclusion: Silymarin users had similar alanine aminotransferase and HCV levels to those of nonusers but fewer symptoms and somewhat better quality-of-life indices. Because its use among these HALT-C participants was self-motivated and uncontrolled, however, only a well-designed prospective study can determine whether silymarin provides benefit to persons with chronic hepatitis C. C1 [Seeff, Leonard B.] NIDDK, NIH, Dept Hlth & Human Serv, Div Digest Dis & Nutr, Bethesda, MD 20892 USA. [Curto, Teresa M.] New England Res Inst, Watertown, MA 02172 USA. [Szabo, Gyongyi] Univ Massachusetts, Sch Med, Dept Med, Div Gastroenterol,Hepatol & Liver Ctr, Worcester, MA 01605 USA. [Everson, Gregory T.] Univ Colorado, Sch Med, Div Gastroenterol & Hepatol, Sect Hepatol, Denver, CO 80202 USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Dept Mol & Struct Biol, Farmington, CT USA. [Bonkovsky, Herbert L.] Univ Connecticut, Ctr Hlth, Liver Biliary Pancreat Canc, Farmington, CT USA. [Dienstag, Jules L.] Massachusetts Gen Hosp, Gastrointestinal Unit, Med Serv, Boston, MA 02114 USA. [Dienstag, Jules L.] Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. [Shifftnan, Mitchell L.] Virginia Commonwealth Univ, Med Ctr, Sect Hepatol, Richmond, VA USA. [Lindsay, Karen L.] Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA USA. [Lok, Anna S. F.] Univ Michigan, Ctr Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. [Di Bisceglie, Adrian M.] St Louis Univ, Sch Med, Div Gastroenterol & Hepatol, St Louis, MO 63103 USA. [Lee, William M.] Univ Texas SW Med Ctr Dallas, Div Digest & Kidney Dis, Dallas, TX 75390 USA. [Ghany, Marc G.] NIDDKD, NIH, Dept Hlth & Human Serv, Liver Dis Branch, Bethesda, MD 20892 USA. RP Seeff, LB (reprint author), NIDDK, NIH, Dept Hlth & Human Serv, Div Digest Dis & Nutr, 31A Ctr Dr,Room 9A27, Bethesda, MD 20892 USA. EM seeffl@extra.niddk.nih.gov RI Lok, Anna /B-8292-2009; OI Yang, Shuman/0000-0002-9638-0890 FU NCRR NIH HHS [M01RR-00042, M01RR-00043, M01RR-00051, M01RR-00065, M01RR-00633, M01RR-00827, M01RR-01066, M01RR-06192]; NIAAA NIH HHS [K24 AA13736]; NIDDK NIH HHS [N01-DK-9-2327, N01-DK-9-2318, N01-DK-9-2319, N01-DK-9-2320, N01-DK-9-2321, N01-DK-9-2322, N01-DK-9-2323, N01-DK-9-2324, N01-DK-9-2325, N01-DK-9-2326, N01-DK-9-2328] NR 55 TC 73 Z9 74 U1 6 U2 15 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-9139 J9 HEPATOLOGY JI Hepatology PD FEB PY 2008 VL 47 IS 2 BP 605 EP 612 DI 10.1002/hep.22044 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 259KZ UT WOS:000252939500030 PM 18157835 ER EF